Meropenem-Vaborbactam as Salvage Therapy for Ceftazidime-Avibactam-Resistant Klebsiella pneumoniae Bacteremia and Abscess in a Liver Transplant Recipient.
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ABSTRACT:
SUBMITTER: Athans V
PROVIDER: S-EPMC6325210 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In February 2022, a critically ill patient colonized with a carbapenem-resistant K. pneumoniae producing KPC-3 and VIM-1 carbapenemases was hospitalized for SARS-CoV-2 in the intensive care unit of Policlinico Umberto I hospital in Rome, Italy. During 95 days of hospitalization, ceftazidime/avibactam, meropenem/vaborbactam, and cefiderocol were administered consecutively to treat 3 respiratory tract infections sustained by different bacterial agents. Those therapies altered the resistome of K. pneumoniae sequence type 512 colonizing or infecting the patient during the hospitalization period. In vivo evolution of the K. pneumoniae sequence type 512 resistome occurred through plasmid loss, outer membrane porin alteration, and a nonsense mutation in the cirA siderophore gene, resulting in high levels of cefiderocol resistance. Cross-selection can occur between K. pneumoniae and treatments prescribed for other infective agents. K. pneumoniae can stably colonize a patient, and antimicrobial-selective pressure can promote progressive K. pneumoniae resistome evolution, indicating a substantial public health threat.
| S-EPMC10617348 | biostudies-literature
Project description:ObjectivesHerein, we describe the epidemiology of carbapenemase-producing Enterobacterales (CPE) before and during the COVID-19 pandemic. Also, we report the emergence of an outbreak of Klebsiella pneumoniae strains co-producing KPC and OXA-181 carbapenemase, resistant to novel β-lactam/β-lactamase inhibitors (βL-βLICs) and cefiderocol.MethodsCPE were collected during a period of 3 years from 2019 to 2021. Antimicrobial susceptibility testing for novel βL-βLICs and cefiderocol was performed by MIC test strips and microdilution with iron-depleted broth. WGS was performed on 10 selected isolates using the Illumina platform, and resistome analysis was carried out by a web-based pipeline.ResultsBetween January 2019 and December 2021, we collected 1430 carbapenemase producers from 957 patients with infections due to CPE. KPC was the most common carbapenemase, followed by VIM, OXA-48 and NDM. During 2021, we identified 78 K. pneumoniae co-producing KPC and OXA-181 carbapenemases in 60 patients, resistant to meropenem/vaborbactam and imipenem/relebactam. Resistance to ceftazidime/avibactam and cefiderocol was observed respectively in 7 and 8 out of the 10 sequenced K. pneumoniae. Genome analysis showed that all isolates were clonally related, shared a common porin and plasmid content, and carried blaOXA-181 and blaKPC carbapenemases. Specifically, 4 out of 10 isolates carried blaKPC-3, while 6 harboured mutated blaKPC. Of note, KPC producers resistant to ceftazidime/avibactam and harbouring mutated blaKPC exhibited higher MICs of cefiderocol (median MIC 16 mg/L, IQR 16-16) than strains harbouring WT blaKPC-3 (cefiderocol 9 mg/L, IQR 1.5-16).ConclusionsOur results highlight the need for continuous monitoring of CPE to limit widespread MDR pathogens carrying multiple mechanisms conferring resistance to novel antimicrobial molecules.
| S-EPMC10433922 | biostudies-literature
Project description:We identified a novel ceftazidime/avibactam resistance mechanism in sequence type 11 Klebsiella pneumoniae carbapenemase 2-producing K. pneumoniae. Plasmid recombination and chromosomal integration formed a novel virulence plasmid and provided an additional promoter for blaSHV-12, leading to blaSHV-12 overexpression and ceftazidime/avibactam resistance. Genetic rearrangement contributed to convergence of hypervirulence and ceftazidime/avibactam resistance.
| S-EPMC10617341 | biostudies-literature
Project description:From January 2019 to April 2020, 32 KPC-producing, ceftazidime-avibactam (CZA)-resistant Klebsiella pneumoniae strains were isolated in a university hospital in Rome, Italy. These strains belonged to the sequence type 512 (ST512), ST101, and ST307 high-risk clones. Nine different CZA-resistant KPC-3 protein variants were identified, five of them never previously reported (KPC-66 to KPC-70). Among the nine, KPC-31, KPC-39, KPC-49, KPC-66, KP-68, KPC-69, and KPC-70 showed amino acid substitutions, insertions, and deletions in the Ω loop of the protein. KPC-29 has a duplication, while the novel KPC-67 has a triplication, of the KDD triplet in the 270-loop, a secondary loop of the KPC-3 protein. Genomics performed on contemporary resistant and susceptible clones underlined that these novel mutations emerged in blaKPC-3 genes located on conserved plasmids: in ST512, all blaKPC-3 mutant genes were located in pKpQIL plasmids, while the three novel blaKPC-3 mutants identified in ST101 were on FIIk-FIA(HI1)-R plasmids. Selection also promoted multiplication of the carbapenemase gene copy number by transposition, recombination, and fusion of resident plasmids. When expressed in Escherichia coli recipient cells cloned in the high-copy-number pTOPO vector, the Ω loop mutated variants showed the CZA-resistant phenotype associated with susceptibility to carbapenems, while KPC variants with insertions in the 270-loop showed residual activity on carbapenems. The investigation of CZA resistance mechanisms offered the unique opportunity to study vertical, horizontal, and oblique evolutionary trajectories of K. pneumoniae high-risk clones.
