Midterm study guide-pharm2

Mechanisms of Bacterial Resistance

(1) inability of penicillins to reach their targets (PBPs), (2) inactivation of penicillins by bacterial enzymes (3) production of PBPs that have a low affinity for penicillins.

Classification based on antimicrobial spectrum fall into four major groups

(1) narrow-spectrum penicillins that are penicillinase sensitive (rendered useless by penicillinase bacteria) (2) narrow-spectrum penicillins that are penicillinase resistant (antistaphylococcal penicillins), (3) broad-spectrum penicillins (aminopenicillins), (4) extended-spectrum penicillins (antipseudomonal penicillins)

Patient-Centered Care Across the Life Span-Antimicrobials 1. Infants Infants are highly vulnerable to drug toxicity. Because of 2. Children/adolescents The tetracyclines are toxic b/c 3. Pregnant women Antimicrobial drugs can cross the 4. Breastfeeding women Antibiotics can enter breast milk, possibly affecting the 5. In the older adult, heightened drug sensitivity is due in large part

1. Infants • ​poorly developed kidney and liver function, neonates eliminate drugs slowly. Use of sulfonamides in newborns can produce kernicterus, a severe neurologic disorder caused by displacement of bilirubin from plasma proteins . 2. Children/adolescents • ​They bind to developing teeth, causing discoloration. 3. Pregnant women • ​placenta, posing a risk to the developing fetus. For example, when gentamicin is used during pregnancy, irreversible hearing loss in the infant may result. Antibiotic use during pregnancy may also pose a risk to the expectant mother. 4. Breastfeeding women • ​the nursing infant. For example, sulfonamides can reach levels in milk that are sufficient to cause kernicterus in nursing newborns. As a general guideline, abx should be avoided; If antimicrobial therapy is considered, the benefits should outweigh the risks. 5. Older adults • to reduced rates of drug metabolism and drug excretion, which can result in accumulation of antibiotics to toxic levels.

Prototype Drugs- Bacteriostatic Inhibitors of Protein Synthesis 1. Tetracycline 2. Macrolide 3. Oxazolidinone 4. Glycylcycline 5. Other

1. Tetracycline 2. Erythromycin 3. Linezolid 4. Tigecycline 5. Clindamycin

Antibiotic Stewardship 1. the single most important cause of the emergence of drug resistance

1. The widespread—and often inappropriate—use of antimicrobial agents Overuse occurs when providers: • fail to perform susceptibility testing. • overprescribe antibiotics for very young and very old patients or patients with multiple medical comorbidities. • succumb to pressure to prescribe.

Macrolides Azithromycin and clarithromycin: Antimicrobial Spectrum

Active against Gr + and Gr -, atypical infections

Selective Toxicity

As applied to antimicrobial drugs, selective toxicity indicates the ability of an antibiotic to kill or suppress microbial pathogens without causing injury to the host. Selective toxicity is the property that makes antibiotics valuable

Clostridiodies difficile Infection • bacteria origin • Toxins/Symptoms • Causes/Transmission

Bacteria origin • C. diff. is a gram-positive, spore-forming, anaerobic bacillus that infects the bowel. Toxins/Symptoms • Injury results from the release of two toxins: toxins A and B. • Symptoms range from mild (abdominal discomfort, nausea, fever, and diarrhea) to very severe (dehydration, electrolyte disturbances, toxic megacolon, pseudomembranous colitis, colon perforation, sepsis, and death) Causes/Transmission • CDI is almost always preceded by the use of abx, which kill off normal gut flora and allow C. diff. to flourish. • Antibiotics most likely to promote CDI are clindamycin, second- and third-generation cephalosporins, and fluoroquinolones • CDI is acquired by ingesting C. diff. spores, which are shed in the feces

Bactericidal drugs vs bacteriostatic drugs

Bactericidal drugs are directly lethal to bacteria at clinically achievable concentrations. • preferred for immunocompromised patients such as those with diabetes, HIV, or cancer and for those who have overwhelming infections • Agents: aminoglycosides, beta-lactams, fluoroquinolones, metronidazole, most antimycobacterial agents, streptogramins, and vancomycin bacteriostatic drugs can slow bacterial growth but do not cause cell death. • goal is to inhibit the bacterial proliferation while the host's immune system does the killing • Agents: clindamycin, macrolides, sulfonamides, and tetracyclines​

Classification of Antimicrobial Drugs • There are two main classification schemes

Classification by Susceptible Organism Antibacterial Drugs • Narrow Spectrum-Gram+ cocci/bacilli, Gram- aerobes, M. tuberculosis • Broad Spectrum-Gram+ cocci and gram- bacilli Antiviral Drugs • Drugs for HIV infection • Drugs for influenza • Other antiviral drugs-acycolvir Antifungal Drugs-amphotericin B; Azoles Classification by Mechanism of Action • Inhibitors of cell wall synthesis • Drugs that disrupt the cell membrane • Bactericidal inhibitors of protein synthesis • Bacteriostatic inhibitors of protein synthesis • Drugs that interfere with synthesis or integrity of bacterial DNA and RNA • Antimetabolites • Drugs that suppress viral replication

Clinical Use of PCNs

Commonly prescribed for infections seen in primary care​ Amoxicillin first line for acute otitis media and sinusitis​ Penicillin used for streptococcal pharyngitis​ Amoxicillin/clavulanate first line for infection following animal or human bites​

Three examples of how we achieve selective toxicity are discussed here.

Disruption of the Bacterial Cell Wall • Several families of drugs (e.g., penicillins and cephalosporins) weaken the cell wall and, hence, promote bacterial lysis. Because mammalian cells have no cell wall, drugs directed at this structure do not affect humans. Inhibition of an Enzyme Unique to Bacteria • bacteria must synthesize folic acid themselves, they cannot take up folic acid from the environment like mammalian cells can • bacteria first take up para-aminobenzoic acid (PABA), a precursor of folic acid, and then convert the PABA into folic acid. Sulfonamides block this conversion Disruption of Bacterial Protein Synthesis • protein synthesis is completed by ribosomes. However, bacterial and mammalian ribosomes are not identical • As a result, we can impair protein synthesis in bacteria while leaving mammalian protein synthesis untouched.

Linezolid • Drug Interactions • Adverse Effects

Drug Interactions • Linezolid is a weak inhibitor of monoamine oxidase (MAO) and hence poses a risk for hypertensive crisis. • MAO-I's can cause severe hypertension if combined with sympathomimetics-pts should avoid them ie: (ephedrine, pseudoephedrine, methylphenidate, cocaine) • Combining linezolid with a SSR) can increase the risk for serotonin syndrome/death; pts should avoid SSRIs (e.g., paroxetine [Paxil], duloxetine [Cymbalta]) Adverse Effects • most common side effects are diarrhea, nausea, & HA • Linezolid can cause reversible myelosuppression, manifesting as anemia, leukopenia, thrombocytopenia, or even pancytopenia. • Risk is related to the duration of use. • CBC counts should be done weekly. • Use cautiously in those with preexisting myelosuppression OR pts taking other myelosuppressive drugs, and those receiving linezolid for more than 2 weeks • Rarely, prolonged therapy has been associated with neuropathy; taking > 5mo

PCN Prescribing Diagram

Evaluating Therapeutic Effects: Monitor for indications of antimicrobial effects—reduction in fever, edema, pain, and inflammation.

