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PubMed2026

Dual β-lactam therapy against high-risk Pseudomonas aeruginosa isolates: a dynamic in-vitro infection model study integrating population genomics with quantitative systems pharmacology modelling and simulations.

BACKGROUND: Pseudomonas aeruginosa has an extraordinary capacity for resistance emergence during treatment, even with newer antipseudomonals. There is a gap in understanding how resistance mechanisms affect the time-course of bacterial response to these newer agents. Traditional approaches for predicting pathogen response to an antibiotic do not apply to combination therapy. We aimed to develop a modelling framework to predict treatment response based on resistome information, using isolates of the worldwide-disseminated high-risk clone sequence type (ST) 235 and β-lactam antibiotics as the example. METHODS: In this hollow-fibre in-vitro infection study, we used three extensively drug-resistant ST235 clinical isolates from the national collection of the Clinical Microbiology Department of the Hospital Son Espases (Palma de Mallorca, Spain) that were hospital-acquired, were isolated following routine microbiological procedures from different patients between 2017 and 2022, were susceptible to ceftolozane-tazobactam, and had different levels of meropenem resistance. The selected isolates (ST235-05, ST235-09, and ST235-10) showed classical β-lactam resistance mechanisms pre-treatment. The isolates were investigated in 240-h dynamic hollow-fibre in-vitro infection models (HFIMs). The studies exposed the isolates to pharmacokinetic profiles of ceftolozane-tazobactam (simulating 1 g of ceftolozane and 0·5 g of tazobactam as a 3-h infusion every 8 h) and meropenem (simulating 6 g per day continuous infusion) as observed in hospitalised patients, as monotherapy and in combination. Treatment response was assessed through the quantification of the time-courses of viable total and resistant bacteria. Whole-genome sequencing identified the mechanisms of emerging resistance. A quantitative systems pharmacology (QSP) approach was used to model total and resistant bacterial counts and corresponding pharmacokinetic data from the HFIM. Monte Carlo simulations were used to predict treatment responses in 1000 virtual infected patients treated with ceftolozane-tazobactam and meropenem as monotherapies or in combination over 10 days. FINDINGS: In the HFIMs, each antibiotic alone amplified resistance by approximately 48 h for all isolates; that is, monotherapies resulted in a higher concentration of resistant bacteria compared with the control treatment at the respective time, except ceftolozane-tazobactam against ST235-10. Combination of ceftolozane-tazobactam and meropenem was synergistic (bacterial counts ≥2 log10 colony forming units [CFU] per mL lower than the best performing monotherapy and initial inoculum) against all isolates and suppressed resistance. Against ST235-10, ceftolozane-tazobactam monotherapy reduced counts to less than 1 log10 CFU per mL from 192 h onwards, whereas the combination reached less than 1 log10 CFU per mL by 24 h. Across strains, population genomics confirmed monotherapy failures were associated with emerging resistance mechanisms (ceftolozane-tazobactam: ampC Ω-loop mutations; meropenem: ftsl mutation). The developed QSP model incorporated baseline resistance mechanisms and those emerging in resistant mutant subpopulations. The model explained and predicted the monotherapy failures involving amplification of these subpopulations, and synergistic killing and resistance suppression by the combination. Simulations using the model predicted bacterial regrowth above the initial inoculum for more than 90% of patients after 0 to approximately 3 days for meropenem monotherapy across all strains and for ceftolozane-tazobactam monotherapy against ST235-05 and ST235-09. For ceftolozane-tazobactam monotherapy against ST235-10, regrowth was predicted for approximately 30% of patients. In contrast, the simulations predicted sustained bacterial killing of at least 2 log10 CFU per mL compared with the initial inoculum by the combination for more than 89% of patients across all strains. INTERPRETATION: To our knowledge, this model is the first to characterise and predict the time-course of responses of clinical isolates to antibiotics only by the resistance mechanisms present and their complex interplay, representing a step towards pathogen-specific, personalised medicine. FUNDING: Australian National Health and Medical Research Council.

Pseudomonas aeruginosa↗

PubMed1998

Bacterial resistance: a worldwide problem.

