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New Antistaphylococcal Agents: Linezolid, Daptomycin, and Tigecycline Cary Engleberg, M.D. Division of Infectious Diseases, University of Michigan Medical School Linezolid (Zyvox®) Linezolid (Zyvox®) Pharmacodynamics of linezolid • Peak concentration of 18µg/ml in 1 -2h • • post-dose Elimination half-life = 4.5 - 5.5 hours Parameter predicting successful therapy: – Time above MIC – Target = >40% of dosing interval Mean plasma linezolid levels following equivalent (375mg) oral and IV doses p.o. (Fasted) (n=12) 10 Plasma linezolid conc. (µg/mL) IV (n=12) Bioavailability = 100% 8 6 4 2 0 0 2 4 6 8 10 12 14 16 Hours After Administration Source: Pharmacia & Upjohn. 18 20 22 24 Linezolid concentrations after 14 days of steady state, bid dosing (Stalker, et al. ICAAC, Toronto, Ontario. 1997) 375 mg BID (n=12) 20 625 mg BID (n=12) 16 MIC-90 S. aureus MIC-90 enterococci Linezolid 12 Conc. (µg/mL) 8 MIC-90 pneumococcus 4 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours After Last Dose 3 Linezolid vs. vancomycin in MRSA infections (Stevens et al. Clin Infect Dis 2002; 34:1481-90) Cure rate (%) of evaluable MRSA Infection Linezolid 600mg bid Skin/soft tissue 27/34 (79.4) Pneumonia 9/12 (75) UTI 0/1 (0) Other sites 3/6 (50) Bacteremia 9/15 (60) All 48/68 (70.6) Vanco 1gm BID 22/30 (73.3) 12/16 (75) 1/1 (100) 2/3 (66.7) 7/10 (70) 44/60 (73.3) Linezolid concentrations in joints and bone (Rana et al. 2002) Sub-MIC effect of linezolid on bacterial virulence • Decreased hemolysin and coagulase • • expression in S. aureus at 1/2, 1/4, and 1/8 MIC Decreased streptolysin O and DNAse production in group A streptococcus Concentrations below the MIC potentiate the opsonophagocytosis of S. aureus and S. pyogenes Resistance to linezolid • Originally thought to be unlikely given chemical • origin and mode of action of the drug 2 of 169 patients treated on a compassionate use protocol developed resistant strains – rRNA mutation (G2576U) – Both involved prolonged indwelling lines • Induction of resistance in the laboratory by prolonged passage: – in staphylococci, frequency is 10-9 - 10-11 – among enterococci, E. faecalis is more likely to develop resistance (G2576U) than E. faecium Linezolid dosing and use • 600mg IV or po q 12 h for serious • • • infections No adjustment necessary for renal dysfunction Adverse effects: most common is GI disturbance; thrombocytopenia after 17 days MAO inhibitor activity: may enhance pressor responses with adrenergic drugs Daptomycin (Cubicin®) Daptomycin Fermentation product of Streptomyces roseosporus Mechanism of action: Interacts with the bacterial plasma membrane via the lipid portion to form a pore. Metabolic death occurs by leakage of electrolytes without lysis of the bacteria Cyclic peptide Lipid (acyl) chain Features of daptomycin kinetics • Linear kinetics • Half life = 8.5 hrs. • 87-94% plasma protein bound • Urine excretion - 80% (66% active) • Limited metabolism; No significant • CyP450 interactions Requires physiologic concentrations of calcium to be active in vitro Daptomycin in the lung • When distributed into the lung, • • daptomycin partitions into the surfactant layer via its lipid moeity. This is a disadvantage, in that little free drug is available to interact with bacteria. Daptomycin should NOT be used to treat pneumonia Comparison of daptomycin activity with other antimicrobial agents MIC90 (µg/ml) Daptomycin Vancomycin Linezolid Synercid® MSSA (50) 0.13 1.0 4.0 1.0 MRSA (50) 0.13 1.0 4.0 1.0 MSSE (25) 0.5 1.0 4.0 0.5 MRSE (50) 0.25 1.0 4.0 0.25 E. faecalis** (25) 1.0 64.0 4.0 16.0 E. faecium** (25) 4.0 64.0 4.0 4.0 **includes some VRE (from Rybak et al: Antimicrob Ag Chemother 2000) Time-kill analysis against MRSA 10 Control 9 8 7 CFU/ml 6 Linezolid Synercid® 5 4 3 2 0 8 24 hours Rybak et al: AAC April 2000 Vancomycin Daptomycin Time-kill analysis against VRE 9 Control Vancomycin 8 7 CFU/ml 6 5 Linezolid Synercid® Daptomycin 4 3 2 0 8 24 hours Rybak et al: AAC April 2000 Daptomycin in S. aureus endocarditis (Fowler et al. NEJM 2006;355:653-65) Daptomycin toxicity • In animal toxicity studies, muscle damage with increased CPK occurred when the drug was dosed frequently • Because daptomycin is rapidly bactericidal, it can be administered once a day to achieve high peaks alternating with periods whent the drug is cleared. • Periods of subtherapeutic levels of daptomycin during the dosing interval in humans makes the likelihood of muscle damage every small • Long term treatment should be followed with weekly CPK levels Tigecycline (Tygacil®) Drug modifications to avoid resistance • Tetracyclines and macrolides both inhibit protein synthesis by binding to the ribosome • Two major types of resistance occurs against both drug classes: – Modification of the ribosomal binding site – Efflux pumps that expel the drug from the bacterial cytoplasm • Minocycline and clarithromycin have been chemically modified by adding side chains to the basic molecule. This has two effects: – Increased ribosomal binding, even with modification – Drug not recognized or mobilized by the efflux system Drug Modifications (additions of side chains) telithromycin clarithromycin minocycline Active against macrolide-resistant S. pneumoniae tigecycline Active against many resistant Gram-negatives, MRSA and VRE Tigecycline • Mechanism of action: –binds to the 30S ribosome and blocks entry of amino-acyl tRNAs to block protein synthesis (like all tetracyclines) –Bacteriostatic, not cidal • Kinetics: –T1/2=24-48 hrs –Distributes to all tissues (large volume of distribution); including alveolar lining fluid • Dosing (adult): 100mg loading, then 50mg q12h Tigecycline: spectrum of activity • Staphylococci (including MRSA and MRSE) • Enterococci (including VRE) • S. pneumoniae (including pen-resistant) • Most Gram-negatives (e.g., E. coli, Citrobacter spp, Klebsiella spp, Serratia spp, Acinetobacter spp, Stenotrophomonas, Haemophilus) • Anaerobes (e.g., Bacteroides, Clostridia) • Chlamydiae, mycoplasmas • NOT Pseudomonas Tigecycline: adverse effects • Nausea (30%); vomiting (20%) –Most common in older women –due to serotonin release and modified by ondansetron • Dental staining (not used in pregnancy or • • children) Decreased clearance of warfarin No significant P450 interactions Tigecycline: studies of efficacy • Non-inferior to imipenem in >1000 adults • • with complicated intra-abdominal infections (2 phase III studies) Non-inferior to vancomycin+aztreonam in complicated skin and soft tissue infections (2 phase III studies) Tigecycline had more nausea/vomiting in all studies