860 ID FINAL EXAM (COMBINED)

Other UTIs

*Catheter-Associated* MOST COMMON HEALTH-CARE ASSOCIATED INFECTION! REMOVE CATHETER ASAP WHEN NO LONGER NEEDED *Asymptomatic Bacteremia* Treating this early will prevent UTIs Dx: 100k+ on 2 samples with no sx DO NOT TREAT: healthy women, older women/men, DM, indwelling catheters, spinal cord injuries ONLY TREAT: pregnant patients on initial visit, prior invasive urologic procedure

Treating HAP/VAP

*<10-20% of S.aureus are MRSA, NOT high risk of mortality (HAP), negative MDR risk (VAP)* Zosyn, cefepime, levofloxacin, meropenem, impenem/cilastatin *20+ S.aureus MRSA or MRSA unknown, no high risk mortality (HAP), negative MDR risk (VAP)* Anti-pseudomonal abx: Zosyn, cefepime/ceftazidime, levo/cipro, penem, aztreonam (PCN allergy) MRSA abx: vanco, linezolid *High risk of mortality or use of IV abx within 90 days (HAP), positive MDR risk with 10%+ GN resistant to monotherapy OR susceptiability unknown (VAP)* Antipseudomonal B-lactam: Zosyn, cefepime/ceftazidime, penem, aztreonam (PCM allergy) Another antipseudomonal: levo/cipro, AGS, polymyxin MRSA: vanco, linezolid *MAXIMIZE TIME ABOVE MIC FOR TIME-DEPENDENT BACTERICIDAL ACTIVITY* Zosyn Cefepime Meropenem *Duration of Therapy* SEVEN DAYS TOTAL abx duration of HAP/VAP Finalized cultures -> deescalation CLINICAL PRESENTATION CONSIDERED BEFORE STOPPING ABX *No Response to Abx* Wrong organism: resistance, mycobacterial, fungal, viral Wrong Dx: pulmonary embolism, malignancy, ARDS Complication: empyema, lung abscess, new infx (C.diff colitis) *Other Abx to Use* MRSA: ceftaroline, delafloxacin MDR P.aeru: ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, cefiderocol MDR Acinetobacter: cefiderocol, imipenem/cliastatin/relebactam(?), eravacycline (maybe) *Preventing VAP* Keep head of pt's bed raised 30-45 degrees to minimize aspiration Daily spontaneous breathing trials (SBTs) and sedation interruption Oral hygiene Chlorhexidine (MAY HAVE INCREASED MORTALITY IN NON-CARDIAC SURGERY PTs)

STD Prevention

*Accurate risk assessment and education to avoid STIs* Sexual behavior changes Prevention services *Pre-exposure vaccination* HPV *Identification of people with asx infection and people with sx from STI* *Effective dx, tx, education* Abstinence Condoms *Evaluation, tx, education of sex partners* Communication Getting tested together

Allylamines and Morpholines Antifungals

*Alllylamine Characteristics* More LIMITED activity than azoles: only effecive against dermatophytes *Allylamine Mechanism* Binds to squalene epoxidase to inhibit squalene to squalene epoxide Decreases sterol content in membrane Builds up squalene which is TOXIC in high amounts *Morpholine Characteristics (Amorolfine)* Binds to delta14-reductase and d8,d7-isomerase to prevent synthesis of ergosterol

DDI Considerations with Maintenance Immunosuppression

*CYP3A4/PGP Substrates* Inducers DECREASE CNI CONCENTRATION (carbamazepine, rifampin) Inhibitors INCREASE CNI CONCENTRATION (azoles) AVOID GRAPEFRUIT *Azathioprine vs Xanthine Oxidase* CONTRAINDICATED WITH FEBUXOSTAT DECREASED 75% DOSE WITH ALLOPURINOL *Mycophenolate Mofetil* Decreases hormal contraception levels Decreased by: antacids, MVI, Mg, PPI, bile acid resins *CAUTION WITH ADDITIVE ADEs* Nephrotoxic drugs together QT prolong drugs together *DO NOT TAKE ANY OTC, HERBAL MEDS, OR NEW MEDS WITHOUT SPEAKING WITH PROVIDERS!!!!*

Amphotericin B

*AmB Deoxycholate (Conventional)* Mech: bind to ergosterol to disrupt membrane -> K ions leak out Resist Mech: downregulation of ergosterol, ergosterol synth inhibition Uses: empiric if suspect mold, severe fungal infection, mucorales Resist: candida lusitaniae, aspergillus terreus Dosing: <1mg/kg (usually 0.7mg/kg) DO NOT CONFUSE CONVENTIONAL DOSING WITH LIPID DOSING Kinetics: micelles are suspended in a D5W solution (line needs to be flushed with D5W TO PREVENT PRECIPITATION) ADE: shake and bake infusion rxn, nephrotoxic (common), renal tubular acidosis, anemia, K/Mg loss, anaphylaxis Cardiac arrhythmias risk due to hypokalemia/hypoMg Usually pre-medicated with Tylenol + Benadryl 30 mins before infusion Can use meperidine for rigors Can use hydrocortisone to prevent venous irritation Given K/Mg supplementation *Liposomal AmB (Ambisome)* Mech: bind to ergosterol to disrupt membrane -> K ions leak out Resist Mech: downregulation of ergosterol, ergosterol synth inhibition Uses: same as conventional AmB but less nephrotoxic and infusion toxic Dosing: 5mg/kg DO NOT CONFUSE LIPID DOSING WITH CONVENTIONAL DOSING Kinetics: spherical shaped liposomes slowly release AmB, higher distribution to brain, no urine excretion MIXED WITH D5W, NOT NS ADE: hypoK, hypoMg, nephrotoxic (less so than conventional) Still pre-medicated with Tylenol, Benadryl Still given K/Mg supplementation DO NOT MISTAKE FOR LIPID COMPLEX FORM (Abelcet) *AmB Lipid Complex (Abelcet)* Mech: bind to ergosterol to disrupt membrane -> K ions leak out Resist Mech: downregulation of ergosterol, ergosterol synth inhibition Uses: same as conventional AmB but less nephrotoxic and infusion toxic Dosing: 5mg/kg DO NOT CONFUSE LIPID DOSING WITH CONVENTIONAL DO NOT GO ABOVE 5mg/kg FOR LIPID COMPLEX Kinetics: disc-shaped particles, degrades faster (more infusion toxic than liposomal) MIX WITH D5W, NOT NS ADE: infusion toxic less than conventional but more than liposomal, less nephrotoxic, hypoK/Mg Still premedicate with Tylenol, Benadryl Still replace K/Mg

Antibiotic Resistance

*Aminoglycoside Resistance Mechanisms* Enzymatic modifications of aminoglycosides by Aminoglycoside Modifying Enzymes (AME) ATP/GDP-dependent aminoglycoside phosphotransferases (APHs) Acetyl-CoA-dependent aminoglycoside acetyltransferaces (AACs) ATP-dependent aminoglycoside nucleotidyltransferaces (ANTs) *Beating Macrolide Resistance* Erythromycin: poor stability with ketone, hydroxyl (inactivated via internal ketalization* Azithromycin: remove ketone to avoid internal ketalization Clarithromycin: masks hydroxyl via O-methylation to avoid internal ketalization *Vancomycin Resistance* Vancomycin-Resistant Enterococci (VRE): alters D-Ala-D-Ala into D-Ala-D-LACTATE Amidine version of vancomycin can bind to D-Lac (+1 charge) AND D-Ala (0 charge) *Other Resistance Mechanisms* Decreases permeability: B-lactams, aminoglycosides Efflux Pump Upregulation: tetracyclines, quinolones, macrolides Altered Targets: B-lactams, quinolones, aminoglycosides, vanco, macrolides, TMP/SMX Enzymatic Inactivation: B-lacatms, aminoglycosides, macrolides *

Targeting Bacteria Ribosome and Protein Synthesis

*Aminoglycosides (streptoMYCIN, neoMYCIN, gentaMICIN)* For enterobacterias and pseudomonas (AEROBIC NEGATIVE) Carb structure with basic AA groups Irreversibly binds to 30S ribosome and creates mistranslation of RNA templates -> bactericidal HAS TO BE INJECTED DUE TO HIGH POLARITY Works best in SLIGHTLY ALKALINE conditions CAUTION: nephro/ototoxicity *Tetracyclines (tetraCYCLINE, doxyCYCLINE)* For rickettsia, mycoplasma, spirochetes (Lyme's) Four ringed structure Blocks tRNA from binding to 30S ribosome -> bacteriostatic Can SPONTANEOUSLY INACTIVATE: water elimination, ring opening, epimerization CAUTION: hepatotoxic, tooth discolor, impaired growth (DO NOT GIVE <12 YRS AND PREGNANT) Polyvalent agents (antacids) should be taken SEPARATELY Tigecycline: overcomes efflux pump + ribosomal protection resistance *Macrolides: erYTHROmycin, azITHROmycin, clarITHROmycin* For strep, H.influenzae, mycoplasma pneumonia 14/15/16-membered lactone ring with a sugar moiety Reversibly binds to 50S -> static Azithromycin/Clarithromycin: commonly used for community-acquired pneumonia Erythromycin: THE WORST ABSORPTION, HL, PENETRATION (internal ketalization) Azithromycin the only one available in IV form COUMADIN DDI *Chloramphenicol* For H.influenzae, bacterial meningitis, brain abscesses IInhibits movement of 50S ribosome along mRNA -> Bacteriostatic Only the R,R ISOMER IS ACTIVE Both hydroxyl groups ESSENTIAL for binding (enzyme can inactivate by acetylating one of these groups) *Lincosamide: clindamycin* For bacteriodes fragilis, S.aureus, Coa-Neg Staph/Strep Inhibit peptidyl transferance at 50S by interfering with amino acyl-tRNA complex -> static Has EXCELLENT bone penetration CAUTION: psuedomembranous colitis, hypersens *Oxazolidinones: linezolid* For RESISTANT POSITIVES Bind to 50S to prevent formation of 70S *Streptogramins: quinuPRISTIN, dalfoPRISTIN* For vanco-resist enterococcus, GAS, methicillin-sens S.aureus/S.pyogenes skin infx Synercid: 7-3 ratio of Dalfo+Quinu where dalfo increases binding activity of Quinu

Renal Toxicity in Antibiotics

*Aminoglycosides* Presentation: AKI with sCr increase of 0.5+, mild or severe Renal function improves over time (either return to baseline, partial improve, or perma damage) Prevention: avoid DEHYDRATION, avoid OTHER NEPHROTOXINS, carefully monitor BUN/sCr AUC should be 70-100 h/L over 24 hours Intermittent dosing with low trough *Vancomycin* Renal damage more rapidly reversible than aminoglycosides AUC should be 400-600 mgh/L (TDM used to adjust doses) Monitor BUN/sCr 2-3x a week *Tenofovir* Used for HIV and Hep B Can accumulate in proximal tubular cell under MRP dysfunction Possible genetic risk if patient has SNP1239 G->A mutation Tenofovir disoproxil fumarate (TDF): 300mg/day, 70-80% urine excretion Tenofovir alafenamide (TAF): 25mg/day, ONLY ONE PERCENT URINE EXECRETION *Amphotericin B* Constricts afferent arterioles Binding to cholesterol can cause membrane damage -> distal tubular acidosis (loss of K and Mg) Loss of these electrolytes causes feedback to further constrict arterioles leading to decreased eGFR EXPECT REDUCTION IN GFR, pre-dose hydration IMPORTANT Avoid OTHER NEPHROTOXINS Monitor SCr, K, Mg (If SCr 2+, hold dose or dose every other day)

Other Intra-abdominal Conditions

*Appendicits* Abx given PRE-OP for less than 24 hrs (prevent surgical infx) If gangrenous or perforated: 4-7 day abx *Traumatic Injuries* Single pre-op dose required if NO HOLLOW VISCUS INJURY If hollow viscus injury: abx continued for less than 24 hrs For established infx: continue 4-7 days or more prn Cefoxitin and ceftriaxone (add metronidazole if bacteroides, C. diff) *Cholelithiasis: stone formation in gall bladder* NOT INFECTIOUS *Cholecystitis* Cholelithiasis leading to inflammation -> blockage -> stasis -> bacterial growth Fever + leukocytosis COMMON Rupture can lead to SYSTEMIC INFX Mild-Mod: cefazolin, cefuroxime, ceftriaxone (enterobac coverage) Severe, Elderly, Immunocomp: penems, Zosyn, FQs, cefepime (ADD METRONIDAZOLE FOR ALL) (GNS, anaerobic, enterobac coverage) STOP THERAPY WITHIN 24 HOURS OF CHOLECYSTECTOMY (unless infection is OUTSIDE wall of gallbladder) *Choledocolithiasis: bile duct obstruction* Lack of bilirubin flow -> increased bilirubin -> jaundice, dilated hepatic ducts NOT INFECTIOUS *Cholangitis* Choledocolithasis WITH AN INFECTION ascending proximal to obstruction Sx: fever, jaundice, RUQ pain, SHOCK Tx: penems, Zosyn, FQs, cefepime (ADD METRO FOR ALL) (GNS and anerobic coverage) *Healthcare-Associated Biliary Infection of ANY severity* Tx: penems, Zosyn, FQs, cefepime (ADD METRO TO ALL) Add vanco if MRSA

Preventing UTIs

*Assess Risk Factors* Correctable urinary tract abormality Sexual practices Use of spermicides or diaphragm *There are NO EVIDENCE TO THESE THINGS* Post-coital voiding Hygiene after urination Douching, tight underwear, polyester, hot tubs *Recurrent UTI Proph* Post-coital abx Short-course abx with onset of sx Chronic abx suppression *Chronic Abx Proph* Bactrim: 1/2 tab daily Trimethoprim: 100mg daily Cipro: 125mg daily Nitrofurantoin: 50-100mg daily Cefaclor: 250mg daily Cephalexin: 125mg daily

Pediatric Community Acquired Pneumonia

*Assessment* Conditions predisposing them to pulmonary infections? Is this really CAP? Abx in last 30 days and which ones? Inpatient care? Can you treat this outpatient? *Risk Factors* Lower SES School age Congenital heart disease Chronic lung disease Asthma Sickle cell Neuromuscular disorder Congential/acquired immunodeficiency *Complications* Pulmonary: pleural effusion/empyema, pneumothorax, lung abscess, bronchpleural fistula, necrotizing PNM, acute resp fail Metastatic: meningitis, pericarditis, endocarditis, osteolmyelitis, septic arthritis Systemic: SIRS, sepsis, hemolytic uremic syndrome *Pathogens* Strep pneu H.influenzae, M.catarrhalis M.pneu, C.pneu Staph aureus Parainfluenza, influenza, rhinovirus, adenovirus, enterovirus *Determining Type of CAP Infection* Bacterial: abrupt onset, febrile, "toxic" apperance, mod-severe resp distress, localized CP (pleural effusion), auscultation has decreased breath sounds and crackles Atypical Bacteria: abrupt present, fever, malaise, HA, photophobia, sore throat, wheezing, chills with no rigors, gradual worsening of non-productive cough despite improvement in other sx, diffuse inspiratory crackles Viral: gradual onset, preceding upper resp tract sx (rhinorrhea, congestion), no toxic appearance, diffuse and bilateral auscultations *Patient should be treated IN-PATIENT IF THE FOLLOWING IS OBSERVED* Moderate-severe CAP (resp distress, hypoxemia) Infants less than 3-6 months of age with suspected CAP Suspected or documented pathogen with increased virulence (MRSA) Concern about observation at home *CAP Work-up* Inpatient: cultures, gram stain, rapid diagnostic test for viral, atypical testing, CMP/CBC with differential, oximetry, chest radiograph Outpatient: rapid dx testing for viral, test for atypicals, chest radiograph if hypoxemia/sig resp distress/fail to respond to initial tx *Consider ICU Care or Cardiac Monitor If 1+ MAJOR criteria or 2+ MINOR criteria* Major: on a vent, fluid refractory shock, acute need for NIPPV, hypoxemia needing more O2 than whats feasible in the current setting Minor: high RR, apnea, increased work of breathing, PaO2/FiO2 ratio <250, multilobal infiltrates, PEWS score 6+, AMS, hypotension, effusion presence, immunosuppressed, unexplained metabolic acidosis

Assessing Respiratory Illness in Pediatrics

*Assessment* Past medical history: birth hx, comorbids FHx and SHx: pulmonary disease, exposure to smoke/irritants/etc Vitals (BE AWARE OF AGE SPECIFIC DIFFERENCES): temp, BP, capillary refill, O2 sats, resp rate Clinical Presentation: HPI, sound of cough, wheezing/retraction, "toxic" appearance *Signs of Respiratory Distress* Tachypnea: 60+ for 0-2mo ; 50+ for 2-12mo ; 40+ for 1-5yrs ; 20+ for 5+ yrs Dyspnea Retractions Grunting Nasal flaring Apnea AMS <90% O2 on room air

Echinocandin Family

*Caspofungin (Cancidas)* Mech: inhibit B(1,3)-D-glucan synthase in cell membrane -> weakens cell wall and causes osmotic lysis (most effective with candida) Mech Resist: FKS subunit mutation Uses: best for candida (FIRST-LINE invasive candiasis), aspergillus, invasive aspergillus refractory to other therapies, usually in combo with something else Resist: glabrata, auris ADE: liver toxic, infusion toxic (rash), generally well-tolerated Risk Factors for Invasive Candidiasis: neutropenia, central venous access devices, parenteral nutrition, major surgery steroid use, multi-site colonization, broad-spectrum abx Prior exposure to fluconazole can increase azole resist -> echinocandin can be used Azole step-down from invasive candidiasis upon improvement *Micafungin (Mycamine)* Mech: inhibit B(1,3)-D-glucan synthase in cell membrane -> weakens cell wall and causes osmotic lysis (most effective with candida) Mech Resist: FKS subunit mutation Use: interchangable with caspofungin Resist: glabrata, auris ADE: liver toxic, infusion toxic (rash), generally well-tolerated Risk Factors for Invasive Candidiasis: neutropenia, central venous access devices, parenteral nutrition, major surgery steroid use, multi-site colonization, broad-spectrum abx Prior exposure to fluconazole can increase azole resist -> echinocandin can be used Azole step-down from invasive candidiasis upon improvement *Anidulafungin (Eraxis)* Mech: inhibit B(1,3)-D-glucan synthase in cell membrane -> weakens cell wall and causes osmotic lysis (most effective with candida) Mech Resist: FKS subunit mutation Use: interchangable with caspofungin and micafungin Resist: glabrata, auris ADE: liver toxic, infusion toxic (rash), generally well-tolerated DO NOT USE IN INFANTS <1 MONTH OLD (formulation contains POLYSORBATE 80) Risk Factors for Invasive Candidiasis: neutropenia, central venous access devices, parenteral nutrition, major surgery steroid use, multi-site colonization, broad-spectrum abx Prior exposure to fluconazole can increase azole resist -> echinocandin can be used Azole step-down from invasive candidiasis upon improvement

Antimalarial Drugs

*Atovaquone-Proguanil (Malarone)* Atovaquone mech: analog of ubiquinone binds to complex III of ECT -> inhibit ATP and nucleic acid synth Proguanil mech: inhibit dihydrofolate reductase -> block synth of nucleic acids One tablet daily dosing Start taking 1-2 days BEFORE travel Must continue taking for 7 days after leaving Uncommon ADEs NO PREGNANCY OR BREASTFEED NO SEVERE RENAL IMPAIR More expensive *(Hydroxy)chloroquine* Mech: block detoxification pathway of plasmodium so accumulated hemoglobin kills parasite One tablet WEEKLY dosing Start taking 1-2 WEEKS BEFORE travel Must continue taking for FOUR WEEKS after leaving Pt may already be taking this for RA... can continue taking Can be used in preggo DO NOT USE IF WENT TO AREA WITH CHLOROQUINE RESIST May worsen psoriasis *Doxycycline* Once daily dosing Start taking 1-2 days BEFORE travel Must continue taking for FOUR WEEKS after leaving Least expensive Pt may already be using for acne or other infx prevention DO NOT USE IN PREGGO DO NOT USE IN <8 YR CHILDREN Risk of yeast infection in women... may take another med ADE: photosens, GI stuff *Mefloquine* Mech: inteferes metabolism of heme and disrupt membrane trafficking Once WEEKLY dosing Start taking 1-2 WEEKS BEFORE travel Continue taking FOUR WEEKS after leaving Can be used in preggo DO NOT USE IF AREA IS RESISTANT TO MEFLOQUINE DO NOT USE IF PT HAS CERTAIN PSYCH CONDITIONS DO NOT USE IF SZ DISORDER DO NOT USE IF ARRHYTHMIAS *Primaquine* Mech: interferes mitochondria -> no ATP Start 1-2 days BEFORE travel Once daily dosing Continue taking 1 week after leaving Most effective for P.vivax proph DO NOT USE IF G6PD DEFICIENT: YOU MUST TEST FOR G6PD BEFORE TAKING THIS MED DO NOT USE IN PREGGO DO NOT USE IN BREASTFEEDING IF INFANT HAS NOT BEEN TESTED FOR G6PD ADE: GI stuff *IV Artesunate* Exclusive for SEVERE malaria If artesunate NOT available: use arthemether-lumefantrine OR atovaquone-proquanil OR quinine OR mefloquine (LAST RESORT) MUST CALL CDC FIRST BEFORE USAGE Does NOT have heart risk compared to quinidine ADE: hemolytic anemia about 4 weeks AFTER therapy *Artemether-Lumefantrine (Coartem)* Arthemether mech: active metabolite dihydroartemisinin makes endoperoxide moiety Lumefantrine mech: inhibit B-hematin formation by forming complex with hemin First-line by WHO MUST TAKE WITH FOOD Repeat dose if pt vomits within 30 minutes Expensive ADE: HA, anorexia, dizzy, asthenia, arthralgia, myalgia, QT PROLONG DDI: CYP3A4 substrate, CYP2D6 inhibitor

Targeting Cell Wall Biosynthesis

*B-Lactams: peniCILLIN, amoxiCILLIN* Mimics D-Ala-D-Ala to irreversibly bind to transpeptidase enzyme -> prevents synthesis of cell wall Contains a B-lactam ring ESSENTIAL for activity with a peptide bond that is highly STRAINED Cis stereochemistry of H5-H6 ESSENTIAL Free carboxylate ESSENTIAL Disubstitution bulkier R-groups are MORE RESISTANT to B-lactamase Augmentin (amoxicillin + clavulanic acid): covalently inhibit B-lactamase for amoxicillin to actually work *Cephalosporins (derivative of B-lactams): CEFazolin, CEFuroxime, CEFtriaxone, CEFepime, CEFtaroline fosamil* Bicyclic structure with B-lactam and dihydrothiazine ring Mechanism similar to penicillin, now with a 3-position leaving group First generation -> greatest NEGATIVE activity Last generation -> greatest POSITIVE activity Both rings IMPORTANT for strain Cis sterochemistry for 6/7 position ESSENTIAL Cefuroxime axetil: prodrug of cefuroxemine that can be given ORALLY Zerbaxa: ceftolozane/tazobactam (for NEGATIVE) Avycaz: ceftazidime/avibactam (for NEGATIVE) *Cephamycins* Extra methoxy substitution at 7-position to resist B-lactamase *Monobactams: aztreonam* Singular B-lactam rings by itself (not fused) Moderate activity against NEGATIVE (neisseria, pseudomonas) *Carbapenems (B-lactam derivative): meroPENEM, imiPENEM, doriPENEM, thienemycin* Double bond on five-membered ring brings high strain along with the peptide bond on B-lactam *Lipoglycopeptides: vancomycin* Directly inhibit transpeptidase AND indirectly inhibits transglycosalase by binding to D-Ala-D-Ala of nascent peptidoglycan -> weakened wall leads to lysis DOES NOT MIMIC D-Ala-D-Ala (unlike B-Lactam) *Lipoglycopeptides: teicoplanin* For POSITIVE infections and methicillin-RESISTANT staph aureus + enterococcus Longer alkyl chains and more sugar rings compared to Vanco Anchors itself with chains to cell membrane to inhibit cell wall synthesis Does NOT dimerize LESS TOXIC THAN VANCO *Lipoglycopeptides: oritaVANCIN, telaVANCIN, dalbaVANCIN* Orita: higher potency than vanco, 250 hr HL Tela: 8 hr HL for once daily IV, for complicated skin infections, TERATOGENIC Dalba: cannot work against vanco-resist enterococci, 6-11 DAY HL for once WEEKLY IV

Beta-Lactamases

*B-lactam Requirements for Activity* Must diffuse through porin channels in NEGATIVE bacteria Must NOT be hydrolyzed by B-lactamases Must NOT be effluxed out by efflux pumps in NEGATIVE bacteria Must bind to PBP (site of action) *Different Classes of B-Lactamases* A/C/D: serine active site B: ZINC active site *E.coli B-Lactamases* TEM-1 has 50+% resists to ampicillin and hyperproduction can resist GC1 (BLI can invalidate this) Mutation in TEM-1 can produce ESBL to resist 3/4GC and Penicllin/BLI (MUST USE CARBAPENEMS) *Klebsiella pneumoniae B-Lactamase* SHV-1 resistant to ampicillin, but susceptible to GCs and piper/BLI Mutations in SHV-1 produces ESBLs: resistant to 3/4GC and piper/tazo (MUST USE PENEMS) *Enterobacter cloacae B-Lactamases* Class C AmpC producing: serratia, psuedomonas, acinetobacter, citrobacter, enterobacter, hafnia, aeromonas, proteus, providencia, morganella Characteristics: inducible, chromosomal, mutational stable de-repression *Acinetobacter spp. B-Lactamases* Class D OXA type (oxacillin): able to hydrolyze oxacillin in CARBAPENEMS *Psuedomonas aeruginosa Multi-factoral Resistance* Less porin proteins compared to E.coli: use imipenem and meropenem for oprD Chromosomal AmpC: can be overcome with more stable abx Efflux Pumps: MexAB-oprM

HCV Management

*Before Tx* Measure: CBC, SCr, INR, hepatic panel Measure: HBV serology, HCV genotype, quantitative HCV RNA, hepatic fibrosis staging Consider preggo test *During Tx* Measure at 4 weeks: SCr, CBC, hepatic panel, quantitative HCV RNA Repeat liver panels if needed OR every 4 weeks if on Zepatier OR weeks 2/4/prn for cirrhosis CBC prn while on ribavirin HBV DNA prn Adherence to contraception, esp on ribavirin HCV RNA at end of tx AND 24wks after (if wanted) *Stopping Tx Early due to ADEs* STOP EARLY IF: ALT increase 10x from baseline OR ALT increases <10x but pt is symptomatic (N, weak, jaundice, vomit, INR/Tbili/AlkPhos increased) Repeat ALT at weeks 6 and 8 if asx + elevated <10x *Stopping Tx Early due to Efficacy* HCV RNA at 4 weeks should be generally UNDETECTABLE If detected: repeat HCV RNA 2 weeks later (if HCV RNA increase 10x THEN STOP TX) If HCV RNA detected at Wk 4 but decreased 2 weeks later: stay the course *After Tx* If fail: CBC/liver panel/INR every 6-12 months, hepatocellular carcinoma screening every 6 months if Metavir F3/F4 If success: follow up as if they never had HCV (F0-2), twice yearly hepatocellular caricoma screen (F3-4) Reorder HCV RNA prn if pt CONTINUES TO BE AT RISK FOR HCV

Donor Compatibility

*Blood Type* ABO Other niche types *Antibodies and Antigens* Human leukocyte antigen (HLA) Panel Reactive Antibody (PRA): tests degree to which recipient is "sensitized" to "non-self" proteins *Grafting* Allograft: transplant from one individual to another Autograft: transplant in the same pt from one site to another Isograft: transplant from a genetically identical donor (twin)

Hepatitis D

*Broken virus that requires HBsAg to cause Hep D infection* Really difficult to manage PegIFN only approved for 48 weeks Variable efficacy *Who to Screen* Immunocompromised HIV Endemic areas Persistent ALT elevation with low HBV DNA

Latent TB Infection Therapy

*CONSIDER BEFORE TREATMENT* Rule out possibility of TB Determine hx Determine CIs Obtain info about current and previouis therapies Recommend HIV testing if risk factors present *Lab Testing* Not routinely indicated Baseline hepatic measures for: liver disorder, HIV infection, preggo women, 3 months postpartum, alcoholism, IVDU, possible DDIs *Treatment* PREFERRED: isonidazid + rifapentine once weekly 3 months, rifampin daily 4 months, isoniazid + rifampin daily 3 months Alternative: isoniazid 6 or 9 months monotherapy DO NOT USE RIFAMPIN BY ITSELF FOR HIV POSITIVE *Follow-up Monitoring* Evaluate MONTHLY: adherence, sx of active disease, ADEs (flu-like sx, hepatitis)

Trichomonas Vaginitis

*Cause* Trichomonads (trichomonas vaginalis) *Risk Factors* Multiple sex partners Prostitution Injection drugs Pregnancy *Symptoms* 50% OF PATIENTS ARE ASYMPTOMATIC Usually during or immediately after menstrual period Dysuria, dysparenunia Lower abd pain 50% of cases have itching *Diagnosis* Positive "whiff" test Pear-shaped flagellate in wet mount Strawberry spots: cervix/upper vaginal exhibit raised, puncutated erythema with surface erosions Copious, frothy, white to greenish yellow discharge pH 5+ *Treatment* Women: oral metronidazole Men: metronidazole single dose Alt for both sex: tinidazole Pregnancy: metronidazole single dose SHOULD TREAT ALL SEXUAL PARTNERS NO MATTER SEX

Vulvovaginal Candiasis (Yeast Infection)

*Causes* 80-90% candida albicans Usually happens when vaginal conditions change (pH change, etc) *Risk Factors* Immunosuppressed Broad-spectrum abx Natural flora inhibition 2-3 wk course of tetracycline Post-tx of trichomoniasis/bacterial vaginitis Pregnancy DM Glycogen changes in uncontrolled women *Symptoms* Perivaginal pruritis Erythema Dysuria Diffuse reddening with small satellite lesions Discharge (thick and curdy like cotton cheese) *Diagnosis* <4.5 pH Negative "Whiff" Test: amine odor from KOH MORE INDICATIVE of BACTERIAL growth Presence of pseudohyphae on wet mount *Severity* Uncomplicated: sporadic/infrequent AND mild-moderate AND likely to be candida albicans AND immunocompetent Complicated: recurrent (3+ episodes in <1yr) OR severe OR non-albicans candida OR DM/immunosuppressed *Uncomplicated Treatment* OTC: clotrimazole cream, miconazole cream/suppository, tioconazole ointment Rx: butoconazole cream, terconazole cream/suppository, oral fluconazole *Complicated Treatment* Severe: oral fluconazole every 3 days for 3 doses OR topical antifungal for 7-14 days Recurrent: 7-14 days of oral/topical induction AND weekly fluconazole for 6 months Tx fail OR non-albicans: intravaginal boric acid for 3 weeks (glabrata) ; intravaginal boric acid for 3 weeks OR non-fluconazole azole for 7-14 days (krusei) *Ibrexafungerp (Brexafemme)* Triterpenoid oral antifungal inhibits 1->3-b-D-glycan synthase For adult and post-menarchal peds females DO NOT USE IN PREGNANCY STRONG CYP3A4 INDUCER

Rocky Mountain Spotted Fever

*Causes* American dog tick Rocky mountain wood tick Brown dog tick (AZ) *Etiology* Rickettsia rickettsii *Tick Removal* Grab tick with TWEEZERS by the head (if grabbed by body, head will get stuck in skin) Pull directly up Immediately wash area with soap *Symptoms* 2-14 day onset after bite Fever, HA, malaise, muscle pain, NV, neuro stuff Rash (small ,flat, non-itchy, pink spots on wrist/forearms/ankles): appears at around day 6, can spread to trunk Severe: thrombocytopenia, anemia, leukopenia, elevated serum transaminases Late stage: definitive rash, neuro stuff, dyspnea, arrhythmias, jaundice, severe abd pain, vasculitis, HIGH MORTALITY *Diagnosis* Confirmation use Serology (IgG) PCR *Treatment* Doxycycline Q12H for around 7-10 days (less likely to stain developing teeth than tetra) YOU CAN USE DOXYCYCLINE FOR CHILDREN <8 YEARS OLD IF THEY HAVE RMSF (any other time is a CI)