The therapeutic crisis produced by emerging antimicrobial resistances has compromised the chemotherapy of hospitalized patients with serious infections. For the most prevalent resistance problems, meropenem, a new carbapenem, appears to provide a potency and spectrum for: 1) extended-spectrum beta-lactamase-producing Enterobacteriaceae; 2) Bush-Jacoby-Merdeiros group 1 enzyme-producing ceftazidime-resistant Enterobacter spp., Citrobacter freundii, and some Serratia spp.; 3) ceftazidime- and imipenem-resistant Pseudomonas aeruginosa; and 4) some Streptococcus spp. with elevated penicillin MICs. Documented in vitro study results using 1997 gram-negative blood stream infection isolates indicate a wider spectrum and a two- to fourfold greater potency for meropenem compared with imipenem. This was especially true for P. aeruginosa where 93.4% of strains were susceptible to meropenem (84.1% for imipenem). Also among over 30,000 reported in vitro meropenem results from the United States and Europe, 90.6% of gram-positive cocci and 99.1% of anaerobes were inhibited at < or = 4 microg/ml. Over 90% of ceftazidime-resistant blood stream infection strains were meropenem susceptible, a rate greater than those of imipenem, ciprofloxacin, and gentamicin. As the clinical utility of many contemporary antimicrobial agents is challenged by emerging resistance, the carbapenems (meropenem, imipenem) appear positioned for a greater role in the treatment of infections in hospitalized patients.

Bacteria↗

PubMed2002

Resistance surveillance in Italy: four-year results from the MYSTIC program.

The MYSTIC program is an international, multicenter surveillance study that compares the activity of meropenem, in centers that are prescribers, with that of imipenem, ceftazidime, piperacillin/tazobactam, ciprofloxacin and gentamicin. These Italian data are from 3 centers (neutropenia, cystic fibrosis and intensive care units). A total of 2,072 (238 Gram-positive and 1,834 Gram-negative) aerobic microorganisms were collected during the study. Pseudomonas aeruginosa (33.4%) was the most isolated species followed by Escherichia coli (14.4%). All except one Enterobacteriaceae strain isolated were fully susceptible to meropenem. Moreover, the activity of meropenem against Enterobacteriaceae was about eight-fold greater than that of imipenem and four- to eight-fold more active than that of ceftazidime. Meropenem was highly active against non-fermentative Gram-negative microorganisms, exceeding the activity of most of the other antimicrobial agents tested. Moreover, meropenem showed increasing activity during the 4 years of study (starting from 86.2% in 1997 to 94.0% in 2000). In conclusion, our results indicate that meropenem has excellent potency and spectrum of activity despite being prescribed for the treatment of seriously ill patients, and appears to be a reliable option for the initial empirical treatment of serious nosocomial infections.

Anti-Bacterial Agents↗

PubMed2002

Carbapenems in the treatment of severe community-acquired pneumonia in hospitalized elderly patients: a comparative study against standard therapy.

In this open, prospective, study were enrolled 204 hospitalized elderly patients with severe (88 males, 116 females, age range 70-94). Patients were randomized to receive one of the following antibiotic treatment regimens: meropenem 500 mg i.v. t.i.d. (52); imipenem/cilastatin 500 mg i.v. t.i.d. (51), clarithromycin 500 mg + ceftriaxone 1 g i.v. b.i.d. (52), clarithromycin 500 mg + amikacin 250 mg i.v. b.i.d. (49). In 99 cases causative germs were isolated (24 meropenem, 26 imipenem, 23 clarithromycin + ceftriaxone, 26 ceftriaxone + amikacin). A satisfactory clinical, bacteriological response was achieved respectively in 86.5% 77% in meropenem; 86.3% 71% in imipenem/cilastatin; 69% 61% in ceftriaxone + clarithromycin and in 85.7% 77% in clarithromycin + amikacin. The mean total cost for each patient was $1,560; $1,620; $1,760 and $1,792 in meropenem, imipenem/cilastatin, clarithromycin + ceftriaxone and clarithromycin + amikacin respectively. This study shows that treatment with either meropenem or imipenem is as efficacious as conventional therapy in the treatment of community acquired pneumonia (CAP), and that meropenem is the most cost-effective.

Aged↗

PubMed2002

Empiric carbapenem monotherapy in pediatric bone marrow transplant recipients.

