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PubMed1998

Carbapenem resistance mediated by beta-lactamases in clinical isolates of Acinetobacter baumannii in Spain.

Four patients colonized/infected with carbapenem-resistant strains of Acinetobacter baumannii are described. The first patient had a decubitus ulcer infection and had been on intravenous imipenem for 50 days. Two other patients, from whom Acinetobacter baumannii was isolated from urine, were hospitalized in the same ward as the first patient. The fourth patient had been mechanically ventilated in the intensive care unit for 4 month and had nosocomial pneumonia. He had been on intravenous meropenem for 1 month. Minimum inhibitory concentrations (MICs) of imipenem (128 mg/l) and meropenem (> 128 mg/l) were the same for the isolates from the first three patients, and all of these isolates had the same repetitive extragenic palindromic polymerase chain reaction (rep-PCR) pattern. The MICs of carbapenems were lower for patient 4's isolate, which also had a different rep-PCR pattern. Beta-lactamases that hydrolyzed imipenem were detected in all four isolates; isoelectric points were 8.6-7.7 in the first three isolates and 6.8-7 in the fourth isolate.

Acinetobacter↗

PubMedDate not supplied

Monobactams and carbapenems for treatment of intraabdominal infections.

During the last decade improved clinical and microbiological methods have resulted in the realization that most intraabdominal infections involve both aerobic and anaerobic bacteria. Papers on the use of different antimicrobial agents directed against the polymicrobial flora of the infected site have been published. In this paper the use of monobactams and carbapenems for treatment of intraabdominal infections is reviewed. The review is based on data published since 1990. Three hundred forty-four patients participated in three trials where aztreonam combined with clindamycin was compared with other antimicrobial agents for treatment of intraabdominal infections. Eighty-six percent of the patients receiving aztreonam plus clindamycin were cured/improved, while 83% of the patients receiving the comparative drugs had favorable outcomes. Eleven trials compared imipenem/cilastatin versus other antimicrobial combinations for therapy of intraabdominal infections. One thousand three hundred seventy-five patients were evaluated in the trials. Eighty percent of patients treated with imipenem/cilastatin had favorable outcomes, while 81% of the patients receiving the comparative drugs were cured/improved. Nine studies including 1,205 patients for evaluation of meropenem versus other antimicrobial agents in the treatment of intraabdominal infections have been published. Cure/improvement was seen in 96% of the patients treated with meropenem and in 91% receiving the comparative drugs. One trial has been published comparing biapenem with imipenem/cilastatin for treatment of intraabdominal infections. Eighty-three patients participated, 65% of the patients in the biapenem group were cured/improved and 68% in the imipenem/cilastatin group.

Abdomen↗

PubMed2001

Influence on Enterobacter cloacae metabolism, cell-surface hydrophobicity and motility of suprainhibitory concentrations of carbapenems.

The impact of postantibiotic effect (PAE) of carbapenems (imipenem, meropenem) on the metabolism (biosynthesis of macromolecules, respiration), cell-surface hydrophobicity and motility of a clinical isolate of Enterobacter cloacae was examined. The metabolism was evaluated after 16 h and after 1 d of cultivation using 2x and 4x minimum inhibitory concentrations (MIC) of both antibiotics for the induction of PAE. Imipenem at 4 x MIC did not induce PAE. After a 16-h cultivation (in the postantibiotic phase of both carbapenems), inhibition of nucleosynthesis and protein synthesis was found; after a 1-d cultivation, during regrowth stimulation of mainly 14C-leucine incorporation was found. The presence of the exogenous intermediates of citrate cycle, viz. 2-oxoglutarate, increased the respiratory activity of the cells. The cell-surface hydrophobicity (evaluated by three methods--bacterial adhesion to hydrocarbon, nitrocellulose-filter test and salt-aggregation test) decreased after PAE of both carbapenems; meropenem was more effective. Motility (an important virulence factor) was inhibited in the postantibiotic phase of both carbapenems; the 4 x MIC caused a higher inhibition.

