Initial clinical trials with daptomycin (2 mg/kg per day) were prematurely suspended because of unexplained treatment failures in patients with bacteremia who were treated with daptomycin, despite in vitro data indicating that the gram-positive cocci causing the infection were susceptible to daptomycin. One explanation for these clinical failures may relate to the relatively high degree of daptomycin protein binding (94%). To evaluate the impact of protein on daptomycin activity, a two-chamber in vitro pharmacodynamic model was used to study and compare the interaction between Staphylococcus aureus (clinical isolate) and either daptomycin or vancomycin, each in the presence and absence of physiologic human albumin concentrations. Low-dose (2 mg/kg) daptomycin, high-dose (6 mg/kg) daptomycin, and 10 mg of vancomycin per kg beta-phase elimination serum-concentration-versus-time curves were simulated by using this in vitro pharmacodynamic model. The bacterial kill rates by all three regimens were decreased in the presence of albumin (P < 0.0002). The average times required for a 99% kill of the initial S. aureus inocula (approximately 5 x i07 CFU/ml) without albumin were 0.81 (low-dose daptomycin), 0.33 (high-dose daptomycin), and 6.18 (vancomycin) h. The average times required for a 99% kill of S. aureus with albumin were 7.66 (low-dose daptomycin), 0.95 (high-dose daptomycin), and 10.52 (vancomycin) h. These data demonstrate that, depending on the concentration of daptomycin, the presence of albumin can profoundly diminish the bactericidal activity of daptomycin.

To determine if ciprofloxacin therapy alters the response to warfarin treatment, 36 adult patients attending three university-affiliated outpatient anticoagulation clinics randomly received a 12-day course of ciprofloxacin (750 mg twice daily) and a 12-day course of placebo; each course was separated by a 2-week washout period. Prothrombin times (PTs), concentrations of S-warfarin and R-warfarin (the isomers of warfarin), and concentrations of clotting factors II and VII were determined three times weekly for 9 weeks. By day 12 of ciprofloxacin therapy, concentrations of S-warfarin remained unchanged compared with those after placebo therapy, but R-warfarin concentrations increased significantly (1.15 times those after placebo therapy; P = .001); concentrations of clotting factors II and VII decreased (0.903 and 0.872 times those after placebo therapy, respectively, P < or = .020). The mean PT ratio after 12 days of ciprofloxacin therapy increased slightly (1.032 times that after placebo therapy; P = .057), but no patient had bleeding or a change in PT that required alteration in warfarin or ciprofloxacin therapy. We conclude that warfarin therapy is not a contraindication to the use of ciprofloxacin.

epoc ABSTRACT: A series of -lactones were generated from the reaction of phenylchlorocarbene, 4-nitrophenylchlorocarbene, diphenylcarbene, bis(4-nitrophenyl)carbene and bis(4-methoxyphenyl)carbene with carbon dioxide and examined by nanosecond time-resolved infrared (TRIR) spectroscopy. Estimated second-order rate constants for the reaction of these carbenes with carbon dioxide indicate that more nucleophilic carbenes react at faster rates, in agreement with previous low-temperature matrix experiments. Spectral TRIR data confirms that the structure oflactones is dependent both on substituents at the -carbon and on solvent polarity, with electron-donating substituents and polar solvents favoring a zwitterionic ring-opened structure as opposed to the three-membered ring oxiranone form. B3LYP calculations using self-consistent reaction field (SCRF) methods also provide support for these experimental investigations.

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