fr-264205 and avibactam

Post-neurosurgical infection caused by extensively drug resistant Pseudomonas aeruginosa (XDR-PA) are becoming a matter of great concern due to limited therapeutic options. Although not approved for these indications, the new BetaLactam-BetaLactamase Inhibitor combinations (BLBLIs) could represent a valid salvage treatment. We describe one nosocomial meningitis and two cervical osteomyelitis due to an XDR-PA who were treated with ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (C/T) and review the literature.. The first and the third patients developed an osteomyelitis following cervical stabilization surgery due to an XDR-PA. Although the first patient started treatment with a high dose of C/T, resistance to C/T occurred, so therapy was switched to CZA plus aztreonam. The third patient switched to aztreonam plus CZA due to development of acute kidney injury during therapy with colistin. The second patient had an XDR-PA meningitis following the insertion of an external ventricular catheter and he was treated with C/T plus meropenem and amikacin.. All three cases reported were successfully conservatively treated thanks to the use of the new BLBLIs with different combinations. Only few experiences demonstrated an equally favorable outcome: one patient treated with C/T plus fosfomycin for otogenic meningitis caused by an XDR-PA and another case of XDR-PA post-surgical meningitis with CZA in combination with colistin. Finally, the combination of CZA plus aztreonam has proven to be effective on XDR-PA only in limited mostly in vitro studies.. These recently developed antibiotics, C/T and CZA are promising and complementary therapy options against post-neurosurgical hard-to-treat P. aeruginosa infections. Further prospective real-life studies are required to validate these findings in this special setting.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Cephalosporins; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Male; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Ceftolozane/tazobactam and ceftazidime/avibactam are 2 novel β-lactam/β-lactamase combination antibiotics. The antimicrobial spectrum of activity of these antibiotics includes multidrug-resistant (MDR) gram-negative bacteria (GNB), including Pseudomonas aeruginosa. Ceftazidime/avibactam is also active against carbapenem-resistant Enterobacteriaceae that produce Klebsiella pneumoniae carbapenemases. However, avibactam does not inactivate metallo-β-lactamases such as New Delhi metallo-β-lactamases. Both ceftolozane/tazobactam and ceftazidime/avibactam are only available as intravenous formulations and are dosed 3 times daily in patients with normal renal function. Clinical trials showed noninferiority to comparators of both agents when used in the treatment of complicated urinary tract infections and complicated intra-abdominal infections (when used with metronidazole). Results from pneumonia studies have not yet been reported. In summary, ceftolozane/tazobactam and ceftazidime/avibactam are 2 new second-generation cephalosporin/β-lactamase inhibitor combinations. After appropriate trials are conducted, they may prove useful in the treatment of MDR GNB infections. Antimicrobial stewardship will be essential to preserve the activity of these agents.

Topics: Azabicyclo Compounds; beta-Lactamase Inhibitors; Ceftazidime; Cephalosporins; Drug Therapy, Combination; Humans

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

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Ceftazidime; Cephalosporins; Drug Combinations; Humans; Leadership; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Treatment options are limited for melioidosis patients who develop nosocomial infections due to extensively drug-resistant (XDR) Gram-negative bacilli. Ceftolozane/tazobactam (C/T) and ceftazidime/avibactam (CZA), which have activity against XDR Gram-negative bacteria, are two potential options. Data regarding the susceptibility of Burkholderia pseudomallei to these agents are limited, especially from Thailand, which is an endemic area for melioidosis.. A total of 28 B. pseudomallei isolates from melioidosis patients in northeast Thailand were tested for susceptibility to C/T and CZA by Etest and the disk diffusion method. Minimum inhibitory concentrations (MICs) for other antibiotics commonly used in melioidosis, including trimethoprim/sulfamethoxazole (SXT), ceftazidime (CAZ), imipenem (IPM) and meropenem, were also determined.. The MIC of C/T was very low for all isolates, ranging from 0.75 μg/mL to 1.0 μg/mL. For CZA, wide inhibitory zones ranging from 34-35 mm and MICs at 0.5 μg/mL were found. All isolates were also susceptible to SXT, CAZ and IPM based on Clinical and Laboratory Standards Institute (CLSI) breakpoints.. C/T and CZA exhibited excellent in vitro activity against B. pseudomallei. Further studies are required to prove efficacy in human subjects.

