Daptomycin is a lipopeptide antibiotic with activity against gram-positive bacteria, including Staphylococcus aureus. We defined the pharmacodynamic parameters that determine the activity of daptomycin for S. aureus using in vitro methods and the Craig (W. A. Craig, J. Redington, and S. C. Ebert, J. Antimicrob. Chemother. 27[Suppl. C]:29-40, 1991) neutropenic mouse thigh infection model. In Mueller-Hinton broth, the MICs for three S. aureus isolates were 0.1 to 0.2 g/ml. In mouse serum, the MICs were 1.0 g/ml. The protein binding of daptomycin was 90 to 92.5% in mouse serum. Single-dose intraperitoneal (i.p.) pharmacokinetic studies with infected mice showed a linear relationship between dose versus the maximum concentration of drug in serum and dose versus the area under the concentration-time curve (AUC). The serum half-life of daptomycin in infected mice was approximately 1.8 h. In single-dose, dose-ranging studies using mice, daptomycin showed a dose-response effect described by an inhibitory sigmoid E max (maximum effect) curve (r ‫؍‬ 0.974; P Ͻ Ͻ 0.001). The density of S. aureus in untreated controls was 8.26 log 10 CFU/g, and the E max was 3.97 log 10 CFU/g. The 50% effective dose (ED 50 ) was 3.7 mg/kg of body weight i.p. and the stasis dose was 7.1 mg/kg. Dose fractionation studies at schedules of Q6h, Q12h, and Q24h, for total 24-h ED 30 , ED 60 , and ED 80 doses of 2.5, 5.6, and 15 mg/kg i.p., showed no difference in effect at each total 24-h dose level by schedule, indicating that the AUC/MIC ratio is the dynamically linked variable.The incidence of community-and nosocomially acquired infections due to the bacterium Staphylococcus aureus is rising (24). From 1990 to 1992 this microorganism was the most common cause of nosocomial pneumonias and surgical wound infections (14). Although the antistaphylococcal beta-lactam antibiotics are the most active agents available for the treatment of methicillin-susceptible S. aureus, the National Nosocomial Infections Surveillance System of the Centers for Disease Control and Prevention reports that in 1997, 56.2% of S. aureus isolates were resistant to these agents (24). Vancomycin is considered the drug of choice for the treatment of methicillin-resistant S. aureus infections. However, this drug is slowly bactericidal and is associated with higher failure and relapse rates than beta-lactam therapy for the treatment of S. aureus endocarditis. Also, strains of S. aureus demonstrating decreased susceptibility to vancomycin have been described in Japan (18,19) and the United States (8).Daptomycin is an acidic lipopeptide antibiotic that is active against gram-positive bacteria, including S. aureus and enterococci (13,20,23,31). Importantly, the mechanism of action of daptomycin is distinctly different from that of other antimicrobial agents (2, 3). Thus daptomycin is active against Staphylococcus and Enterococcus species that are resistant to vancomycin (6, 31; N. V. Jacobus, J. R. McDermott, J. M. Lonks, J. M. Boyce, and D. R. Snydman, Abstr. 38th Intersci. Conf....

In this study we defined the pharmacodynamic parameter that optimizes outcome in deep-seated Candida albicansinfections treated with fluconazole. Using a murine model of systemic candidiasis, we conducted single-dose dose-ranging studies with fluconazole to determine the dosage of this drug that resulted in a 50% reduction in fungal densities (50% effective dose [ED50]) in kidneys versus the fungal densities in the kidneys of untreated controls. We found that the ED50 of fluconazole given intraperitoneally was 4.56 mg/kg of body weight/day (95% confidence interval, 3.60 to 5.53 mg/kg/day), and the dose-response relationship was best described by an inhibitory sigmoid maximal effect (E max) curve. To define the pharmacodynamics of fluconazole, we gave dosages lower than, approximating, and higher than the ED50 of fluconazole (range, 3.5 to 5.5 mg/kg/day, equivalent to the ED16 to the ED75) to various groups of infected animals using three dose-fractionation schedules. For each total dose of fluconazole examined, the dose-fractionation schedules optimized the ratio of the area under the concentration-time curve (AUC) to the MIC (the AUC/MIC ratio), the ratio of the maximum concentration of drug in serum (C max) to the MIC, and the time that the drug remained above the MIC for the infecting C. albicansisolate. Similar reductions in fungal densities in kidneys were seen between groups that received the same total dose of fluconazole in one, two, or four equally divided doses. Thus, dose-fractionation studies demonstrated that the pharmacodynamic parameter of fluconazole that best predicted outcome was the AUC/MIC ratio.

In vitro time-kill studies and a rabbit model of endocarditis and pyelonephritis were used to define the impact that the order of exposure of Candida albicans to fluconazole (FLC) and amphotericin B (AMB), as sequential and combination therapies, had on the susceptibility of C. albicans to AMB and on the outcome. The contribution of FLC-induced resistance to AMB for C. albicans also was assessed. In vitro, AMB monotherapy rapidly killed each of four C. albicans strains; FLC alone was fungistatic. Preincubation of these fungi with FLC for 18 h prior to exposure to AMB decreased their susceptibilities to AMB for 8 to >40 h. Induced resistance to AMB was transient, but the duration of resistance increased with the length of FLC preincubation. Yeast sequentially incubated with FLC followed by AMB plus FLC (FLC3AMB؉FLC) showed fungistatic growth kinetics similar to that of fungi that were exposed to FLC alone. This antagonistic effect persisted for at least 24 h. Simultaneous exposure of C. albicans to AMB and FLC [AMB؉FLC(simult)] demonstrated activity similar to that with AMB alone for AMB concentrations of >1 g/ml; antagonism was seen using an AMB concentration of 0.5 g/ml. The in vitro findings accurately predicted outcomes in our rabbit infection model. In vivo, AMB monotherapy and treatment with AMB for 24 h followed by AMB plus FLC (AMB3AMB؉FLC) rapidly sterilized kidneys and cardiac vegetations. AMB؉FLC(simult) and FLC3AMB treatments were slower in clearing fungi from infected tissues. FLC monotherapy and FLC3AMB؉FLC were both fungistatic and were the least active regimens. No adverse interaction was observed between AMB and FLC for the AMB3FLC regimen. However, FLC3AMB treatment was slower than AMB alone in clearing fungi from tissues. Thus, our in vitro and in vivo studies both demonstrate that preexposure of C. albicans to FLC reduces fungal susceptibility to AMB. The length of FLC preexposure and whether AMB is subsequently used alone or in combination with FLC determine the duration of induced resistance to AMB.With the increased capacity of medical science to prolong the lives of the immunocompromised host, the incidence of systemic Candida albicans infections is rising (5). Yet despite treatment with fluconazole (FLC) or amphotericin B (AMB) monotherapy, the mortality associated with deep-seated candidal infections remains substantial (2,22,23,25,30).In an attempt to improve survival rates, there is much interest in using FLC and AMB in combination. However, the interaction between FLC and AMB remains poorly characterized when these drugs are used concurrently or sequentially. In vitro studies in which FLC and AMB were simultaneously or sequentially introduced to cultures of C. albicans frequently showed this drug combination to be antagonistic (13,19,21,28; P. Banerjee, Q.-F. Liu, A. Louie, M. Shayegani, H. Taber, G. Drusano, and M. Miller, Abstr. 97th Gen. Meet. Am. Soc. Microbiol., abstr. C-252a, p. 164, 1997). Further, using time-kill studies, Vazquez et al. (28) demonstrated that sequential expo...

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