Antimicrobial agents and chemotherapy
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Antimicrob. Agents Chemother. · Mar 2010
Pharmacokinetics of acyclovir and its metabolites in cerebrospinal fluid and systemic circulation after administration of high-dose valacyclovir in subjects with normal and impaired renal function.
Valacyclovir, the L-valyl ester prodrug of acyclovir (ACV), is widely prescribed to treat infections caused by varicella-zoster virus or herpes simplex virus. Rarely, treatment is complicated by reversible neuropsychiatric symptoms. By mechanisms not fully understood, this occurs more frequently in the setting of renal impairment. ⋯ The average steady-state concentrations of acyclovir, CMMG, and 8-OH-ACV were greater in both the systemic circulation and the CSF among subjects with impaired renal function than among subjects with normal renal function. However, the CSF penetration of each analyte, reflected by the CSF-to-plasma area under the concentration-time curve over the 6- or 12-h dosing interval (AUC(tau)) ratio, did not differ based on renal function. Renal impairment does not alter the propensity for ACV or its metabolites to distribute to the CSF, but the higher concentrations in the systemic circulation, as a result of reduced elimination, are associated with proportionally higher concentrations in CSF.
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Antimicrob. Agents Chemother. · Mar 2010
Activity of a new cephalosporin, CXA-101 (FR264205), against beta-lactam-resistant Pseudomonas aeruginosa mutants selected in vitro and after antipseudomonal treatment of intensive care unit patients.
CXA-101, previously designated FR264205, is a new antipseudomonal cephalosporin. We evaluated the activity of CXA-101 against a highly challenging collection of beta-lactam-resistant Pseudomonas aeruginosa mutants selected in vitro and after antipseudomonal treatment of intensive care unit (ICU) patients. The in vitro mutants investigated included strains with multiple combinations of mutations leading to several degrees of AmpC overexpression (ampD, ampDh2, ampDh3, and dacB [PBP4]) and porin loss (oprD). ⋯ CXA-101 MICs of pan-beta-lactam-resistant strains ranged from 1 to 4 microg/ml (mean, 2.5 microg/ml). As described for the in vitro mutants, CXA-101 retained activity against the natural AmpD-PBP4 double mutants, even when these exhibited additional overexpression of the MexAB-OprM efflux pump. Therefore, clinical trials are needed to evaluate the usefulness of CXA-101 for the treatment of P. aeruginosa nosocomial infections, particularly those caused by multidrug-resistant isolates that emerge during antipseudomonal treatments.
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Antimicrob. Agents Chemother. · Mar 2010
Efficacy of rifampin and its combinations with imipenem, sulbactam, and colistin in experimental models of infection caused by imipenem-resistant Acinetobacter baumannii.
There are currently no defined optimal therapies available for multidrug-resistant (MDR) Acinetobacter baumannii infections. We evaluated the efficacy of rifampin, imipenem, sulbactam, colistin, and their combinations against MDR A. baumannii in experimental pneumonia and meningitis models. The bactericidal in vitro activities of rifampin, imipenem, sulbactam, colistin, and their combinations were tested using time-kill curves. ⋯ In the meningitis model rifampin alone or rifampin plus colistin reduced cerebrospinal fluid bacterial counts (-2.6 and -4.4 log(10) CFU/ml). Rifampin in monotherapy or with imipenem, sulbactam, or colistin showed efficacy against MDR A. baumannii in experimental models of pneumonia and meningitis. Imipenem or sulbactam may be appropriate for combined treatment when using rifampin.