mk-7655 and Pseudomonas-Infections

Topics: Anti-Bacterial Agents; beta-Lactamases; Drug Resistance, Bacterial; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Taiwan

Antimicrobial susceptibility was determined for clinical gram-negative isolates from Czech Republic, Hungary, and Poland, where published data for ceftolozane/tazobactam (C/T) and imipenem/relebactam (IMI/REL) is scarce. C/T was active against 94.3% of Enterobacterales, 10-18% higher than the tested cephalosporins and piperacillin/tazobactam. IMI/REL was the most active tested agent against non-Morganellaceae Enterobacterales (99.7% susceptible). C/T was the most active among all studied agents except colistin against Pseudomonas aeruginosa (96.0% susceptible); susceptibility to IMI/REL was 90.7%. C/T maintained activity against 73.7-85.3% of β-lactam-resistant or multidrug-resistant P. aeruginosa subsets. C/T and IMI/REL could represent important treatment options for patients from these countries.

Topics: Anti-Bacterial Agents; Cephalosporins; Czech Republic; Humans; Hungary; Imipenem; Microbial Sensitivity Tests; Poland; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

To evaluate the in-vitro activity of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-relebactam and comparator agents against contemporary Pseudomonas aeruginosa isolates from US hospitals.. In total, 3184 isolates were collected consecutively from 71 US medical centres in 2020-2021, and susceptibility tested by reference broth microdilution. Clinical Laboratory Standard Institute breakpoints were applied.. Ceftazidime-avibactam [97.0% susceptible (S)], ceftolozane-tazobactam (98.0%S), imipenem-relebactam (97.3%S) and tobramycin (96.4%S) were the most active agents against the aggregate P. aeruginosa isolate collection, and retained good activity against piperacillin-tazobactam-non-susceptible, meropenem-non-susceptible and multi-drug-resistant (MDR) isolates. All other antimicrobials tested showed limited activity against piperacillin-tazobactam-non-susceptible, meropenem-non-susceptible and MDR isolates. The most common infections were pneumonia (45.9%), skin and skin structure infections (19.0%), urinary tract infections (17.0%) and bloodstream infections (11.7%); ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam showed consistent activity against isolates from these infection types. Susceptibility to piperacillin-tazobactam and meropenem was lower among isolates from pneumonia compared with other infection types.. Ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam were highly active, and exhibited similar coverage against a large contemporary collection of P. aeruginosa isolates from US hospitals. Cross-resistance among the newer β-lactams/β-lactam inhibitors (BL/BLIs) varied markedly; ≥72.1% of isolates resistant to one of the three newer BL/BLIs approved for P. aeruginosa treatment remained susceptible to at least one of the other two BL/BLIs, indicating that all three should be tested in the clinical laboratory. These three BL/BLIs represent valuable therapeutic options for P. aeruginosa infection.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Ceftazidime; Cephalosporins; Drug Combinations; Hospitals; Humans; Imipenem; Lactams; Meropenem; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

To describe and characterize the emergence of resistance to ceftolozane/tazobactam, ceftazidime/avibactam and imipenem/relebactam in a patient receiving ceftazidime/avibactam treatment for an MDR Pseudomonas aeruginosa CNS infection.. One baseline (PA1) and two post-exposure (PA2 and PA3) isolates obtained before and during treatment of a nosocomial P. aeruginosa meningoventriculitis were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. The impact on β-lactam resistance of mutations in blaPDC and mexR was determined through cloning experiments and complementation assays.. Isolate PA1 showed baseline resistance mutations in DacB (I354A) and OprD (N142fs) conferring resistance to conventional antipseudomonals but susceptibility to ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. Post-exposure isolates showed two divergent ceftazidime/avibactam-resistant phenotypes associated with distinctive mutations affecting the intrinsic P PDC β-lactamase (S254Ins) (PA2: ceftolozane/tazobactam and ceftazidime/avibactam-resistant) or MexAB-OprM negative regulator MexR in combination with modification of PBP3 (PA3: ceftazidime/avibactam and imipenem/relebactam-relebactam-resistant). Cloning experiments demonstrated the role of PDC modification in resistance to ceftolozane/tazobactam and ceftazidime/avibactam. Complementation with a functional copy of the mexR gene in isolate PA3 restored imipenem/relebactam susceptibility.. We demonstrated how P. aeruginosa may simultaneously develop resistance and compromise the activity of new β-lactam/β-lactamase inhibitor combinations when exposed to ceftazidime/avibactam through selection of mutations leading to PDC modification and up-regulation of MexAB-OprM-mediated efflux.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Ceftazidime; Cephalosporinase; Cephalosporins; Drug Combinations; Humans; Imipenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