Healthcare-Associated Ventriculitis and Meningitis

*Causes* CSF shunts/drains (4-17% INCIDENCE) Intrathecal drug therapy Deep brain stimulation Neurosurgery Head trauma *Presentation* New HA, nausea, lethargy, sz Erythema and tenderness over shunt Fever and increased WBC New or worsening AMS *Diagnosis* CSF analysis CSF gram stain CSF cultures Blood cultures MRI *Etiology* Gram Positive: staph aureus, coag-neg staph (epidemidis), enterococcus, propionibacterium (shunt) Gram Negative: E.coli, enterobacter, citrobacter, Kleb, P.aeru *Empiric Therapy* Standard: vanco + ceftazidime/cefepime/meropenem Alternative: vanco + aztreonam/cipro *Targeted Therapy* MSSA: nafcillin/oxacillin (alt: vanco) MRSA: vanco (alt: dapto, Bactrim, linezolid) C.acnes: PCN (alt: 3CS, vanco, dapto, linezolid) P.aeru: 3/4CS or meropenem (alt: aztreonam, cipro) Enterobacteria: 3CS (alt: meropenem, aztrenonam, cipro) ESBL GNB: meropenem (alt: FQ) Acinetobacter: meropenem (alt: colistin, polymyxin B) 10-14 days: Coag-Neg Staph, P.acnes, staph aureus 10-21 days: GNB If repeated positive CSF cultures: 10-14 days AFTER last positive

Lung Abscesses

*Causes* Complication of ASPIRATION PNEUMONIA Aspiration of gastric content Periodontal disease or gingivitis *Risk Factors* alcoholism, frequent vomiting, intubation *Etiology* Bacterial pneumonia: MRSA, nocardia, mycobacterium, TB Fungal Bronchial obstruction (TUMOR) *Treatment* BROAD-SPECTRUM DUE TO POLYMICROBIAL FLORA Metronidazole COMBINED WITH: clindamycin, cefoxitin, penicillin, Augmentin, ampicillin/sulbactam, Zosyn, moxifloxacin, meropenem

Community-Acquired Pneumonia

*Causes* Host defense defects Aspiration of oropharyngeal secretions Inhalation of highly virulent organism Inhalation of overwheming inoculum of organism Hematogenous seeding of lungs *Risk Factors* Alcoholism, liver disease Asthma, COPD Asplenia, immunosuppression, HIV Instituionalization 70+ age Neuro disorders HF DM Ethnic minority Homelessness *Presentation* Cough: dry or wet Fever/chills Pleuritic chest pain Dyspnea Crackles (rales) on chest auscultation Signs of consolidation in only 30% cases Old, immunocompromised may have more SUBTLE/CONFUSING case and maybe AMS *Diagnosis* Clinical presentation with index of risk factors Physical exams CANNOT DIFFERENTIATE pneumonia from acute bronchitis CXR: can have false-positive reading (CT MORE ACCURATE) Sputum/blood culture: 25+ PMN, <5 epithelial Broncho-alveolar lavage (BAL): 10^6+ Protected specimen brush (PSB): 10^3+ Urine antigen tests: legionella, S.pneumo C-reactive Protein (CRP) determines if abx needed <20mcg/mL: no abx 20-100: delay abx 100+: IMMEDIATE ABX START Procalcitonin: released by cells in response to bacterial toxins (NOT viral) NOT recommended to determine abx use Should use clinical presentation and radiograph to confirm *Etiology* MOST COMMON: strep pneu, myco pneu, chlamydophila pneu POSSIBLE RESISTANT: MRSA, resistant strep pneu (DRSP), H. influenzae, M. catarrhalis, enterobac, P.aeruginosa *Classifying Severity* Pneumonia Severity Index (PSI/PORT/Fine): complicated but well-validated CURB-65: confusion, uremia, respiratory rate, low BP, age 65+ (simpler, more common) *Classifying SEVERE CAP* Need ONE major criteria or 3+ minor criteria Major: septic shock with need for vasopressors, resp fail requiring mech vent Minor: resp rate 30+, PaO2/FiO2 <250, multilobar infiltrates, confusion/disorientation, uremia (BUN 20+), leukopenia (<4k cells), thrombocytopenia (<100k), hypothermia (36C+), hypotension requiring aggressive fluids

Brain Abscesses

*Causes* Immunocompromised: HIV/AIDS, high dose steroids, organ transplant therapy, prolonged/severe neutropenia, usually of fungal/nocardia/atypical infx Immunocompetent: chronic infection, DM, cryptogenic *Presentation* HEADACHE: fever or AMS may/may not be present Behavior changes (frontal/right temporal lobe) Cranial nerve palsy of gait abnormal (brain stem) Hydrocephalus (brainstem) Seizures (25% of cases) Focal neuro signs Signs of pre-disposing infx for hematogenous spread *Diagnosis* CBC, CRP, ESR, cultures Lumbar puncture if NOT CI (if mass or hydrocephalus, do CT BEFORE LP, then CONSULT NEUROSURGERY) MRI if available, CT if urgent/MRI not available Otolaryngology eval Cardio eval with ECG Odontoiatric eval Skin inspection Abd US, CXR *Extent of Treatment* Conservative: no neuro impair, small abscess, multiple abscesses, detected pathogen, CI for surgery (CONSIDER SURGERY IF NO IMPROVEMENT FOR 1-2 WEEKS) Neurosurgical Tx *Empiric Therapy* FIRST-LINE: cefotaxime or ceftriaxome PLUS metronidazole Alternative: meropenem MRSA risk: add vanco Transplant pt: add voriconazole Nocardia risk: Bactrim HIV pt: RIPE for TB and/or Bactrim for toxoplasma *Targeted Therapy* Actinomyces: PCN Bacteroides: metronidazole Enterobacteria: 3CS H.influenae: 3CS Listeria: amp or PCN Tuberculosis: isoniazid, rifampin Nocardia: Bactrim P.aeru: metronidazole MSSA: nafcillin or oxacillin MRSA: vanco Strep: PCN Aspergillus: voriconazole Candida, Cryptococcus, Mucorales: amphotericin B T.gondii: pyrimethamine + sulfadiazine

Bacterial Vaginosis

*Causes* Vaginal condition changes (5+ pH) Overgrowth of faculative/anaerobic bacteria Increased amine production *Risk Factors* Endometritis Pelvic inflammatory disease Invasive gynecologic procedure Pregnancy Sexual transmission Diaphagm/sponge use *Pathogens* Prevotella sp. Gardnerella vaginalis Bacteroides Mycoplasma Mobiluncus *Diagnosis* Positive "Whiff" Test: amine odor from KOH MORE INDICATIVE of BACTERIAL growth Malodorous discharge initial complaint Epithelial cells covered with coccibacillary forms, clue cells Homogenous, thin, white fluid pH 4.5+ *Treatment* Usual: oral/gel metronidazole, clindamycin cream Alt: oral/ovules clindamycin, secnidazole, tinidazole Pregnancy: oral metronidazole or clindamycin Homeopathic: oral lactobacillus replacement, vaginal lactobacillus replacement DO NOT USE LATEX/RUBBER PRODUCTS WITHIN 72 HOURS OF USING OVULE CLINDA

Cephalosporins

*Cefazolin* Purpose: surgical procedures, staph/strep proph Protein Binding 80-95%, but ONLY THE FREE DRUG IS ACTIVE Free drug renally excreted by GFR, free + bound can be secreted tubularly Dose: 2g most patients, 3g for 120+ kg weight (does not distribute well to adipose) -> redose every 4 hours *Cefoxitin* Purpose: surgical procedures (esp lower intestines) Improved GN activity (enterobacterales) with moderate anaerobic activity Alternative: cefazolin + metronidazole (colorectal procedures) 1 hour half life -> 2 hour redose *Perioperative Bowel Preps* Non/poorly absorbed abx to reduce bacterial gut count Neomycin 1g PO + Erythromycin 1g PO @ 19, 18, 9 hours before operation *Cefazolin + Metronidazole* 2g cefazolin + 500mg metronidazole 6-8 h halflife with NO RE-DOSE Admin over 20 minutes (cefazolin can be given IV push, BUT NOT METRONIDAZOLE) *Cefazolin + Vancomycin* Purpose: Known or past infection with MRSA Vanco dose: 15mg/kg with 1000mg/h infusion (DO NOT RAPID INFUSE) ADE: RED MAN syndrome, itching/redness of upper torso, hypotension, lightheadedness HL: 6 hours in adults, 2.5-3 hours in CHILDREN Redose: every 2 HL *Cefazolin Allergy* Patients having a PENICILLIN ALLERGY IS NOT A CONTRAINDICATION FOR CEFAZOLIN Patient having rxn to other B-lactams is NOT a CI for cefazolin (very distinct structures) If allergy is unknown, can STILL give cefazolin (true allergies are NOT common) Contraindications: cefazolin allergy, history of severe non-IgE-mediated/non-anaphylactic rxns (nephritis, hepatits, SJS, TEN, DRESS, etc)

Pertussis (Whooping Cough) in Pediatrics

*Characteristics* "100 day cough" Prolonged, contagious Increased incidence in US Greatest mortaility: <6 months *Etiology* Bordetella pertussis *Stages of Presentation* Catarrhal (1-2 weeks): common cold appearance, gradual INCREASE in cough Paroxysmal (2-6 weeks): cough persistence and severity INCREASES, paroxysmal attacks (WHOOPING cough), post-tussive emesis Convalescent (weeks to months): cough decreases, but may reappear in later URIs *Treatment* <1 month: azitrhomycin 1-5 month: azithromycin, Bactrim (DO NOT USE <2mo) 6+ mon and children: azithromycin, Bactrim Adults: azithromycin, Bactrim *Prevention* VACCINATION: DTaP for <7 years, Tdap for 7+ years or for each pregnancy or wound management Must take Tdap booster every 10 years *Post-Exposure Proph* All household contacts of a pertussis case Infants and women in 3rd trimester of pregnancy (within 21 days of contact) Pre-existing health conditions that may be exacerbated by pertussis (within 21 days of contact) Persons in close contact with infants <12mo, pregnant women, individuals at high risk of severe illness

Amphotericin B

*Characteristics* "POLYENE" antifungal with a hepaene macrolide group and ring forming hemiketal group Macrolide ring and mycosamine group linked by rotatable b-glycosidic bond Amphiphilic compound composed of hydrophilic polyhydroxyl chain along one side and lipophilic polyene hydrocarbon chain on other (POORLY SOLUBLE IN WATER) Zwitterionic behavior due to ionizable carboxyl/amine group VERY INSOLUBLE IN WATER *Coverage* Yeasts: Candida (EXCEPT lusitanae), cryptococcus Molds: Aspergillus, zygomeces Dimorphics: blastomyces, coccidioides, histoplasma Candida: NOT FIRST LINE!!!!!!! Only use for RESISTS to azoles/echinocandins Cryptococcus: induction therapy for 3-6 weeks Aspergillus: 2nd line for refractory cases *Uses* Empiric therapy on immunocompromised Serious molds Any serious/life-threatening fungal infx Yeast likely to be resistant to azoles Cryptococcus meningitis *Mechanism of Binding to Ergosterol* Ergosterol has a CYLINDRICAL SHAPE in all rotations Binds better to hydrophobic side of Ampho B Can also bind to membrane for ion channel formation that leaks vital cytoplasmic contents (C35-OH CRITICAL FOR CHANNEL FORMATION) C2'deOAmB: experimental drug that ONLY binds to ergosterol instead of cholesterol -> less cytotoxicity *Formulations* Toxicity of AmB also depends on formulation (higher plasma levels) Different formulations can also reduce distribution to kidneys BLOOD VESSEL AT SITE OF INFX MORE PERMEABLE THAN THOSE OF NORMAL TISSUE: large suspended particles of LIPID formulations CAN PENETRATE SITE OF INFX Fungizone: powder -> reconstituted for IV Abelcet: lipid suspension Amphotec: cholesteryl injection AmBisome: liposomal powder in single-use vial -> reconstituted in water for IV *Fungizone Micelle Formulation* Micellar preparation (COLLOIDAL DISPERSION) prepared with detergent, NaDeoxycholate Adv: broad spectrum activity (Candida, cryptococcus, molds, histoplasma) Disadv: HIGH INCIDENCE OF SEVERE NEPHROTOXIC *AmBisome Liposomal Formulation* Integrated into small UNILAMELLAR LIPOSOMES: known to have LONG CIRCULATION TIMES Liposomal powder reconstituted in water for IV Less renal toxicity and fewer infusion-related rxns *Abelcet Lipid Complex* Two phospholipids form a ribbon-like complex Therapeutic index better than Abelcet Colloidal characteristics make them QUICKLY REMOVED FROM CIRCULATION -> hepatic disorders *Adverse Effects* Infusion Related Toxicity (Shake and Bake): fever and chills, chest tightness, SOB, hypotension, anaphylaxis, thrombophlebitis (peripheral line), anemia ADE Prevention: INFUSE OVER 4-6 HOURS, pretreat with APAP and Benadryl, hydrocortisone, meperidine (rigors), heparin (throboplebitis), erythropoietin (anemia) *Nephrotoxicity* 80% of cases when dose is greater than ONE GRAM Most reversible but PERMANENT LOSS may occur Presentation: azotemia to 2-3 mg/dL, renal wasting of K and Mg Monitor: SCr every 1-2 days, review other drugs depending on renal clearance, K and Mg Management: K/Mg supplementation, K-sparing diuretic (amiloride) if hypoK is severe, sodium loading 1L of saline, alternate day dosing, hold/reduce dose *Resistance* Reduced ergosterol content Modification of ergosterol molecule No susceptibility breakpoint *Nystatin* Polyene with same mech and spectrum as AmB GREATER TOXICITY TOPICAL USE ONLY: oral swish and swallow, vaginal, cutaneous

Malaria

*Characteristics* 1/5 deaths in Africa due to MALARIA Each child contracts 1.6-5.4 episodes PER YEAR Pregnancy THE HIGHEST RISK OF DYING Most endemic in AFRICAN COUNTRIES Mostly eliminated in the US, most cases from mosquitos *Etiology* Plasmodium falciparum: SHORTEST incubation, MOST SEVERE Plasmodium vivax: sx can be delayed for weeks or months Plasmodium malariae: LONGEST incubation Plasmodium ovale: sx can be delayed for weeks or months *Symptoms* General: fever, chills, sweating, HA, NV, body aches, malaise, enlarged spleen (people usually self-treat if in endemic areas) Falciparum: mild jaundice, hepatomegaly, increased resp rate *Severe Sx Symptoms (FALCIPARUM)* Cerebral malaria -> abnormal behavior, impaired consciousness, sz, coma, other neuro stuff Severe anemia Hemoglobinuria Pulmonary edema, ARDS (even after decreased parasite counts) Abnormalities in blood coag and thrombocytopenia Cardio collapse and shock Acute renal disease Hyperparasitemia Metabolic acidosis from hypoglycemia Hypoglycemia (common in preggo, or after quinine tx) *Travel Precautions* Stay and sleep in screened/AC rooms, use a bed net if needed Cover exposed skin with long clothes Use EPA-registered insect repellants with DEET, etc (apply sunscreen FIRST then repellant) Do NOT use OLE/PMD repellants on <3yr children DO NOT USE PERMETHRIN DIRECTLY ON SKIN *Diagnosis* RDT (falciparum vs other species) Thick/thin blood smears PCR (positive false negative due to chance of delayed infection) *Chemoprophylaxis* OVERDOSE ON CHLOROQUINE CAN BE FATAL Can be started if concerns about tolerance Minor ADE shouldnt stop usage Longer HL drugs which are taken weekly has HIGHER MARGIN OF ERROR if missed dose G6PD deficiency with primaquine CAN BE FATAL: MUST CHECK THIS FIRST

Tuberculosis

*Characteristics* About 1/3 of the world is actually infected, however 90% of cases are LATENT (NOT INFECTIOUS) Second leading infectious killer in world Mostly endemic to Africa, India, South/Southeast Asia Rare in US, 85% of people successfully treated *Mycobacterium tuberculosis* Aerobic bacilli with thick, waxy cell wall VERY SLOW GROWING Has a silent, latent infection or progressive, active infection Transmitted via aerosol drops in which the TB is ACTIVE (cough/sneeze expel) *Risk Factors for Sx* Immunosuppressed Substance abuse DM Children <2 years HIV/AIDS (STRONGEST RISK) *Prevention* Identify ACTIVELY infected patients VACCINATION IN CHILDREN: BCG vaccine *Diagnosis* Physical MHx: sx, hx of TB, past TB tx, demographic risks, conditions that increase risk for TB Mantoux TST or IGRA Chest radiograph: CANNOT CONFIRM, appearance may look unusual for HIV positive Bacteriologic/histologic exam *Symptoms* General: fever and chills, night sweats, appetite loss and weight loss, fatigue Pulmonary: chronic, productive cough for 2+ wks, hemoptysis, CP *Mantoux Tuberculin Skin Test (TST)* Useful for testing TB infections in everyone Can detect infection even when not ill Can determine how many people in group are infected Can be used for people with TB sx Inject 0.1mL PPD tuberculin intracutaneously -> produces 6-10mm wheal Read reaction 48-72 hours AFTER injection Measure ONLY THE INDURATION, NOT THE REDNESS Record reaction in mm 5-10mm reaction: HIV POSITIVE, recent TB contact, fibrotic CXR, organ transplants, immunosuppressed 10-15mm reaction: recent arrival from endemic countries, IVDU, residents/employee of high-risk settings, mycobacteriology lab personnel, high risk clinical conditions, children <4 yrs, children exposed to high-risk adults 15mm+ reaction: NO KNOWN RISK FACTORS FOR TB False Positives: nontuberculosis mycobacteria, BCG vax Note that skin test is NOT CONTRAINDICATED for BCG-vax people -> BCG vax people with 10+mm reaction should be considered for tx Boosting occurs for people who did NOT respond to initial skin test False Negative: very young (<6 mo), live-virus vax, overwhelming TB disease, immunosuppressed *Interferon Gamma Release Assays (IGRA)* Measures immune rxn to M.tuberculosis Forms: Quantiferon Gold, T-SPOT Pros: results in 24 hours, nothing to read, no "boosting" response, BCG vax doesnt affect results Cons: NOT APPROVED FOR <5 YRS, may NOT be accurate for immunocompromised, cannot differentiate between latent and active, more expensive *Specimen Collection and Testing* Needs THREE sputum specimens for smear and culture Acid Fast Facilli (AFB) Smear: RED = TB Cultures: USED FOR CONFIRMATION, culture ALL specimens EVEN IF SMEAR IS NEGATIVE, usually takes 10-14 days *Nucleic Acid Amplification Test (NAAT)* More sensitive and specific than smears Results available hours to days Forms: MTD, Xpert MTB/RIF

Pediatric Croup

*Characteristics* Acute URI Self-limiting Most common 6mo to 6 years of age Most common in late fall to early winter *Etiology* Mostly VIRAL: parainfluenza most common, influenza A, RSV, adenovirus, rhinovirus *Symptoms* "Barking cough" Mild-mod hoarseness Inspiratory stridor with slightly increased RR Flaring nostril, possible cyanosis Suprasternal, infrasternal, intercostal retractions Preferred upright position, sx worse at night Low grade fever, but can elevate higher (rare) *Management* Airway management Supportive care: humidified air, hydration, oxygen supplementation if hospital Drugs: maybe abx, steroids definitely, racemic epi Leaning/drooling without cough: ALERT Epiglottitis: IMMEDIATE MEDICAL ATTENTION *Treatment* Dexamethasone IM Epinephrine solution via nebulizer: dilute in 3mL NS, use half dose if L-epi, WATCH FOR REBOUND OBSTRUCTION/STRIDOR (2 HOURS)

Bronchiolitis in Pediatrics

*Characteristics* Acute VIRAL infection Inflammation, edema, increased mucus, bronchospasm of lower resp tract Mortality greatest with: congenital heart disease, premature birth, CF, immunocompromised *Etiology* Mostly RSV Parainfluenza 3, adenovirus, influenza, rhinovirus MAY HAVE SIMULTANEOUS M.pneu *Symptoms* Preceded by URI Afebrile or low-grade fever Cough (productive or not), rhinorrhea, nasal congestion Increased work of breathing: dyspnea, rales, rhonchi, wheezing, tachypnea, cyanosis, hypoxia, shallow breaths, pleural CP Decreased appetite *Management* Supportive care: humidifier, hydration, start O2 sat if persistently falls under 90% Chest physiotherapy: DO NOT ROUTINELY USE Hydration, PO/IV Fluids: should be assessed and provided *Treatment* Nebulized hypertonic saline 3%: EFFECTIVE IN HOSPITALS Albuterol: used as a trial (most common in practice) Epinephrine: used as trial Ipratropium: used as trial, ONLY UP TO 3 DOSES DO NOT ROUTINELY USE: STEROIDS, RIBAVIRIN, MONTELUKAST *RSV Prevention in High Risk Peds: palivizumab (Synagis)* Dose: 15mg/kg/dose IM every month during Nov-March EXTREMELY EXPENSIVE Candidates for RSV Proph: Prematurity (<29 weeks GA, less than 12 months at start of RSV season) Chronic Lung Disease in <12months (<32 weeks GA, required 21+% oxygen for first month of life) Chronic Lung Disease in 2+ years (<32 weeks GA), req 21+% O2 for first month of life, requires medical support like steroids and supplemental O2) Hemodynamic Significant Congenital Heart Disease for <12mo (acyanotic HD receiving meds and will need surgery, mod-severe pulmonary HTN) Hemodynamic Sig Congenital Heart Disease for 2+ years (undergoing cardiac transplantation during RSV season) Pulmonary abnormalities or neuromuscular disorders (<12months, condition impairs ability to clear secretions in airway) Immunocompromised (<24mo, profoundly compromised during RSV season like high dose steroids or transplant or chemo) DO NOT USE IN DOWN SYNDROME OR CF

Pelvic Inflammatory Disease

*Characteristics* Ascending infection of endometrium and/or fallopian tubes 85% of pts DELAY SEEKING MEDICAL HELP *Complications* INFERTILITY: 75% after 3rd episode Peritubal adhesions 6-FOLD INCREASE OF ECTOPIC PREGGO Chronic pelvic pain *Etiology* Difficult to determine exact due to being a mixed infection Difficult to culture *Risk Factors* Hx of PID Vaginal douching IUD user Multiple sex partners Pregnancy: high risk of morbidity, high risk of fetal wastage, high risk of preterm deliveries *Recommended IV Treatment* Ceftriaxone + doxy + metronidazole Cefotetan + doxy Cefoxitin + doxy Transition to oral doxy or metro after improvement *Alternative IV Treatment* Amp-Sulbactam + doxy Clinda + gentamicin *Oral/IM Treatment* IM Ceftriaxone + oral doxy + oral metro IM cefoxitin + oral probenecid + oral doxy + oral metro IM 3CS + oral doxy + oral metro If patient weights 150+kg, administer ONE GRAM of ceftriaxone *Prevention* Sexual hygiene and STD prevention Condoms, oral contraceptive NO VAGINAL DOUCHING Chlamydia screening Early dx and completed tx with ADHERENCE

Viral Infections Post-Transplant

*Common Pathogens* Influenza A/B RSV Type 3 Parainfluenza Rhinovirus Coronavirus Adenovirus: kerato-conjunctivitis, pharyngitis, enteritis, diarrhea, hemorrhagic cystitis, pancreatitis, hepatitis, viremia and disseminated infx Herpes virus: HSV, CMV, EBV, varicella-zoster, HHV6/7/8 Polyoma virus Enterovirus Parvovirus B19 *Diagnosis* HIGH LEVEL OF SUSPICION IN NEUTROPENIA Common sx: fever, rash, elevated LDH Dx: cultures, PCR *HSV, CMV, EBV, VZV Tx* Acyclovir or valacyclovir Ganciclovir or valganciclovir UL97 CMV mutation: RESISTS ganci/valganciclovir -> USE GANCICLOVIR + FOSCARNET UL54 CMV mutation: resists ganciclovir/valganciclovir, foscarnet, cidofovir *Respiratory Viruses Tx* Nothing done unless SIGNIFICANT risk

Viruses and Antiviral Targets

*Characteristics* Can be either RNA or DNA Can be in a capsid or membrane Infects only SPECIFIC cells which causes an immune response NOT ALL VIRUSES ARE BAD Simpler than bacteria/mammal cells They are considered PARASITES: can ONLY synthesize protein using a host cell ribosome Mutates frequently *Viral Replication* Virus attaches to target cell Cell engulfs virus via endocytosis Viral contents are released -> viral RNA enters nucleus where it's replicated by viral RNA polymerase New viral particles are made and released into extracellular fluid, cell continues to make new viruses Viral mRNA then used to make viral proteins *Antiviral Targets* Neuraminidase inhibitors block release of new viral products into extracellular fluid M2 channel inhibitors block emptying or viral contents in cell PA endonuclease inhibitors block conversion of nascent mRNA to viralmRNA Protease Inhibitors in HepC NS5A/B Polymerase inhibitors in HepC

Herpes Simplex Virus

*Characteristics* DNA virus Can cause herpes labialis, genital herpes, encephalitis, disseminated infections *Locations* Gingivostomatitis Esophagitis Pneumonia Ecephalitis Ophthalmic infections Hepatitis *Other HSV Diseases* Herpetic keratoconjuncuvitis: unilateral/bilateral conjunctivitis, variable pain or ocular irritation, photophobia/epiphora common, vision may or may not be affected HSV Encephalitis (most sporadic form): acute fever, HA, decreased consciousness, sz Diagnosis with CT/MRI/CSF/brain biopsy 70% CHANCE OF DEATH IF NO TX *Stages* Primary: more severe than recurrent Latent: virus travels up nerve ganglion and enters dormant stage Recurrence *Reactivation Sx* First 6 hours: pain (most severe at start), burning, tingling itching 2 days of vesicles forming on lips Vesicles bursts and crusts, stays for about 3-4 days Heals in 8-10 days *Causes for Recurrence* Stress: physical and emotional UV light Tissue dmg *Resistance* Usually occurs with long-term antiviral use Thymidine kinase deficient virus *Treatment* Neonatal: acyclovir Severe: acyclovir, valacyclovir, famciclovir Recurrent labial: topical penciclovir, acyclovir (can also use for suppression) Herpetic keratoconjuncuvitis: topical trifluridine, oral acyclovir reduces recurrence, topical acyclovir ointment HSV Encephalitis: acyclovir with IV fluids (higher dose often used in neonates) TOPICAL ACYCLOVIR NOT EFFECTIVE

Cryptococcus (Cryptococcosis)

*Characteristics* Encapsulated yeast with budding daughter cells Usually in bird poop (pidgeons) Mostly primary pulmonary infections: disseminated in immunocompromised, can spread to CNS *Diagnosis* CSF antigen detection, cultures Demonstration of organism in path specimen (staining) EIA for antibody is VERY non-specific *Treatment* Mild-Mod Pulmonary: fluconazole, lipid AmB Severe pulmonary OR CNS OR disseminated: AmB with/without 5-FC induction, then fluconazole maintenance Switch to fluconazole in meningitis when CSF antigen decreases and pt shows clinical improvement (4-6 weeks) Can use fluconazole instead of 5-FC (less data) Duration: 6+ months depending on immune status and HIV status

Aspergillus (Aspergillosis)

*Characteristics* Environmental mold: construction or black pepper *Differentiation* Hypersens Lung Disease: extrinsic asthma, farmer's lung Allergic bronchpulmonary: sinuses and lung involvement with elevated aspergillus IgE and total IgE Mucoid Impaction Syndrome: colonization of lungs with mucus plugs in COPD/asthma pts Aspergilloma (fungus ball): hemoptysis Invasive aspergillosis: tissue invasion, immunocompromised *Diagnosis* Clinical and histological Culture: ONLY SUPPORTIVE *Allergic Tx* Steroids Antifungal: intraconazole, other mold-active azole *Fungus Ball Tx* Prolonged antifungal Monitor with imaging Surgical removal *Invasive Tx* FIRST-LINE: VORICONAZOLE with/without echinocandin, isavuconazonium SECOND-LINE: lipid AmB, caspofungin, itraconazole Duration: 6-12 weeks to LIFETIME *Prophlaxis* Candidates: lung transplants, acute leukemia, HSCT Drug: inhaled AmB, liposomal AmB, posaconazole, echinocandin, voriconazole

Fungal Cells

*Characteristics* Eukaryotic (single-cells or multi-cellular fillaments called HYPHAE) Not usually contagious Skin and lungs usual entry sites Primary (true) pathogens: virulence factors allow them to invade and grow in host Opportunistic pathoegns: weak virulence that only pops up when host is immunocompromised Aspergillus causes MOST DEATHS IN FUNGAL, followed by Cryptococcus and Candida *Fungi vs Mammalian Cells* Fungal cell walls contain CHITIN, glucans, and MANNOPROTEINS ERGOSTEROL is equivalent to cholesterol

Varicella Zoster Virus

*Characteristics* First appears as chickenpox (varicella), especially in children Reactivates as shingles (zoster), especially for elderly and immunocompromised HIGHLY CONTAGIOUS, transmitted via respiratory route *Locations* Cutaneous infx Pneumonitis Hepatitis Encephalitis *Presentation* Immunocompetent children: vesicles and scabs, lesions on mucous membranes (RARE), malaise, pruritis, anorexia, lasts for 1wk Severe older children/adult: encephalitis, varicella pneumonitis Immunocompromised: more severe illness, prolonged sx, high risk for complications Reactivation: pain/burning preceding rash by 48-72hrs, unilateral vesicular rash, postherpetic neuralgia in 25-50% of pts *Immunocompetent Treatment* Neonates: acyclovir 10mg/kg Children <12: acyclovir 20mg/kg Adults: valacyclovir, famciclovir, acyclovir Last trimester preggo: acyclovir Pneumonitis or other severe infx: acyclovir *Immunocompromised Tx* Steroid or low dose cytotoxic use: Valacyclovir/famciclovir/acyclovir Organ transplant, hematologic transplant or cancer: IV acyclovir HIV infected: IV acyclovir, PO valacyclovir/famciclovir/acyclovir *Reactivation Immunocompetent Tx* PRIMARY GOAL IS TO REDUCE PAIN AND PREVENT PHN Age <50 with mild pain: sx tx Age <50 with opthalmic rash: PO valacyclovir, famciclovir, acyclovir, eye exam Age 50+ with mod/severe pain: PO valacyclovir, famciclovir, acyclovir Start within 48-72 hrs of sx onset *Reactivation Immunocompromised Tx* Steroid/low dose cytotoxic use: PO valacyclovir, famciclovir, acyclovir Organ transplant, blood transplant, cancer: IV acyclovir, PO valacyclovir, famciclovir HIV infected: PO valacyclovir, famciclovir, acyclovir Disseminated: IV acyclovir Acyclovir RESISTANT: foscarnet, cidofovir *Postherpetic Neuralgia (PHN)* Inflammatory dmg to sensory nerves, ganglia, nerve roots Tx: capsaicin, topical lidocaine, mexiletine, TCAs, anticonvulsants, TENS OFTEN RESISTANT TO NSAIDS AND NARCOTICS *Post-exposure Prophylaxis* Recommended with Varicella-zoster IG or high dose acyclovir Eligibility: leukemia, lymphoma, immunocompromised, newly born with mother onset within 5 days before or 48 hours after delivery, premature neonates Give within 96 hrs of exposure *Varicella Vaccines: Varivax, Proquad (MMRV)* LIVE VACCINE For immunocompetent children 1+ yr old with NO hx of varicella (two dose series 3 months apart) ADE: inj rxns, skin rash, severe rxns rare *Zoster Vaccines: Shingrix* Approved for 50+ yrs old whether hx or not, or 18+ yrs old if immunocompromised ADE: inj site rxns Zostavax is NOT PREFERRED ANYMORE Live vaccine

Bacterial Infections Post-Transplant

*Common Pathogens* Gram Positive: coag-neg staph (skin), staph aureus (skin), MRSA (skin), enterococcus (GU), VRE (GU), strep viridans (mouth), strep pneu, strep pyogenes Gram Negative: E.coli, Kleb, enterobacter, P.aeru, citrobacter, acinetobacter, stenotrophomonas maltophilia *Gram Negative Treatment* Tx depends on days past since transplant and duration of neutropenia: usually FQs or IVIG depending on IgG concentrations *Grams Positive Tx* Not usually prescribed unless SIGNIFICANT risk (chronic graft-versus-host disease GVHD) *Mycobacterium Tx* Avium complex (MAC): nothing happens unless SIGNIFICANT risk (clarithro/azithromycin, rifabutin, rifampin) Tuberculosis (latent): meds based on screening tests and exposure, usually INH + pyridoxine *C.diff Infection* Sx: enterocolitis and diarrhea Tx: PO vanco OR fidaxomicin OR metronidazole (but don't)

Syphilis

*Characteristics* MOST COMMON WITH MSM INTERACTIONS Most common with black people *Etiology* Treponema pallidum *Screening* Veneral Disease Research Lab (VDRL): best for latent Rapid Plasma Reagin (RPR): best for latent Fluorescent Treponemal Ab Absorbed (FTA-ABS): best for late stage Treponema pallidum-Particle agglutination (TP-PA): best for latent Enzyme Linked immunoassay (ELIZA): best for primary and latent *Recommended Treatment* Primary/secondary/early latent adults (including preggo and HIV): benzathine penicilllin G IM single dose Late latent adults (includes preggo and HIV): benzathine penicillin G IM one dose per week for 3 weeks Neurosyphilis, ocular syphilis, otosyphilis: aqueous crystalline pencillin G IV Q4H or infusion for 10-14 days Children or congenital syphilis *Alternative Tx* Neurosyphilis, ocular syphilis, otosyphilis: procaine penicillin G IM + probenecid QID for 10-14 days *Penicillin Allergy* Low risk: HA, itching without rash, localized rash, delayed onset rash 24hrs+, sx unknown, FHx of allergy, pt denies allergy BUT on record Skin tests to identify people at risk of allergy: benzylpenicilloyl polylysine injection (MAJOR DETERMINANT) with commerical histamine for positive control and saline diluent for negative control If patient has positive skin test: must undergo ORAL DESENSITIZATION PROTOCOL THE ONLY TREATMENT FOR SYPHILIS IS PENICILLIN!

