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Background Successful use of carbapenems in combination with cefazolin or oxacillin for treatment of MSSA bacteraemia has been described; however, comparative data to standard treatment approaches are lacking. Methods This was a multicentre, retrospective study of adult patients with MSSA bacteraemia for >48 h. Standard treatment was considered monotherapy with cefazolin, oxacillin or nafcillin. Combination therapy was defined as the addition of ertapenem or meropenem to standard treatment for at least 24 h. The primary outcome was duration of bacteraemia defined as time from administration of an antibiotic with in vitro activity to first negative blood culture. Time to blood culture sterilization was compared through risk-set matching with aid of a propensity score. Results Overall, 238 patients were included; 66% (157/238) received standard treatment and 34% (81/238) received combination therapy. The median (IQR) time to carbapenem initiation was 4.7 (3.63–6.5) days. Patients who received combination therapy were younger (P  = 0.012), more likely to have endocarditis (P  = 0.034) and had longer median duration of bacteraemia (P  < 0.001). After applying risk-set matching, patients who received combination therapy experienced faster time to blood culture sterilization compared with control patients [HR = 1.618 (95% CI; 1.119–2.339) P  = 0.011]. Using a paired hazard model, 90 day mortality rates were not statistically different among patients who received combination therapy versus matched controls [HR = 1.267 (95% CI; 0.610–2.678), P  = 0.608]. Discussion Carbapenem combination therapy resulted in faster time to blood culture sterilization, but no differences in overall mortality rates. Randomized trials are critical to determine the utility of carbapenem combination therapy. [ABSTRACT FROM AUTHOR]

Background Use of anti-carbapenem-resistant Enterobacterales (anti-CRE) agents such as ceftazidime/avibactam has been associated with improved clinical outcome in cohorts that primarily include patients infected with CRE that are resistant to meropenem (MCRE). Objectives To clarify whether patients with CRE resistant to ertapenem but susceptible to meropenem (ertapenem-only-resistant Enterobacterales; EORE) benefit from therapy with anti-CRE agents. Methods Patients treated for CRE infection in hospitals in the USA between 2016 and 2019 and enrolled in the CRACKLE-2 study were included. The primary outcome was the desirability of outcome ranking (DOOR) assessed at 30 days after index cultures. Results The EORE group included 213 patients and the MCRE group included 643. The demographics were similar between the groups except for the patients' race and origin before admission. The MCRE group received anti-CRE agents for definitive therapy significantly more frequently compared with the EORE group (30% versus 5% for ceftazidime/avibactam). We did not observe a significant difference between the groups in the adjusted DOOR probability of a more desirable outcome for a randomly selected patient in the EORE group compared with the MCRE group (52.5%; 95% CI, 48.3%–56.7%). The MCRE group had a similar proportion of patients who died at 30 days (26% versus 21%) and who were discharged to home (29% versus 40%), compared with the EORE group. Conclusions Patients with clinical EORE infection rarely received anti-CRE agents, but attained similar outcomes compared with patients with MCRE infection. The findings support current IDSA treatment guidance for meropenem- or imipenem-based therapy for treatment of EORE infections. [ABSTRACT FROM AUTHOR]

A study published in the Journal of Antimicrobial Chemotherapy examined the development of resistance to ertapenem and meropenem among a type of bacteria called Enterobacterales. The researchers found that resistance to ertapenem occurred more easily than resistance to meropenem. They also observed that using ertapenem could potentially lead to resistance to meropenem. These findings emphasize the need to monitor and manage the use of carbapenem antibiotics to prevent resistance. Another study compared the effects of ertapenem and meropenem on carbapenem-resistant Enterobacteriaceae isolates. The study found that ertapenem isolates showed greater reductions in susceptibility compared to meropenem isolates. The authors suggest that this may support the use of meropenem over ertapenem in hospitals for treating these infections, but more research is needed. The study was funded internally and the authors have no conflicts of interest. [Extracted from the article]

Objectives The aims of this study were: (i) to assess the ability of the meropenem screening breakpoint as part of the screening rapid antimicrobial susceptibility testing (sRAST) of EUCAST for the detection of OXA-48 carbapenemase-producing Klebsiella pneumoniae directly from positive blood cultures (BCs); and (ii) to evaluate the inclusion of ertapenem and temocillin discs into the sRAST to enhance the detection of OXA-48-producing isolates. Methods BC bottles were spiked with a total of 117 K. pneumoniae isolates, including 77 previously characterized OXA-48 producers and 40 non-OXA-48 producers. Disc diffusion assays were directly performed from positive BCs with meropenem (10 µg), ertapenem (10 µg) and temocillin (30 µg) discs, and inhibition zones were manually measured after 4, 6 and 8 h of incubation. The screening cut-off values of sRAST were applied to evaluate their capability in detecting OXA-48-producing isolates. Receiver operating characteristic curves were constructed to illustrate the performance efficacy of the disc diffusion assays to detect OXA-48 producers. Results The meropenem cut-off values of sRAST only detected 90.91% of the OXA-48-producing isolates after 6 and 8 h of incubation. With the proposed cut-off points for ertapenem [<19 mm (4/6 h) and <20 mm (8 h)] and temocillin [<10 mm (4 h) and <11 mm (6/8 h)], all OXA-48-positive isolates were detected without any false-positive results at any reading time. Conclusions In healthcare settings with a high prevalence of OXA-48 producers, the inclusion of ertapenem and temocillin discs in the sRAST procedure may improve the detection of OXA-48-producing K. pneumoniae isolates directly from positive BCs, providing reliable results after only a 4 h incubation period. [ABSTRACT FROM AUTHOR]