To determine susceptibility to the novel β-lactam/β-lactamase inhibitor combination imipenem/relebactam in clinical isolates recovered from intra-abdominal (IAI), urinary (UTI), respiratory (RTI) and bloodstream (BSI) infections in the SMART (Study for Monitoring Antimicrobial Resistance Trends) study in SPAIN during 2016 - 2020.. Broth microdilution MICs for imipenem/relebactam and comparators were determined by a central laboratory against isolates of Enterobacterales and Pseudomonas aeruginosa. MICs were interpreted using EUCAST-2021 breakpoints.. In total, 5,210 Enterobacterales and 1,418 P. aeruginosa clinical isolates were analyzed. Imipenem/relebactam inhibited 98.8% of Enterobacterales. Distinguishing by source of infection susceptibility was 99.1% in BSI, 99.2% in IAI, 97.9% in RTI, and 99.2% in UTI. Of intensive care unit isolates (ICU) 97.4% were susceptible and of non-ICU isolates 99.2% were susceptible. In Enterobacterales, activity against Class A, Class B and Class D carbapenemases was 96.2%, 15.4% and 73.2%, respectively. In P. aeruginosa, imipenem/relebactam was active in 92.2% of isolates. By source of infection it was 94.8% in BSI, 92.9% in IAI, 91.7% in RTI, and 93.1% in UTI. An 88.7% of ICU isolates and 93.6% of non-ICU isolates were susceptible to imipenem/relebactam. Imipenem/relebactam remained active against P. aeruginosa ceftazidime-resistant (76.3%), cefepime-resistant (73.6%), imipenem-resistant (71.5%) and piperacillin-resistant (78.7%) isolates. Of all multidrug-resistant or difficult-to-treat resistance P. aeruginosa isolates, 75.1% and 46.2%, respectively, were susceptible to imipenem/relebactam.. Imipenem/relebactam showed high rates of susceptibility in Enterobacterales and P. aeruginosa isolates from different sources of infection as well as depending on patients' location (ICU or non-ICU scenarios).

Topics: Anti-Bacterial Agents; beta-Lactamase Inhibitors; Humans; Imipenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Spain

Pseudomonas aeruginosa isolates were consecutively collected from patients with pneumonia in 29 medical centers in 2020 and susceptibility tested by broth microdilution method. Ceftazidime-avibactam (95.5% susceptible), imipenem-relebactam (94.3% susceptible), and ceftolozane-tazobactam (93.3% susceptible) were the most active compounds after colistin (99.5% susceptible). Susceptibility rates for the β-lactam/β-lactamase inhibitor combinations (BL/BLIs) varied against isolates resistant to piperacillin-tazobactam, meropenem, imipenem, and/or ceftazidime. Ceftazidime-avibactam was the most active BL/BLI against resistant subsets from Western Europe, whereas imipenem-relebactam was slightly more active than other BL/BLIs against resistant subsets from Eastern Europe. Susceptibility rates were markedly lower in Eastern Europe than Western Europe.

Topics: Azabicyclo Compounds; beta-Lactamase Inhibitors; Ceftazidime; Cephalosporins; Drug Combinations; Drug Resistance, Multiple, Bacterial; Hospitalization; Humans; Imipenem; Jupiter; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

To analyse the dynamics and mechanisms of stepwise resistance development to ceftolozane/tazobactam and imipenem/relebactam in XDR Pseudomonas aeruginosa clinical strains.. XDR clinical isolates belonging to ST111 (main resistance mechanisms: oprD-, dacB-, CARB-2), ST175 (oprD-, ampR-G154R) and ST235 (oprD-, OXA-2) high-risk clones were incubated for 24 h in Müeller-Hinton Broth with 0.125-64 mg/L of ceftolozane + tazobactam 4 mg/L or imipenem + relebactam 4 mg/L. Tubes from the highest antibiotic concentration showing growth were reinoculated into fresh medium containing concentrations up to 64 mg/L for 7 consecutive days. Two colonies per strain from each of the triplicate experiments were characterized by determining the susceptibility profiles, whole genome sequencing (WGS), and in vitro fitness through competitive growth assays.. Resistance development occurred more slowly and reached a lower level for imipenem/relebactam than for ceftolozane/tazobactam in all tested XDR strains. Moreover, resistance development to imipenem/relebactam remained low even for ST175 isolates that had developed ceftolozane/tazobactam resistance during therapy. Lineages evolved in the presence of ceftolozane/tazobactam showed high-level resistance, imipenem/relebactam hypersusceptibility and low fitness cost, whereas lineages evolved in the presence of imipenem/relebactam showed moderate (borderline) resistance, no cross-resistance to ceftolozane/tazobactam and high fitness cost. WGS evidenced that ceftolozane/tazobactam resistance was mainly caused by mutations in the catalytic centres of intrinsic (AmpC) or acquired (OXA) β-lactamases, whereas lineages evolved in imipenem/relebactam frequently showed structural mutations in MexB or in ParS, along with some strain-specific mutations.. Imipenem/relebactam could be a useful alternative for the treatment of XDR P. aeruginosa infections, potentially reducing resistance development during therapy.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Cephalosporins; Clone Cells; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Topics: Amino Acids; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Drug Combinations; Humans; Imipenem; Microbial Sensitivity Tests; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; United States