Cytomegalovirus (CMV)

*Characteristics* Member of Herpes family Infection common and USUALLY ASX 40% of kids seropositive 70% of adults seropositive Infectious mononucleosis-like Congenital CMV develops in utero *Locations* Pneumonitis Ophthalmic infx Enteritis Hepatitis Viremia and disseminated infx *Treatment* Proph: acyclovir (NO IN VITRO ACTIVITY) Ganciclovir or valganciclovir (CAN RESIST) Foscarnet Cidofovir

5-Fluorocytosine Antifungal

*Characteristics* Prodrug conversion that ONLY HAPPENS IN FUNGI (5-FC -> 5-FU) Used IN COMBO with amphotericin B Bacterial flora in human guy can convert 5-FC to 5-fluorouracil causing N/V/D AND BONE MARROW SUPPRESSION *Coverage* Candida Cryptococcus *Uses* Cryptococcal meningitis: induction and maintenance Serious Candida infx *Mechanism* 5-FC -> 5-FU 5-FU -> FUMP -> FUTP -> incorporate into RNA -> protein synth inhibition 5-FU -> FdUMP -> inhibits thymidylate synthetase -> DNA synth inhibition *Adverse Effects* NVD Myelotoxic with Cmax 100+ *Resistance* C.glabrata and C.albicans can have cytosine mutation to have resistance Cytosine permease deficiency in Candida species

Medications to Induce Immunosuppression

*Characteristics* Short-term Period of HIGHEST RISK OF REJECTION First dose is ALWAYS in the operating room Agents used depend on organ, donor, recipient, transplant center Stronger agents used for higher immunologic risk (high PRA) *Anti-thymocyte Globulin* Polyclonal antibodies from horse or rabbits Mech: T-cell depletion/suppression of activation Tx: induction, rejection PK/PD: 24 hour onset, 2-3 day HL, 6-12 months of T-cell depletion ADE: fevers, chills, hypo/hypertension, tachycardia, thrombocytopenia, leukopenia, peripheral edema, infx, cytokine storm Can prevent cytokine storm with steroid/tylenol/benadryl pre-medication *Basiliximab (Simulect)* Mech: mAb blocks IL-2 receptor -> blocks T-cell proliferation Tx: kidney induction (off-label: other organs) PK/PD: 7-10 day HL, 1 month T-cell depletion ADE: HTN, edema, NVD, HA, infx Pre-meds NOT required *Alemtuzumab (Campath)* Mech: mAb binds to CD52 on B/T-cells -> Ab-dependent cellular lysis/depletion Tx: B-cell chronic lymphocytic leukemia, relasping MS, off-label induction PK/PD: 6-14 day HL, 6-12 month depletion ADE: INFECTIONS, HA, rash, N/V, infusion rxn, lymphocytopenia BBW: BONE MARROW SUPPRESSION, INFUSION RXN HX, CURRENT INFX *Methylprednisolone (Solu-Medrol)* Mech: bind to glucosteroid response elements in DNA -> prevent cytokine transcription Tx: induction, rejection, pre-med regimen PK/PD: 2-3 hr HL, 1 hr peak, hepatic metabolism Short-term ADE (most are dose-dependent): hypergly, HTN, mood changes, insomnia, wt gain, inc appetite, fluid retention, infx

Medications to Maintain Immunosuppression

*Characteristics* Started IMMEDIATELY after transplantation Dosed down over time as rejection risk decreases Combine different agents that target multiple sites of T-cell activation LIFELONG *Tacrolimus (Prograf, Envarsus XR, Astagraf XL)* Calcineurin Inhibitor stops NFAT from being phosphorylated and entering nucleus Mech: binds to FK binding protein complexed with calcineurin dependent proteins -> inhibit calcineurin phosphatase activity Tx: rejection proph Monitoring: goal trough levels are 4-12 ng/mL where the first three months should be the upper limit of goal ADE: HTN, NEW ONSET DM AFTER TRANSPLANT, alopecia, HA, tremor, neurotoxic, nephrotoxic, infx, QT PROLONG, K/Mg imbalance Many DDIs as a PGP substrate DECREASED ABSORPTION IF TAKEN WITH FOOD *Cyclosporine (Gengraf, Neoral, Sandimmune)* Calcineurin Inhibitor Mech: inhibit IL-2 activation in resting T-cells Tx: rejection proph Non-modified PK/PD (Sandimmune): dependent on food and a functioning GI system Modified PK/PD (Gengraf, Neoral): increased overall absorption, not as dependent on food Monitoring: 75-350ng/mL trough goal with the first 3 months having the highest limit goal ADE: HTN (50% of cases), less frequent new DM, hirsutism, gingival hyperplasia, HLD, nephrotoxic, infx, QT prolong, K/Mg imbalance Try to take AS CLOSE TO 12 HOURS APART AS POSSIBLE if BID Take meds AFTER labs Call transplant team if EXTREME TREMORS OR CONFUSION Oral solutions: mix with OJ/apple juice and drink IMMEDIATELY, rinse with more juice and drink again to get full dose *Mycophenolate (Mofetil = Cellcept ; Mycophenolic Acid = Myfortic)* Antiproliferative agent Mech: inhibit inosine monophos dehydrogenase, inhibit de novo guanosine nucleotide synthesis -> stops proliferation of T/B-cells Tx: rejection proph ADE: infx, NVD, leukopenia, TERATOGENIC (REMS) REMS: need to have TWO METHODS OF CONTRACEPTION unless you have an IUD, sterilization surgery, or partner had a vasectomy *Azathioprine (Imuran)* Purine antimetabolite Mech: incorporates itself into DNA to halt replication, blocks purine synth Tx: rejection proph ADE: NVD, leukopenia, infx, hepatotoxic Consider testing for TPMT and NUDT15 deficiency if pt has severe bone marrow toxic *Prednisone* Mech: reduce activity and volume or lymphatic system Tx: rejection proph Absorption can be altered by hepatic/kidney fail Long-term ADE: poor wound healing, adrenal suppression, Cushing's syndrome, DM, HTN, osteoporosis, acne *Sirolimus (Rapamune)* mTor inhibitor (SECOND LINE) Mech: binds to FKBP-12 to form complex that inhibit mTOR -> suppress cytokine T-cell proliferation -> stop cell cycle from G1 to S progression Tx: rejection proph Monitoring: LFTs, CBC, lipids, BUN/SCr, urine Goal of 8-12 ng/mL, levels collected 4-5 days after initiate/adjustment ADE: anemia, thrombocytopenia, pneumonitis, bronchitis, cough, hepatic artery thrombosis BBW: POOR WOUND HEALING *Everolimus (Zortress, Afinitor, Afinitor Disperz)* mTOR inhibitor (SECOND-LINE) Mech: binds to FKBP-12 to form complex that inhibit mTOR -> suppress cytokine T-cell proliferation -> stop cell cycle from G1 to S progression Tx: rejection proph BRAND NAMES ARE NOT INTERCHANGABLE ADE: anemia, leukopenia, infx, URI, renal/hepatic artery thrombosis, edema BBW: POOR WOUND HEALING Monitoring: LFTs, CBC, lipids, BUN/SCr, urine Goal of 3-8 ng/mL, levels collected 4-5 days after initiate/adjustment All formulations have DECREASED BIOAVAILABILITY WITH FOOD, but different decreases *Belatacep (Nulojix)* Costimulation blocker Mech: binds to CD80/86 receptors on APC -> blocks interaction with APC and T-cell to stop activation Tx: KIDNEY rejection proph with EBV positive (off label lung proph) ADE: HTN, hypotension, edema, infx, arthralgia, NVD, delayed onset HA (hours to days after infusion) BBW: INCREASED RISK OF POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD)

Fluoroquinolones and Folic Acid Antagonists

*Ciprofloxacin (Cipro)* Mech: inhibits DNA gyrase and Topo IV to stop DNA replication Resist Mech: mutations in targets, changes in enzymes that lower binding affinity, porin loss, efflux Coverage: enterobacterales, P.aeru, MSSA (borderline), streptococci (NOT strep pneu) Uses: GN SSSI, complicated UTIs, intraabd infx, only oral agent with P.aeru activity Resists: ESBL enterobacterales, uncomplicated UTI (NOT FIRST-LINE) Toxic: CNS excitation, insomnia, sz, peripheral neuropathy, tendinopathy, aortic aneurysm, QT prolong DDIs: metal cations can chelate (DO NOT TAKE AT ALL), mild CYP3A4 inhibitor, other QT prolonging drugs, DO NOT USE WITH STEROIDS IN ELDERLY Do NOT use for acute bronchitis, uncomplicated UTI, or URIs Must have AST to guide use *Levofloxacin (Levoquin)* Mech: inhibits DNA gyrase and Topo IV to stop DNA replication Resist Mech: mutations in targets, changes in enzymes that lower binding affinity, porin loss, efflux Coverage: similar to Cipro but better at GP than GN, can hit strep pneu Uses: SSSI with GN focus, complicated UTI, CAP with increased risk of b-lactam resist Resist: ESBL enterbacterales, uncomplicated UTI Toxic: CNS excitation, insomnia, sz, peripheral neuropathy, tendinopathy, aortic aneurysm, QT prolong DDIs: metal cations can chelate (DO NOT TAKE AT ALL), other QT prolonging drugs, DO NOT USE WITH STEROIDS IN ELDERLY Do NOT use for acute bronchitis, uncomplicated UTI, or URIs Must have AST to guide use Is considered a RESPIRATORY FQ due to activity on strep pneu *Moxifloxacin (Avelox)* Mech: inhibits DNA gyrase and Topo IV to stop DNA replication Resist Mech: mutations in targets, changes in enzymes that lower binding affinity, porin loss, efflux Coverage: similar to Cipro but BETTER activity on strep pneu than levofloxacin, can hit mycobacterium TB, not active against P.aeru with least GN activity, anaerobics Uses: CAP with strep pneu resist, mycobacterial infx, second-line enterococcus infx, intraabd infx (others are better) Resists: P. aeru Toxic: Toxic: CNS excitation, insomnia, sz, peripheral neuropathy, tendinopathy, aortic aneurysm, QT prolong DDIs: metal cations can chelate (DO NOT TAKE AT ALL), small but consistent QT prolonging effect, DO NOT USE WITH STEROIDS IN ELDERLY DO NOT USE WITH UTIs Is considered a RESPIRATORY FQ due to activity on strep pneu Must have AST to guide use *Delafloxacin (Baxdela)* Mech: inhibits DNA gyrase and Topo IV to stop DNA replication Resist Mech: mutations in targets, changes in enzymes that lower binding affinity, porin loss, efflux Coverage: Similar to other FQs, specifically designed for staph aureus and MRSA Use: SSSI Resists: ESBL enterobacterales, uncomplicated UTI Toxic: Toxic: CNS excitation, insomnia, sz, peripheral neuropathy, tendinopathy, aortic aneurysm, QT prolong DDIs: metal cations can chelate (DO NOT TAKE AT ALL), DO NOT USE WITH STEROIDS IN ELDERLY CAN BE USED FOR SSSI MRSA, not popular because physicians are drilled into their heads to NOT use FQs for MRSA *Trimethoprim* Mech: binds to tetrahydrofolate reductase enzyme to prevent dihydrofolate conversion to tetrahydrofolate -> blocks synthesis of nucleic acids Resist Mech: efflux, mutations in dihydrofolate reductase Coverage: GP, GN, enterobacterales, staph saprophyticus Use: mainly used for UTIs caused by enterobacterales Resists: E.coli, Kleb, Proteus, enterobacter Toxic: hypersensitivity, hyperkalemia (more important with higher doses, renal impair, K-holding drugs, K supplements), pseudonephrotoxicity (artifical increase in SCr due to blocking of proximal tubule cells that elimiate creatinine) Mostly combo with sulfamethoxazole (Bactrim) *Sulfamethoxazole-Trimethoprim aka TMP/SMX, SXT (Bactrim)* Mech: same trimethoprim but sulfamethoxazole inhibits dihydropteroate synthase which is another step in folic acid synthesis Resist Mech: efflux, mutations in targets Coverage: nocardia, pneumocystis jirovecii, stenotrophomonas maltophilia, many things Uses: uncomplicated UTIs, many other infections Resists: community resistance Toxic: hypersensitivity, hyperkalemia (more important with higher doses, renal impair, K-holding drugs, K supplements), pseudonephrotoxicity (artifical increase in SCr due to blocking of proximal tubule cells that elimiate creatinine), SULFA ALLERGY, DRESS, SJS HIV patients have HIGHER incidence of skin rxns with SXT (can be desensitized with ultra low doses and escalating every 15-20 mins, DO NOT INTERRUPT OR START OVER) DO NOT RECHALLENGE IF HAD DRESS OR SJS

Skin and Soft Tissue Infections

*Classification* Primary vs Secondary Uncomplicated vs Complicated Necrotizing vs Nonnecrotizing Purulent vs Nonpurulent *Complicated Infections* Deep infections Needs surgical intervention Comorbid factors: DM, PVD, HIV *Impetigo* Presentation: vesicles (clear to purulent) that will break open -> yellow crusting Mostly staph aureus infection Common in 2-5 age children, especially in summer months TRANSMISSIBLE! Topical abx (mupirocin) for mild cases Oral abx for severe cases (dicloxacillin, cephalexin) TMP-SMX, doxycycline, clinda if MRSA concern 7 day durations *Folliculitis* Presentation: smaller hair follicle lesions with red central pustule at peak Only limited to epidermis (superficial) Usually leave it alone, but can use warm saline compresses and mupirocin Oral abx RARELY indicated *Furuncles/Carbuncles* Furuncle (Boils) present: infx of hair follicle with purulent material EXTENDING INTO DERMIS AND SUBCUT TISSUE Carbuncle: group of inflamed follicles into one mass with drainage (MORE SEVERE) Mostly staph aureus infection, occasionally strep Usually seen on neck, face, axillae, butt Incision and drainage -> cultures from drainage Can use warm compresses Can use short-course oral abx after I+D, maybe empiric coverage for MRSA (bactrim, etc) *Cellulitis* One of the most common infectious diseases Erythema, edema, warmth, pain, systemic sx (fever) Involves dermis and subcutaneous fat Usually comes after wound or trauma *Animal Bites* Dog Bites: pastuerella species, anaerobes (prevotella), RABIES Cat Bites: pastuerella multocida, bartonella (CAT SCRATCH DISEASE) Human Bites: eikenella corrodens, strep, anareobes Irrigate wounds with soap/povidine-iodine, debridement, elevation + immobilize, find hx of biter (VACCINATIONS) Abx indications: immunocompromised, asplenia, wounds to hand/face/genitals, deep puncture wounds, close proximity to bone/joints, adv liver disease *Animal Bite Abx Proph* PREFERRED: Augmentin Alternatives: doxy, Bactrim, cefuroxime, fluoroquinolone + metro/clinda Duration: 3-5 days *INFECTED Animal Bite Tx* Use oral abx for less severe Hospital + IV abx needed for severe: ampicillin-sulbactam, Zosyn, cefoxitin, ertapenem, fluoro + metro/clinda RABIES: immunoglobulin + vaccine Tetanus booster *Hospitalization for Severe Infections* Fevers and chills (rigors) Mental Status Changes Shock Dramatic Skin Infections *Outpatient Treatment for Severe SSTIs* Abx tx usually 5-14 days Erysipelas: penicillin/amoxicillin (strep infection) Nonpurulent Cellulitis: dicloxacillin/cephalexin Purulent Cellulitis: I+D, MRSA + strep coverage *Inpatient Treatment for Severe SSTIs* Blood cultures more indicated for more severe cases Erysipelas: cefazolin/ceftriaxone Non-purulent Cellulitis: Broad spectrum coverage (vanco + gram negative coverage for more severe) Purulent: vanco

Secondary Peritonitis

*Classification* Uncomplicated: intramural inflammation of GI Complcated: extends beyond viscus of origin into peritoneal space -> abscess formation or peritonitis Severity depends on physiologic scoring systems, immune status, comorbid conditions: Delay in initial intervention (24+ hrs) High severity of illness (APACHE 15+) Advanced age Comorbids and degree of organ dysfunction Low albumin Poor nutrition Degree of peritoneal involvement or diffuse peritonitis Inability to achieve adequate debridement or drainage control Presence of malignancy *Abscess in SP* Intraperitoneal (75% of cases), visceral (liver, kidney, spleen) Due to other GI tract problems: appedicitis, diverticulitis, surgery, perforated ulcer *Etiology* Gram-neg: E. COLI, enterobacter, kleb, proteus Gram-pos: enterococci, strep, staph Anaerobic: bacteroides, C.diff Fungi Bacterial synergism: aerobic + anaerobic combo can INCREASE SEVERITY *Presentation* Abd pain with voluntary guarding and rigid tensing Shallow rapid respirations Fever Tachycardia and LOWERED urine output (fluid loss into peritoneum) SEPSIS AND HYPOVOLEMIC SHOCK IF UNTREATED *Treatment Goals* Source control: drainage and surgery Support of vital functions via IV fluids Appropriate antimicrobials to cover aerobic and anaerobics (DO NOT DELAY ABX FOR CULTURES) Nutrition support, especially for ileus *Community-Acquired Tx* Single Agent Peds: penems, ticarcillin-clavulanate, Zosyn Single Agent Mild-Mod: cefoxitin, penem, moxifloxacin, tigecycline, ticar-clauvaunic Single Agent Severe: penems, Zosyn Combo Peds: 1/2/3CS + metronidazole, gentamicin/tobramycin + metronidazole/clindamycin (can also include ampicillin) Combo Mild-Mod: 123CS/FQ + metronidazole Combo Severe: cefepime/ceftazidime/FQs with metronidazole *Healthcare-Acquired Tx* <20% resistant P.aeruginosa, ESBL enterobac, acinetobacter, other MDR GNB: carbapenem, Zosyn, ceftazidime/cefepime + metronidazole ESBL enterobac: carbapenem, Zosyn, AGS 20%+ P.aeruginosa resistant to ceftazidime: penem, Zosyn, AGS MRSA: Vanco *Other Coverage* Enterococcal: no adv in covering if community Fungal (candida sp.): if immunosupressed, post-op, recurrent, perforated ulcer on acid-supressant Fluconazole PREFERRED Echinocandins if fluconazole RESIST

Urine Cultures

*Clean Catch* Collect urine midstream in a sterile container *Catheter Specimen/Suprapubic Puncture* Do NOT collect from foley catheter Differentiate between catheter associated asymptomatic bacteriuria and catheter associated UTI Do NOT treat CA-ASB with abx unless bacteriuria persists 48+ hours AFTER REMOVING CATHETER *Evaluation* Pyuria: WBC 10+ (notify lab if pt is neutropenic) UTI: WBC 10^5 CFU/m (can be as low as 10^3 for females -> SUSCEPTIBILITY TESTING) *Contamination* Normal flora: staph epidemidis, virdians strep, cornyebacteria, enterococcus Normal perineum flora: E.coli, klebsiella, proteus mirabilis (UNLESS 100K+) Catheters/stents: staph aureus

Clindamycin, Macrolides and Oxazolidiones

*Clindamycin* Mech: inhibits 50S ribosome from synthesizing peptides Resist Mech: methylation of ribosome (MLSb) Coverage: MSSA, strep pyogenes, some MRSA, anaerobic (NOT bacteroides), group B strep Use: surgical proph for b-lactam allergy, SSSI, group B strep in PREGGO, adjunctive to reduce toxin production in strep/staph, dental infections with allergy to PCN or no response to PCN Resist: MSSA/MRSA/strep pyogenes can have selective resist, strep pneu D-Test MUST BE DONE to exclude resistance for MRSA Good for cellulitis in SSSI *Erythromycin* Mech: inhibits 50S ribosome from synthesizing peptides Resist Mech: methylation of ribosome (MLSb) Coverage: strep pneu, cutibacterium acnes Use: strep throat if PCN allergy, acne vulgaris, gastroparesis Resist: ERM Has relatively HIGH rate of GI ADEs (other macrolides have less GI ADEs) Strong CYP3A4 inhibit -> DDI risks QT PROLONGATION RISK *Azithromycin (Zithromax, Z-Pak)* Mech: inhibits 50S ribosome from synthesizing peptides Resist Mech: methylation of ribosome (MLSb) Coverage: strep pneu, H.influenzae, legionella, mycoplasma, chlamydophila, Use: CAP, URI, atypical infx with B-lactam Resist: S.pneu (erythromycin resist PREDICTS other macrolide resist, penicillin resist ASSOCIATED with macrolide resist) Usually OVERUSED Much lower ADE than erythromycin Less QT prolong, but still relatively higher than amoxicillin *Clarithromycin* Mech: inhibits 50S ribosome from synthesizing peptides Resist Mech: methylation of ribosome (MLSb) Coverage: S.pneu, H.influenzae, atypical resp pathogens, H.pylori (adjunct), mycobacteria Use: acute bacterial excaerbations with COPD, H.pylori adjuct with PPI and metronidazole Resist: S.pneu (erythromycin resist PREDICTS other macrolide resist, penicillin resist ASSOCIATED with macrolide resist) In the middle of the macrolides with GI ADEs QT PROLONGATION CYP3A4 inhibitor -> DDI risk *Linezolid* Mech: inhibits 50S ribosome via blocking initiation complex Resist Mech: altering target binding site via polymorphisms Coverage: Staph aureus, coagulase negative staph, enterococci (E.faecium VRE), strep pneu Resist: E.faecium can resist (SUSCEPTIBILITY TEST) Toxic: myelosuppression, neuropathy, serotonin syndrome, hypoglycemia and metabolic acidosis (RARE) DDIs: SSRI, SNRI, MAOI, other psych meds (SEROTONIN SYNDROME) Great for infections that can be managed in less than two weeks Needs CLOSE MONITORING due to toxicity SSRI and SNRIs can be stopped TWO WEEKS BEFORE starting linezolid (but this is UNREASONABLE, just MONTIOR THEM CLOSELY) Immediately DISCONTINUE if ANY signs of NEUROPATHY (unless benefits outweigh risks) *Tedizolid (Sivextro)* Mech: inhibits 50S ribosome via blocking initiation complex Resist Mech: altering target binding site via polymorphisms Coverage: staph aureus, coagulase negative staph, enterococci (E.faecium VRE), strep pneu Resist: mostly seen in enterococci (SUSCEPTABILITY TEST) Toxic: Toxic: myelosuppression, neuropathy, serotonin syndrome DDIs: SSRI, SNRI, MAOI, other psych meds (SEROTONIN SYNDROME) PRODRUG Might be better tolerating than linezolid Immediate DC if ANY signs of NEUROPATHY DO NOT USE IF RECENTLY DC'D FROM LINEZOLID DUE TO NEUROPATHY

Fungal Infections Post-Transplant

*Common Pathogens* Pneumocystis jiroveci: pneumonia Candida Aspergillus, zygomyces, coccidioides, histoplasma, blastomyces *Diagnosis* Neutropenia high suspicion Imaging Biopsy 1 -> 3-beta-D-glucan testing Aspergillus galactomannan testing Fungitell *Pneumocystis Pneumonia (PCP) Tx* Bactrim with or without steroids *Aspergillus, Histoplasma, Coccidioidomycosis Tx* Voriconazole or posaconazole Fluconazole for coccidiomycosis Itraconazole for histoplasma *Candida Tx* Fluconazole, itraconazole, voriconazole, posconazole Depends on risk factors and proph for molds

Protozoal Infections Post-Transplant

*Common Pathogens* Toxoplasma gondii: CNS, dissemination Cryptosporidium parvum: diarrhea *Toxoplasma Tx* Bactrim *Cryptosporidium Tx* Nitazoxanide

Sexual Assault

*Common STDS After Assault* Trichomonas, BV GC, chlamydia *Other STDS* Syphilis HBV: can take vaccine HPV: can take vaccine HIV: test and consider PEP *Recommended Proph* Women: Ceftriaxone IM single dose + doxy oral + metro oral Men: ceftriaxone IM single dose + doxy oral

Genital Herpes

*Course of Disease* Pustules appear about a week after sexual contact Systemic sx and lesions appear -> doctor is usually contacted Wet ulcer appear with new lesions and local sx Lesions start to heal -> dry crusting Sx begin to resolve unless lesions are irritated Lesions healed about 20 days after first sx *Recommended Tx* First episode: oral acyclovir OR famiciclovir OR valacyclovir Suppressive therapy for recurrence: oral acyclovir OR valacyclovir OR famiciclovir Episodic therapy for recurrence: oral acyclovir OR famiciclovir OR valacyclovir Daily suppressive therapy in HIV infx: oral acyclovir OR famiciclovir OR valacyclovir Episodic therapy in HIV infx: oral acyclovir OR famiciclovir OR valacyclovir Daily suppressive therapy in PREGNANCY: oral acyclovir OR valacyclovir

Acute Cystic Fibrosis Pulmonary Exacerbations

*Cystic Fibrosis* Inherited, AUTOSOMAL-RECESSSIVE, multi-organ disease Affects pulmonary, GI, sweat glands, reproductive Life expectancy: 43 years *CF Effect on Pulmonary Cell* CF Transmembrane Conductance Regulator (CFTR) has no response to cAMP Decreased Cl exit to lumen Increased Na entry into cell -> increased water entry into cell Increased water CREATES THICK, VISCOUS SURFACE LIQUID that is difficult to clear (obstruction) Increased susceptibility for infection *Pharmacokinetics in CF* Absorption: gastric pH differences and slower GI motility Distribution: larger volume of distribution (more hydrophilic) Metabolism: possible hepatic clearance diff Elimination: increased clearance, decreased resorption *CF Lung Disease Severity* Mild: FEV1 70%+ Moderate: FEV1 40-69% Severe: FEV1 <40% Factors affecting severity: CF mutation, non-CF genetics, comorbids, control of CF-related DM, nutritional status, adherence *Acute Pulmonary Exacerbation (APE) in CF* Acute worsening of signs and sx: weight loss, inc cough, inc sputum, hemoptysis, malaise Acute decrease in FEV1 lung function (10% or more from baseline) Etiology: P.aeru most common, MRSA, S.maltophila, non-TB mycobacteria, achromobacter, B.cepacia These are NOT TYPICAL COMPARED TO CAP Multi-drug resistance IS COMMON Abx selection factors: cultures/susceptibilites in past and present, age, organ function, hx of allergies and ADE, screening for DDI *Antibiotics for APE-CF* Outpatient: at least 2 drugs of oral + nebulized + increased CPT OR IV +- oral + increased CPT Inpatient: at least 2 drugs of IV +- oral + increased CPT DO NOT ROUTINELY USE NEBULIZED AGENTS, THEY ARE USED FOR SUPPRESSION MSSA: nafcillin, cefazolin MRSA: vanco, Bactrim, mino/doxycycline, linezolid if allergy or resistant or PO home use, clindamycin (D-test) Other MRSA agents: ceftaroline (LAST RESORT), everything else has limited CF or no CF data DO NOT USE DAPTOMYCIN: NO LUNG EFFICACY P.aeru: Zosyn, cefepime, Cipro, meropenem, aztreonam, ceftazidime (add AGS or another anti-pseudomonas to any of these) AGS agents for P.aeru: tobramycin, amikacin (DO NOT USE GENTAMICIN) Other P.aeru agents: imipenem (more GI ADE), ceftazidime/avibactam, ceftolozane/tazobactam, imipenem-relebactam, polymixin B in combo, inhaled aztreonam/amikacin/polymixin E S.maltophilia: Bactrim (PREFERRED), levo/moxifloxacin Nocardia: Bactrim (PREFERRED), minocycline H.influenzae: everything for P.aeru (may not need double coverage) Burkholderia: Bactrim, meropenem, Cipro (may need combo, known to be resistant) Most Candida sp: fluconazole Aspergillus: itraconazole, voriconazole Scedosporium apiospermum: voriconazole *Monitoring* Respiratory function: FEV1 (4-6 years) at every clinic visit/admission/discharge, sputum production daily and every visit, cough daily and every visit Vitals (esp O2): daily and every visit CXR: on admission CBC with differential: every 3-7 days if needed, or annually Therapeutic drug monitoring Renal function panel: 1-3x a week Audiology testing, IgE levels: annual ADEs: daily and every visit

Empiric Treatment Post-Infection

*DO NOT DELAY TREATMENT IF PATIENT HAS NEUTROPENIC FEVER AND IS IN SHOCK* Administer gram-negative therapy FIRST: penems, cephalosporins, extended B-lactams, FQs, aztreonam (PCN allergy) Then gram-positive therapy Then other therapies depending on risks *Initial Flowchart* Patient has fever and neutropenia Low Risk neutropenia: <7 days of it and clinically stable with no comorbids, outpatient fever onset If adequate outpatient structure: oral Cipro + Augmentin -> observe first dose 4-24 hours -> discharge if stable If inadequate outpatient structure OR NPO: IV Zosyn/penem/cefepime/ceftazidime -> consider step down PO if stabilizing and no positive culture High Risk neutropenia: 7+ days of it and unstable with comorbids, onset fever inpatient IV Abx: Zosyn, penem, cefepime, ceftazidime Add IV vanco for cellulitis/PMN/sepsis/shock/known MRSA If under septic shock, GN bacteremia/PMN: add AGS or FQ *2-4 Days Reassessment Flowchart* If documented infection: modify abx according to susceptibility If responding: continue 7-14 days depending on infx and until ANC 500+ If unexplained fever/undocumented infx with low risk: Continued fever: admit to hospital if outpatient and continue/initiate IV abx Defervesced stable: continue oral/IV abx until ANC 500+, DC vanco if no compelling indication found, consider step-down PO, consider outpatient management If responding: continue 7-14 days depending on infx and until ANC 500+ If unexplained fever/undocumented infx with high risk: Continued fever OR unchanged sx while stable: do NOT change regimen Defervesced stable: continue oral/IV abx until ANC 500+, DC vanco if no compelling indication found, consider step-down PO, consider outpatient management If recrudescent fever or clinicall unstable for any reason: modify coverage (add vanco, add additional GN agent), consider fungal coverage, reexamine infection if worsening *4-7 Days Ressassment Flowchart* Clinically stable, rising ANC, myeloid recovery imminent: observe with no changes Clinically stable, myelod recovery NOT imminent: initiate antifungal (echinocandin, voriconazole, lipid amphotericin B) Clinically UNSTABLE or worsening infx: review coverage, broaded coverage for MDR, add antifungal (consider candida and aspergillus)

