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Antimicrobial Therapy

Antimicrobial Therapy. Dr. Hesham Amgad. Antibiotics. I. BETA-LACTAMS . Penicillins , Cephalosporins , Carbapenems , Monobactam Cell wall inhibitors: bind Penicillin-binding proteins in cell membrane and inhibit cell wall cross-linking . Bactericidal.

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Antimicrobial Therapy

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  1. Antimicrobial Therapy Dr. HeshamAmgad

  2. Antibiotics

  3. I. BETA-LACTAMS • Penicillins, Cephalosporins, Carbapenems, Monobactam • Cell wall inhibitors: bind Penicillin-binding proteins in cell membrane and inhibit cell wall cross-linking. • Bactericidal. • Main side effects: Hypersensitivity reactions including anaphylaxis, rashes, bone marrow suppression, interstitial nephritis, GI (nausea, diarrhea, and C.diff).

  4. A. PENICILLINS • Combined PCN/Beta-Lactamase Inhibitors: gains broader coverage including anaerobes. • A. AUGMENTIN (Amoxicillin/Clavulanate ) , UNASYN (Ampicillin/Sulbactam ) • Gram (+), Gram (-), Anaerobes, but no Pseudomonas. Used for variety of infections, including respiratory infections, some skin/soft tissue infections, some intra-abdominal infections, and more. • B. TAZOCIN (Piperacillin/Tazobactam): as above, but also covers Pseudomonas. Many uses: Hospital-acquired PNA, severe skin/soft tissue infections including diabetic ulcers, empiric sepsis, intra-abdominal infections. Great empiric drug. • Does not cover: MRSA, VRE, Atypicals (Chlamydia, Mycoplasma, Legionella), ESBLs.

  5. B. CEPHALOSPORINS • Higher resistance to beta-lactamases with better anti-staph activity. • Estimated ~10% cross-reactivity with PCN allergy, but less with higher gen cephalosporins. • No Cephalosporin covers Enterococcus or Atypicals. Only Ceftazidime/Cefepime cover Pseudomonas. • 3rd Gen: • A. CEFTRIAXONE (Rocephin), CEFOTAXIME (Claforan); good gram(+) and gram(-), but not pseudomonas or anaerobes. Used for Community Acquired PNA (with Azithromycin), Meningitis (excellent CSF penetration), Spontaneous Bacterial Peritonitis, Skin/Soft tissue infections, Bacteremia/Endocarditis. • B. CEFTAZIDIME (Fortum); only Gram(-) including Pseudomonas, virtually no Gram (+). Used for pseudomonal infections, also can be used for neutropenic fever. • 4th Gen: CEFEPIME (Maxipime); broad spectrum: gram (+) and gram (-) including pseudomonas, but weak anaerobes. Used for empiric neutropenic fever, hospital acquired PNA, meningitis if suspect gram negatives, and more.

  6. C. CARBAPENEMS • IMIPENEM/CILASTIN (Tienam), MEROPENEM (Meronem) • Broadest spectrum antibiotics, cover Gram(+), Gram(-) including Pseudomonas and ESBL (extended spectrum beta lactamase producers), also anaerobes. • Great penetration virtually everywhere, including CSF. • Only class that reliably covers ESBL producing organisms. • Very broad – easier to remember what it doesn’t cover: MRSA,VRE, Atypicals, Stenotrophomonas. • Main additional side effect: Lower seizure threshold – greatest risk w/ Imipenem, less w/ Meropenem.

  7. II. PROTEIN SYNTHESIS INHIBITORS • Bind to either 30 S or 50 S ribosomal unit. • Most are bacteriostatic, except for Aminoglycosides which are generally considered cidal due to irreversible binding, but also disruption of outer cell membrane.

  8. A. MACROLIDES • CLARITHROMYCIN, AZITHROMYCIN • Azithromycin is drug of choice for Atypical coverage (Chlamydia, Mycoplasma, Legionella), also some activity vs. Gram(+) cocci and some gram(-). • Commonly used for low-risk bronchitis or community-acquired pna, sinusitis, and others. Used in conjunction with Ceftriaxone for CAP that requires hospitalization. • Research suggests immunomodulatory and anti-inflammatory properties of Azithromycin. • Side effects: QT prolongation, GI side effects, rash.