Selecting the correct antibiotic involves special considerations to decrease the spread of antibiotic-resistant strains of bacteria • List the 4 factors considered when selecting a DOC

Host Pathogens Syndrome Drugs

Treatment of C. Diff • IDing the culprit Abx • Selecting the DOC • Initial episode: mild or moderate • Initial episode: fulminant • Treating recurrence

IDing the culprit Abx • after CDI has been diagnosed, the antibiotic that facilitated C. diff. overgrowth must be stopped because doing so (1) will reduce the risk for reinfection after CDI has cleared (2) in 25% of patients with mild CDI, it will cause the infection to resolve. Selecting the DOC • At the same time, an antibiotic to eradicate C. diff. should be started; Drug selection is based on number of previous episodes and infection severity as judged by two laboratory values: • WBC counts and SCr values Initial episode: mild or moderate • For initial occurrences of CDI, treatment with oral vancomycin or fidaxomicin, a narrow spectrum macrolide, is recommended Initial episode: fulminant • If the infection is diagnosed as fulminant—characterized by shock, megacolon, or hypotension—oral vancomycin is preferred. Treating recurrence • For the first recurrence of CDI, a pulsed vancomycin regimen with taper should be attempted. Metronidazole can be used in situations where oral vancomycin or fidaxomicin is not available

Patient-Centered Care Across the Life Span-Aminoglycosides Infants • Aminoglycosides are approved to treat bacterial infections in infants younger than Children/adolescents • Aminoglycosides are Pregnant women • There is evidence that use of aminoglycosides in pregnancy can Breastfeeding women • (blank) is probably safe to use during lactation Older adults • Caution must be used regarding decreased

Infants • 8 days. Dosing is based on weight and length of gestation. Children/adolescents • safe for use against bacterial infections in children and adolescents. Pregnant women • harm the fetus. Breastfeeding women • Gentamicin; although there is limited information Older adults • renal function in the older adult.

Patient-Centered Care Across the Life Span-Penicillins Infants • Penicillins are used safely in infants with Children/adolescents • Penicillins are a common drug used to treat Pregnant women • Although there are no well-controlled studies in pregnant women Breastfeeding women • (blank) is safe for use in breastfeeding mothers. Older adults • Doses should be adjusted in older adults with

Infants • bacterial infections, including syphilis, meningitis, and group A streptococcus. Children/adolescents • bacterial infections in children. Pregnant women • evidence we do have suggests there is no second or third trimester fetal risk. Breastfeeding women • Amoxicillin; Data are lacking regarding transmission of some other penicillins from mother to infant through breast milk. Older adults • renal dysfunction.

Patient Education 1. Finishing the Prescribed Course

It is imperative that antibiotics not be discontinued prematurely. Accordingly, patients should be instructed to take their medication for the entire prescribed course, even though symptoms may subside before the full course has been completed. Early discontinuation is a common cause of recurrent infection, and the organisms responsible for relapse are likely to be more drug resistant than those present when treatment began

Patient-Centered Care Across the Life Span-Tetracyclines Children/adolescents • Tetracyclines should not be used in children younger than Pregnant women • Animal studies reveal that tetracyclines can cause Breastfeeding women • Use of tetracyclines during tooth development can cause Older adults • Tetracyclines can interact with drugs, including

Life Stage Patient Care Concerns Children/adolescents • 8 years because they may cause permanent discoloration of the teeth. Pregnant women • fetal harm in pregnancy. Thus this class of drugs should be avoided in pregnant women. Breastfeeding women • permanent staining. Tetracyclines should be avoided by breastfeeding women. Older adults • digoxin. In the older adult who takes many medications, check for interactions.

Patient-Centered Care Across the Life Span Cephalosporins, Carbapenems, and Others Infants • Third-generation cephalosporins are used to Children/adolescents • Cephalosporins are commonly used to treat Pregnant women • (blank) carries a black box warning Breastfeeding women • (blank) are generally not expected to cause adverse effects in breastfed infants. Older adults • Doses should be adjusted in older adults with

Life Stage Patient Care Concerns Infants • treat bacterial infections in neonates as well as infants. Children/adolescents • bacterial infections in children, including otitis media and gonococcal and pneumococcal infections. Pregnant women • Televancin; secondary to risk for adverse developmental outcomes. All cephalosporins appear safe for use in pregnancy. Breastfeeding women • Cephalosporins Older adults • decreased renal function.

Clindamycin • Mechanism of Action • Antimicrobial Spectrum • Therapeutic Uses • Adverse Effects

Mechanism of Action • Clindamycin is usually bacteriostatic • Clindamycin binds to the 50S subunit of bacterial ribosomes and thereby inhibits protein synthesis • its binding site overlaps the binding sites for erythromycin and chloramphenicol making it an antagonizer of these drugs Antimicrobial Spectrum • is active against most anaerobic bacteria (gram-positive/negative) and most gram-positive aerobes ie: B. fragilis, Fusobacterium species, Clostridium perfringens, and anaerobic streptococci • Gram-negative aerobes are generally resistant • Resistance can be a significant problem with B. fragilis. Therapeutic Uses • Because of its efficacy against gram-positive cocci, clindamycin is widely as an alternative to penicillin • employed primarily for anaerobic infections outside the CNS (it does not cross the blood-brain barrier • Clindamycin is the DOC for severe group A streptococcal infection and for gas gangrene (an infection caused by Clostridium perfringens) b/c it can rapidly suppress synthesis of bacterial toxins Adverse Effects • Black Box Warning: Clindamycin can cause potentially fatal C. difficile assoc diarrhea (CDAD). Patients should promptly report any diarrhea to their health care provider. • CDAD is characterized by profuse, watery diarrhea (10 to 20 watery stools per day), abdominal pain, fever, and leukocytosis. Stools often contain mucus and blood • Sx may persist 4 to 6 weeks after clindamycin withdrawal • Tx of CDAD follows with oral vancomycin or metronidazole & Vigorous replacement therapy with fluids and electrolytes

Macrolides • Erythromycin will be the prototype for the macrolide family; The newer macrolides are azithromycin and clarithromycin • Mechanism of Action • Antimicrobial Spectrum • Therapeutic Uses

Mechanism of Action • Protein synthesis inhibition: erythromycin binds to the 50S ribosomal subunit and thereby blocks the addition of new amino acids to the growing peptide chain. • The drug is usually bacteriostatic but can be bactericidal against highly susceptible organisms or when present in high concentrations • its selectively toxic to bacteria because ribosomes in the cytoplasm of mammalian cells do not bind the drug Antimicrobial Spectrum • has an antibacterial spectrum similar to that of PCN • drug is active against most gram-positive bacteria as well as some gram-negative bacteria. • Bacterial sensitivity is determined by the ability of erythromycin to gain access to the cell interior Therapeutic Uses • erythromycin is the treatment of choice for acute diphtheria and for eliminating the diphtheria carrier state as well as Bordetella pertussis • may be used as an alternative to PCNs in pts w/allergy • macrolides and tetracyclines are DOC for certain chlamydial infections (urethritis, cervicitis) and for pneumonia caused by Mycobacterium pneumoniae

Linezolid • Linezolid (Zyvox) is a first-in-class oxazolidinone antibiotic • Mechanism of Action • Antimicrobial Spectrum • Therapeutic Uses

