Compassionate use of a novel β-lactam enhancer-based investigational antibiotic cefepime/zidebactam (WCK 5222) for the treatment of extensively-drug-resistant NDM-expressing <i>Pseudomonas aeruginosa</i> infection in an intra-abdominal infection-induced sepsis patient: a case report

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Abstract

Infections in critically-ill patients caused by extensively-drug-resistant (XDR)- Pseudomonas aeruginosa are challenging to manage due to paucity of effective treatment options. Cefepime/zidebactam, which is currently in global Phase 3 clinical development (Clinical Trials Identifier: NCT04979806, registered on July 28, 2021) is a novel mechanism of action based β-lactam/ β-lactam-enhancer combination with a promising activity against a broad-range of Gram-negative pathogens including XDR P. aeruginosa. We present a case report of an intra-abdominal infection-induced sepsis patient infected with XDR P. aeruginosa and successfully treated with cefepime/zidebactam under compassionate use. The 50 year old female patient with past-history of bariatric surgery and recent elective abdominoplasty and liposuction developed secondary pneumonia and failed a prolonged course of polymyxins. The organism repeatedly isolated from the patient was a New-Delhi metallo β-lactamase-producing XDR P. aeruginosa resistant to ceftazidime/avibactam, imipenem/relebactam and ceftolozane/tazobactam, susceptible only to cefepime/zidebactam. As polymyxins failed to rescue the patient, cefepime/zidebactam was administered under compassionate grounds leading to discharge of patient in stable condition. The present case highlights the prevailing precarious scenario of antimicrobial resistance and the need for novel antibiotics to tackle infections caused by XDR phenotype pathogens.

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The online version contains supplementary material available at 10.1186/s12941-023-00606-x.

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Most cited references 11

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Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America.

Peter Pappas, Carol A Kauffman, David Andes … (2015)

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

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International Consensus Guidelines for the Optimal Use of the Polymyxins

Brian T Tsuji, Jason Pogue, Alexandre P Zavascki … (2019)

The polymyxin antibiotics colistin (polymyxin E) and polymyxin B became available in the 1950s and thus did not undergo contemporary drug development procedures. Their clinical use has recently resurged, assuming an important role as salvage therapy for otherwise untreatable gram-negative infections. Since their reintroduction into the clinic, significant confusion remains due to the existence of several different conventions used to describe doses of the polymyxins, differences in their formulations, outdated product information, and uncertainties about susceptibility testing that has led to lack of clarity on how to optimally utilize and dose colistin and polymyxin B. We report consensus therapeutic guidelines for agent selection and dosing of the polymyxin antibiotics for optimal use in adult patients, as endorsed by the American College of Clinical Pharmacy (ACCP), Infectious Diseases Society of America (IDSA), International Society of Anti-Infective Pharmacology (ISAP), Society for Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) endorses this document as a consensus statement. The overall conclusions in the document are endorsed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). We established a diverse international expert panel to make therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, polymyxin agent selection, dosing, dosage adjustment and monitoring of colistin and polymyxin B, use of polymyxin-based combination therapy, intrathecal therapy, inhalation therapy, toxicity, and prevention of renal failure. The treatment guidelines provide the first ever consensus recommendations for colistin and polymyxin B therapy that are intended to guide optimal clinical use.

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Clinical and economic consequences of hospital-acquired resistant and multidrug-resistant Pseudomonas aeruginosa infections: a systematic review and meta-analysis

Dilip Nathwani, Gowri Raman, Katherine Sulham … (2014)