Background Third-generation cephalosporin-resistant Enterobacterales (3GCRE) are increasing in prevalence, leading to greater carbapenem consumption. Selecting ertapenem has been proposed as a strategy to reduce carbapenem resistance development. However, there are limited data for the efficacy of empirical ertapenem for 3GCRE bacteraemia. Objectives To compare the efficacy of empirical ertapenem and class 2 carbapenems for the treatment of 3GCRE bacteraemia. Methods A prospective non-inferiority observational cohort study was performed from May 2019 to December 2021. Adult patients with monomicrobial 3GCRE bacteraemia receiving carbapenems within 24 h were included at two hospitals in Thailand. Propensity scores were used to control for confounding, and sensitivity analyses were performed in several subgroups. The primary outcome was 30 day mortality. This study is registered with clinicaltrials.gov (NCT03925402). Results Empirical carbapenems were prescribed in 427/1032 (41%) patients with 3GCRE bacteraemia, of whom 221 received ertapenem and 206 received class 2 carbapenems. One-to-one propensity score matching resulted in 94 pairs. Escherichia coli was identified in 151 (80%) of cases. All patients had underlying comorbidities. Septic shock and respiratory failure were the presenting syndromes in 46 (24%) and 33 (18%) patients, respectively. The overall 30 day mortality rate was 26/188 (13.8%). Ertapenem was non-inferior to class 2 carbapenems in 30 day mortality (12.8% versus 14.9%; mean difference −0.02; 95% CI: −0.12 to 0.08). Sensitivity analyses were consistent regardless of aetiological pathogens, septic shock, source of infection, nosocomial acquisition, lactate levels or albumin levels. Conclusions Ertapenem may be of comparable efficacy to class 2 carbapenems in the empirical treatment of 3GCRE bacteraemia. [ABSTRACT FROM AUTHOR]

Background We found a carbapenem-resistant Escherichia coli without known carbapenemase-encoding genes and performed a study to identify the possible new carbapenemase. Methods The production of carbapenemase was examined using the modified carbapenem inactivation method. The strain was subjected to short- and long-read genome sequencing and the complete genome was obtained by hybrid assembly. The gene encoding a potential new OXA-type carbapenemase was cloned. The enzyme was purified and was then subjected to kinetic assays. Molecular docking analysis of the enzyme was performed using the MOE software suite. Mating experiments were attempted to obtain the plasmid carrying the corresponding gene. Results We identified and characterized a novel class D carbapenem-hydrolysing β-lactamase, OXA-1041, in a carbapenem-resistant E. coli clinical strain. OXA-1041 had 89.77% (237/264) amino acid identity with OXA-427, a known carbapenemase. By cloning in an E. coli laboratory strain, bla OXA-1041 was found to reduce susceptibility to ertapenem by 16 times (MIC 0.25 versus 0.016 mg/L) and meropenem by four times (MIC 0.06 versus 0.016 mg/L) but did not significantly reduce susceptibility to imipenem and doripenem. Enzyme kinetic measurement of purified OXA-1041 showed that OXA-1041 could hydrolyse ertapenem and meropenem with a turnover number (k cat)/Michaelis constant (K M) of 8.57 and 3.63 mM−1s−1, respectively. The complete genome contained a single plasmid (223 341 bp, IncF, containing five replicons), which was self-transmissible. bla OXA-1041 was downstream of insertion sequence IS CR1 and there were three tandem copies of IS CR1 - bla OXA-1041- creD Δ (encoding an envelope protein) on this plasmid. Conclusions The above findings suggest OXA-1041 is a new plasmid-encoded carbapenemase with preferential activity against ertapenem. [ABSTRACT FROM AUTHOR]

REFERENCES 1 Bernabeu S, Bonnin RA, Dortet L. Comparison of three lateral flow immunochromatographic assays for the rapid detection of KPC, NDM, IMP, VIM and OXA-48 carbapenemases in Enterobacterales. We recently published a manuscript entitled 'Comparison of three lateral flow immunochromatographic assays for the rapid detection of KPC, NDM, IMP, VIM and OXA-48 carbapenemases in Enterobacterales' by Bernabeu I et al. i [1] This correspondence aimed to compare the performances of three lateral flow immunoassays (LFIAs) for the detection of carbapenemases. [Extracted from the article]