Ceftolozane-tazobactam (C/T), imipenem-relebactam (IMR), and ceftazidime-avibactam (CZA) were tested against 2,531 P. aeruginosa strains isolated from patients in the United States from 2018 to 2020 as part of the SMART (Study for Monitoring Antimicrobial Resistance Trends) surveillance program. MICs were determined by CLSI broth microdilution and interpreted using CLSI M100 (2021) breakpoints. Imipenem-, IMR-, or C/T-nonsusceptible isolates were screened for β-lactamase genes: 96.4% of all isolates and ≥70% of multidrug-resistant (MDR), pan-β-lactam-nonsusceptible, and difficult-to-treat resistance (DTR) isolates were C/T-susceptible; 52.2% of C/T-nonsusceptible isolates remained susceptible to IMR compared to 38.9% for CZA; and 1.7% of isolates tested were nonsusceptible to both C/T and IMR versus 2.2% of isolates with a C/T-nonsusceptible and CZA-resistant phenotype (a difference of 12 isolates). C/T and IMR modal MICs for pan-β-lactam-nonsusceptible isolates remained at or below their respective susceptible MIC breakpoints from 2018 to 2020, while the modal MIC for CZA increased 2-fold from 2018 to 2019 and exceeded the CZA-susceptible MIC breakpoint in both 2019 and 2020. Only six of 802 molecularly characterized isolates carried a metallo-β-lactamase, and two isolates carried a GES carbapenemase. Most P. aeruginosa isolates were C/T-susceptible, including many with MDR, pan-β-lactam-nonsusceptible, DTR, CZA-resistant, and IMR-nonsusceptible phenotypes. While C/T was the most active antipseudomonal agent, IMR demonstrated greater activity than CZA against isolates nonsusceptible to C/T.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Ceftazidime; Cephalosporins; Drug Combinations; Hospitals; Humans; Imipenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam; United States

To evaluate the activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam against a clinical and laboratory collection of ceftolozane/tazobactam- and ceftazidime/avibactam-resistant Pseudomonas aeruginosa β-lactamase mutants.. The activity of cefiderocol, imipenem/relebactam, cefepime/taniborbactam, cefepime/zidebactam and comparators was evaluated against a collection of 30 molecularly characterized ceftolozane/tazobactam- and/or ceftazidime/avibactam-resistant P. aeruginosa isolates from patients previously treated with cephalosporins. To evaluate how the different β-lactamases in the clinical isolates affected the resistance to these agents, a copy of each blaPDC, blaOXA-2 and blaOXA-10 ancestral and mutant allele from the clinical isolates was cloned in pUCp24 and expressed in dual blaPDC-oprD (for blaPDC-like genes) or single oprD (for blaOXA-2-like and blaOXA-10-like genes) PAO1 knockout mutants. MICs were determined using reference methodologies.. For all isolates, MICs were higher than 4 and/or 8 mg/L for ceftolozane/tazobactam and ceftazidime/avibactam, respectively. Cefiderocol was the most active agent, showing activity against all isolates, except one clinical isolate that carried an R504C substitution in PBP3 (MIC = 16 mg/L). Imipenem/relebactam was highly active against all isolates, except two clinical isolates that carried the VIM-20 carbapenemase. Cefepime/zidebactam and cefepime/taniborbactam displayed activity against most of the isolates, but resistance was observed in some strains with PBP3 amino acid substitutions or that overexpressed mexAB-oprM or mexXY efflux pumps. Evaluation of transformants revealed that OXA-2 and OXA-10 extended-spectrum variants cause a 2-fold increase in the MIC of cefiderocol relative to parental enzymes.. Cefiderocol, imipenem/relebactam, cefepime/taniborbactam and cefepime/zidebactam show promising and complementary in vitro activity against ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa. These agents may represent potential therapeutic options for ceftolozane/tazobactam- and ceftazidime/avibactam-resistant P. aeruginosa infections.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Borinic Acids; Carboxylic Acids; Cefepime; Cefiderocol; Ceftazidime; Cephalosporins; Cyclooctanes; Humans; Imipenem; Piperidines; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