  9. B. CLINDAMYCIN • Excellent activity vs. Anaerobes and Gram positive cocci – Strep and Staph, including ~ 50% of community-acquired MRSA, but NOT enterococci. • Reasonable empiric drug for cellulitis due to Strep/Staph coverage, but beware of resistant MRSA. • Used often for its Antitoxin effect in Toxic Shock Syndrome or Necrotizing Fasciitis due to Group A Strep. Does not penetrate CSF. • Traditionally causes highest rate of C.diff among all Abxs (~10%).

  10. C. AMINOGLYCOSIDES • GENTAMICIN, AMIKACIN • Extremely effective vs. aerobic Gram (-)'s including Pseudomonas. No activity vs. Gram(+) or anaerobes. • Can be used with beta-lactams against gram(+) for synergistic effect, especially in Endocarditis. • Poor urine and CSF penetration. Also less effective at low pH such as in lung/bronchial secretions, not great for PNA. • Can be used as double coverage agent vs. gram negatives with Beta-lactam for Hospital Acquired PNA. • Exhibit concentration-dependent killing, more effective with higher peak concentration relative to MIC (vs time-dependent killing of beta lactams – more important to maintain levels above MIC). • Dosing methods: “Traditional” dosing q8-q12 hr dosing, vs. “Once Daily” dosing; takes advantage of concentration-dependent killing and long “post-antibiotic effect” (killing/inhibition of bacteria even when abx is cleared). Other potential advantage is lower toxicity. • Side effects: Nephrotoxicity - Acute Tubular Necrosis (classically manifests after ~ 5 days) and Ototoxicity. May be irreversible.

  11. III. FLUOROQUINOLONES • DNA Gyrase and Topoisomerase inhibitors. • Bactericidal. • Side Effects: QT prolongation, tendon rupture (esp if on steroids), cartilage damage, dizziness/HA’s, rashes, teratogenic.

  12. A. CIPROFLOXACIN • Best gram(-) coverage of FQs, but virtually no gram(+) coverage. • All fluoroquinolones have atypical coverage (but Cipro is relatively weaker against Chlamydia and Mycoplasma, but good vsLegionella). • Used for many purposes; UTIs, double coverage of Pseudomonas including for Hospital acquired PNA, prostatitis, GI/intra-abdominal coverage - often with Flagyl. • Not used in community-acquired PNA due to lack of Streptococcus pneumoniae coverage.

  13. B. LEVOFLOXACIN • “Respiratory Fluoroquinolone”, excellent activity vs. Gram (+) in particular Streptococcus pneumoniae, slightly less reliable Pseudomonas coverage than Cipro. • Not typically recommended for Staph aureus infections. Good for atypicals. • Used for Community Acquired PNA (can use as monotherapy), also UTI’s and double coverage of Pseudomonas including hospital acquired PNA.

  14. IV. SULFONAMIDES • TMP/SMX • Inhibit sequential steps in folate synthesis. • Bacteriostatic. • Uses: Pneumocystis PNA (drug of choice), Community-acquired MRSA Skin infections, UTIs, Nocardia, Listeria, gram(+),Gram(-) including Salmonella and Shigella, Stenotrophomonas. • Good choice for cellulitis due to MRSA coverage (best CA-MRSA coverage out of oral Abxs except for Linezolid), but weak strep coverage. • Many side effects: Bone marrow suppression, interstitial nephritis and acute tubular necrosis, hyperkalemia, aseptic meningitis, hypersensitivity (sulfas) and rashes, hemolysisin G6PD deficiency, falsely elevated creatinine (blocks Cr secretion into tubules), transaminitis/cholestas

  15. V. NITROFURANTOIN • Excreted into urine, where its active metabolites attack multiple sites within bacteria. Only used for UTI’s (cystitis), not pyelenephritis or any other infection. • Reliable activity vs. E.coli and Staph saphropyticus, also some Enterococcus including VRE, and some other gram negatives. • Not used much anymore due to potentially very bad side effects: HypersentivityPneumonitis and Chronic Pulmonary Fibrosis. • Contraindicated in renal failure.