Background: Reporting of outpatient parenteral antimicrobial therapy (OPAT) outcomes with national benchmarking is key to informing service development and supporting quality improvement.Objectives: To analyse and report on data collected by the BSAC OPAT National Outcomes Registry from 2015 to 2019.Methods: Quarterly data to 2020 was extracted from the BSAC National Outcomes Registry and analysed.Results: 57 organizations submitted data on 27 841 patient episodes and 442 280 OPAT treatment days. A diverse range of infections and antimicrobials were reported with a mean OPAT treatment duration of 16.7 days (adults) and 7.7 days (paediatrics). In adults, the top five conditions treated were skin and soft tissue (27.6%), bronchiectasis (11.4%), urinary tract infections (7.6%), and diabetic foot infections (5.5%). Ceftriaxone followed by teicoplanin, ertapenem and piperacillin/tazobactam were the most-used antimicrobials. A median of 1.4 vascular-device-related complications were observed per 1000 OPAT treatment days (range 0.11 to 10.4) with device infections in 0.3 per 1000 OPAT days (range 0.1 to 1.7). Other adverse events (rash, blood dyscrasias, antibiotic-associated diarrhoea) were observed in a median of 1.9 per 1000 OPAT days. OPAT infection outcome (cured/improved) was 92.4% and OPAT outcome (success/partial success) was 90.7%.Conclusions: This report demonstrates the safety, breadth, and complexity of modern UK OPAT practice. Future analyses of OPAT data should focus on infection- and service-specific quality indicators. OPAT registries remain central to planning and assessing safe, effective, and efficient delivery of patient-centred care and should be an important focus for UK and global OPAT practice. [ABSTRACT FROM AUTHOR]

Objectives: Carbapenem-heteroresistant (cHR) Enterobacteriaceae strains have been reported worldwide; however, the prevalence among clinical ESBL-producing Enterobacteriaceae isolates obtained from patients with repeated hospital admissions remains largely unknown.Methods: Heteroresistance was screened by disc diffusion and confirmed by a modified population analysis profiling (PAP) method against ertapenem, imipenem, meropenem and ceftolozane/tazobactam. MIC testing was performed by broth microdilution against carbapenems and a panel of agents with potential activity against ESBL-producing strains.Results: One hundred and seventy-three ESBL-producing meropenem-susceptible Escherichia coli and Klebsiella pneumoniae isolates were selected for testing. A total of 519 bacteria/carbapenem combinations were screened by disc diffusion; 84 combinations were identified as cHR. Modified PAP confirmed 70 bacteria/carbapenem combinations as heteroresistant; most (63%, 44/70) confirmed cHR colonies grew within the ertapenem zone of inhibition, followed by imipenem (30%, 21/70), then meropenem (7%, 5/70). In total, one-third of the unique patient isolates (32%, 55/173) were identified as being heteroresistant to at least one carbapenem; of those patients, 16% (9/55) had a carbapenem-non-susceptible isolate on subsequent visits. Only two cHR isolates screened positive for ceftolozane/tazobactam heteroresistance (1%, 2/173), of which one was confirmed heteroresistant by modified PAP. cHR isolates were more likely to be collected from a non-urinary source (e.g. respiratory) compared with non-cHR isolates (31% versus 19%, P = 0.02). MIC distributions of all tested antibiotic agents did not differ between non-cHR and cHR isolates.Conclusions: Our findings raise concerns for the continued use of carbapenems as first-line therapy for ESBL infections and for the potential selection for strains with full carbapenem resistance. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the carbapenem resistance mechanism of a carbapenem-resistant clinical Pseudomonas aeruginosa isolate.Methods: A carbapenem-resistant P. aeruginosa isolate was recovered from a tracheal swab from a patient of a general ward in central Germany. Various phenotypic tests confirmed production of a carbapenemase that could not be identified further by PCR. A novel bla gene was identified by WGS and its carbapenemase activity was verified by heterologous expression in an Escherichia coli cloning strain. Kinetic parameters of the novel β-lactamase were determined by spectrophotometric measurements using purified enzyme.Results: WGS confirmed the presence of a novel class A carbapenemase. The novel bla gene was named GPC-1 (GPC standing for German Pseudomonas Carbapenemase) and exhibited 77% amino acid identity to BKC-1. WGS also showed that blaGPC-1 was located on the chromosome surrounded by multiple ISs as part of a 26 kb genetic island. Heterologous expression of GPC-1 in E. coli TOP10 led to increased MICs of penicillins, oxyimino-cephalosporins, aztreonam and imipenem, but not of meropenem or ertapenem. Spectrophotometric measurements supported the MIC studies, but detected a slight hydrolysis of ertapenem and meropenem when using high concentrations of purified enzyme.Conclusions: The biochemical characterization of GPC-1 emphasizes the ongoing emergence of novel carbapenemases. Strains expressing a weak carbapenemase like GPC-1 might go unrecognized by routine diagnostics due to low MICs for the bacterial strains producing such enzymes. [ABSTRACT FROM AUTHOR]

