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Worldwide threatening prevalence of carbapenem-resistant Pseudomonas aeruginosa

Published online by Cambridge University Press:  19 September 2025

Mohammad Hossein Ahmadi Open the ORCID record for Mohammad Hossein Ahmadi [Opens in a new window] ,
Zeinab Fagheei Aghmiyuni  and
Shahriar Bakhti
Mohammad Hossein Ahmadi*
Affiliation:
Department of Microbiology, Faculty of Medicine, https://ror.org/01e8ff003 Shahed University , Tehran, Iran
Zeinab Fagheei Aghmiyuni
Affiliation:
Department of Microbiology, Faculty of Medicine, https://ror.org/01e8ff003 Shahed University , Tehran, Iran
Shahriar Bakhti
Affiliation:
Department of Microbiology, Faculty of Medicine, https://ror.org/01e8ff003 Shahed University , Tehran, Iran
*
Corresponding author: Mohammad Hossein Ahmadi; Email: mhahmadi@shahed.ac.ir
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Abstract

β-Lactam/β-lactamase inhibitor combinations and carbapenems are the first-line treatments for multidrug-resistant Pseudomonas aeruginosa (P. aeruginosa) infections. However, carbapenem resistance is increasing globally at an alarming rate, which is especially concerning given the pivotal role of these agents. This study comprehensively evaluated the global distribution of carbapenem resistance in clinical P. aeruginosa isolates. The keywords including ‘Pseudomonas’, P. aeruginosa’, ‘P. aeruginosa’, ‘resistance’, ‘susceptibility’, ‘carbapenem antibiotics’, ‘carbapenems’, ‘imipenem’, ‘meropenem’, ‘ertapenem’, ‘doripenem’, as well as ‘prevalence’ and ‘incidence’ were searched in electronic databases as the appropriate keywords. After screening, 160 studies were excluded, with 87 eligible studies from diverse geographic regions retained for final analysis. A comprehensive meta-analysis was then conducted on the data collected. The mean resistance rates (95% CI) were 33.3% (imipenem), 23.3% (meropenem), 60.9% (ertapenem), and 36.7% (doripenem). The time trend analysis showed that the resistance to meropenem has increased from the year 1997 to 2023. Meta-analysis showed substantial heterogeneity (I2 = 92%, p < 0.05) but no significant publication bias by Egger’s or Begg’s test. Global carbapenem resistance is alarmingly high in clinical P. aeruginosa isolates. The increasing prevalence of carbapenem-resistant P. aeruginosa is a major global health threat requiring urgent action through new antimicrobials and improved antibiotic stewardship to protect these last-line drugs.

Keywords

carbapenem resistancedoripenemertapenemimipenemmeropenemP. aeruginosa

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Type
Original Paper
Information
Epidemiology & Infection , Volume 153 , 2025 , e114
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Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
© The Author(s), 2025. Published by Cambridge University Press

Introduction

Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative, aerobic, non-fermentative bacillus and opportunistic pathogen [Reference Terahara and Nishiura1–Reference Yin3]. This ubiquitous bacterium thrives in moist environments and poses a significant threat in healthcare settings [Reference Terahara and Nishiura1, Reference Abdeta2]. It commonly causes urinary tract infections, surgical site infections, healthcare-associated pneumonia, and bloodstream infections [Reference Terahara and Nishiura1, Reference Abdeta2, Reference Kaluba4]. P. aeruginosa causes high mortality, especially in cystic fibrosis patients with chronic infections, burn victims, and the immunocompromised individuals [Reference Yin3–Reference Reynolds and Kollef6] P. aeruginosa infections are managed through prevention, bacterial culture, and early antimicrobial therapy [Reference Reynolds and Kollef6].

Antimicrobial therapy is the primary method for controlling bacterial infections [Reference Terahara and Nishiura1, Reference Yin3, Reference Reynolds and Kollef6]. Antipseudomonal antibiotics, including carbapenems, fluoroquinolones, and aminoglycosides, treat severe infections. Their misuse can increase antimicrobial resistance [Reference Terahara and Nishiura1]. P. aeruginosa develops antibiotic resistance through drug inactivation, efflux pumps, and modifications to target sites or outer membranes [Reference Chatterjee7].