OBJECTIVE: To determine which carbapenem (imipenem/cilastatin or meropenem) was the preferable empiric antibiotic monotherapy in pre-engrafted pediatric bone marrow transplant (BMT) patients in terms of patient tolerance, therapeutic efficacy, and cost. METHODS: We prospectively analyzed 16 pediatric BMT patients who received meropenem, and retrospectively analyzed 16 matched patients who had received imipenem/cilastatin for BMT procedures during the prior 2-year period. We evaluated the patients for evidence of bacterial infection, necessity for concurrent antibiotics, vomiting episodes, duration of concurrent total parenteral nutrition (TPN), and cost of therapy. RESULTS: We found no differences in the number of culture proven or clinically suspected breakthrough bacterial infections or the need for concurrent additional antibiotics between the groups. Our analysis found that patients who received meropenem experienced significantly less vomiting than those in the imipenem/cilastatin cohort. Our data showed both direct and indirect cost savings for the meropenem group. The statistical and clinical differences in the number of vomiting episodes between these groups impacted other aspects of patient care, antiemetic use, and TPN duration. CONCLUSIONS: By switching to meropenem, we reduced the cost of antiemetic therapy per patient treatment course, and also showed a trend toward reduced duration of TPN. We found that meropenem provided both clinical and fiscal advantages over imipenem/cilastatin as empiric antibiotic monotherapy in neutropenic pediatric BMT patients.

Adolescent↗

PubMed1993

Susceptibility to antimicrobial agents of Pseudomonas aeruginosa attached to siliconized latex urinary catheters.

The effect of siliconized latex urinary catheters on the in vitro activity of amikacin, ceftazidime, ciprofloxacin, norfloxacin and meropenem against Pseudomonas aeruginosa was determined by a microdilution assay. MICs of amikacin and meropenem increased at least 4-fold and 16-fold respectively in the presence of catheter material. The effect of catheter material on meropenem activity was not strain dependent and was similar for different brands of catheters. The susceptibility to antimicrobial agents of Pseudomonas aeruginosa attached to catheters for 6 and 24 hours was also evaluated. When bacteria attached for 6 hours were used as inoculum, MBCs increased at least 8-fold for amikacin, 64-fold for ceftazidime, 64-fold for ciprofloxacin, 32-fold for norfloxacin and 2048-fold for meropenem. Similar results were observed when bacteria attached to catheters for 24 hours were used as inoculum. It is concluded that catheter material itself affected the in vitro activity of meropenem, and that the bactericidal activity of all antimicrobial agents against Pseudomonas aeruginosa present in biofilms on the surface of siliconized latex urinary catheters decreased dramatically, this effect being more pronounced with meropenem.

Anti-Bacterial Agents↗

PubMed1997

In vitro and in vivo antibacterial activities of GV129606, a new broad-spectrum trinem.

GV129606 is a new parenteral trinem antibiotic belonging to the beta-lactam class. It combines broad-spectrum activity (against gram-negative and -positive bacteria, aerobes and anaerobes), with high potency and resistance to beta-lactamases. Comparative in vitro and in vivo antibacterial activities were determined for GV129606 against more than 400 recent clinical isolates (aerobes, including beta-lactamase producers, and anaerobes), using representative antibacterial agents (meropenem, piperacillin, ceftazidime, cefpirome, ciprofloxacin, and gentamicin for aerobes and metronidazole, cefoxitin, piperacillin, and clindamycin for anaerobes). Against methicillin-susceptible staphylococci and streptococci, GV129606 and meropenem were the most active of the drugs tested. GV129606 showed an MIC for 90% of strains tested (MIC90) ranging from < or =0.015 to 0.06 microg/ml against methicillin-susceptible staphylococci and Streptococcus sanguis, Streptococcus pyogenes, and Streptococcus agalactiae. Against penicillin-susceptible and -resistant Streptococcus pneumoniae isolates, GV129606, meropenem, and cefpirome showed MIC90s of < or =0.015 and 1 microg/ml, respectively. Meropenem was the most active compound against members of the family Enterobacteriaceae with MIC90s of < or =0.5 microg/ml. Against these species, GV129606 possessed activity superior to those of piperacillin, ceftazidime, cefpirome, and gentamicin, with MIC90s of < or =8 microg/ml, but its activity was two- to sixfold less than that of ciprofloxacin (with the exception of Proteus rettgeri and Providencia stuartii). Haemophilus spp., Moraxella catarrhalis, Neisseria gonorrhoeae, and Pseudomonas aeruginosa were also included in the spectrum of GV129606. GV129606 showed good antianaerobe activity, similar to metronidazole. It was stable against all clinically relevant beta-lactamases (similar to meropenem). The in vitro activity was confirmed in vivo against septicemia infections induced in mice by selected gram-positive and -negative bacteria with 50% effective doses (ED50s) of < or =0.05 and < or =0.5 mg/kg of body weight/dose, respectively. GV129606 was as effective as meropenem against septicemia in mice caused by ceftazidime-resistant Pseudomonas aeruginosa, exhibiting an ED50 of 0.33 mg/kg/dose.

