Past Exam 2 Pharmacotherapy

CAP Prevention - pneumococcal vaccine

1. Pneumococcal vaccine -13 valent conjugate vaccine- PCV13 (Prevnar 13) -23 valent polysaccharide vaccine PPSV23 (Pneumovax 23) 2. Pneumococcal vaccine ACIP Guidelines a. Adults 65 and older -Single dose of PPCV23 -Optional PCV13 based on shared decision making -PCV13 first followed by PPCV23 at least 1 year later b. Adults 19 years or older with immunocompromising conditions, CSF leaks, cochlear implants -PCV13 followed by PPSV23 8 weeks later -Second dose PPSV23 after 5 years for person with immunocompromising conditions

CAP

1. Pneumonia is the most common infectious cause of mortality worlwide 2. Second most common cause of hospitalization -1.5 million hospitalization due to CAP each year in the US 3. Risk factors -Old age -Chronic comorbidities a. COPD and other chronic lung diseases, heart disease, stroke, diabetes b. Viral respiratory infection c. Smoking

Determining Site of Care

1. Pneumoniae Severity Index (PSI)- more validated -Demographic factors -Comorbid conditions -Vital signs -Labs -Radiographic findings Class I-0.1%- Outpatient Class II- 0.6%- Outpatient Class III- 0.9%- Outpatient or short observational stay Class IV- 9.3%- Hospital Class V- 27%- Hospital 2. CURB-65 a. Confusion: 1 b. Urea > 20 mg/dL : 1 c. RR >/= 30 breaths/min : 1 d. Systolic BP <90 or diastolic </= 60 : 1 e. Age >/= 65: 1 Curb Score 0-1- low risk (mortality)- Outpatient 2 points- Moderate Risk (mortality)- consider hospital 3-5 points- High Risk 15- Hospital

Glucose Non-fermenting GNRs

1. Pseudomonas aeruginosa 2. Acinetobacter baumani 3. Strentrophomonas maltophila 4. Burkholderia cepacia Pseudomonas and S. aureus are the most concerning

Diagnosis (Influenza)

1. Rapid influenza antigen test -Influenza A and B antigen detection -Low sensitivity (not great at detecting true disease), high specificity (good at detecting when disease is not present) 2. Rapid influenza molecular test -Nucleic acid amplification tests -Influenza A and B viral RNA -High sensitivity, high specificity 3. Testing is recommended when influenza viruses are circulating in the community in: -Hospitalized patients with signs and symptoms suggestive of influenza -Outpatients when results will influence clinical management

Take Home Points

1. Risk factors for MRSA and Pseudomonas will influence empiric CAP therapy -Deescalate based on rapid MRSA nasal PCR or culture results 2. Duration of therapy is generally 5 days -base duration of therapy on clinical response 3. Influenza is common seasonal illness caused by Influenza A and B viruses 4. Influenza treatment options include neuraminidase inhibitors and the endonuclease inhibitor baloxavir 5. Treatment is recommended in patients at high risk, patients with severe illness, and all patients hospitalized with influenza 6. Greatest clinical benefit when influenza treatment is started early 7. Vaccination is key for prevention

Pneumonia

1. Acute inflammation of the lung parenchyma -Defect in host defenses -Exposure to virulent microorganisms -Very high inoculum 2. Pathogens gain entry to lower respiratory tract -Aspiration -Inhalation of aerosolized material -Seeding from blood (less common)

Influenza Treatment options

1. Adamantanes/M2 inhibitors (Type A) -Amantadine and rimantadine ->99% of current circulating flu A strains are resistant 2. Neuraminidase inhibitors (Type A and Type B) Oseltamivir (Tamiflu) Zanamivir (Relenza) Peramivir 3. Endonuclease Inhibitor (Type A and B) -Baloxavir (Xofluza)

Patients at high risk of complications from flu

1. Age < 2 and >/= 65 2. Chronic conditions -Pulmonary (including asthma) -Cardiovascular (except hypertension alone) -Renal -Hepatic -Hematologic -Diabetes -Neurologic conditions 3. Persons with immunosuppression 4. Women who are pregnant or postpartum 5. Children up to age 18 receiving long term aspirin (risk of Reye syndrome) 6. American Indian/Alaska Native people 7. Extreme obesity (BMI </= 40) 8. Residents of nursing homes and other long term care facilities

Other Beta Lactams

1. Amoxicillin/clavulanate PO 500/125 mg TID 875/125 mg BID 2000/125 mg BID 2. PO cephalosporins Cefpodoxime Cefuroxime 3. IV beta lactams Ampicillin/sulbactam Cefotaxime Ceftriaxone Ceftaroline - MRSA activity 4. Typical pathogens S. pneumoniae- yes H. infulenza- yes Moraxella catarrhalis- yes 5. Atypical pathogens 1. Chlamydia pneumonia- no 2. Mycoplamsa pneumoniae- no 3. Legionella spp.- no 6. Staphylococcus aureus 1. MSSA- yes 2. MRSA- no (except ceftaroline)

Empiric CAP Therapy Outpatient with comorbidities (e.g chronic heart, lung, liver, or renal disease, diabetes, malignancy)

1. Amoxicillin/clavulanate or cephalosporin (e.g cefpodoxime) PLUS a macrolide or doxycycline 2. or respiratory fluoroquinolone (Levofloxacin or Moxifloxacin)

HAP Most Common Pathogens

1. S. aureus (MRSA and MSSA) 2. Gram negative aerobes 3. Pseudomonas aeruginosa 4. HAP can also still be caused by CAP pathogens like S. pneumoniae and H. influenzae -usually associated with pseudomonas occurring earlier in admissions 5. Less common pathogens: -Candida spp, Aspergillus spp, and anaerobes 6. This is because patients who have been hospitalized for a long time often pick up different colonizers. Highest risk patients are ventilated patients. Endotracheal tubes severely impair host defenses and clearance of secretions.

