Activity and Specific Beta-Lactamase Susceptibility of Cefoperazone and Moxalactam

Mouton, R. P.; Bongaerts, G.P.A.; Gestel, M Van; Bruggeman-Ogle, K M

doi:10.1159/000237999

Cited by 6 publications

(1 citation statement)

References 12 publications

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“…The structures of a substrate, loracarbef, 19 and an inhibitor, cloxacillin 20 (Figure 2), were determined in complex with a deacylation deficient mutant AmpC, Q120L/Y150E. The structure of another inhibitor, moxalactam 21 (Figure 2), was determined in complex with wildtype (WT) AmpC. These structures suggest a mechanism that draws together earlier, seemingly incompatible results into a consistent picture for the rate-determining hydrolytic step in the mechanism of group I β-lactamases.…”

Section: Introductionmentioning

confidence: 99%

Crystal Structures of Substrate and Inhibitor Complexes with AmpC β-Lactamase: Possible Implications for Substrate-Assisted Catalysis

2000

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Group I β-lactamases are major resistance determinants to β-lactam antibiotics. Despite intense study, the identity of the catalytic base, the direction of hydrolytic attack, and the functional difference between β-lactam substrates and β-lactam inhibitors remain controversial. To explore these questions, we determined the X-ray crystal structures of several representative β-lactams in their acyl−adduct complexes with the group I β-lactamase AmpC. A complex with the substrate loracarbef and a deacylation-deficient mutant enzyme reveals an ordered water molecule that is consistent with β-face attack of the catalytic water in group I β-lactamases. The ring nitrogen of the substrate is placed to hydrogen-bond with this water in the position it is thought to adopt in the deacylation transition state. In complexes with the inhibitors cloxacillin and moxalactam, conformational restrictions displace the equivalent ring nitrogens, sterically blocking the formation of the presumed deacylation transition-state structure. In conjunction with earlier studies, these acyl−enzyme structures suggest that both Tyr150 and the ring nitrogen of the substrate itself stabilize the hydrolytic transition state, and that β-lactam inhibitors of group I β-lactamases can act by physically blocking this activation.

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Section: Introductionmentioning

confidence: 99%

Crystal Structures of Substrate and Inhibitor Complexes with AmpC β-Lactamase: Possible Implications for Substrate-Assisted Catalysis

2000

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Antimicrobial Activity, Pharmacokinetics, Adverse Reactions, and Therapeutic Indications of Cefoperazone

Funk

Strausbaugh

1982

Pharmacotherapy

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Cefoperazone is a parenteral cephalosporin antibiotic that is pending approval by the U. S. Food and Drug Administration. Compared to most other cephalosporins cefoperazone has a greatly expanded spectrum of bactericidal activity that encompasses most aerobic gram-positive bacteria except enterococci, most aerobic gram-negative bacteria, including a majority of Pseudomonas aeruginosa strains, and a number of pathogenic anaerobic bacteria. Its long serum half-life, approximately two hours, permits a twelve hourly dosing schedule. No dosage modification is required in patients with renal insufficiency, and only minor modification is needed in patients with hepatic insufficiency or biliary obstruction. Clinical trials have established cefoperazone's efficacy in lower respiratory tract infections, urinary tract infections, and a variety of other bacterial infections. Adverse reactions have been infrequent, and few serious reactions have been identified. Cefoperazone is a promising new agent for the treatment of gram-negative bacillary and polymicrobial infections, especially in settings that require empiric therapy.

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A Comparative Evaluation of Moxalactam: Antimicrobial Activity, Pharmacokinetics, Adverse Reactions, and Clinical Efficacy

Fitzpatrick

Standiford

1982

Pharmacotherapy

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Although moxalactam is not, technically speaking, a cephalosporin it is chemically and microbiologically so closely related to those compounds that it can be viewed as a member of the cephalosporin family. Moxalactam has a spectrum of activity that includes both gram positive and gram negative bacteria. Its gram positive activity is less than earlier cephalosporins, but its activity against the Enterobacteriaceae is similar to that of the aminoglycoside family of antibiotics in most comparative studies. Although moxalactam is considerably less active against gram positive bacteria than cefotaxime, another third generation cephalosporin, its higher and more prolonged serum levels probably offset this disadvantage. Compared to cefoperazone, the stability of moxalactam to many types of beta lactamases produced by gram negative bacteria may be advantageous in the therapy of infections caused by hospital-acquired pathogens. Clinical studies suggest that moxalactam can be used for empiric therapy of suspected gram negative infections when Pseudomonas and other non-fermentative bacteria, such as Acinetobacter, are not suspected. Impressive improvements in the survival of patients with gram negative enteric bacillary meningitis have been reported. Although moxalactam, cefotaxime, and cefoperazone have activity against Pseudomonas aeruginosa, none of these antibiotics should be used alone as therapy for suspected or proven severe systemic infections caused by this pathogen. Cost is a major problem with all of the new cephalosporin-like antibiotics. While this high cost may be partially balanced by the use of a single agent compared to an antibiotic combination for therapy in some situations, these antibiotics are not cost effective for prophylactic use. Superinfection with fungi, such as Candida, and Streptococcus faecalis have occurred, and toxicities, such as bleeding due to vitamin K deficiency and disulfuram-like reactions, have also been reported. Reports of resistance to moxalactam and the other third generation cephalosporins are of major concern and indicate the need to closely monitor antibiotic susceptibility patterns of hospital acquired organisms if these antibiotics are to be used for empiric therapy of suspected gram negative non-pseudomonas sepsis.

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Activity and Specific Beta-Lactamase Susceptibility of Cefoperazone and Moxalactam

Cited by 6 publications

References 12 publications

Crystal Structures of Substrate and Inhibitor Complexes with AmpC β-Lactamase: Possible Implications for Substrate-Assisted Catalysis

Crystal Structures of Substrate and Inhibitor Complexes with AmpC β-Lactamase: Possible Implications for Substrate-Assisted Catalysis

Antimicrobial Activity, Pharmacokinetics, Adverse Reactions, and Therapeutic Indications of Cefoperazone

A Comparative Evaluation of Moxalactam: Antimicrobial Activity, Pharmacokinetics, Adverse Reactions, and Clinical Efficacy

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