Gene/Protein Disease Symptom Drug Enzyme Compound
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Carbapenem-hydrolyzing beta-lactamases of several Ambler molecular classes have been reported as the source of acquired beta-lactam antibiotic resistance in Gram negative bacteria. The metallo-enzymes of Ambler class B are the most prevalent enzymes in this case. These clavulanic-acid resistant enzymes have a large spectrum of hydrolysis including penicillins, cephalosporins (third and fourth generations), carbapenems but not monobactams. They are responsible for acquired resistance in several Gram negative species of clinical relevance in human medicine. IMP-1 was the first reported as acquired in Japan, mostly from Serratia marcescens and Pseudomonas aeruginosa isolates, and has been detected in Europe recently. Several variants of IMP-1 (IMP-2 to -9) have been characterized, possessing 85 to 99% amino acid identity, mostly from P. aeruginosa isolates. In addition, VIM-1 to -3 beta-lactamases have also been described, first in Europe (Italy, France, and Greece) and now in Korea. The VIM series shares 30% amino acid identity with the IMP-series. Most of these class B enzymes have genes that are integron- and plasmid-located. Finally, a few Ambler class A (SME-1, NMC-A, IMI-1, KPC-1) and class D (OXA-23 to -27) beta-lactamases involved in carbapenem hydrolysis have been reported also from rare isolates of Gram-negative rods. This review underlines the worldwide spread of carbapenem-hydrolyzing beta-lactamases as representing an important threat for efficacy of antibiotics in the near future.
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PMID:Acquired carbapenem-hydrolyzing beta-lactamases and their genetic support. 1202 55

Doripenem (S-4661), a new parenteral carbapenem, was tested against over 250 clinical isolates, mutants, and transconjugants of Enterobacteriaceae and Acinetobacter spp., selected or derived for their beta-lactamase expression characteristics. Imipenem, meropenem, and ertapenem were tested as comparators, along with cephalosporins and piperacillin-tazobactam, by using National Committee for Clinical Laboratory Standards agar dilution methodology. Doripenem MICs were from 0.03 to 0.25 microg/ml for Klebsiella isolates, irrespective of the presence of extended-spectrum beta-lactamases (ESBLs) or plasmid-mediated AmpC or hyperproduced K1 beta-lactamase. Similarly, MICs of doripenem for both AmpC-inducible and -derepressed Enterobacter isolates were 0.06 to 0.5 microg/ml. ESBL production did not raise the MICs of doripenem for Escherichia coli transconjugants, and studies with known expression mutants confirmed that neither inducible nor depressed AmpC beta-lactamase expression was protective in Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, or Morganella morganii. In all of these respects, doripenem resembled meropenem and imipenem, whereas the MICs of ertapenem were raised (but still < or =1 microg/ml) for many ESBL-producing klebsiellas and AmpC-derepressed E. cloacae and C. freundii strains. Resistance to all carbapenems, including doripenem (MICs of mostly 16 to 64 microg/ml, compared with 0.25 to 1 microg/ml for typical strains), was seen in Acinetobacter isolates with metallo-beta-lactamases or OXA-carbapenemases. Isolates of Klebsiella and Serratia spp. with IMP, KPC, and SME beta-lactamases also were resistant to doripenem (MICs, 8 to >64 microg/ml) and to other carbapenems, although the continued apparent susceptibility (MICs, < or =0.5 microg/ml) of E. coli derivatives with cloned IMP-1 and NMC-A beta-lactamases suggested that carbapenem resistance might require other factors besides the enzymes.
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PMID:Comparative activities of doripenem versus isolates, mutants, and transconjugants of Enterobacteriaceae and Acinetobacter spp. with characterized beta-lactamases. 1504 35

Between March and July 2002, total of 612 clinical isolates of Serratia marcescens, Enterobacter cloacae, and Citrobacter freundii (201 S. marcescens, 228 E. cloacae, and 183 C. freundii) were collected from 13 clinical laboratories in a nationwide distribution. Imipenem and meropenem minimum inhibitory concentrations (MICs) were determined using the agar dilution method according to the National Committee for Clinical Laboratory Standards guidelines. For the isolates with a decreased susceptibility to carbapenems (MICs of >or=2 microg/mL), isoelectric focusing, polymerase chain reaction (PCR) amplification of the carbapenemase genes (bla(IMP-1), bla(VIM-2), bla(SME-1), bla(OXA-23), bla(OXA-25), bla(KPC-1)), and sequencing were performed. The prevalence of S. marcescens, E. cloacae, and C. freundii with a decreased susceptibility to imipenem was 17.9% (36/201), 0.4% (1/228), and 0.5% (1/183), respectively, and to meropenem, it was 11.4% (23/201), 0% (0/228), and 0.5% (1/183), respectively. The bla(VIM-2) was the only carbapenemase detected, and was found in 0.5% (1/201) of S. marcescens and 0.5% (1/183) of C. freundii isolate.
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PMID:Prevalence of decreased susceptibility to carbapenems among Serratia marcescens, Enterobacter cloacae, and Citrobacter freundii and investigation of carbapenemases. 1599 52

