meropenem and temocillin

Existing clinical studies concerning the impact of therapy with third-generation cephalosporins or cefepime on infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are retrospective, non-randomised, and have been carried out with a small number of patients and low-dosage schedules that lack PK-PD correlations with clinical efficacy. Rates of clinical failure and mortality are higher than those in studies with non-ESBL- producing Enterobacteriaceae. Therefore, in settings with a high prevalence of ESBL-producing Enterobacteriaceae, empirical therapy with advanced cephalosporins should be avoided. Temocillin, an old beta-lactam that is stable in the presence of both ESBLs and AmpC beta-lactamases, seems to deserve revival, although clinical data are limited.

Topics: Anti-Bacterial Agents; beta-Lactams; Cephalosporins; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Penicillins; Thienamycins

Alternatives to carbapenems are needed in the treatment of third-generation cephalosporin-resistant. Multicentre, open-label, randomised, controlled, pragmatic phase 3 trial. Patients with bacteraemia due to 3GCR-E will be randomised to receive intravenously temocillin (2 g three times a day) or carbapenem (meropenem 1 g three times a day or ertapenem 1 g once daily). The primary endpoint will be clinical success 7-10 days after end of treatment with no recurrence or death at day 28. Adverse events will be collected; serum levels of temocillin will be investigated in a subset of patients. For a 10% non-inferiority margin, 334 patients will be included (167 in each study arm). For the primary analysis, the absolute difference with one-sided 95% CI in the proportion of patients reaching the primary endpoint will be compared in the modified intention-to-treat population.. The study started after approval of the Spanish Regulatory Agency and the reference institutional review board. Data will be published in peer-reviewed journals.. NCT04478721.

Topics: Bacteremia; Cephalosporins; Clinical Trials, Phase III as Topic; Enterobacteriaceae; Humans; Meropenem; Multicenter Studies as Topic; Penicillins; Pragmatic Clinical Trials as Topic; Randomized Controlled Trials as Topic

Chronic respiratory infection with

Topics: Administration, Inhalation; Administration, Oral; Anti-Bacterial Agents; Burkholderia cenocepacia; Burkholderia Infections; Child, Preschool; Cystic Fibrosis; Humans; Levofloxacin; Male; Maxillary Sinus; Maxillary Sinusitis; Meropenem; Nasal Lavage; Otorhinolaryngologic Surgical Procedures; Penicillins; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Anti-Bacterial Agents; beta-Lactamases; Biomarkers; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Genes, MDR; Meropenem; Microbial Sensitivity Tests; Penicillins; Whole Genome Sequencing

While carbapenem resistance in Gram-negative bacteria is mainly due to the production of efficient carbapenemases, β-lactamases with a narrower spectrum may also contribute to resistance when combined with additional mechanisms. OXA-10-type class D β-lactamases, previously shown to be weak carbapenemases, could represent such a case. In this study, two novel OXA-10 variants were identified as the sole carbapenem-hydrolyzing enzymes in meropenem-resistant enterobacteria isolated from hospital wastewater and found by next-generation sequencing to express additional β-lactam resistance mechanisms. The new variants, OXA-655 and OXA-656, were carried by two related IncQ1 broad-host-range plasmids. Compared to the sequence of OXA-10, they both harbored a Thr26Met substitution, with OXA-655 also bearing a leucine instead of a valine in position 117 of the SAV catalytic motif. Susceptibility profiling of laboratory strains replicating the natural

Topics: Amino Acid Substitution; Anti-Bacterial Agents; Base Sequence; beta-Lactam Resistance; beta-Lactamases; Catalytic Domain; Cefoxitin; Cloning, Molecular; Enterobacteriaceae; Gene Expression; Hospitals; Humans; Hydrolysis; Isoenzymes; Kinetics; Meropenem; Microbial Sensitivity Tests; Models, Molecular; Oxacillin; Penicillins; Plasmids; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure, Secondary; Recombinant Proteins; Substrate Specificity; Wastewater

