Emergence of Ceftolozane-Tazobactam-Resistant Pseudomonas aeruginosa during Treatment Is Mediated by a Single AmpC Structural Mutation

MacVane, Shawn H.; Pandey, Ramesh C.; Steed, Lisa L.; Kreiswirth, Barry N.; Chen, Liang

doi:10.1128/aac.01183-17

Cited by 75 publications

(51 citation statements)

References 10 publications

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“…One of the 14 mutations shared by all of the CZA-resistant isolates was a nonsynonymous G548A nucleotide substitution in a chromosomal AmpC cephalosporinase gene, bla PDC-5 (44). Importantly, the resulting G183D amino acid substitution has been previously described in PDC beta-lactamases in P. aeruginosa and has been shown to confer resistance to both CZA and C/T (45)(46)(47).…”

Section: Resultsmentioning

confidence: 96%

Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime-Avibactam Resistance in Pseudomonas aeruginosa Acute Infection

Khil

Chiang

et al. 2019

mBio

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Strains of Pseudomonas aeruginosa with deficiencies in DNA mismatch repair have been studied in the context of chronic infection, where elevated mutational rates (“hypermutation”) may facilitate the acquisition of antimicrobial resistance. Whether P. aeruginosa hypermutation can also play an adaptive role in the more dynamic context of acute infection remains unclear. In this work, we demonstrate that evolved mismatch repair deficiencies may be exploited by P. aeruginosa to facilitate rapid acquisition of antimicrobial resistance in acute infection, and we directly document rapid clonal succession by such a hypermutating lineage in a patient. Whole-genome sequencing (WGS) was performed on nine serially cultured blood and respiratory isolates from a patient in whom ceftazidime-avibactam (CZA) resistance emerged in vivo over the course of days. The CZA-resistant clone was differentiated by 14 mutations, including a gain-of-function G183D substitution in the PDC-5 chromosomal AmpC cephalosporinase conferring CZA resistance. This lineage also contained a substitution (R656H) at a conserved position in the ATPase domain of the MutS mismatch repair (MMR) protein, and elevated mutational rates were confirmed by mutational accumulation experiments with WGS of evolved lineages in conjunction with rifampin resistance assays. To test whether MMR-deficient hypermutation could facilitate rapid acquisition of CZA resistance, in vitro adaptive evolution experiments were performed with a mutS-deficient strain. These experiments demonstrated rapid hypermutation-facilitated acquisition of CZA resistance compared with the isogenic wild-type strain. Our results suggest a possibly underappreciated role for evolved MMR deficiency in facilitating rapid adaptive evolution of P. aeruginosa in the context of acute infection. IMPORTANCE Antimicrobial resistance in bacteria represents one of the most consequential problems in modern medicine, and its emergence and spread threaten to compromise central advances in the treatment of infectious diseases. Ceftazidime-avibactam (CZA) belongs to a new class of broad-spectrum beta-lactam/beta-lactamase inhibitor combinations designed to treat infections caused by multidrug-resistant bacteria. Understanding the emergence of resistance to this important new drug class is of critical importance. In this work, we demonstrate that evolved mismatch repair deficiency in P. aeruginosa, an important pathogen responsible for significant morbidity and mortality among hospitalized patients, may facilitate rapid acquisition of resistance to CZA in the context of acute infection. These findings are relevant for both diagnosis and treatment of antimicrobial resistance emerging in acute infection in the hypermutator background and additionally have implications for the emergence of more virulent phenotypes.

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Section: Resultsmentioning

confidence: 96%

Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime-Avibactam Resistance in Pseudomonas aeruginosa Acute Infection

Khil

Chiang

et al. 2019

mBio

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“…It is estimated that by 2050, global deaths due to antimicrobial resistance will balloon to 10 million people per year and become the leading cause of mortality (4). Multiple Gram-negative species are resistant to nearly all available antibiotics (3), including newer combination agents (5, 6). Although multiple drugs in the antibiotic pipeline are promising, there is a prudent need to maximize clinical efficacy and safety of currently available agents (7).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Dose Fractionated Polymyxin B on Acute Kidney Injury: A Translational In Vivo Model

Liu

Pais

Avedissian

et al. 2019

Preprint

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2 0 injury, biomarker, KIM1 2 1 2 2 Acknowledgements: None 2 3 Polymyxin B dose fractionation Abstract 2 4The polymyxins are last-line defense for highly resistant infections. Nephrotoxicity, however, is a dose-limiting 2 5factor. Yet, approaches to mitigate nephrotoxicity are poorly defined. This study aimed to investigate the impact of 2 6 dose fractionated (once, twice and thrice daily) polymyxin B (PB) on acute kidney injury (AKI) in a pre-clinical 2 7model. Secondarily, we aimed to describe the pharmacokinetic (PK) profile of PB. Sprague-Dawley rats were 2 8 assigned to experimental groups with different dosing intervals but constant total daily exposure (12 mg/kg/day into 2 9 single, twice daily, and thrice daily doses) and controls received normal saline subcutaneously over 3 days. Blood 3 0 and urine samples were collected, and kidneys were harvested at necropsy. A three-compartment model best 3 1 described the data and Bayesian observed vs. predicted concentration demonstrated bias, imprecision, and R 2 of 3 2 0.129 mg/L, 0.729 mg 2 /L 2 and 0.652, respectively. PB exposure (i.e. AUC 24h ) were similar across treatment groups 3 3 over time (p=0.87). As a representative, urinary KIM-1 were elevated on days 1 and 2 for experimental groups 3 4 compared to controls, and thrice daily group experienced the most KIM-1 increase [mean increase (95% CI) day 1 3 5 from day -1, 4.44 (0.89, 8.00) ng/mL; p=0.018] as compared to control [mean increase (95% CI) day 1 from day -1, 3 6 0.03 (-0.42, 0.49) ng/mL; p=0.99]. Correspondingly, significant histopathological damage was observed with the 3 7same group (p=0.013) (controls as a referent). Our findings suggested that fractionating the PB dose thrice daily 3 8 resulted in the most injury in a rat model.

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“…Comparing findings from multiple publications may be made unnecessarily difficult; resolving ambiguity in assignment may be extremely challenging. For example, a reference to Gly at position 183 in PDC may refer to a site that is described as having a clinically relevant mutation if numbering begins with Met 1 of the precursor form but would refer to a different glycine, 26 residues away, if alignment-based numbering was used (10,11).…”

mentioning

confidence: 99%

A Standard Numbering Scheme for Class C β-Lactamases

Mack

Barnes

Taracila

et al. 2020

Antimicrob Agents Chemother

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Unlike for classes A and B, a standardized amino acid numbering scheme has not been proposed for the class C (AmpC) β-lactamases, which complicates communication in the field. Here, we propose a scheme developed through a collaborative approach that considers both sequence and structure, preserves traditional numbering of catalytically important residues (Ser64, Lys67, Tyr150, and Lys315), is adaptable to new variants or enzymes yet to be discovered and includes a variation for genetic and epidemiological applications.

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Emergence of Ceftolozane-Tazobactam-Resistant Pseudomonas aeruginosa during Treatment Is Mediated by a Single AmpC Structural Mutation

Cited by 75 publications

References 10 publications

Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime-Avibactam Resistance in Pseudomonas aeruginosa Acute Infection

Dynamic Emergence of Mismatch Repair Deficiency Facilitates Rapid Evolution of Ceftazidime-Avibactam Resistance in Pseudomonas aeruginosa Acute Infection

Evaluation of Dose Fractionated Polymyxin B on Acute Kidney Injury: A Translational In Vivo Model

A Standard Numbering Scheme for Class C β-Lactamases

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