Background: Antibiotic administration by subcutaneous (SC) injection is common practice in French geriatric wards as an alternative to the intravenous (IV) route, but few pharmacokinetic/pharmacodynamic data are available. Ertapenem is useful for the treatment of infections with ESBL-producing enterobacteria.Objectives: To report and compare ertapenem pharmacokinetic data between IV and SC routes in older persons.Methods: Patients >65 years of age receiving ertapenem (1 g once daily) for at least 48 h (IV or SC, steady-state) were prospectively enrolled. Total ertapenem concentrations [residual (C0), IV peak (C0.5) and SC peak (C2.5)] were determined by UV HPLC. Individual-predicted AUC0-24 values were calculated and population pharmacokinetic analyses were performed. Using the final model, a Monte Carlo simulation involving 10 000 patients evaluated the influence of SC or IV administration on the PTA. Tolerance to ertapenem and recovery were also monitored. ClinicalTrials.gov identifier: NCT02505386.Results: Ten (mean ± SD age=87±7 years) and 16 (age=88±5 years) patients were included in the IV and SC groups, respectively. The mean C0 and C2.5 values were not significantly different between the IV and SC groups (C0=12±5.9 versus 12±7.4 mg/L, P=0.97; C2.5=97±42 versus 67±41 mg/L, P=0.99). The mean C0.5 was higher in the IV group compared with the SC group (C0.5=184±90 versus 51±66 mg/L, P=0.001). The mean individual AUCs (1126.92±334.99 mg·h/L for IV versus 1005.3±266.0 mg·h/L for SC, P=0.38) and PTAs were not significantly different between groups. No severe antibiotic-related adverse effects were noted.Conclusions: SC administration of ertapenem is an alternative to IV administration in older patients. [ABSTRACT FROM AUTHOR]

Background: Double carbapenem therapy has been promoted as an alternative treatment for infections due to carbapenemase-producing Enterobacteriaceae where carbapenemase inhibitors are unavailable or when other agents have demonstrated toxicity with equally limited evidence. The capacity of other β-lactams and β-lactamase inhibitors to provide synergistic activity with carbapenems is unclear.Objectives: This study sought to investigate the in vitro synergistic potential of other β-lactam/β-lactamase combinations with meropenem against KPC producers.Methods: Time-kill assays were performed on 24 unique strains of KPC-producing Klebsiella pneumoniae. Combinations evaluated included meropenem or imipenem with one of the following: ertapenem, piperacillin/tazobactam or ceftolozane/tazobactam. Concentrations used for each drug were those considered physiologically attainable in patients with a time above the concentration exceeding 40%-50% of the dose interval. Combinations were considered to be synergistic when they reduced bacterial cfu/mL by ≥2 log10 at 24 h as compared with the single most active agent.Results: The combination of piperacillin/tazobactam with meropenem was found to be synergistic against 70.8% of the isolates, followed by ertapenem with meropenem (58.3%) and ceftolozane/tazobactam with meropenem (41.7%). The piperacillin/tazobactam combination was found to be more bactericidal than the other combinations, with 58.3% of isolates demonstrating a ≥4 log10 cfu/mL reduction at 24 h, as compared with 37.5% for ertapenem and 20.8% for ceftolozane/tazobactam combinations.Conclusions: The combination of piperacillin/tazobactam with meropenem may be a potential therapy against KPC-producing K. pneumoniae when other therapies are unavailable or prohibitively toxic. [ABSTRACT FROM AUTHOR]

Background: Infections caused by carbapenemase-producing Enterobacterales (CPE) constitute a major global health concern and are associated with increased morbidity and mortality. Nitroxoline is an old antibiotic, which has recently been re-launched for the treatment of uncomplicated urinary tract infection. Because of low resistance rates it could be an interesting option for treatment of MDR isolates, yet data on CPE susceptibility are scarce.Objectives: To analyse the in vitro activity of nitroxoline against CPE.Methods: MICs of nitroxoline were determined by agar dilution for a collection of well-characterized carbapenemase producers (n = 105), producing OXA-48-like (n = 36), VIM (n = 21), IMI (n = 9), IMP (n = 6), NDM (n = 22), KPC (n = 11), OXA-58 (n = 2) and GES (n = 2). For comparison, MICs of ertapenem, imipenem and meropenem were determined by agar gradient diffusion.Results: For all 105 isolates, the MIC50/90 of nitroxoline was 8/16 mg/L. All Escherichia coli isolates (30/30, 100%) showed low MICs of 2-8 mg/L and were susceptible to nitroxoline. MICs of 32 mg/L were recorded for five isolates of VIM- and IMI-producing Enterobacter cloacae (n = 3) and OXA- and VIM-producing Klebsiella pneumoniae (n = 2).Conclusions: Nitroxoline exhibited excellent in vitro activity against most isolates producing common and rare carbapenemases. If the current EUCAST susceptibility breakpoint of ≤16 mg/L for E. coli in uncomplicated urinary tract infections was applied, 95.2% (100/105) of isolates would be classified as susceptible. Nitroxoline could therefore be an alternative oral option for treatment of uncomplicated urinary tract infections caused by CPE. [ABSTRACT FROM AUTHOR]