Carbapenemase-producing Enterobacteriaceae (CPE) are difficult to identify among carbapenem non-susceptible Enterobacteriaceae (NSE). We designed phenotypic strategies giving priority to high sensitivity for screening putative CPE before further testing.. Presence of carbapenemase-encoding genes in ertapenem NSE (MIC > 0.5 mg/l) consecutively isolated in 80 French laboratories between November 2011 and April 2012 was determined by the Check-MDR-CT103 array method. Using the Mueller-Hinton (MH) disk diffusion method, clinical diameter breakpoints of carbapenems other than ertapenem, piperazicillin+tazobactam, ticarcillin+clavulanate and cefepime as well as diameter cut-offs for these antibiotics and temocillin were evaluated alone or combined to determine their performances (sensitivity, specificity, positive and negative likelihood ratios) for identifying putative CPE among these ertapenem-NSE isolates. To increase the screening specificity, these antibiotics were also tested on cloxacillin-containing MH when carbapenem NSE isolates belonged to species producing chromosomal cephalosporinase (AmpC) but Escherichia coli.. Out of the 349 ertapenem NSE, 52 (14.9%) were CPE, including 39 producing OXA-48 group carbapenemase, eight KPC and five MBL. A screening strategy based on the following diameter cut offs, ticarcillin+clavulanate <15 mm, temocillin <15 mm, meropenem or imipenem <22 mm, and cefepime <26 mm, showed 100% sensitivity and 68.1% specificity with the better likelihood ratios combination. The specificity increased when a diameter cut-off <32 mm for imipenem (76.1%) or meropenem (78.8%) further tested on cloxacillin-containing MH was added to the previous strategy for AmpC-producing isolates.. The proposed strategies that allowed for increasing the likelihood of CPE among ertapenem-NSE isolates should be considered as a surrogate for carbapenemase production before further CPE confirmatory testing.

Topics: Algorithms; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; beta-Lactams; Carbapenems; Cefepime; Cephalosporins; Clavulanic Acids; Drug Resistance, Bacterial; Enterobacteriaceae; Ertapenem; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Penicillanic Acid; Penicillins; Tazobactam; Thienamycins; Ticarcillin

A flow cytometry test was developed to identify carbapenemase production by Enterobacteriaceae and to discriminate between the different types of carbapenemases (classes A, B, and D). It is based on the detection of meropenem activity against bacteria, coupled with different carbapenemase inhibitors, which is assessed by flow cytometry. It represents a convenient, fast, and reliable approach (100% sensitivity and 100% specificity) for the detection and characterization of different carbapenemases.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Boronic Acids; Cloxacillin; Edetic Acid; Enterobacteriaceae; Enterobacteriaceae Infections; Enzyme Inhibitors; Flow Cytometry; Gene Expression; Humans; Meropenem; Penicillins; Thienamycins

A temocillin minimal inhibitory concentration ≥ 128 mg/L combined with the results of meropenem double disc synergy testing was used to (i) discriminate carbapenemase production from other resistance mechanisms leading to decreased carbapenem susceptibility; and (ii) differentiate Ambler classes in carbapenemase-producing enterobacteriaceae (CPE). The suggested test algorithm discriminated all extended spectrum ß-lactamase/AmpC from CPE isolates, which could further be divided correctly into Ambler classes A and B enzymes as well as OXA-48 in all cases. The algorithm is simple to implement as part of the daily routine in a standard microbiology laboratory with limited access to or resources for molecular biological tools.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Penicillins; Thienamycins

We evaluated the activities of meropenem, imipenem, temocillin, piperacillin, and ceftazidime by determination of the MICs for 66 genotypically characterized Burkholderia cepacia isolates obtained from the sputum of cystic fibrosis patients. In vitro synergy assays, as performed by the time-kill methodology, of two- and three-drug combinations of the beta-lactams with tobramycin, rifampin, and/or ciprofloxacin were also performed with 10 strains susceptible, intermediate, or resistant to fluoroquinolones. On the basis of the MICs, meropenem and temocillin were the most active beta-lactam agents, with MICs at which 90% of isolates are inhibited of 8 and 32 micrograms/ml, respectively. The addition of ciprofloxacin significantly enhanced the killing activities of piperacillin, imipenem, and meropenem against the 10 strains tested (P < 0.05). The best killing activity was obtained with the combination of meropenem and ciprofloxacin, with bactericidal activity of 3.31 +/- 0.36 log10 CFU/ml (P < 0.05). Compared to the activity of the two-drug beta-lactam-ciprofloxacin combination, the addition of rifampin or tobramycin did not significantly increase the killing activity (P > 0.05). The three-drug combinations (with or without ciprofloxacin) significantly enhanced the killing activities of piperacillin, imipenem, and meropenem relative to the activities of the beta-lactams used alone (P < 0.05). The combination beta-lactam-ciprofloxacin-tobramycin was the combination with the most consistently synergistic effect.

Topics: Burkholderia cepacia; Burkholderia Infections; Ceftazidime; Ciprofloxacin; Cystic Fibrosis; Drug Synergism; Drug Therapy, Combination; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Penicillins; Piperacillin; Rifampin; Thienamycins; Tobramycin