To study the in vitro activity of imipenem/relebactam and comparators and the imipenem/relebactam resistance mechanisms in a Pseudomonas aeruginosa collection from Portugal (STEP, 2017-18) and Spain (SUPERIOR, 2016-17) surveillance studies.. P. aeruginosa isolates (n = 474) were prospectively recovered from complicated urinary tract (cUTI), complicated intra-abdominal (cIAI) and lower respiratory tract (LRTI) infections in 11 Portuguese and 8 Spanish ICUs. MICs were determined (ISO broth microdilution). All imipenem/relebactam-resistant P. aeruginosa isolates (n = 30) and a subset of imipenem/relebactam-susceptible strains (n = 32) were characterized by WGS.. Imipenem/relebactam (93.7% susceptible), ceftazidime/avibactam (93.5% susceptible) and ceftolozane/tazobactam (93.2% susceptible) displayed comparable activity. The imipenem/relebactam resistance rate was 6.3% (Portugal 5.8%; Spain 8.9%). Relebactam restored imipenem susceptibility to 76.9% (103/134) of imipenem-resistant isolates, including MDR (82.1%; 32/39), XDR (68.8%; 53/77) and difficult-to-treat (DTR) isolates (67.2%; 45/67). Among sequenced strains, differences in population structure were detected depending on the country: clonal complex (CC)175 and CC309 in Spain and CC235, CC244, CC348 and CC253 in Portugal. Different carbapenemase gene distributions were also found: VIM-20 (n = 3), VIM-1 (n = 2), VIM-2 (n = 1) and VIM-36 (n = 1) in Spain and GES-13 (n = 13), VIM-2 (n = 3) and KPC-3 (n = 2) in Portugal. GES-13-CC235 (n = 13) and VIM type-CC175 (n = 5) associations were predominant in Portugal and Spain, respectively. Imipenem/relebactam showed activity against KPC-3 strains (2/2), but was inactive against all GES-13 producers and most of the VIM producers (8/10). Mutations in genes affecting porin inactivation, efflux pump overexpression and LPS modification might also be involved in imipenem/relebactam resistance.. Microbiological results reinforce imipenem/relebactam as a potential option to treat cUTI, cIAI and LRTI caused by MDR/XDR P. aeruginosa isolates, except for GES-13 and VIM producers.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Humans; Imipenem; Intensive Care Units; Microbial Sensitivity Tests; Portugal; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Spain

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Carbapenems; Ceftazidime; Cephalosporins; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Lactams; Microbial Sensitivity Tests; Monobactams; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

The limited armamentarium against multidrug-resistant Gram-negative bacilli led to the development of a new generation of β-lactam/β-lactamase inhibitor combinations (BL/BLI).. To evaluate the in vitro activity of ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, and imipenem/relebactam against Pseudomonas aeruginosa isolates recovered from patients hospitalized with skin and soft tissue infections (SSTIs) in several countries around the world.. A total of 360 P. aeruginosa isolates were consecutively collected from 47 medical centers located in Western Europe, Eastern Europe, the Asia-Pacific region, and Latin America. Susceptibility testing was performed by broth microdilution method at a monitoring laboratory. EUCAST breakpoints were applied.. Ceftazidime/avibactam (98.3% susceptible), ceftolozane/tazobactam (98.6% susceptible), and imipenem/relebactam (98.3% susceptible) were the most active compounds after colistin (100.0% susceptible) and retained activity against isolates nonsusceptible to piperacillin/tazobactam, meropenem, imipenem, and/or ceftazidime. Meropenem-vaborbactam was active against 94.2% of isolates. Ceftazidime/avibactam was the most active BL/BLI against meropenem-nonsusceptible (92.6% susceptible) and imipenem-resistant (93.8% susceptible) isolates, whereas ceftolozane/tazobactam was the most active BL/BLI against piperacillin/tazobactam-resistant (91.1% susceptible) and ceftazidime-resistant (91.7% susceptible) isolates.. The recently approved BL/BLIs demonstrated potent activity and broad coverage against contemporary P. aeruginosa isolates from patients with SSTIs.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Boronic Acids; Ceftazidime; Cephalosporins; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Soft Tissue Infections; Tazobactam