Animals↗

PubMed2003

Antimicrobial susceptibility testing of carbapenems: multicenter validity testing and accuracy levels of five antimicrobial test methods for detecting resistance in Enterobacteriaceae and Pseudomonas aeruginosa isolates.

From January 1996 to May 1999, Project ICARE (Intensive Care Antimicrobial Resistance Epidemiology) received 448 nonduplicate clinical isolates of Enterobacteriaceae and Pseudomonas aeruginosa that were reported to be imipenem intermediate or resistant. However, broth microdilution (BMD) confirmatory testing at the Project ICARE central laboratory confirmed this result in only 11 of 123 (8.9%) Enterobacteriaceae isolates and 241 of 325 (74.2%) P. aeruginosa isolates. To investigate this overdetection of imipenem resistance, we tested 204 selected isolates from the Project ICARE collection plus five imipenem-resistant challenge strains at the Centers for Disease Control and Prevention against imipenem and meropenem by agar dilution, disk diffusion, Etest (AB BIODISK North America, Inc., Piscataway, N.J.), two MicroScan WalkAway conventional panels (Neg MIC Plus 3 and Neg Urine Combo 3) (Dade MicroScan, Inc., West Sacramento, Calif.), and two Vitek cards (GNS-116 containing meropenem and GNS-F7 containing imipenem) (bioMérieux Vitek, Inc., Durham, N.C.). The results of each test method were compared to the results of BMD testing using in-house-prepared panels. Seven imipenem-resistant and five meropenem-resistant isolates of Enterobacteriaceae and 43 imipenem-resistant and 21 meropenem-resistant isolates of P. aeruginosa were identified by BMD. For Enterobacteriaceae, the imipenem and meropenem test methods produced low numbers of very major and major errors. All test systems in the study produced low numbers of very major and major errors when P. aeruginosa was tested against imipenem and meropenem, except for Vitek testing (major error rate for imipenem, 20%). Further testing conducted in 11 of the participating ICARE hospital laboratories failed to pinpoint the factors responsible for the initial overdetection of imipenem resistance. However, this study demonstrated that carbapenem testing difficulties do exist and that laboratories should consider using a second, independent antimicrobial susceptibility testing method to validate carbapenem-intermediate and -resistant results.

Carbapenems↗

PubMedDate not supplied

High-level gentamicin-resistant enterococci: in vitro activity of double and triple combinations of antimicrobial drugs.

The ability of double and triple combinations of antimicrobials with different mechanisms of action, such as teicoplanin, meropenem, gentamicin and sparfloxacin, to achieve synergisms was investigated in vitro on some moderate-level gentamicin-resistant (MLGR: 8 < or = MIC < or = 256 mg/l) and high-level gentamicin-resistant (HLGR: MIC > 500 mg/l) enterococci. On MLGR strains, a constant synergistic effect was achieved by a combination of teicoplanin with gentamicin or with meropenem, while generally addition, sometimes close to synergism, was exhibited by gentamicin-meropenem, gentamicin-sparfloxacin and teicoplanin-sparfloxacin associations. Triple combinations of teicoplanin, meropenem and gentamicin, or teicoplanin, sparfloxacin and gentamicin, always showed a remarkable advantage in terms of synergism over double combinations. On HLGR enterococci, the only double association showing an additive effect, sometimes close to synergism, was teicoplanin plus meropenem, while the triple combination of teicoplanin with gentamicin and meropenem always showed a marked synergistic effect. An effect very close to synergism was also shown by the combination of teicoplanin with sparfloxacin and gentamicin.

Anti-Bacterial Agents↗

PubMed1995

Carbapenems: monotherapy in intra-abdominal sepsis.