Objectives The CANWARD surveillance study was established in 2007 to annually assess the in vitro susceptibilities of a variety of antimicrobial agents against bacterial pathogens isolated from patients receiving care in Canadian hospitals. Methods 42   936 pathogens were received and CLSI broth microdilution testing was performed on 37   355 bacterial isolates. Limited patient demographic data submitted with each isolate were collated and analysed. Results Of the isolates tested, 43.5%, 33.1%, 13.2% and 10.2% were from blood, respiratory, urine and wound specimens, respectively; 29.9%, 24.8%, 19.0%, 18.1% and 8.2% of isolates were from patients in medical wards, emergency rooms, ICUs, hospital clinics and surgical wards. Patient demographics associated with the isolates were: 54.6% male/45.4% female; 13.1% patients aged ≤17 years, 44.3% 18–64 years and 42.7% ≥65 years. The three most common pathogens were Staphylococcus aureus (21.2%, both methicillin-susceptible and MRSA), Escherichia coli (19.6%) and Pseudomonas aeruginosa (9.0%). E. coli were most susceptible to meropenem and tigecycline (99.9%), ertapenem and colistin (99.8%), amikacin (99.7%) and ceftolozane/tazobactam and plazomicin (99.6%). Twenty-three percent of S. aureus were MRSA. MRSA were most susceptible to ceftobiprole, linezolid and telavancin (100%), daptomycin (99.9%), vancomycin (99.8%) and tigecycline (99.2%). P. aeruginosa were most susceptible to ceftolozane/tazobactam (98.3%) and colistin (95.0%). Conclusions The CANWARD surveillance study has provided 10 years of reference antimicrobial susceptibility testing data on pathogens commonly causing infections in patients attending Canadian hospitals. [ABSTRACT FROM AUTHOR]

Background: OXA-2 is a class D β-lactamase that confers resistance to penicillins, as well as narrow-spectrum cephalosporins. OXA-2 was recently reported to also possess carbapenem-hydrolysing activity. Here, we describe a KPC-2-encoding Klebsiella pneumoniae isolate that demonstrated reduced susceptibility to ceftazidime and ertapenem due to production of OXA-2.Objectives: To elucidate the role of OXA-2 production in reduced ceftazidime and ertapenem susceptibility in a K. pneumoniae ST258 clinical isolate.Methods: MICs were determined by the agar dilution method. WGS was conducted to identify and compare resistance genes between isolates. Expression of KPC-2 was quantified by quantitative RT-PCR and immunoblotting. OXA-2 was expressed in Escherichia coli TOP10, as well as in K. pneumoniae ATCC 13883, to define the relative contribution of OXA-2 in β-lactam resistance. Kinetic studies were conducted using purified OXA-2 enzyme.Results: K. pneumoniae 1761 belonged to ST258 and carried both blaKPC-2 and blaOXA-2. However, expression of blaKPC-2 was substantially reduced due to an IS1294 insertion in the promoter region. K. pneumoniae 1761, K. pneumoniae ATCC 13883 and E. coli TOP10 carrying blaOXA-2-harbouring plasmids showed reduced susceptibility to ertapenem and ceftazidime, but meropenem, imipenem and cefepime were unaffected. blaOXA-2 was carried on a 2910 bp partial class 1 integron containing aacA4-blaOXA-2-qacEΔ1-sul1 on an IncA/C2 plasmid, which was not present in the earlier ST258 isolates possessing blaKPC-2 with intact promoters. Hydrolysis of ertapenem by OXA-2 was confirmed using purified enzyme.Conclusions: Production of OXA-2 was associated with reduced ceftazidime and ertapenem susceptibility in a K. pneumoniae ST258 isolate. [ABSTRACT FROM AUTHOR]

Background: Optimal treatment of prosthetic joint infection and chronic osteomyelitis consists of surgical removal of biofilm-embedded bacteria, followed by a 6-12 week course of antimicrobial therapy. However, when optimal surgery is not feasible, oral prolonged suppressive antibiotic therapy (PSAT) is recommended to prevent prosthesis loosening and/or relapse of infection. Since 2010, we have used infection salvage therapy using off-label subcutaneous (sc) injection of a β-lactam as PSAT for patients in whom oral PSAT is not possible.Methods: A single-centre prospective cohort study (2010-18) reporting treatment modalities, efficacy and safety in all patients receiving sc PSAT. NCT03403608.Results: The 10 included patients (median age 79 years) had polymicrobial (n = 5) or MDR bacterial (n = 4) prosthetic joint infection (knee, n = 4; hip, n = 3) or chronic osteomyelitis (n = 3). After initial intensive therapy, seven patients received ertapenem, three patients received ceftriaxone and one patient received ceftazidime by sc injection (one patient received 8 days of ceftriaxone before receiving ertapenem). In one patient, sc PSAT failed with recurrent signs of infection under treatment. In three patients, sc PSAT had to be discontinued due to side effects; in only one of these was the sc route implicated (skin necrosis following direct sc injection and not gravity infusion). Median treatment duration was 433 days. In six patients, sc PSAT was successful with favourable outcome at the time of writing. Interestingly, three patients with MDR bacterial carriage at baseline lost this under PSAT during follow-up.Conclusions: As salvage therapy, sc PSAT delivered by gravity infusion is a safe and interesting alternative when an optimal surgical strategy is not feasible and no oral treatment is available. [ABSTRACT FROM AUTHOR]