Pseudomonas aeruginosa is an opportunistic human pathogen and a major cause of nosocomial infections. The global spread of carbapenem-resistant strains is growing rapidly and has become a major public health challenge. Imipenem-relebactam (I/R) is a novel carbapenem-beta-lactamase inhibitor combination that can overcome carbapenem resistance. In this study, we aimed to understand the mechanism underlying resistance to imipenem and imipenem-relebactam. For this purpose, we performed a genomic comparison of 40 new clinical P. aeruginosa strains with different antibiotic sensitivity patterns as well as the presence/absence of carbapenemases. Results indicated the presence of a reduced flexible genome (15% total) mostly represented by phages and defense mechanisms against them, showing an important role in evolution and pathogenicity. We found a high diversity of antibiotic resistance genes grouped in small clusters mobilized via integrative and conjugative elements and facilitated by the high homologous recombination detected. Ortholog genes were found in several pathogenic strains from distantly related taxa in different mobile elements with a global distribution. The microdiversity found in those strains without carbapenemases did not reveal a clear pattern that could be associated with carbapenem resistance, suggesting multiple mechanisms of resistance in the core genome. Our results provide new insight into the dynamics and high genomic plasticity by which clinical strains of P. aeruginosa acquire resistance. This knowledge can be applied to other multidrug-resistant microbes to create predictive frameworks for assessing common molecular mechanisms of antibiotic resistance and integrated into new strategies for their prevention.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamases; Drug Combinations; Drug Resistance, Multiple, Bacterial; Genomics; Humans; Imipenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Multidrug-resistant (MDR) bacteria are frequently defined using the criteria established by Magiorakos et al [Clin Microbiol Infect 2012;18:268-81]. Difficult-to-treat resistance (DTR) [Kadri et al, Clin Infect Dis 2018;67:1803-14] is a novel approach to defining resistance in gram-negative bacilli focusing on treatment-limiting resistance to first-line agents (all β-lactams and fluoroquinolones).. Clinical and Laboratory Standards Institute-defined broth microdilution minimum inhibitory concentrations (MICs) were determined for imipenem/relebactam, ceftolozane/tazobactam, and comparators against respiratory, intraabdominal, and urinary isolates of Enterobacterales (n = 10 516) and Pseudomonas aeruginosa (n = 2732) collected in 26 US hospitals in 2015-2017.. Among all Enterobacterales, 1.0% of isolates were DTR and 15.6% were MDR; 8.4% of P. aeruginosa isolates were DTR and 32.4% were MDR. MDR rates for Enterobacterales and DTR and MDR rates for P. aeruginosa were significantly higher (P < .05) in isolates collected in intensive care units (ICUs) than in non-ICUs and in respiratory tract isolates than in intraabdominal or urinary tract isolates. In addition, 82.4% of DTR and 92.1% of MDR Enterobacterales and 62.2% of DTR and 82.2% of MDR P. aeruginosa were imipenem/relebactam-susceptible, and 1.5% of DTR and 65.8% of MDR Enterobacterales and 67.5% of DTR and 84.0% of MDR P. aeruginosa were ceftolozane/tazobactam-susceptible.. MDR phenotypes defined using the Magiorakos criteria may overcall treatment-limiting resistance in gram-negative bacilli. In the US, DTR Enterobacterales were infrequent, while MDR Enterobacterales isolates and DTR and MDR P. aeruginosa were common. Imipenem/relebactam (Enterobacterales, P. aeruginosa) and ceftolozane/tazobactam (P. aeruginosa) retained in vitro activity against most DTR and MDR isolates.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Cephalosporins; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Microbial Sensitivity Tests; Phenotype; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam; United States

Broth microdilution was used to determine the in vitro activities of imipenem-relebactam and comparators versus 4260 Enterobacterales and 1324 Pseudomonas aeruginosa clinical isolates. Excluding Serratia marcescens, 96.7% to 100% of Enterobacterales species were susceptible to imipenem-relebactam. Susceptibility of P. aeruginosa isolates to imipenem-relebactam and imipenem was 91.3% and 59.1%, respectively.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Canada; Drug Combinations; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Genotype; Humans; Imipenem; Microbial Sensitivity Tests; Phenotype; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactam Resistance; beta-Lactamases; Colistin; Humans; Imipenem; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections

We analysed the dynamics and mechanisms of resistance development to imipenem alone or combined with relebactam in Pseudomonas aeruginosa WT (PAO1) and mutator (PAOMS; ΔmutS) strains.. PAO1 or PAOMS strains were incubated for 24 h in Mueller-Hinton Broth with 0.125-64 mg/L of imipenem ± relebactam 4 mg/L. Tubes from the highest antibiotic concentration showing growth were reinoculated in fresh medium containing concentrations up to 64 mg/L of imipenem ± relebactam for 7 days. Two colonies per strain, replicate experiment and antibiotic from early (Day 1) and late (Day 7) cultures were characterized by determining the susceptibility profiles, WGS and determination of the expression of ampC and efflux-pump-coding genes. Virulence was studied in a Caenorhabditis elegans infection model.. Relebactam reduced imipenem resistance development for both strains, although resistance emerged much faster for PAOMS. WGS indicated that imipenem resistance was associated with mutations in the porin OprD and regulators of ampC, while the mutations in imipenem/relebactam-resistant mutants were located in oprD and regulatoras of MexAB-OprM. High-level imipenem/relebactam resistance was only documented in the PAOMS strain and was associated with an additional specific (T680A) mutation located in the catalytic pocket of ponA (PBP1a) and with reduced virulence in the C. elegans model.. Imipenem/relebactam could be a useful alternative for the treatment of MDR P. aeruginosa infections, potentially reducing resistance development during treatment. Moreover, this work deciphers the potential resistance mechanisms that may emerge upon the introduction of this novel combination into clinical practice.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; Caenorhabditis elegans; Imipenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Relebactam is a small molecule β-lactamase inhibitor under clinical investigation for use as a fixed-dose combination with imipenem/cilastatin. Here we present a translational pharmacokinetic/pharmacodynamic mathematical model to support optimal dose selection of relebactam.. Data derived from in vitro checkerboard and hollow fiber infection studies of imipenem-resistant strains of Pseudomonas aeruginosa were incorporated into the model. The model integrates the effect of relebactam concentration on imipenem susceptibility in a semi-mechanistic manner using the checkerboard data and characterizes the bacterial time-kill profiles from the hollow fiber infection model data.. Simulations demonstrated that the ratio of the area under the concentration-time curve for free drug to the minimum inhibitory concentration (fAUC/MIC) was the pharmacokinetic driver for relebactam, with a target fAUC/MIC=7.5 associated with 2-log kill. At a clinical dose of 250mg relebactam, greater than 2-log reductions in bacterial load are projected for imipenem-resistant strains with an imipenem/relebactam MIC≤4μg/mL.. The study confirms that the pharmacokinetic/pharmacodynamic driver for relebactam is fAUC/MIC, that an fAUC/MIC ratio of 7.5 is associated with 2-log kill in vitro, and that a 250mg clinical dose of relebactam achieves this target value when delivered in combination with imipenem/cilastatin.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Cilastatin; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Humans; Imipenem; Microbial Sensitivity Tests; Models, Theoretical; Pseudomonas aeruginosa; Pseudomonas Infections

Imipenem resistance in Pseudomonas aeruginosa most often entails loss of the 'carbapenem-specific' porin OprD; more rarely it reflects acquired carbapenemases. Loss of OprD only confers resistance to imipenem if AmpC β-lactamase is expressed, and we investigated whether this mechanism was overcome by relebactam, a developmental diazabicyclooctane β-lactamase inhibitor.. Consecutive P. aeruginosa isolates causing bacteraemia or hospital-onset lower respiratory tract infections were collected between 2014 and 2016 under the aegis of the BSAC Resistance Surveillance Programme. Imipenem MICs were determined centrally by BSAC agar dilution, with relebactam at a fixed concentration (4 mg/L).. For most imipenem-susceptible P. aeruginosa (726/759, 95.7%), the MICs of imipenem alone were 0.5-2 mg/L and were decreased 3- to 4-fold by addition of relebactam, as based on geometric means or modes. For most imipenem-resistant P. aeruginosa (82/92, 89%), imipenem MICs were 8-16 mg/L, and were reduced to 1-2 mg/L by relebactam. These patterns applied regardless of whether the isolates were susceptible to penicillins and cephalosporins or had phenotypes suggesting derepressed AmpC or up-regulated efflux. Imipenem MICs for five P. aeruginosa with MBLs remained high (≥16 mg/L) regardless of relebactam.. Potentiation of imipenem by relebactam was almost universal, in accordance with the view that endogenous pseudomonal AmpC ordinarily protects against this carbapenem to a small degree. Imipenem MICs were reduced to the current breakpoint, or lower, except for MBL producers. Potentiation was not compromised by derepression of AmpC or up-regulation of efflux.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacteremia; Drug Resistance, Bacterial; Drug Synergism; Humans; Imipenem; Microbial Sensitivity Tests; Phenotype; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections

Relebactam is a diazabicyclooctane non-β-lactam inhibitor of Ambler class A and C β-lactamases that is in clinical development in combination with imipenem/cilastatin. The current study evaluated the in vitro activity of imipenem/relebactam against 5447 isolates of Pseudomonas aeruginosa submitted to the SMART global surveillance programme in 2015-17 by 67 clinical laboratories in 22 European countries.. MICs were determined using the CLSI broth microdilution reference method (Eleventh Edition: M07, 2018). Relebactam was tested at a fixed concentration of 4 mg/L in combination with doubling dilutions of imipenem. MICs were interpreted using EUCAST clinical breakpoints (version 8.1); imipenem breakpoints were applied to imipenem/relebactam.. Rates of susceptibility to imipenem and imipenem/relebactam (MIC ≤4 mg/L) were 69.4% and 92.4%, respectively, for all isolates of P. aeruginosa. Over one-third of all isolates (34.9%, 1902/5447) were MDR; lower respiratory tract isolates (38.3%, 1327/3461) were more frequently MDR than were intraabdominal (28.5%, 355/1245) or urinary tract (29.7%, 212/714) isolates. Of all MDR isolates, 78.2% were susceptible to imipenem/relebactam, a rate that was 50-77 percentage points higher than the rate of susceptibility to imipenem or any other β-lactam tested; rates of susceptibility to imipenem/relebactam were similar for MDR isolates from lower respiratory tract (77.8% susceptible), intraabdominal (80.3%) and urinary tract (76.4%) infections. Overall, relebactam restored imipenem susceptibility to 75.2% (1254/1668) of imipenem-non-susceptible isolates of P. aeruginosa and to 69.6% (947/1361) of imipenem-non-susceptible isolates with an MDR phenotype.. Relebactam restored in vitro susceptibility to imipenem for most imipenem-non-susceptible and MDR clinical isolates of P. aeruginosa from European patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Child; Child, Preschool; Drug Resistance, Multiple, Bacterial; Europe; Female; Humans; Imipenem; Infant; Infant, Newborn; Male; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Young Adult

A total of 2732 isolates of Pseudomonas aeruginosa collected at 26 United States clinical laboratories in 2015-2017 were tested for susceptibility to imipenem-relebactam. Imipenem-relebactam MICs were interpreted using 2018 CLSI M100 imipenem breakpoints for P. aeruginosa. A total of 93.9% of P. aeruginosa isolates were susceptible to imipenem-relebactam. Among MDR isolates (n = 750), susceptibility to imipenem-relebactam was 79.7%, 46-73 percentage points higher than to other β-lactams tested. Relebactam restored imipenem susceptibility to 78.3% of imipenem-nonsusceptible isolates (n = 766) and to 69.6% of imipenem-nonsusceptible isolates with MDR phenotypes (n = 500).

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Public Health Surveillance; United States

