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At least 19 recordsLinked to original sources
PubMed2006

Potency of carbapenems for the prevention of carbapenem-resistant mutants of Pseudomonas aeruginosa: the high potency of a new carbapenem doripenem.

The potencies of the carbapenems; doripenem (DRPM), meropenem (MEPM) and imipenem (IPM) in preventing the emergence of carbapenem-resistant mutants were examined in Pseudomonas aeruginosa strains. The carbapenems predominantly selected carbapenem-resistant mutants or carbapenem mutants with reduced susceptibilities that were specifically resistant to carbapenems and had arisen as a result of the reduced level of expression of the outer membrane protein with a molecular weight of about 48,000 (OprD). The potency of carbapenems in preventing the growth of the mutants differed for DRPM, MEPM and IPM. The isolation frequency of the mutant was examined on agar plates containing each of the carbapenems at a concentration of 1/2 or 1/4 MIC of each carbapenem for that mutant. Mutants were not selected on agar containing DRPM at a frequency of greater than 10(-9) per cell per generation, whereas mutants of each strain were selected on agar containing MEPM or IPM at frequencies of 10(-7) to 10(-9) per cell per generation. The drug concentrations and the drug concentration range for the selective increase of carbapenem resistant mutants in the broth culture containing each carbapenem differed for each carbapenem. DRPM exhibited both the lowest drug concentration and the narrowest range of drug concentration for selection of the carbapenem-resistant mutants. The results shown in this report indicated that DRPM exhibited the greatest ability to prevent the emergence of the mutant.

Anti-Bacterial Agents↗
PubMed2005

Contribution of acquired carbapenem-hydrolyzing oxacillinases to carbapenem resistance in Acinetobacter baumannii.

Carbapenem-hydrolyzing oxacillinases are reported increasingly in Acinetobacter baumannii. Since they hydrolyze carbapenems at low levels, the roles of carbapenem-hydrolyzing oxacillinases OXA-23, OXA-40, and OXA-58 in A. baumannii were determined. The bla(OXA-23), bla(OXA-40), and bla(OXA-58) genes were inserted in broad-host-range plasmid pAT801 and transformed in Escherichia coli DH10B and in A. baumannii CIP 70.10 and its point mutant derivative A. baumannii BM4547, which overexpresses the efflux pump AdeABC. Natural plasmids harboring the bla(OXA-23) and bla(OXA-58) genes were also transformed in A. baumannii CIP 70.10. In addition, the bla(OXA-40) gene was inactivated at its chromosome location in A. baumannii CLA-1. Intermediate levels of resistance or reduced susceptibilities to carbapenems were observed for A. baumannii transformants expressing OXA-23, OXA-40, and OXA-58. The inactivation of bla(OXA-40) in A. baumannii CLA-1 yielded reduced susceptibilities to carbapenems. Carbapenem-hydrolyzing oxacillinases OXA-23, OXA-40, and to a lesser extent OXA-58 play a role in carbapenem resistance in A. baumannii, and overexpression of efflux pump AdeABC may also contribute to higher levels of resistance to beta-lactams, including carbapenems.

Acinetobacter baumannii↗
PubMed2005

Carbapenem-based prodrugs. Design, synthesis, and biological evaluation of carbapenems.

Syntheses of racemic trans-3-hydroxycarbonyl-6-(phenylacetamido)carbapenem (13), trans-3-phosphono-6-(phenylacetamido)carbapenem (17), and beta-lactam based prodrugs 19 and 22 were accomplished. Carbapenem 13 was found to possess antibacterial activity, comparable with imipenem (+)-3, against Staphylococcus aureus FDA 209P, S. aureus 95, Escherichia coli ATCC 39188, Klebsiella pneumoniae NCTC 418, Pseudomonas aeruginosa 1101-75, P. aeruginosa 18S-H, and Xanthomonas maltophilia GN 12873. Like imipenem ((+)-3), carbapenem 13 was not stable to X. maltophilia oxyiminocephalosporinase type II. Its phosphonate analog 17, however, was neither a significant antibacterial agent nor a good beta-lactamase inhibitor. Chemical combinations of trans carbapenem 13 with cis carbapenem 6 (compound 19) as well as clavulanic acid (20) with cis carbapenem 6 (compound 22) via a tetrachloroethane linker exhibited remarkable activity against beta-lactamase producing microorganisms in vitro.

Anti-Bacterial Agents↗
PubMed2001

Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae.