Meropenem is the first of a new class of dehydropeptidase-stable carbapenems which is highly active against the microflora associated with intra-abdominal infection. Three randomised, prospective multicentre studies, have compared meropenem monotherapy with imipenem/cilastatin and cefotaxime plus metronidazole in the treatment of intra-abdominal infections: meropenem (1 g) versus cefotaxime (2 g) plus metronidazole (500 mg); meropenem (1 g) versus imipenem/cilastatin (1 g); meropenem (500 mg) versus imipenem/cilastatin (500 mg), all administered intravenously every 8 hours. Of the 641 patients with intra-abdominal infections randomised to treatment, 555 (87%) were clinically evaluable and 445 (69%) were bacteriologically evaluable. At the end of treatment a majority of the patients in each of the 3 studies was clinically cured or improved (91-100%). There were no clinically significant differences between the treatment regimens. Meropenem was effective over a range of intra-abdominal infections and as well tolerated as imipenem/cilastatin, and cefotaxime plus metronidazole.

Adult↗

PubMed2004

In vitro killing of parenteral beta-lactams against standard and high inocula of extended-spectrum beta-lactamase and non-ESBL producing Klebsiella pneumoniae.

Minimum inhibitory concentrations and time-kill curves were performed against 8 Klebsiella pneumoniae (4 non-extended-spectrum beta-lactamase[ESBL] and 4 ESBL) for piperacillin/tazobactam (40/5 microg/mL), cefepime (20 microg/mL), and meropenem (4 microg/mL) by using a standard and high inocula. Imipenem was evaluated only at the standard inoculum for the non-ESBL and ESBL isolates. Samples were withdrawn at 7 predetermined time-points over 24 hours and plated on trypticase soy agar plates. Minimum inhibitory concentrations were: piperacillin/tazobactam 4 to 8 microg/mL (ESBL and non-ESBL), cefepime 1 to 2 microg/mL (ESBL) and 0.06 to 0.125 microg/mL (non-ESBL), imipenem 0.125 to 0.25 microg/mL (ESBL and non-ESBL), and meropenem 0.03 to 0.06 microg/mL (ESBL and non-ESBL). Each antibiotic reached and maintained bactericidal killing (> or =3 log killing) for 24 hours against all non-ESBL isolates for both the standard and high inoculum. Cefepime, imipenem, and meropenem showed the same bactericidal activity against each ESBL isolate at the standard inoculum, whereas piperacillin/tazobactam showed bactericidal killing against only 1 ESBL isolate. At the high inoculum, cefepime and piperacillin/tazobactam were unable to maintain bactericidal activity against any of the ESBL isolates. Only meropenem was able to maintain bactericidal killing over 24 hours against the ESBL isolates at the high inoculum. In summary, meropenem and imipenem maintained bactericidal activity against non-ESBL and ESBL K. pneumoniae irrespective of the inoculum size. While piperacillin/tazobactam and cefepime are bactericidal against non-ESBL K. pneumoniae, their activity against ESBL K. pneumoniae is limited and based on the size of the inoculum. Until more data are available, piperacillin/tazobactam and cefepime should not be used for the treatment of ESBL K. pneumoniae.

Anti-Bacterial Agents↗

PubMed2006

Absence of convulsive liability of doripenem, a new carbapenem antibiotic, in comparison with beta-lactam antibiotics.

beta-Lactam antibiotics have been suggested to have some degree of convulsive activity and neurotoxicity in experimental animals as well as in clinical situations. We examined the convulsive activities of a new carbapenem antibiotic, (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-[(sulfamoylamino)methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxic acid monohydrate (doripenem) using several animals and compared them with beta-lactam antibiotics. In intravenous (IV) injection studies, imipenem/cilastatin, at 400/400mg/kg produced seizure discharges on electroencephalogram (EEG) accompanied with clonic convulsions in rats. Meropenem showed only wet dog shaking behavior at 200 and 400mg/kg. Doripenem caused no changes in the EEG and behavior in rats at 400mg/kg. Imipenem/cilastatin IV potentiated the pentylenetetrazol (PTZ)-induced convulsions in mice at 250/250 mg/kg, while meropenem, panipenem/betamipron, cefazolin or doripenem did not cause any marked effects at up to 500 mg/kg. In mouse intracerebroventricular (ICV) injection studies, imipenem, panipenem and cefazolin induced clonic convulsions in a dose-dependent manner in mice. Doripenem and meropenem did not induce convulsions at up to 100 microg/mouse. In dog ICV injection studies, imipenem produced generalized seizure discharge with clonic convulsions at 100 microg/dog. Meropenem also produced spikes or seizure discharges at 100, 300 and 1,000 microg/dog. However, doripenem had no effects on the EEG and behavior in dogs at any doses. In in vitro binding studies, imipenem, panipenem, cefazolin and meropenem inhibited [(3)H]muscimol binding to the GABA(A) receptor in mouse brain homogenates while doripenem did not cause any inhibition at up to 10mM. In addition, doripenem had no influence on the anti-convulsant actions of valproic acid in the PTZ- or bicuculine-induced convulsive model. These results clearly indicate that doripenem has no convulsive activity, suggesting that its neurotoxicity may be negligible in clinical use.