Enterobacteria produce elementary chromosomal enzymes, Beta-lactamases of class A: TEM and SHV (Escherichia coli, Klebsiella pneumoniae). These can give rise to plasmid-coded broad-spectrum Beta-lactamases (ESBL) discovered in 1980 (E. coli, K. pneumoniae, Enterobacter cloacae). The first cefotaximase (CTX-M, MEN-1) was reported in Europe in 1990. This enzyme is far more active against cefotaxime than against ceftazidime and aztreonam. Chromosomal hyperpoduction of K1 Beta-lactamase differs from all other ESBLs due its sensitivity to ceftazidime (Klebsiella oxytoca). However, not all enterobacteria are resistant only because of ESBLs, but also as a result of the action of chromosomally or plasmid coded AmpC Beta-lactamase of class C (MIR-1, CMY-1, BIL-1, FOX-1, MOX-1, DHA-1, ACC-1), resistant to Beta-lactamase inhibitors and to cefoxitin (Enterobacter spp., Proteus vulgaris, Citrobacter freundii, Morganelle spp., Serratia spp.). With the loss of outside-membrane porins (OMP) they can become resistant to carbapenem an tibiotics. The 100% resistance of enterobacteria to carbapenems that so far exists in this country is elsewhere in the world compromised by the incidence of carbapenem-hydrolysing plasmid-determined Beta-lactamase of class B (IMP-1, VIM-1) and of class A (KPC-1) in K. pneumoniae, (SME-1) in Serratia marcescens and (IMI-1, NMC-A) in E. clocae. Carbapenemases in enterobacteria are only effective in the presence of impermeability and other resistance mechanisms.
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PMID:[Development of Beta-lactamase resistance in enterobacteria]. 1705 71

Emergence and dissemination of Enterobacteriaceae isolates harboring carbapenemases in various geographic regions represents a significant threat to the management of nosocomial infections. Enterobacteriaceae isolates from the SENTRY Antimicrobial Surveillance Program (2000-2004) demonstrating decreased susceptibility to imipenem and meropenem (minimum inhibitory concentration [MIC], > or =2 mg/L) were evaluated for the production of metallo-beta-lactamases and serine carbapenemases using disk approximation and polymerase chain reaction (PCR) tests. Carbapenemase-producing strains were epidemiologically typed by automated riboprinting and pulsed-field gel electrophoresis (PFGE) to establish clonality. Among 37,557 Enterobacteriaceae (5 genus groups) evaluated, 119 (0.32%) had increased carbapenem MIC values, and a carbapenemase was identified in 51 (42.9%) of these strains. KPC-2 and KPC-3 were the most frequently occurring carbapenemases (24 isolates, 20.2%) in the United States and were detected in Klebsiella spp, Citrobacter spp., Enterobacter spp., and Serratia marcescens strains isolated in New York, Arkansas, and Virginia. SME-2-producing S. marcescens were isolated in the New York City area, Texas, and Ohio, while NMC-A was found in one E. cloacae strain from New York. In contrast, metallo-beta-lactamases were prevalent in Europe. IMP-1-producing E. cloacae (11 isolates) were detected in Turkey, while VIM-1-producing strains were found in Italy (Enterobacter spp.) and Greece (Klebsiella pneumoniae). Clonal dissemination of carbapenemase-producing strains was observed in several medical centers on both continents. The occurrence of carbapenemases in various Enterobacteriaceae remains rare but appears to be spreading geographically (not in Latin America), mainly with metallo-beta-lactamases being found in Mediterranean Europe and KPC enzymes in the New York City area.
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PMID:Occurrence and characterization of carbapenemase-producing Enterobacteriaceae: report from the SENTRY Antimicrobial Surveillance Program (2000-2004). 1722 6