Influenza Prophylaxis

1. Annual influenza vaccination 2. Neuraminidase inhibitors a. 70-90% effective in preventing influenza 2. Post exposure antiviral prophylaxis (after exposure to a person with influenza) -Not routinely recommended except in institutional outbreaks -Consider in some scenarios a. People at high risk during first 2 weeks of vaccination b. People at high risk who cannot receive influenza vaccine due to contraindication c. People with severe immune deficiencies who might not respond to influenza vaccination -Begin within 48 hours first exposure -Oseltamivir daily duration of potential exposure to a person with influenza and continued for 7 days after last known exposure. For scenario 1 above, duration is until immunity develops (2 weeks in adults) 3. Pre-exposure (or seasonal) antiviral prophylaxis -Not recommended

Influenza Epidemiology

1. Annually in the US (CDC estimate) a. 5-20% of the population become infected b. CDC estimates between 140,000-810,000 hospitalizations c. Between 12,000-61,000 deaths 2. Complications: a. Exacerbation of respiratory conditions (asthma, COPD) b. Primary influenza viral pneumonia or secondary bacterial pneumonia c. Exacerbate existing cardiac disease d. Myocarditis or pericarditis e. Encephalitis f. Multi-organ failure (septic shock, renal failure respiratory failure)

Antigenic drift and and antigenic shift (Influenza)

1. Antigenic drift- Type A and B -Gradual change in protein due to mutations, substitutions, and deletions- reason for vaccine every year 2. Antigenic Shift- Type A only -Drastic change in surface proteins -Results in new emerging virus -Responsible for epidemics and pandemics

Pneumonia and Influenza

1. S. aureus pneumonia and influenza are associated with each other in terms of prevalence

Opportunities fro Antimicrobial Stewardship in CAP

1. Appropriate empiric antibiotic selection 2. Tailoring therapy based on culture results -Reassess therapy at 48 hours. De-escalate in accord with culture results that do not yield MRSA or pseudomonas -MRSA nasal screening 3. IV to PO switch 4. Duration of therapy

What if prolonged QTc?

1. Avoid fluoroquinolones and macrolides 2. doxycycline + beta lactam -photosensitivity -Separate antacids -tetracycline- teeth staining -Espohagitis = dont lie down 30 mins and take with water

Macrolides

1. Azithromycin (IV, PO) 2. Clarithromycin (PO) 3. MOA: inhibits protein synthesis by binding to the 50S ribosomal subunit 4. QTC prolongation 5. Clarithromycin and erythromycin- CYP3A4 inhibitors 3. Typical pathogens S. pneumoniae- not really (sort of) H. infulenza- yes Moraxella catarrhalis- yes 4. Atypical pathogens 1. Chlamydia pneumonia- yes 2. Mycoplamsa pneumoniae- yes 3. Legionella spp.- yes

Pseudomonas Coverage

1. Aztreonam 2. Cefepime 3. Ceftazidime 4. Piperacillin-tazobactam

Do not cover MSSA

1. Aztreonam 2. Ceftazadime

Endonuclease Inhibitor

1. Baloxavir 2. Dose -40 < 80 kg: one 40 mg dose 3. Age -Treatment: 12 years and older -Prophylaxis: not recommended 3. A/Es: tolerated similar to placebo in clinical trials 4. Avoid administration with antacids and cation (Ca, Mg, Fe) containing products 5. No available data for treating pregnant women, immunocompromised, or severe influenza

Diagnostic Workup

1. Based on the diversity of pathogens, very important to obtain respiratory sample for culture for all patients whenever feasible 2. Criteria for acceptable sputum specimens still apply Acceptable specimens for culture -< 10 squamous epithelial cells per HPF (comes from mouth) -> 25 polymorphonuclear (PMN) cells per HPF (deeper in the lung... immune responders and indicates an infection) 3. Gram stain performed initially when specimen arrives in lab -> however, may be misleading -Organisms seen on Gram Stain may be determined to be normal oral flora once culture grows -never base HAP regimen solely on Gram stain because could be multiple organisms HPF = high power field

Empiric CAP Therapy Inpatient (non-severe) without risk factors for MRSA or P. aeruginosa

1. Beta lactam PLUS macrolide or 2. Respiratory Fluoroquinolone

Empiric CAP Therapy Inpatient (severe) without risk factors for MRSA or P. aeruginosa

1. Beta lactam PLUS macrolide, or 2. Beta-lactam PLUS respiratory fluoroquinolone

Antibiotics in HAP

1. Beta lactam/ monobactam 2. Fluoroquinolone 3. Aminoglycoside 4. Glycopeptide 5. Oxazolidinone

CAP typical pathogens- S. pneumoniae

1. Beta lactams -Amoxicillin, amoxicillin-clavulanate, ampicillin-sulbactam, cefuroxime, cefpodoxime, ceftriaxone 2. Respiratory fluoroquinolone -Levofloxacin, moxifloxacin 3. Variable activity -Doxycycline- resistance (20%) -Azithromycin- resistance in US (>30%) *Ciprofloxacin is not a respiratory fluoroquinolone because it has poor S. pneumoniae activity

B

1. SK is a 58 YOM with no PMH who was admitted following a motor vehicle accident. He required emergent intubation but was extubated on day 8. He was transferred to the floor on day 13, when he had a fever and increased sputum production. His O2 sat dropped to 90% on RA, requiring O2 by NC. Vital signs are stable. Blood and sputum cultures were obtained. Local MRSA prevalence is 5%. What empiric antimicrobial regimen would you recommend? a. Cefepime 2g IV q8h + linezolid 600mg IV q12h b. Piperacillin/tazobactam 4.5g IV q6h c. Cefepime 2g IV q8h + levofloxacin 750mg IV q24h + vancomycin 15mg/kg IV q8-12h d. Piperacillin/tazobactam 4.5g IV q6h + gentamicin 5mg/kg IV q24h

SARS-COV-2 positive?