Background Increasing rates of resistant and multidrug-resistant (MDR) P. aeruginosa in hospitalized patients constitute a major public health threat. We present a systematic review of the clinical and economic impact of this resistant pathogen. Methods Studies indexed in MEDLINE and Cochrane databases between January 2000-February 2013, and reported all-cause mortality, length of stay, hospital costs, readmission, or recurrence in at least 20 hospitalized patients with laboratory confirmed resistant P. aeruginosa infection were included. We accepted individual study definitions of MDR, and assessed study methodological quality. Results The most common definition of MDR was resistance to more than one agent in three or more categories of antibiotics. Twenty-three studies (7,881 patients with susceptible P. aeruginosa, 1,653 with resistant P. aeruginosa, 559 with MDR P. aeruginosa, 387 non-infected patients without P. aeruginosa) were analyzed. A random effects model meta-analysis was feasible for the endpoint of all-cause in-hospital mortality. All-cause mortality was 34% (95% confidence interval (CI) 27% – 41%) in patients with any resistant P. aeruginosa compared to 22% (95% CI 14% – 29%) with susceptible P. aeruginosa. The meta-analysis demonstrated a > 2-fold increased risk of mortality with MDR P. aeruginosa (relative risk (RR) 2.34, 95% CI 1.53 – 3.57) and a 24% increased risk with resistant P. aeruginosa (RR 1.24, 95% CI 1.11 – 1.38), compared to susceptible P. aeruginosa. An adjusted meta-analysis of data from seven studies demonstrated a statistically non-significant increased risk of mortality in patients with any resistant P. aeruginosa (adjusted RR 1.24, 95% CI 0.98 – 1.57). All three studies that reported infection-related mortality found a statistically significantly increased risk in patients with MDR P. aeruginosa compared to those with susceptible P. aeruginosa. Across studies, hospital length of stay (LOS) was higher in patients with resistant and MDR P. aeruginosa infections, compared to susceptible P. aeruginosa and control patients. Limitations included heterogeneity in MDR definition, restriction to nosocomial infections, and potential confounding in analyses. Conclusions Hospitalized patients with resistant and MDR P. aeruginosa infections appear to have increased all-cause mortality and LOS. The negative clinical and economic impact of these pathogens warrants in-depth evaluation of optimal infection prevention and stewardship strategies. Electronic supplementary material The online version of this article (doi:10.1186/2047-2994-3-32) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Dilip Dubey: drdilipdubey2d@gmail.com

Balaji Veeraraghavan: vbalaji@cmcvellore.ac.in

Journal

Journal ID (nlm-ta): Ann Clin Microbiol Antimicrob

Journal ID (iso-abbrev): Ann Clin Microbiol Antimicrob

Title: Annals of Clinical Microbiology and Antimicrobials

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-0711

Publication date (Electronic): 5 July 2023

Publication date PMC-release: 5 July 2023

Publication date Collection: 2023

Volume: 22

Electronic Location Identifier: 55

Affiliations

[1 ]Institute of Critical Care medicine, Medanta, Lucknow India

[2 ]GRID grid.414739.c, ISNI 0000 0001 0174 2901, Department of Pulmonary Medicine, , Sher-I-Kashmir Institute of Medical Sciences, ; Soura, Srinagar, India

[3 ]GRID grid.414540.0, ISNI 0000 0004 1768 0436, Department of Critical Care Medicine, , ERA’s Lucknow Medical College and Hospital, ; Lucknow, India

[4 ]Department of Microbiology, Medanta, Lucknow India

[5 ]GRID grid.11586.3b, ISNI 0000 0004 1767 8969, Department of Clinical Microbiology, , Christian Medical College and Hospital, ; Vellore, India

Article

Publisher ID: 606

DOI: 10.1186/s12941-023-00606-x

PMC ID: 10324185

PubMed ID: 37408075

SO-VID: 0cfe971c-a304-451a-8aa0-711ef2bdc277

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 13 February 2023

Date accepted : 23 June 2023

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ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: cefepime/zidebactam,β-lactam-enhancer,pseudomonas,new-delhi metallo-β-lactamase,extensively-drug-resistant

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ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: cefepime/zidebactam, β-lactam-enhancer, pseudomonas, new-delhi metallo-β-lactamase, extensively-drug-resistant

Compassionate use of a novel β-lactam enhancer-based investigational antibiotic cefepime/zidebactam (WCK 5222) for the treatment of extensively-drug-resistant NDM-expressing Pseudomonas aeruginosa infection in an intra-abdominal infection-induced sepsis patient: a case report

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Most cited references 11

Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America.

International Consensus Guidelines for the Optimal Use of the Polymyxins

Clinical and economic consequences of hospital-acquired resistant and multidrug-resistant Pseudomonas aeruginosa infections: a systematic review and meta-analysis

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