Objectives: To examine the impact on carbapenem resistance of mutations in Escherichia coli PBP2 detected in clinical isolates showing increased MICs of imipenem, but not of meropenem.Methods: The mutations in the PBP2-encoding gene mrdA were introduced into E. coli DH5α using the helper plasmid pTKRED. β-Lactam MICs were determined by broth microdilution and interpreted according to EUCAST. Mutants were screened for secondary mutations by WGS. To detect a possible fitness cost related to these mutations, the generation times of the mutants and E. coli DH5α were measured and their cell morphology was examined.Results: The 10 mutation patterns introduced into mrdA increased the MICs of imipenem and doripenem in all cases and of meropenem and mecillinam in some cases, but had no effect on ertapenem resistance. While no significant alteration of the generation time of the mutants could be detected, several mutants showed increased transverse diameters and thus altered cell morphology.Conclusions: Here we describe mutation patterns in PBP2 that contribute to increased MICs of carbapenems for clinical isolates of E. coli. We show that different mutations affect carbapenem MICs differently and that the mutations do not impact generation time, although some mutations affect cell morphology. [ABSTRACT FROM AUTHOR]

Background: Emergence of reduced susceptibility to vancomycin warrants the development of new antimicrobial agents for the treatment of MRSA. We evaluated the activity of dalbavancin, a novel lipoglycopeptide antibiotic, both alone and combined with β-lactams, in combination MIC testing and time-kill assays against resistant phenotypes of Staphylococcus aureus.Methods: S. aureus isolates included 50 organisms with varying susceptibility patterns. Dalbavancin was tested alone and in combination with five β-lactams: cefazolin, cefepime, ceftaroline, ertapenem and oxacillin. MIC values of the antibiotics were determined for all isolates. After initial MIC testing, dalbavancin MICs were determined in the presence of 0.5 × MIC of each β-lactam to determine the effect of each β-lactam on dalbavancin MIC. Time-kill assays were performed with dalbavancin and β-lactams tested at 0.5 × MIC for randomly selected organisms representing each MRSA phenotype. Time-kill curves were generated by plotting mean colony counts (log10 cfu/mL) versus time.Results: Dalbavancin MIC50 was 0.0313 mg/L and MIC90 was 0.0625 mg/L. Dalbavancin MICs decreased by zero to greater than five 2-fold dilutions in combination with each β-lactam. In time-kill assays, dalbavancin was synergistic with cefazolin, cefepime and ertapenem against all strains and the combination of dalbavancin and ceftaroline was synergistic against all but one. The combination of dalbavancin and oxacillin was synergistic against 5/8 strains.Conclusions: Dalbavancin was active against all MRSA strains tested, including heteroresistant vancomycin-intermediate S. aureus, vancomycin-intermediate S. aureus, daptomycin-non-susceptible and linezolid-resistant isolates. The synergy demonstrated against these organisms supports the use of dalbavancin in combination with β-lactams against resistant phenotypes of S. aureus. Further evaluation is warranted. [ABSTRACT FROM AUTHOR]

Background: In Klebsiella pneumoniae, loss-of-function mutations in the transcriptional repressors RamR and OqxR both have an impact on the production of efflux pumps and porins relevant to antimicrobial efflux/entry.Objectives: To define, in an otherwise isogenic background, the relative effects of OqxR and RamR loss-of-function mutations on envelope protein production, envelope permeability and antimicrobial susceptibility. We also investigated the clinical relevance of an OqxR loss-of-function mutation, particularly in the context of β-lactam susceptibility.Methods: Envelope permeability was estimated using a fluorescent dye accumulation assay. Antimicrobial susceptibility was measured using disc testing. Total envelope protein production was quantified using LC-MS/MS proteomics and quantitative RT-PCR was used to measure transcript levels.Results: Loss of RamR or OqxR reduced envelope permeability in K. pneumoniae by 45%-55% relative to the WT. RamR loss activated AcrAB efflux pump production ∼5-fold and this reduced β-lactam susceptibility, conferring ertapenem non-susceptibility even in the absence of a carbapenemase. In contrast, OqxR loss specifically activated OqxAB efflux pump production >10 000-fold. This reduced fluoroquinolone susceptibility but had little impact on β-lactam susceptibility even in the presence of a β-lactamase.Conclusions: Whilst OqxR loss and RamR loss are both seen in K. pneumoniae clinical isolates, only RamR loss significantly stimulates AcrAB efflux pump production. This means that only RamR mutants have significantly reduced β-lactamase-mediated β-lactam susceptibility and therefore represent a greater clinical threat. [ABSTRACT FROM AUTHOR]