Mechanism of Action • drug binds to the 23S portion of the 50S ribosomal subunit and thereby blocks formation of the initiation complex. As a result, cross-resistance with other agents is unlikely • Resistance: is rare and only occured with prolonged use Antimicrobial Spectrum • active primarily against aerobic and facultative gram-positive bacteria • Susceptible pathogens include Enterococcus faecium (vancomycin-sensitive/resistant strains), Enterococcus faecalis (vancomycin-R strains), S. aureus (methicillin-sensitive/resistant strains), Staphylococcus epidermidis (including methicillin-R strains), and Streptococcus pneumoniae (penicillin-sensitive/resistant strains). Linezolid is not active against gram-negative bacteria, which readily export the drug. Therapeutic Uses • Linezolid is active against multidrug-resistant gram-positive pathogens, including VRE & MRSA; use should be limited this to prevent development of resistance • has 5 approved indications: • 1. Infections caused by VRE • 2. HAP caused by S. aureus (methicillin-S/R) or S. pneumoniae (penicillin-S only) • 3. CAP caused by S. pneumoniae (penicillin-S only) • 4. Complicated skin and skin structure infections caused by S. aureus (methicillin-S/R strains), Streptococcus pyogenes, or Streptococcus agalactiae • 5. Uncomplicated skin and skin structure infections caused by S. aureus (methicillin-S only) or S. pyogenes

Aminoglycosides • gentamicin, tobramycin, and amikacin • Mechanism of Action • Antimicrobial Spectrum • Therapeutic Uses

Mechanism of Action • these drugs bind to the 30S ribosomal subunit, causing inhibition & premature termination of protein synthesis, & production of abnormal proteins; these last two features is why they are bactericidal & NOT bacteriostatic • Cell kill is concentration dependent • resistance: Gram neg bacteria can produce of enzymes that can inactivate aminoglycosides; amikacin is least susceptible to inactivation by bacterial enzymes Antimicrobial Spectrum • Bactericidal effects are limited to aerobic gram-negative bacilli-including E. coli, Klebsiella pneumoniae, Serratia marcescens, Proteus mirabilis, and P aeruginosa • are inactive against most gram-positive bacteria & anaerobic organisms b/c their transport across the cell membrane is O2 dependent Therapeutic Uses • Parenteral Therapy: tx of serious infections from aerobic gram-negative bacilli. • Primary target organisms are P. aeruginosa (common in pts with Cystic Fibrosis) and the Enterobacteriaceae ie: E. coli, Klebsiella and Serratia species, P. mirabilis • gentamicin—is used in combination with either vancomycin or a beta-lactam Abx to treat serious infections with certain gram-positive cocci: Enterococcus species, some streptococci, and S. aureus • Selection depends on resistance; in settings where resistance to gentamicin and tobramycin is common, amikacin may be preferred • Topical Therapy: Gentamicin and tobramycin can treat eye infections, neomycin is for infections of ear and eye

Acquired Resistance to Antimicrobial Drugs • Over time, an organism that had once been highly sensitive to an antibiotic may become less susceptible, or it may lose drug sensitivity entirely. In some cases, resistance develops to several drugs

Organisms for which drug resistance is currently a serious problem include • Enterococcus faecium- • Staphylococcus aureus • Enterobacter species • Pseudomonas aeruginosa • Acinetobacter baumannii • Klebsiella species • lostridiodies difficile

Narrow-spectrum penicillins: penicillinase sensitive

Penicillin G, Penicillin V Susceptible Pathogens • Penicillin G is active against most gram-positive bacteria, gram-negative cocci (Neisseria meningitidis and non-penicillinase-producing strains of Neisseria gonorrhoeae), anaerobic bacteria, and spirochetes (including Treponema pallidum) • most gram-negative bacilli are resistant • most S. Aureus bacteria are resistant Pharmacokinetics • PCN V is given by IM (not stable in stomach as oral); comes bound with 4 salt compounds • PCN G is not acid sensitive and is given oral with food Distribution • In the absence of inflammation, penetration is poor in the cerebrospinal fluid, joints, and the eyes but enhanced when inflammation is present Metabolism and excretion • undergoes minimal metabolism and is eliminated by the kidneys Side Effects and Toxicities • Penicillin G is the least toxic of all antibiotics and is among the safest of all medications. • Probenecid (antigout med) prolongs the half-life of PCNs and increases risk for toxicity • allergic reactions, the principal concern with penicillin

Macrolides • Pharmacokinetics • Adverse Effects • Drug Interactions

Pharmacokinetics • Absorption and bioavailability: PO tabs are available in three forms: erythromycin base and two derivatives; The base is unstable in stomach acid; the derivatives were synthesized to improve bioavailability; food decreases absorption of all except erythromycin ethylsuccinate • Distribution: Erythromycin readily distributes to most tissues and body fluids including the placenta but harm to the fetus hasn't been found • Erythromycin is eliminated primarily by hepatic mechanisms concentrated in the liver and then excreted in the bile Adverse Effects • is considered one of the safest antibiotics. • there's a rare risk for sudden cardiac death from QT prolongation; When erythromycin is combined with a CYP3A4 inhibitor, there is a fivefold increase in the risk for sudden cardiac death—class IA or III antidysrhythmic drugs AND CYP3A4 inhibitors: • calcium channel blockers (verapamil and diltiazem • azole antifungal drugs e.g., ketoconazole, • HIV protease inhibitors (e.g., ritonavir, saquinavir • nefazodone-an antidepressant • GI disturbances (epigastric pain, nausea, vomiting, diarrhea) are the most common side effects; These can be reduced by administering erythromycin with meals. but should only be with erythromycin ethylsuccinate or enteric-coated formulations of erythromycin base Drug Interactions • Erythromycin is a CYP450 inhibitor can increase the plasma levels and half-lives of several drugs: • theophylline, carbamazepine (used for szs and bipolar disorder), and warfarin may become elevated • prevents binding of chloramphenicol & clindamycin to bacterial ribosomes, thereby antagonizing their antibacterial effects; should NOT be used concurrently • drugs that can inhibit erythromycin metabolism and can raise its levels are CYP3A4 inhibitors verapamil, diltiazem, HIV protease inhibitors, and azole antifungal drugs

Cephalosporins • Pharmacokinetics • Adverse Effects • Drug Interactions

Pharmacokinetics • Because of poor absorption from the (GI) tract, many cephalosporins must be administered IM or IV; some can be admin by PO • Distribution: Therapeutic concentrations are achieved in pleural, pericardial, and peritoneal fluids; concentrations in ocular fluids are low. Penetration to the CSF by 1st/2nd-generation drugs is unreliable • bactericidal CSF levels can be achieved with 3rd, 4th and 5th-generation drugs • Elimination: all cephalosporins are eliminated by the kidneys, In patients with renal insufficiency, dosages of most cephalosporins must be reduced, One ceph—ceftriaxone—is eliminated largely by the liver Adverse Effects • Hypersensitivity reactions are the most frequent adverse event ie: Maculopapular rash that develops several days after • Cephalosporins have been reported with type I allergic reactions, serum sickness-like reactions, and other skin rashes, arthralgia, and fever • the incidence of cross-reactivity has been low: only 1% of PCN-allergic patients experience an allergic reaction; but cephs are contraindicated it pts with severe PCN allergies Drug interactions • cefazolin and cefotetan—can induce a state of alcohol intolerance; the disulfiram effect can be very dangerous pts taking these drgs should avoid alcohol • Cefotetan, cefazolin, and ceftriaxone can promote bleeding as they interfere with Vitamin K metabolism; Caution is needed if these drugs are combined with other bleeding agents (anticoagulants, thrombolytics, NSAIDs, and other antiplatelet agents)

