Bactericidal killing activities of cefepime, ceftazidime, cefotaxime, and ceftriaxone against Staphylococcus aureus and beta-lactamase-producing strains of Enterobacter aerogenes and Klebsiella pneumoniae in an in vitro infection model

Abstract

Cefepime (CP) is a new injectable cephalosporin with a broad spectrum of activity and stability against common chromosomally and plasmid-mediated ␤-lactamases. The bactericidal activities of CP, ceftazidime (CZ), cefotaxime (CTX), and ceftriaxone (CAX) against reference and clinical strains of Staphylococcus aureus, an isogenic pair of Enterobacter aerogenes strains (wild type and a CZ-resistant derepressed mutant), and a Klebsiella pneumoniae isolate possessing a TEM-10 ␤-lactamase were investigated in a two-compartment pharmacodynamic in vitro infection model which simulates human pharmacokinetics. An inoculum of ϳ10 6 CFU/ml was used in all model experiments. Antibiotics were administered to simulate the following regimens: CP at 2 g every 12 h (q12h), CZ at 2 g q8h, CTX at 2 g q8h, and CAX at 2 g q24h. Human albumin was added during experiments with CAX and staphylococci to simulate protein binding. Samples were removed at multiple time points over a 48-h period to determine the inoculum size for time-kill curves. Development of resistance was detected by inoculating samples obtained at 0, 24, and 48 h onto antibiotic-containing agar plates. The time to 99.9% killing was used to compare drug regimens. Against staphylococci, the time to bacterial eradication was significantly delayed with CAX-albumin. All regimens had similar activities against the wild-type Enterobacter strain; however, regrowth was noted with CZ, CTX, and CAX against the CZresistant strain. There were no differences between the CP, CTX, and CAX regimens against K. pneumoniae. Of interest, no regrowth of any organism was noted with CP. These data indicate that CP has activity against S. aureus and CZ-resistant gram-negative bacilli.Cefepime is a new injectable cephalosporin with a broad spectrum of activity against many gram-positive and gramnegative bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa. It has poor affinity for inducible chromosomally mediated cephalosporinases (Bush group 1) and is resistant to hydrolysis by most common chromosomally and plasmid-mediated enzymes, including the recently described extended-broad-spectrum ␤-lactamases of the Bush 2bЈ classification (4, 5). In vitro data indicate that cefepime retains activity against gram-negative organisms which have developed resistance to other broad-spectrum cephalosporins and thus may be useful for the treatment of infections involving these bacteria. Like other broad-spectrum cephalosporins, cefepime will probably be used empirically in patients for whom the infecting pathogen has not yet been identified. Therefore, activity against gram positive organisms that is comparable to those of other commonly used agents will be necessary. The purpose of this investigation was to compare the bactericidal activity of cefepime with those of ceftazidime, cefotaxime, and ceftriaxone against S. aureus and ␤-lactamase-producing strains of Enterobacter aerogenes and Klebsiella pneumoniae. MATERIALS AND METHODSBacterial strains. Two strains of methicillin-sensitive S. au...

Modulation of Cell Wall Structure and Antimicrobial Susceptibility by a Staphylococcus aureus Eukaryote-Like Serine/Threonine Kinase and Phosphatase

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Rifampin Combination Therapy for Nonmycobacterial Infections

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Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents

“…First, protein supplements, such as human or bovine serum albumin or human serum, may be added to the growth media to mimic physiological binding conditions in in vitro settings. Although there is no general consensus on the amount of protein to be added, 4 g/dl is typically regarded as the target concentration, as it resembles normal physiological conditions (16,17,20,21,26,27,(118)(119)(120)(121)(122). Selection of the serum concentration is even more difficult, as bacterial growth is often inhibited once the serum content exceeds 70% of the growth medium (16).…”