Topics: Azabicyclo Compounds; Burkholderia pseudomallei; Ceftazidime; Cephalosporins; Humans; Melioidosis; Pseudomonas aeruginosa; Tazobactam; Thailand

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

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

Topics: Anti-Bacterial Agents; Ceftazidime; Cephalosporins; Child; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Hematologic Neoplasms; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Tazobactam

To evaluate the genotypic and ceftazidime/avibactam-susceptibility profiles amongst ceftolozane/tazobactam-non-susceptible (NS), MBL-negative Pseudomonas aeruginosa in a global surveillance programme.. Isolates were collected as part of the ERACE-PA Global Surveillance programme. Carbapenem-resistant P. aeruginosa deemed clinically relevant by the submitting laboratories were included. Broth microdilution MICs were conducted per CLSI standards to ceftolozane/tazobactam, ceftazidime/avibactam, ceftazidime and cefepime. Genotypic carbapenemases were detected using CarbaR and CarbaR NxG (research use only). Isolates negative for carbapenemases by PCR were assessed via WGS. Isolates were included in the analysis if they were ceftolozane/tazobactam-NS and lacked detection of known MBLs.. Of the 807 isolates collected in the ERACE-PA programme, 126 (16%) were ceftolozane/tazobactam-NS and lacked MBLs. Cross-resistance to ceftazidime and cefepime was common, with only 5% and 16% testing susceptible, respectively. Ceftazidime/avibactam retained in vitro activity, with 65% of isolates testing susceptible. GES was the most common enzymology, detected in 57 (45%) isolates, and 89% remained susceptible to ceftazidime/avibactam. Seven isolates harboured KPC and all tested susceptible to ceftazidime/avibactam. In the remaining 62 isolates, WGS revealed various ESBLs or OXA β-lactamases. While 39% remained susceptible to ceftazidime/avibactam, marked variability was observed among the diverse resistance mechanisms.. Ceftazidime/avibactam remained active in vitro against the majority of ceftolozane/tazobactam-NS, MBL-negative P. aeruginosa. Ceftazidime/avibactam was highly active against isolates harbouring GES and KPC β-lactamases. These data highlight the potential clinical utility of genotypic profiling as well as the need to test multiple novel agents when carbapenem-resistant P. aeruginosa are encountered.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Carbapenems; Cefepime; Ceftazidime; Cephalosporins; Drug Combinations; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Historically, multi-drug resistant organisms have been associated with the ICU setting. The present study sought to define the frequency of isolation from ICU versus non-ICU, phenotypic and genotypic profiles of carbapenem-resistant Pseudomonas aeruginosa (CR-PA) from a global cohort.. Multicenter surveillance study (17 centers from 12 countries) including 672 CR-PA isolates from 2019 to 2021. Phenotypic carbapenemase testing was assessed. Genotypic carbapenemase testing was conducted (CarbaR and CarbaR NxG) to detect β-lactamases. Broth microdilution MICs were established for ceftazidime, cefepime, ceftolozane/tazobactam, and ceftazidime/avibactam.. 59% of CR-PA were isolated from patients outside the ICU. The most common source in ICU and non-ICU patients was respiratory (55% and 30%, respectively). In the ICU, 35% of isolates were phenotypically carbapenemase-positive versus 29% for non-ICU. VIM was the most common carbapenemase (54% and 44%, respectively) followed by GES (27% and 28%, respectively). Susceptibility to ceftazidime or cefepime were relatively low in ICU (39% and 41% of isolates, respectively) and non-ICU (47% and 52% of isolates, respectively). Ceftolozane/tazobactam and ceftazidime/avibactam were more active with 56% and 66% of isolates susceptible in the ICU while 65% and 76% in non-ICU, respectively. When carbapenemase-negative, 86% and 88% of ICU isolates were susceptible to ceftolozane/tazobactam and ceftazidime/avibactam. Similarly, in the carbapenemase-negative, non-ICU isolates 88% and 92% of isolates were susceptible, respectively.. Although multidrug resistant pathogens are often regarded as a challenge in the ICU population, the majority of CR-PA were isolated from non-ICU patients. Implementing phenotypic/genotypic testing will assist in guiding treatment. Carbapenem-resistance in P. aeruginosa should be regarded as a surrogate for MDR and this phenotype is increasingly prevalent outside the ICU.

Topics: Carbapenems; Cefepime; Ceftazidime; Phenotype; Pseudomonas aeruginosa; 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