The prevalence of antibiotic resistance is increasing, and multidrug-resistant Pseudomonas aeruginosa has been identified as a serious threat to human health. The production of β-lactamase is a key mechanism contributing to imipenem resistance in P. aeruginosa. Relebactam is a novel β-lactamase inhibitor, active against class A and C β-lactamases, that has been shown to restore imipenem susceptibility. In a series of studies, we assessed the interaction of relebactam with key mechanisms involved in carbapenem resistance in P. aeruginosa and to what extent relebactam might overcome imipenem non-susceptibility.. Relebactam demonstrated no intrinsic antibacterial activity against P. aeruginosa, had no inoculum effect, and was not subject to efflux. Enzymology studies showed relebactam is a potent (overall inhibition constant: 27 nM), practically irreversible inhibitor of P. aeruginosa AmpC. Among P. aeruginosa clinical isolates from the SMART global surveillance program (2009, n = 993; 2011, n = 1702; 2015, n = 5953; 2016, n = 6165), imipenem susceptibility rates were 68.4% in 2009, 67.4% in 2011, 70.4% in 2015, and 67.3% in 2016. With the addition of 4 μg/mL relebactam, imipenem susceptibility rates increased to 87.6, 86.0, 91.7, and 89.8%, respectively. When all imipenem-non-susceptible isolates were pooled, the addition of 4 μg/mL relebactam reduced the mode imipenem minimum inhibitory concentration (MIC) 8-fold (from 16 μg/mL to 2 μg/mL) among all imipenem-non-susceptible isolates. Of 3747 imipenem-non-susceptible isolates that underwent molecular profiling, 1200 (32%) remained non-susceptible to the combination imipenem/relebactam (IMI/REL); 42% of these encoded class B metallo-β-lactamases, 11% encoded a class A GES enzyme, and no class D enzymes were detected. No relationship was observed between alleles of the chromosomally-encoded P. aeruginosa AmpC and IMI/REL MIC.. IMI/REL exhibited potential in the treatment of carbapenem-resistant P. aeruginosa infections, with the exception of isolates encoding class B, some GES alleles, and class D carbapenemases.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamases; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Kinetics; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Relebactam inhibits Ambler class A and C β-lactamases. Imipenem/relebactam has completed one phase 3 clinical study of patients infected with imipenem-non-susceptible Gram-negative bacilli. Two more phase 3 clinical studies are in progress for the treatment of patients with hospital-acquired and ventilator-associated bacterial pneumonia, complicated intra-abdominal infections and complicated urinary tract infections. In the current study, clinical Pseudomonas aeruginosa isolates cultured by medical centre laboratories in seven geographic regions (Africa, Asia, Europe, Latin America, Middle East, USA/Canada, South Pacific) were tested for susceptibility to imipenem/relebactam and comparators.. A total of 12170 isolates collected as part of the 2015-2016 Study for Monitoring Antimicrobial Resistance Trends (SMART) global surveillance program were tested using the Clinical and Laboratory Standards Institute (CLSI)-defined broth microdilution method. Relebactam was tested at a fixed concentration of 4μg/mL in combination with doubling dilutions of imipenem. Imipenem/relebactam MICs were interpreted using current CLSI breakpoints for imipenem.. At the imipenem susceptible breakpoint (≤2μg/mL), imipenem/relebactam inhibited 90.8% of all P. aeruginosa isolates and 70.7% of multidrug-resistant (MDR) isolates (n=3708). Relebactam restored imipenem susceptibility to 70.3% (2656/3776) of imipenem-non-susceptible isolates and increased percent susceptibility to imipenem against isolates with ceftazidime-non-susceptible (by 35.2%), piperacillin/tazobactam-non-susceptible (by 36.6%), cefepime-non-susceptible (by 36.8%) and MDR (by 41.9%) phenotypes. Across the seven geographic regions studied, susceptibility to imipenem/relebactam ranged from 84.0% (Latin America) to 96.0% (South Pacific).. Imipenem/relebactam could provide an important treatment option against infections with P. aeruginosa isolates that are non-susceptible to several currently available antipseudomonal β-lactams.

Topics: Africa; Anti-Bacterial Agents; Asia; Azabicyclo Compounds; Europe; Humans; Imipenem; Microbial Sensitivity Tests; Middle East; North America; Phenotype; Pseudomonas aeruginosa; Pseudomonas Infections; Public Health Surveillance

There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here we assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also discuss the potential clinical application of chemical inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymatic inhibitors, such as the derivatives of the β-lactamase inhibitor avibactam, are closer to the clinic than other molecules. For example, MK-7655, in combination with imipenem, is in clinical development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addition, other molecules targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections.

Topics: Azabicyclo Compounds; beta-Lactamase Inhibitors; Drug Resistance, Microbial; Enterobacteriaceae Infections; Humans; Imipenem; Pseudomonas Infections

The β-lactamase inhibitor relebactam inactivates class A β-lactamases, including KPC-type carbapenemases, and class C β-lactamases. Relebactam combined with imipenem is in clinical development for several indications, including hospital-acquired and ventilator-associated pneumonia. Employing CLSI-defined broth microdilution methodology, we evaluated the activities of imipenem-relebactam (using imipenem MIC breakpoints) and comparators against non-Proteeae Enterobacteriaceae (n=853) and Pseudomonas aeruginosa (n=598) isolated from lower respiratory tract infection samples in 20 hospital laboratories in the United States participating in the 2015 SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance program. Imipenem-relebactam and imipenem susceptibilities were 97.2% and 91.6% for non-Proteeae Enterobacteriaceae and 93.1% and 68.1% for P. aeruginosa. Relebactam restored imipenem susceptibility to 66.7% and 78.5% of imipenem-non-susceptible non-Proteeae Enterobacteriaceae isolates (n=72) and P. aeruginosa (n=191), respectively. Further development of imipenem-relebactam as therapy for lower respiratory tract infections is warranted given relebactam's ability to restore activity to imipenem against non-susceptible non-Proteeae Enterobacteriaceae and P. aeruginosa.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Drug Therapy, Combination; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Imipenem; Microbial Sensitivity Tests; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Pseudomonas Infections; United States