1. Screen at hospital- treat symptomatic

Diagnostic Evaluation

1. Signs and symptoms 2. Chest radiograph 3. Hospitalized patients with CAP -sputum cultures -blood cultures 4. Other diagnostic tests -Legionella spp -S. pneumoniae antigen -respiratory viral panel -rapid nasal MRSA PCR screen -procalcitonin -testing for circulating viruses (influenza, SARS-COV-2)

Patient Case 1: Variation b Antibiotic Regimen

1. Broad spectrum antibiotics that cover both typical and pseudomonas a. Piperacillin tazobactam b. Cefepime c. Meropenem d. Imipenem Ceftazipime + aztreonam loses S. pneumoniae coverage

Take Home points

1. CAP is pneumonia acquired in the community and is distinguished from nosocomial pneumonia by its common causative organism less resistance 2. Diagnosis is based on Chest radiograph and clinical signs/symptoms 3. Our knowledge of the microbial etiology of CAP has changed over time 4. Most patients will be treated with an antimicrobial regiment that covers both typical and atypical organisms 5. Risk factors for MRSA and pseudomonas should be considered and will change empiric choices for CAP

Pneumonia Categories

1. CAP: community acquired pneumonia 2. Nosocomial pneumonia HAP: Hospital acquired pneumonia VAP: ventilator associated pneumonia 3. HCAP retired in 2019 guidelines -Intended to identify patients at risk for multidrug resistant pathogens, but definition was overly sensitive -Uneccessary broad spectrum antibiotic use

Pathogenesis

1. Sources of pathogens a. Healthcare devices b. Environment i. Water, air, or equipment c. Transfer between staff and patients 2. Host and bacterial exposure interaction a. Colonization of respiratory tract b. Inoculation via healthcare devices c. Infection occurs when inoculum overcomes host's weakened defenses -Mechanical (ciliary and mucus) -Humoral (antibody/ compliment) -Cellular

Getting to Know Your Pathogens: Staphylococcus aureus

1. Staphylococcus aureus -Highly virulent Gram positive coccus -MSSA colonizes skin of 30% of adults -MRSA colonizes skin, nares, axilla, and groin of 2-5% of adults MS= methicillin susceptible MR= methicillin resistant 2. Methicillin susceptibility used to predict activity of other beta lactams (e.g cefazolin) 3. S. aureus has exotoxin that can cause scalded skin syndrome in children

Typical CAP pathogens

1. Streptococcus pneumoniae 2. Haemophilus influenzae 3. Moraxella catarrhalis

What causes CAP?

1. Changes in etiology over time -Streptococcus pneumoniae (aka pneumococcus) a. 90-95% of cases in the pre-antibiotic era b. 5-15% of cases in US today (20-25% in Europe) 2. Respiratory virus (20-27%) 3. No identified cause in more than half of cases 4. Misdiagnosis a. Other cause found in 17% of patients in a prospective study b. Pulmonary edema, malignancy, interstitial lung disease, eosinophilic pneumonia, diffuse alveolar hemorrhage

Atypical CAP pathogens

1. Chlamydia pneumoniae 2. Mycoplasma pneumoniae 3. Legionella spp. 4. Lack a cell wall reason atypical 5. Difficult to recover from. isolates and does not Gram Stain 6. Beta lactams + vancomycin do not have activity against atypical organisms

Nasal MRSA PCR

1. Common antimicrobial stewardship strategy for vancomycin de-escalation among hospitalized patients with pneumonia 2. High negative predictive value -Useful for ruling out MRSA -Negative result provides good evidence that MRSA is not the causative pathogen -Can be used to guide antibiotic de-escalation -Results are rapid 3. Positive results are less informative -MRSA could be in the nares but not necessarily.. this does not mean it is a false positive however 2-3 hr test

Influenza

1. Symptoms a. Respiratory symptoms, fever, other constitutional symptoms (body aches, pain) b. Abrupt onset c. Incubation period (time between exposure to first symptoms) 1-4 days (average 2 days) d. Symptoms usually last 3-7 days e. Viral shedding a. 24-48 hours before illness onset b. Average duration 4-5 days in healthy adults c. Longer duration of shedding in children, older adults, patients with chronic illness, immunocompromised 2. Spread from person to person a. Droplet b. Respiratory transmission

Newer Drugs for CAP

1. Delafloxacin -Broad spectrum fluroquinolone -IV and PO -FDA approved for CAP and acute bacterial skin and skin structure infections (ABSSSI) 2. Omadacycline -Aminomethylcycline, derivative of tetracycline -Broad activity against many resistant pathogens -IV and PO -FDA approved for CAP and ABSSI 3. Lefamulin -First in class pleuromutilin antibacterial -Activity against CAP pathogens plus broad Gram positive coverage -FDA approved for CAP

CAP diagnosis

1. Diagnosis a. New pulmonary infiltrate on chest radiograph **b. AND syndrome clinically consistent with pneumonia -New or increased cough -Sputum production -Shortness of breath -Pleuritic chest pain -Fever -Leukocytosis

HAP (hospital acquired pneumonia); CXR, started in hospital and had fever; S. aureus and Pseudomonas aeruginosa (most common)

1. Diagnosis: hospital-acquired pneumonia 2. Criteria: fever, new O2 requirements, CXR suggesting LLL pneumonia >> HAP because patient has been admitted >48h 3. Pathogens: Staphylococcus aureus & Pseudomonas aeruginosa; other GNR Sources: healthcare devices, transfer between patients and staff, environment (water, air, equipment)