Background: Ertapenem is a therapeutic option in patients with Gram-negative bone and joint infection (BJI). The subcutaneous (sc) route of administration is convenient in the outpatient setting and has shown favourable pharmacokinetics (PK), but available data on ertapenem are limited. Objectives: To perform population PK analysis and pharmacokinetic/pharmacodynamic (PK/PD) simulation of ertapenem administered by the intravenous (iv) or sc route to patients with BJI. Patients and methods: This was a retrospective analysis of PK data collected in patients with BJI who received iv or sc ertapenem. Measured ertapenem concentrations were analysed with a non-parametric population approach. Then, simulations were performed based on the final model to investigate the influence of ertapenem route of administration, dosage and renal function on the probability of achieving a pharmacodynamic (PD) target, defined as the percentage of time for which free plasma concentrations of ertapenem remained above the MIC (fT>MIC) of 40%. Results: Forty-six PK profiles (13 with iv and 33 with sc ertapenem) with a total of 133 concentrations from 31 subjects were available for the analysis. A two-compartment model with linear sc absorption and linear elimination best fitted the data. Creatinine clearance was found to significantly influence ertapenem plasma clearance. Simulations showed that twice daily dosing, sc administration and renal impairment were associated with an increase in fT>MIC and target attainment. Conclusions: Our results indicate that 1 g of ertapenem administered twice daily, by the iv or sc route, may optimize ertapenem exposure and achievement of PK/PD targets in patients with BJI. [ABSTRACT FROM AUTHOR]

Background: Ceftazidime/avibactam combines an established oxyimino-cephalosporin with the first diazabicyclooctane β-lactamase inhibitor to enter clinical use. We reviewed its activity against Gram-negative isolates, predominantly from the UK, referred for resistance investigation in the first year of routine testing, beginning in July 2015.Methods: Isolates were as received from referring laboratories; there is a bias to submit those with suspected carbapenem resistance. Identification was by MALDI-TOF mass spectroscopy, and susceptibility testing by BSAC agar dilution. Carbapenemase genes were sought by PCR; other resistance mechanisms were inferred using genetic data and interpretive reading.Results: Susceptibility rates to ceftazidime/avibactam exceeded 95% for: (i) Enterobacteriaceae with KPC, GES or other Class A carbapenemases; (ii) Enterobacteriaceae with OXA-48-like enzymes; and (iii) for ESBL or AmpC producers, even when these had impermeability-mediated ertapenem resistance. Almost all isolates with metallo-carbapenemases were resistant. Potentiation of ceftazidime by avibactam was seen for 87% of ceftazidime-resistant Enterobacteriaceae with 'unassigned' ceftazidime resistance mechanisms, including two widely referred groups of Klebsiella pneumoniae where no synergy was seen between cephalosporins and established β-lactamase inhibitors. Potentiation here may be a diazabicyclooctane/cephalosporin enhancer effect. Activity was seen against Pseudomonas aeruginosa with derepressed AmpC, but not for those with efflux-mediated resistance.Conclusions: Of the available β-lactams or inhibitor combinations, ceftazidime/avibactam has the widest activity spectrum against problem Enterobacteriaceae, covering all major types except metallo-carbapenemase producers; against P. aeruginosa it has a slightly narrower spectrum than ceftolozane/tazobactam, which also covers efflux-type resistance. [ABSTRACT FROM AUTHOR]

Objectives: β-Lactam antibiotics are commonly used in outpatient parenteral antimicrobial therapy (OPAT), but data regarding outcomes of long-term therapy are limited. The purpose of this study was to compare treatment success, readmission and antibiotic switch rates in patients treated with β-lactam antibiotics as OPAT. Methods: We carried out a retrospective review of all patients, discharged from Tufts Medical Center with cefazolin, ceftriaxone, ertapenem or oxacillin, between January 2009 and June 2013. A competing risks analysis was used to compare the cumulative incidence of first occurrence of treatment success, antibiotic switch and 30 day readmission for each drug. Results: Four hundred patientswere identified (cefazolin n=38, ceftriaxone n=104, ertapenem n=128 and oxacillin n=130). Baseline demographics were similar. Treatment success rates were higher for ceftriaxone and ertapenem (cefazolin 61%, ceftriaxone 81%, ertapenem 73% and oxacillin 58%; P<0.001). Thirty-day all-cause readmissions were similar (cefazolin 21%, ceftriaxone 14%, ertapenem 20% and oxacillin 15%; P=0.46). In 400 OPAT courses, 37 out of 50 antibiotic switches were accomplished without readmission. Adverse drug events (ADEs) were the most common reason for outpatient antibiotic switches (31/37, 84%). The ADE rate was higher for the oxacillin group (cefazolin 2.0 versus ceftriaxone 1.5 versus ertapenem 2.9 versus oxacillin 8.4 per 1000 OPAT days; P<0.001). Conclusions: OPAT with β-lactam antibiotics is effective, but antibiotic switches for adverse events were more frequent with oxacillin use. Clinicians should be cognizant of the risk of readmissions and ADEs in OPATpatients, as the value of OPAT lies in reducing patientmorbidity and readmissions bymanaging ADEs and preventing clinical failures. [ABSTRACT FROM AUTHOR]