Carbapenems↗

PubMed2004

Determination of epidemic clonality among multidrug-resistant strains of Acinetobacter spp. and Pseudomonas aeruginosa in the MYSTIC Programme (USA, 1999-2003).

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Programme was initiated in 1997 (1999 for the United States). This program monitors resistance in participant medical centers where carbapenems are prescribed and drug use data can be obtained. An earlier report found antimicrobial use was not a clear cause of local or aggregate changes in resistance rates. This study addresses the role of dissemination of resistant clones on susceptibility rates for nonfermentors, Acinetobacter spp. (ACB) and Pseudomonas aeruginosa (PSA). Carbapenem (CARB)-multidrug-resistant strains (MDR) from among 236 ACB and 1,111 PSA were tested by reference broth microdilution methods, automated ribotyping, and pulsed field gel electrophoresis to determine possible clonal dissemination. Each strain was also tested for metallo-beta-lactamases (MbetaL) (phenotypic and polymerase chain reaction); and then analyzed by CARB-R rate and defined daily dose (DDD)/100 days use groupings (high, moderate, and low). For the aggregate 15 sites in the MYSTIC Programme each year, the CARB-resistant rate decreased over 5 years; but other drug-resistance rates generally escalated. Changes were not related to antimicrobial use calculations. The discovered clonally spread MDR-PSA strains were more frequent in high- (1.8 clones/site) and moderate-resistance (0.6 clones/site) rate centers (21.7% to 29.5% were clonal), compared with unique strains in low-resistance hospitals. ACB clonality was extreme in one geographic area, with dissemination of 5 different clones (931.7/B, C, or D; 1090.2/A; 167.5/A) in 4 centers (02, 04, 06, and 18). Resistance rates in ACB and PSA were clearly related to clonal occurrence and spread, and one MbetaL (VIM-7) was detected. Decreased CARB resistance rates from 1999 through 2002 were directly attributed to the disappearance of resistance clones in some locations. In conclusion, ACB and PSA CARB and MDR resistance rates in MYSTIC Programme institutions have been greatly influenced by clonal dissemination and less by antimicrobial use patterns. The most serious examples of resistance were the clonality observed among ACB in New York City and the documented endemic nature of VIM-7-producing PSA (0.09% of all PSA isolates). Meropenem remained the most active antimicrobial agent tested in the program, and surveillance networks must implement epidemiologic typing to accurately assess the role of clonal spread on the study results.

Acinetobacter↗

PubMed2005

Prevalence of decreased susceptibility to carbapenems among Serratia marcescens, Enterobacter cloacae, and Citrobacter freundii and investigation of carbapenemases.

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.

Anti-Bacterial Agents↗

PubMed2006

Emergence of serine carbapenemases (KPC and SME) among clinical strains of Enterobacteriaceae isolated in the United States Medical Centers: report from the MYSTIC Program (1999-2005).

Among 8885 Enterobacteriaceae tested in the 1999 to 2005 period as part of the USA Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program, 51 strains with increased imipenem and meropenem MIC values (> or =2 microg/mL) were detected. bla(KPC) was identified from 28 Klebsiella pneumoniae from 3 medical centers in the New York City area (8 ribotypes), 2 Klebsiella oxytoca from Arkansas (same ribotype), 7 Citrobacter freundii (6 from New York [5 ribotypes] and 1 from Delaware), 4 Enterobacter spp. from New York (2 species, different ribotypes), 3 Escherichia coli (2 from New York and 1 from Ohio, same ribotype), and 1 Serratia marcescens (New York). Sequencing confirmed KPC-2 or -3 in all of the strains. S. marcescens strains harboring SME-1 (2 isolates, same ribotype) and SME-2 (1 isolate) were identified from medical centers in Illinois and Washington state, respectively. Our results indicate that bla(KPC-2/3) has emerged widely (New York City area, Arkansas, Delaware, and Ohio) among Enterobacteriaceae isolated in the MYSTIC Program participant sites (2000-2005) and continues to be isolated from multiple species, as a result of clonal expansion and horizontal gene transfer. The escalating occurrence (0.35%) of serine carbapenemases could compromise the role of carbapenems and other beta-lactams in USA clinical practice although observed in only a few locations to date.