Disrupting Cellular Membranes

*Daptomycin* Lipophilic tail and high molecular weight UNABLE TO PENETRATE OUTER MEMBRANE (DOES NOT WORK ON GRAM NEGATIVE) Binds to cell membrane of GRAM POSITIVE in a Ca-dependent process -> intracellular K is lost *Polymyxin E (Colistin)* Polycatonic peptide with hydrophilic and lipophilic groups Displaces Mg and Ca ions in outer membrane LAST RESORT DRUG ONLY FOR MULTI-DRUG RESISTANT P.AERUGINOSA AND OTHER GRAM-NEGATIVES Can cause SEVERE NEPHROTOXICITY

Empyema

*Definition* Purulent fluid collection within pleural space mostly caused by UNDERLYING PNEUMONIA *Etiology* Invasion of pleural space by microbes Can be TB or non-TB (mycobacterium) *Diagnosis* Thoracentesis to sample fluid and culture 40% OF CASES WILL NOT ID BACTERIA (anaerobics difficult to culture) *Treatment* Therapeutic thoracentesis to drain if purulent and sx relief necessary Abx based on bacterial source: S.pneu, S.anginosus, anaerobes, S.aureus, E.coli, Kleb, P.aeru

Hospital-Acquired/Ventilator-Associated Pneumonia

*Definitions* Hospital-Acquired (HAP): pneumonia occurring 48+ hours after admission Ventilator-associated (VAP): pneumonia occurring 48+ hours after endotracheal intubation *Acute Respiratory Distress Syndrome (ARDS)* MAIN CONSEQUENCE OF HAP/VAP Alveolar inflammatory syndrome -> alveolar injury and acute hypoxemia and infiltrates Can also cause edema and fluid overload Persists for days to weeks Supportive care: mech vent Lung injury consequences: impaired gas exchange, decreased lung compliance, pulmonary HTN *Risk Factors* INTUBATION/MECH VENT MDR RISK WITH IV ABX EXPOSURE IN LAST 90 DAYS DURATION OF HOSPITALIZATION Immunocompromised 60+ age Preexisting lung disease Multiple organ system failure Enteral feeding, supine positioning Utilization of acid suppressing meds (H2RAs, PPI) *More Risk Factors for VAP* ARDS before VAP Acute renal replacement therapy before VAP Septic shock at time of VAP HOSPITAL STAY 5+ DAYS BEFORE DEVELOPING VAP -> HIGHER RISK OF MDR PATHOGEN *Presentation* Fever of 101F+ or 100.4+ for 1+ hour Cough Leukocytosis/leukopenia (12k+ or <4) Decline in oxygen Purulent secretions Chest CT/CXR with new/progressive infiltrates *Diagnosis* Non-invasive cultures: sputum, endotracheal aspirate Invasive: BAL, PSB, bronchoscopy Rapid flu swab if flu season COVID-19 test nowadays *Etiology* Gram-negative: E.coli, Kleb, enterobacter, proteus, P.aeru, acinetobacter Gram-positive: MRSA, strep pneu SOME CAN BE MDR DEPENDING ON RISK FACTORS

Human Papillomavirus (HPV)

*External Anogenital Warts* Patient-applied: imiquimod cream OR podofilox solution/gel OR sinecatechins ointment Provider-admin: cryotherapy with liquid nitrogen or cryoprobe OR surgical removal OR tri/bichloroacetic acid solution *Urethral Meatus Warts* Cryosurgery OR surgery *Vaginal warts* Cryotherapy Surgery TCA/BCA solution *Cervical Warts* Cryotherapy Surgery TCA/BCA *Intra-anal warts* Cryotherapy Surgery TCA/BCA *Vaccination* HPV vaccination can protect against SIX DIFFERENT TYPES OF CANCER: cervical, pharyngeal, anus, vulva, penis, vagina Dose #1 usually started 11-12 years, dose #2 6-12 months after first dose MUST GET THREE DOSES IF STARTED AT AGE 15 Can also vaccinate through age 26 Anyone older can get vaccinated if recommended by doctor, however it's now less beneficial

Diabetic Foot Infections

*Diabetic Foot Ulcers* Infection consequence of foot ulcers Abx ONLY NEEDED IF INFECTED (NOT ALL ULCERS ARE INFECTED) Presentation of INFECTED ulcers: purulence, erythema, pain, warmth, induration, tenderness *IDSA Infection Severity* Mild: 2+ signs of infection, redness 0.5-2cm around ulcer, no systemic sx Moderate: local infection with redness 2+cm around ulcer or involvement of deeper skin tissue, no systemic inflammatory signs (SIRS) Severe: Local infection with 2+ SIRS (temp, HR, RR, WBC), metabolic abnormalities *Cultures* NEARLY ALL infected wounds should be cultured AVOID superficial swabs Deep tissue culture preferred Most infected wounds polymicrobial -> broad spectrum coverage *Pathogens from Foot Infections* Cellulitis with open skin wound: B-hemolytic strep + staph Ulcer + abx naive: B-hemolytic strep + staph Chronic ulcer or previously tx: Staph, B-hemo strep, enterobacteriaceae Macerated ulcer that has been soaking: pseudomonas (combo with other microbes) Long duration non-healing wounds with prolonged, broad-spectrum abx: aerobic gram positive cocci (staph, coagulase-neg staph, enterococci, diphtheroids, enterobacteriaceae, pseudomonas, nonfermetative gram negative rods, fungi Fetid foot (necrosis and malodorous): mixed aerobic gram positive cocci (with enterococci), eneterobacteraceae, nonfermatative gram negative rods, obligate anaerobes *Treatment* There is no optimal regimen Start broad, go narrow once cultures come back Mild MSSA strep: dicloxacillin, clinda (D-TEST), cephalexin, levofloxacin (NOT GOOD AGAINST STAPH), Augmentin Mild MRSA: doxy, Zosyn Moderate MSSA strep with enterobacteriaceae and obligate anaerobes: levofloxacin, cefoxitin, ceftriaxone, ampicillin-sulbactam (good if NO pseudomonas), moxifloxacin, ertapenem (NO PSEUDOMONAS), tigecycline (high ADE), levo/ciprofloxacin with clinda, imipenem-cilastatin (ONLY USE FOR ESBL-PRODUCERS) Moderate MRSA: linezolid (DO NOT USE 2+ WEEKS), daptomycin, vanco Moderate Pseudomonas: pip-tazo Severe MRSA with other microbes: vanco with ceftazidime/cefepime/pip-tazo/aztreonam/penem

Candida Infections (Candidiasis)

*Diagnosis* Definitive: culture of organism, endophtalmitis (from isolation), burn wound infection (from isolation), peritonitis (from paracentesis isolation) Likely: TWO positive blood cultures 24hrs apart without central line, TWO positive cultures 24+hrs apart after removal of central line, THREE or more colonized sites with supporting evidence of systemic infx History and clinical findings *Mucocutaneous Candidiasis* Oropharyngeal (Thrush): newborns, chemotherapy, acute leukemia, mucosal dmg, immunocompromised, abx, steroids, AIDS Local tx: clotrimazole troches, nystatin suspension Oral tx: fluconazole, itraconazole oral solution, AmB solution Esophageal: AIDS, steroids, chemo, DM, abx, esophageal stasis disorders Tx: fluconazole (esp in HIV), echinocandin (refractory), AmB (refractory) GI: mucositis, GI inflammation Vaginal (COMMON IN REPRODUCTIVE YEARS): abx, oral contraceptives, preggo, DM, poor hygiene, steroids Usually from C.albicans Tx: topical azole, single dose fluconazole (do NOT use in preggo), combo of topical/local azole + topical polyene + boric acid (refractory) Drug Risks: abx, steroids, IL-17 blockers, oral contraceptives, hormone replacement therapy, SGLT2 inhibitors for DM *Chronic Mucocutaneous Candidiasis (CMC)* Hereditary, relatively rare deficiency of immunity (TH-17) Chronic persisting/recurrence of skin, mucus membranes, nail infections Tx: chronic suppressive tx with fluconazole *Onychomycosis: infection of finger/toe nails* Topical tx: ciclopirox, efinaconazole for 48 weeks Oral tx: terbinafine (DERMATOPHYTES ONLY), itraconazole for 12 weeks *Ringworm and Athlete's Foot* Tx: topical azoles, topical polyene (nystatin), topical allylamine (DERMATOPHYTE ONLY) Refractory Tx: terbinafine topical, butenafine *Invasive Candidiasis: bloodstream infection or other organ infection* Risk Factors: major surgery (non CNS), neutropenia, high dose steroids, DM, central venous access device (ESPECIALLY WITH PARENTERAL NUTRITION) Etiology: Albicans MOST COMMO

Managing GI Infections

*Diagnosis* Selective Testing for E.coli O57:H7 (bloody diarrhea, hemolytic uremic syndrome) Selective Testing for salmonella, shigella, campylobacter, E.coli (1+ day of diarrhea and fever, bloody stools, systemic infection, severe dehydration, recent abx exposure, day-care attendance) "3 Day Rule" for Hospitalized Patients (C.diff) *Oral Rehydration Therapy (ORT)* Elements: water, Na, glucose, K, Cl BEWARE OF HIGH OSMOLALITY (DILUTE WITH WATER) Mild-Moderate Dehydration: 50-100mL/kg over 3-4 hours (CHILDREN) or 2-4L for adults Severe Dehydration: 10mL/kg boluses (INFANTS) or isotonic crystaloid boluses up to 20ml/kg until normal pulse/perfusion/mental status (CHILDREN, ADULTS) *Antidiarrheal Therapy: loperamide (Imodium)* DO NOT USE IF LESS THAN 18 YEARS DO NOT USE IF TOXIC MEGACOLON Risks: CNS depression (CHILDREN), colonic dilation (DYSENTARY), increased ESBL-producing pathogel acquisition with other abx *Antisecretory Therapy: bismuth subsalicylate (Pepto-Bismol)* Great for traveler's diarrhea and <3 wk proph Has handful of drug interactions EFFECT DELAYED UP TO 4 HOURS ADE: unpleasant taste, tinnitus, black tongue *Supplements* Oral Zinc: reduces duration of diarrhea for 6mo - 5 yrs if malnourished or Zn deficiency Probiotics: DO NOT RECOMMEND IF IMMUNOCOMPROMISED *Fecal Microbiota Transplant (FMT)* Increasingly commercialized source of probiotics *Antibiotics: azithromycin, levofloxacin, cipro, ofloxacin, rifamycin, rifaximin* 50+ healthy adults improve within 2 days WITHOUT abx therapy Empiric abx for bloody diarrhea AND: <3mo age with bacterial etiology, immunocompetent ppl with fever/abd pain/dysentary, recent intl travel with 38.5+ fever and/or sepsis, immunocompromised pt with severe illness REQUIRED FOR: dystenteric shigellosis, cholera, pseudomembraneous enterocolitis, parasitic infx, persistent GI infx RECOMMENDED FOR: non-cholera vibrios, campylobacter (MUST START BEFORE DAY 4), immunocompromised, seriously ill, pt with vascular/orthopedic protheses, extremely old/young pts DETERIMENTAL FOR: enterohemorrhagic E.coli, friendly intestinal flora, resistance

Clostridioides difficile

*Diagnosis: C.diff Toxin/GDH With Reflex to PCR* GDH and toxin positive: infx LIKELY GDH and toxin negative: infx UNLIKELY One positive one neg: perform PCR Positive PCR: infx likely Negative PCR: infx unlikely *Risk Factors* Broad-spectrum abx (90% OF HEALTH-CARE CASES) Gastric acid suppressing agents: PPI/H2RA Elderly Severe underlying disease Nonsurgical GI procedures Presence of nasogastric tube Long-term hospital admission *Symptoms* C. diff enterotoxin causes GI inflammation, mucus secretion, mucosal dmg Diarrhea (POTENTIALLY SEVERE) Abd pain Fever Significant acute increases WBC *Complications* SEVERE dehydration from diarrhea SEVERE electrolyte imbalances from diarrhea Hypotension Pseudomembranous colitis Toxic megacolon *BI/NAPI/027 Variant* Also known as NAP-I TOXIN PRODUCTION INCREASE x3-23 *Vancomycin* FIRST-LINE ORAL FORM: LOW BIOAVAILABILITY MAKES EFFECT ON INFX LONGER Can also be administered rectally *Other Abx* Fidaxomicin: may decrease NON-NAPI STRAIN RECURRENCE compared to VANCO Metronidazole: oral or IV, increasing resistance -> NO LONGER FIRST-LINE *Adjunct Therapies* Cholestyramine (Prevalite, Questran): absorbs toxin, no effect on stool flora, MAY HAVE BINDING ISSUES WITH DRUGS Probiotics: NO MONOTHERAPY Fecal Microbiota Transplant: LAST RESORT *Prevention of C. diff* Bezlotoxumab (Zinplava Injection): binds and neutralizes toxins by C.diff to reduce recurrence, can cause SERIOUS HF/fatigue/N/fever/HA

Histoplasma (Histoplasmosis)

*Differentiation* Acute pulmonary infx: can be self-limiting with flu-like sx, self-limiting with arthritis/EN/pericarditis/mediastinal granulomas, or inflammatory fibrotic Chronic pulmonary infx: progressive, inflammatory, calcified granulomas Acute Dissemination: fever, anemia, leukopenia, thrombocytopenia, hepatosplenomegaly in immunocompromised or small children with lymphoproliferative disorders Subacute Dissemination: wt loss, weakness, fatigue, focal destruction lesions Chronic: wt loss, wkness, fatigue, CNS involvement (common in immunosuppressed) *Treatment* Life-threatening/Severe: lipid AmB Chronic Pulmonary or Disseminated: itraconazole, posa/voriconazole (salvage) Non-infx lesions: NSAIDs (pericarditis, rheumatologic)

Blastomyces (Blastomycosis)

*Differentiaton* Acute pulmonary: asx, self-limiting with fever/chills/wet cough Subacute/Chronic: night sweats, wt loss, resembles TB Disseminated: 1-3 years AFTER acute pulmonary infx, skin > bone > soft tissue > CNS (RARE) *Treatment* Life-threatening/Severe: lipid AmB followed by fluconazole Mild-Mod: itraconazole Salvage: posa/cona

Gonorrhea

*Etiology* Neisseria gonorrhoeae bacteria *Screening* Women for GU: culture via endocervical swab specimen -> NAAT ; NAAT on urine Men for urethral: intraurethral swab specimen (depends on storage and transport) -> NAAT ; NAAT on urine Men/women for rectal/pharyngeal: rectal/pharyngeal swab -> selective medium for oxidase-positive GN diplococci *Recommended Treatment* Uncomplicated cervix/urethra/rectal in adults: ceftriaxone IM single dose Uncomplicated pharynx in adults: ceftriaxone IM single dose Uncomplicated VV/cervix/urethra/pharynx/prostate in infants and children <45kg: ceftriaxone IV/IM single dose Uncomplicated VV/cervix/urethra/pharynx/prostate in infants and children 45kg+: same as adults Pregnancy: ceftriaxone IM single dose Conjunctivitis: ceftriaxone IM single dose Disseminated: ceftriaxone IM/IV daily Ocular proph in neonates: erythromycin opthalmic ointment in each eye at birth one time only Opthalmia in neonates/infants: ceftriaxone IV/IM single dose *Alternative Treatments* Uncomplicated adult if CS allergy: gentamicin IM single dose + azithromycin oral single dose Uncomplicated adult if ceftriaxone not available or feasible: cefixime oral single dose Disseminated: cefotaxime IV Q8H, ceftizoxime IV q8H Opthalmia in neonates/infants if also being given IV calcium: cefotaxime IV/IM single dose *Education* Males mostly sx, females mostly asx Untreated cervical gono -> PID, infertility, ectopic preggo Untreated urethral gono -> epididmyitis, penile edema, abscesses, stricture Gono pts more likely to transmit/acquire HIV DO NOT HAVE SEX UNTIL 7 DAYS AFTER RESOLUTION OF SX

Cyclines and Aminoglycosides

*Doxycycline* Mech: Bind to 30S ribosome to block tRNA docking -> prevent chain elongation Resist Mech: porin loss, efflux Coverage: strep pneu, chlamydophila, mycoplasma, legionella, other strep, MSSA, community MRSA, bartonella, STDs, H.influenzae, M.catarrhalis, atypicals Uses: respiratory infections, skin infections and diseases, animal bites, cat scratch fever, STDs, tick-borne diseases Resist: recent abx exposure can have S.pneu resist, HOSPITAL-acquired MRSA Toxic: teeth staining in children, TAKE THIS SITTING UP RIGHT DUE TO POSSIBLE PERFORATION IF STUCK IN THROAT (DO NOT LIE DOWN FOR AT LEAST 15 MINS), phototoxic, drug-induced hepatitis, DO NOT USE IN PREGGO OR LACTATION DDI: antacids chelates and ruins tetracyclines (do NOT take metal cations like diary, vitamins, antacids etc) *Minocycline* Mech: Bind to 30S ribosome to block tRNA docking -> prevent chain elongation Resist Mech: porin loss, efflux Coverage: MSSA, strep, community MRSA, nocardia, atypical mycobacteria, enterococcus VRE, stenotrophomonas, penem-resist Acinetobacter (CRAB) Uses: skin infections/diseases (acne, rosacea), prosthetic joint infections Toxic: teeth staining in children, TAKE THIS SITTING UP RIGHT DUE TO POSSIBLE PERFORATION IF STUCK IN THROAT (DO NOT LIE DOWN FOR AT LEAST 15 MINS), phototoxic, drug-induced hepatitis, DO NOT USE IN PREGGO OR LACTATION, vertigo, skin pigmentation DDI: antacids chelates and ruins tetracyclines (do NOT take metal cations like diary, vitamins, antacids etc) IV is expensive Lower risk for C.diff than other abx *Tigecycline (Tygacil)* Mech: Bind to 30S ribosome to block tRNA docking -> prevent chain elongation Resist Mech: porin loss Coverage: similar to doxycycline Uses: complicated intrabd infx, complicated SSSI, CAP Toxic: N/V, HIGHER MORTALITY THAN THER ABX (UNKNOWN CAUSE) *Ervacycline (Xerava)* Mech: Bind to 30S ribosome to block tRNA docking -> prevent chain elongation Resist Mech: porin loss Coverage: similar to doxycycline, also hits GP, GN, anaerobics, VRE, stenotrophomonas, CRAB Uses: resistant to tetracycline Toxic: similar to doxy Only IV formulation is available right now Better against CRAB than tigecycline *Omdadacycline (Nuzyra)* Mech: Bind to 30S ribosome to block tRNA docking -> prevent chain elongation Resist Mech: porin loss Coverage: similar to doxy and erava, VRE, stenotrophomonas, CRAB Use: tetracycline resists Resist: P.aeru Toxic: similar to doxy VERY EXPENSIVE *Gentamicin* Mech: inhibit A-site of 30S Resist Mech: AGS-modifying enzymes Coverage: GP (do NOT use alone), GN, P.aeru, atypicals Uses: serious GN infx with resist to other options, empiric therapy, selected GP infx with b-lactam or vanco, selected atypicals Resists: AACs, ANTs, APHs Toxic: nephrotoxicity (target AUC 70-100), ototoxicity, neurotoxicity (especially pts with MYASTHENIA GRAVIS) Can be taken orally but ONLY for intraluminal effects *Tobramycin* Mech: inhibit A-site of 30S Resist Mech: AGS-modifying enzymes Coverage: more P.aeru effect, atypicals, GNs Use: serious GNs resistant to other options, selected atypicals Resist: AACs, ANTs, APHs Toxic: nephrotoxicity (target AUC 70-100), ototoxicity, neurotoxicity (especially pts with MYASTHENIA GRAVIS) Can be taken orally but ONLY for intraluminal effects Has a inhalation formulation (nebulizer) for respiratory exacerbations in CYSTIC FIBROSIS and P.aeru infections *Amikacin* Mech: inhibit A-site of 30S Resist Mech: AGS-modifying enzymes Coverage: resistance to gentamicin and tobramycin, atypicals Uses: GN infx resistant to EVERYTHING and other AGS, selected atypicals resist: AAC, ANT, APH Toxic: nephrotoxicity (target AUC 70-100), ototoxicity, neurotoxicity (especially pts with MYASTHENIA GRAVIS)

Antiviral M2 Channel Inhibitors

*Drugs* Amantadine (Symmetrel) Rimantadine (Flumadine) *Purpose* Block emptying of viral contents into cell *Mechanism* Targets M2-S31N channel which is common in MDR viruses *NOT RECOMMENDED FOR INFLUENZA* High resistance risk If must use for the flu, ONLY TYPE A

Antiviral PA Endonuclease Inhibitor

*Drugs* Baloxavir *Purpose* Inhibit entering of viral contents into nucleus *Mechanism* PA subunit houses the cap-dependent endonuclease (CAP) which cleaves capped nascent mRNA to become viral mRNA PA endonuclease inhibitors blocks the cleavage of the cap which stops viral mRNA synthesis

Echinocandins

*Drugs* Caspofungin Micafungin Anidulafungin *Characteristics* Glucan polysaccharide contain D-glucose monomers with cyclic lipopeptides that interfere with fungal cell wall synth N-linked acyl lipid side-chain that changes depending on drug (caspofungin: fatty acid ; Micafungin: aromatic ; Anidula: aromatic terphenyl) Side chain is ESSENTIAL TO INSERT INTO PHOSPHOLIPID BILAYER IV only with VERY LONG half-life, SLOW metabolism, and LITTLE RENAL EXCRETION *Mechanism of Action* Binds to Fks1p in transmembrane complex in cell wall Unable to synthesize b-1:3 glucan Ser678Pro subtitution CAN RESIST ECHINOCANDINS in Aspergillus *Range of Antifungal Activity* MOST: Candida, aspergillus, pneumocystis Some: coccidioides, blastomyces, scedosporium, paecilomyces, histoplasma NO ACTIVITY: zygomycetes, cryptococcus, fusarium, trichosporon *Uses* All: esophageal candidiasis Caspo: candidemia + intraabd absess/peritonitis/pleural space Candida infx, invasive aspergillosis (refractory/resistance to other options), empiric therapy in FEBRILE NEUTROPENIA Mica: proph of invasive candida and aspergillus infx in HIGH-RISK pts, tx of candidemia/acute disseminated candidiasis/candida perionitis/candida abscess Anidula: candidemia and other invasive candida infx FIRST-LINE for suspected/proven serious candida infx (empiric and definitive) SECOND-LINE for refractory aspergillus and coccidioides (COMBO ONLY) *Resistance* Ser678Pro subtitution CAN RESIST ECHINOCANDINS in Aspergillus Intrinsic/Relative: C.parapsilosis, C.gilliermondii Up-reg of chitin

HSV (Herpes Simplex) and CMV (Cytomegalovirus) Targets

*Drugs* Cidofovir (deoxycytidine analog) Acyclovir, Valacyclovir, Famciclovir, Ganciclovir, Valganciclovir, Penciclovir (deoxyguanosine analog) *Mechanism* DNA polymerase inhibitors and DNA synthesis terminators ACYCLOVIR MUST BE ACTIVATED BY HSV THYMIDINE KINASE -> SPECIFICALLY TARGETS HSV-INFECTED CELLS Valacyclovir + 6-doexyacyclovir -> acyclovir -> acyclovir monophosphate -> acyclovir diphosphate -> acyclovir triphosphate Famicyclovir -> peniciclovir via esterase and oxidase -> ganciclovir *Acyclovir* Uses: initial and recurrent mucosal HSV, mucocutaneous HSV in immunocomp, chronic suppression for frequent recurrence, herpes encephalitis, chickenpox, shingles, prevention of HSV re-activation in immunocomp ADEs: nephrotoxic at high doses/IV, CNS effects, NVD, anorexia, thrombocytopenia, hemolytic uremic syndrome USE IV FOR MORE SERIOUS INFECTIONS Bioavailability DECREASES with greater PO doses Use IBW or ADJUSTED BODY WEIGHT FOR OBESE PATIENTS POOR CMV ACTIVITY *Valacyclovir* Prodrug that eventually converts to acyclovir in liver Able to achieve HIGHER BLOOD LEVELS Uses: shingles, initial + recurrent genital herpes, suppression of recurrent genital herpes, reduction of transmission of genital herpes, tx of herpes labialis, chickenpox *Famciclovir* DO NOT USE FOR SYSTEMIC USE *Ganciclovir* For CMV Uses: proph and tx of CMV infections in SOT or HSCT pts, tx of congenital CMV infections, CMV retinitis Resistance: mutations in UL97 and UL54 ADE: myelosuppression, thrombocytopenia, CNS *Valganciclovir* Valine ester PRODRUG of ganciclovir Better bioavailability for oral administration *Cidofovir* IV ONLY Does NOT need viral kinase or phosphotransferase for activation Uses: broad antiviral activity (adenovirus, intralesional for genital/anal warts, BK virus) Mech: diphosphate form competes with deoxycytidine binding in DNA polymerase to inhibit chain elongation Resist: point mutations in viral polymerase ADE: nephrotoxic (DO NOT USE IF SCr 1.5+), neutropenia, acute iritis Usually THIRD LINE for CMV tx (toxicity) Can prevent nephrotoxic with saline infusions before dose *Topical Agents* Acyclovir 5% cream, Penciclovir 1% cream, Docosanol 10% cream: contains 22 carbon aliphatic alcohol to inhibit viral fusion to membranes Trifluorothymidine 1% for herpes keratitis Ganciclovir 0.15% gel for herpes keratitis

HBV (Hepatits B Virus) Targets

*Drugs* Entecavir: deoxyguanosine Lamivudine: deoxycytidine Telbivudine: L-isomer of thymidine Adefovir: deoxyadenosine Tenofovir disproxil fumarate: deoxyadenosine *Mechanism* All drugs are DNA reverse transcriptase inhibitors All drugs mimic some of kind of nucleotide/side to inhibit *Tenofovir Disproxil* Mech: competitive inhibitor of DNA reverse transcriptase and is a chain terminator to prevent DNA elongation Tenofovir -> esterased into intermediate -> phosphonated -> AMP kinase gives it another phosphate group -> AMP kinase gives it a third phosphate group -> tenofovir diphosphate = triphosphate active molecule NOTE: THE TRIPHOSPHATE FORM IS NOT THE ACTIVE FORM, DIPHOSPHATE FORM IS ACTIVE Adefovir folllows this same mechanism and metabolism

Azole Antifungals

*Drugs* Imidazole-derivatives: clotrimazole, miconazole, ketoconazole First Gen Triazoles: fluconazole, itraconazole Second Gen Triazoles: voriconazole, posaconazole, isavuconazonium sulfate (higher potency, hits molds/yeasts, less toxic, greater CNS permeability) *Mechanism* Inhibits 14a-demethylation in lanosterol to inhibit ergosterol synth Basic nitrogen on azole ring is TIGHTLY BOUND TO HEME IRON OF FUNGAL CYP450 -> prevents substrate and O2 binding Accumulation of 14-a-methylsterols which impairs other important enzymes *Ketoconazole* Has EXTENSIVE metabolism through CYP3A4 and other CYP450s (high list of DDIs due to CYP450 metabolism) Replaced by BETTER AZOLES (TRIAZOLES) that have better water solubility, higher index, bigger spectrum, and lower risk of DDI NEEDS TO BE TAKEN WITH FOOD FOR ACID ABSORPTION For superficial fungal infections (topical) Has anti-androgenic activity: seborrheic dermatitis, androgenic alopecia ADE: male anti-androgenic side effects, menstrual irregularities, decreased cortisol secretion, N/V/D, hepatitis (RARE) *Fluconazole (Diflucan)* Coverage: Candida (NOT krusei), cryptococcus, coccidioides PO absorption excellent with great CNS penetration Minor substrate and inhibitor of CYP3A4 Major inhibitor of CYP2C9 (WARFARIN DDI) ADE: N/V/D (may need antiemetic), reversible alopecia, hepatotoxic *Itraconazole (Sporonox)* Formulations: PO (needs food for acid absorption), oral solution (needs food), SUBA capsule Coverage: histoplasma, blastomyces, coccidiodes (skeletal infx), mucosal candidiasis (oral sol only), onychomycosis, sporotrichosis, tinea corporis, tinea versicolor, some aspergillus activity Strong CYP3A4 inhibitor ADE: sterol biosynth, hepatotoxic, N/V/D, HEART FAILURE (DO NOT USE IN PRE-EXISTING HF) *Voriconazole (Vfend)* Coverage: similar to fluconazole and itraconazole but adds C.krusei, and better aspergillus activity Use: inasive aspergilliosis, invasive mold infections (NOT mucorales) Similar kinetics to fluconazole Different genotypes can affect therapeutic index (CYP2C19 polymorphisms) ADE: visual disturbances, hallucinations and psychosis, N/V/D, liver toxic, phototoxic, periosteitis, FLUOROSIS (THREE FLUORIDE GROUPS IN STRUCTURE) *Posaconazole (Noxafil)* Coverage: similar to voriconazole but adds Mucorales Uses: proph of invasive fungal infections in high-risk pts (transplants, chemotherapy), Zygomycetes infx (maybe) TAKE WITH HIGH FAT MEAL (HIGHER ABSORPTION) ADE: similar to voriconazole but NO visual disturbances, same DDI as itraconazole Do NOT use with acid suppressors IV/oral suspension VERY EXPENSIVE *Isavuconazole (Cresemba)* Uses: aspergillosis, Mucorales (ONLY FDA APPROVAL) Prodrug cleaved by plasma/liver esterases ADE: NVD, liver toxic, maybe less DDI VERY EXPENSIVE *Resistance* More efflux Mutation/overexpression of P450 14a-demethylase

Antiviral Neuraminidase Inhibitors

*Drugs* Oseltamivir (Tamiflu) Zanamivir (Relenza) Peramivir *Purpose* Block release of new viral products into extracellular fluid *Mechanism* Before viruses are released, they are still stuck on a membrane protein Neuraminidase hydrolyzes of sialic acid linkage to release virions NA Inhibitors inhibit this hydrolysis which stops release *Oseltamivir* Needs to be HYDROLYZED TO THE ACTIVE FORM: oseltamivir carboxylate which mimics an important oxocarbonium intermediate Active against BOTH Influenza A+B ADE: N/V, maybe psych stuff *Zanamivir* ONLY INHALED FOR AIRWAY DISEASES

