The comparative in vitro activity and synergy of cefepime were evaluated with clinical isolates of Pseudomonas aeruginosa and Pseudomonas cepacia from cystic fibrosis patients. The activity of cefepime, both alone and in combination, was comparable to those of other antibiotics. The clinical efficacy of cefepime in cystic fibrosis patients merits investigation.Cefepime is a new, broad-spectrum cephalosporin antibiotic with pronounced activity against many gram-negative pathogens (2,6,7). It is more active than some of the currently marketed broad-spectrum cephalosporins against Pseudomonas aeruginosa and is stable against hydrolysis by common P-lactamases. Moreover, it has been found to be active against most gram-negative bacteria, including P. aeruginosa, that have developed resistance to other broadspectrum cephalosporins (3). The objectives of the present study were to assess the comparative in vitro activity of cefepime against clinical isolates of P. aeruginosa and Pseudomonas cepacia obtained from cystic fibrosis patients and to determine the frequency of in vitro synergy in combinations of cefepime with other antipseudomonal agents against these same pseudomonal species.Clinical isolates of P. aeruginosa (n = 100) and P. cepacia (n = 25) cultured from the sputa of cystic fibrosis patients and identified by standard microbiological methods were selected for the determination of the comparative activity of cefepime. Multiple isolates from the same patient were differentiated on the basis of colony morphology and antibiograms. of isolates susceptible to each antibiotic were determined. In addition, the extent of activity of cefepime against isolates not susceptible to ceftazidime, tobramycin, and ciprofloxacin was assessed.Isolates of P. aeruginosa (n = 100) and P. cepacia (n = 20) also derived from cystic fibrosis patient sputa and identified by standard methods were used to study synergy (most, but not all, were also used in the comparative activity component of this study). Two-drug combinations consisting of cefepime and ciprofloxacin, tobramycin, and aztreonam were evaluated. Synergy was determined by the standard checkerboard technique. MICs were determined by microbroth dilution testing as described above but with antibiotic concentrations ranging from 1,024 to 0.062 ,ug/ml. Ten microliters of a 1:100 dilution of bacterial broth was added to each microdilution well, which contained 100 ,ul of antibiotic solution, such that a final inoculum of 5 x 105 ,ug/ml was produced. Microtiter plates were sealed in plastic bags and incubated overnight at 35°C. Synergy was defined as a fourfold or greater decrease in the MICs of both antibiotics (i.e., a cumulative fractional inhibitory concentration index of cO.5). Antagonism was defined as a fourfold or greater increase in the MIC of either antibiotic (i.e., a cumulative fractional inhibitory index of >4). Thus, the percentage of isolates of each species affected synergistically by each antibiotic combination was determined. The rate of synergy with organisms r...
The in vitro activities of two-drug combinations of aztreonam, ciprofloxacin, and ceftazidime were studied in 96 clinical isolates of Pseudomonas aeruginosa and in 20 clinical isolates of Pseudomonas cepacia from cystic fibrosis patients. Some synergy was observed with each combination used against P. aeruginosa, but synergy was rare when the combinations were used against P. cepacia.Pulmonary exacerbations of cystic fibrosis associated with antibiotic-resistant isolates of Pseudomonas aeruginosa and Pseudomonas cepacia continue to present a clinical problem in the care of affected patients despite the continuing introduction of new antipseudomonal agents. The concomitant use of two or more antibiotics is often necessary, especially in patients infected with multiple strains of P. aeruginosa or with both P. aeruginosa and P. cepacia. The objective of the present study was to explore the in vitro synergy of two-drug combinations of aztreonam, ciprofloxacin, and ceftazidime used against clinical isolates of these two pathogens.Ninety-six isolates of P. aeruginosa and 20 isolates of P. cepacia cultured from the sputa of cystic fibrosis patients at the University of Utah Intermountain Cystic Fibrosis Center were studied. All isolates were identified by standard microbiological methods and stored at room temperature on tryptic soy agar slants without glucose or were lyophilized and frozen until the time of the study. At the time of the study, all isolates were transferred to blood agar plates and checked for purity. They were then transferred to Trypticase soy broth (BBL Microbiology Systems, Cockeysville, Md.) and incubated overnight at 35°C. The turbidity of each bacterial broth suspension was then standardized to a 0.5 McFarland standard. From each of these suspensions, 0.1 ml was transferred to 9.9 ml of Mueller-Hinton broth which was supplemented with calcium and magnesium (final concentrations, 50 and 25 mg/ml, respectively), yielding a 1:100 dilution.The antibiotics studied were supplied as follows: aztreonam, E. R. Squibb & Sons, Princeton, N.J.; ciprofloxacin, Miles Pharmaceuticals, West Haven, Conn.; and ceftazidime, Glaxo, Inc., Research Triangle Park, N.C. Stock solutions were prepared from dry powders and used immediately or frozen at -32°C. All frozen solutions were used within 3 months of preparation. The antibiotic concentrations tested were twofold dilutions ranging from 1,024 to 0.0156 ,ug/ml. MICs were determined by broth microdilution. Microdilution plates (Dynatech Laboratories, Inc., Alexandria, Va.) were prepared with the antibiotic solutions (100 ,ul per well) and either used immediately or stored in * Corresponding author. 487 sealed plastic bags at -32°C for up to 1 month before use. Ten microliters of the 1:100 bacterial broth dilution was added to each microdilution well with an inoculator (Dynatech MIC-2000), producing a final inoculum of .5 x 105. The plates were resealed in plastic bags and incubated overnight at 35°C. Synergy was defined as a fourfold or greater reduction of the MIC...
Twelve isolates of Streptococcus pneumoniae with decreased susceptibility by oxacillin screen were susceptible by the FOX panel (Micro Media Systems, Cleveland, Ohio), a commercial microdilution system designed for fastidious organisms. These organisms were found to be moderately susceptible or resistant by broth macrodilution and agar dilution methods. This discrepancy indicates that the FOX panel is not reliable for susceptibility testing of S. pneumoniae.
The pharmacokinetics of azlocillin were studied in 10 cystic fibrosis patients, ranging in age from 11 to 28 years. The patients received a 9- to 23-day course of 350 mg of azlocillin per kg in four or six divided daily doses in combination with am aminoglycoside. Blood and urine samples were collected at specified times after the last dose of the course of azlocillin therapy and then assayed for azlocillin content. Pharmacokinetic parameters were determined by noncompartmental analysis. Mean values for serum half-life (1.74 h), disposition constant (0.41 h-1), total body clearance (123 ml/kg per h), and renal clearance (58 ml/kg per h) were determined. All patients exhibited improvement with respect to clinical and laboratory parameters and displayed no adverse reactions. The pharmacokinetic analysis offers further evidence of the dose-dependent nature of azlocillin elimination, but elimination did not appear to be altered in cystic fibrosis patients.
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