Tetracyclines • Pharmacokinetics • Adverse Effects • Drug and Food Interactions

Pharmacokinetics • Individual tetracyclines differ significantly in their pharmacokinetic properties. • Of particular significance are differences in half-life and route of elimination. • food/acidity decreases absorption of some Adverse Effects • Gastrointestinal Irritation Tetracyclines irritate the (GI) tract causing: epigastric burning, cramps, nausea, vomiting, and diarrhea. • These SE may be minimized by giving with meals, although food may decrease absorption • Because diarrhea may result from superinfection of the bowel (in addition to nonspecific irritation), it is important that the cause of diarrhea be determined • Tetracyclines bind to calcium in developing teeth, resulting in yellow or brown discoloration and hypoplasia of the enamel; after the fourth month of gestation can cause staining of teeth of the infant • Discoloration of permanent teeth occurs when tetracyclines are taken by children aged 4 months to 8 years; avoid in children <8 yrs • Superinfection: due to broad-spectrum action • Hepatotoxicity-Tetracyclines can cause fatty infiltration of the liver; highest risk when administered IV in high doses >2 g/d; Pregnant and postpartum women with kidney disease are at especially high risk • Renal Toxicity-tetracycline and demeclocycline are contraindicated in pts with renal impairment (these drugs are excreted by kidneys); doxycycline or minocycline are safe with renal impairment because these drugs are eliminated primarily by the liver Drug and Food Interactions • tetracyclines can form nonabsorbable chelates with certain metal ions (calcium, iron, magnesium, aluminum, zinc) found in milk products, calcium supplements, iron supplements, magnesium-containing laxatives, and most antacids resulting in decreased absorption • To minimize interference with absorption, tetracyclines should be administered at least 1 hour before or 2 hours after ingestion of chelating agents

Aminoglycosides • pharmacokinetics • Drug Interactions • Adverse Effects

Pharmacokinetics • aminoglycosides are highly polar & cannot readily cross membranes. As a result, they are not absorbed from the GI tract, do not enter CSF fluid, and are rapidly excreted by the kidneys • Interpatient Variation: in pts receiving the same dosage (mg/kg of body weight) there is widely different serum levels; as such peak/trough levels must be monitored • Distribution: Aminoglycosides bind tightly to renal tissue, causing nephrotoxicity; they can penetrate readily into the lymph of the inner ears and can thereby cause ototoxicity; this is associated with high trough levels more-so than peak levels • Aminoglycosides can cross the placenta and may be toxic to the fetus • they are eliminated primarily by the kidneys. These drugs are not metabolized; dosages must be reduced in patients with kidney disease Drug Interactions • The risk for injury to the ears is increased by concurrent use of loop diuretics—these combinations should be avoided. • The risk for renal damage is increased by concurrent therapy with other nephrotoxic agents Adverse Effects • Black Box Warning: Ototoxicity: All aminoglycosides can accumulate within the inner ears, causing irreversible injury that can impair both hearing and balance • Black Box Warning: Neurotoxicity: sx may include numbness, tingling, muscle twitching, and seizures • Black Box Warning: Nephrotoxicity: highest risk increases in pts w/ prolonged use and with preexisting renal impairment; injury to the kidneys usually reverses after aminoglycoside use is stopped • This risk of all of the above increases in pts on prolonged use and in pts with preexisting renal impairment

PCN classification diagram

Streptococcus spp. are anaerobic, Gram positive, spherical or ovoid cocci that usually occur in chains, but may also be single or in pairs

Prototype: Imipenem (Primaxin) • Susceptible Pathogens/Therapeutic Use • Mechanism of Action • Pharmacokinetics • Drug Interactions • Adverse Effects

Susceptible Pathogens/Therapeutic Use • imipenem is the most effective β-lactam antibiotic for use against anaerobic bacteria • The drug is effective for serious infections caused by gram-positive/negative cocci, gram-negative bacilli, and anaerobic bacteria • Its broad spectrum makes it useful for mixed infections ie: aerobic/anaerobic bacteria • should not be given alone for P. aeruginosa, as resistant organisms have emerged Mechanism of Action • Imipenem binds to two PBPs, causing weakening of the bacterial cell wall with subsequent cell lysis and death • Antimicrobial effects are enhanced by the drug's resistance to practically all β-lactamases and by its ability to penetrate the gram-negative cell envelope Pharmacokinetics • not absorbed from the GI tract and, hence, must be given IV; it does penetrate the CSF • elimination is primarily renal Drug Interactions • Imipenem can reduce blood levels of valproate, an anti-seizures med; the combo should be avoided Adverse Effects • GI effects (nausea, vomiting, and diarrhea) are most common • Superinfections with bacteria/fungi develop in about 4% of patients • Hypersensitivity reactions (rashes, pruritus, and drug fever) have occurred in pts with cross-sensitivity allergies to other β-lactam abx

Mechanism of Action of Cephalosporins

The cephalosporins are bactericidal drugs with a mechanism similar to that of the penicillins. These agents bind to PBPs and, hence, (1) disrupt cell wall synthesis (2) activate autolysins • cephalosporins are most effective against cells undergoing active growth and division

Monitoring Antimicrobial Therapy

The frequency of monitoring is directly proportional to the severity of infection. Important clinical indicators of success are reduction of fever and resolution of signs and symptoms related to the affected organ system (e.g., improvement of breath sounds in patients with pneumonia Success of therapy is indicated by the disappearance of infectious organisms from posttreatment cultures. • Cultures may become sterile within hours of the onset of tx (ie: UTIs), or take weeks (Ie: TB).

Other Inhibitors of Cell Wall Synthesis Telavancin • Therapeutic Use/Pathogen Susceptibility • Adverse Effects • Drug Interactions

Therapeutic Use/Pathogen Susceptibility • telavancin is active only against gram-positive bacteria: S. aureus (including MRSA), Streptococcus pyogenes/agalactiae, Streptococcus anginosus group, and Enterococcus fecalis (but only vancomycin-sensitive strains). • To delay development of resistance, telavancin should be reserved for treating vancomycin-resistant infections or for use as an alternative to linezolid (Zyvox), Adverse Effects • can cause multiple adverse effects. The most common are taste disturbance, nausea, vomiting, and foamy urine • Black Box Warning: • used to treat HAP/VAP in patients with a Cr clearance of less than 50 mL/min, has been associated with increased mortality • can prolong the QT intervals • Contraindicated in pregnancy Drug Interactions • should be used with caution with drugs that damage the kidneys (e.g., NSAIDs, ACE-inhibitors, and aminoglycosides) and in drugs that prolong the QT interval (e.g., clarithromycin and ketoconazole)

Vancomycin • Therapeutic Use/Pathogen Susceptibility • Mechanism of Action • Pharmacokinetics • Adverse Effects