Alanine↗

PubMed2001

MYSTIC program: summary of European data from 1997 to 2000.

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program is a global study providing in-vitro surveillance data on microbial susceptibility in centers that prescribe meropenem. This paper summarizes data on the activity of meropenem and five comparator agents against 13,793 clinical isolates from 31 centers in 10 European countries, 1997-2000. Meropenem and imipenem demonstrated broad-spectrum activity against the tested organisms, including beta-lactamase-producing strains that were co-resistant to quinolones and aminoglycosides. The carbapenems were active against the most frequently isolated pathogens including staphylococci (98-100% susceptible), Pseudomonas aeruginosa (65-82% susceptible) and Klebsiella pneumoniae (98-100% susceptible). Resistance to penicillins and cephalosporins was observed, particularly among Enterobacter species in Southern and Eastern Europe. Eastern Europe showed a high prevalence of AmpC beta-lactamase and extended-spectrum beta-lactamase-producing strains in Russia (2000); 47% and 28% of Enterobacteriaceae isolates were AmpC or ESBL-producers, respectively. There was no significant decrease in susceptibility to the carbapenems throughout the four-year period. Meropenem and imipenem appear to remain reliable options for the treatment of serious nosocomial infections.

Enterobacter↗

PubMed1995

In vitro activity of BMS-181139, a new carbapenem with potent antipseudomonal activity.

The in vitro activities of the carbapenem BMS-181139 were determined in comparison with those of imipenem, meropenem, ciprofloxacin, ceftriaxone, and vancomycin. BMS-181139 was the most active against species of Pseudomonas and related genera Alteromonas and Burkholderia, with MICs for 147 of 149 isolates of < 4 micrograms/ml. Of 22 imipenem-resistant (MIC > 8 micrograms/ml) P. aeruginosa strains, only 1 required an MIC of BMS-181139 of > 4 micrograms/ml, compared with 14 requiring the same meropenem MIC. BMS-181139 was the most active carbapenem against the majority of other gram-negative species except members of the tribe Proteeae, against which meropenem was more active. Although imipenem was more active against gram-positive species, BMS-18139 MICs at which 90% of strain tested were inhibited were < 1 microgram/ml for these species. BMS-181139 was generally active against isolates resistant to ciprofloxacin or broad-spectrum cephalosporins, including those containing plasmid-encoded beta-lactamases or high levels of chromosome-encoded beta-lactamases, as well as anaerobes except Clostridium difficile. Inoculum effects were noted for all three carbapenems against Klebsiella pneumoniae, Enterobacter cloacae, and Serratia marcescens but not Escherichia coli, Pseudomonas aeruginosa, or Staphylococcus aureus. BMS-181139's inoculum effect tended to be more marked. BMS-181139 exhibited bactericidal activity at the MIC for some strains and up to four to eight times the MIC for others. The postantibiotic effect of BMS-181139 was equal to or less than that of imipenem and, like meropenem, exhibited intraspecies variability. BMS-181139 was 30-fold more stable than imipenem and 7-fold more stable than meropenem to hydrolysis by hog kidney dehydropeptidase.

Carbapenems↗

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↗

PubMed2000

Carbapenems in serious infections: a risk-benefit assessment.

The tolerability of the 2 most frequently used carbapenems, imipenem/cilastatin and meropenem, is reviewed. Both of these drugs, but especially imipenem, are potentially neurotoxic and may cause seizures if overdosed relative to renal function and/or bodyweight. The therapeutic margin is considerably narrower with imipenem/cilastatin which cannot be given at doses required for treatment of bacterial meningitis. Meropenem on the other hand, is considerably less prone to cause seizures and its tolerability and efficacy are well documented in 3 relatively large, controlled studies in adults and children with meningitis. They showed that meropenem was as effective and well tolerated as cefotaxime or ceftriaxone. Another potential advantage of meropenem over imipenem/cilastatin is that it can be given intravenously at a high rate without increased risk of nausea or vomiting. An obvious reason for using a carbapenem instead of a cephalosporin for empirical treatment of life-threatening infections is that both imipenem/cilastatin and meropenem have a broader spectrum of activity. They are also more resistant to hydrolysis by the most common beta-lactamases, including the class I cephalosporinase frequently produced by Enterobacter spp. and Pseudomonas spp. and the extended spectrum enzymes, now commonly found in Escherichia coli and Klebsiella spp.