A Klebsiella pneumoniae isolate showing moderate to high-level imipenem and meropenem resistance was investigated. The MICs of both drugs were 16 microg/ml. The beta-lactamase activity against imipenem and meropenem was inhibited in the presence of clavulanic acid. The strain was also resistant to extended-spectrum cephalosporins and aztreonam. Isoelectric focusing studies demonstrated three beta-lactamases, with pIs of 7.2 (SHV-29), 6.7 (KPC-1), and 5.4 (TEM-1). The presence of bla(SHV) and bla(TEM) genes was confirmed by specific PCRs and DNA sequence analysis. Transformation and conjugation studies with Escherichia coli showed that the beta-lactamase with a pI of 6.7, KPC-1 (K. pneumoniae carbapenemase-1), was encoded on an approximately 50-kb nonconjugative plasmid. The gene, bla(KPC-1), was cloned in E. coli and shown to confer resistance to imipenem, meropenem, extended-spectrum cephalosporins, and aztreonam. The amino acid sequence of the novel carbapenem-hydrolyzing beta-lactamase, KPC-1, showed 45% identity to the pI 9.7 carbapenem-hydrolyzing beta-lactamase, Sme-1, from Serratia marcescens S6. Hydrolysis studies showed that purified KPC-1 hydrolyzed not only carbapenems but also penicillins, cephalosporins, and monobactams. KPC-1 had the highest affinity for meropenem. The kinetic studies also revealed that clavulanic acid and tazobactam inhibited KPC-1. An examination of the outer membrane proteins of the parent K. pneumoniae strain demonstrated that the strain does not express detectable levels of OmpK35 and OmpK37, although OmpK36 is present. We concluded that carbapenem resistance in K. pneumoniae strain 1534 is mainly due to production of a novel Bush group 2f, class A, carbapenem-hydrolyzing beta-lactamase, KPC-1, although alterations in porin expression may also play a role.

Amino Acid Sequence↗
PubMed2003

Carbapenem-resistant strain of Klebsiella oxytoca harboring carbapenem-hydrolyzing beta-lactamase KPC-2.

We investigated a Klebsiella oxytoca isolate demonstrating resistance to imipenem, meropenem, extended-spectrum cephalosporins, and aztreonam. The MICs of both imipenem and meropenem were 32 microg/ml. The beta-lactamase activity against imipenem and meropenem was inhibited in the presence of clavulanic acid. Isoelectric focusing studies demonstrated five beta-lactamases with pIs of 8.2 (SHV-46), 6.7 (KPC-2), 6.5 (unknown), 6.4 (probable OXY-2), and 5.4 (TEM-1). The presence of the bla(SHV) and bla(TEM) genes was confirmed by specific PCR assays and DNA sequence analysis. Transformation and conjugation studies with Escherichia coli showed that the beta-lactamase with a pI of 6.7, Klebsiella pneumoniae carbapenemase-2 (KPC-2), was encoded on an approximately 70-kb conjugative plasmid that also carried SHV-46, TEM-1, and the beta-lactamase with a pI of 6.5. The bla(KPC-2) determinant was cloned in E. coli and conferred resistance to imipenem, meropenem, extended-spectrum cephalosporins, and aztreonam. The amino acid sequence of KPC-2 showed a single amino acid difference, S174G, when compared with KPC-1, another carbapenem-hydrolyzing beta-lactamase from K. pneumoniae 1534. Hydrolysis studies showed that purified KPC-2 hydrolyzed not only carbapenems but also penicillins, cephalosporins, and aztreonam. KPC-2 had the highest affinity for meropenem. The kinetic studies revealed that KPC-2 was inhibited by clavulanic acid and tazobactam. An examination of the outer membrane proteins of the parent K. oxytoca strain demonstrated that it expressed detectable levels of OmpK36 (the homolog of OmpC) and a higher-molecular-weight OmpK35 (the homolog of OmpF). Thus, carbapenem resistance in K. oxytoca 3127 is due to production of the Bush group 2f, class A, carbapenem-hydrolyzing beta-lactamase KPC-2. This beta-lactamase is likely located on a transposon that is part of a conjugative plasmid and thus has a very high potential for dissemination.

Amino Acid Sequence↗
PubMed1997

Novel C-2 substituted carbapenem derivatives. Part III. Synthesis and biological activity of 2-(functionalised ethenyl, oxyiminomethyl and alpha-[hydroxy]benzyl)-carbapenems.

