Carbapenems: the pinnacle of the beta-lactam antibiotics or room for improvement?

Edwards, Jeffrey R.; Betts, Michael J.

doi:10.1093/jac/45.1.1

Cited by 45 publications

(33 citation statements)

References 14 publications

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“…Over the past 3 decades, many other potent ␤-lactam antibiotics, such as cephems, monobactams, and carbapenems, have been developed and are currently being utilized to treat a wide range of bacterial infections. In fact, the high efficacy, high specificity, and low rate of adverse reactions make ␤-lactam antibiotics the most prescribed antimicrobial agents worldwide (12). All ␤-lactam antibiotics show structural mimicry to the natural substrates of the bacterial DD-transpeptidases.…”

mentioning

confidence: 99%

Crystal Structure and Activity Studies of the Mycobacterium tuberculosis β-Lactamase Reveal Its Critical Role in Resistance to β-Lactam Antibiotics

Wang

Cassidy

Sacchettini

2006

Antimicrob Agents Chemother

144

216

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␤-Lactam antibiotics are extremely effective in disrupting the synthesis of the bacterial cell wall in both gram-positive and gram-negative bacteria. However, they are ineffective against Mycobacterium tuberculosis, due to the production of a ␤-lactamase enzyme encoded on the chromosome of M. tuberculosis that degrades these antibiotics. Indeed, recent studies have demonstrated that deletion of the blaC gene, the only gene encoding a ␤-lactamase in M. tuberculosis, or inhibition of the encoded enzyme resulted in significantly increased sensitivity to ␤-lactam antibiotics. In this paper we present a biochemical and structural characterization of M. tuberculosis BlaC. Recombinant BlaC shows a broad range of specificity with almost equal penicillinase and cepholothinase activity. While clavulanate is a mechanism-based inhibitor to class A ␤-lactamase with high potency (typically K i < 0.1 M), it is a relatively poor inhibitor of the M. tuberculosis BlaC (K i ‫؍‬ 2.4 M). The crystal structure of the enzyme, determined at a resolution of 1.7 Å, shows that the overall fold of the M. tuberculosis enzyme is similar to other class A ␤-lactamases. There are, however, several distinct features of the active site, such as the amino acid substitutions N132G, R164A, R244A, and R276E, that explain the broad specificity of the enzyme, relatively low penicillinase activity, and resistance to clavulanate.

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confidence: 99%

Crystal Structure and Activity Studies of the Mycobacterium tuberculosis β-Lactamase Reveal Its Critical Role in Resistance to β-Lactam Antibiotics

Wang

Cassidy

Sacchettini

2006

Antimicrob Agents Chemother

144

216

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“…Due to their broad spectrum of activity and stability to hydrolysis by most ␤-lactamases, the carbapenems have been the drugs of choice for treatment of infections caused by penicillin-or cephalosporin-resistant gram-negative bacteria (6,13,17,22). However, carbapenem resistance has been observed more commonly in nonfermenter species such as Pseudomonas aeruginosa and Acinetobacter spp.…”

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confidence: 99%

Evaluation of a New Etest for Detecting Metallo-β-Lactamases in Routine Clinical Testing

Bolmström²,

et al. 2002

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“…These advantages make carbapenems an attractive class for further pharmaceutical development (6), especially since strains that have ESBLs and that hyperproduce AmpC ␤-lactamases continue to accumulate in hospitals (11,12,18) and are beginning to be seen in nursing home patients (2,18), perhaps selected by community use of oral oxyimino-aminothiazolyl cephalosporins.…”

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confidence: 99%

In Vitro Activities of Ertapenem (MK-0826) against Recent Clinical Bacteria Collected in Europe and Australia

Livermore¹,

Carter²,

Bagel³

et al. 2001

Antimicrob Agents Chemother

121

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Ertapenem (MK-0826, L-749,345) is a 1-␤-methyl carbapenem with a long serum half-life. Its in vitro activitywas determined by broth microdilution against 3,478 bacteria from 12 centers in Europe and Australia, with imipenem, cefepime, ceftriaxone, and piperacillin-tazobactam used as comparators. Ertapenem was the most active agent tested against members of the family Enterobacteriaceae, with MICs at which 90% of isolates are inhibited (MIC 90 s) of <1 g/ml for all species. Ertapenem also was more active than imipenem against fastidious gram-negative bacteria and Moraxella spp.; on the other hand, ertapenem was slightly less active than imipenem against streptococci, methicillin-susceptible staphylococci, and anaerobes, but its MIC 90 s for these groups remained <0.5 g/ml. Acinetobacter spp. and Pseudomonas aeruginosa were also much less susceptible to ertapenem than imipenem, and most Enterococcus faecalis strains were resistant. Ertapenem resistance, based on a provisional NCCLS MIC breakpoint of >16 g/ml, was seen in only 3 of 1,611 strains of the family Enterobacteriaceae tested, all of them Enterobacter aerogenes. Resistance was also seen in 2 of 135 anaerobes, comprising 1 Bacteroides fragilis strain and 1 Clostridium difficile strain. Ertapenem breakpoints for streptococci have not been established, but an unofficial susceptibility breakpoint of <2 g/ml was adopted for clinical trials to generate corresponding clinical response data for isolates for which MICs were as high as 2 g/ml. Of 234 Streptococcus pneumoniae strains tested, 2 required ertapenem MICs of 2 g/ml and one required an MIC of 4 g/ml, among 67 non-Streptococcus pyogenes, non-Streptococcus pneumoniae streptococci, single isolates required ertapenem MICs of 2 and 16 g/ml. These streptococci also had diminished susceptibilities to other ␤-lactams, including imipenem as well as ertapenem. The Etest and disk diffusion gave susceptibility test results in good agreement with those of the broth microdilution method for ertapenem.

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Carbapenems: the pinnacle of the beta-lactam antibiotics or room for improvement?

Cited by 45 publications

References 14 publications

Crystal Structure and Activity Studies of the Mycobacterium tuberculosis β-Lactamase Reveal Its Critical Role in Resistance to β-Lactam Antibiotics

Crystal Structure and Activity Studies of the Mycobacterium tuberculosis β-Lactamase Reveal Its Critical Role in Resistance to β-Lactam Antibiotics

Evaluation of a New Etest for Detecting Metallo-β-Lactamases in Routine Clinical Testing

In Vitro Activities of Ertapenem (MK-0826) against Recent Clinical Bacteria Collected in Europe and Australia

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