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Newer Antibiotics and How We Should Use Them

Newer Antibiotics and How We Should Use Them. Mahesh C. Patel, M.D. Division of Infectious Diseases February 3, 2010. Antibacterials. Timeline. Concentration-Dependent vs. Time-Dependent Killing. Time-Dependent (or Conc. Independent)

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Newer Antibiotics and How We Should Use Them

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  1. Newer Antibiotics and How We Should Use Them Mahesh C. Patel, M.D. Division of Infectious Diseases February 3, 2010

  2. Antibacterials

  3. Timeline

  4. Concentration-Dependent vs. Time-Dependent Killing • Time-Dependent (or Conc. Independent) • Eliminate bacteria only when time during which drug concentration is greater than MIC • Concentration-Dependent • Eliminate bacteria when their concentrations are above the MIC of the organism • Post-antibiotic effect

  5. MIC vs. MBC

  6. Bacteriostatic vs. Bactericidal • Bactericidal: Kill bacteria • Bacteriostatic: Reversibly inhibit growth • Continuum • No rigorous studies exist showing superiority of one type over another • However, -cidal agents preferred in endocarditis, meningitis, neutropenic hosts, sepsis • Static: MIC<MBC; Cidal: MIC=MBC

  7. Bacteriostatic Tetracyclines Sulphonamides Trimethoprim Chloramphenicol Macrolides Linosamides (clindamycin) Bactericidal Beta-Lactams Daptomycin FQs Aminoglycosides Metronidazole TMP/SMX Nitrofurantoin -Static vs. -Cidal

  8. Oxazolidinone Inhibits Protein Synthesis Bacteriostatic 600mg po/iv No renal adjustment Time-Dependent Killing Linezolid (Zyvox)

  9. Linezolid Spectrum of Activity • Clinically important Gram + organisms • MSSA/MRSA, Coag – Staph, E. faecium and faecalis, Strep. (bactericidal) • MTb, MAI

  10. Linezolid: What to use it for • Complicated skin and soft tissue structure infections (does not include osteomyelitis) • Nosocomial Pneumonia (MRSA) • VRE (including bacteremia) • DO NOT USE for bacteremias • **(Osteomyelitis, endocarditis, meningitis, intraabdominal infections, etc.)—ID consult

  11. Linezolid: Side Effects • Relatively well-tolerated with GI symptoms • Serotonin Syndrome • Fever, agitation, MS changes, tremors if on serotonergic agents • Reversible, nonselective monoamine oxidase inhibitor • Reversible myelosuppresion • Thrombocytopenia (47% if >10d or rx) >>anemia>neutropenia • Duration of treatment > 2 weeks • Neuropathy (peripheral, optic, etc.); Lactic Acidosis, …

  12. Daptomycin • First in a novel class: cyclic lipopeptides • Side-lined in 1991 as Phase II trials showd skeletal muscle toxicity with Q12H dosing • Binds to cell membranes of Gram + organisms • Bactericidal • Concentration-Dependent • Pregnancy Category B • 4 to 6 mg/kg iv Q24H (Q48H if CrCl<30 mL/min)

  13. Daptomycin (Cubicin)

  14. Daptomycin: Spectrum of Activity • Like Glycopeptides, though works on organisms where vancomycin is not effective • MSSA/MRSA, E faecalis and faecium, Coag negative Staph, Strep. • Resistance emerging: If decreased sens to vancomycin, greater likelihood of decreased sens to daptomycin. • Development of resistance during treatment of Enterococcal infections

  15. Daptomycin: What to use it for • Complicated SSTI (4mg/kg) • S. aureus bacteremia and endocarditis (6mg/kg) • Osteoarticular infections (but would use higher dose of 8-10mg/kg and use another agent given lower bone levels and resistance emergence on therapy • Enterococcal infections • DO NOT USE: Pulmonary infections (inactivated by surfactant)

  16. Daptomycin: Side Effects • No increased GI • Paresthesias, dysesthesias, and peripheral neuropathies • No QTc issues • Muscle toxicity • Begin 7 days after therapy • Resolve during therapy or about 3 days after daptomycin is stopped • Monitor CK when used with other “muscle toxic” agents (ie HMG-CoA reductase inhibs)

  17. Tetracycline class Inhibit bacterial protein synthesis (30S) Bacteriostatic 100mg iv once, then 50mg iv Q12H with no adjustment needed for renal issues Pregnancy Category D (bone growth and teeth staining) Tigecycline (Tygacil)

  18. Tigecycline: Spectrum of Activity • Broad range of pathogens • NO Pseudomonas, Proteus, Morganella, or Providencia • Acinetobacter • MRSA/MSSA, VRE • Anaerobes • Resistance by efflux pumps or ribosomal changes

  19. Tigecycline: What to use it for • FDA Approved: • Skin and soft tissue infections • Intra-Abdominal infections • Community-acquired pneumonia • NOT indicated for blood stream infections • At NBHN, reserved for patients with resistant GNRod infections (non-bacteremic)

  20. Tigecycline: Side Effects • Nausea (35%) • Vomiting (25%) • Phlebitis • Increased LFTs (6%) • Thrombocytopenia, increased PTT and INR, eosinophilia • Headache, somnolence, taste perversion • Remember: No kids under 8yo