The synthesis, antibacterial activity and stability to human dehydropeptidase-1 (DHP-1) of three small series of carbapenems carrying carbon-linked substituents at C-2 are described. C-2 Ethenyl carbapenems showed moderate antibacterial activity but poor stability to DHP-1, C-2 Oxyiminomethyl carbapenems demonstrated variable activity and stability C-2 alpha-(Hydroxy)benzyl carbapenems were the most promising and showed good potency and DHP-1 stability.

Carbapenems↗
PubMed1985

Studies on the biosynthesis of carbapenem antibiotics. IV. Beta-alanine in the C-3 pantetheinyl side chain of the OA-6129 group of carbapenems.

Radioactive beta-alanine was specifically incorporated into the beta-alanine moiety of the C-3 pantetheinyl side chain of the OA-6129 group of carbapenems by Streptomyces sp. OA-6129, while no added radioactive pantothenate was taken up into the mycelia. The extracellular concentrations of beta-alanine and pantothenate in the broth of Streptomyces sp. OA-6129 increased with the production of the carbapenems. The production levels of beta-alanine and pantothenate markedly differed between carbapenem-producing streptomycetes and nonproducers, with the exception of Streptomyces cattleya, a thienamycin producer, suggesting a possible relation of carbapenem biosynthesis with the levels of beta-alanine and pantothenate.

Alanine↗
PubMed2005

Study of the synergism between carbapenems and vancomycin or teicoplanin against MRSA, focusing on S-4661, a carbapenem newly developed in Japan.

S-4661 is a methylcarbapenem antibiotic newly developed in Japan. We evaluated the combined actions of carbapenems, including S-4661 and vancomycin or teicoplanin, against 27 strains of methicillin-resistant Staphylococcus aureus (MRSA) isolated from the blood of patients admitted to Keio University Hospital, using the checkerboard technique. The minimum inhibitory concentrations (MICs) were determined by the Mueller-Hinton agar method. Most of the strains were highly resistant to carbapenems. Synergy with S-4661, panipenem, meropenem or imipenem, and vancomycin was detected against 92% of the strains tested. Synergy with S-4661, panipenem, meropenem or imipenem, and teicoplanin was detected against 74% of the strains tested. The results of our study suggest that combination therapy of vancomycin or teicoplanin with any of S-4661, panipenem, meropenem, or imipenem would be effective for severe infections due to MRSA strains that are resistant to carbapenems.

Anti-Bacterial Agents↗
PubMed1990

Cephalosporins to carbapenems: 1-oxygenated carbapenems and carbapenams.

The photo "Wolff" rearrangement of readily available 2-diazoceph-3-em oxides (1) directly affords carbapen-2-ems, allowing a facile entry into a ring system previously accessible only by total synthesis, lengthly semisynthesis or fermentation. The chirality of the cephalosporin is accurately translated into the corresponding carbapenem. The resulting 1-oxocarbapenems (2) were selectively transformed through reduction into 1-oxygenated carbapenems and carbapenams (3 and 4, respectively). On microbiological screening, a carbapenem (3c) was found to possess a broad spectrum of activity. An interesting antibacterial profile was discovered for a carbapenam (26).

Anti-Bacterial Agents↗
PubMed2004

Emergence of carbapenem-resistant Klebsiella species possessing the class A carbapenem-hydrolyzing KPC-2 and inhibitor-resistant TEM-30 beta-lactamases in New York City.

Nineteen isolates of carbapenem-resistant Klebsiella species were recovered from 7 hospitals in New York City. Most K. pneumoniae belonged to a single ribotype. Nucleotide sequencing identified KPC-2, a carbapenem-hydrolyzing beta -lactamase. In 3 strains, TEM-30, an inhibitor-resistant beta -lactamase, was detected. Carbapenem-resistant Klebsiella species possessing KPC-2 are endemic in New York City. This study documents the identification of an inhibitor-resistant TEM beta -lactamase in the United States.

Carbapenems↗
PubMed2001

[Antimicrobial activities and mechanisms of carbapenem resistance in clinical isolates of carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter spp].