Adult↗

PubMed1999

In vitro activity of newer broad spectrum beta-lactam antibiotics against enterobacteriaceae and non-fermenters: a report from Austrian intensive care units. Austrian Carbapenem Susceptibility Surveillance Group.

We compared the in vitro activity of broad spectrum beta-lactam antibiotics against 573 gram-negative isolates (enterobacteriaceae and non-fermenters) collected between November 1996 and May 1997 from 9 laboratories serving intensive care units throughout Austria. MIC's (Minimal Inhibitory Concentration) were obtained with the E-test for meropenem, imipenem, ceftazidime, cefepime, cefpirome and piperacillin/tazobactam. Pseudomonas aeruginosa was the most frequently isolated organism (22%), followed by E. coli (19%), Klebsiella spp. (16%), and Enterobacter spp. (14%). Acinetobacter spp., Proteus spp., Serratia spp., Stenotrophomonas maltophilia, Citrobacter spp., Morganella morganii, Burkholderia cepacia and Salmonella enteritidis were isolated less frequently. Overall meropenem, imipenem and ceftazidime were the most active compounds in vitro, inhibiting 90%, 89%, and 87% of the isolates, respectively. Pseudomonas aeruginosa was inhibited by piperacillin/tazobactam in 89%, by cefepime in 87% and by ceftazidime in 85%. Imipenem, meropenem and cefpirome were less active (79%, 75% and 69% respectively). All E. coli strains were inhibited by meropenem, 99% were inhibited by imipenem, cefepime and cefpirome. Ceftazidime was active against 95% and piperacillin/tazobactam against 92% of E. coli. All Klebsiella spp. were inhibited by meropenem, cefepime and cefpirome. Imipenem inhibited 99% and ceftazidime 98% of the Klebsiella isolates. Piperacillin/tazobactam was active against 95% of Klebsiella spp. In vitro carbapenems are still the most active of all antibiotics tested. The relatively high resistance of Pseudomonas spp. and Acinetobacter spp. to carbapenems reflects the wide use of carbapenems during the last years. However, most bacterial isolates are still sensitive to the tested broad spectrum beta-lactams.

Acinetobacter↗

PubMed2003

[Comparative clinical and epidemiological evaluation of beta-lactam antibiotics in the treatment of intraabdominal infections].

We performed a retrospective, comparative study to evaluate efficacy, safety and economic outcomes of empiric cefoperazone/sulbactam monotherapy compared with the meropenem, imipenem/cilastatine and combination of cefepime plus metroindazol in patients with intra-abdominal infection. A total of 468 patients diagnosed with intra-abdominal abscess, peritonitis, pancreatitis were included in the study (the severity of infection according to scale APACHE II was less than 15). Patients were randomized to be treated with either 500 mg meropemen i.v. every 8 hours or 500 mg imipenem/cilastatine i.v. every 8 hours or 2 g cefepime i.v. every 12 hours plus 500 mg metronidazol twice daily or cefoperazone/sulbactam 2 g daily administered every 12 hours. Overall positive clinical responses (cure or improvement) were achieved at the end of treatment for 87.5 patients in meropenem group, 86.6% in the imipenem/cilastatin group, 85.3% in the cefepime group and 86.8% in cefoperazone/sulbactam group. Total cost of the treatment per 100 patients with intra-abdominal infections for cefoperazone/sulbactam was 1957031 roubles, for combinations of cefepime with metronidazol--2497815 roubles. For carbapenem group cost achieved for meropenem--3085291 rub., for imipenem/cilastatin--2653388 roubles. Rate "cost-effectiveness" in total: 784.47$ for cefepime, and 834.39$ for imipenem/cilastatine, 970.21$ for meropenem and 615.4$ for cefoperazone/sulbactam. The most expensive treatment was considered to be with meropenem and imipenem/cilastatine, main share is determined by initial cost of preparations. Less expensive was treatment by cefoperazone/sulbactam with cefepime and by metronidazol.

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