Treating Community-Acquired Pneumonia

*Empiric Antibiotics* NO EVIDENCE TO SUPPORT ONE REGIMEN OVER ANOTHER Should cover MOST LIKELY pathogens No comorbids or risk factors for MRSA/P.aeruginosa: amoxicillin OR doxy OR macrolide if resistance is <25% With comorbids: Augmentin/cephalosporin + macrolide/doxy, monotherapy RESPIRATORY FQ (levo, moxi, gemi) *Abx depending on Risk of Resistance* Standard non-severe: B-lactam + macrolide, resp FQ Risk of MRSA non-severe: MRSA coverage, re-culture to confirm or deescalate Risk of P.aeru non-severe: P.aeru coverage, re-culture to confirm or deescalate Recent hospitalization, recent abx non-severe: withhold MRSA/P.aeru coverage until cultures are positive Standard severe: B-lactam + macrolide OR B-lactam + resp FQ Risk of MRSA non-severe: MRSA coverage, re-culture to confirm or deescalate Risk of P.aeru non-severe: P.aeru coverage, re-culture to confirm or deescalate Recent hospital, recent abx: add MRSA/P.aeru coverage, re-culture to confirm or deescalate *Treating Specific Bacteria* Strep pneu MIC <2: penicillin, amoxicillin Strep pneu MIC 2+: cefotaxime, ceftriaxone, resp FQ Non-resist H.influenzae: amoxicillin Resist H. influenzae: 2/3CS, Augmentin Mycoplasma/chlamydophila pneu: macrolide, tetracycline Legionella: resp FQ, azithromycin Enterobacteriaceae: 3CS, penem (WATCH FOR ESBL) P.aeru: anti P.aeru B-lactam + resp FQ or AGS Burkholderia pseudomallei: penem, ceftazadime Acinetobacter: penem MSSA: antistaph penicillin MRSA: vanco, linezolid Bordetella pertussis: macrolide Anaerobe: B-lactam with b-lactamase inhibit, clindamycin Influenza virus: oseltamivir, zanamivir *Antiviral Treatment* If virus is confirmed, only use ONE NAI (oseltamivir, etc) and DO NOT OCMBO Consider antiviral proph if: high risk and vaccine is CI, immunocompromised, recent stem cell transplant or lung transplant, high risk but hasnt received vaccine *Corticosteroids* Can be used adjunctive to antimicrobial for anti-inflammatory effect ONLY recommended for CAP with refractory septic shock *Reasons for Lack of Response* Correct organism, incorrect abx Resistance Wrong dose (obese, fluid overload, etc) Abx no administered Infection is loculated (empyema) Obstruction Incorrect organism No ID Noninfectious Drug-induced fever Presence of unrecognized, concurrent infection *Transitioning from IV to Oral Abx* Able to ingest oral agents HR <100, SBP 90+ O2 90+ RR <25 Return to baseline cognitive status Temperature <100.9F (38.3C) *Immunizations* Assess for pneumococcal and influenza vaccine status ADMINISTER BEFORE DISCHARGE

Detecting Molecular Resistance

*Enterococcus faecalis/E.faecium* vanA gene -> vancomycin-resistant *Staphylococcus Aureus* mecA/C (methicillin-resistant) *Enterobacterales (E.coli, K.pneu)* CTX-M (ESBL producing): can detect ESBL via blood culture (BUT MOST LABS USE AST RATHER THAN DIRECTLY TESTING FOR ESBL) KPC/NDM/IMP/OXA/VIM (carbapenemases)

Urinary Tract Infection

*Epidemiology* Women are MORE at risk than men (smaller urinary tract) Young adults and middle-aged adults get more UTIs *UTIs are categorized by where the infection is* Upper Tract: Uterer, kidneys Lower Tract: Urethra, bladder, prostate, epididymis Uncomplicated: no structural or functional abnormality, common in healthy women of child-bearing age Complicated: lesions, congenital, stones, catheter problem, prostatic hypertrophy, obstruction, MALE Recurrent: Multiple sx episodes with asx period in between *Pathogenesis* Ascending infection from external genitalia Hematogenous: more likely in hospitalized pts Lymphatic: very rare *Host Defenses* Low pH, high osmolality (urea, organic acids), prostatic secretions in males Voiding clears bacteria *Risk Factors for COMPLICATED UTI* MALE Old DM Immunosupressed Childhood UTI, recent urinary tract instrumentation, indwelling urinary catheter Functional or anatomical abnormality Sx 7+ days after present Hospital-acquired Recent abx use Pregnant *Presentation* Lower UTI (Cystitis): dysuria, urgency, frequency, gross hematuria, nocturia, suprapubic heaviness Upper UTI (pyelonephritis): FEVER, N/V, malaise, FLANK PAIN, costovertebral angle tenderness Elderly: AMS, GI sx, change in eating pattern *Diagnosis* Urinalysis: presence of nitrites means bacteria can convert nitrate to nitrite, WBC 10+, leukocyte esterace = pyuria, inc in pH = urea-splitter (proteus) Urine Culture (NOT necessary in uncomplicated, non-recurrent): 100k+ indicative, 10-50k correlates with sx Urine Collection: clean-catch, mid-stream (NOT GREAT), catherterization, suprapubic aspiration *Microbiology* Mostly monoorganism from translocated bowel flora Most likely will be E.coli (increase in resistance recently) Some cases of staph saprophyticus Some cases of enterococcus, klebsiella, proteus, enterobacter Pseudomonas RARELY seen in community-acquired UTI

Other Viral Infections

*Epstein-Barr Virus* Infectious mononucleosis Post-transplantation lymphoproliferative disease B-cell stimulation Can be single-organ or multi-organ involvement (esp CNS) Tx: rituximab, cytotoxic T-cells Antivirals have questionable efficacy *Human Herpes Virus 6* Presentation: roseola, rash, graft fail if bone-marrow transplant, diffuse alveolar hemorrhage Tx: foscarnet, cidofovir, ganciclovir *Paramyxovirus* Measles and mumps Tx and prevention: MMR vaccine *Togavirus* Rubella Tx and prevent: MMR vaccine *Lyssavirus* Rabies Tx: human rabies IG *Orthopoxvirus* Smallpox Tx: maybe cidofovir, just get the vaccine dummy *Filoviridae* Ebola Tx: Ansuvimab, atoltivimab/mafivimab/odesivimab-ebgn *Flavivirus* West nile virus, dengue, zika *Enterovirus* Polio, coxsackie, echovirus Tx and prevention: vaccine

Carbapenem Family

*Ertapenem (Invanz)* Mech: inhibit PBPs via irreversible binding Resist Mech: porin loss, efflux, carbapenemases, mutation Coverage: MSSA, strep, ESBL enterobacterales (MAJOR USE), AmpC enterobacterales, anaerobes Uses: bacteremia with ESBL GN, 3/4CS resistant, anaerobes Resists: MRSA, enterococci, P.aeru, Acinetobacter ONCE DAILY DOSING IS CONVENIENT (EXPENSIVE) Do NOT use with VALPROATE *Imipenem-Cilastatin (Primaxin)* Mech: inhibit PBPs via irreversible binding Resist Mech: porin loss, efflux, carbapenemases, mutation Coverage: MSSA, strep, ESBL enterobacterales (MAJOR USE), AmpC enterobacterales, anaerobes, P.aeru, Acinetobacter, enterococci, Nocardia Uses: bacteremia with ESBL GN, 3/4CS resistant, anaerobes, antipseudomonal Resists: MRSA, stenotrophomonas maltophilia Cilastatin combined with imipenem to prevent hydrolysis into nephrotoxic metabolite by DHPI SEIZURE RISK Do NOT use with VALPROATE *Meropenem* Mech: inhibit PBPs via irreversible binding Resist Mech: porin loss, efflux, carbapenemases, mutation Coverage: MSSA, strep, ESBL enterobacterales (MAJOR USE), AmpC enterobacterales, anaerobes, P.aeru Uses: bacteremia with ESBL GN, 3/4CS resistant, anaerobes, antipseudomonal Resist: MRSA, stenotrophomonas, KPC/metallo-b-lactamase/OXA GN Usually used for cephalosporin resistance Dosing efficiency best with TIME OVER MIC *Imipenem-Cilastatin-Relebactam (Recarbio)* Mech: inhibit PBPs via irreversible binding Resist Mech: porin loss, efflux, carbapenemases, mutation Coverage: MSSA, strep, ESBL enterobacterales (MAJOR USE), AmpC enterobacterales, anaerobes, P.aeru, Acinetobacter, enterococci, Nocardia, KPC enterobacterales, P.aeru Uses: resistance to imipenem-cilastatin, resistant to 3/4CS and FQs, anaerobes Resist: MRSA, stenotrophomonas Do NOT use with VALPROATE Bypasses KPC resist Does NOT inhibit metallo-b-lactamase resists *Meropenem-Vaborbactam (Vabomere)* Mech: inhibit PBPs via irreversible binding Resist Mech: porin loss, efflux, carbapenemases, mutation Coverage: MSSA, strep, ESBL enterobacterales (MAJOR USE), AmpC enterobacterales, anaerobes, P.aeru, KPC GN Use: resistant to penems without BLI, resistant to 3/4CS and FQs, anaerobes, antipsuedomonal Resist: MRSA, stenotrophomonas Best for resistance to mero/imi/ertapenem by themselves Usually used for KPC enterobacterales Do NOT use with VALPROATE

Carbapenem-associated Seizures

*Ertapenem has a RELATIVELY HIGH RISK OF SEIZURES compared to other penems* *Imipenem MIGHT have a higher risk than other penems* Watch renal function Maybe underlying CNS pathology *PENEMS SHOULD NOT BE USED WITH VALPROATES DUE TO INCREASED CLEARANCE OF VALPROATE* Increased clearance of valproate -> BREAKTHROUGH SEIZURES

Chlamydia

*Etiology* Chlamydia trachomatis *Screening* GU Women: NAAT on endocervical swab or urine, can use antibody test, can culture Urethral men: NAAT on intraurethral swab or urine, can culture Rectal/pharyngeal women and men: culture on rectal or pharynx swab with MOMP stain, can use antibody test with MOMP stain *Recommended Tx* Adults: oral doxy Children <45kg: oral erythromycin QID, oral ethylsuccinate QID Children 45kg+, <8yrs: oral azithromycin single dose Children 8+ yrs: oral azithromycin single dose OR oral doxy Opthalmia or PNM in neonates: erythromycin QID, ethylsuccinate QID *Alternative Tx* Adults: oral azithromycin single dose, oral levofloxacin Pregnancy: oral amoxicillin Neonates: azithromycin suspension

Uncomplicated Malaria Flowchart

*Falciparum, knowlesi, or unknown species* Admit to hospital and monitor Knowlesi: (hydroxy)chloroquine P.falciparum: check for resistance (Hydroxy)chloroquine if no resist Coartem (preferred) OR Malarone OR quinine + tetracycline/doxy/clinda OR mefloquine (LAST RESORT) if chloroquine resist Coartem (preferred) OR Malarone OR quinine + tetra/doxy/clinda if mefloquine resist *Malariae* (Hydroxy)chloroquine *Ovale or vivax without chloroquine resist* (Hydroxy)chloroquine TEST G6PD FIRST then: Primaquine before acute infection tx Tafenoquine if chloroquine being used acutely (DO NOT USE IF <16 YRS) *Vivax with chloroquine resist* Coartem or Malarone or quinine + tetra/doxy/clinda or mefloquine (LAST RESORT) TEST G6PD FIRST then: Primaquine before acute infection tx Tafenoquine if chloroquine being used acutely (DO NOT USE IF <16 YRS)

Azole Medications for Fungal Infections

*Fluconazole (Diflucan)* Mech: inhibit CYP51a in fungus -> block formation of ergosterol Resist Mech: efflux pump overexpression, CYP51a overexpression, CYP51a alteration Uses: candida species EXCEPT krusei (glabrata variable), cryptococcus, coccidioides Resists: candida krusei, glabrata variable Kinetics: halflife is long so loading dose needed for bloodstream infection, penetrates well through CSF ADE: N/V, reversible alopecia with chronic admin, DILI, QT PROLONG DDI to drugs sensitive to CYP2C19 and CYP2C9 Some patients have a worse or stronger CYP2C19 *Itrazonazole (Sporonox)* Mech: inhibit CYP51a in fungus -> block formation of ergosterol Resist Mech: efflux pump overexpression, CYP51a overexpression, CYP51a alteration Uses: aspergillus, dermatophytes, histoplasmosis, blastomycosis, some coccidioides (esp skeletal), worse activity with candida Resist: candida, aspergillosis in the lungs/invasive Kinetics: SOLUTION taken on EMPTY stomach, CAPSULES taken with a HIGH FAT MEAL ADE: N/V, DILI (more common than fluconazole), QT PROLONG DO NOT TAKE CAPSULES WITH H2RA/PPI DO NOT TAKE WITH CONGESTIVE HEART FAIL *Posaconazole (Noxafil)* Mech: inhibit CYP51a in fungus -> block formation of ergosterol Resist Mech: efflux pump overexpression, CYP51a overexpression, CYP51a alteration Uses: prophylaxis for high-risk hematologic cancer and after bone marrow tansplants, oropharyngeal candidiasis refractory to fluconazole/itraconazole, aspergillus, 2nd line coccidiodomycosis, mucorales in combo with amphotericin or step-down Resist: break-through infections with aspergillus Kinetics: <50 CLCr should have SHORTEST duration ADE: N/V, DILI, QT PROLONG More DDI than fluconazole *Voriconazole (VFend)* Mech: inhibit CYP51a in fungus -> block formation of ergosterol Resist Mech: efflux pump overexpression, CYP51a overexpression, CYP51a alteration Uses: best for aspergillus, scedosporium, sporothrix, candida (including krusei) Resist: mucorales, no difference in advantage for glabrata Kinetics: no concerns with food or acid, oral best for CLCr <50 ADE: N/V< DILI, QT PROLONG, phototoxic, periostitis (FLUORIDE TOXIC), reversible alopecia In AZ, use posaconazole for 2nd line coccidioidomycosis due to phototoxic *Isavuconazonium Sulfate (Cresemba)* Mech: inhibit CYP51a in fungus -> block formation of ergosterol Resist Mech: efflux pump overexpression, CYP51a overexpression, CYP51a alteration Use: best for aspergillus, MUCORALES Resist: break-through with molds Kinetics: prodrug, mostly liver metabolized ADE: N/V, DILI, SHORTENS QT INTERVAL (does NOT prolong) DO NOT USE IN PATIENT WITH SHORT QT SYNDROME Can be used as a good substitute if patient has prolonged QT Do NOT use with CYP450 inducing medications (rifampin, phenobarbital, phenytoin, etc) Extremely expensive *Azoles for Local/Vaginal Tx of Vaginal Candidiasis* Mech: inhibit CYP51a in fungus -> block formation of ergosterol Resist Mech: local conditions, dysbiosis, non-albicans species, abnormalities in mucosal immune Uses: 90% of cases of VC are candida albicans (but glabrata/krusei/auris exists and are difficult to treat) Risk Factors: HIV infection, abx use, preggo Rx options: oral fluconazole, Gynezole-1 (2% butoconazole nitrate cream single dose), Terconazole vaginal cream 0.8% for 3 days OTC products: Monostat-1 (single dose of miconazole 1200mg), Monostat-3 (3 doses of miconazole 200mg for 3 days), Monostat-7 (100mg cream doses for 7 days), Vagistat-1 (6.5% tioconazole cream) SEE PROVIDER FOR DX ON FIRST EPISODE, STI/preggo concern, tx fail Future episodes with similar presentation can be treated OTC Azole + steroid combo NOT recommended DO NOT HAVE SEX UNTIL RESOLVED

Targeting DNA Replication

*Fluoroquinolones: ciproFLOXACIN, oFLOXCACIN* Targets DNA gyrase (E.coli/N.gonorrhoeae) OR Topo IV (S.aureus/S.pneumoniae) Topo II IS NOT AFFECTED BY QUINOLONES Polyvalent agents (antacids) should be taken SEPARATELY FROM QUINOLONES

Targeting Folate Biosynthesis (Antifolates)

*Folates* Folates essential for nucleic acid generation as well as Met and His Bacteria must synthesize their own folates to survive (can target these enzymes to stop synthesis) *Sulfonamides: Sulfamethoxazole/Trimethoprim (TMP/SMX)* Blocks dihydropteronate synthase -> inhibit cell division, DNA/RNA synth, repair, protein synth

Preventing GI Conditions

*Foodborne* Be careful in hotels, cruise ships, resorts, restaurants, etc Don't consume unpasteurized milk/dairy Don't consume raw meet or poultry Don't consume unpasteurized fruit juices and dirty vegetables Don't consume undercooked eggs Be careful around raw shellfish WASH YO HANDS DUDE *Contact* Be careful swimming/drinking in untreated fresh water Be careful swimming in rec water facility with treated water Be careful in healthcare facilities Be careful in child care centers Note recent antimicrobial therapy Be careful while traveling to third-world countries Be careful around pet diarrhea and pig feces Be careful when touching young poultry and reptiles Be careful in a farm or petting zoo WASH YO HANDS DUDE *Risk Factors* Age group Underlying immunocompromised Hemochromatosis/hemoglobinopathy AIDS Anal-genital, oral-anal, digital-anal contact *WASH YO HANDS DUDE!!!!!!!!!!!!!!!!!!!!!*

Treating Pediatric CAP

*Fully Immunized Presumed Bacterial Empiric Inpatient* PREFERRED: ampicillin, penicillin G Alternatives: ceftriaxone, cefotaxime Add vanco or clindamycin if suspected MRSA *Fully Immunized and NOT Fully Immunized Atypical Bacterial Empiric Inpatient* PREFERRED: azithromycin (add b-lactam if doubting atypical PNM) Alternatives: clarithromycin, erthromycin, doxy for 7+ years, levofloxacin if fully matured in growth OR cannot tolerate macrolides *NOT Fully Immunized Presumed Bacterial Empiric Inpatient* PREFERRED: ceftriaxone or cefotaxime Alternatives: levofloxacin Add vanco or clinda if suspected MRSA *Presumed Bacteria Empiric Outpatient* <5 years: amoxicillin 5+ years: amoxicillin with or without azithromycin (alt: Augmentin) *Atypical Bacteria Empiric Outpatient* <5 years: azithromycin (alt: clarithro/erythromycin) 5+ years: azithromycin (alt: clarithro/erythromycin, doxy if 7+ yrs) *Viral Pediatric CAP: Oseltamivir* 9-23months: 4mg/kg/day 2+ years <15kg: 60mg/day 2+ years 15-23kg: 90mg/day 2+ years 23-40kg: 120mg/day 2+ years 40+kg: 150 mg/day

Cephalosporin Class Antibiotics

*GENERAL NOTES* Gram Negative activity increases as generations go up Gram Positive activity decreases as generations go up There are no cephalosporins (EXCEPT CEFOXITIN) that can treat anaerobic GNs (combo with metro to cover) *Cefazolin (1GC)* Coverage: staph, MSSA, strep pyogenes, E.coli wild type, Proteus wild type Use: surgical proph, cellulitis, surgical site infections (MSSA, strep), Bacteremia and serious MSSA NOT involving CNS, orthopedic infections and diabetic foot infections with MSSA MOE: inhibit PBP by irreversibly binding to active site Resistance: MRSA, enterococci, strep pneumoniae, S.agalactiae, viridans, klebsiella pneumoniae Oral Analogs: Cephalexin 250-500mg Q6H, Cefadroxil 250-500mg Q12H Cefoxitin with/without metronidazole should be used instead if high risk for anaerobics surgical infection Use nafcillin for CNS infections instead *Cefoxitin (2GC)* Coverage: MSSA and strep pyogenes (less potent than 1GC), E.coli wild type, better with enterobacterales, moderate to anaerobics MOE: inhibit PBP by irreversibly binding to active site Uses: Surgical proph (lower intestinal surgery-transect bowel), low risk diabetic foot infx Resistance: MRSA, enterococcus, enterobacterales based on susceptibility, ESBLs No oral analog, usually use 1GC with metro or Augmentin Also can use for gynecologic surgery proph Better against AmpC b-lactamase *Cefuroxime AKA Ceftin (2GC)* Coverage: MSSA + strep similar to cefazolin, enterobacterales a little better than 1GC, H.influenzae, strep pneumoniae, cardiac surgery proph Use: mostly for respiratory infections like CAP (FIRST-LINE) MOE: inhibit PBP by irreversibly binding to active site Resistance: MRSA, enterococcus, enterobacterales based on susceptability Oral Analogs: Cefuroxime axetil prodrug 250-500mg Q12H WITH FOOD *Ceftriaxone AKA Rocephin (3GC)* Coverage: strep including pneumoniae and viridans, MSSA (less active than 1GC), enterobacterales (do NOT use for AmpC or ESBL or psuedomonas), H.influenzae, E.coli, Proteus, Klebsiella Uses: respiratory infections including CAP (combo with macrolide or doxy), UTI or URI, step-down agent from parenteral therapy MOE: inhibit PBP by irreversibly binding to active site Resistance: MRSA, enterococcus, enterobacterales based on susceptibility (60-90 day previous exposure) Oral Analog: Cefdinir, Cefpodoxime, Ceftibuten, Cefditoren (NONE matches activity of Ceftriaxone, but can use as step-down) Excellent against strep and strep pneumoniae with ONCE DAILY dosing ADJUST FOR RENAL INSUFFICIENCY (<30 CrCl and INC ALK PHOS) DO NOT ADMIN IV CALCIUM OR ELSE IT WILL PRECIPITATE -> BILIARY OBSTRUCTION CI: PRE-MATURE BABIES *Cefotaxime AKA Claforan (3GC)* Coverage: Same as ceftriaxone Uses: respiratory, mostly used as alternative for neonates/infants with hyperbilirubinemia (ceftriaxone can displace bilirubin in neonates, cannot handle) MOE: inhibit PBP by irreversibly binding to active site Resistance: MRSA, enterococcus, enterobacterales based on susceptibility (60-90 day prior exposure) Do NOT have to renal adjust unless high dose OR liver disease Same oral analogs as Ceftriaxone Useful for any patient with possible biliary stasis or stones Do NOT substitute single dose tx for gonorrhea *Ceftazidime AKA Fortaz, Tazicef (3GS)* Coverage: Similar to ceftriazone, but also more potent against enterobacterales, pseudomonas, some acinetobacter Use: hospital-acquired infections, GN infections with pseudomonas risk factors MOE: inhibit PBP by irreversibly binding to active site Resistance: MRSA, enterococcus, MSSA (much more poor than 1GS), strep, selective de-repression AmpC enterobacterales (3GS should be AVOIDED altogether for these), citrobacter There are no oral analogs Best for GN with pseudomonas (85%) Need susceptibility testing for Acinetobacter *Cefepime AKA Maxipime (4GS)* Coverage: strep, MSSA, GN, pseudomonas, AmpC enterobacterales (enterobacter, citrobacter) Uses: hospital-acquired infections, suspected GN with psuedomonas, neutropenic fever for broad coverage, can use for ESBLs but penems are usually better MOE: inhibit PBP by irreversibly binding to active site Resistance: MRSA, enterococcus, ESBL E.coli/klebsiella/other GNRs, carbapenemase-producing GNRs No oral analogs Best for immunocompromised pts, high healthcare exposure, prior abx exposure *Ceftaroline AKA Teflaro (5GS)* Coverage: MRSA, 3GS-resistant strep pneumoniae, MSSA and other strep, GN coverage similar to 3GS Uses: CAP, SSTIs with MRSA Resistances: enterococcus, ESBL E.coli/klebsiella, AmpC GNRs, carbapenemase GNRs No oral analogs Used in combo with Vanco/Dapto for MRSA Monotherapy for serious MRSA/MSSA is NOT WELL STUDIED *Cefiderocol AKA Fetroja (3/4GS)* Coverage: enterobacterales (AmpC), pseudomonas, acinetobacter, stenotrophomonas, acromobacter, burholderia, last resort for B-lactam resist GNs Use: CAP, complicated UTIs MOE: inhibit PBP by irreversibly binding to active site, able to chelate iron to get across outer membrane Resist: GPs, anaerobes No oral analogs This is a LAST RESORT CHOICE: consider ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam first *Ceftazidime-Acibactam (3GS + BLI)* Coverage: enterobacterales (ESBL + AmpC), better pseudomonas coverage, klebsiella Use: resistance to cefepime/Zosyn/penems, ESBLs to reduce penem use Resistances: MRSA, enterococcus, MSSA, strep, AmpC (ceftazidime ALONE), anaerobes No other oral analogs Penems are LESS EXPENSIVE, still drug of choice FIRST-LINE FOR KPC ENTEROBACTERALES (KLEBSIELLA) *Ceftolozane-Tazobactam AKA Zerbaxa (5GS + BLI)* Coverage: enterobacterales, ESBLs, pseudomonas (better than cefepime, ceftazidime, meropenem), anaerobes Uses: psuedomonas resistant to cefepime, Zosyn, penems Resistances: MRSA, enterococcus, strep, AmpC No oral analogs *Aztreonam (Azactam)* Coverage: GN similar to ceftriaxone/cefotaxime, psuedomonas (less than ceftazidime, cefepime, meropenem), metallo-B-lactam producers Use: hospital-acquired infx (limited), pts with a TRUE penicillin allergy MOE: inhibit PBP by irreversibly binding to active site In combo with other B-lactams Resistances: ALL GRAM-POSITIVES, ESBL, AmpC No oral analogs NOT hydrolyzed by metallo-B-lactamases ZERO cross-allergy with true pencillin allergies Expensive, and potential for misuse (1% of pts actually have true allergy)

HBV Management

*Goals* Achieve HBeAg serconversion (can stop tx if this is achieved in some cases) Loss of HBsAg (has higher likelihood of maintaining remission) Minimizing/halting liver dmg progression Reduce risk of HCC *Reasons for Tx Failure* Lamivudine resist: switch to tenofovir OR add tenofovir Telbivudine resist: switch to tenofovir OR add tenofovir Adefovir resist: switch to tenofovir Entecavir resist: switch to tenofovir OR add tenofovir Tenofovir resist: switch to entecavir OR add entecavir MDR: switch to tenofovir OR use both tenofovir and entecavir NOTE: SWITCHING IS THE BEST STRAT UNLESS MDR *Inactive Chronic HBV* HBeAb+, HBV DNA <2k but detectable, ALT normal: no tx needed Monitor ALT every 3 months for first year Monitor ALT every 6-12 months afterwards (inc monitor if ALT elevates) Check HBsAg yearly *Immune-Tolerant Chronic HCV* HBeAg+, HBV DNA high, ALT normal: no need to tx Consider liver biopsy if ALT borderline/persistantly high If HBV DNA 20k+, consider tx IF: ALT > 2x ULN, F2+, A3+ Wait 6 months if HBV DNA between 2-20k (seroconversion may be ongoing) *Immune-Active Chronic HBV* High ALTs, HBeAg+, HBV DNA 20k+: need tx High ALTs, HBeAg-, HBV DNA 2k+: need tx Use PegIFN, TFV, entecavir PegIFN duration: 48 weeks if HBeAg+. 1 year if HBeAg- PegIFN has HIGH RATES OF SUCCESS *Cirrhosis* Compensated: tx needed if DNA 2k+ (LIFELONG TX), consider tx if DNA <2k (reduces HCC risk) Decompensated: tx needed if DNA detected, monitor closely if not detected PegIFN NOT preferred in compensated cirrhosis (DO NOT USE IF DECOMP) *Other Cases* Persistent DNA 2k+ (96+ weeks of therapy) on nonPegIFN therapies: continue TFV, entecavir monotherapy Viral breakthrough on therapy (10x increase in DNA): assess adherence, obtain resistance testing, switch to TFV or consider TFV + entecavir HBsAg spontaneously disappears: 1% chance, monitor as if inactive chronic HBV *After Tx* Immune-active HBeAg+ seroconverts to negative: continue tx for 1+ yr after seroconversion Immune-active HbeAg-: likely lifelong tx

Altering Site of Actions for Resistance

*Gram Negatives* PBP CONSERVED Resistance via changed target UNCOMMON (exception: penem resist in proteus/providencia/morganella morganii) *Gram Positives* Staph aureus Enterococcus Strep pneumoniae

Antibiotic Selection based on Bacteria

*Group A Strep* Penicillin G Ampicillin/Amoxicillin First Generation Cephalosporin (1GC) and Second Generation Cephalo (2GC) for MSSA Ceftriaxone/Cefotaxime Clindamycin for penicillin allergy Doxycycline *Viridians Strep* Penicllin G Amp/Amoxicillin 1GC/2G (NO ADVANTAGES OVER OTHERS) Vancomycin for penicillin allergy/resistance *Strep Pneumoniae* Third Generation Cephalo (3GC) Ceftriaxone/Cefotaxime FIRST-LINE in HOSPITAL Amp/Amoxicillin FIRST-LINE in AMBULATORY (BEWARE OF RESISTANCE) 1GC and ceftazidime has POOR activity 2GC has decent oral agents Ceftaroline for 3GC resistance Vancomycin Levo/Moxifloxacin *Enterococcus spp.* Faecalis: Amp/Amox/Penicillin FIRST-LINE, can combine with ceftriaxone, use vanco for allergy Faecium (B-LACTAM RESISTANT): Daptomycin, linezolid *Staph Aureus* MSSA: Oxacillin/Naficillin/Cefazolin FIRST-LINE, can use 2GC but NO advantage MRSA: Vancomycin/daptomycin/linezolid FIRST-LINE, SXT/Doxycycline/Clindamycin for CA-MRSA *E.Coli and Proteus Mirabilis* Fourth Gen Cephalo (4GC) FIRST-LINE Can use penicllin with BLI Carbapenem for ESBL PRODUCING STRAINS Piperacillin-Tazobactam used for uncomplicated ESBL producing UTI Aminoglycoside (TOXICITY RISK) *Klebsiella Pneumoniae* Ceftriaxone FIRST-LINE, other 2GC/3GC/4GC can be used Carbapenem for ESBL PRODUCING STRAINS Piperacillin-Tazobactam used for uncomplicated ESBL producing UTI *AmpC Producing Enterobacterales* 4GC and carbapenems FIRST LINE Penicillins NOT active due to AmpC, even with BLI 1GC/2GC NOT active Aminoglycosides (TOXIC RISK) *Psuedomonas aeruginosa* Ceftazidime (3GC) or Cefepime (4GC) Piperacillin-Tazobactam Penems *Acinetobacter spp.* USE IMIPENEM OVER MEROPENEM Can use Ampicillin/Sulbactam Use Cefiderocol for Carbapenem-Resistant Acinetobacter Baumannii (CRAB) *Haemophilus Influenzae* CEFTRIAXONE (3GC) FIRST-LINE 100% ACTIVE Can also use fluoroquinolones *Moraxella catarrhalis* Penicillin/BLI has ZERO resists (DO NOT USE AMP/AMOXICILLIN BY ITSELF) ALL GCs are ACCTIVE Can use azithromycin and doxycycline too *Anaerobic Bacteria* Pencillin/BLI (amp-sulfbactam, piper-tazobactam) FIRST-LINE Carbapenems have EXCELLENT activity Metronidazole can be used too (NO POSITIVE RODS)

Osteomyelitis

*Hematogenous Osteomyelitis* Infection derived from BLOODSTREAM Most common in children and long-boned people Vertebrae most infected for adults Newborn infx: staph aureus, group B strep, E.coli <5 age children infx: staph, strep, kingella, H.influenaze (IF NOT VAX) 5+ age children and adults infx: staph, e.coli in vertebrae IV Drug Abusers: pseudomonas *Contiguous Osteomyelitis* Spreads from ADJACENT TISSUES Subclassifed according to absence of vascular flow Most commonly seen in adults Mostly staph infx (polymicrobial if DM, PVD, trauma, surgery, puncture) *Direct Inoculation Osteomyelitis* From trauma, surgery, puncture wounds, bites, etc Mostly staph infx (polymicrobial if DM, PVD, trauma, surgery, puncture) *Diagnosis* Sx: tenderness/pain, swelling, fever/chills, dec ROM, malaise, weight loss Labs: ESR, CRP, elevated WBC, cultures Xrays, MRIs, biopsys *Hematogenous Treatment* Newborn: vanco + cefotaxime Children <5: vanco + ceftriaxone Children 5+ and adults: vanco + ceftriaxone (IF VERTEBRAL) IV Drug Abusers: vanco + cipro/cefepime *Contiguous Treatment* Supportive care Surgery Narrow abx based on cultures