Therapeutic Use/Pathogen Susceptibility • Vancomycin should be reserved for serious infections • DOC for infections caused by MRSA, S. epidermidis, and severe not mild C. Diff Mechanism of Action • vancomycin inhibits cell wall synthesis and, therefore, promotes bacterial lysis and death • in contrast to the β-lactams, vancomycin does not interact with PBPs. Instead, it disrupts the cell wall by binding to molecules that serve as precursors for cell wall biosynthesis Pharmacokinetics • Absorption from the GI tract is poor. Hence vancomycin is given parenterally for most infections. • PO admin is employed only for C. Diff infections • Vancomycin is well distributed to most body fluids and tissues. Although it enters the CSF, levels are insufficient to treat meningitis • Vancomycin is eliminated unchanged by the kidneys. In patients with renal impairment, dosage must be reduced Adverse Effects • Renal toxicity remains a major adverse effect; risk is increased by concurrent use of other nephrotoxic drugs e.g., aminoglycosides, cyclosporine, and NSAIDs

Broad-spectrum penicillins (aminopenicillins)

ie: Ampicillin, Amoxicillin Susceptible Pathogens • same antimicrobial spectrum as penicillin G, • plus increased activity against certain gram-negative bacilli, including Haemophilus influenzae, E. coli, and Salmonella and Shigella species. • The broadened spectrum is mainly due to an increased ability to penetrate the gram-negative cell envelope • rendered ineffective by β-lactamases and, hence, are useless against most S. aureus • Ampicilin is indicated for Enterococcus fecalis, Proteus mirabilis • Amoxicillin is available in a fixed-dose combination with clavulanic acid, an inhibitor of bacterial β-lactamases Pharmacokinetics • In oral therapy, amoxicillin is preferred Adverse effects • Ampicillin: rash and diarrhea are most common with ampicillin than any other Abx; non-allergic rash in 5% to 10% of children • Amoxicillin causes milder diarrhea when compared with ampicillin

Narrow-spectrum penicillins: penicillinase resistant (antistaphylococcal penicillins)

ie: Nafcillin, Oxacillin, Dicloxacillin Susceptible Pathogens • chemists have created a group of penicillins that are highly resistant to inactivation by β-lactamases • These agents have a very narrow antimicrobial spectrum; used only against staphylococcal infections w/ penicillinase ie: S. aureus and S. epidermidis • not affective against MRSA; vanc is the DOC Pharmacokinetics • dicloxacillin is better absorbed than ampicillin

Extended-Spectrum Penicillins (Antipseudomonal Penicillins)

ie: piperacillin Susceptible Pathogens • H. influenzae, E. coli, enterococci, Neisseria gonorrhoeae, ​ used mainly for Pseudomonas aeruginosa, Enterobacter species, Proteus species (indole positive), Bacteroides fragilis, and many Klebsiella species. to increase killing of P. aeruginosa can be combined with an aminoglycoside ie: gentamicin, tobramycin • susceptible to β-lactamases and, hence, is ineffective against most strains of S. aureus. • available in a fixed-dose combination with tazobactam, a β-lactamase inhibitor (Zosyn) Pharmacokinetics • acid labile and, hence, must be administered parenterally, usually by the IV Adverse effects • can cause bleeding secondary to disrupting platelet function • Dosage should be reduced in patients with renal impairment

Tetracyclines • Mechanism of Action • Antimicrobial Spectrum • Therapeutic Uses

ie:—tetracycline, demeclocycline, doxycycline, eravacycline Mechanism of Action • tetracyclines are bacteriostatic • tetracyclines suppress bacterial growth by inhibiting protein synthesis by binding to the 30S ribosomal subunit and thereby inhibit binding of transfer RNA to the messenger RNA-ribosome complex. As a result, addition of amino acids to the growing peptide chain is prevented. • Selective toxicity of the tetracyclines results from their poor ability to cross mammalian cell membranes Antimicrobial Spectrum • broad-spectrum abx, active against a wide variety of gram-positive/negative bacteria. • Sensitive organisms include Rickettsia, spirochetes, Brucella, Chlamydia, Mycoplasma, H. pylori, Borrelia burgdorferi, Bacillus anthracis, and Vibrio cholerae Therapeutic Uses • Because of resistance and because abx with greater selectivity and less toxicity are now available, tetracyclines are rarely drugs of first choice • Disorders for which they are DOC include (1) rickettsial diseases (e.g., Rocky Mountain spotted fever, typhus fever, Q fever) (2) infections caused by Chlamydia trachomatis (trachoma, lymphogranuloma venereum, urethritis, cervicitis); (3) brucellosis; (4) cholera; (5) pneumonia caused by Mycoplasma pneumoniae; (6) Lyme disease; (7) anthrax; (8) gastric infection with H. pylori. Other uses • Tetracyclines are used topically and orally for severe acne vulgaris • H. pylori- causing PUD. Tetracyclines, in combination with metronidazole and bismuth subsalicylate, are DOC • Periodontal Disease-Doxycycline is used orally and topically whereas minocycline is used only topically

Common Misuses of Antibiotics Prolonged empiric antimicrobial treatment without clear evidence of bacterial infection. ​

​ • Some noninfectious, inflammatory, or neoplastic processes can present with s/sx that mimic infectious diseases - fever of unk origin • ie: connective tissue disorders that present with high fever; drug-induced fever; the fever associated with PE; lymphoma; and Wegener granulomatosis, cavitary pulmonary nodules, and recurrent sinusitis; the only time ​fever, by itself is tx'ed with abx is in severely immunocompromised host • Responsible prescribing: use antibiotics for the shortest effective duration. • ​if symptoms are not resolved by antibiotic therapy, consider further investigation.​ • avoid antibiotic treatment for community-acquired, mostly viral, upper respiratory tract infections​; these infections are usually viral patients are exposed to all the risks of abx but have no chance of receiving benefits

Cephalosporins Therapeutic Uses • the similarities among cephalosporins are more pronounced than the differences. • aside from cost, there is frequently no rational basis for choosing one drug over another in the outpatient setting • The main differences btw Ceph generations are (1) antimicrobial spectrum, (2) adverse effects, (3) pharmacokinetics

• 1. First-generation have a narrow spectrum; used for Gram-positive Staph/streptococci, as an alternative in pts with a mild PCN allergy, surgical prophylaxis • 2. Second generation have a broader spectrum; used for Gram-positive/negative infections ie: H. influenzae, Klebsiella, pneumococci, and staphylococci Otitis, sinusitis, and respiratory tract infections • 3. Third generation have a broader spectrum than 1st/2nd; used for Gram-negative infections: P. aeruginosa, N. gonorrhoeae, and Klebsiella, Serratia Meningitis • 4. Fourth-generation have a narrow spectrum; used for Gram-negative, P. aeruginosa, Hospital-acquired pneumonia (HAP) and complicated intra-abd and UTIs • 5. Fifth generation have a narrow spectrum; used for Gram-positive MRSA

Community-Associated Methicillin-Resistant Staphylococcus aureus

• 20% and 30% of the population is colonized, typically on the skin and in the nostrils • CA-MRSA causes mild infections of the skin and soft tissues, manifesting as boils, impetigo, and so forth. However, CA-MRSA can also cause more serious infections, including necrotizing fasciitis, severe necrotizing pneumonia but these are rare • CA-MRSA infection is seen primarily in young, healthy people with no recent exposure to health care facilities. Individuals at risk include athletes in contact sports (e.g., wrestling), men who have sex with men, and people who live in close quarters ie: inmates, college students • To eradicate the carrier state, intranasal application of a topical antibiotic—mupirocin or retapamulin—can be effective. Like HCA-MRSA, CA-MRSA does not respond to β-lactam antibiotics, except ceftaroline, a fifth generation cephalosporin.