We tested the antimicrobial activities of meropenem (MEPM), imipenem (IPM), panipenem (PAPM), piperacillin (PIPC), cefepime (CFPM), aztreonam (AZT), amikacin (AMK), and levofloxacin (LVFX) against 106 clinical Pseudomonas aeruginosa isolates and 64 clinical Acinetobacter spp. isolates with reduced susceptibility to carbapenems. Using NCCLS breakpoints, the percentages of P. aeruginosa strains susceptible to AMK and Acinetobacter spp. strains susceptible to LVFX were found to be 51.1% and 55.6%, respectively, which represented the highest activity among 8 antimicrobial agents in each organism. Referring to the correlations among MICs of carbapenems, MEPM showed a higher activity than IPM and PAPM in both organisms; 29 of the 94 strains (30.9%) of IPM-resistant P. aeruginosa were susceptible to MEPM. Further study for resistance mechanisms to carbapenems by the disk diffusion method using 2-mercaptopropionic acid revealed that 8 of the 64 Acinetobacter spp. isolates (12.5%) were metallo-beta-lactamase producers, while none of 106 P. aeruginosa isolates were metallo-beta-lactamase producers. PCR analysis using blaIMP-specific primers confirmed that 4 of the 8 metallo-beta-lactamase-producing Acinetobacter spp. isolates detected by the disk diffusion method were carrying the blaIMP gene. The identification of metallo-beta-lactamase-producing Acinetobacter spp. isolates implies that metallo-beta-lactamase genes have been disseminated among various gram-negative pathogens.

Acinetobacter↗
PubMed2000

Characterization of a nosocomial outbreak caused by a multiresistant Acinetobacter baumannii strain with a carbapenem-hydrolyzing enzyme: high-level carbapenem resistance in A. baumannii is not due solely to the presence of beta-lactamases.

From February to November 1997, 29 inpatients at Ramón y Cajal Hospital, Madrid, Spain, were determined to be either colonized or infected with imipenem- and meropenem-resistant Acinetobacter baumannii (IMRAB) strains (MICs, 128 to 256 microg/ml). A wide antibiotic multiresistance profile was observed with IMRAB strains. For typing IMRAB isolates, pulsed-field gel electrophoresis was used. For comparative purposes, 30 imipenem- and meropenem-susceptible A. baumannii (IMSAB) strains isolated before, during, and after the outbreak were included in this study. The molecular-typing results showed that the outbreak was caused by a single IMRAB strain (genotype A). By cloning experiments we identified a class D beta-lactamase (OXA-24) encoded in the chromosomal DNA of this IMRAB strain which showed carbapenem hydrolysis. Moreover, the outer membrane profile of the IMRAB strain showed a reduction in the expression of two porins at 22 and 33 kDa when compared with genetically related IMSAB isolates. In addition no efflux mechanisms were identified in the IMRAB strains. In summary, we report here the molecular characterization of a nosocomial outbreak caused by one multiresistant A. baumannii epidemic strain that harbors a carbapenem-hydrolyzing enzyme. Although alterations in the penicillin-binding proteins cannot be ruled out, the reduction in the expression of two porins and the presence of this OXA-derived beta-lactamase are involved in the carbapenem resistance of the epidemic nosocomial IMRAB strain.

Acinetobacter↗
PubMed1992

Synthesis and in vitro activity of novel quaternary ammonium carbapenems: 2-pyridiniopropyl and 1-pyridinioethyl carbapenems.

The synthesis of new carbapenems having either a pyridiniopropyl group at the 2-position or a pyridinioethyl group at the 1-position is described, along with the preparation of their corresponding hydroxy and acetoxy analogs. The antibacterial activity, susceptibility to dehydropeptidase-I (DHP-I) enzyme and chemical stability of these new carbapenems are also reported. 2-Pyridiniopropyl-carbapenem 4 was found to possess excellent antibacterial activity. It was more stable chemically and less susceptible to the DHP-I enzyme than the thio analog 3. 1-Pyridinioethylcarbapenem 5 showed significantly reduced antibacterial activity as compared to 2-pyridiniopropylcarbapenem 4.

Carbapenems↗
PubMed1988

Mutagenesis of OA-6129 carbapenem-producing blocked mutants and the biosynthesis of carbapenems.

Streptomyces fulvoviridis A933 17M9 1501 is an A933 acylase-defective mutant derived from S. fulvoviridis A933 17M9 and thus produces the OA-6129 group of carbapenems and carbapenams. By further mutation of mutant 1501, 4 types of mutants (OA-6129 A + B1 + B2 producers; OA-6129 A + B2 producers; an OA-6129 A producer; non-producers) were obtained. The second type of mutant strains 4N 3607, 5NA 3949-40 and 5NE 252 proved useful for the fermentative production of carbapenem OA-6129 B2. These results of mutagenesis demonstrated that the sequence of carbapenem bioconversion in the horizontal route was hydroxylation at C-8----isomerization at C-6----sulfation at C-8 hydroxyl.