  16. VI. “SUPER GRAM POSITIVE ANTIBIOTICS” • Cover both MRSA and VRE (except Vancomycin), also Coagulase-negative staph, Strep, Enterococcus.

  17. A. VANCOMYCIN • Glycopeptide, inhibits cell wall synthesis in Gram positives. • Slowly cidal drug (compared to beta-lactams), but static vs. Enterococcus. • Covers Staph/Strep/nonVREenterococcus. No gram negative coverage. • Used for all sorts of gram positive infections including bacteremia, meningitis, PNA, skin/soft tissue, and more. • PO form is not absorbed – used for severe C.diff infections (shown to be superior to Flagyl). • Side effects: Red man syndrome (due to histamine release , use slow infusion rate), low rate of nephrotoxicity (ATN) and ototoxicity (reversible), bone marrow suppression. • Relative diffusion from blood into CSF good only with inflammation; CSF:blood level ratio: Normal meninges: Nil; Inflamed meninges: 20% to 30%.

  18. B. LINEZOLID • Oxazolidinone class, unique ribosomal inhibitor (acts on 50S subunit). • Covers all gram positives including strep, MRSA and VRE. Bacteriostatic. • Has both PO and IV form. May be better for MRSA pneumonia than Vancomycin ; better lung penetration and antitoxin effect. • Side effects: Expensive, Bone marrow suppression especially thrombocytopenia. • Bacteriostatic; not typically used for endocarditis.

  19. C. TIGECYCLINE • New glycylcycline antibiotic; structurally related to Tetracyclines. • Inhibits protein synthesis by binding to the 30S ribosomal subunit. • Bacteriostatic. • Broad spectrum Gram (+) including MRSA and VRE, gram negative, anaerobes, and atypicals. • No Pseudomonas or Proteus. • Used mostly for intra-abdominal infections, but also PNA, skin/soft tissue infections. • Usually kept in reserve for serious and resistant infections (Acinetobacter). • Main side effects: GI (nausea/vomiting/diarrhea) and elevated LFTs.

  20. D. Rifampin • Rifamycin class, inhibits bacterial DNA-dependent RNA synthesis. • Used in the management of infections due to mycobacteria, Staph, Neisseria and Legionella. • Often used in combination therapy both to achieve additive or synergistic antibacterial efficacy and to reduce risk of resistance (eg. with Vancomycin in Staph CSF infections). • Has significant and important drug-drug interactions.

  21. VII. “SUPER GRAM NEGATIVE ANTIBIOTICS” THAT COVER PSEUDOMONAS • For serious infections due to suspected Pseudomonas, generally recommended to double cover with 2 antibiotics until susceptibilities identified, then narrow appropriately to one drug. Double coverage involves a beta-lactam plus either Fluoroquinolone or Aminoglycoside. • Listed is the In-vitro activity vs. Pseudomonas • A. Piperacillin/Tazobactam - 93% • B. Carbapenems - Meropenem - 90%, Imipenem - 83%. • C. Ceftazidime, Cefepime- 81% • D. Fluoroquinolones: Ciprofloxacin (~74% coverage) > Levofloxacin (~70%) • E. Aminoglycosides – Amikacin (94%), Gentamicin (82%) (never use as monotherapy)

  22. F. COLISTIN • Polymyxin antibiotic that changes bacterial membrane permeability. • Bactericidal . • Kept in reserve for multidrug-resistant gram negatives, usually Pseudomonas and Acinetobacter. • Often used in Cystic Fibrosis patients with resistant gram negative infections, sometimes used in aerosolized form. • Had been abandoned for routine use due to its toxicity, Nephrotoxicity and Neurotoxicity, but experiencing a comeback due to rise in resistant gram negatives.

  23. VIII. ANTIBIOTICS WITH ANAEROBE COVERAGE • A. Metronidazole: Active vs. anaerobes (including C.diff), and protozoans. • Classically for anaerobes below the diaphragm, mainly due to weak coverage of Peptostreptococcus (gram positive oral anaerobe). • Side effects: nausea, diarrhea, metallic taste, dose-dependent and possibly cumulative peripheral neuropathy (avoid multiple courses for recurrent C.diff). • B. Clindamycin : better for gram positive anaerobes. Classically for infections above the diaphragm, mainly due to some resistance among Bacteroides species (gram negative anaerobes from GI tract) • C. Combined PCN/Beta-Lactamase inhibitors: Augmentin, Unasyn, Tazocin. • D. Carbapenems (Imipenem, Meropenem). • G. Tigecycline.