Skin tests for penicillin allergy

• Allergy to penicillin can decrease over time. Hence in patients with a history of penicillin allergy, skin tests can be used to assess current risk • These tests are performed by injecting a tiny amount of allergen intradermally and observing for a local allergic response. • A positive test indicates the presence of IgE antibodies, which can mediate severe penicillin allergy. Accordingly, if skin testing is negative, anaphylaxis is unlikely • skin testing can be dangerous: in patients with severe penicillin allergy, the skin test itself can precipitate an anaphylactic reaction. Accordingly, providers should have epinephrine and respiratory support immediately available

Host • First, consider the patient or host. Host factors that influence prescribing include:​

• Allergy: history of allergy, cross-allergy or intolerance Severe allergic reactions are more common with PCNs​; Skin testing is available to distinguish true penicillin allergy from other reactions • Preexisting conditions: HIV, cancer, autoimmune disorders, diabetes​-immunocompromised host: our only hope lies with drugs that are rapidly bactericidal, and even these may prove inadequate • Renal/hepatic function: doses may need to be reduced. Creatinine clearance must be considered.​ • Age: dose adjustments may be required for pediatric and geriatric patients. Weight-based doses may be appropriate. ​ • Pregnancy and lactation: Teratogenic effects of certain classes of medications must be considered.​ Recent antibiotic use: Possible drug resistant bacteria must be considered.​ • Exposure history: travel, congregate care settings, close contacts • Genetic Factors: pts with glucose-6-phosphate dehydrogenase (G6PD) should not be given SULFA antibiotics that are likely to induce red cell lysis

Common Misuses of Antibiotics Omission of Surgical Drainage

• Antibiotics may be unable to penetrate abscesses b/c of the presence of foreign material, necrotic tissue, or exudate. • Hence, when appropriate, surgical drainage and cleansing should be performed to promote antimicrobial effects

Penicillins Combined With a β-Lactamase Inhibitor

• By combining a β-Lactamase Inhibitorwith a penicillinase-sensitive penicillin, we can extend the antimicrobial spectrum of the penicillin • The following 5 PCN/β-Lactamase Inhibitors are listed below • Ampicillin/sulbactam (Unasyn) • Amoxicillin/clavulanate (Augmentin and Clavulin ) • Piperacillin/tazobactam (Zosyn & Tazocin) • adverse effects that occur with the combination products are due to the penicillin.

Altered Penicillin-Binding Proteins (3) production of PBPs that have a low affinity for penicillins.

• Certain bacterial strains, known collectively as MRSA, have a unique mechanism of resistance: production of PBPs with a low affinity for penicillins and all other β-lactam antibiotics. • MRSA developed this ability by acquiring genes that code for low-affinity PBPs from other bacteria • MRSA, are resistant not only to methicillin (now obsolete), but also to all penicillins and most cephalosporins as well. • The basis of MRSA resistance is acquisition of genes that code for PBPs that have very low affinity for penicillins and cephalosporins • There are two distinct types of MRSA, referred to as health care−associated MRSA (HCA-MRSA) and community-associated MRSA (CA-MRSA) • HCA-MRSA infection is generally more serious and harder to treat and more prevalent

Combination therapy of Aminoglycosides & drugs that weaken the cell wall

• Drugs that weaken the bacterial cell wall act in concert with aminoglycosides to enhance bacterial kill As such Aminoglycosides are frequently given with Beta-lactam drugs • penicillins • cephalosporins • vancomycin

Common Misuses of Antibiotics Treatment of a positive clinical culture in the absence of signs and symptoms of active infection.

• Examples: colonization of the urinary tract in women of advanced age or in the presence of an indwelling urinary catheter, colonization of endotracheal tubes in mechanically ventilated patients, and colonization of chronic wounds. ​ • Responsible prescribing: obtain cultures from the site and treat only when signs of active infection are present​

health care−associated MRSA (HCA-MRSA)

• For complicated skin and soft tissue infections in adults, the preferred drugs are intravenous (IV) vancomycin, linezolid (Zyvox), daptomycin • IV vancomycin is the preferred drug for children • Preferred drugs for pneumonia in adults and children are IV vancomycin, linezolid, and clindamycin. • Because most strains of MRSA are multidrug resistant, many other antibiotics are ineffective, including tetracyclines, clindamycin, trimethoprim/sulfamethoxazole, and β-lactam agents (except ceftaroline).

Other Inhibitors of Cell Wall Synthesis Fosfomycin

• Fosfomycin (Monurol) is a unique antibiotic approved for single-dose therapy in women with uncomplicated UTIs (i.e., acute cystitis) caused by E. coli or E. faecalis • Sx of cystitis should improve in 2 to 3 days. If symptoms fail to improve, additional doses will not help but will increase the risk for side effects.

Common Misuses of Antibiotics Excessive use of certain antimicrobial agents

• Frequent use of certain agents or antibiotic classes in a particular setting may result in organisms that are resistant to that antibiotic. ​ • Example: increased use of fluoroquinolones may be partly responsible for the epidemic of a fluoroquinolone-resistant strain of C difficile.​ • Responsible prescribing: avoid the excessive prescribing of a single class of antibiotic

Alternative drugs to patients with a history of penicillin allergy

• If the allergy is mild, a cephalosporin is often an appropriate alternative • oral cephalosporin is preferred (because the risk for a severe reaction is lower than with parenteral therapy • For many infections, vancomycin, erythromycin, and clindamycin are effective and safe alternatives • a life-threatening infection (e.g., enterococcal endocarditis) may req the use of PCNs in this case a desensitization schedule should be used • In this procedure, an initial small dose is followed at 60-minute intervals by progressively larger doses until the full therapeutic dose has been achieved

Common Misuses of Antibiotics Improper Dosage

• If the dosage is too low, the patient will be exposed to a risk for adverse effects without the benefit of antibacterial effects. • If the dosage is too high, the risks for superinfection and adverse effects become unnecessarily high • A superinfection is a new infection that appears during the course of treatment for a primary infection. They develop when abx (ie broad spectrum) eliminate the inhibitory influence of normal flora, thereby allowing a second infectious agent to flourish

Mechanism of Action of Penicillins

• Inside the cytoplasmic membrane of bacteria, osmotic pressure is very high. Hence, were it not for the rigid cell wall, which prevents expansion, bacteria would take up water, swell, and then burst. • Penicillins weaken the cell wall, causing bacteria to take up excessive amounts of water and rupture. As a result, penicillins are generally bactericidal. • Penicillins weaken the cell wall by two actions: (1) inhibition of transpeptidases • Transpeptidases create cross-bridges between the peptidoglycan strands, giving the cell wall added strength. By inhibiting transpeptidases, penicillins prevent cross-bridge synthesis and, hence, weaken the cell wall (2) disinhibition (activation) of autolysins • Autolysins are bacterial enzymes that cleave bonds in the cell wall • The molecular targets of the PCN's (transpeptidases, autolysins) are collectively known as penicillin-binding proteins (PBPs) Bacteria express PBPs only during growth and division. • Accordingly, because PBPs must be present for penicillins to work, these drugs work only when bacteria are growing

