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Newer Antibiotics and How We Should Use Them

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Presentation on theme: "Newer Antibiotics and How We Should Use Them"— Presentation transcript:


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


7 MIC vs. MBC


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<MBC; Cidal: MIC=MBC

10 -Static vs. -Cidal Bacteriostatic Bactericidal 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 1st 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

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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