The development of resistance to ceftolozane/tazobactam and ceftazidime/avibactam during treatment of Pseudomonas aeruginosa infections is concerning.. Characterization of the mechanisms leading to the development of OXA-10-mediated resistance to ceftolozane/tazobactam and ceftazidime/avibactam during treatment of XDR P. aeruginosa infections.. Four paired ceftolozane/tazobactam- and ceftazidime/avibactam-susceptible/resistant isolates were evaluated. MICs were determined by broth microdilution. STs, resistance mechanisms and genetic context of β-lactamases were determined by genotypic methods, including WGS. The OXA-10 variants were cloned in PAO1 to assess their impact on resistance. Models for the OXA-10 derivatives were constructed to evaluate the structural impact of the amino acid changes.. The same XDR ST253 P. aeruginosa clone was detected in all four cases evaluated. All initial isolates showed OprD deficiency, produced an OXA-10 enzyme and were susceptible to ceftazidime, ceftolozane/tazobactam, ceftazidime/avibactam and colistin. During treatment, the isolates developed resistance to all cephalosporins. Comparative genomic analysis revealed that the evolved resistant isolates had acquired mutations in the OXA-10 enzyme: OXA-14 (Gly157Asp), OXA-794 (Trp154Cys), OXA-795 (ΔPhe153-Trp154) and OXA-824 (Asn143Lys). PAO1 transformants producing the evolved OXA-10 derivatives showed enhanced ceftolozane/tazobactam and ceftazidime/avibactam resistance but decreased meropenem MICs in a PAO1 background. Imipenem/relebactam retained activity against all strains. Homology models revealed important changes in regions adjacent to the active site of the OXA-10 enzyme. The blaOXA-10 gene was plasmid borne and acquired due to transposition of Tn6746 in the pHUPM plasmid scaffold.. Modification of OXA-10 is a mechanism involved in the in vivo acquisition of resistance to cephalosporin/β-lactamase inhibitor combinations in P. aeruginosa.

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

Ceftazidime/avibactam (C/A) and ceftolozane/tazobactam (C/T) are two novel antibacterials with known efficacy against Gram-negative bacteria (GNB). We aimed to describe the efficacy and safety of surgical management combined with C/A or C/T treatment for bone and joint infections (BJIs).. We conducted an observational, bicentric study of patients treated with C/A or C/T for a BJI between May 2016 and June 2019. Failure was defined as the need for unplanned additional antibiotic treatment or orthopaedic surgery, or death due to the BJI up to the patient's latest visit.. Overall, 15 patients were included. Nine patients were treated with C/A, mainly for polymicrobial BJI due to multidrug-resistant (MDR) bacteria (Enterobacteriaceae, n = 7). Six patients were male, the median age was 66 years and the median Charlson comorbidity index (CCI) was 5. It was the first septic episode at the site in 3/9 patients. The cure rate was 7/9 (median follow-up, 272 days). Two patients showed C/A-related confusion. Five patients were treated with C/T for BJI involving MDR Pseudomonas aeruginosa. Four patients were male, the median age was 53 years and the median CCI was 2. All patients had previous septic episodes at the infection site. The cure rate was 3/5 (median follow-up, 350 days). One patient was successfully treated by C/T then C/A for multistage spondylodiscitis.. In our experience, C/A and C/T are two effective and safe options, even as salvage treatment for BJI due to MDR-GNB despite the absence of label, however more data are warranted.

Topics: Aged; Azabicyclo Compounds; Ceftazidime; Cephalosporins; Cohort Studies; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Tazobactam

To assess performance of disc diffusion, gradient tests and Vitek 2 system to determine the susceptibility of clinical Pseudomonas aeruginosa strains to ceftolozane/tazobactam (C/T) and ceftazidime/avibactam (CZA).. Two-hundred non-duplicate P. aeruginosa strains isolated by 47 French medical laboratories were selected to cover a wide range of C/T and CZA MICs. Performance of C/T disc (30/10 μg, Bio-Rad), CZA discs (10/4 μg) (Thermo Fisher and Bio-Rad), C/T and CZA gradient tests (Etest, BioMérieux; MIC Test Strip, Liofilchem), and AST-XN12 card of Vitek 2 system (BioMérieux) were compared with a broth microdilution (BMD) method (Thermo Fisher). MIC and disc results were interpreted using current EUCAST breakpoints.. Twenty percent and 17% of strains were resistant to C/T and CZA, respectively. All the methods tested satisfactorily determined the susceptibility of P. aeruginosa to C/T [Category Agreement (CA) ≥95%] except the disc diffusion method. Because of the high rates of Major Errors (MEs) (12.5%), this latter method tends to overestimate the resistance. For CZA, only the gradient tests yielded more than 90% of CA. The Vitek 2 system and disc diffusion misclassified 18.1%, 10.1% (disc Bio-Rad) and 11.9% (disc Thermo Fisher) of susceptible strains, respectively.. The gradient tests (MIC Test Strip and Etest) and Vitek 2 card XN12 performed the best to determine the susceptibility of P. aeruginosa to C/T, whereas gradient tests were an acceptable alternative to BMD to assess CZA susceptibility.

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

A clinical

Topics: Amino Acid Substitution; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Ceftazidime; Cephalosporins; Drug Combinations; Gene Expression; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Topics: Azabicyclo Compounds; Ceftazidime; Cephalosporins; Pathology, Molecular; Pseudomonas aeruginosa; Tazobactam

Topics: Azabicyclo Compounds; Ceftazidime; Cephalosporins; Pathology, Molecular; Pseudomonas aeruginosa; Tazobactam

Topics: Azabicyclo Compounds; Burkholderia cepacia complex; Burkholderia gladioli; Ceftazidime; Cephalosporins; Cystic Fibrosis; Drug Combinations; Humans; Tazobactam