P. aeruginosa strains with extensive drug resistance (XDR), defined as susceptibility to only one or two antibiotic classes, and multidrug resistance (MDR), resistance across ≥3 antimicrobial categories, pose an increasing global health threat [Reference Horcajada8]. The 2018 difficult-to-treat resistance classification for P. aeruginosa identifies isolates non-susceptible to all first-line antibiotics, including carbapenems (imipenem-cilastatin, meropenem), antipseudomonal β-lactams (ceftazidime, cefepime, and piperacillin-tazobactam), fluoroquinolones (ciprofloxacin, levofloxacin), and aztreonam [Reference Kadri9]. A 2020 ECDC (European Center for Disease Prevention and Control) report showed concerning antibiotic resistance in P. aeruginosa, with 30.1% of isolates resistant to at least one agent in five core antimicrobial classes and 17.3% exhibiting cross-resistance to at least two [Reference Karruli10].

Carbapenems are last-line antibiotics for severe multidrug-resistant infections [11]. Carbapenems are broad-spectrum ß-lactam antibiotics that include doripenem, ertapenem, imipenem, and meropenem [11]. P. aeruginosa’s carbapenemase genes confer carbapenem resistance, significantly reducing the effectiveness of common antipseudomonal agents [Reference Tenover, Nicolau and Gill12]. Carbapenemases in P. aeruginosa, including Class A (KPC, GES), metallo-β-lactamases (IMP, NDM, SPM, VIM), and Class D (OXA-48) enzymes, exhibit regional variation [Reference Tenover, Nicolau and Gill12]. Carbapenem-resistant P. aeruginosa (CRPA) infections exhibit resistance to multiple antibiotics [Reference Wei13]. In healthcare settings, CRPA spreads easily between patients via contaminated hands, surfaces, or equipment [Reference Reynolds and Kollef6].

The World Health Organization (WHO) has nominated CRPA as a life-threatening-priority pathogen, highlighting the urgent need for new antimicrobial drugs [Reference Shrivastava, Shrivastava and Ramasamy14]. Prevalence studies to prevent and monitor CRPA distribution exist, but published reports often focus on single healthcare facilities or geographical locations within countries [Reference Terahara and Nishiura1]. Therefore, globally assessing the prevalence of CRPA strains in clinical isolates is crucial.

This study used a PRISMA-guided meta-analysis to estimate carbapenem resistance prevalence in clinical P. aeruginosa isolates worldwide [Reference Moher15].

Methods

Search strategy

This meta-analysis searched Web of Science, Scopus, PubMed, and Google Scholar from January 1997 to May 2023 for original English articles reporting the prevalence or incidence of carbapenem-resistant P. aeruginosa. Keywords included ‘Pseudomonas’, ‘P. aeruginosa’, ‘P. aeruginosa’, ‘resistance’, ‘susceptibility’, ‘carbapenem antibiotics’, ‘carbapenems’, ‘imipenem’, ‘meropenem’, ‘ertapenem’, ‘doripenem’, ‘prevalence’, and ‘incidence’, combined with Boolean operators (AND, OR).

Study selection framework

This study included original research articles reporting P. aeruginosa resistance rates to carbapenems (imipenem, meropenem, ertapenem, and doripenem). Excluded were meta-analyses, reviews, theses, studies using non-human samples, articles lacking sufficient data for analysis, reports of genus-level (not species-level) antibiotic resistance, irrelevant titles, congress abstracts, and duplicate publications.

Data extraction

The extracted dataset included publication year, study design, first author name, geographic region, participant demographics, specimen category, total isolates, resistance detection method, and resistant isolate counts per antibiotic. Two independent reviewers extracted data, resolving discrepancies through discussion.

