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

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Presentation on theme: "Newer Antibiotics and How We Should Use Them Mahesh C. Patel, M.D. Division of Infectious Diseases February 3, 2010."— Presentation transcript:

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

3 Antibacterials

4 Timeline

5 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

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7 MIC vs. MBC

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9 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

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

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

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

13 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

14 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, …

15 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)

16 Daptomycin (Cubicin)

17 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

18 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)

19 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)

20 Tigecycline (Tygacil) 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)

21 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

22 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)

23 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

24 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

25 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

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

27 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

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

29 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

30 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

31 Polymyxins: Side Effects Dose-Related Reversible Nephrotoxicity Dose-Related Reversible Neurotoxicity manifest as neuromuscular blockade

32 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

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

34 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)

35 Anti-Fungals

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

37 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 1 st Caspofungin vs. Micafungin for invasive Candidiasis  similar results

38 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

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

40 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.

41 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

42 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)

43 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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