Patient 2 Case diagnosis

1. Diagnosis: pneumoniae based on infiltrate on CXR

Sputum Culture

1. Diagnostic utility 2. Quality of sputum specimen a. < 10 squamous epithelial cells per HPF - not good quality specimen b. > 25 polymorphonuclear cells per HPF 3. Obtained prior to antibiotic administration 4. Timeliness of specimen processing 5. Interpreting results a. Colonizing organism from upper respiratory tract b. Higher yield/ easy to grow organisms and relative amount of growth -Mixed flora vs predominant pathogen -Clinical correlation (fastidious organism like S. pneumoniae, atypical pathogens.. usually pneumonia one of two predominant pathogens, Candida and Enterococcus not typical to cause pneumonia

Determine Need for Double Pseudomonas Coverage

1. Double Pseudomonas coverage if: -IV antibiotics within last 90 days OR -High risk of mortality (ventilator support, or sepsis) OR -if local resistance rates of Pseudomonas aeruginosa to first line agents is > 10% 2. Second drug should be a fluoroquinolone or aminoglycoside -Fluoroquinolone: ciprofloxacin & levofloxacin -Aminoglycosides: tobramycin and amikacin

Tetracyclines

1. Doxycycline 2. MOA: inhibits protein synthesis by binding to 30S ribosomal subunit 3. Antacids and other cations decrease absorption and separate administration 4. Adverse reactions a. Photosensitivity b. Esophagitis 5. Typical pathogens S. pneumoniae- (sort of) H. infulenza- yes Moraxella catarrhalis- yes 6. Atypical pathogens 1. Chlamydia pneumonia- yes 2. Mycoplamsa pneumoniae- yes 3. Legionella spp.- yes

Glucose fermenting GNRs

1. E. coli 2. Klebsiella pneumoniae 3. Enterobacter cloacae 4. Serratia marescens 5. All other members of Enterobacteriaceae family *would change agar color to pink from yellowGlucose non-fermenting = group of bacteria that are unable to metabolize glucose MacConkey agar - used in the micro lab to differentiate various organisms - Organisms that can ferment lactose will turn the agar from yellow to pink -Other non-fermenters: Acinetobacter, Moraxella, Stenotrophomonas, Legionella, Burkholderia, Bordetella

Determine Primary Pseudomonas Coverage

1. Empiric HAP therapy should include an agent that covers Pseudomonas aeruginosa in ALL patients 2. Single antipseudomonal agent is sufficient in most cases -Piperacillin/tazobactam -Cefepime -Meropenem -Imipenem/cilastatin (all of these also cover MSSA) -Levofloxacin (not good for S. aureus) 3. Aminoglycosides are not recommended as monotherapy (cant use it alone because we dont get adequate concentration to the site of infection)

Determine Gram Positive Coverage

1. Empiric MSSA coverage should be considered in all patients -MSSA options for HAP -Piperacillin/tazobactam, cefepime, imipenem/cilastatin, or meropenem -vancomycin & linezolid (options if beta lactam allergic) 2. If infection determined to be caused by MSSA alone, consider narrowing to one of the following a. Nafcillin, Oxacillin, or cefazolin 3. Consider empiric MRSA coverage if:* a. IV antibiotics in last 90 days OR b. Increased mortality risk (need for ventilator, septic shock) OR c. MRSA prevalence is > 20% or unknown 4. If empiric MRSA coverage needed -Vancomycin or linezolid -Daptomycin is not an option for pneumonias (destroyed by surfactant in the lungs)

Key points to remember for Empiric Therapy

1. Empiric therapy for HAP should always include coverage of MSSA and Pseudomonas aeruginosa 2. Patient specific and antibiogram data dictate: -Need for MRSA and/or -Need for double Pseudomonas coverage

Oxazolidinone (Linezolid)

1. Example: Linezolid 2. Spectrum: Gram positive organisms, including MRSA 3. MOA: ribosomal agent; prevents formation of functional 70S ribosome complex via binding of 23S subunit 4. Side effects: neutropenia, thrombocytopenia, increased risk of serotonin syndrome *weak monoamine oxidase inhibitor so need to be careful if on multiple serotonergic drugs

Monobactam (Aztreonam)

1. Example: aztreonam 2. Spectrum: Gram negative organisms including Pseudomonas spp 3. MOA: cell wall active agent, binds to penicillin binding proteins -Time dependent antibacterial activity 4. Side effects: well tolerated 5. Place in therapy: severe beta lactam allergy

Aminoglycoside (gentamicin)

1. Example: gentamicin, tobramycin, amikacin 2. Spectrum: Gram-negative organisms, including Pseudomonas spp. -Gentamicin sometimes used synergistically for Gram positive infections 3. MOA: ribosomal agent; interferes with protein synthesis via 30S binding -Concentration dependent antibacterial activity (CMAX/MIC) 4. Side effects: nephrotoxicity and ototoxicity Therapeutic drug monitoring warranted

Glycopeptide (vancomycin)

1. Example: vancomycin (primarily IV) 2. Spectrum: Gram-positive organism, including MRSA -Also covers Clostridiodes difficile (C. diff), an anaerobic Gram positive organism (orally) 3. MOA: cell wall active agent; binds to D-Ala-D-Ala portion of cell wall precursor, thus inhibiting cell wall synthesis 4. Side effects: nephrotoxicity, Red Man's Syndrome -Therapeutic drug monitoring warranted

Getting to Know Your Pathogens: Pseudomonas aeruginosa

1. Glucose/lactose non-fermenting Gram negative rod (GNR) 2. potential to become highly drug resistant 3. Nosocomial pathogen that frequently drives empiric drug selection 4. Limited antibiotic options *yellow- non fermenting- so does not use lactose- pigment so yellow.. if ferment lactose agar changes to pink

CAP typical Pathogens- Haemophilus influenzae, and Moraxella catarrhalis

1. Good activity -Beta lactams a. Amoxicillin-clavulanate, ampicillin-sulbactam, cefuroxime, cefpodoxime, ceftriaxone b. Respiratory fluoroquinolone -Levofloxacin, moxifloxacin c. doxycycline d. Azithromycin 2. Beta lactamase producing- amoxicillin lacks activity *need a beta lactamase inhibitor/ amoxicillinis not good against H. influenza nor Moraxella catarrhalis because 25-50% of H. influenzae and 95% of M. catarrhalis produce beta lactamases