Academic Medical Centers↗

PubMed2004

Antimicrobial susceptibility of clinical isolates of Enterobacteriaceae producing complex beta-lactamase patterns including extended-spectrum enzymes.

The antimicrobial susceptibility of 103 clinical isolates of Enterobacteriaceae to 11 antibiotics, was investigated, using a conventional inoculum size (5 x 10(5) CFU) and a higher inoculum size (5 x 10(8) CFU). All the isolates produced complex beta-lactamase patterns, including an extended-spectrum beta-lactamase (ESBL) of the TEM- or SHV-type plus other enzymes (a TEM-type or an SHV-type non-ESBL and/or a class C enzyme). The following repertoire of ESBLs was produced by the isolates: TEM-15, TEM-19, TEM-26, TEM-52, TEM-72, TEM-87, TEM-92, SHV-2a, SHV-5 and SHV-12, as assessed by sequencing. Production of the other enzymes was showed by analytical isoelectric focusing. Overall, meropenem was the most active agent and less influenced by inoculum size, while other beta-lactams showed a lower activity and a significant inoculum size effect. In conclusion, from its in vitro performance, meropenem could be considered as the last resource drug against strains producing complex beta-lactamase patterns including an ESBL.

Anti-Bacterial Agents↗

PubMed1998

Structural comparison of 1 beta-methylcarbapenem, carbapenem and penem: NMR studies and theoretical calculations.

Structural comparisons of meropenem (1), desmethyl meropenem (2) and the penem analogue (3) which contain the same side chains at both C-2 and C-6 were performed using 1H NMR measurements together with 3-21G* level of ab initio MO and molecular mechanics calculations. The ab initio MO calculations reproduced the skeletons of these strained beta-lactam rings in good agreement with the crystallographic data. 1H NMR measurements in aqueous solution together with molecular modeling studies indicated that there were conformational differences of the C-2 and C-6 side chains in this series of compounds. These observations suggested that the conformational differences could affect their biological activities.

Anti-Bacterial Agents↗

PubMed2003

Susceptibility of multi-drug-resistant Pseudomonas aeruginosa in intensive care units: results from the European MYSTIC study group.

The MYSTIC program monitors worldwide in vitro susceptibilities of clinical bacterial isolates from centers that prescribe meropenem. This report focuses on 107 isolates of multi-drug resistant (MDR) Pseudomonas aeruginosa, which commonly causes infections that are difficult to treat in hospitalized patients. We chose samples from patients from 33 European intensive care units (ICUs). There was considerable inter-country variation in the proportion of P. aeruginosa that were MDR, ranging from 50% in Turkey to < or =3% in Spain, the UK, Germany, Bulgaria and Malta. Amongst the MDR isolates, the percentage resistance (MIC50/90 in mg/L) to the antibiotics tested were amikacin 18.7% (32/>128), meropenem 29.1% (8/64), imipenem 44.9% (16/64), cefepime 49.5% (32/64) and piperacillin/tazobactam 57.9% (128/>128).

Anti-Bacterial Agents↗

PubMed2001

Novel mechanism of hydrolysis of therapeutic beta-lactams by Stenotrophomonas maltophilia L1 metallo-beta-lactamase.