| S-EPMC8448114 | biostudies-literature
Project description:ObjectivesTo investigate the increase in the rates of OXA-48-like-producing isolates during 3 years of global surveillance.MethodsAmong 55?>162 Enterobacterales isolates, 354 carbapenem-resistant isolates carried genes encoding OXA-48-like enzymes. Isolates were susceptibility tested for ceftazidime/avibactam and comparators by broth microdilution methods. Analysis of β-lactam resistance mechanisms and MLST was performed in silico using WGS data.ResultsOXA-48-like-producing isolates increased from 0.5% (94/18 656) in 2016 to 0.9% (169/18?>808) in 2018. OXA-48 was the most common variant; isolates primarily were Klebsiella pneumoniae (318/354 isolates) from Europe and adjacent countries. MLST analysis revealed a diversity of STs, but K. pneumoniae belonging to ST395, ST23 and ST11 were observed most frequently. Thirty-nine isolates harboured MBLs and were resistant to most agents tested. The presence of blaCTX-M-15 (258 isolates), OmpK35 nonsense mutations (232) and OmpK36 alterations (316) was common among OXA-48 producers. Ceftazidime, cefepime and aztreonam susceptibility rates, when applying CLSI breakpoints, were 12%-15% lower for isolates carrying ESBLs alone and with either or both OmpK35 stop codons and OmpK36 alterations. Meropenem and, remarkably, meropenem/vaborbactam were affected by specific OmpK36 alterations when a deleterious mutation also was observed in OmpK35. These mechanisms caused a decrease of 12%-42% in the susceptibility rates for meropenem and meropenem/vaborbactam. Ceftazidime/avibactam susceptibility rates were >98.9%, regardless of the presence of additional β-lactam resistance mechanisms.ConclusionsGuidelines for the treatment of infections caused by OXA-48-producing isolates are scarce and, as the dissemination of these isolates continues, studies are needed to help physicians understand treatment options for these infections.
| S-EPMC8598286 | biostudies-literature
Project description:Carbapenem-resistant Enterobacterales, such as Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae, represent a major threat to public health due to their rapid spread. Novel drug combinations such as ceftazidime-avibactam (CZA), combining a broad-spectrum cephalosporin along with a broad-spectrum β-lactamase inhibitor, have recently been introduced and have been shown to exhibit excellent activity toward multidrug-resistant KPC-producing Enterobacterales strains. However, CZA-resistant K. pneumoniae isolates are now being increasingly reported, mostly corresponding to producers of KPC variants. In this study, we evaluated in vitro the nature of the mutations in the KPC-2 and KPC-3 β-lactamase sequences (the most frequent KPC-type enzymes) that lead to CZA resistance and the subsequent effects of these mutations on susceptibility to other β-lactam antibiotics. Single-step in vitro selection assays were conducted, resulting in the identification of a series of mutations in the KPC sequence which conferred the ability of those mutated enzymes to confer resistance to CZA. Hence, 16 KPC-2 variants and 10 KPC-3 variants were obtained. Production of the KPC variants in an Escherichia coli recombinant strain resulted in a concomitant increased susceptibility to broad-spectrum cephalosporins and carbapenems, with the exceptions of ceftazidime and piperacillin-tazobactam, compared to wild-type KPC enzymes. Enzymatic assays showed that all of the KPC variants identified exhibited an increased affinity toward ceftazidime and a slightly decreased sensitivity to avibactam, sustaining their impact on CZA resistance. However, their respective carbapenemase activities were concurrently negatively impacted.
| S-EPMC8370223 | biostudies-literature
Project description:Vaborbactam (formerly RPX7009) is a new ?-lactamase inhibitor based on a cyclic boronic acid pharmacophore with potent inhibitory activity against Klebsiella pneumoniaecarbapenemases (KPC). It has been developed in combination with meropenem. The objective of these studies was to identify the concentrations of both agents associated with the selection or prevention of single-step mutations leading to reduced sensitivity to the combination and to characterize the selected mutations. Eighteen strains of KPC-producing Klebsiella pneumoniae with various degrees of sensitivity to meropenem (MICs, 8 to 512 ?g/ml) and meropenem-vaborbactam (MICs, ?0.06 to 32 ?g/ml) and preexisting resistance mechanisms were selected from a worldwide collection of isolates recovered from surveillance studies, emphasizing strains for which MICs were in the upper range of the meropenem-vaborbactam MIC distribution. Meropenem and vaborbactam at 8 ?g/ml each suppressed the drug resistance mutation frequency to <1 × 10-8 in 77.8% (14/18) of strains, and all strains were inhibited when the meropenem concentration was increased to 16 ?g/ml. Mutants selected at lower drug concentrations showed phenotypes associated with previously described carbapenem resistance mechanisms, including ompK36 inactivation in mutants selected from OmpK36-proficient strains and an increased blaKPC gene copy number in strains with partially functional ompK36 No mutations in the coding region of blaKPC were identified. These data indicate that the selection of mutants with reduced sensitivity to meropenem-vaborbactam from KPC-producing Klebsiella pneumoniae strains is associated with previously described mechanisms involving porin mutations and the increase in the blaKPC gene copy number and not changes in the KPC enzyme and can be prevented by the drug concentrations achieved with optimal dosing of the combination.