Objectives A consensus exists among clinicians that imipenem/cilastatin is the most epileptogenic carbapenem, despite inconsistencies in the literature. Methods We conducted a meta-analysis of all randomized controlled trials comparing carbapenems with each other or with non-carbapenem antibiotics to assess the risk of seizures for imipenem, meropenem, ertapenem and doripenem. Results In the risk difference (RD) analysis, there were increased patients with seizure (2 per 1000 persons, 95% CI 0.001, 0.004) among recipients of carbapenems versus non-carbapenem antibiotics. This difference was largely attributed to imipenem as its use was associated with an additional 4 patients per 1000 with seizure (95% CI 0.002, 0.007) compared with non-carbapenem antibiotics, whereas none of the other carbapenems was associated with increased seizure. Similarly, in the pooled OR analysis, carbapenems were associated with a significant increase in the risk of seizures relative to non-carbapenem comparator antibiotics (OR 1.87, 95% CI 1.35, 2.59). The ORs for risk of seizures from imipenem, meropenem, ertapenem and doripenem compared with other antibiotics were 3.50 (95% CI 2.23, 5.49), 1.04 (95% CI 0.61, 1.77), 1.32 (95% CI 0.22, 7.74) and 0.44 (95% CI 0.13, 1.53), respectively. In studies directly comparing imipenem and meropenem, there was no difference in epileptogenicity in either RD or pooled OR analyses. Conclusions The absolute risk of seizures with carbapenems was low, albeit higher than with non-carbapenem antibiotics. Although imipenem was more epileptogenic than non-carbapenem antibiotics, there was no statistically significant difference in the imipenem versus meropenem head-to-head comparison. [ABSTRACT FROM PUBLISHER]

Background Although metallo-β-lactamases (MBLs) hydrolyse most β-lactams, including carbapenems, MBL-producing Enterobacteriaceae very often remain susceptible to carbapenems in vitro. We studied the in vivo efficacy of imipenem, meropenem, ertapenem and aztreonam against a carbapenem-susceptible MBL-producing clinical Escherichia coli strain in a rabbit intra-abdominal abscess model. Methods Rabbits were inoculated intraperitoneally with 108 cfu/mL of VIM-1-positive E. coli and were assigned to receive no treatment (controls) or intravenous imipenem/cilastatin (imipenem) 70 mg/kg/12 h or meropenem 125 mg/kg/12 h or ertapenem 60 mg/kg/12 h or aztreonam 70 mg/kg/12 h. Dosing regimens were chosen on the basis of preliminary pharmacokinetic studies so that T>MIC was achieved for ≥50% of the dosing interval for all tested antibiotics. A total of eight doses were administered before sacrifice and the abscesses were harvested and quantitatively cultured. Results MICs of imipenem, meropenem, ertapenem and aztreonam for the infecting isolate were 1, ≤0.25, 1.5 and ≤0.25 mg/L, respectively. The log10 cfu/g (mean ± SD) viable counts in pus were as follows: controls (n = 16), 8.71 ± 1.34 (P < 0.001 versus all other groups); imipenem (n = 15), 4.89 ± 2.42; meropenem (n = 15), 4.24 ± 2.44; ertapenem (n = 16), 3.17 ± 1.85 (P = 0.022 versus imipenem); and aztreonam (n = 15), 3.62 ± 3.05. Mortality among treated rabbits was significantly reduced compared with controls. Four animals in the aztreonam group (26.7%) had culture-negative pus and no mortality was noted among aztreonam-treated animals. Conclusions In the rabbit experimental model, carbapenems were shown to be effective in the treatment of intra-abdominal infection due to an extended-spectrum β-lactamase-negative carbapenem-susceptible VIM-1-producing clinical E. coli strain, but treatment with aztreonam resulted in a more favourable outcome overall. [ABSTRACT FROM PUBLISHER]

This article reports on three case studies of double-carbapenem regimen in pandrug-resistant Klebsiella pneumoniae bloodstream infections. Topics discussed include the clinical history of the patients, the role of double-carbapenem regimens containing ertapenem, and the synergic activity and clinical effectiveness of double-carbapenem regimen. The bactericidal effect of ertapenem plus meropenem is explored.

The article focuses on a study which examined the presence of carbapenem resistance in faecal samples from healthy individuals over a six month period. A Mueller-Hinton agar was used to test for the presence of extended-spectrum &Beta-lactamases (ESBL) in enterobacteriaceae. Results of the study showed that 23.9% of the samples were ESBL producers. It also identified Escherichia coli and Klebsiella species in five percent of the samples. The study did not found any carbapenem resistance.