  21. Ertapenem (Invanz) • Beta-Lactam • Bind to PCN-binding proteins (PBPs) • Concentration-Dependent Killing • Bactericidal • Long half life of 4h permits QD dosing • Renal adjustment required

  22. Ertapenem: Spectrum of Activity • Kinda like ceftriaxone and metronidazole • Gram + bacteria, Enterobacteriaceae, MSSA, Anaerobes • NOT: MRSA, Enterococcus; No Pseudomonas, Acinetobacter • Resistance: Alteration in PBPs, Beta Lactamase production, Efflux pumps, decreased permeability

  23. Ertapenem: What to use it for • Intraabdominal infections • Pneumonia • Bacteremia • Bone and soft tissue infections • Complicated UTIs • OB/Gyn infections

  24. Doripenem (Doribax) • Much greater Enterobacteriaceae activity including Pseudomonas, Acinetobacter • Lower MICs for GNRs than imipenem or meropenem • Resistance to Imipenem does not mean resistance to Doripenem or meropenem, or vice versa • Less beta-lactamase unstable

  25. Carbapenem: Side Effects • Rash, urticaria, cross-reaction with PCNs, nausea, immediate hypersensitivity • Less epileptogenic than imipenem

  26. Polymyxins • Very old drugs (1947) • Fell into disuse by 1980 due to nephrotoxicity; topical and oral use • Polymyxin B and Polymyxin E (Colistin) • Polymyxin B (colistemethate) iv • Colistin for inhalation therapy • Penetrate into cell membranes and disrupt • Bactericidal and Concentration-Dependent • Renal adjustment necessary • Poor levels in pleura, joint, CSF, biliary tract

  27. Polymyxins: Spectrum of Activity • Broad GNR coverage • Gram +, Gram – cocci, and most anaerobes are RESISTANT • Has been used intrathecally and intraventricularly • Colistimethate as efficacious as piperacillin, imipenem, and ciprofloxacin for treatment of Pseudomonas

  28. Polymyxins: Side Effects • Dose-Related Reversible Nephrotoxicity • Dose-Related Reversible Neurotoxicity manifest as neuromuscular blockade

  29. Telavancin (Vibativ) • FDA-approved on Sept 11, 2009 • Lipoglycopeptide • Synthetic derivative of vancomycin • Bactericidal • Inhibits cell wall synthesis; bacterial membrane depolarizer • Once daily iv (10mg/kg) • Renal adjustment needed

  30. Telavancin: Spectrum of Activity and Uses • MRSA • Gram positives (but not VRE) • Uses • cSSSI • Nosocomial Pneumonia (with Gram negative coverage; non-FDA approved)

  31. Telavancin: Side Effects • Mild taste disturbance (33%) • Nausea (27%) and Vomiting (14%) • Insomnia • Coagulation test interference: PT/INR, PTT, Factor Xa; BUT NO increased risk of bleeding • Less common: Headache, Red-man Syndrome, Nephrotoxicity, Diarrhea, Foamy Urine (13%) • QTc prolongation in 1.5% (vs. 0.6% in vancomycin)

  32. Anti-Fungals

  33. Echinocandins • Caspofungin (Cancidas), Micafungin (Mycamine), Anidulafungin (Eraxis) • Inhibit glucan synthesis (in cell wall); like “PCN of antifungals” • Pregnancy category C • No renal adjustment required

  34. Echinocandins: Spectrum of Activity • Candida spp of all types (fungicidal) • Aspergillus spp (fungistatic) • Anidalufungin likley with fewer drug-drug interactions • Micafungin has most data in kids • Caspofungin was 1st • Caspofungin vs. Micafungin for invasive Candidiasis  similar results

  35. Echinocandins: Uses • Invasive and esophageal candidiasis • Caspo, Anidal., Mica. • Prophylaxis in HSCT patients • Mica. • Invasive aspergillosis in refractory or intolerant patients • Caspo • Fever and neutropenia • Caspo

  36. Echinocandins: Side Effects • Not cytochrome P450 metabolized • NOT nephrotoxic or hepatotoxic • Relatively few/minor side effects

  37. Newer Azoles • Voriconazole (VFend), Posaconazole (Noxafil) • Many clinically relevant drug-drug interactions (P450) • Voriconazole is available in both iv and po formulations • Posaconzole available in suspension • Both with extensive distribution and penetration into tissues.

  38. Voriconazole • Invasive aspergillosis (superior to Ampho B deoxycholate) • Invasive fusarium and scedosporum • Esophageal candidiasis (not licensed) • NOT FDA approved for fever and neutropenia and possibly inferior to liposomal Ampho B

  39. Voriconazole: Side Effects • Similar to other triazoles, EXCEPT: • Visual disturbance unique • 30% reported altered or enhanced light perception for ½ hour 30 mins after dose • Blurred vision, color vision changes, photophobia • Rarely results in discontinuation • Mechanism unknown • Hallucinations (12 of 72 in one study) within 24hrs • Photosensitivity, QTc prolongation (rare)

  40. Posaconazole (Noxafil) • Only available orally and bioavailability affected by food (fat increases absorption) • No dose adjustment for renal issues • “Moderate” number of drug-drug interactions • Indications: • Prophylaxis of Invasive fungal infections in high risk patients • Oropharyngeal candidiasis • Molds (Aspergillosis, fusariosis, Coccidi., eumycetoma, chromoblastomycosis) • Side Effects: GI and headache

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