Penicillin Allergy

• Penicillins are the most common cause of drug allergy • Severity can range from a minor rash to anaphylaxis • there is no direct relationship between the size of the dose and the intensity of the response • Because of cross sensitivity, patients allergic to one penicillin should be considered allergic to all other penicillins. In addition, a few patients (approximately 1%) display cross sensitivity to cephalosporins • patients with penicillin allergy should not be treated with any member of the penicillin family • The use of cephalosporins depends on the intensity of allergic response • Penicillin reactions are classified as immediate, accelerated, and delayed. Immediate reactions occur 2 to 30 minutes (anaphylaxis) after drug administration; accelerated reactions occur within 1 to 72 hours; and delayed reactions occur within days to weeks

Other Inhibitors of Cell Wall Synthesis Vancomycin

• Principal indications are C. difficile infection, MRSA infection, and tx of serious infections with susceptible organisms in patients allergic to PCNs • Unlike most other drugs discussed here, vancomycin does not contain a β-lactam ring

Common Misuses of Antibiotics Prolonged prophylactic therapy

• Prolonged prophylaxis use of antibiotics promotes the emergence of antimicrobial resistance. ​ • Responsible prescribing: to prevent post-op infection, evidence supports the use of a single, preoperative dose of an antimicrobial agent.

Common Misuses of Antibiotics Failure to narrow antimicrobial therapy when a causative organism is identified.

• Responsible prescribing: once culture and susceptibility data are available, select an antibiotic with the narrowest possible spectrum for continuation of therapy. ​ • broad-spectrum agents do the most to facilitate emergence of resistance

Prophylactic Use of Antimicrobial Drugs • Much of this prophylactic use is uncalled for • Generally approved indications for prophylaxis include

• Surgery: cardiac surgery, peripheral vascular surgery, orthopedic surgery, G and Iwomen undergoing a hysterectomy or an emergency cesarean section; should be given before the surgery; a first-generation cephalosporin (e.g., cefazolin) will suffice usually a one-time dose unless surgery was unusually prolonged • Bacterial Endocarditis: Individuals with congenital or valvular heart disease and those with prosthetic heart valves are susceptible to bacterial endocarditis. They should receive abx prophylaxis for certain dental and medical procedures that dislodge bacteria into the bloodstream. • Neutropenia: benefits must be > risks • Other Indications: exposure to STDs, recurrent urinary tract infection and prophylaxis against influenza

Gram-Negative Cell Envelope (1) inability of penicillins to reach their targets (PBPs),

• The cell envelope of gram-positive bacteria has only two layers, and can be readily penetrated by penicillins • the outer membrane of gram neg bacteria is difficult to penetrate. As a result, only certain penicillins (e.g., ampicillin) are able to cross it and, thus, reach PBPs on the cytoplasmic membrane

Patient Education & Provider monitoring

• The first sign of impending cochlear damage is high-pitched tinnitus. Ototoxicity is largely irreversible. • Accordingly, aminoglycosides should be withdrawn at the first sign of damage (i.e., tinnitus, persistent headache, or both). • hearing loss begins in the high-frequency range then progresses to Loss of low-frequency • The first sign of impending vestibular damage is headache, which may last for 1 or 2 days. • After that, nausea, unsteadiness, dizziness, and vertigo begin to appear. • Pts should be informed about the sx of vestibular and cochlear damage and instructed to report them • Aminoglycoside-induced nephrotoxicity usually manifests as acute tubular necrosis. • Prominent sx are proteinuria, casts in the urine, production of dilute urine, and elevations in serum creatinine and (BUN).

Summary of Key Prescribing Considerations-Penicillin

• Therapeutic Goal: Treatment of infections caused by sensitive bacteria, Defining tests (rapid strep) vs. empiric method, and Cost • Baseline Data: Samples for microbiologic culture to identify the infecting organism • Monitoring: Renal impairment can cause penicillins to accumulate to toxic levels. Monitor function in patients with renal disease, allergy symptoms​, C.diff diarrhea​ • Identifying High-Risk Patients: Penicillins should be used with extreme caution in patients with a history of severe allergic reactions to penicillins, cephalosporins, or carbapenems. • Evaluating Therapeutic Effects: Monitor for indications of antimicrobial effects—reduction in fever, edema, pain, and inflammation. • Minimizing Adverse Effects: For patients with prior allergic responses, a skin test may be ordered to assess current allergy status.

Summary of Key Prescribing Considerations-Carbapenems

• Therapeutic Goal: Treatment of infections caused by susceptible organisms. • Baseline Data: Take samples for culture to determine the identity and sensitivity of the infecting organism. • Monitoring: No routine laboratory monitoring is suggested. • Identifying High-Risk Patients: Patients using valproate to control seizures should not be placed on imipenem. • Evaluating Therapeutic Effects: Monitor for indications of antimicrobial effects, including reduction in fever, pain, edema, and inflammation. Minimizing Adverse Effects: Dosage should be reduced in patients with renal impairment

Summary of Key Prescribing Considerations-Cephalosporins

• Therapeutic Goal: Treatment of infections caused by susceptible organisms. • Baseline Data: Take samples for culture to determine the identity and sensitivity of the infecting organism. • Monitoring: Renal fxn for prolonged therapy • Identifying High-Risk Patients: Cephalosporins are contraindicated for patients with a history of allergic reactions to cephalosporins or severe reactions to penicillin. • Evaluating Therapeutic Effects: Monitor for indications of antimicrobial effects, including reduction in fever, pain, edema, and inflammation. • Minimizing Adverse Effects: All cephalosporins can promote C. difficile infection. Instruct patients to report an increase in stool frequency

Summary of Key Prescribing Considerations-Vancomycin

• Therapeutic Goal: Treatment of serious infections, including C. diff. infection, infection with methicillin-resistant S. aureus, and serious infections caused by susceptible organisms in patients allergic to penicillin. • Baseline Data: Take samples for culture to determine the identity and sensitivity of the infecting organism. • Monitoring: Vancomycin drug levels should be monitored during IV administration. • Identifying High-Risk Patients: Use with caution in patients with renal impairment. • Evaluating Therapeutic Effects: Monitor for indications of antimicrobial effects, including reduction in fever, pain, edema, and inflammation.

Pathogens • consider the pathogens that may be causing the illness. Although there are outliers, there are typical pathogens that cause infection for each body system.