| S-EPMC5700310 | biostudies-literature
Project description:Objective: Metallo-β-lactamase (MBL)-producing Enterobacteriaceae, particularly those that co-harbor serine β-lactamases, are a serious emerging public health threat given their rapid dissemination and the limited number of treatment options. Pre-clinical and anecdotal clinical data support the use of aztreonam in combination with ceftazidime-avibactam against these pathogens, but other aztreonam-based combinations have not been explored. The objective of this study was to evaluate the in vitro activity and compare synergy between aztreonam in combination with ceftazidime-avibactam and meropenem-vaborbactam against serine and MBL-producing Enterobacteriaceae via time-kill analyses. Methods: 8 clinical Enterobacteriaceae strains (4 Escherichia coli and 4 Klebsiella pneumoniae) co-producing NDM and at least one serine β-lactamase were used for all experiments. Drugs were tested alone, in dual β-lactam combinations, and in triple drug combinations against all strains. Results: All strains were resistant to ceftazidime-avibactam and meropenem-vaborbactam and 7/8 (87.5%) strains were resistant to aztreonam. Aztreonam combined with ceftazidime-avibactam was synergistic against all 7 aztreonam-resistant strains. Aztreonam combined with meropenem-vaborbactam was synergistic against all aztreonam-resistant strains with the exception of an OXA-232-producing K. pneumoniae strain. Neither triple combination was synergistic against the aztreonam-susceptible strain. Likewise, neither dual β-lactam combination was synergistic against any strain. Conclusions: These data suggest that aztreonam plus meropenem-vaborbactam has similar activity to aztreonam plus ceftazidime-avibactam against Enterobacteriaceae producing NDM and other non-OXA-48-like serine β-lactamases. Confirmation of these findings in future in vitro and in vivo models is warranted.
| S-EPMC6879249 | biostudies-literature
Project description:BackgroundPatients with bacteremia due to carbapenem-resistant Enterobacterales (CRE) experience delays until appropriate therapy and high mortality rates. Rapid molecular diagnostics for carbapenemases and new β-lactam/β-lactamase inhibitors may improve outcomes.MethodsWe conducted an observational study of patients with CRE bacteremia from 2016 to 2018 at 8 New York and New Jersey medical centers and assessed center-specific clinical microbiology practices. We compared time to receipt of active antimicrobial therapy and mortality between patients whose positive blood cultures underwent rapid molecular testing for the Klebsiella pneumoniae carbapenemase (KPC) gene (blaKPC) and patients whose cultures did not undergo this test. CRE isolates underwent antimicrobial susceptibility testing by broth microdilution and carbapenemase profiling by whole-genome sequencing. We also assessed outcomes when ceftazidime-avibactam and polymyxins were used as targeted therapies.ResultsOf 137 patients with CRE bacteremia, 89 (65%) had a KPC-producing organism. Patients whose blood cultures underwent blaKPC PCR testing (n = 51) had shorter time until receipt of active therapy (median: 24 vs 50 hours; P = .009) compared with other patients (n = 86) and decreased 14-day (16% vs 37%; P = .007) and 30-day (24% vs 47%; P = .007) mortality. blaKPC PCR testing was associated with decreased 30-day mortality (adjusted odds ratio: .37; 95% CI: .16-.84) in an adjusted model. The 30-day mortality rate was 10% with ceftazidime-avibactam monotherapy and 31% with polymyxin monotherapy (P = .08).ConclusionsIn a KPC-endemic area, blaKPC PCR testing of positive blood cultures was associated with decreased time until appropriate therapy and decreased mortality for CRE bacteremia, and ceftazidime-avibactam is a reasonable first-line therapy for these infections.
| S-EPMC10200298 | biostudies-literature
Project description:We report patient-to-patient transmission of Enterobacter hormaechei isolates with reduced susceptibility to ceftazidime-avibactam due to production of KPC-40, a variant of KPC-3 with a two-amino-acid insertion in the ?-loop region (L167_E168dup). The index patient had received a prolonged course of ceftazidime-avibactam therapy, whereas the second patient had not received the agent and still became colonized with the KPC-40-producing strain. The complex dynamics of KPC (Klebsiella pneumoniae carbapenemase) described here highlight several key diagnostic and therapeutic considerations.
| S-EPMC6761506 | biostudies-literature