Empiric Therapy

1. Guided by knowledge of local pathogens and patient's severity of illness 2. All hospitals recommended to generate HAP/VAP & ICU specific antiograms 3. Empiric antibiotics regimen should be based on antibiogram if available since resistance patterns vary among regions, hospitals, and units 4. Severely ill patients must be treated broadly to ensure best chance of survival

Role of Antibiogram

1. Helps guide empiric therapy decisions 2. Collates susceptibility data of organisms over period of time specific to the sample population -Provides a "batting average" for each antibiotic tested against an organism 3. Allows you to determine prevalence of MRSA 4. Examples -Of the 75 isolates of Organism B tested, 98% of the isolates tested susceptible to ABX 2 -ABX I has a better chance of effectively covering organism A than ABX 2

Influenza

1. Hemagglutin- attqches to sialic acid 2. Neuraminidase- helps virus to escape the after infecting cell

Renal Dysfunction?

1. Hemodialysis 2. Kidney transplant 3. Ceftriaxone (not renally cleared) -other beta lactams need renal adjustment -no aminoglycosides or vancomycin in renal dysfunction

Patient Case 1: Variation b

1. Here need cefepime (Pseudomonas coverage isolated from respiratory specimen 3 months ago..+ typical coverage), azithromycin (atypical coverage), + vancomycin (MRSA coverage)

Definitions

1. Hospital acquired pneumonia (HAP) -Pneumonia occurring > 48 hours after hospital admission that was not incubating upon admission 2. Ventilator associated pneumonia (VAP) -Pneumonia occurring > 48 hours after endotracheal intubation 3. Diagnostic criteria applied in surveillance studies a. New or progressive infiltrate or consolidation AND 2 of 4 following symptoms: a. Fever b. Leukocytosis c. Decreased oxygenation d. Purulent sputum

CAP de-escalation of therapy

1. IV to PO 2. Tailoring therapy based on known pathogen -Will depend on microbiology information available -Results of respiratory viral tests often not useful for de-escalation -Relevant for patients initially treated with regimens for MRS and/or P. aeruginosa -Respiratory cultures -Rapid nasal PCR MRSA test 3. Viral test not useful for de-escalation, regimens that cover MRSA/ P. aeruginosa not common CAP, test used

Prevention

1. Infection control measures (alcohol based hand disinfection, isolation, etc.) 2. Head of bed (HOB) maintained at 35-45 degrees 3. Enteral nutrition preferred over parenteral 4. Oral chlorhexidine rinses- like used in dentist 5. Daily interruption of sedation 6. Intensive glucose control

CAP Respiratory viruses

1. Influenza 2. Respiratory synctial virus (RSV) 3. Rhinovirus 4. Human metapneumovirus 5. Parainfluenza

Influenza Treatment: Inpatient

1. Inpatient management a. All patients who are hospitalized with influenza regardless of time of onset 2. Benefit a. reduce length of hospitalization b. Reduce the risk of mechanical ventilation c. Reduce mortality in some high risk populations d. Possible benefit even when started < 48 hours after onset of illness

B (needs double pseudomonas coverage due to IV antibiotics within 90 days as well as MRSA coverage)

1. JJ a 76 YOM was admitted to an OSH 2 months ago for an intrabdominal infection where he received IV antibiotics for 4 days. Three weeks ago, he was admitted to the ICU at UNC after a MVA. Five days ago, he was moved to the floor and a few days later he developed confusion and low O2 Sat and was transferred back to the ICU for intubation. Two days ago, the patient becomes febrile with sputum production and leukocytosis. Due to concern for VAP and empiric antibiotics will be started. Which of the following would be most appropriate for this patient? a. Piperacillin/tazobactam 4.5g IV q6h + vancomycin 15mg/kg IV q8h b. Cefepime 2g IV q8h + ciprofloxacin 400mg IV q8h + vancomycin 15mg/kg IV 18h c. Ceftazidime 2g IV q8h + levofloxacin 750mg IV q24h d. Cefepime 2g IV q8h + imipenem 500mg IV q6h + linezolid 600mg IV q12h

B

1. JM is an 80 YOM who presents with acute respiratory failure requiring intubation. His wife reports that he had a productive cough, fever, and SOB starting 3 days ago. His O2 Sat was low, so he is admitted to the ICU. The resident requests a recommendation for empiric antibiotics. Which of the following regimens would you recommend? Vitals: BP 157/86 mmHg, HR 64 bpm, Tmax: 39C, RR 32 breaths/min Allergies: azithromycin (tongue swelling) a. Ceftriaxone 1g IV q24h + azithromycin 500mg IV/PO q24h b. Ceftriaxone 1 g IV q24h + levofloxacin 750 mg IV/PO q24h c. Moxifloxacin 400 mg IV/PO q24h d. Ceftriaxone 1 g IV q24h + linezolid 600mg IV q12h

C

1. KG is a 63 YOM who presented to the ED 2 days ago with a fever, productive cough, and SOB with an O2 Sat of 90%. KG was administered oxygen via nasal cannula and is admitted to start ceftriaxone and azithromycin. KG has been receiving empiric antibiotics for 3 days and he has improved substantially. The resident consults you for a recommendation about the total duration of antibiotic therapy for this patient, what is your recommendation? a. 10 days since KG is clinically improving b. 15 days since KG is clinically improving c. 5 days since KG is clinically improving d. Stop the antibiotics now since KG seems fine