Stopped-flow tryptophan fluorescence under single turnover and pseudo-first-order conditions has been used to investigate the kinetic mechanism of beta-lactam hydrolysis by the Stenotrophomonas maltophilia L1 metallo-beta-lactamase. For the cephalosporin substrates nitrocefin and cefaclor and the carbapenem meropenem, a substantial quench of fluorescence is observed on association of substrate with enzyme. We have assigned this to a rearrangement event subsequent to formation of an initial collision complex. For the colorimetric compound nitrocefin, decay of this dark inter- mediate represents the overall rate-determining step for the reaction and is equivalent to decay of a previously observed state in which the beta-lactam amide bond has already been cleaved. For both cefaclor and meropenem, the rate-determining step for hydrolysis is loss of a second, less quenched state, in which, however, the beta-lactam amide bond remains intact. We suggest, therefore, that the mechanism of hydrolysis of nitrocefin by binuclear metallo-beta-lactamases may be atypical and that cleavage of the beta-lactam amide bond is the rate-determining step for breakdown of the majority of beta-lactam substrates by the L1 enzyme.

Catalysis↗

PubMed2005

Escherichia coli: development of carbapenem resistance during therapy.

A 76-year-old woman had recurrent urosepsis due to extended-spectrum beta -lactamase-positive Escherichia coli. Imipenem resistance was detected after long-term imipenem-meropenem therapy. The carbapenem-hydrolyzing enzyme gene was identified as blaKPC-3. To our knowledge, this is the first documented case in which carbapenem-resistant E. coli emerged during therapy with imipenem and meropenem, and the first identification of the carbapenem-hydrolyzing enzyme in E. coli isolates.

Aged↗

PubMed1996

Diffusion of carbapenems through the outer membrane of enterobacteriaceae and correlation of their activities with their periplasmic concentrations.

Scarce information is available on the real mechanism by which carbapenemes penetrate in Enterobacteriaceae, although a considerable amount of evidence suggests that in many species of this family the lack of certain outer membrane proteins is associated with the acquisition of resistance to these antibiotics. The existance of specific pathways for the carbapenems has never been demonstrated, although at times it has been postulated in both wild and mutant strains, on the basis of evident discordances between permeability patterns and suceptibility data. By using the Zimmerman and Rosselet technique, which requires the strain under investigation to harbor a suitable beta-lactamase, the permeability of intact Escherichia coli and Enterobacter cloacae cells to meropenem and imipenem was investigated by transferring a constructed vector carrying the carbapenem hydrolyzing CphA metallo-beta-lactamase gene into the parental strains and their porin-deficient mutants. Reduced amounts of nonspecific porins significantly reduced the penetration of both carbapenems. The virtual absence of porins caused the MICs of meropenem to increase, mostly in Enterobacter cloacae, while it did not affected the MICs of imipenem. No evidence of specific porin pathways of the type described in Pseudomonas aeruginosa was found.

Bacterial Outer Membrane Proteins↗

PubMed1995

Extended-spectrum plasmid-mediated beta-lactamases.

Extended-spectrum beta-lactamases (ESBLs) are mutant enzymes which derive from TEM or SHV (class A) enzymes. They confer variable levels of resistance to cefotaxime, ceftazidime and other broad-spectrum cephalosporins and to monobactams such as aztreonam but have no detectable activity against cephamycins and carbapenems. Recently, new plasmid-mediated ESBLs, not derived from TEM or SHV enzymes but related to cephalosporinases of Enterobacteriaceae (class C enzymes), that confer resistance to all cephalosporins including cephamycins, have been reported. However, to date there have been no reported outbreaks due to strains producing transferable cephalosporinases. Klebsiella pneumoniae is the species in which the ESBL enzymes have been most commonly reported around the world. Most of the clinical isolates that produce TEM- or SHV-derived ESBL, come from hospitalised patients and have frequently caused nosocomial outbreaks. Care should be taken in the selection of a beta-lactam for the treatment of infections because the presence of an ESBL does not prevent other mechanisms of resistance, such as decreased permeability, from emerging. Broad-spectrum cephalosporins including cefepime and cefpirome are hydrolysed by ESBL. However, low level resistance to cefotaxime, ceftriaxone, cefepime and aztreonam does occur in some strains producing certain TEM-derived ESBL. It remains to be seen, therefore, whether such isolates are clinically susceptible to these drugs. The combination of a third-generation cephalosporin and a beta-lactamase inhibitor such as sulbactam could be of interest against some strains producing certain ESBLs. Among the 7-alpha-methoxy cephalosporins, cefotetan and latamoxef are the most active. However, cephamycins should be used with caution to treat infections caused by ESBL-producing K. pneumoniae because of the relative ease with which clinical strains decrease the expression of outer membrane proteins. The most active beta-lactams are the carbapenems, imipenem and meropenem, which are highly resistant to hydrolysis by TEM and SHV related beta-lactamases. Meropenem is intrinsically the more active agent, with MICs (0.03-0.12 mg/L) generally lower than those of imipenem (0.06-0.5 mg/L) and appears stable to all the beta-lactamases belonging to class A or C, including those with an extended-spectrum against third-generation cephalosporins.

