ABSTRACT
OBJECTIVES: Fosfomycin penetrates well into cerebrospinal fluid (CSF) and is considered for treatment of infections of the central nervous system (CNS). This study evaluated the influence of human CSF on the antimicrobial activity of fosfomycin. METHODS: Time-kill curves were performed in Mueller-Hinton broth (MHB) and in pooled human CSF using fosfomycin concentrations ranging from 0.25x to 8x MIC for a clinical Staphylococcus aureus isolate. To estimate the activity of fosfomycin at the target site, the concentration-time curve measured in CSF of a patient at steady state was simulated in vitro in human CSF using two S. aureus isolates. RESULTS: In CSF a higher fosfomycin concentration (8x MIC) was required to achieve sustained bacterial killing than in MHB (1x MIC). In vitro simulation of the pharmacokinetic profile measured in CSF of the selected patient showed initial killing, but terminal re-growth of both test strains. CONCLUSIONS: The antibacterial activity of fosfomycin is lower in CSF than in MHB, and drug concentrations slightly exceeding the MIC may not be sufficient to achieve bactericidal effects in the CNS.
Subject(s)
Anti-Bacterial Agents/antagonists & inhibitors , Cerebrospinal Fluid/metabolism , Fosfomycin/antagonists & inhibitors , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/pharmacology , Fosfomycin/pharmacology , Humans , Microbial Sensitivity Tests/methods , Microbial Viability , Models, Theoretical , Time FactorsABSTRACT
Antagonism between fosfomycin and antipseudomonal penicillins, cefotaxime, and ceftriaxone was observed in Pseudomonas aeruginosa RYC212. Fosfomycin, a non-beta-lactam antibiotic that acts on bacterial cell wall synthesis, decreased the expression of penicillin-binding protein 3 and induced beta-lactamase. The antagonistic effect was reduced in the presence of high concentrations of the beta-lactamase inhibitor tazobactam or in fosfomycin-resistant mutants. We suggest that products resulting from fosfomycin cell wall damage could interact with a system that regulates penicillin-binding protein and beta-lactamase production.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins , Carrier Proteins , Fosfomycin/antagonists & inhibitors , Hexosyltransferases/metabolism , Multienzyme Complexes/metabolism , Muramoylpentapeptide Carboxypeptidase , Peptidyl Transferases/metabolism , Pseudomonas aeruginosa/metabolism , Bacterial Outer Membrane Proteins/metabolism , Cefotaxime/pharmacology , Ceftriaxone/pharmacology , Hexosyltransferases/biosynthesis , Microbial Sensitivity Tests , Multienzyme Complexes/biosynthesis , Penicillin-Binding Proteins , Penicillins/pharmacology , Peptidyl Transferases/biosynthesis , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , beta-Lactamases/biosynthesisABSTRACT
The present work analyzes pt44 mutation in Sh. flexneri resulting in the appearance of the following phenotypical properties: resistance to phosphomycin, avirulence, pleiotropic disturbances in carbohydrate utilization. The data provided by the biochemical and genetic analysis have indicated that pts44 mutation occupies the region between purC and ptsI loci on the chromosome of Sh. flexneri. Merodiploids containing the mutant allele pts44 and the plasmid including purC-ptsI-ptsH genes from E. coli K12 acquired the capacity for fermenting carbohydrates, but at the same time retained resistance to phosphomycin and avirulent properties. The presence of phosphoenol pyruvate-dependent carbohydrate phosphotransferase system in Sh. flexneri has been proved.