C

1. LP is a 75 YOF with HAP who was started on broad spectrum antibiotics two days ago - vancomycin + piperacillin/tazobactam + metronidazole. She is now afebrile, does not require supplemental oxygen, and her leukocytosis has resolved. You are rounding with the team and they note that cultures returned 2+ for MSSA. What is your recommendation? a. Continue all antibiotics as currently prescribed since she has not received 7-10 days of therapy b. Discontinue vancomycin and metronidazole; keep piperacillin/tazobactam as prescribed c. Discontinue vancomycin, metronidazole, and piperacillin/tazobactam; initiate oxacillin d. Discontinue vancomycin and piperacillin/tazobactam; continue metronidazole and initiate oxacillin

Fluoroquinolones

1. Levofloxacin, moxifloxacin MOA: binds to DNA gyrase which prevents DNA strands from being separated during replication 2. Adverse reactions -C. difficile infection -QT prolongation -Tendon rupture or tendonitis -Peripheral neuropathy -Blood glucose disturbances -CNS side effects -Aortic aneurism, aortic dissection 3. Typical pathogens S. pneumoniae- yes H. infulenza- yes Moraxella catarrhalis- yes 4. Atypical pathogens 1. Chlamydia pneumonia- yes 2. Mycoplamsa pneumoniae- yes 3. Legionella spp.- yes Fluoroquinolones typically reserved for acute bacterial sinusitis, bacterial exacerbation of chronic bronchitis, and uncomplicated UTI

Amoxicillin

1. MOA: Beta-lactam -Binds to penicillin binding proteins and inhibits cell wall synthesis 2. Adverse effects -Allergic reactions, rash -GI side effects 3. Dose: 1 g PO TID CAP pathogens 4. Typical pathogens S. pneumoniae- yes H. infulenza- sort of Moraxella catarrhalis- no 5. Atypical pathogens 1. Chlamydia pneumonia- no 2. Mycoplamsa pneumoniae- no 3. Legionella spp.- no

Lefamulin

1. MOA: pleuromutilin class- inhibits protein synthesis by binding to 50S ribosomal subunit 2. ADR a. LFT elevation b. GI side effects c. Infusion site reactions 3. Typical pathogens S. pneumoniae- yes H. infulenza- yes Moraxella catarrhalis- yes 4. Atypical pathogens 1. Chlamydia pneumonia- yes 2. Mycoplamsa pneumoniae- yes 3. Legionella spp.- yes

Pathogens for HAP

1. MSSA 2. Pseudomonas aeruginosa Antibiotics that cover pseudomonas aeruginosa will cover additional Gram - aerobes that may cause HAP

HAP Bugs and Drug Chart

1. MSSA Naficillin/oxacillin- + Piperacillin-tazobactam- + Cefazolin- + ceftazidime- no Cefepime- + Imipenem-cilastin- + Meropenem- + Ciprofloxacin and Levofloxacin- No Tobramycin and Amikacin- No Vancomycin- + (plus MRSA) Linezolid - + (plus MRSA) 2. MSSA + Pseudomonas Cefepime Imipenem-cilastin Meropenem Piperacillin-tazobactam

Antibiotics for atypical pathogens

1. Macrolides (azithromycin, clarithromycin) 2. Doxycycline 3. Fluoroquinolones Atypical Legionella Mycoplamsa pneumoniae Chlamydia pneumoniae

IDSA/ATS Criteria for Severe CAP

1. Major critieria a. Septic shock with need for vasopressors b. Respiratory failure requiring mechanical ventilation 2. Minor criteria a. Respiratory rate >/= 30 breaths/min b. PaO2/FlO2 ratio </= 250 c. Multilobar infiltrates d. Confusion/disorientation e. Uremia (blood urea nitrogen level >/= 20 mg/dl) f. Thrombocytopenia (platelet count below <100,000) g. Leukopenia (white blood cell count <4,000) h. Hypothermia (core temperature < 36 degrees C) i. Hypotension requiring aggressive fluid resuscitation

HAP and sputum culture

1. Majority of cases of HAP are culture negative (no organisms grow)

Red Man's syndrome

1. Massive histamine release attributed to rapid IV infusions of vancomycin 2. Symptoms: -Pruritic, erythematous rash (face, neck, and upper torso) -Tachycardia -Fever, chills, nausea/vomiting -Angioedema, hypotension (rare) 3. Management: -slow the infusion (60-120 minutes) -Pre-medicate with H1/H2 antagonist

Patient Case 1: Variation a

1. Need ceftriaxone (for typical pathogens) + azithromycin (for atypical coverage) + vancomycin now (because MRSA was isolated from a respiratory specimen 3 months ago) -de-escalate vancomycin based on micro results

Elderly?

1. No fluoroquinolone because lead to CNS side effects 2. Tendinopathy

Patient Case 2

1. No risk factors for MDR based on info 2. double coverage not necessary because no risk factors. Previous IV antibiotic in last 90 days? 3. -Pathogens: Staphylococcus aureus (MSSA/MRSA), Pseudomonas aeruginosa, other Gram-negative rods (e.g., Klebsiella, E coli, Enterobacter) Risk factors: not based on this information -Additional: recent IV ABX? Local resistance rate of Staph aureus (>20%) and Pseudomonas (>10%)? Allergies? Renal function? -Regimen: if resistance ≤20%: Pip/tazo, cefepime, imipenem, meropenem; if resistance >20%: vanco/linezolid + pip/tazo, cefepime, ceftaz, G2 carbapenem, aztreonam -Double: not necessary for this patient; if we knew resistance to first line option >10%, we would add FQ or AG

What if refuse admission?