Mutation↗
PubMed1991

Comparative study of certain antibiotics on epileptogenic property, including (1Rpi, 5S, 6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6-yl)] thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate (LJC10627), a carbapenem antibiotic with broad antimicrobial spectrum.

The epileptogenic effects of (1R, 5S, 6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6- yl)]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate (LJC10627), a new derivative of carbapenem were studied in comparison with those of imipenem (imipenem/cilastatin), cefazolin and penicillin G. In intraventricular injection in rats, LJC10627 caused no epileptogenic activity at a dose of 32 micrograms. In contrast, imipenem, cefazolin and penicillin G showed dose-related seizure signs, continuous rhythmic spikes or high voltage spike-wave complexes and convulsive behaviors at doses higher than 10 micrograms. After intravenous injection of LJC10627, no epileptogenic signs on the electroencephalogram (EEGs) or in behavioral symptoms were observed, even at a dose of 500 mg/kg in rats and 300 mg/kg in rabbits, respectively. By contrast, imipenem/cilastatin provoked severe seizure patterns characterized by high voltage spikes-wave complex and convulsive behavior, both in rats and rabbits, using the same doses of LJC10627. Cefazolin and penicillin G also induced obvious epileptogenic signs in both rats and rabbits after intravenous injection. From these results, it was concluded that LJC10627, unlike imipenem (imipenem/cilastatin) and cefazolin, dose not elicit epileptogenic activity, and may therefore be safely used for clinical purpose.

Animals↗
PubMed1984

Studies on the biosynthesis of carbapenem antibiotics. I. Biosynthetic significance of the OA-6129 group of carbapenem compounds as the direct precursors for PS-5, epithienamycins A and C and MM 17880.

Based on the working hypothesis that the OA-6129 group of carbapenem compounds might be the direct precursors for PS-5, epithienamycins A and C and MM 17880, Streptomyces fulvoviridis A933 17M9, a producer of PS-5, PS-6, PS-7, PS-8, epithienamycins A, B, C and D, MM 17880, MM 13902 and MM 4550, was subjected to NTG-mutation to provide a blocked mutant numbered 1501 which was found to produce OA-6129 A, OA-6129B1, OA-6129B2 and OA-6129C instead of PS-5, epithienamycins A and C and MM 17880, respectively. In a cell-free system, the parent strain demonstrated an ability to convert OA-6129A to NS-5, whereas the mutant did not. The L- and D-amino acid acylases were also shown to depantothenylate the OA-6129 group of carbapenems.

Amidohydrolases↗
PubMed1991

Carbapenem and penem antibiotics. VII. Synthesis and antibacterial activity of 1 beta-methyl-2-(quaternary heteroaromatic-thiomethyl) carbapenems.

The synthesis and antibacterial activity of a series of 1 beta-methylcarbapenems having quaternary heteroaromatic-thiomethyl groups at the C-2 position are described. Both 2-hydroxymethyl and 2-chloromethyl carbapenems (1 and 7) respectively served as the common key intermediates for the preparation of these compounds. Of these, the 4-pyridiniothiomethyl derivatives exhibited the best antibacterial properties and turned out to possess high in vivo efficacy as well.

Animals↗
PubMed1996

Novel C-2 substituted carbapenem derivatives. Part II. Synthesis and structure-activity relationships of isoxazolin-2-yl, isoxazolidin-2-yl and 2-pyrazolin-2-yl carbapenems generated using 1,3-dipolar cycloaddition chemistry.

A series of carbapenems containing novel C-2 semisaturated heterocyclic substituents were synthesised by 1,3 dipolar cycloaddition reactions of nitrile oxides, nitrile imines and a nitrone to 2-vinylcarbapenem. The isoxazoline and isoxazolidine compounds showed potent antibacterial activity but moderate stability to human dehydropeptidase 1 (DHP-1). Stability to DHP-1 was improved by methyl substitution in the isoxazoline ring, but at the expense of antibacterial activity. The pyrazolines exhibited excellent stability to DHP-1, but reduced potency against Gram-negative organisms.

Carbapenems↗