Affinity of cephalosporins for beta-lactamases as a factor in antibacterial efficacy

Phelps, D J; Carlton, Donna; Farrell, Cathy A.; Kessler, R E

doi:10.1128/aac.29.5.845

Cited by 75 publications

(52 citation statements)

References 14 publications

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“…In addition, cefepime appears to have a low affinity for chromosomally derived P-lactamases (23). Clinical experience indicates that cefepime is safe and well tolerated when single or multiple (every 8 or 12 h) doses of 250 to 2,000 mg are given by the intravenous (4, 5) or intramuscular (9) routes of administration.…”

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confidence: 99%

Lack of pharmacokinetic interaction between cefepime and amikacin in humans

Barbhaiya

Knupp

Pfeffer

et al. 1992

Antimicrob Agents Chemother

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The interaction potential between cefepime and amikacin was investigated in a steady-state pharmacokinetic study in 16 healthy male subjects. Eight subjects (group A) received a first course of 2,000 mg of cefepime; this was followed by a second course of 2,000 mg of cefepime with 300 mg of amikacin and a third course of 2,000 mg of cefepime. Eight other subjects (group B) received a first course of 300 mg of amikacin, a second course of 300 mg of amikacin with 2,000 mg of cefepime, and a third course of 300 mg of amikacin. Each course consisted of four consecutive doses administered every 8 h as 30-min intravenous infusions. Serial plasma and urine samples, which were collected after administration of the fourth dose of each course, were assayed for cefepime and/or amikacin by validated high-performance liquid chromatographic assays. Trough levels of cefepime and amikacin indicated that these antibiotics attained a steady state prior to administration of the fourth dose of each course. Key pharmacokinetic parameters for each antibiotic were determined by noncompartmental methods. The peak concentrations of cefepime and amikacin in plasma when the drugs were given alone were about 160 and 27 ,g/ml, respectively. Levels of each antibiotic in plasma declined, with an apparent half-life of approximately 2.2 h. Urinary recovery of cefepime and amikacin accounted for more than 85% of the administered dose of each antibiotic. Mean renal clearances for cefepime and amikacin ranged from 79 to 95 ml/min and suggested that glomerular filtration is the primary excretion mechanism. The results of the statistical analyses indicated that the pharmacokinetic parameters of cefepime following the concurrent administration of amikacin and following the discontinuation of the amikacin therapy were not significantly altered. Similarly, the pharmacokinetic parameters of amikacin following the concurrent administration of cefepime and following the discontinuation of the cefepime therapy were not significantly altered. Cefepime and amikacin can be coadministered to patients with normal renal function by using the standard recommended dosing regimens.Cefepime (BMY-28142) is a new parenteral cephalosporin with significant potential advantages over other new cephalosporins and nontraditional ,3-lactam antibiotics with respect to its antimicrobial spectrum of activity (12,15). In addition, cefepime appears to have a low affinity for chromosomally derived P-lactamases (23). Clinical experience indicates that cefepime is safe and well tolerated when single or multiple (every 8 or 12 h) doses of 250 to 2,000 mg are given by the intravenous (4, 5) or intramuscular (9) routes of administration. The pharmacokinetics of this cephalosporin are linear (4, 5, 9). Over 80% of the administered dose of cefepime is recovered in urine in an unchanged form (4, 5, 7-9).In the most severely infected patients, empiric therapy consists of the administration of antibacterial therapy before pathogen identification. The standard approach has been to use an ant...

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confidence: 99%

Lack of pharmacokinetic interaction between cefepime and amikacin in humans

Barbhaiya

Knupp

Pfeffer

et al. 1992

Antimicrob Agents Chemother

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“…In agreement with the notion that low hydrolysis rates at low sub;trate concentrations represent the most important factor in producing truly P-lactamase-stable compounds, they share low affinities or high Km values for type I enzymes and are therefore expected to be hydrolyzed much more slowly in pharmacologically relevant situations. These compounds include cefepime (BMY-28142) (14), cefpirome (HR-810) (7), and E-1040 (23). They are characterized by containing, at the 3 position, substituents with quaternary nitrogen atoms (Fig.…”

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confidence: 99%

Outer membrane permeability and beta-lactamase stability of dipolar ionic cephalosporins containing methoxyimino substituents

Nikaido

Liu

Rosenberg

1990

Antimicrob Agents Chemother

140

104

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Some enteric bacteria, such as Enterobacter cloacae, can develop high-level resistance to broad-spectrum cephalosporins by overproducing their chromosomally encoded type I P-lactamases. This is because these agents are hydrolyzed rapidly at pharmacologically relevant, low (0.1 to 1 ,uM), concentrations, owing to their high affinity for type I enzymes. In contrast, the more recently developed cephalosporins, with quaternarynitrogen-containing substituents at the 3 position, show increased efficacy against ,I-lactamase-overproducing strains and, indeed, have a much lower affinity for type I enzymes. However, the possible contribution of an improved outer membrane permeability in their increased efficacy has not been studied. We found by proteoliposome swelling assays that cefepime, cefpirome, and E-1040 all penetrated the porin channels of Escherichia coli and E. cloacae much more rapidly than did ceftazidime and at least as rapidly as did cefotaxime. Considering that the influx of anionic compounds such as cefotaxime and ceftazidime will be further retarded in intact cells, owing to the Donnan potential, we expect that the newer compounds will penetrate intact cells 2 to 10 times more rapidly than will cefotaxime and ceftazidime. The kinetic parameters of hydrolysis of these agents by E. cloacae P-lactamase showed that at 0.1 ,M, they were hydrolyzed much more slowly than was cefotaxime and at about the same rate as or a lower rate than was ceftazidime. The combination of these two effects explains nearly quantitatively why these newer agents are more effective against some of the 3-lactamase-overproducing gram-negative bacteria.Conventional assays showed that many of the more recently developed cephalosporins, such as cefoxitin, cefuroxime, and the broad-spectrum cephalosporins, including cefotaxime and ceftazidime, were totally resistant to hydrolysis by commonly encountered ,-lactamases, including the type I or class C chromosomally encoded P-lactamases of members of the family Enterobacteriaceae (for an example, see reference 18). Nevertheless, the widespread use of these agents was followed by the emergence of resistant mutant strains of organisms such as Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa which constitutively produced high levels of type I ,-lactamases (15). This puzzling finding led to the proposal that the resistance was due to nonhydrolytic substrate binding by ,-lactamase molecules (15,20,21,24).Vu and Nikaido (22) concluded, however, from quantitative considerations of outer membrane permeability and the number of P-lactamase molecules present in the cell, that such a nonhydrolytic trapping mechanism cannot explain the high level of resistance found in E. cloacae strains overproducing the type I P-lactamase. Furthermore, Livermore (8) and Vu and Nikaido (22) pointed out that conventional P-lactam hydrolysis assays with very high (0

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“…A considerable number of ceftazidime/cefotaxime-resistant Gram-negative bacteria were found to be inhibited by BMY-28142. This may be explained, in part, by the finding of PHELPS et al 15) that BMY-28142 has low binding affinity for (3-lactamases combined with high resistance to hydrolysis. The anti-pseudomonal bactericidal activity of BMY-28142 was similar to that of ceftazidime.…”

Section: Discussionmentioning

confidence: 96%