1. Oral regimen 2. Levofloxacin best 3. If QTC and refused admission -Augmentin and doxcycline

Neuraminidase (NA) Inhibitors

1. Oseltamivir a. Capsule or oral suspension b. Tx duration: 5 days c. Age: - Treatment: any age - Prophylaxis: 3 months and older d. A/E -Nausea and Vomiting -Headache e. requires renal adjustment 2. Zanamivir a. Inhalation (device + drug) b. Tx duration: 5 days c. Age -Treatment: 7 years and older -Prophylaxis: 5 years and older d. A/Es: -Respiratory SEs (5%) -Not recommended for people with underlying respiratory disease (asthma, COPD) 3. Peramivir a. Intravenous -Adult dose 600 mg x 1 b. Age -Treatment: 2 years and older -Prophylaxis: not recommended c. A/E -diarrhea d. Requires renal adjustment

Influenza: Treatment Outpatient

1. Outpatient management: -Any age with severe or progressive illness -High risk for complication from influenza -Consider if they do not meet the above criteria and have symptoms < 48 hours 2. Outpatient Benefit a. Initiation <36-48 hours from onset- decrease in duration of symptoms by 1-2 days as well as severity b. Reduce extent and quantity of viral shedding c. Reduces the risk for hospitalization among patients at high risk

Empiric CAP Therapy Outpatient without comorbidities

1. Outpatients without comorbidities a. Amoxicillin 1 g TID b. Doxycyline 100 mg BID or c. Macrolide (in areas with macrolide resistance to S. pneumo <25%) *Most areas in the US have S.pneumoniae macrolide resistance rates > 30% More than 1 day in ICU

What if preceding viral illness?

1. 2 wks VTI- rhinovirus -admitting for CAP- S. aureus

Example of De-Escalation

1. 43% prevalence of MRSA- need vancomycin here 2. HAP patient so has to have at least one antipseudomonal agent 3. Double pseudomonal coverage is not needed because Pseudomonal resistance is less than 10% 4. So vancomycin and Cefepime probably the best therapy

Duration of Antibiotic Treatment in CAP

1. A 5 day course of antibiotic treatment was as effective as traditional longer durations in hospitalized patients with CAP who respond early to therapy 2. non inferior trial- randomized into two groups- duration by provider vs clinical guidelines to stop

D (could do Levofloxacin or respiratory fluoro but not cipro)

1. AM is a 73 YOF who presents to the ED with a productive cough, fever, SOB and generalized fatigue. He has tachypnea, tachycardia, crackles, and he complains of pleuritic chest pain, but is otherwise stable and alert. AM has COPD, diabetes, GERD, and HTN. What is the most appropriate antimicrobial regimen for AM today? a. Amoxicillin 1000mg PO TID b. Ciprofloxacin 400mg PO q8h c. Doxycycline 100mg PO BID d. Cefuroxime 500mg PO BID + azithromycin 500mg PO x 1 day then 250mg PO daily

When are sputum cultures helpful?

1. Absence of growth of a fastidious organism does not rule out that organism as a pathogen 2. Absence of growth of an easy to grow organisms provides strong evidence that these are not the causative pathogens a. S. aureus b. P. aeruginosa 3. If sputum cultures do not yield S. aureus or P. aeruginosa, the antibiotic regimen can be de-escalated to a regimen that does not cover these organisms

After Empiric Selection

1. Target based on respiratory culture if able -Do not use aminoglycoside alone 2. Used most targeted spectrum therapy 3. Duration: 7 days for most patients -Depends on clinical response

Influenza: Treatment

1. Treat as early as possible for any confirmed or suspected influenza who: -is hospitalized -Has severe complicated or progressive illness OR -is at higher risk for influenza complications 2. Oseltamivir is the recommended antiviral for patients with severe influenza and for hospitalized patients 3. Treatment may be considered for low risk outpatients if treatment can be initiated within 48 hours of illness onset 4. Clinical benefit is greatest when started early

Duration of Treatment- 2019 IDSA/ATS Guideline Recommendation

1. Treat for a minimum of 5 days 2. Duration should be guided by measures of clinical stability -Resolution of vital sign abnormalities -HR, RR< blood pressure, oxygen saturation, temperature 3. Ability to eat 4. Normal mentation

Influenza more

1. Type A -Most common -Diverse protein structure -Many different types of surface proteins -Subtypes are based on two surface proteins hemagluttin (H) and neuraminidase (N) -Naming is baed on which type of H and N is present -H3N2 and H1N1 are currently dominant today 2. Type B -Only infect humans -Less diverse protein structure

De-Escalation Strategies

1. Useful in setting of culture-negative pneumonia with patient responding to broad spectrum antimicrobial therapy 2. Step down de-escalation with a watch and wait period after each step -Remove double Pseudomonas coverage, THEN -Remove MRSA coverage, THEN -REMAIN on single broad spectrum agent (piperacillin/tazobactam, cefepime, ceftazidime, etc.) -Transition from IV to PO therapy -***Ability to de-escalate and strategy used varies per patient case****

Antibiotics for MRSA pneumonia

1. Vancomycin 2. Ceftaroline- more expensive but is an option 3. Linezolid *Daptomycin is not effective for pulmonary infection because it is inactivated by pulmonary surfactant

Cover MRSA

1. Vancomycin 2. Linezolid

Empiric CAP therapy- Hospitalized Patients

1. When to add MRSA or pseudomonas coverage a. Locally validated risk factors present b. Strongest risk factors 1. Prior isolation of these organisms, especially from respiratory tract 2. Recent hospitalization and exposure to IV antibiotics (usually within the past 90 days) Other risk factors MRSA: recurrent skin infection, severe pna Pseudomonas: tracheostomy, structural lung disease, bronchiestasis, severe COPD

Designing an ID Pharmacotherapy Plan

1. Where is the suspected infection? 2. What organisms typically causes that type of infection? 3. What antimicrobial option cover those organism? 4. Does the antimicrobial get to the site of infection in adequate cocentrations? 5. Incorporate patient specific data a. Age? b. Allergies? c. Renal function? d. Hepatic function 6. Incorporate microbiological data: a. Cultures obtained? b. Which organism isolated? c. what are the susceptibilities?

If Penicillin Allergy ?

