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Suboptimal Concentrations of Ceftazidime/Avibactam (CAZ-AVI) May Select for CAZ-AVI Resistance in Extensively Drug-Resistant Pseudomonas aeruginosa: In Vivo and In Vitro Evidence.

ABSTRACT: This study correlates in vivo findings in a patient with an extensively drug-resistant (XDR) P. aeruginosa infection who developed resistance to ceftazidime-avibactam (CAZ-AVI) with in vitro results of a 7-day hollow-fiber infection model (HFIM) testing the same bacterial strain. The patient was critically ill with ventilator-associated pneumonia caused by XDR P. aeruginosa ST175 with CAZ-AVI MIC of 6 mg/L and was treated with CAZ-AVI in continuous infusion at doses adjusted for renal function. Plasma concentrations of CAZ-AVI were analyzed on days 3, 7, and 10. In the HIFM, the efficacy of different steady-state concentrations (Css) of CAZ-AVI (12, 18, 30 and 48 mg/L) was evaluated. In both models, a correlation was observed between the decreasing plasma levels of CAZ-AVI and the emergence of resistance. In the HIFM, a Css of 30 and 48 mg/L (corresponding to 5× and 8× MIC) had a bactericidal effect without selecting resistant mutants, whereas a Css of 12 and 18 mg/L (corresponding to 2× and 3× MIC) failed to prevent the emergence of resistance. CAZ/AVI resistance development was caused by the selection of a single ampC mutation in both patient and HFIM. Until further data are available, strategies to achieve plasma CAZ-AVI levels at least 4× MIC could be of interest, particularly in severe and high-inoculum infections caused by XDR P. aeruginosa with high CAZ-AVI MICs.

SUBMITTER: Lopez-Montesinos I

PROVIDER: S-EPMC9686790 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Suboptimal Concentrations of Ceftazidime/Avibactam (CAZ-AVI) May Select for CAZ-AVI Resistance in Extensively Drug-Resistant Pseudomonas aeruginosa: In Vivo and In Vitro Evidence.

Lopez-Montesinos Inmaculada I Montero María Milagro MM Domene-Ochoa Sandra S López-Causapé Carla C Echeverria Daniel D Sorlí Luisa L Campillo Nuria N Luque Sonia S Padilla Eduardo E Prim Nuria N Grau Santiago S Oliver Antonio A Horcajada Juan P JP

Antibiotics (Basel, Switzerland) 20221022 11

This study correlates in vivo findings in a patient with an extensively drug-resistant (XDR) P. aeruginosa infection who developed resistance to ceftazidime-avibactam (CAZ-AVI) with in vitro results of a 7-day hollow-fiber infection model (HFIM) testing the same bacterial strain. The patient was critically ill with ventilator-associated pneumonia caused by XDR P. aeruginosa ST175 with CAZ-AVI MIC of 6 mg/L and was treated with CAZ-AVI in continuous infusion at doses adjusted for re ...[more]

PMID: 36358110

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Project description:Extensively drug-resistant Pseudomonas aeruginosa (XDRPA) infection is a significant public health threat due to a lack of effective therapeutic options. New β-lactam-β-lactamase inhibitor combinations, including ceftazidime-avibactam (CZA), have shown a high resistance rate to XDRPA. This study was therefore conducted to describe the underlying genomic mechanism of resistance for CZA nonsusceptible XDRPA strains that are non-metallo-β-lactamase (MBL) producers as well as to examine synergism of CZA and other antipseudomonal agents. Furthermore, the synergistic antibacterial activity of the most effective antimicrobial combination against non-MBL-producing XDRPA was evaluated through in vitro experiments. The resistance profiles of 15 CZA-resistant XDRPA strains isolated from clinical specimens in China-Japan Friendship Hospital between January 2017 to December 2020 were obtained by whole-genome sequencing (WGS) analysis. MBL genes blaIMP-1 and blaIMP-45 were found in 2 isolates (2/15, 13.3%); the other underlying CZA-resistance mechanisms involved the decreased OprD porin (13/13), blaAmpC overexpression (8/13) or mutation (13/13), and upregulated efflux pumps (13/13). CZA-imipenem (CZA-IPM) combination was identified to be the most effective against non-MBL-producing XDRPA according to the results of WGS analysis and combined antimicrobial susceptibility tests, with an approximately 16.62-fold reduction in MICs compared to CZA alone. Furthermore, the results of checkerboard analysis and growth curve displayed the synergistic antimicrobial activity of CZA and IPM against non-MBL-producing XDRPA. Electron microscopy also revealed that CZA-IPM combination might lead to more cellular structural alterations than CZA or IPM alone. This study suggested that the CZA-IPM combination has potential for non-MBL-producing XDRPA with blaAmpC overexpression or mutation, decreased OprD porin, and upregulated efflux pumps. IMPORTANCE Handling the infections by extensively drug-resistant Pseudomonas aeruginosa (XDRPA) strains is challenging due to their complicated antibiotic resistance mechanisms in immunosuppressed patients with pulmonary diseases (e.g., cystic fibrosis, chronic obstructive pulmonary disease, and lung transplant), ventilator-associated pneumonia, and bloodstream infections. The current study suggested the potentiality of the ceftazidime-avibactam-imipenem combination against XDRPA with blaAmpC overexpression or mutation, decreased OprD porin, and/or upregulated efflux pumps. Our findings indicate the necessity of combined drug sensitivity tests against XDRPA and also lay a foundation for the development of prevention, control, and treatment strategies in XDRPA infections.