Carbapenems↗

PubMed1997

Potentiation of beta-lactams against Pseudomonas aeruginosa strains by Ro 48-1256, a bridged monobactam inhibitor of AmpC beta-lactamases.

Ro 48-1256 is a bridged monobactam inhibitor of Class C beta-lactamases, without significant antibacterial activity of its own. It was tested in combination with imipenem, meropenem, piperacillin and ceftazidime against Pseudomonas aeruginosa isolates, mutants and transconjugants. Imipenem was potentiated against all strains where the AmpC enzyme was inducible or derepressed, with its MICs being reduced from 1-2 mg/L to 0.25-0.5 mg/L for most isolates and from 8-16 mg/L to 1-2 mg/L for those lacking OprD (D2 porin). Ro 48-1256 also abolished in-vitro selection of OprD-deficient mutants by imipenem. Ceftazidime and piperacillin were potentiated against strains derepressed for AmpC enzyme, but not against those where the enzyme remained inducible. For over 90% of AmpC-derepressed organisms, the MICs of ceftazidime were reduced to < or = 8 mg/L by Ro 48-1256 (4 mg/L) and those of piperacillin were reduced to < or = 16 mg/L. Meropenem, which is very stable to AmpC, was not potentiated. Ro 48-1256 did not potentiate piperacillin, ceftazidime or carbapenems when resistance was mediated by Class A, B or D enzymes. Tazobactam, tested as control, had opposite behaviour to Ro 48-1256, potentiating beta-lactams when resistance was due to Class A beta-lactamases but failing to reverse resistance mediated by AmpC. Ro 48-1256 could be used with imipenem to overcome resistance mediated by loss of OprD, or with ceftazidime or piperacillin to overcome derepression of AmpC.

Anti-Bacterial Agents↗

PubMed2005

Pharmacodynamics of antibiotics with respect to bacterial killing of and release of lipoteichoic acid by Streptococcus pneumoniae.

OBJECTIVES: There are marked differences in the amount of immunoreactive components such as lipoteichoic acid (LTA) released from Gram-positive bacteria following exposure to different antibiotics. Little is known about the kinetics and amount of release of such components in relation to bacterial killing. METHODS: Bacterial killing and LTA release from Streptococcus pneumoniae type 3 during exposure to ceftriaxone, meropenem, rifampicin, rifabutin, quinupristin/dalfopristin, and trovafloxacin in tryptic soy broth were quantified microbiologically and by ELISA, respectively. We applied a mathematical model to characterize quantitatively the amount of lipoteichoic acid released and the statistical moments of this release. RESULTS: The model approach revealed that (i) the lag time to release of LTA was very similar for individually killed bacterial cells (approximately 120 min), whatever the killing mechanism effected by the antibiotic, and (ii) the amount of LTA released per killed bacterial cell, a value that we regard as an indicator of the relation between antibacterial efficacy and possible adverse immunostimulatory effects due to release of cell wall components, differs markedly between antibiotics, even at antibiotic concentrations inducing equal killing. Rifamycins were most effective in killing S. pneumoniae while causing the least LTA release per killed bacterial cell; the amount released was about one-half that by quinupristin-dalfopristin and trovafloxacin, and one-quarter that by ceftriaxone and meropenem. CONCLUSIONS: In the evaluation of antibacterial drugs, the present model provides useful information on the whole process of bacterial killing and release of immunoreactive components from the bacterial cell wall.