Vascular Access Infections

*IV Catheter-Associated Infections* Peripheral Central Non-Tunneled Tunneled Port-a-Cath *Blood Cultures obtained from line and peripheral stick* If line culture positive 2+ hrs before peripheral culture -> vascular access infection more likely *Microbiology* Staph aureus Coagulase neg staph Enterococci Candida: DO NOT IGNORE THIS Other *Staph Aureus Tx* REMOVE CATHETER IF POSSIBLE MOST PATHOGENIC MSSA: nafcillin, oxicillin, cefazolin MRSA: vanco Duration depends on patient criteria Either 4-6 weeks OR 14+ days if pt is: NOT DM, immunocompromised No prosthetic IV device No evidence of endocarditis Catheter removed Fever resolved and neg blood culture 72+ hrs No evidence of metastatic infection *Coagulase Negative Staph Tx (Staph epi)* REMOVE CATHETER IF POSSIBLE Possible skin contaminant! Tx: vanco 5-7 days (tends to be MRSA) *Enterococci species Tx* Not usually life-threatening short term (sometimes asymptomatic) REMOVE CATHETER IF POSSIBLE Tx depends on susceptibility: Ampicilin with/without gentamicin, vanco, dapto, linezolid *Candida species Tx* REMOVE CATHETER IF POSSIBLE Potential skin contaminant... BUT POSITIVE CULTURE SHOULD BE TREATED Duration: 14 days after last positive blood culture with fluconazole, amphotericin B, echinocandin *Line Lock Therapy: if the catheter cannot be removed due to some reason* Abx, alcohol, acid Heparin to keep to line patent and non-clotting (only used if abx is used) Abx: vanco, ceftazidime, cefazolin, cipro, gentamicin, ampicillin, dapto (MAKE SURE FLUID HAS Ca LIKE LACTATED RINGERS) *Special Considerations* After infection, must determine correct time/site/type of line when replacing a line (if a line is still needed!) CONSIDER ENDOCARDITIS IF BACTEREMIA *Preventing IV Catheter-Associated Infections* Hand hygiene Barrier precautions upon insertion Optimal catheter site selection Daily review of line necessity

Micellaneous Antifungals

*Ibrexafungerp (Brexafemme)* Mech: inhibit B(1,3)-D-glucan synthase in cell membrane -> weakens cell wall and causes osmotic lysis (most effective with candida) Mech Resist: FKS subunit mutation Use: best with candida for tx of vulvovaginal candidasis Resist: nothing yet (approved 2021) Kinetics: EAT WITH HIGH FAT MEAL ADE: NVD, abd pain DO NOT USE IN PREGGO Expensive Honestly just use fluconazole dude *Terbinafine (Lamisil)* Mech: inhibit squalene epoxidase to prevent formation of ergosterol Resist: point mutations of enzyme in dermatophytes Uses: dermatophytes (especially trichophyton), some candida activity, onychomycosis, tinea capitis, ringworm and other tinea infections Resist: trichophyton in India Kinetics: duration is longer for fingernail infection and toenail infections ADE: acute liver fail, loss of smell and taste DO NOT USE WITH PRE-EXISTING LIVER DISEASE Discontinue if loss of smell and taste Screen for DDIs (strong inhibtor of CYP2D6) Some people say it's better to drink nail infections non-pharm due to liver toxic potential Terbinafine 1% cream OTC used for tinea pedis/cruris/corporis

Drug-induced Hepatocellular Toxicity (Liver Injury)

*Idiosyncratic DILI* Adaptive immune system activation leads to apoptosis *Intrinsic DILI* Reactive metabolite or innate immune response Organ stress and dysfunction Cell death via apoptosis and necrosis *Hepatocellular pattern of DILI* ALT/AST increased 5x above ULN or ratio 5+ Meds: Tylenol, diclofenac, disulfram, fenofibrate, isoniazid, lamotrigine, nitrofurantoin, pyrazinamide, rifampicin, sulfonamide *Cholestatic pattern of DILI* ALP is 2x above ULN or ratio <2 Meds: Augmentin, androgens, cephalosporins, erythromycin, contraceptives, penicillins, sulfonamides, terbinafine *Mixed pattern of DILI* Ratio 2-5 Meds: carbamazepine, lamotrigine, phenytoin, sulfonamides *Autoimmune-like Hepatitis* Looks like acute/chronic DILI with serological and histological markers Meds: adalimumab, methyldopa, diclofenac, herbal supplements, infliximab, nitrofurantoin, statins *Vanishing bile duct (ductopenic) Syndrome* Cholestasis with gradual loss of intrahepatic bile ducts Meds: Augmentin, azathioprine, carbamazepine, erythromycin, phenytoin, terbinafine *Chronic DILI* ALT 2x ULN Mostly abx that causes this Cefazolin (1-4wk onset sx): jaundice, itching, N, illness, fever, rash, eosinophilia, abd pain, abnormal LFT for 6+ months Augmentin (MOST COMMON CAUSE BEHIND TYLENOL): fatigue, loss of appetite, itching, jaundice Mostly older white men May take years to resolve HLA-B*5701 haplotype may have greater risk (especially flucloxacillin) Azithromycin (rare): jaundice, abd pain, N, pruritis, rash, fever *DILI from Isoniazid* Common drug in RIPE therapy for anti-tuberculosis #1 CAUSE OF DILI IN DILIN DATABASE Risk Factors: 60+ age, women, preggo, poor nutrition, alcohol, viral hepatitis, NAT2 and CYP2E1 genotypes, MnSOD and GST genotypes *Azole DILI* Fluconazole most common All the rest are pretty rare and unlikely

Respiratory Viral Infections

*Influenza A+B* Classic Sx: rapid fever/myalgia/HA/malaise/nonprod cough/sore throat/rhinitis Children Sx: N/V, otitis media Primary PMN sx: fever, dry cough -> prod cough with blood -> dyspnea, hypoxemia, cyanosis Secondary PMN sx: fever, prod cough Primary PMN risks: PREGGO, heart disease Secondary PMN risks: underlying lung disease Dx: radiologic bilateral infiltrates (primary PMN), consolidation (secondary PMN) Tx and proph: oseltamivir, peramivir, baloxavir, zanamivir (INHALE ONLY), amantadine/rimantadine (HIGH RESIST), IVIG Immunizations YEARLY for 6+ mos of age *Respiratory Syncytial Virus (RSV)* MAJOR CAUSE IN CHILDREN Mostly seasonal Tx (immunocompromised): ribavirin, palivizumab (VERY EXPENSIVE), RSV-IVIG *Parainfluenza, Rhinovirus, Coronavirus* Common causes for common cold Coronavirus cause for SARS, MERS, COVID-19 Common Cold tx: supportive care COVID-19 tx: nothing established yet, EUA for remdesivir

C.diff Guidelines

*Initial Episode* Fidaxomicin 200mg BID PREFERRED Vanco 125mg QID Metronidazole 500mg TID (NON-SEVERE: WBC <15k or SCr <1.5) *First Recurrence* Fidaxomicin 200mg BID PREFERRED Vanco in a TAPERED AND PULSED REGIMEN Vanco 125mg QID Bezlotoxumab 10mg/kg IV inj for prevention CONSIDER VANCO IF METRONIDAZOLE USED IN INITIAL *Second Recurrence* Fidaxomicin 200mg BID Vanco in TAPERED/PULSED regimen Vanco 125mg QID FOLLOWED BY rifaximin 400mg TID Fecal microbiota transplant Bezlotoxumab 10mg/kg IV inj for prevention *Fulminant C.diff: hypotension/shock, ileus, megacolon* Vancomycin 500mg QID oral or nasogastric tube If ileus: consider adding rectal vanco IV Metronidazole admin TOGETHER WITH oral/rectal vanco (especially if ileus present)

Monitoring Endocarditis

*Initiation before or at completion of therapy* ECG to establish new baseline Drug rehab referral for IVDA Educate signs of endocarditis and need for abx proph for dental/surgical/invasive procedures Thorough dental eval and tx if not performed earlier in eval Prompt removal of IV catheter at completion of IV therapy *Short-term Followup* 3+ sets of cultures from separate sites for any febrile illness and before initiation of abx therapy Physical for evidence of HF Eval for toxicity from current/past abx therapy *Long-term Followup* 3+ sets of cultures from separate sites for any febrile illness and before initation of abx therapy Evaluate valvular/ventricular function with ECG Scrupulous oral hygiene and frequent dental visits

Beta-Lactam Allergies

*Intolerance* NON-ALLERGIC EVENT (NO IMMUNE REACTION) ADE: N/V/D, HA, dizzy *Allergy History* Low Risk: FHx, itching without rash, unknown rxn, occurring 10+ years ago, denies allergy listed in record High-Risk: Delayed hypersensitivity, anaphylaxis, SJS/TEN, erythema multiforme, drug-induced hepatitis, serum sickness, DRESS, acute generalized exanthamatous rxn, drug-induced thrombocytopenia, hemolytic anemia, drug fever, dystonia *Delayed Hypersensitivity* Amp/Amoxicillin MOST COMMON Delayed after 5-7 days post exposure Presentation: maculopapular rash Associated with viral infection Usually self-limiting May or may not recur with repeated exposure Limited cross-allergy *IgE-mediated Anaphylaxis (IMMEDIATE Hypersensitivity)* Presentation: throat tightness, tongue swelling, significant angioedema, wheezing, SOB, bronchospasm, hypotension, syncope Onset: Within 72 hours of REPEAT exposure More rapid = more severe Moderate risk: rash with hives / wheal and flare *Management* Anaphylaxis: establish risk, oral amoxicillin challenge, desensitization, PAST, may outgrow allergy Other High Risk Rxns: avoid re-exposure, AVOID ALL BETA-LACTAMS IF HX OF SJS/TENS

COVID-19 Targets

*Main Protease Mpro and 3CLpro* Combined together forms Nsp5 Involved in polyprotein cleavage for DMV formation Cysteine protease with high substrate preference for Glutamine *Papain-like Protease PLpro* Also called Nsp3 Involved in the same thing as Nsp5 *RNA-dependent RNA Polymerase (RdRp): Remdesivir, EIDD2801* Mechanism: drug uptaken by cell which is then metabolized into nucleoside triphosphate -> inhibits RdRp

Foscarnet

*Mechanism* Blocks pyrophosphate binding site on viral DNA polymerase Prevents cleavage of pyrophosphate from deoxynucleotide triphosphate *Resistance* Mutations in viral DNA polymerase in prolonged therapy *Toxicity* Nephrotoxic: 2+ SCr in 30% of cases, nephrogenic diabetes insipidus, hypoCa, hypoMg, hypoK, hyper/hypoP Genital ulcerations Seizures from electrolyte abnormals

Colony-Stimulating Factors for Neutropenic Fever

*Medications* Filgastrim Pegfilgastrim Sargramostim *Primary Proph* For HIGH RISK of neutropenic fever based on myelotoxicity from planned chemo If not as high risk: consider depending on age, performance status, radiation ports, admin of chemo, bone marrow cancer, poor nutrition, open wound presence, active infx, previous surgery, poor renal/liver function, lack of abx proph *Secondary Proph* Hx of neutropenic fever from chemo Reduced dose may be used *Tx of Neutropenic Fever* Should NOT be used for afebrile neutropenia ONLY USE FILGASTRIM OR SARGRAMOSTIM FOR TX Consider in patients with high risk of infx-associated complications, ANC < 100, expected prolonged neutropenia (10+ days), 65+ age, uncontrolled primary disaese, sepsis, infx with hypotension and multiorgan dysfunction, PMN, invasive fungal infx, hospitalization with fever *Reduction of Neutropenia Duration in HSCT* RECOMMENDED to use BEFORE chemo in order to reduce duration of neutropenia after autologous PBPC transplantation

Pharmacokinetics and Pharmacodynamics of Antibiotics

*Minimum Inhibitory Concentration: the lowest concentration needed to inhibit growth of a bacteria* Bacterial Killing Curves: time-concentration curves with increasing concentration from MIC to determine how fast bacteria dies Post Antibiotics Effects (PAE): residual effects on growth after brief abx exposure *Adaptive Resistance* Antibiotic naive bacteria: abx is bactericidal Abx experienced bacteria: abx is bacteriostatic associated with metabolic changes Biphasic killing: initial rapid killing, then slow to no killing *Pharmacodynamic Parameters: Cmax/MIC, AUC/MIC, Time Above MIC (%)* Cmax/MIC (CONCENTRATION-dependent): aminoglycosides, fluoroquinolones (mixed) AUC/MIC (CONCENTRATION/TIME-dependent): most abx EXCEPT beta-lactams Time Above MIC (TIME-dependent): beta-lactams *Bacterial Killing* Concentration Dependent: strong dependence on concentration in time-kill studies when concentration is SIGNIFICANTLY GREATER than MIC Concentration Independent: maximum killing at concentration around the MIC

Mitochondrial Toxicity in Antibiotics

*Mitochondria* Evolved from GRAM-NEGATIVE bacteria Structure: outer membrane (porins), inter-membrane space, inner membrane with ETC, and matrix Houses aerobic respiration that produces NADH ETC uses NADH to produce ATP ETC can also result in reactive oxygen species (small = cell signaling; moderate = inflammation and immune response; large = cell injury and death Actions: divide via fission, fuse, extensive repair processes, mitophagy (self-destruction) *Linezolid Mitotoxicity* Linezolid inhibits mitochondrial protein synth by binding to mitochondria ribosomes Variations in mtDNA (SNPs) may affect individual sensitivity to toxicity Monitor CBC WEEKLY: WBC (neutropenia), platelets (thrombocytopenia), RBCs (anemia) Watch for peripheral neuropathy, lactic acidosis (RARE), optic neuropathy (RARE) Use for SSSI: 2-4 weeks Use for TB, atypical mycobacteria, nocardia: LONG-TERM *Aminoglycoside Ototoxicity* Cochlear or vestibular toxicity Binds to decoding site of 28S ribosome in mitochondria -> dysfunction SNPs exist with increased binding affinity Hair cells in cochlea and vestibule most sensitive -> hearing loss (no reapirs, perma loss, 2-30% incidence) Dizziness may be severe and permanent: ask patients when monitoring and have them get up and walk if safe, stand with eyes closed, and/or dynamic visual acuity test Intra-tympanic administration: treats vertigo (Menier's disease) 20mg inj, repeat in 2-4 weeks with post-tx monitoring Topical Otic Drops: for tympanic perforation with tympanostomy (FQs now more used) Monitor: SCr, BUN, audiology, AE monitoring *Daptomycin Myopathy* Necroptosis: unprogrammed cell death where mitochondira is involved in death (not really mitochondrial toxicity) Initial low dose (2mg/kg q12h) to offset this but 1/3 still had CPK elevations and failed to treat endocarditis due to high protein binding Later made it 4mg/kg daily for complicated SSSI -> less frequency could minimize toxic and recover period to fall below "threshold" Current: 8-12mg/kg daily dose for SERIOUS staph aureus Clcr <30: same dose at q48h Rhabdomyolysis: breakdown skeletal muscle where myoglobin is released to bloodstream -> AKI Risk factors for rhabdo: concomitant HMG-CoA reductase inhibitor, hypoCa/P, infection/shock, thermal injury, dapto, quinupristin/dalfopristin, other drugs Monitor: baseline and weekly CK, muscle tenderness/pain/soreness, eosinophils (eosinophilic pneumonitis) *Drug-Induced Neutropenia: ANC < 1000/uL* Vancomycin: usually late in therapy (3+ weeks) Beta-lactams: similar onset like vanco *Aplastic Anemia in Chloramphenicol* Removed from US market due to rare aplastic anemia AE caused by eye drop formulation Aplastic anemia is FATAL without bone marrow transplant Gray baby syndrome: liver damage in baby makes them turn gray, LIFE-THREATENING

TB Drug Resistance

*Multi-Drug Resistant TB (MDR-TB) is VERY RARE in the US* 0.9% of TB cases resistant to both RIF + INH 8% of cases resistant to only INH *Types of Drug-Resist TB* Primary: initially infected with resistant organism Secondary (Acquired): resistant develops DURING TREATMENT *Risk Factors* Hx of TB tx Contact with drug-resist TB Foreign-born people from high endemic areas Smears/cultures remain positive 2+ months into TB tx Received inadequate tx regimens for 2+ weeks *Treating INH Resistant TB* CAREFULLY MANAGE TO AVOID MDR-TB DEVELOPMENT If suspected: DC INH -> add levofloxacin with the other three drugs -> take for SIX MONTHS DO NOT ADD IV AGENTS *Treating Multi-Drug Resist TB* Treatment MUST be individualized SEEK EXPERT CONSULT ALWAYS USE DOT TO ENSURE ADHERENCE Step 1: levofloxacin OR moxifloxacin Step 2: BOTH bedaquiline and linezolid (PRIORITY) Step 3: BOTH clofazimine and cycloserine/terizidone (PRIORITY) Total of FIVE DRUGS If unable to get all five drugs: consider amikacin or streptomycin If oral preferred over injectable: consider delamanid, pyrazinamide, ethambutol If limited options: ethionamide, imipenem-cilastatin/clavulanate, meropenem/clavulanate, P-aminosalicylic acid DO NOT USE: capreomycin, kanamycin, Augmentin, azithromycin, clarithromycin *Treating EXTENSIVELY Multi-Drug Resist TB* Resistant to INH, RIF, FQs, 1+ of amikacin/kanamycin/capreomycin Good luck bro lol

Management of SSTIs FLOWCHART

*NON-PURULENT* Mild: Oral abx (penicillin, cephalosporin, dicloxacillin, clinda) Moderate: IV abx (penicillin, ceftriaxone, cefazolin, clinda) Severe: Emergent surgical inspection to rule out NECROTIZATION with empiric abx (vanco WITH Zosyn) -> test for susceptibility Severe Strep pyogenes: peniclllin + clinda Severe clostridial sp.: penicillin + clinda Severe vibrio vulnificus: doxycycline + ceftazidime Severe aeromonas hydrophila: doxycycline + cipro Severe polymicrobial infx: vanco + zosyn *PURULENT* Mild: incision and drainage Moderate: incision and drainage with susceptibility testing Moderate empiric coverage: TMP/SMX or doxy Moderate MRSA coverage: TMP/SMX Moderate MSSA coverage: dicloxacillin or cephalexin Severe: incision and drainage -> susceptibility testing Severe empiric coverage: vanco, dapto, linezolid, televancin, ceftaroline Severe MRSA infection: continue empiric abx Severe MSSA infection: nafcillin, cefazolin, clinda NOTE: DO NOT USE DAPTOMYCIN FOR CHILDREN, USE VANCO

Urinary Antiseptics and C.diff Drugs

*Nitrofurantoin (Macrobid, Macrodantin)* Mech: nitroreductases reduce nitro substituents to form reactive intermediates that binds to proteins/nucleic acids -> cell death Resist Mech: lack of nitroreductases Coverage: E.coli, kleb pneu, enterococcus, staph saprophyticus Uses: UNCOMPLICATED UTI Resist: proteus, P.aeru, serratia Toxic: acute/chronic pulmonary hypersens rxn, DO NOT USE IN ELDERLY OR <30 CLCr, drug-induced liver disease in long duration, peripheral neuropathy in long use Uncomplicated UTI duration is 5 days Can be used for proph of UTI DO NOT USE IF FEVER OR FLANK PAIN (PYELONEPHRITIS) Take with food *Methenamine* Mech: hydrolyzed to 6 molecules of formaldehyde at <6.5 pH which kills off cells Mech Resist: insufficent excretion, inadequate dwell time in bladder, inadequate conversion to formaldehyde Coverage: similar to nitrofurantoin Uses: uncomplicated UTI (measure MORNING pH for effectiveness), can be useful for MDR or XDR since it's NON-ABX Resist: do NOT use for proteus (proteus can have HIGHER pH) Toxic: formaldehyde is a carcinogen (but mostly inhalation) Lower pH the better Need retention in bladder (NIGHTTIME DOSE MOST IMPORTANT) Do NOT use in catheter Do NOT use in pyelonephritis or complicated UTI *Fosfomycin (Monurol)* Mech: UDP-N-acetylglucosamine enol pyruvyl transferase inhibition Mech resist: rare Coverage: E.coli, enterococcus faecalis, enterococcus faecium, enterobacteriales Uses: uncomplicated UTI, severe CDI in combo with vanco Resist: acinetobacter, VRE, P.aeru (variable) Toxic: very little Mostly used for uncomplicated UTIs in women Single dose but expensive (100 dollars) Can be used for ESBL/MDR enterobacterales but insurance might not like this *Metronidazole* Mech: reduced by pyruvate-ferredoxin oxidoreductase which makes reactive radicals -> activated drug interacts with DNA Resist Mech: downregulation of PFOR or ferredoxin Coverage: anaerobivs, bacteroides, parasites (giardia, entamoeba, trichomonas), C.diff Uses: trichomonas vaginalis, bacterial vaginosis, some parasite infections Resist: GP rods (cutibacterium acnes, lactobacilli, actinomyces) Toxic: GI stuff, metallic after taste, peripheral neuropathy (CAN BE PERMANENT, STOP IF SUSPECTED), antabuse reaction with alcohol Neuropathy at 42g of total therapy (not very supported) *Tinidazole (Tendamax)* reduced by pyruvate-ferredoxin oxidoreductase which makes reactive radicals -> activated drug interacts with DNA Resist Mech: downregulation of PFOR or ferredoxin Coverage: same as metronidazole, protozoal infx, C.diff Uses: trichomonas vaginalis, bacterial vaginosis, some parasite infections Toxic: GI stuff, metallic after taste, peripheral neuropathy (CAN BE PERMANENT, STOP IF SUSPECTED), antabuse reaction with alcohol More convenient dosing for protozoal infx and bacterial vaginosis *Fidaxomicin (Dificid)* Mech: inhibits RNA polymerase sigma (protein synth inhibitor) Resist Mech: rare, spontaneous mutants Coverage: C.diff (more selective) Use: C.diff Resist: rare Toxic: none FIRST LINE FOR C.DIFF Very expensive! Some hospitals will still use vanco first-line due to this cost Less alteration with natural GI flora compared to vanco Less recurrence than vanco Less risk of C.diff mutant that releases more toxins

COVID-19 Nonhospitalized Adult Management

*No Hospital or Oxygen* mAB agents eligible for pts high risk for disease progression mAB agents: bamlanivimab + etesevimab, casirivimab + imdevimab, sotrovimab DO NOT USE DEXAMETHASONE OR SYSTEMIC STEROIDS *Discharged from Hospital, no Oxygen* STOP USING REMDESIVIR, DEXAMETHASONE, BARICITINIB *Discharged from Hospital, needs Oxygen* No evidence to either stop or continue the above drugs *Discharged from ED, still needs new or increasing oxygen* Dexamethasone 6mg PO once daily for duration of supplemental oxygen Do NOT exceed 10 days DO NOT USE BARICITNIB

COVID-19 Hospitalized Adult Management

*No Oxygen Needed* DO NOT USE DEXAMETHASONE OR STEROIDS No evidence for or against remdesivir *Oxygen Needed* Use ONE of the following: Remdesivir (for minimal oxygen) Dexamethasone + remdesivir (for increasing oxygen) Dexamethasone (when remdesivir cant be used) *Oxygen Needed through High-Flow device or non-invasive vent* Use ONE of the following: Dexamethasone Dexamethasone + remdesivir For rapidly increasing O2 needs and systemic inflammation: Add barcitinib OR IV tocilizumab to above If neither can be used, use tofacitinib (sub for bar) or sarilumab (sub for tocili) *Requires IMV or ECMO* Dexamethasone If 24 hours within ICU admission: Dexamethasone + tocilizumab (sarilumab if no tocili)

Targets for Antifungals

*Nucleic Acid and/or Protein Synth Inhibitors* 5-Flucytosin: blocks translation from RNA to DNA in nucleus *Sterol Synth Inhibitors* Terbinafine: blocks conversion from squalene to lanosterol Azoles: blocks conversion from lanosterol to ERGOSTEROL *Cell Wall Synth Inhibitors* Morpholines: binds to ergosterol in cell wall to weaken it Amphotericin B and Nystatin: binds to fungal cell wall to weaken Echinocandins: blocks B-glucans Synthase to prevent cell wall synth Nikkomycin-Z: binds chitin on wall to weaken

Peritoneal Dialysis Peritonitis

*Occurence* 80% of pts in first year of PD 20-30% recurrence Frequent cause of catheter loss, interruption of CAPD, switching to HD *Pathogenesis* Contamination Immunocompromised Macrophages/cytokines removed with dialysis *Etiology* Gram positive (60-80%): staph epi, Staph aureus, strep Gram negative (15-30%): pseudomonas, E.coli, Kleb, proteus Rare: fungal, polymicrobial *Presentation* Fever Abd pain, N/V Cloudy effluent *Diagnosis* WBC 100+ PMN 50%+ Gram stain and culture *Treatment* Empiric: gram positive coverage (1CS, vanco if MRSA) and gram negative coverage (ceftazidime, cefepime, penem, AGS) mixed with dialysate and given INTRA-PERITONEAL Can be given continuously or intermittently (once daily) Management: abx adjusted when cultures arrive Improvement should happen in about 48 hrs (repeat cell count and culture if NO improvement) Failure to respond to abx within 5 days WARRANTS CATHETER REMOVAL When effluent clears: continue for ONE WEEK and NO LESS THAN 14 DAYS TOTAL Staph aureus/gram-neg/enterococcal usually more severe -> THREE WEEKS RECOMMENDED

MRSA Skin Infections

*Outpatient MRSA* TMP-SMX for strep coverage Clindamycin (IF D-TEST POSITIVE, DO NOT USE CLINDA) Tetracyclines Oxazolididnones: linezolid/tedizolid *Inpatient MRSA* Vanco Linezolid/Tedizolid Daptomycin Ceftaroline Lipoglycopeptides: tele/dalba/oritavancin Omadacycline

Complicated UTI Management and Treatment

*Parenteral IV Therapy* Fluoroquinolones: Cipro, Levo, Dela (switch to oral when possible) Aminoglycoside: Amikacin, Gentamicin, Tobramicin (RESERVED FOR MDR BACTERIA) Cephalosporins: cefazolin, ceftriaxone, ceftazidime, cefepime, ceftaroline (for NOSOCOMIAL/BACTEREMIA FROM URINARY SOURCE) BLI Combos: Amp-Sulbactam, Zosyn, Ceftazidime-Avibactam, Ceftolozane-Tazobactam (for NOSOCOMIAL/BACTEREMIA FROM URINARY SOURCE) Carbapenems: Erta, Imi, Imi-Ralebactam, Mero, Mero-Vaborbactam (RARE FOR UTIs) Aztreonam: ONLY FOR GN + PEN ALLERGY Vancomycin: empiric for GP MDR

Pharyngitis (Strep Throat)

*Pathophysiology* Infection and inflammation of the phayrnx (STREP THROAT) *Presentation* Sudden sore throat Fever HA N/V, abd pain Tonsillopharyngeal inflammation Patchy tonsillopharyngeal exudates Palatal petechiae Anterior cervical adenitis (tender lymph nodes) Winter/early spring presentation Hx of exposure to strep pharyngitis Scarlatiniform rash (this is normal looking to gingers) *Diagnosis* Based on BOTH presentation AND group A strep confirm Rapid Antigen Detecting Test (RADT): BACK UP WITH THROAT CULTURE FOR CHILDREN Do NOT use RADT: strong presentation of VIRAL cause (cough, rhinorrhea, hoarseness, oral ulcers), children <3 yrs, asx household members *Treatment* Penicillin V 10 days Amoxicillin 10 days Benzathine Penicillin G for ONE DOSE Penicillin Allergy: cephalexin 10 days, clindamyxin 10 days, azithromycin 5 days (WATCH FOR RESIST), clarithromycin 10 days (WATCH FOR RESIST)

Antibiotic-Associated Encephalopathy

*Presentation* Encephalopathy Confusion Delirium (ICU Delirium): 40-60% of ICU pts develop delirium which results in POOR OUTCOMES Sz Neuropathy/toxicity Mania Hallucination Psychosis *Type 1: Seizures* Onset within days with myoclonus or seizures Abnormal EEG but normal brain MRI Resolves in days Abx risk: PCN, CS, penems *Type 2: Psychosis* Onset within days Frequent psychosis Abnormal EEG with normal brain MRI Resolves in days Abx risk: procaine PCN, sulfonamides, FQ, macrolides *Type 3: Cerebellar* Onset WEEKS after start Cerebellar dysfunction (seizures are RARE) Abnormal EEG AND MRI Resolves in days Abx risk: metronidazole *Cefepime Neurotoxicity* Mechs: blocks GABA as competitive antagonist -> glutamate released more -> over-excitation of electrical activity of neurons -> seizures 4g per day with adjustment for renal impairment to avoid neurotoxic

Sinusitis

*Pathophysiology* Inflammation of mucosal lining of paranasal sinuses *Presentation and Diagnosis* Must have at least 2 major OR 1 major and 2+ minor for ACUTE BACTERIAL SINUSITIS DOES NOT DIFFERENTIATE BETWEEN BACTERIAL AND VIRAL Major: purulent nasal discharge, nasal congestion/obstruction, facial congestion/fullness, facial pain/pressure, hyposomnia/ansomnia, fever Minor: HA, ear pain/pressure/fullness, halitosis, dental pain, cough, fever, fatigue *Diagnosing Acute BACTERIAL Sinusitis in CHILDREN* MUST HAVE AN ACUTE URI Persistent illness: nasal discharge, daytime cough lasting 10+ days without improvement Worsening or new onset of nasal discharge, daytime cough or fever Severe onset with 39C+ fever and purulent nasal discharge for 3+ consecutive days *Classification* Acute: <4wks sx duration Subacute: 4-12wks sx duration Chronic: 12+ weeks with or without acute exacerbations *Peds Risk Factors* Recent viral URI Daycare Allergic rhinitis Anatomic obstructions (polyps) Mucosal irritants (smoke) Sudden changes in atmospheric pressure *Adult Risk Factors* 45+ yrs Smoking Air travel Exposure to atmospheric pressure changes, swimming Asthma Allergic rhinitis Dental disease Immunodeficient *Risk Factors for Resistance* Abx within past month Age <2 yrs or 65+ yrs Daycare Prior hospital in past 5 days Comorbids Immunodeficient *Determining if Pt Needs Abx* Onset with persistent sx lasting 10+ days without improvement Onset with SEVERE sx, signs of 39C+ fever, purulent discharge, facial pain lasting 3-4 consecutive days Onset of worsening sx with fever, HA, increased nasal discharged FOLLOWING a typical URI that initially improved Persistent uncomplicated ABS is the ONLY one where CHILDREN do NOT need immediate abx *Etiology* Strep pneu H.influenzae Moraxella Less common: strep pyogenes, enterobacterales, anaerobes *Treatment for Children* FIRST-LINE: Augmentin 45mg/kg/day SECOND-LINE: Augmentin 90mg/kg/day (high dose) Type I Hypersens Allergy: levofloxacin Non-Type I Hypersens Allergy: Clindamycin + cefixime OR cefpodoxime Risk for abx resist OR failed initial therapy: Augmentin high dose, clindamycin + cefixime, cefpodoxime, levofloxacin, linezolid + cefixime Severe infx requiring hospital: ampicillin/sulbactam, ceftriaxone, cefotaxime, levofloxacin Duration: 10-14 days *Treatment for Adults* FIRST-LINE: Augmentin SECOND-LINE: Augmentin high dose B-lactam allergy: doxycycline, levo/moxifloxacin Risk for resist: levo/moxifloxacin Severe infx require hospital: ampicillin/sulbactam, levo/moxifloxacin, ceftriaxone, cefotaxime Duration: 5-7 days OR minimum 10 days *Adjunctive Treatments* Intranasal steroids Saline irrigation Nasal decongestant, mucolytics, antihistamines (not very good for children)

