Post on 13-Jan-2016
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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)– 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
MIC vs. MBC
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
-Static vs. -Cidal
• Bacteriostatic– Tetracyclines– Sulphonamides– Trimethoprim– Chloramphenicol– Macrolides– Linosamides
(clindamycin)
• Bactericidal– Beta-Lactams– Daptomycin– FQs– Aminoglycosides– Metronidazole– TMP/SMX– Nitrofurantoin
Linezolid (Zyvox)
• Oxazolidinone• Inhibits Protein
Synthesis• Bacteriostatic• 600mg po/iv• No renal adjustment• Time-Dependent
Killing
Linezolid Spectrum of Activity
• Clinically important Gram + organisms– MSSA/MRSA, Coag – Staph, E. faecium and
faecalis, Strep. (bactericidal)– MTb, MAI
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
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, …
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)
Daptomycin (Cubicin)
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
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)
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)
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)
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
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)
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
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
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
Ertapenem: What to use it for
• Intraabdominal infections
• Pneumonia
• Bacteremia
• Bone and soft tissue infections
• Complicated UTIs
• OB/Gyn infections
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
Carbapenem: Side Effects
• Rash, urticaria, cross-reaction with PCNs, nausea, immediate hypersensitivity
• Less epileptogenic than imipenem
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
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
Polymyxins: Side Effects
• Dose-Related Reversible Nephrotoxicity
• Dose-Related Reversible Neurotoxicity manifest as neuromuscular blockade
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
Telavancin: Spectrum of Activity and Uses
• MRSA
• Gram positives (but not VRE)
• Uses– cSSSI– Nosocomial Pneumonia (with Gram negative
coverage; non-FDA approved)
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)
Anti-Fungals
Echinocandins
• Caspofungin (Cancidas), Micafungin (Mycamine), Anidulafungin (Eraxis)
• Inhibit glucan synthesis (in cell wall); like “PCN of antifungals”
• Pregnancy category C
• No renal adjustment required
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
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
Echinocandins: Side Effects
• Not cytochrome P450 metabolized
• NOT nephrotoxic or hepatotoxic
• Relatively few/minor side effects
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.
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
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)
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