Project description:Klebsiella pneumoniae carbapenemase (KPC)-producing Pseudomonas aeruginosa (KPC-PA) has been reported sporadically. However, epidemiological and antimicrobial susceptibility data specific for KPC-PA are lacking. We collected 374 carbapenem-resistant P. aeruginosa (CRPA) isolates from seven hospitals in China from June 2016 to February 2019 and identified the blaKPC-2 gene in 40.4% (n = 151/374) of the isolates. Approximately one-half of all KPC-PA isolates (n = 76/151; 50.3%) were resistant to ceftazidime-avibactam (CAZ-AVI). Combining Kraken2 taxonomy identification and Nanopore sequencing, we identified eight plasmid types, five of which carried blaKPC-2, and 13 combination patterns of these plasmid types. In addition, we identified IS26-ΔTn6296 and Tn1403-like-ΔTn6296 as the two mobile genetic elements that mediated blaKPC-2 transmission. blaKPC-2 plasmid curing in 28 strains restored CAZ-AVI susceptibility, suggesting that blaKPC-2 was the mediator of CAZ-AVI resistance. Furthermore, the blaKPC-2 copy number was found to correlate with KPC expression and, therefore, CAZ-AVI resistance. Taken together, our results suggest that KPC-PA is becoming a clinical threat and that using CAZ-AVI to treat this specific pathogen should be done with caution. IMPORTANCE Previous research has reported several cases of KPC-PA strains and three KPC-encoding P. aeruginosa plasmid types in China. However, the prevalence and clinical significance of KPC-PA are not available. In addition, the susceptibility of the strains to CAZ-AVI remains unknown. Samples in this study were collected from seven tertiary hospitals prior to CAZ-AVI clinical approval in China. Therefore, our results represent a retrospective study establishing the baseline efficacy of the novel β-lactam/β-lactamase combination agent for treating KPC-PA infections. The observed correlation between the blaKPC copy number and CAZ-AVI resistance suggests that close monitoring of the susceptibility of the strain during treatment is required. It would also be beneficial to screen for the blaKPC gene in CRPA strains for antimicrobial surveillance purposes.

Project description:Ceftazidime-avibactam (CZA) is currently one of the last resorts used to treat infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa. However, KPC variants have become the main mechanism mediating CZA resistance in KPC-producing gram-negative bacteria after increasing the application of CZA. Our previous study revealed that CZA-resistant KPC-33 had emerged in carbapenem-resistant P. aeruginosa (CRPA) and had resulted in death due to hypervirulence and extensive drug resistance; however, the evolutionary path of KPC-33-producing CRPA has not been investigated. Here, we observed the emergence of blaKPC-33 in CRPA under drug pressure, leading to resistance to CZA. We further elucidated the pathway of resistance development due to blaKPC mutations in P. aeruginosa. Three KPC-producing P. aeruginosa (KPC-PA) strains (including one blaKPC-33-positive strain and two blaKPC-2-positive strains) were successively isolated from a hospitalized patient. The blaKPC-33-positive CZA-resistant strain SRPA0656 (CZA MIC >128 μg/mL, imipenem MIC = 32 μg/mL) was isolated after the blaKPC-2-positive P. aeruginosa SRP2863 (CZA MIC = 1 μg/mL, imipenem MIC >128 μg/mL) was treated with CZA. The subsequent use of carbapenems to treat the infection led to the re-emergence of the KPC-2-producing strain SRPA3703. Additionally, we collected four other KPC-33-producing P. aeruginosa strains. Antimicrobial susceptibility testing revealed that all the KPC-33-bearing P. aeruginosa strains in this study were multidrug-resistant but susceptible to colistin and amikacin. Whole-genome sequencing indicated that blaKPC-33 was located on two Tn4401-like transposons contained in the plasmids and that most of these plasmids could be transferred into P. aeruginosa PAO1Rif isolates. Growth rate determination demonstrated that the relative growth rate of P. aeruginosa harboring blaKPC-33 was faster than that of P. aeruginosa harboring blaKPC-2 in the logarithmic phase. Global phylogenetic analysis revealed that most KPC-PA strains were isolated from China and the USA. MLST revealed that the most common ST in KPC-PA was ST463, which was detected only in China, and that all the strains carried blaKPC-2 or its derivatives. These results indicated that the use of CZA for the treatment of KPC-2-producing P. aeruginosa may have contributed to the evolution of KPC-33. The widespread dissemination of KPC-PA (especially the ST463) and Tn4401 transposons may increase the spread of CRPA isolates carrying blaKPC-33. Close attention to the development of resistance to CZA during clinical treatment of CRPA infection and monitoring CZA-resistant strains is necessary to prevent further spread.

Dataset Information

Suboptimal Concentrations of Ceftazidime/Avibactam (CAZ-AVI) May Select for CAZ-AVI Resistance in Extensively Drug-Resistant Pseudomonas aeruginosa: In Vivo and In Vitro Evidence.

Publications

Suboptimal Concentrations of Ceftazidime/Avibactam (CAZ-AVI) May Select for CAZ-AVI Resistance in Extensively Drug-Resistant <i>Pseudomonas aeruginosa</i>: In Vivo and In Vitro Evidence.

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