Four Candida albicans isolates and six non-albicans Candida isolates were evaluated by time-kill methods to characterize the relationship between nystatin concentrations, the rate and extent of fungicidal activity, and the postantifungal effect (PAFE). Against Candida species, nystatin exhibits concentration-dependent fungicidal activity and a pronounced PAFE.The incidence of superficial infections and disseminated fungal infections has steadily risen over the past decade (1). Candida now ranks as the fourth most frequently encountered microbe among nosocomial bloodstream pathogens (11). Nystatin, a polyene antifungal agent produced by Streptomyces noursei, exhibits antifungal activity against a broad spectrum of fungal pathogens. Clinical studies have reported nystatin to be effective against azole-resistant strains of Candida and, in some cases, amphotericin B-resistant strains of Candida albicans (1, 6).Currently, knowledge of the pharmacodynamic characteristics of nystatin is limited. We have previously described the in vitro concentration-response characteristics of several antifungal agents, including fluconazole, flucytosine, amphotericin B, and the echinocandins (3-5, 9). Knowledge of the concentration-effect relationship allows for description of the rate and extent of antifungal activity and provides a more rational basis for determining optimal dosing regimens. The purpose of this study was twofold: (i) to describe the concentration-effect relationship of nystatin for a variety of Candida species, and (ii) to characterize the postantifungal effect (PAFE) of nystatin on these isolates.Nystatin (Sigma Chemical Company, St. Louis, Mo.) was utilized for MIC determination, carryover demonstrations, and time-kill curve procedures. Dimethyl sulfoxide (DMSO) was used to aid in solubilizing nystatin. The final concentration of DMSO comprised less than 1% (vol/vol) of the total solution concentration used for each experiment in the study. Growth curves have been determined in previous studies and displayed no inhibition of fungal growth in the presence of DMSO when used at similar concentrations (2, 9). Stock solution was separated into unit-of-use vials and frozen at Ϫ70°C until needed.Ten Candida isolates were obtained from the Division of Medical Microbiology, Department of Pathology, The University of Iowa College of Medicine, for use in this study. The strains used included four Candida albicans strains (OY31.5, 142-5609, 2733A, and ATCC 90028) and two strains each of Candida glabrata (582 and 350), Candida krusei (37-5696A, ATCC 6258), and Candida tropicalis (2697 and 3829). Test isolates were stored in sterile water at room temperature until used.The MIC for each isolate was determined by broth microdilution techniques as outlined by the National Committee for Clinical Laboratory Standards (10). The MIC of nystatin was defined as the lowest concentration of drug that resulted in complete inhibition of visible fungal growth at 48 h.Prior to performing time-kill studies, carryover effects were examined as ...

ABT-492 is a novel quinolone with potent activity against gram-positive, gram-negative, and atypical pathogens, making this compound an ideal candidate for the treatment of community-acquired pneumonia. We therefore compared the in vitro pharmacodynamic activity of ABT-492 to that of levofloxacin, an antibiotic commonly used for the treatment of pneumonia, through MIC determination and time-kill kinetic analysis. ABT-492 demonstrated potent activity against penicillin-sensitive, penicillin-resistant, and levofloxacin-resistant Streptococcus pneumoniae strains (MICs ranging from 0.0078 to 0.125 g/ml); ␤-lactamase-positive and ␤-lactamase-negative Haemophilus influenzae strains (MICs ranging from 0.000313 to 0.00125 g/ml); and ␤-lactamase-positive and ␤-lactamase-negative Moraxella catarrhalis strains (MICs ranging from 0.001 to 0.0025 g/ml), with MICs being much lower than those of levofloxacin. Both ABT-492 and levofloxacin demonstrated concentration-dependent bactericidal activities in time-kill kinetics studies at four and eight times the MIC with 10 of 12 bacterial isolates exposed to ABT-492 and with 12 of 12 bacterial isolates exposed to levofloxacin. Sigmoidal maximal-effect models support concentration-dependent bactericidal activity. The model predicts that 50% of maximal activity can be achieved with concentrations ranging from one to two times the MIC for both ABT-492 and levofloxacin and that near-maximal activity (90% effective concentration) can be achieved at concentrations ranging from two to five times the MIC for ABT-492 and one to six times the MIC for levofloxacin.

Objective: To review the published in vitro, in vivo, and clinical data and FDA background documents that led to the approval of voriconazole. Data Sources: Articles were identified by the referenced package insert and by a MEDLINE search (1966–October 2002) using the terms voriconazole, azole antifungal, aspergillosis, and UK-109, 496. Additionally, journal Web sites and abstracts from major infectious disease meetings were researched to obtain newly published data. Study Selection: All animal and human data published in journals, abstracts, and FDA background documentation were used. The only in vitro susceptibility testing studies used were those that incorporated a large number of fungal isolates. Data Synthesis: Voriconazole is a novel monotriazole antifungal agent that inhibits the fungal cytochrome P450–mediated 14 α-lanosterol demethylation. In vitro susceptibility studies, in vivo clinical trials, and case reports have shown potent activity against various Aspergillus spp., Scedosporium, and Fusarium. Additionally, voriconazole has shown in vitro activity against dimorphic fungi and yeast, including Candida spp. and Cryptococcus neoformans. The efficacy of voriconazole has been evaluated in 4 clinical trials. The clinical studies indicate that it is at least as effective as amphotericin B for the treatment of acute invasive aspergillus infection. The most common adverse effects in clinical trials included visual disturbances, rash, and elevated liver function tests. Voriconazole is metabolized by CYP2C19, CYP2C9, and CYP3A4 and thus causes multiple serious drug–drug interactions. Conclusions: Voriconazole provides an advance in therapy for the treatment of acute invasive aspergillus infection.