Meningitis

*Pathophysiology* Inflammation of subarachnoid space or CSF Can start as a URI and then invade through intravascular space Cross BBB and enter CSF to multiply -> inflammatory response *Presentation* FEVER NUCHAL RIGIDITY ALTERED MENTAL STATUS Chills N/V Photophobia, severe HA Irritability, delirium, drowsy, lethargy, coma SEIZURES MORE COMMON IN CHILDREN Brudzinski's Sign: flexing of the legs when neck is flexed Kernig's Sign: inability to straighten leg when flexing from a 90 degree angle *Risk Factors* Exposure Recent infx (especially resp or ear) Penetrating head trauma CSF otorrhea or rhinorrhea Cochlear implants Anatomic defects Neurosurgical procedure No immunization *Etiology* 1-3mo: group B strep, GNB, S.pneu 3mo - 3 yrs: S.pneu, N.meninitidis, group B strep, H.influenzae 3-10 yrs: S.pneu, N.meningitidis 10-19yrs: N. meningitidis <50 yo adults: N. meningitidis, S.pneu 50+ yo adults: Strep pneu, N.meningitidis, H.influenzae, Listeria *Strep Pneuoniae Meningitis* LEADING CAUSE IN ADULTS 50% usually resulted from infection of ear/sinuses SEIZURES/COMA MORE COMMON Risk Factors: PNM, endocarditis, CSF leaf, splenectomy, alcoholism, sickle cell, bone-marrow transplant *Neisseria Meningitidis Meningitis* 5 different serotypes: A, B, C, Y, W-135 Spread via respiratory droplets or pharyngeal secretions Seizures/coma uncommon 60% of adults and 90% of children develop PUPURIC LESIONS/PETECHIAE/BOTH *Haemophilus Influenzae Meningitis* Type B: parameningeal focus (middle ear/paranasal/CSF leak) *Listeria Monocytogenes Meningitis* RARE IN HEALTHY Most cases in neonates, alcoholics, immunocompromised, preggo, 50+ yrs Transmission from GI -> foodborne *Diagnosis* CBC with platelet count Basic metabolic panels Cultures LUMBAR PUNCTURE: done BEFORE abx if possible CT Scan BEFORE LP if: hx of CNS disease, immunocompromised, new onset sz, abnormal neuro findings, papilledema, possible brain herniation with ELEVATED INTRACRANIAL PRESSURE *CSF Analysis Differentiation* Bacterial: 200-500 pressure, cloudy CSF, 1-5k WBC, 80-95% neutrophils, 100-500 protein, less glucose Viral: 100-1000 WBC, lymphocytes 50%, 30-150 protein, more protein Gram Positive Cocci: S.pneu, staph, B-hemolytic strep (agalactiae) Gram positive rods: listeria Gram negative cocci: neisseria Gram negative rods: H.influenzae, E.coli, Kleb, P.aeru *Empirical Abx Therapy* <1 mo: amp + cefotaxime OR amp + AGS 1mo - 50 yrs: vanco + 3CS 50yrs: vanco + amp + 3CS *Targeted Abx Therapy* S.pneu: vanco + 3CS (alt: meropenem, FQ) N.meningitidis: 3CS (alt: PCN, amp, FQ, aztreonam) Listeria: amp or PCN (alt: Bactrim, meropenem) S.agalactiae: amp or PCN (alt: 3CS) H.influenzae: 3CS (alt: 4CS, meropenem, FQ) E.coli: 3CS (alt: 4CS, meropenem, FQ, Bactrim, aztreonam) 7 day duration: N.meningitidis, H.influenzae 10-14 days: S.pneu 14-21 days: S.agalactiae 21+ days: listeria, aerobic GNB *Abx Therapy from Susceptibility Testing* S.pneu MIC <0.06: switch to PCN or amp S.pneu MIC 0.12+: switch to ceftriaxone or cefotaxime S.pneu 3CS MIC 1+: continue vanco + ceftriaxone N.meningitidis MIC <0.1: switch to PCN or amp N.meningitidis MIC 0.1-1.0: continue 3CS H.influenzae B-lactamase neg: switch to amp H.influenzae B-lactamase positive: continue 3CS *Dexamethasone Adjunctive Therapy* Can help with inflammatory response in subarachnoid space May protect from hearing loss in H.influenzae for children Adults with S.pneu may have decreased unfavorable neurologic outcomes *Prevention* VACCINATION: S.pneu, N.meningitidis, H.influenzae Chemoproph for high risk: rifampin (do NOT do this for S.pneu)

Acute Otitis Media (AOM)

*Pathophysiology* Rapid onset of signs and sx of inflammation in middle ear (region past the ear drum) Negatively effects eustachian tube (responsible for air pressure equilibration, nasopharyngeal secretion protection, drainage of middle ear into nasopharynx) Shorter eustachian tube in CHILDREN creates larger angle *Risk Factors* <2 years age Day care Male Recent URI Tobacco smoke exposure Bottle feeding (especially in bed) Pacifier use Sick contacts Race: native american, inuit, australian Allergies to things Immunodeficient Low socioeconomic status Cleft palate and other craniofacial abnormals *Presentation* Bulging and erythematous TM Purulent/cloudy TM Impaired TM mobility Hemorrhagic TM Ear tugging and excessive crying Irritability and difficult sleeping Decreased activity and appetite Fever *Classification* Uncomplicated: no discharge from ear Non-severe: mild otalgia (ear pain), temp below 39C Severe: mod-severe otalgia with temp 39C+ *Differentiations* Otitis Media with Effusion (OME): inflammation with liquid in middle ear (NO ACUTE INFECTION) Middle Ear Effusion (MEE): liquid in middle ear without any cause (NO INFLAMMATION) Otitis Externa: infection of auditory canal (Swimmer's Ear) *Etiology* Strep pneu H.influenzae Moraxella catarrhalis (B-lactamase ALWAYS) Can also be viral *Non Abx Treatment* Tylenol 10-15mg/kg Q4-6H (max 75mg/kg/day) Advil 5-10mg/kg Q6-8H (max 40mg/kg/day) Antipyrene/Benzocaine to fully fill ear canal Q1-2H *Determining Abx Treatment Needed* <6 mo: MUST USE ABX 6mo - 2 yrs: ABX USUALLY USED, except if only unilateral without otorrhea (can watch and wait) 2+ years: can watch and wait if AOM without otorrhea *Abx Treatment* FIRST-LINE: amoxicillin 80-90mg/kg/day Q12H (HIGH DOSE) OR Augmentin (14:1 ratio reduces diarrhea) Alternatives: cefdinir, cefuroxime, cefpodoxime, ceftriaxone (IM) If amoxicillin by itself used within 30 days, MUST USE AUGMENTIN Penicillin allergy: 3CS if mild, clindamycin if SEVERE Penicillin resist: clindamycin (limited against H.influenzae) FIRST-LINE AFTER FAILURE: Augmentin OR ceftriaxone (IM) Alternatives after FAILURE: ceftriaxone (IM), clindamycin with/without 2/3CS, tympanocentesis, specialist Duration: 10 day course if <2 years OR severe 7-10 day course if 2+ years DO NOT USE AZITRHOMYCIN: LIMITED EFFECT ON H.influenzae AND STREP

Endocarditis

*Pathophysiology* Trauma/injury to endocardial surface (usually cardiac valve) Surface deposition of platelets and fibrin Colonization of bacteria on platelet/fibrin Vegetation formation *Signs/Sx* Fever/night sweats Anorexia/weight loss Malaise Heart murmur Skin, oral mucosa, conjunctival petechiae (Janeway lesions) *Modified Duke Criteria for Infectious Endocarditis* Positive blood cultures: 2 separate positive cultures for HACEK group, viridans, strep gallolyticus, staph aureus Persistently positive blood culture (12+ hrs apart, 3/3 or 4+ cultures) Single positive culture for Coxiella burnetii or anti-phase 1 IgG antibody titer 1:800+ Envidence of endocardial involvement with ECG: oscilatting intracardiac mass on valve/supporting structures, abscesses, new valvular regurgitation Predisposing heart condition/IV drug use Fever 38C+ Vascular phenomena: embolism, septic infarcts, mycotic, aneurysm, intracranial hemorrhage, Janeway lesions Immunologic phenomena: glomerulonephritis, osler nodes, roth spots, rheumatoid factors Microbiologic evidence: positive cultures with organism consistent with IE but not meeting major criteria Definite IE: 2 major OR 1 major + 3 minor OR 5 minor Possible IE: 1 major + 1 minor OR 3 minor *Pathologic Critera for Infective Endocarditis* Microorganisms demonstrated in valve vegetation, or on vegetation that has embolized, or in intracardiac abscess Vegetation or intracardia absess present, confirmed by histology and showing active endocarditis *Diagnosis* Echocardigraphy (ECHO): transthoracic ECG (TTE), transesophageal ECG (TEE) REJECTED DIAGNOSIS: firm alternative dx explaining evidence of IE, resolution of IE with anti-infective therapy of <4 days, no pathologic evidence of IE after <4 days of anti-infective tx *Risk Factors* Injection drug use Previous endocarditis Valve disease: mitral valve prolapse, rheumatic fever, etc Prosthetic valve Poor dental hygiene Long-term dialysis DM *Microbiology* Viridans strep: MOST COMMON CAUSE, oral cavity common source, high cure rate with low mortality Staph aureus: SECOND most common cause, mostly seen in right-sided IE for IVDU, HIGH mortality rate Coag-neg staph: most common cause of prosthetic valve IE Enterococci: THIRD most common cause, HIGH mortality HACEK group (haemophilus, actinobacillus, cardiobacterium, eikenella, kingella): mostly mouth organisms Sometimes difficult to culture Large friable vegetations -> EMBOLI Enteric GN rods: RARE cause, most cases from IVDU, HIGH mortality Fungi (candida, aspergillus): RARE cause, most causes from IVDU or prolonged IV abx/parenteral nutrition, VALVES ARE USUALLY REPLACED

Encephalitis

*Pathopsychology* Inflammation of brain parenchyma Has similar presentation of meningitis, differentiation usually blurred *Presentation* Has similar presentation of meningitis, differentiation usually blurred AMS, motor/sensory deficits, altered behavior, personality changes, speech/movement disorders *Herpes Simplex Virus (HSV) Etiology* MOST COMMON CAUSEOF SPORADIC ENCEPHALITIS (HSV-1) SIGNIFICANT MORTALITY *Diagnosis* CSF analysis Viral culture (rarely does anything) PCR testing MRI to see temporal lobe involvement Brain biopsy (not used anymore when PCR exists) *Treatment* Acyclovir 10mg/kg IV Q8H over 1hr for 14-21 days NEEDS ADEQUATE HYDRATION

Duration of CAP Abx Flowchart

*Patient is receiving IV/oral abx for CAP* If MRSA: 7-21 days if no metastatic, 7-10 days if rapid improve If no MRSA: continue down *Initial Tx not active? Extrapulmonary Infx? Documented P.aeru/S.aureus/Legionella/uncommon bacterial infx? Necrotizing/empyema/lung abscess?* If yes to ANY: individualized duration based on response and comorbids If no to ALL: continue down *Afebrile for 48-72 hours? Supplemental O2 not needed unless for preexisting condition? No more than one of the following: HR 100+, RR 24+, SBP <90* If ALL apply: dc abx after 5-7 days If NOT all apply: continue abx until stable, reevaulate at 7 days

Pediatric Pulmonary Disorders in a Nutshell

*Peds CAP* Population: any age Sx: depends Pathogens: depends Tx: depends Prevent: vaccine Larger doses of amoxicillin/ampicillin/penicillin used to get past resistance *Croup* Pop: 6mo - 6 years Sx: barking cough Pathogen: parainfluenzae Tx: IM dexamethasone with racemic epi nebulizer Preventing: handwashing Almost always viral, DO NOT USE ABX Stay hydrated! *Bronchiolitis* Pop: <1 yr Sx: wheezing Pathogen: RSV Tx: albuterol, hypertonic saline (hospital) Prevention: handwashing, palivizumab (only for select pts) Almost always viral, NO ABX Stay hydrated *Pertussis* Pop: <1 yr (DEADLY) Sx: whooping cough Pathogen: Bordetella pertussis Tx: azithromycin or Bactrim Prevent: vaccine, PEP (select pts) Selection of abx depends on age INFANTS HIGHEST MORTALITY *APE-CF* Pop: anyone that has CF Sx: increased productive cough Pathogens: P.aeru, MRSA, others Tx: depends, but will usually double cover P.aeru Prevent: infection control guidelines, handwashing CF patients will have DIFFERENT PATHOGENS THAN TYPICAL RESP INFECTIONS Differents in PK/PD will make dosing abx DIFFERENT

Penicillin Class Antibiotics

*Penicillin G (Benzyl Penicillin)* Coverage: Treponema pallidum, Strep, Actinomyces, Enterococcus (NOT FAECIUM) Use: tertiary syphilis, late secondary syphilis, strep pyogenes (strep throat), narrow spectrum infx MOE: inhibit PBP by irreversibly binding to active site Resistance: MSSA, MRSA, anaerobic GNRs, all beta-lactamase, gram negatives in general Oral Analog: Penicillin VK 250-500mg Q6H ADJUST FOR RENAL FUNCTION CAUTION: HYPERKALEMIA *Nafcillin* Coverage: MSSA (and PSSA), strep (not better than penicllin G) Use: MSSA infection, skin and soft tissue infections with MSSA and strep MOE: inhibit PBP by irreversibly binding to active site Resistance: MRSA, gram negatives in general Oral Analog: Dicloxacillin 250-500mg Q6H Cefazolin is usually preferred over nafcillin due to cost and tolerance CAUTION: OVERDOSE IN CrCl <20-25, ESPECIALLY IN LIVER/KIDNEY DISEASE Monitor: serum creatinine (AKI), delayed skin rash, blood eosinophils (500+), renal biopsy if needed, ALT/AST for hepatitis *Ampicillin* Coverage: Strep, listeria, 70% H.influenzae, Enterococcus (NOT FAECIUM), some gram-negative (E.coil and Proteus) Uses: bacterial URI (children), meningitis in 50+ adults (listeria), enterococcus faecalis, CAP MOE: inhibit PBP by irreversibly binding to active site Resistances: MSSA, MRSA, many anaerobic GNRs, all B-lactamase Oral Analogs: Ampicillin 250-500mg Q6H, Amoxicillin 500-1000mg Q8-12H or 857mg Q12H or 80-90 mg/kg/day Q12H for children IV Ampicillin used for empiric meningitis and enterococcal infections If oral, Amoxicillin PREFRERRED due to possible precipitation of ampicillin, better absorption, tolerance *Ampicillin/Sulbactram (Unasyn)* Coverage: MSSA, H.influenzae (99% with BLI), Moraxella (100% with BLI), Strep pneumoniae, anaerobic GN, E.coli (75% with BLI) Use: bite wounds, SSTIs, E.faecalis MOE: inhibit PBP by irreversibly binding to active site Resistances: MRSA, anerobic GNRs 10% resist Oral Analogs: Augmentin 250 or 500 or 875mg/125mg, Augmentin ER 1000mg/62.5mg Augmentin for URIs, mild-moderate SSTIs, sinusitis, otitis media Do NOT use Augmentin susceptibility to predict Unasyn susceptibility *Piperacillin-Tazobactam (Zosyn)* Coverage: Strep, some enterococci, MSSA, GN, AmpC enterobacteriales (still avoid due to selective depression), pseudomonas aeruginosa (75%+) Uses: anaerobes, intra-abd infections, severe SSTIs, pneumonia (post-obstructive or aspiration) There is no oral analog Useful for sepsis with suspected pseudomonas Can add Vanco to cover MRSA (AKI RISK), usually step-off after 48 hours

UTI in Special Populations

*Pregnancy* More common in 2nd and 3rd trimesters Lower UTI: nitrofurantoin and cephalosporins Upper UTI: hospitalize for IV abx (amp-genta, extended-spectrum b-lactam) AVOID FLUOROQUINOLONES AND TETRACYCLINES AVOID BACTRIM IF 1ST TRIMESTER Duration: 7 days, proph can be given *Children* More common in boys below 6 months age (correlated with non-circumcision) Ages 1-6: UTIs more common in girls AVOID FLUOROQUINOLONES AND TETRACYCLINES Duration: 7 days *Men* All male cases of UTI are COMPLICATED Higher incidence 65+, BPH, urinary tract instrumentation E.coli most common organism Tx: drug choices SIMILAR TO WOMEN Duration: 7-14 days

Coccidiodes (Coccioidomycosis)

*Presentation* Fatigue Night sweats Dry cough CP, dyspnea, hemoptysis HA, arthralgia Fever Wt loss Erythema nodosum/multiforme Pulmonary infiltrates Hilar adenopathy Pleural effusions Pulmonary cavity Unexplained eosinophilia *Complications* Pulmonary: persistant PMN, cavitation, chronic fibrocavitary PMN, fulminant PMN, extrapulmonary dissemination *Risk Factors* Immunosuppression DM Preggo Race Elderly? *Treatment* AVOID TX FOR SELF-LIMITING, LOW-RISK FOR COMPLICATIONS Fluconazole, itraconazole (skeletal infx), posaconazole, voriconazole AmB for LIFE-THREATENING infx HAART therapy and CD4 count recovery for AIDS Fluconazole for solid organ transplant (infx during transplant may result in LONG-TERM OR LIFELONG AZOLE TREATMENT Disseminated bone/joint infx: LONG-TERM/LIFELONG AZOLE TX Meningitis: LIFELONG fluconazole Pregnancy: lipid AmB, may use azoles BUT DO NOT USE 1ST TRIMESTER

Primary Bacterial Peritonitis (Spontaneous Bacterial Peritonitis or SBP)

*Presentation* Fever (80% OF CASES) Ascites Abd pain/tenderness (may NOT always be present) Encephalopathy, malaise, fatigue -> POSSIBLE CIRRHOTIC *Diagnosis* Ascitic fluid infx with no surgical treatable source Ascitic fluid gram stain + culture Elevated ascitic fluid absolute polymorphonuclear leukocyte (PMN): 250+ Blood culture *Etiology* E.coli + Kleb pneu (70% of cases) S. pneu and other streptococci (25% of cases) Rare: staph, anaerobes *Treatment: COVER GRAM-NEG AEROBIC BACILLI AND GRAM-POST COCCI* Empiric coverage NOT required Cefotaxime 2g IV Q8H Alt: ceftriaxone 2g IV daily Response seen <72hrs Should last for 5 days if rapid improvement Drainage NOT required *SBP Flowchart* Suspicion of SBP due to sx -> diagnostics: fluid culture, blood culture, urine/sputum culture, PMN IMMEDIATELY START: cefotaxime If SCr 1+, BUN 30+, or bili 4+: ALSO START IV ALBUMIN

Septic Arthritis

*Presentation* Inflammatory rxn within joint space causing destruction of cartilege and bone Primarily hematogenous Sx: Fever, painful swelling joints, dec ROM, tenderness, warmth, redness *Risk Factors* Preexisting arthritis Chronic illnesses DM Trauma Steroid use *Diagnostics* ESR, EBC, cultures Synovial fluid aspirate: leukocyte count 50-150k, gram stain *Nongonococcal Septic Arthritis* Mostly staph, but can have strep and gram-neg bacilli Infants <1 month: vanco + aminoglycoside Children <5 yrs: Vanco with/without H.influenzae coverage Children 5+ yrs and adults: vanco IV drug abusers: pseudomonas coverage Duration: 10-21 days *Gonoccocal Septic Arthritis* Mostly Neisseria gonorrhea Can get growths/vesicles near the joint Ceftriaxone ABX OF CHOICE Duration: 10-21 days *Management* Surgery Joint drainage and rest

Pressure Ulcers

*Presentation* Pressure injury over bony prominences due to immobility Can hold resistant pathogens *Management* Nutrition Wound healing and care: dressing changes, debridement Tx of infection: silver containing antiseptics, deep infx

Medications for UTIs

*Principles* Uncomplicated cases require ONLY short-course therapeutic urine abx levels (enough to just wash through the kidneys and tract but NOT enough to absorb into other tissues) Complicated cases requires tissue abx levels with longer course Oral PREFERRED unless NPO or critically ill BEWARE RESISTANCE *Trimethoprim-Sulfamethoxazole (TMP/SMX): Bactrim, Septra* Generally well-tolerated Low costs Dosing: 160/800mg BID x3days Can be resisted by E.coli Monitor: K (prolonged use can cause HYPERKALEMIA) AVOID IF SULFA ALLERGY BEWARE SJS/TENS DOSE ADJUST FOR RENAL DYSFUNCTION (CrCl <30) -> ACCUMULATION *Nitrofurantoin: Macrobid* For both tx and proph Low cost Tx Dosing: 100mg BID x5 days Long term proph dosing: 50-100mg daily Resistances uncommon Does NOT work as quickly as other drugs Monitor: liver to prevent cholestasis AVOID PYELONEPHRITIS AVOID IF CrCl <30 CAUTION: RISK OF PULMONARY TOXIC *Fosfomycin* Singular dose for uncomplicated UTI VERY EXPENSIVE (80-120 dollars) Dosing: 3gm single dose Susceptibility testing not frequently done in US Can cover a bunch of other stuff (VRE, pseudomonas, ESBL, klebsiella carapenemase KPC) AVOID IN PYELONEPHRITIS *Fluoroquinolones: Cipro, Levofloxacin, Delafloxacin* Can be used in renal dysfunction! (DOSE ADJUST) Cipro Dose: 250-750mg BID x3 days OR 500mg ER x3 days Levo Dose: 250-750mg daily x3days E.coli resistance varied DO NOT USE MOXIFLOXACIN: DECREASED URINARY EXCRETION WARNING: TENDON RUPTURE, QTc PROLONG *Beta-Lactams (amoxicillin, Augmentin) + Cephalosporins (cephalexin, cefadroxil, cefuroxime, cefaclor, cefpodoxime, cefdenir)* Duration: 3-7 days Frequency: 2-4 times daily Oral B-lactams LESS EFFECTIVE than other agents PENICILLIN ALLERGIES Adjust dose at CrCl cutoffs *Using IV Abx for UTIs* Fluoroquinolones Aminoglycosides (only IV) Cephalosporins B-lactam + B-lactamase inhibitor Carbapenems Monobactam Glycopeptide *Non-Abx Therapy* Hydrate, but do NOT overhydrate (reduces abx concentration) Phenazopyridine (Azo): urinary analgesic for dysuria, use an actual analgesic for SEVERE pain Cranberry Juice: NO EVIDENCE FOR EFFICACY

Surgical Site Infection Antibiotics

*Prophylaxis* Cefazolin: STANDARD Cefoxitin: bacteroides fragilis and/or anaerobic coverage *Elective Surgery Proph* Abd/Vaginal Hysterectomy: cefazolin/cefoxitin/cefuroxime Hip/Knee Arthroplasty: cefazolin/cefuroxime Cardio/Vascular: cefazolin/cefuroxime Oral Regimen for Colorectal: neomycin + erythromycin / neomycin/metronidazole Parental Regimen for Colorectal: cefoxitin / cefazolin + metrodiazole or ertapenem *Elective Surgery Proph if Allergic to Above* Abd/Vaginal Hysterectomy: Clinda + Gent / Clinda + Cipro / Metro + Gent / Metro + Cipro Hip/Knee: Vanco/Clinda Cardiovascular: Vanco/Clinda Colorectal: same as abd/vag *Abx During the Procedure* 2 hours into surgery: shorter-acting (cefoxitin) 4 hours into surgery: longer-acting (cefazolin) *Indications for Vanco during Surgery* B-lactam allergy Prior MRSA history High risk due to hospitalization or LTC setting in past year Inc MRSA facility-wide Procedure specific Chronic wound care or dialysis Continuous inpatient stay 24+ hours before procedure *Timing of Abx* BEST GIVEN DURING INDUCTION OF ANESTHESIA AND BEFORE THE FIRST CUT NO EVIDENCE OF BENEFIT GIVING ABX AFTER PROCEDURE Recommended to NOT give abx more than 24 hours

HCV (Hepatitis C Virus) Targets

*Protease Inhibitors* First Gen: telaprevir, boceprevir (covalent, reversible) Second Gen: simeprevir, paritaprevir *NS5A/B Polymerase Inhibitors* NS5A: ledipasvir, ombitasvir NS5B: sofosbuvir (nucleotide analog), dasabuvir (non-nucleotide analog)

Targeted Testing for Tuberculosis

*Purpose* Find people with LATENT TB INFECTION (LTBI) who would benefit Find people with ACTIVE TB who would benefit *Targeted Groups for Testing* Close contacts Foreign-born persons from TB endemic areas Residents/employees at high-risk congregate settings HEALTHCARE WORKERS SERVING HIGH-RISK CLIENTS Medically underserved, low-income pops High-risk racial/ethnic minority pops Children exposed to adults in high-risk categories Illict drug users

Susceptibility Testing

*Purpose* Growth of bacteria to measure ability of abx Uses well-standardized media with defined additives for certain bacteria *Interpreting AST* Susceptible (S): probability of efficacy with usual dosing and routes and kinetics acceptable Intermediate (I): probability of efficacy may be acceptable if HIGHEST DOSE is used Susceptible Dose Dependent (SDD): similar to I, HIGHEST DOSE used Resistant (R): probability of efficacy low, USE ALTERNATIVE *Breaking Points* Epidemiologic: characterizes wild-types from deviations on organism strains only Pharmacodynamic: defines relationship between exposure and outcome (Time > Minimum Inhibitory Concentration MIC of 70% usually positive outcomes) Clinical: evidence of reduced efficacy at MIC threshold

Active TB Treatment

*RIPE Therapy: RIF, INH, PZA, EMB* Duration of TWO MONTHS for the initial phase Rifampin (RIF) is the BACKBONE of this therapy Dose: 10mg/kg daily capsules or injectable ADE: rash, GI, hepatotoxic DDI as CYP3A4 inducer May DISCOLOR secretions Isoniazid (INH) Dose: 5mg/kg once daily tablets, syrup, injectable ADE: asx increase in AST/ALT, hepatitis, PERIPHERAL NEUROPATHY Pyrazinamide (PZA) Dose: 20-25 mg/kg daily tablets ADE: MAJOR HEPATOTOXIC, GI, polyarthralgias, uric acid increase Adjust dose in RENAL FAIL Ethambutol (EMB) 15-20 mg/kg daily tablets ADE: MAJOR OCULAR TOXIC, rash, least hepatotoxic After two months: reduce to RIF + INH for FOUR MONTHS as continuation phase Extend continuation duration if initial CXR shows CAVITARY DISEASE or cultures at 2 months are POSITIVE *Vitamin B6: Possible 5th Drug* Dose: 25-50mg per day Best for MALNOURISHED pts on INH to prevent neuropathy Also best for pts prone to neuropathy (DM) *HIV Negative Treatment* Include ALL of RIPE for initial phase Adjust regimen when susceptibility known Can drop EMB if INH + RIF susceptible, BUT KEEP PZA FOR TOTAL 8 WEEKS *HIV Positive Treatment* Include ALL of RIPE for initial phase Rifampin regimens recommended for: HIV pts NOT on antiretroviral and PIs/NNRTIs not recommended (rifampin can still be used with some PIs/NNRTIs) For patients receiving PIs or NNRTIs: replace rifamycin with rifabutin OR non-rifamycin drug like streptomycin (SM) *Special Population Tx* Extrapulmonary TB: same regimen (RIPE) Pregnant: nine months of RIF + INH + EMB Children: same regimen as adults Bone/Joint/Miliary TB, TB Meningitis in Children: treat for MINIMUM OF 12 MONTHS Infants: DO NOT WAIT FOR LABS, TX IMMEDIATELY IF SUSPECTED *Ensuring Adherence* Tx is long and complicated... BUT THE PATIENT MUST DO IT CORRETLY Directly Observed Treatment Short-Course (DOTS): healthcare worker MUST WATCH PT SWALLOW EACH DOSE Consider DOT for ALL PATIENTS for ALL REGIMENS *Monitoring Response* Evaluate patient MONTHLY until cultures are negative After TWO MONTHS of therapy and cultures are positive or sx do not resolve: consider resistance and nonadherence Monitor baseline measures and individualized ADEs Tell pt to IMMEDIATELY report ADEs *Determing Infectiousness* Infectious: coughing, positive smear, not receiving therapy, just started therapy, poor response to therapy Non-infectious: adequate therapy, significant response to therapy, 3 consecutive negative smears *Pharmacist Reporting* Pharmacist filling 2+ drugs of a certain list of medications MUST REPORT THIS TO THE STATE HEALTH DEPARTMENT WITHIN 5 WORKING DAYS OF FILLING THE RX

Microbiomes

*Skin* Sebaceous: cutibacterium acnes Moist: staph spp. (INCREASED IN CHILDREN), cornyebacterium spp. Dry: cutibacterium acnes, strep spp. Fungi (lower in #s): malassezia, aspergillus (foot), cryptococcus (foot) *GI Tract* Firmicutes, Bacteroides, Proteobacteria, Actinobacteria Stomach: H.pylori can cause PUD, gastritis, immune disorders Jejenum: 28% is strep, 20% is proteobacteria (mostly E.coli) Colon: 57% are firmicutes, 30% are bacteriodetes Dysbiosis is imbalance of flora and can cause IBD, autoimmune diseases, etc (RIFAXIMIN useful for IBS) *Vagina* Lactobacillus spp. predominant Decrease in lacto and increase in everything else is dysbiotic

Traveler's Diarrhea

*Sources* Raw/undercooked food Drinking water Dairy products *Onset and Duration* Starts in about 1 week after exposure Lasts for about 3-4 days, USUALLY SELF-LIMITING *Bacterial Etiology* E.coli (80% OF INFX) Shigella Campylobacter Salmonella Viruses *Treatment* Mild: do NOT use abx, MAY USE loperamide/BSS Moderate: can use abx, do NOT use loperamide if bloody stools or diarrhea WITH fever, can use loperamide BY ITSELF Severe: USE ABX (azithromycin preferred), can use FQs/rifaximin if NONDYSTENTERIC

HCV Medications

*Ribavirin* Used for sustained virologic response Used in ALL decompensated cirrhotic patients unless ineligible ADEs: MI, anemia, hyperbilirubinemia, HA, cognitive stuff, depression/irritability, TERATOGENIC CIs: UNSTABLE/SIGNIFICANT HEART DISEASE, PREGNANCY (UNTIL 6 MONTHS AFTER TX) DISCONTINUE IF: WBC: <1k ANC: < 500 cells Hgb: <8.5 Plts: <25 *Harvoni: sofosbuvir/ledipasvir* NS5A+NS5B inhibitor Approved for genotypes 1,4,5,6 (less recommendation with 5,6) Used for both pts with/without cirrhosis (add ribavirin for decomp cirrhosis) Duration: 8wks (if meet criteria), 12wks (normal), 24wks (decomp cirrhosis pts that cant have ribavirin) ADE: fatigue, HA, irritability, rash DDIs: amiodarone, PPIs, P-gp inducers, CYP3A inhibitors If taking antacids: separate by 4 hours If taking H2RAs: may take together or 12hrs apart If taking PPIs are a MUST: take Harvoni and PPI at the same time in the morning on an empty stomach *Epclusa: sofosbuvir/velpatasvir* NS5A+NS5B inhibitor Approved for all genotypes (1-6), but preferred for 3-6 Used for both cirrhosis/non-cirrhosis (add ribavirin for decomp cirrhosis) Duration: 12wks (normal), 24wks (decomp cirrhosis without ribavirin) ADE: fatigue, HA, N/V, rash DDIs: DDIs: amiodarone, PPIs, P-gp inducers, CYP3A inhibitors If taking antacids: separate by 4 hours If taking H2RAs: may take together or 12hrs apart If taking PPIs are a MUST: take Epclusa with food, take PPI 4 hrs after Epclusa *Vosevi: sofosbuvir/velpatasvir/voxilaprevir* NS3/NS4A + NS5A + NS5B inhibitor Used for all genotypes Reserved for pts who already tried a HCV medication Duration: 12wks ADE: fatigue, HA, N/D, rash DDIs: amiodarone, PPIs, P-gp inducers, CYP3A inhibitors, DO NOT USE ATANZANVIR *Mavyret: glecaprevir/pibrentasvir* NS3/NS4A + NS5A inhibitor Used for all genotypes Most common HCV medication (low cost, short duration) Do NOT use for decomp cirrhosis Duration: 8wks (naive, non-cirrhotic, compensated), 12wks (HIV + compensated cirrhosis) ADE: N, HA, fatigue DDIs: amiodarone, PPIs (maybe), P-gp inducers, CYP3A inhibitors *Zepatier: elbasvir/grazoprevir* NS3.NS4A + NS5A inhibitor Used for genotypes 1 and 4 (also good efficacy with 3 and 6) Used for comp cirrhosis (do NOT use for decomp) Duration: 12wks (normal), 16wks for baseline RAS to elbasvir (add ribavirin) ADE: fatigue, HA, irritability, mild chance to increase LFT DDI: NO interactions with PPIs, P-gp inducers/inhibits, CYP3A inhibits

Targeting RNA Polymerase

*Rifamycin* For mycobacteria (tuberculosis, leprosy, MAC) Inhibit DNA-dependent RNA Polymerase Usually used in combo with other drugs