  24. IX. “(VERY) BROAD SPECTRUM ANTIBIOTICS” • Definition: Cover both Gram(+) (MSSA, Strep) and Gram(-) including Pseudomonas • Do NOT cover: MRSA, VRE, Atypicals, among others. • A. Cefepime; main weakness is weak anaerobe coverage, also Enterococcus. • B. Piperacillin/Tazobactam; broader due to excellent anaerobe coverage, some nonVREenterococcus. • C. Carbapenems (except Ertapenem); broadest yet due to strong anaerobes, some enteroccocus, plus ESBL.

  25. Antifungals

  26. I. AZOLES • Inhibit Ergosterol synthesis (important component of fungal cell membranes) • Main metabolism is hepatic, main toxicity is elevated LFTs.

  27. A. FLUCONAZOLE • Drug of choice for non-severe Candida infections, including C.albicans, except C.glabrata (can overcome with higher doses) and C.krusei (completely resistant) • Also used for Cryptococcus infections (maintenance phase for cryptococcal meningitis after induction with Ampho B), Coccidioidomycosis, Histoplasmosis, and others. • Toxicity: elevated LFTs, also GI side effects. • Great CSF and urine penetration (only azole with good urine penetration).

  28. B. VORICONAZOLE • Cidal for many molds, drug of choice for Invasive Aspergillosis. • Also effective against most Candida, but little reason to use over Fluconazole. • One important hole in coverage is no Zygomycetes (Mucormycosis) • Liver toxicity, also visual toxicity; transient visual changes, but also rare visual hallucinations.

  29. C. POSACONAZOLE • Newest Azole with broad spectrum of activity; yeast, molds, endemic fungi, Zygomycetes (only azole with activity). • Main problem is that it is only available PO, and must be given with fatty foods for maximal absorption. • Used as 2nd-line / salvage therapy for many severe fungal infections.

  30. D. ITRACONAZOLE • Used for non-severe Histoplasmosis, also Blastomycosis, sometimes Cocci and Paracocci infections. • Toxicity: LFTs and also negative inotrope, can worsen or cause CHF in predisposed patients.

  31. II. AMPHOTERECIN B • Polyene , binds ergosterol in membrane and forms membrane pores. • Drug of choice for many severe fungal infections: Zygomycetes, Cryptococcal Meningitis (induction phase with flucytosine), Severe Histoplasmosis/Blastomycosis/Coccidioidomycosis. • 2nd-line for invasive aspergillosis (Voriconazole is DOC) • 2nd-line for candida infections (Echinocandins are at least as effective, and less toxic) • Some candida are resistant, often C.lusitaniae and C.guilliermondi • Significant toxicity: Nephrotoxic (including Mg and K wasting), hypotension, bradycardia, fevers/chills during infusion, seizures. • ABELCET, AMBISOME: Lipid preparations that are likely as effective and much less toxic (esp. renal toxicity), although more expensive. • Allow for much higher doses thanks to lower toxicity. • Only lipid preparations have good CSF penetration.

  32. Blood Cultures • Blood cultures should be drawn prior to starting antibiotics whenever possible. • If empiric treatment is a must, blood cultures should be drawn as soon as possible after starting antibiotics. • There are no data to suggest that the timing of culture in relation to the appearance of fever or chills will maximize the yield. • Single sets should not be used to evaluate any patient with suspected bacteremia or candidemia. The optimal yield is obtained with three or four sets of blood cultures. • Total blood sample volume should be equal to 1% of patients’ total blood volume (74 ml/kg).

  33. Meningitis • Every patient with suspected meningitis should have CSF obtained unless a lumbar puncture is contraindicated. • CSF analysis and culture should be done as soon as possible. • CSF analysis can indicate the type of meningitis. • Blood cultures are often positive in patients with meningitis.

  34. Thank You

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