1. ask them about penicillin allergy 2. <10% of patients in the US reports penicillin allergy 3. 90% of pts with IgG mediated allergy lose sensitivity after 10 years 4. If anaphylaxis to penicillin- use respiratory fluoroquinolone 5. Admitted and IV antibiotics- need MRSA coverage -vancomycin or linezolid 6. There are penicillin skin tests

Example Antibiogram #2

1. bacteria recovered from adult urinary specimen

Pregnant?

1. beta lactam can use azithromycin 2. off the table would be a. doxycycline b. Fluoroquinolones

Patient Case 3

1. empiric therapy is not warranted now 2. de-escalate vancomycin and metronidazole, but KEEP cefepime as monotherapy because need coverage for MSSA which cefepime has or switch to nafcillin/oxacillin because primary agent against MSSA 3. Empiric therapy: no longer necessary as patient is improving Optimize: de-escalate to nafcillin/oxacillin/cefazolin IV to PO: this is a very patient specific question to ask, and a lot of factors are considered, such as drug-drug interactions, patient disposition, comorbidities, etc. Overall, this patient appears to be doing well since therapy was initiated, so she could likely transition to oral therapy. If an oral regimen is pursued, we would want to choose an oral antibiotic that was active against MSSA or whatever was isolated.

Patient Case 3

1. febrile 2. hypotensive 3. comorbidities 4. multiloblar filtrates

Not appropriate regimen (cefepime treats pseudomonas and vancomycin for MRSA and has no risk factors.. there is also no coverage for atypical pathogens like a macrolide or doxycycline... should have used a beta lactam plus macrolide here.. second choice a respiratory fluoroquinolone because inpatient non severe without risk factors for Pseudomonas nor MRSA)

1. if negative rapid nasal MRSA PCR.. we can de-escalate vancomycin and rule out MRSA.. use azithromycin for atypical pathogens and ceftriaxone for typical pathogens 2. Ceftriaxone (more targeted) + azithromycin most common inpatient regimen 3. MRSA PCR has low positive predictive value- not a necessary test- + does not mean has MRSA so a positive result would not have influenced antibiotic regimen

CAP Prevention- Influenza Vaccine

1. influenza vaccine annually in all persons older than 6 months 2. Trivalent (H1N1, H3N2, + 1 influenza B strain) 3. Quadrivalent (H1N1, H3N2, + 2 influenza B strains) 4. Influenza vaccine products -Standard quadrivalent (Alfuria, Fluarix, FluLaval, Fluzone) -Egg free a. Cell based vaccines (Flucelvax) b. Recombinant vaccine (Flublok) c. Intransal live vaccine -Live attenuated (FluMist) age 2-49 Approved for 65 and older -Adjuvanted influenza vaccine (FLUAD and FLUAD quadrivalent) -High dose (Fluzone High-Dose) 5. Advisory Committee on Immunization Practices (ACIP) gives no preference for any particular vaccine over another

Patient Case 2

1. need to know if it is pneumonia 2. chest imaging 3. category severity

Unable to swallow pills?

1. other dosage form suspensions -see if can be crushed

Antibiotics for Pseudomonas pneumonia

1. piperacillin tazobactam 2. Ceftazidime- poor gram + coverage a. good negative coverage but poor gram + coverage and does not cover S. pnuemoniae 3. Cefepime 4. Imipenem 5. Meropenem 6. Aztreonam- poor Gram + coverage only gram - aerobes

Patient Case 1

CURB Score-2- Moderate risk- consider hospital (RR and urea) Class IV- PSI- 9.3% mortality

Neumraninidase Inhibitor and Baloxavir MOA

Hemaglutinin—holds on to sialic acid, helping the virus enter the cell Neuraminidase—helps the virus exit the cell, it helps cut the virus loose from the sialic acid. Amantadine or rimantidine—inhibits M2 protein which is an ion channel necessary for uncoating of the virus. The M2 protein is only present in influenza A, so this drug is never effective for influenza B. Since 2012 influenza A has been resistant as well, so these drugs are no longer recommended. (due to mutated forms of M2) Baloxavir—a small molecule prodrug that selectively inhibits cap-dependent endonuclease preventing polymerase function and inhibiting influenza mRNA replication (Influenza polymerase complex is essential for the replication of influenza A and influenza B virus)

Acute decompensation after 72 hr of hospitilization?

Sepsis if CAP only issue- reconsider antibiotic coverage -better pseudomonal coverage

True

T/F Pseudomonas can be highly drug resistant

False (for pseudomonas may need double coverage.. make sure agent is active against MSSA/MRSA but double coverage is not needed)

T/F S. aureus requires double coverage if it is MRSA

Fluoroquinolone (Ciprofloxacin or Levofloxacin not Moxifloxacin because does not cover pseudomonas) or aminoglycoside (never use aminoglycoside as monotherapy in HAP- need to get in lung + there is resistance)

Two classes of antibiotics that may be used as 2nd anti-pseudomonal agent

CAP pathogens

Typical 1. Streptococcus pneumoniae (gram + cocci) 2. Haemophilus influenzae (gram - coccobacilli) 3. Moraxella catarrhalis (gram - diplococci) Atypical 1. Chlamydia pneumoniae 2. Mycoplasma pneumoniae 3. Legionella spp. Viruses Other organisms -Staphylococcus aureus -MSSA -MRSA -Pseudomonas aeruginosa (more common for nosocomial pneumonia than CAP based on risk factors)

Doxycycline 100 mg PO BID x 7 days (Levofloxacin 750 mg daily x 5d is not empiric treatment for those without comorbidities... Azithrmocyin 500 mg x1 to 250 mg daily x 4... there is too much resistance.. same with clarithromycin 250 mg PO BID x 7 d.. too much resistance for empiric treatment)

What is the best antibiotic regimen recommendation for RJ?

Streptococcus pneumoniae (odds is a virus.. of bacteria though streptococcus pneumoniae)

What is the most likely bacterial organism causing RJ's pneumonia?

Yes (it is greater than 20% with a MRSA prevalence of 39.7%)

Would empiric MRSA coverage be warranted in this scenario?