Acute Tracheobronchitis

*Risk Factors* Cold climate Smoking Air pollution *Etiology* Common cold viruses Influenza Adenovirus RSV Chlamydophila pneumoniae, mycoplasma pneumoniae, bordetella pertussis Ozone, NH3, Cl, SO2 in the air *Presentation* Cough: either productive or nonproductive Afebrile or low-grade fever Preceded by cold sx Coarse breath sounds, expiratory wheezes *Diagnosis* Clinical, rule out other causes of cough If pertussis suspected: nasopharygneal swab *Treatment* HYDRATION Antipyretics if fever Antitussives: dextromethorphan, codeine EXPECTORANTS ARE NOT EFFECTIVE Bronchodilators: b2 only tx with effect, may require 6-8 wks Steroids: inhaled or systemic Abx NOT indicated unless long duration, high-risk, or pertussis suspected (macrolide, doxy) *Antiviral Tx* Influenza: oseltamivir (Tamiflu) Parainfluenza: self-limit RSV: self-limit COVID: none Adenovirus: self-limit Rhinovirus: self-limit *Abx Tx* Bordetella pertussis: macrolides FIRST LINE (azithro/erythro/clarithomycin), Zosyn SECOND LINE Mycoplasma pneumoniae: azithromycin/doxy, can be self-limit Chlamydophila pneumoniae: azithromycin/doxy, can be self-limit

Invasive Candidiasis

*Risk Factors* Non CNS major surgery Neutropenia High dose steroids DM Central venous access device (ESPECIALLY WITH PARENTERAL NUTRITION) *Etiology* Albicans MOST COMMON Glabrata has some resistance to azoles Krusei has FULL RESISTANCE TO AZOLES Tropicalis associated with hemotologic cancer Parapsilosis usually environmentally acquired, also contaminated medical stuff Auris has MDR *Diagnosis* Collect culture BUT DO NOT WAIT FOR REPORT Positive culture NOT ENOUGH to confirm: use Fungitell assay, T2 Candida panel *Candidemia* Fluconazole first line (DO NOT USE FOR GLABRATA OR KRUSEI) Echinocandin if resistant to fluconazole Lipid AmB: alternative if neutropenic or risk for mold infx *Candiduria* Does pt have marker of invasive disease? Localized UTI sx? Urinary obstruction? Tx (NOT INDICATED FOR MOST): fluconazole, AmB, 5-FC Echinocandins and most azoles have VERY LOW URINARY CONCENTRATIONS *Empiric Therapies* For high risk invasive infections: febrile neutropenia unresponsive to GN coverage and anti-MRSA, HSCT, BMT, immunosuppression *Prophlaxis* Usually for critical care and trauma ICU has a HIGH RATE of invasive candida Risk versus benefit: proph prevents IFI but increases resistance and shift towards resistant species

Mucorales (Mucormycosis)

*Risk Factors* Uncontrolled DM and ketoacidosis Immunocompromised Voriconazole exposure (relatively rare) *Management* Extensive and repeated debridement Reduce immunosuppression Control DM *Initial Tx* Lipid AmB: general, brain, SOT Posaconazole and Isavuconazole: preexisting renal dysfunction, oral step-down from AmB if stabilizing AVOID DEOXYCHOLATE AmB *Salvage Tx* Liposomal AmB: progressive Isavuconazole/Posavonazole: progressive, toxicity from first option

Hepatitis C

*Routes of Transmission* Primary: IVDU, blood/organ donations, needlesticks, birth from HCV+ mother Uncommon: sharing vectors that may have HCV+ blood, sex *Risk Factors* IVDU Received blood before July 1992, or received clotting factor concentrates before 1987 Chronic hemodialysis HIV positive individuals Persons with known exposures (needlesticks) *Pathophysiology* Acute: HCV infection increases IFNa/y to block viral replication (however only 30% completely eliminates virus) Chronic: Infected hepatocytes eventually become necrotic (ISG expression in 50% of chronic patients) Liver cirrhosis and hepatocellular carcinoma: liver become cirrhotic -> hyperplastic/dysplastic liver nodule -> carcinoma (15-25% of CHC get cirrhosis, 3% of cirrhotic patients get carcinoma) *Transcription Factors* NS3/NS4A: protein complex that cleaves HCV polypeptide NS5A: promotes viral reproduction by inhibiting hepatocyte cell defenses NS5B: codes for RNA-dependent RNA polymerase (no proofreading capability) *Genotypes* Genotype 1a/b: most common (1a makes up 2/3 of cases with LOWER CURE RATE) Genotype 3: most difficult to manage with faster fibrosis *Diagnosis* Test for HCV antibody If nonreactive: no HCV, may or may not test for RNA If HCV antibody reactive: test for HCV RNA If not detected: no infection, but can do additional testing if needed If HCV RNA detected: current infection *Who to test for HCV* One time testing for people born between 1945-1965 IVDU Received HD Received blood products/organs before routine HCV screen Children born to HCV+ mothers Anyone potentially exposed (needlesticks) HIV Incarceration at any point Prior to starting PrEP Solid organ donors Unexplained liver disease or hepatitis *Pharmacy Roles in HCV* Renal function (not as important anymore) Liver status: cirrhosis often requires therapy mods DDIs Age/race/sex: may alter tx duration (PREGNANY SHOULD BE AVOIDED DURING HCV TX) *FIB-4 Estimations* A preferred way to identify cirrhosis 3.25+ indicates likely cirrhosis *Child-Pugh Scoring* Determines if cirrhosis is compensated or decompensated Class A (compensated): 5-6 pts Class B (decompensated): 7-9 pts Class C (decompensated): 10-15 pts *BLACK BOX WARNINGS* TREATING HCV MAY REACTIVATE HBV (CAN LEAD TO DEATH) ENSURE CHRONIC HBV IS BEING TREATED AND MONITOR CLOSELY *Critical Factors to Consider when Tx HCV* Insurance will likely NOT APPROVE tx for IVDU (may need 6+ months or more of negative drug screens to consider) Adherence: DO NOT START IF ANY DOUBTS ABOUT ADHERENCE Urgency: HIV, genotype 3, chronic HBV coinfection *Missing Doses and Nonadherence* Make pt keep log of administration times If forgot: take med as soon as remembered If dose missed: add them to end of therapy (NEVER STOP AT 12 WEEKS EXACTLY IF TABLETS STILL REMAINING) 1-3 missed doses MIGHT be okay, but insurance might deny more fills if they notice lack of adherence (unless on medicare) *Inpatient Considerations* TAKE YOUR MEDICATION WITH YOU TO THE HOSPITAL: they will NOT have these very expensive meds on formulary (very common cause of therapy interruption and fail) WORSENING LIVER DISEASE TX MAY WIPE OUT HCV TX: high dose PPI may wipe out meds so try to lower dose (if no compromise can be reached, just stop HCV therapy)

Hepatitis B

*Routes of Transmission* Sex: semen, vaginal fluid Sharing needles Birth from infected mom Needlesticks Sharing items that could have broken skin/mucous membranes (razors, toothbrushes, etc) HIGHLY INFECTIOUS AND CAN SURVIVE IN THE ENVIRONMENT FOR 7 DAYS Can be present in sweat, tears, urine, breast milk, saliva (low concentrations, usually not a problem) *Who to Screen* Persons born in regions of high/intermediate HBV: Africa, N/SE/E Asia, Aussie, South Pacific, Middle East (except Israel), Eastern Europe (except Hungary), Spain, Malta, Greenland, Alaska, northern Canada, Guatemala, Honduras, Ecuador, Guyana, Suriname, Venezuela, Amazon area, Carribeans US people not vaxxed as infant and parents born in high HBV area IVDU Homo sex Immunosuppressed Elevated ALT and AST due to unknown reasons Blood/organ donors HSRD, ESRD, dialysis in general All preggos Infants born to HBsAg+ mothers People with chronic liver disease like HCV HIV Needle-sharing or sexual contact with HBsAg+ people People not in long-term, monogamous relationships People seeking evaluation/tx for STD Healthcare workers at risk for occupational exposure to blood/blood-contaiminated body fluids Residents and staff of facilities for developmentally disabled people Travelers to countries with intermediate/high HBV Inmates, incarcerated people Unvaxxed people with DM aged 19-59 *Who to Vax if Seronegative* US people not vaxxed as infant and parents born in high HBV area IVDU Homo sex Elevated ALT and AST due to unknown reasons HSRD, ESRD, dialysis in general People with chronic liver disease like HCV HIV Needle-sharing or sexual contact with HBsAg+ people People not in long-term, monogamous relationships People seeking evaluation/tx for STD Healthcare workers at risk for occupational exposure to blood/blood-contaiminated body fluids Residents and staff of facilities for developmentally disabled people Travelers to countries with intermediate/high HBV Inmates, incarcerated people Unvaxxed people with DM aged 19-59 *Stages of HBV* Acute (but not really acute): takes about 60 days to see ALT elevations and 90 days for jaundice, some may be asx (but 30-50% of people are sx), general malaise before jaundice Chronic: 4 different phases of chronic that are not in order and can bounce between different phases, HBsAg+ persists for 6+ months *Phases of Chronic HBV* Immune tolerance: HBsAg+, very high HBV DNA Immune clearance: High ALT, HBsAg+, variable HBV DNA, significant liver histology Inactive carrier: HBsAg-, positive anti-HBs, undetectable HBV DNA Reactivation: high ALT, HBsAg-, anti-HBs, variable HBV DNA (lower than positive infection), significant liver histology

Vascular Access Infections Flowcharts

*SHORT-TERM* *LONG-TERM*

Severe Malaria Flowchart

*Severe Malaria OR pt cannot tolerate oral medication no matter the species* Admit to ICU and CALL CDC IV artesunate If artesunate available: follow-up with Coartem or Malarone or quinine + doxy/clinda or mefloquine (LAST RESORT) If artesunate unavailable: Coartem or Malarone or quinine or mefloquine (LAST RESORT) Monitor parasite density every 12-24 hours

Maintenance Immunosuppression Regimens

*Standard of Care (FIRST-LINE)* Tacrolimus Mycophenolate mofetil With or without prednisone *Second-Line Alternatives* CNI (TAC, CSA) with/without antimetabolite (MMF, azathioprine) mTOR Prednisone *Third-Line Alternative* Belatacept Everolimus Prednisone

Transplant Rejection

*Sx of Rejection* Heart: SOB, hypotension, tachycardia, atrial flutter, vent arrhythmias Kidney: decreased urine output, wt gain, edema, HTN Intestine: GI sx, fever Liver: encephalopathy, jaundice, ascites, ileus, anorexia Lung: SOB, impaired gas exchange, malaise, anxiety Pancreas: abd pain, ileus, malaise *Lab Signs of Rejection* Heart: leukocytosis, biopsy positive mononuclear infiltrates Kidney: inc SCR/BUN, leukocytosis, biopsy positive lymphocytic infiltration Intestine: biopsy Liver: abnormal LFTs, increased bilirubin/AP/ALTs, biopsy positive with tissue damage Lung: CXR infilitrate, decreased FEV, biopsy positive Pancreas: hypergly, leukocytosis, decreased C-peptide, urine amylase *Stages of Rejection* Hyperacute: usually in the operating room due to mismatch Acute: rejection within first 3 months Chronic: over extended period of time -> slow failure of organ *Cellular Rejection* Direct attack of allograft by T-cells Risks: delayed graft function, retransplant, PRA 50%+, low immunosuppression dosing/levels, poor adherence Tx: pulsed steroids, thymoglobulin, increased maintenance immunosuppression, consider restarting infx proph *Antibody Mediated Rejection* Activated RECIPIENT B-cells produce antibodies to allograft -> mark organ for destruction Risks: positive cross match, preformed ab Tx: plasmapharesis, IVIG, rituximab

Fluoroquinolone Safety

*Tendinopathy* Levo > Cipro with incidence Onset: earliest of 2 days to 6 months post exposure (50% of cases occur within 14 days) Presentation: insertional, abrupt pain but can happen without it Risk Factors: elderly, athletes, steroid use, male, normal BMI, chronic renal disease *Aortic Aneurysm* Incidence: 16/100000 males, 9/100000 females Risk Factors: age, smoking, HTN, DM, Marfan Syndrome 50%+ mortality with aortic rupture *FQ-Induced Neuropathy* Sensory Sx: burning, numbness, pain, loss of reflexes, loss of sensation to touch Motor Sx: muscular weak, problems with mobility, coordination, respiration Metronidazole worse, but FQ shown to also have a higher risk *CNS Toxicity* Seizures: FQs can bind to GABA receptors and inhibit CYP-1A2 (inc exposure to caffeine/theophylline) Acute Encephalopathy: unknown relationship, but cephalosporins and Pencillin G also shown to cause this *Psychiatric ADEs* Acute Psychosis/Delirium: 3.6% for Cipro, 4.5% for Moxi, very few cases for Levo Mania/Hypomania Acute anxiety + insomnia: observed in Levo *Myasthenia Gravis: autoimmune disease directed at nicotinic receptors* 20/100000 incidence, females <30 yrs, males 50+ Sx (5 Ds): diplopia/pitosis, dysarthria, dysphagia, dyspnea, descending weakness Other drugs that cause MG: aminoglycosides (HIGH RISK), ketolide like telithromycin (HIGH RISK), macrolides, hydroxychloroquine *QT Prolongation (Torsades de Pointe)* Blocks HERG channels Risk Factors: HypoK/Mg, bradycardia, underlying CVD, SHD, female, prolonged QT at baseline, Levo worse than Cipro, concomitant drugs that prolong QT, impaired drug elim, congenital long QT syndrome Concomitants: Class III antiarrythmics (amiodarone, sotolol, dronedarone), macrolides, azole antifungals (fluconazole), and more Rare, but 20-40 per million incidence CAUTION WITH QTc 500+ ms *Phototoxicity* Unclear if fully FQ effect Drugs are directly toxic to skin cells, but the addition of UA-A light makes them toxic AVOID EXTENSIVE SUN EXPOSURE UV-ACTIVATED FQ ARE POTENTIALLY CARCINOGENIC *Dysglycemia* Hypo: greater risk after first exposure Hyper: after several days of exposure due to anti-insulin hormones, Levo worse than Cipro *Collateral Damage to Flora* Main reason why FQs ARE NOT FIRST-LINE for uncomplicated UTI: nitrofurantoin has MINIMAL effect on flora Can supress enterobacterales and increases resistance of enterobacterales + ESBL Increases odds of MRSA Levo worse than all *C.diff Infection* NAP1/BI/027 strain associated with MOXIFLOXACIN use (and less so other FQs) Has HIGH-LEVEL FQ RESISTANCE with INCREASED TOXIN PRODUCTION

HBV Medications

*Tenofovir* Both formulations (disoproxil fumurate, alafenamide) PREFERRED agents Widespread use in chronic HBV and HIV Mech: competitively inhibits HBV DNA polymerase Improves fibrosis/cirrhosis, reduces risk of carcinoma, can work for HBV resist to other things *Tenofovir Disoproxil* High success, easy to tolerate ADE: decreased bone density, increased renal dysfunction, GI ADE when initiating DO NOT USE IF CrCL < 60 *Tenofovir Alafenamide* New and improved formulation with even lower rates of ADE More susceptible to P-gp effects DO NOT USE IF CrCL < 15 (can use in HD pts) DO NOT USE IF PREGGO *Entecavir* Another PREFERRED agent Equal benefits to TFV but less barrier to resists Mech: inhibits HBV polymerase as guanosine analogue Low rate of ADE even at long-term use ADEs: HA, nausea, ALT increase, lactic acidosis (RARE), hepatomegaly (RARE) Dosing: 0.5mg daily if naive, 1mg if lamivudine-experienced OR decomp cirrhosis Dose adjust if CrCl <50 HAS CROSS-RESIST TO LAMIVUDINE: use tenofovir instead *Adefovir* Worse than tenofovir at everything Less active and slower-active ADE: HA, nausea, abd pain, renal toxic (UNCOMMON) Can develop resist: use tenofovir to get past this *Lamivudine* Well-tolerated, but does nothing High resist rates Usually in a dual-drug regimen Mech: cytidine analogue ADE: nausea, bloating *Emtricitabine* Structure is EXTREMELY SIMILAR TO LAMIVUDINE Cross-resist to lamivudine Usually used for HBV + HIV coinfections: dual regimen of emtricitabine + TFV (all PrEP and most PEP) *PegIFN* Very small niche that is NOT for everyone (only ones that want a shorter duration) DO NOT USE IN DECOMP CIRRHOSIS Genotypes A/B more responsive, higher ALT has better outcomes, lower HBV DNA has better outcomes Weekly injectable that be continued for more than one year in resist pts ADE: GI problems, flu-like sx, cognitive problems, HA, alopecia, ALT increase, inj site reaction, neutropenia

Other Antifungals

*Terbinafine (Lamisil)* Coverage: dermatophytes (tineas), C.albicans (poor) Uses: onchomycosis, dermatophyte infx 99%+ BOUND TO PROTEINS EXTREMELY HIGH HALF-LIFE ADE: liver fail, neutropenia, skin rash (rarely serious) Inhibits CYP2D6 enzymes DO NOT TAKE WITH RIFAMPIN *Griseofulvin* Mech: inhibits fungal mitosis by interacting with microtubules Coverage: only dermatophytes (tineas) Uses: 2nd line superficial dermatophyte infx (oral), 2nd line onychomycosis Worse than terbinafine but works FASTER EAT WITH FATTY MEAL ADE: HA, CNS problems

Antibiotic Stewardship

*The Five Rs* Right PATIENT Right TIME Right DRUG Right DOSE Right ROUTE *Empiric Therapy* Treating the most likely causative organisms without a diagnostic confirmation Consider susceptibility patterns: risk factors for resistance, site of infection, kinetics, physiologic alterations *Design Dose Regimen* Site of infection Pathogen with MIC Pharm Dynamic target Dose/Route/Frequency to optimize PK/PD ADJUST for renals, body size, etc *Antibiotic Stewardship* Is antibiotic therapy appropriate? If so, initiate empiric therapy Reevaluate selections based on culture results and susceptibility results Escalate or deescalate (streamline, IV/PO switch, stepdown) Consider appropriate duration Consider costs, ADEs, and convenience

Treating Endocarditis

*Two-Fold Management* Antibiotic therapy SURGICAL therapy: valve replacement due to severe failure, drain peri-valvular abscesses *Empiric Treatment* Evaluate risk factors *Native Valve IE from viridans (VGS) or strep gallo* Penicillin MIC <=0.12 mcg/mL 4 weeks of penicillin G, ceftriaxone, vanco (if B-lactam allergy) 2 weeks (if uncomplicated, rapid response, no renal disease) of pencillin G + gentamicin, ceftriaxone + gentamicin Penicillin MIC 0.12-0.5 mcg/mL 4 weeks of penicillin G + (gentamicin x2 weeks), ceftriaxone + (gentamicin x2 weeks), vanco Penicillin MIC 0.5+ mcg/mL 4 weeks of penicillin G + (gentamicin x2 weeks), ceftriaxone + (gentamicin x2 weeks), vanco *Prosthetic Valve Endocarditis from Strep* Same as native VGS, but increase to SIX WEEKS *Strep Pneumoniae* Native valve endocarditis (NVE): penicillin, cefazolin, ceftriaxone, vanco x4 weeks Prosthetic valve endocarditis (PVE): same as above BUT SIX WEEKS Vanco + rifampin + cefotaxime (or ceftriaxone) depending on resistance *Strep Pyogenes* Penicillin G or ceftriaxone or vanco x 4-6weeks *Groups B,C,F,G B-hemolytic strep* Penicillin or ceftriaxone x 4-6 weeks + gentamicin for initial 2 weeks if applicable *Native Valve Endocarditis from Staph* Cefazolin Nafcillin/oxacillin Vanco Duration: 6 weeks uncomplicated, 6+ weeks complicated *Prosthetic Valve Endocarditis from Staph* 6+ weeks of nafcillin/oxacillin + rifampin (+ genta x2weeks if applicable), vanco + rifampin (+ genta x2weeks if applicable) *Native/Prosthetic Valve Infx from Enterococci susceptible to penicillin, genta, vanco* 4-6 weeks of ampicillin + gentamicin, penicillin G + gentamicin, double B-lactam (ampicillin + ceftriaxone), vanco + genta *Native/Prosthetic Valve Infx from Enterococci resistant to penicillin* 6 weeks of amp + genta, vanco + genta *Native/Prosthetic Valve Infx from Enterococci resistant to penicillin/genta/vanco* 6+ weeks of dapto, linezolid 6 weeks of dapto + amp/ceftaroline (if persistent bacteremia or high MIC dapto) *Native/Prosthetic Valve Infx from HACEK with amp/penicilli resistance* 4 weeks of ceftriaxone, cipro *Native/Prosthetic Infx from Candida* SURGICAL INTERVENTION RECOMMENDEND 6+ weeks of amphotericin, micafungin (with or without long-term oral azole suppression therapy) FLUCONAZOLE BY ITSELF NOT RECOMMENDED

Necrotizing Fasciitis

*Type I* Occurs in certain populations: DM, PVD, immunocompromised, surgical Usually occurs in male genitalia OR perineum of either gender (FORNIER'S GANGRENE) Usually less progressive Polymicrobial *Type II* Occurs in basically anyone May follow even minor skin trauma Usually monomicrobial (Strep pyogenes most common) RAPIDLY PROGRESSING TO SHOCK AND ORGAN FAILURE, SEVERE PAIN *Type III* Involves skeletal muscle with gas production and muscle necrosis Usually casued by clostridium perfringens RAPIDLY PROGRESSIVE *Diagnosis* Rapidly progressive Initially difficult to differentiate with cellulitis Pain OUT OF PROPORTION to appearance Blister and bullae Systemic sx Hard, wooden feeling Labs: LRINEC score, blood cultures Imaging *Treatment* Surgical debridement (MORTALITY BASICALLY 100% IF NO SURGERY) Broad spectrum -> narrow based on cultures Strep + Clostridium: penicillin + clinda Staph: naficillin/cefazolin/vanco for resist/clinda Aeromonas: doxy + cipro/ceftriaxone Vibrio: doxy + ceftriaxone/ceftoaxime Mixed: Zosyn + Vanco/Imipenem-cilastatin/meropenem/ertapenem/cefoaxime + metro or clinda

Non-tuberculosis Mycobacterium

*Types of Mycobacterium* Slow growing (1+ week): avium complex, kansasii, xenopii Rapid growhing (within 1 week): abscessus (mostly pulmonary), fortuitum, chelonae *Symptoms* Pulmonary disease: usually with underlying structural airway disease (COPD, CF, etc) *Diagnosis (need BOTH methods)* Radiologic: CXR and CT showing bronchiectasis with nodules Microbiologic: positive culture from 2+ sputum samples OR positive culture from one bronchial wash/lavage OR transbronchial/lung biopsy with positive culture from sputum or wash *Treatment Regimens depend on species* Nodular/Bronchiectactic M.avium: azithro/clarithromycin + rifampicin + ethambutol three times a week Cavitary M.avium: azithro/clarithromycin + rifampicin + ethambutol daily Refractory M.avium: azithro/clarithromycin + rifampicin + ethambutol + amikacin inhalation/IV daily Take for 12+ MONTHS AFTER CULTURE CONVERSION M.kansaii: azithro/clarithromycin + rifampicin + ethambutol OR INH + rifampicin + EMB Take about 12 months M.xenopi: azithro/clarithromycin +/- moxifloxacin + rifampicin + EMB + amikacin Take for 12+ MONTHS AFTER CULTURE CONVERSION Initial Macrolide Susceptible Abscessus: 1-2 parenteral amikacin/imipenim/tigecycline AND 2 oral azithromycin/clarithromycin/clofazimine/linezolid Continuation Macrolide Susceptible Abscessus: 2-3 oral/inhaled azithromycin/clarithromycin/clofazimine/linezolid/amikacin Initial Macrolide RESIST Abscessus: 2-3 parenteral amikacin/imipenim/tigecycline AND 2-3 oral azithromycin/clarithromycin/clofazimine/linezolid Continuation Macrolide RESIST Abscessus: 2-3 oral/inhaled azithromycin/clarithromycin/clofazimine/linezolid/amikacin

Blood Cultures

*Types* Regular blood and plasma Cerebral spinal fluid Joint fluid Sputum Wound drainage Urine *True Infections via Blood Culture* Staph aureus Strep pyogenes/agalactiae/pneumoniae Eneterobacterales Pseudomonas aerguinosa Bacteroides fragilis Candida spp *Skin Contaminants* Coagulase negative Staph spp Baccilus (NON ANTHRAX) Cornebacterium Cutibacterium Clostridium perfrengens Micrococcus

Management of UTIs

*Uncomplicated UTI* Durations: single dose, 3 days, 5 days, 7 days (HIGHER FAIL RATE WITH SINGLE DOSE) Sx usually improve within 72 hours Nitrofurantoin 100mg PO BID x5days Bactrim 160/800 mg BID x3 days Fosfomycin 3gm PO for one dose Fluoroquinolones ARE NOT FIRST-LINE *Uncomplicated UTI Flowchart* Women with acute uncomplicated cystitis comes in If fever, flank pain, or other sx of pyelonephritis: consider alternate dx If no fever, flank pain, pyelonephritis sx: check for allergies, availability, tolerance, cost Nitrofurantoin (AVOID IF PYELONEPHRITIS NOT RULED OUT) Bactrim (AVOID IF RESISTANCE 20%+ OR UTI IN PREVIOUS 3 MONTHS) Fosfomycin (AVOID IF PYELONEPHRITIS NOT RULED OUT) Pivamecillinam 400mg BID x5days (AVOID IF PYELONEPHRITIS NOT RULED OUT, NOT AVAILABLE IN US) If none of the above drugs can be used: Fluoroquinolones (resistance can be high) B-lactams with B-lactamase inhibitor (REQUIRES CLOSE FOLLOW-UP) *Uncomplicated Pyelonephritis* IV abx is probably needed due to susceptibility and spread of infection Can start IV empirically for 1-2 days and then move to PO once improving (1-14 days for mild, or full 14 days if severe) Rehydration and analgesics if needed Suscepibility unknown: empiric fluoroquinolones Susceptability known: Bactrim, extended-spectrum cephalosporin if gram-negative rod, may continue fluoroquinolone *Urethritis Syndrome* Dx: urethritis sx in sexually active women, WBC found in urinalysis, negative culture in urine Urethritis in sexually active males probably gonorrhea and/or non-gonococcal urethritis Can have lack of usual abx response due to possible STI (chlamydia) Tx: Azithromycin 1gm for one dose OR doxycycline 100mg BID x7 days *Other Things to Consider* ALWAYS DO A PREGNANCY TEST FOR CHILD-BEARING WOMEN

Infections Prophylaxis After Transplant

*Vaccines* Obtail ALL age and disease appropriate vax BEFORE transplant DO NOT USE LIVE VACCINES: CONTRAINDICATION Do NOT give vaccines within first 3 months of transplant *Anti-microbial Proph* Short term low doses at time of highest risk of infx STARTED IMMEDIATELY AFTER TRANSPLANT Valganciclovir: CMV Bactrim: PJP, Toxoplasmosis Fluconazole: valley fever (coccidiomycosis) *Other Infx Proph* Bacterial: broad-spectrum (cephalosporins, FQs) PCP: Bactrim, pentamidine Viral: ciclovirs, IVIG Fungal: azoles, echinocandins *Neutropenia* Based on ANC = Total WBC x % Neutrophils % neutrophils = % segmented + % band ANC < 500 IS CONSIDERED NEUTROPENIC -> INFECTION Neutropenic fever: neutropenia with 38.3C+ temp OR 38C for 1+ hrs, usually with no other inflammatory response *Risk-Based Proph Strats with Neutropenia* HIGH risk (<100 ANC, malignancy, allogenic HSCT, GVHD with high dose steroids, alemtuzumab use): FQ for bacteria, product selection for fungal and viral Moderate risk (<500 for 7-10 days, autologous HSCT, multiple myeloma, lymphoma, chronic lymphocytic leukemia, purine analog therapy): FQ for bacteria, product selection for fungal/viral Low risk (<500 for less than 7 days, solid tumor treated with standard chemo): do NOT use medications, viral proph considered if hx of HSV

Lipo/Glyco/Lipoglycopeptide Families

*Vancomycin* Mech: binds to pentapeptide chain (D-Ala D-ala) to prevent crosslinking Coverage: MSSA, MRSA, strep, enterococci, C.diff, Cornebacterium Uses: MRSA, MSSA if b-lactams unusable, strep resists to penicillin (S.pneu), C.diff, resistant GP, proph to MRSA Resists: VISA/VRSA, VRE (E.faceium) Usually given IV, but given ORALLY/RECTALLY for C.diff Toxic: rapid infusion rxn (flushing, rash, hypotension), allergy, nephrotoxic, ototoxic PLAN AHEAD if surgical proph with vanco needed (1H infusion) Efficacy for MSSA is LOWER than first-line agents *Dalbavancin (Dalvance)* Mech: same as vanco, but lipid moiety anchors molecule to membrane to increase affinity -> dimerization Coverage: similar to vanco, but hits VISA Use: alternative MRSA option for outpatient parenteral therapy (OPAT) Resist: VIR, VRE, ALL GRAM NEGATIVES Toxic: Red Man Syndrome (fast infusion rxn), allergy, nephrotoxic Dose reduction at CLcr <30 EXTREMELY EXPENSIVE *Oritavancin (Orbactiv)* Mech: inhibits peptidoglycan synth, binds to D-ala Dala, disrupts membrane interaction with lipophilic side chain Coverage: similar to vanco, but hits VISA/VRSA/VRE Uses: alternative MRSA option for outpatient parenteral therapy (OPAT) Resist: ALL GRAM NEGATIVES Toxic: VIR, allergy, nephrotoxic EXTREMELY EXPENSIVE *Daptomycin (Cubicin)* Mech: lipid tail inserted into membrane via Ca ions -> more dapto molecules recruited for oligomerization -> transmembrane ion channel forms Coverage: similar to vanco but has better gram positive and hits VRSA/VRE Uses: MRSA alternative to vanco, VRE (E. faecium), MSSA allergic to B-lactams Resist: ALL GRAM NEGATIVES Toxic: myopathy (WATCH FOR CPK), allergy (DRESS) MRSA alternative to vanco not showing response or intolerant FIRST-LINE: VRE *Polymyxin B* Mech: surfactant properties disrupt membrane Mech of Resist: remodeling of lipopolysaccharide structure to limit binding Coverage: gram-negative (enterobacterales, P.aeru) Resist: morganella, proteus, providencia, serratia, burkholderia Toxic: nephro, neuro, neuromuscular block RESERVED AS A LAST-RESORT OPTION IF NOTHING WORKS: KPC kleb/P.aeru Even then, ceftazidime/avibactam and cefiderocol still works better and is safer *Colistimethate* Mech: surfactant properties disrupt membrane Mech of Resist: remodeling of lipopolysaccharide structure to limit binding Coverage: gram-negative (enterobacterales, P.aeru) Resist: morganella, proteus, providencia, serratia, burkholderia Toxic: nephro, neuro, neuromuscular block Basically the same as Polymixin B but is a prodrug that is coverted to colistin Said to be best for UTIs since it's excreted in urine more

Viral Infection Prophlaxis

*Viral infection prophylaxis is CONTROVERSIAL* Depends on risk factors Resist issues Mixed results *Reasons to Consider Prophylaxis* Potential for more dangerous infection Higher incidence of infections Safer drugs or vaccine Detecting of infection (easier detection = LESS need for proph)

Prostatitis

*Why does my patient keep coming back for UTIs from the same organism???* Prostatis: inflammation of prostate gland from infections due to reflux of infected urine into gland Acute or chronic Increases with age, especially 30+ 50% of men will have this Mostly E.coli, but cases of kleb, proteus, pseudo, gonorrhea, chlamydia *Signs and Sx* Acute: chills, dysuria, fever, inc urinary freq, irritation, localized rectal pain, urinary straining Chronic: diff urinating, epididymitis, low back pain, recurrent UTIs, urethritis *Treatment* Fluoroquinolones or Bactrim if susceptible Alternatives: cephalosporins, penicillins Acute Duration: 2-4 weeks Chronic Duration: 6-12 weeks *Management* Improvement SHOULD OCCUR WITHIN 48-72 HOURS Follow-up urine culture