• Understanding the common pathogens and the antibiotics to which they are susceptible is essential to proper prescribing. ​ • Cultures are the most accurate way to identify pathogens. Understanding the sensitivity and resistance reporting on an organism grown from a culture is critical to determining appropriate treatment. • The quickest, simplest, and most versatile technique for identifying microorganisms is microscopic examination of a Gram-stained preparation • A relatively new method, known as the polymerase chain reaction (PCR) test or nucleic acid amplification test, can detect very low titers of bacteria and viruses • Compared with Gram staining, PCR tests are both more specific and more sensitive. It may take several days for a culture to grow. Once culture results are available, treatment may be adjusted accordingly. ​ • samples for cultures should be obtained before drug therapy starts. • Before cultures result-drug selection must be based on clinical evaluation and knowledge of which microbes are most likely to cause infection at a particular site. If necessary (for severe NOT limited infections), a broad-spectrum agent can be used for initial treatment Determining Drug Susceptibility • sensitivity testing is not always needed. Rather, testing is indicated only when the infecting organism is one in which resistance is likely ie: A streptococci-are susceptible to penicillin G (so sensitivity testing is unnecessary). In contrast, resistance is common, with S. aureus and the gram-negative bacilli, (so tests for drug sensitivity should be performed) How is susceptibility determined? • ​Antimicrobial Susceptibility Testing (AST) • ​Lab test to determine how pathogen grows while exposed to specific drugs (in a petri dish)​ Results are reported as • ​susceptible • ​resistant • ​intermediate​

How can the spread of C Diff (CDI) be controlled? The IDSA guidelines offer the following recommendations:

• Use antibiotics judiciously, especially those associated with a high risk for CDI (clindamycin, cephalosporins, and fluoroquinolones). • If possible, isolate patients with CDI in a private room or have them share a room with another CDI pt. • Wear gloves/gown when caring for a patient with CDI. • wash hands with soap and running water. Soap and water will not kill C. diff. spores but will flush them off the hands. Alcohol-based hand rubs will not kill spores and will not remove them from the hands. • Use disposable medical equipment when possible. • decontaminate surfaces with a chlorine-containing cleaning agent (or any other agent that can kill C. diff. spores).

Syndrome • consider the syndrome, or presenting illness.​

• What system is impacted?​ • How aggressive is the infection?​ • Consider non-bacterial causes of symptoms (i.e. viral, fungal, or non-infections)​ • Carefully examine the clinical presentation of illness.​ • Site of Infection-drug access can be impeded in meningitis (because of the blood-brain barrier), endocarditis (because bacterial vegetations in the heart are difficult to penetrate), and infected abscesses (because of poor vascularity and the presence of purulent material)

Drugs • Once careful consideration is given to the host, syndrome, and pathogen, antibiotics may be prescribed. Antibiotic selection is based on a drug's unique features and selective toxicity to pathogens. Considerations include: ​

• adverse effects​ • cost​ • drug interactions​ • need for therapeutic monitoring ​serum drug concentrations required for some drugs with narrow therapeutic window, like vancomycin and aminoglycosides​-peak and trough levels must be drawn to ensure safety and efficacy​ • efficacy at infection site-​only a few drugs penetrate barriers at the brain, joints, eyes, and testes​ • ​Dosage and Duration of Treatment: Success requires that the antibiotic be present at the site of infection in an effective concentration for a sufficient time; Drug levels 4 to 8 times the MIC are often desirable; Duration of therapy depends on the status of host defenses, the site of the infection, and the identity of the infecting organism

Intro to Aminoglycosides

• are narrow-spectrum antibiotics used primarily against aerobic gram-negative bacilli. • They disrupt protein synthesis, resulting in rapid bacterial death • Because of these toxicities, indications for these drugs are limited; mainly for systemic infections • absorbed poorly in (GI) tract and must be administered parenterally

Intro to Carbapenems Four carbapenems are available: • imipenem, meropenem, ertapenem, and doripenem

• are β-lactam antibiotics that have very broad antimicrobial spectra • none is active against MRSA • these drugs should be reserved for patients who cannot be treated with a more narrow-spectrum agent

Other Inhibitors of Cell Wall Synthesis Aztreonam

• belongs to a class of β-lactam antibiotics known as monobactams. These agents contain a β-lactam ring, but the ring is not fused with a second ring Therapeutic Use/Pathogen Susceptibility • has a narrow antimicrobial spectrum, being active only against gram-negative aerobic bacteria: • Susceptible organisms include Neisseria species, H. influenzae, P. aeruginosa, and Enterobacteriaceae (e.g., E. coli, Klebsiella, Proteus, Serratia, Salmonella, and Shigella) • not active against gram-positive bacteria and anaerobes

Classification and Antimicrobial Spectra of Cephalosporins

• cephalosporins can be grouped into five "generations" based on the order of their introduction to clinical use • as we progress from first-generation agents to fifth-generation agents, there is (1) increasing activity against gram-negative bacteria and anaerobes, (2) increasing resistance to destruction by β-lactamases, (3) increasing ability to reach the cerebrospinal fluid (CSF)

Indications for Antibiotic Combinations • Therapy with a combination of antimicrobial agents is indicated only in specific situations. • routine use of two or more antibiotics results in resistance

• initial Therapy of Severe Infection of unknown etiology, especially in the neutropenic host • Mixed Infections; common in brain abscesses, pelvic infections, and perforation of abdominal organs • Preventing Resistance as in txing TB • Enhanced Antibacterial Action-additive (2=1+1) or potentiative/synergistic (2> 1+1) • Decreased Toxicity

Intro to Cephalosporins

• similar in structure and actions to the penicillins • All cephalosporins are derived from the same nucleus. This nucleus contains a β-lactam ring which is req for antibacterial activity • are bactericidal, often resistant to β-lactamases, and active against a broad spectrum of pathogens. . • Their toxicity is low • B/c of these attributes, cephalosporins represent our most widely used group of antibiotics.

Major Precautions AND Patient Education

• tetracycline and demeclocycline—are eliminated primarily in the urine and hence will accumulate to toxic levels in patients with kidney disease. • Tetracyclines can cause discoloration of deciduous and permanent teeth. Avoid use in pregnant women and children younger than 8 years of age. • Diarrhea may indicate a potentially life-threatening superinfection of the bowel. Advise patients to notify the prescriber if diarrhea occurs. • High-dose IV therapy has been associated with severe liver damage, particularly in pregnant and postpartum women with kidney disease. As a rule, these women should not receive tetracyclines • Sun Exposure Risk With Tetracyclines-All tetracyclines can increase the sensitivity of the skin to UV light resulting in sunburn. Advise patients to avoid prolonged exposure to sunlight, to wear protective clothing, and to apply sunscreen to exposed skin

Bacteria Resistance to Cephalosporins

• the principal cause of cephalosporin resistance is production of β-lactamases, enzymes that cleave the β-lactam ring • Not all cephalosporins are equally susceptible to β-lactamases. • first-generation cephalosporins are easily destroyed by β-lactamases • second-generation cephalosporins are less sensitive to destruction • third-, fourth-, and fifth-generation cephalosporins are highly resistant. • bacterial resistance ALSO results from producing altered PBPs that have a low affinity for cephalosporins ie: MRSA • Ceftaroline, a fifth-generation cephalosporin, has demonstrated activity against (MRSA)

Introduction to the Penicillins

• they have a β-lactam ring in their structure, the penicillins are known as β-lactam antibiotic • The β-lactam family also includes the cephalosporins, carbapenems, and aztreonam • All of the β-lactam antibiotics share the same mechanism of action: disruption of the bacterial cell wall • they are bactericidal; bacteria must be actively growing for them to work

Penicillinases (β-Lactamases) (2) inactivation of penicillins by bacterial enzymes

• β-Lactamases are enzymes that cleave the β-lactam ring and, therefore, render penicillins and other β-lactam antibiotics inactive • Bacteria produce a large variety of β-lactamases; some are specific for penicillins, some are specific for other β-lactam antibiotics (e.g., cephalosporins) • β-Lactamases that act selectively on penicillins are known as penicillinases • The genes that code for β-lactamases are located on chromosomes and on plasmids (extrachromosomal DNA). The genes on plasmids may be transferred from one bacterium to another, thereby promoting the spread of penicillin resistance. • Transfer of resistance is of special importance with Staphylococcus aureus