A total of 104 carbapenemase (serine- and metallo-beta-lactamase [MbetaL])-producing strains of the Enterobacteriaceae family collected from 2000 to 2005 in medical centers distributed worldwide were tested against tigecycline and 25 comparators by reference broth microdilution methods. The most frequent carbapenemase was KPC-2 or -3 (73 strains), followed by VIM-1 (14), IMP-1 (11), SME-2 (5), and NMC-A (1). All serine carbapenemases were detected in the United States, while MbetaL-producing strains were isolated in Europe. Carbapenemase-producing Enterobacteriaceae showed high rates of resistance to most antimicrobial agents tested. The rank order of in vitro activity against these strains was as follows: tigecycline (100.0% susceptible) > polymyxin B (88.1%) > amikacin (73.0%) > imipenem (37.5%). Tigecycline was very active (MIC(90), 1 microg/ml) against this significant, contemporary collection of well-characterized strains and appears to be an excellent option compared to the polymyxins for treatment of infections caused by these multidrug-resistant Enterobacteriaceae.
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PMID:Antimicrobial activities of tigecycline and other broad-spectrum antimicrobials tested against serine carbapenemase- and metallo-beta-lactamase-producing Enterobacteriaceae: report from the SENTRY Antimicrobial Surveillance Program. 1807 Sep 60

The stability of doripenem to hydrolysis by beta-lactamases from molecular classes A to D was compared to the stability for imipenem and meropenem. Doripenem was stable to hydrolysis by extended-spectrum beta-lactamases and AmpC type beta-lactamases and demonstrated high affinity for the AmpC enzymes. For the serine carbapenemases SME-3 and KPC-2 and metallo-beta-lactamases IMP-1 and VIM-2, doripenem hydrolysis was generally 2- to 150-fold slower than imipenem hydrolysis. SPM-1 hydrolyzed meropenem and doripenem fourfold faster than imipenem.
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PMID:Hydrolysis and inhibition profiles of beta-lactamases from molecular classes A to D with doripenem, imipenem, and meropenem. 1988 79

In 2010, a three months survey of multidrug-resistant Enterobacteriaceae was conducted by Ministry of Health, Labour and Welfare of Japan. A total of 153 isolates were obtained through this survey and we performed PCR using the NDM-1 type, KPC type, IMP-1 type, IMP-2 type and VIM-2 type carbapenemase genes specific primers. Of 153 analyzed isolates, 72 (47.1%) were positive for IMP-1 type bla(IMP), and two isolates from two patients were positive for bla(NDM-1). None of those patients had traveled abroad. Two isolates from a single patient who had traveled and hospitalized in abroad were positive for bla(KPC). 77 (50.3%) isolates were all negative for those five carbapenemase genes. It was shown that IMP-1 type is the most predominant carbapenemase gene among Enterobacteriaceae in Japan.
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PMID:[Three months survey of multidrug-resistant Enterobacteriaceae in Japan]. 2241 16

Carbapenem is the last resort for infections due to Gram-negative bacteria. However, carbapenem-resistant Enterobacteriaceae such as KPC-producing bugs were reported in the United States from early this decade and now worldwide. According to the nationwide surveillance study in Japan performed between September and December, 2010, two bla(KPC)-harboring Klebsiella pneumoniae were identified among 153 multi-drug-resistant Enterobacteriaceae. Moreover, 72 out of 153 multi-drug-resistant Enterobacteriaceae harbored bla(IMP-1). The results of this surveillance study demonstrated that the most epidemic carbapenemase in Japan is not bla(KPC) but bla(LMP-1). Although the bla(KPC)-harboring strain is very rare in Japan, detection of KPC-producing Gram-negative bacteria may be difficult based on the CLSI recommended method. Development of effective screening methods is needed in the Japanese healthcare environment.
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PMID:[KPC carbapenemase producing Gram-negative bacteria]. 2241 30

Among 228 carbapenem-nonsusceptible Enterobacteriaceae isolated in China, 65 were carbapenemase-producing Enterobacteriaceae (CPE). Among them, 41, 22, 1, and 1 produced KPC-2, IMP-4, IMP-8, and IMP-1, respectively. KPC-2-producing CPE showed higher resistance than IMP-4-producing ones. Furthermore, the first outbreak of ST11 KPC-2-producing Klebsiella pneumoniae in a Beijing second-degree hospital was identified.
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PMID:Molecular characteristics of carbapenemase-producing Enterobacteriaceae in China from 2008 to 2011: predominance of KPC-2 enzyme. 2421 Dec 18


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