Anti-Bacterial Agents↗

PubMed2001

Convalescent phase outpatient parenteral antiinfective therapy for children with complicated appendicitis.

BACKGROUND: Children with a perforated or gangrenous appendix become clinically stable after medical and/or surgical therapy but often remain in the hospital solely to complete parenteral antibiotic therapy. This prospective study investigates the outcomes when children who meet specified criteria are discharged to complete parenteral antibiotic therapy at home. METHODS: Children age 1 to 17 years with appendicitis complicated by generalized peritonitis or intraabdominal abscess were eligible to participate. Subjects whose fever was decreasing, who were able to tolerate oral liquids and for whom further parenteral antibiotic therapy was deemed necessary were discharged from the hospital to receive outpatient parenteral antiinfective therapy (OPAT) with meropenem. Therapy was administered by a family member and supervised by home care nurses. Study personnel visited the home daily to collect data on adverse events, compliance and resource utilization. Pa tients served as their own controls in models of reduced hospitalization and net cost savings. RESULTS: Discharged on average on the fourth postoperative day, 87 children received 4.5 +/- 2.1 days of OPAT. Six (7%) children were subsequently readmitted for complications including bowel obstruction (4 children), intraabdominal abscess (1 child) and pleural effusion (1 child). Another child developed a viral syndrome during OPAT. All other patients recovered uneventfully. Six (7%) children discontinued meropenem prematurely because of rash (4 patients) or diarrhea (2 patients). According to models in which each day of OPAT replaced a day of inpatient care, discharge to OPAT reduced hospitalization by 42 +/- 15% and saved a median of $2908 (10th to 90th percentile range, $1,077 to $4,707) per patient. CONCLUSION: Convalescent phase OPAT is a cost-effective alternative to continued hospitalization for children with complicated appendicitis who are clinically stable yet require further parenteral antibiotic therapy.

Abdominal Abscess↗

PubMed1998

New antibiotics.

Three broad-spectrum antibiotics are reviewed, each from a different class. Meropenem is closely related to imipenem and was recently approved for use in children. Its advantages over imipenem include greater activity against gram-negative bacteria and lack of association with seizures. Cefepime is a fourth generation cephalosporin with the gram-positive activity of cefotaxime and the gram-negative spectrum of ceftazidime. Trovafloxacin is a fluoroquinolone with an exceptionally broad antibacterial spectrum. Meropenem is approved for use in children, cefepime is approved for use in adults only, and trovafloxacin is still undergoing clinical trials. These agents should be reserved for treatment of serious infections, especially those in immunocompromised patients or polymicrobial infections.

Anti-Infective Agents↗

PubMed1999

Relationship between morphological changes and endotoxin release induced by carbapenems in Pseudomonas aeruginosa.

The relationship between morphological changes and endotoxin release induced in vitro by carbapenems in a clinical isolate of Pseudomonas aeruginosa was examined. The time-course and magnitude of endotoxin release induced varied among imipenem, panipenem, meropenem and biapenem and related to the morphological changes caused by these agents which variously affected cell shape, cell-wall disintegration and cell lysis. The amount of endotoxin released by carbapenem-treated cells correlated with both the cell-wall morphology and bacterial shape immediately before lysis. Meropenem and biapenem caused markedly increased endotoxin release during cell lysis and cell-wall disintegration, whereas imipenem and panipenem caused much less release of endotoxin.

Carbapenems↗