Statistical analysis

Carbapenem resistance prevalence was analysed using Comprehensive Meta-Analysis software (v3.7z, Bio stat) and expressed as pooled estimates with 95% confidence intervals. Heterogeneity was assessed using Cochran’s Q statistic and I2 statistic. If substantial heterogeneity was present (I2 > 50%), a random-effects model was used. Publication bias was evaluated via funnel plot symmetry, Begg’s test, and Egger’s test (p < 0.05). Each study was assigned a relative weight, and a meta-regression using the random-effect model (method of moments) has been performed [Reference Kelley and Kelley16, Reference Thompson and Higgins17].

Bivariate linear regression using GraphPad Prism (v9.5) assessed temporal trends in P. aeruginosa carbapenem resistance (1997–2023), with average resistance rates and 95% confidence intervals reported. For antibiotics with sufficient data, the linear regression equation and R2 value were also calculated.

Results

Database searches (Web of Science, Scopus, Google Scholar, and PubMed) yielded 247 articles. After title screening, 119 articles were excluded (61 duplicates and 58 irrelevant titles). During subordinate screening, 21 publications were omitted due to either non-human specimen or article type (reviews). Full-text evaluation led to the exclusion of 20 more studies due to genus-level reporting (no species-level antibiotic resistance data) and/or deficient data. Ultimately, 87 articles published from January 1997 to May 2023 were included in the final analysis (Figure 1 and Table 1).

Figure 1. Flow chart of the literature search, systematic review and study selection.

The ultimate analysis merged data from 41 countries worldwide, including 49 Asian studies, 13 European investigations, 14 African reports, and 15 North/South American datasets (Table 1). The study population comprised diverse male and female patients from multiple care settings, outpatient clinics, general hospital wards, and intensive care units, all with confirmed P. aeruginosa infections. The included patients with hospital-acquired and healthcare-associated P. aeruginosa infections, across multiple clinical presentations: intra-abdominal, pulmonary, cutaneous/soft tissue, bloodstream, surgical site, urinary tract, as well as burn-related, cystic fibrosis-associated, COVID-19, and osteomyelitis cases (Table 1). Samples in the included studies consisted of blood, sputum, endotracheal secretions, bronchoalveolar lavage fluid, catheter tips, urine (mid-stream and catheterized), nasopharyngeal specimens, throat, ear, and eye swabs, abscess/wound samples, tissue, body fluid, and cerebrospinal fluid (CSF) (Table 1). Antimicrobial susceptibility testing in these studies focused on imipenem, meropenem, ertapenem, and doripenem. Mean resistance rates for P. aeruginosa isolates were 33.3% (imipenem), 23.3% (meropenem), 60.9% (ertapenem), and 36.7% (doripenem) (95% CI). Figures 2–4 show the forest plots of the meta-analysis for resistance rate of P. aeruginosa to the antibiotics. Table 2 shows the range and pooled resistance rates of P. aeruginosa isolates to antibiotics.

Table 1. Studies included in meta-analysis after final evaluation

Abbreviations: NM: not measured; NS: not specified; ICU: Intensive care unit; CSF: cerebrospinal fluid; ET: Endo-tracheal tract secretions, BAL: bronchoalveolar lavage; CT: Catheter tip; UTI: urinary tract infection.

Figure 2. Forest plot of the meta-analysis of resistance rate of P. aeruginosa to imipenem.

Figure 3. Forest plot of the meta-analysis of resistance rate of P. aeruginosa to meropenem.

Figure 4. Forest plots of the meta-analysis of resistance rate to ertapenem (a) and doripenem (b) for P. aeruginosa.

Table 2. Meta-analysis results for resistance rate of Pseudomonas aeruginosa in included studies

Note: a: Kendall’s tau without continuity correction; b: Kendall’s tau with continuity correction.

a Pooled resistance rate (based on random effects).

b Begg and Mazumdar rank correlation.

c Egger’s regression intercept.

Time trend analysis (Pearson correlation) revealed a significant increase in P. aeruginosa resistance to meropenem from 1997 to 2023 (r = 0.593, p = 0.002, 95% CI: 0.2491–0.8040), indicating a strong correlation with year of publication. Figure 5 illustrates the resistance rates of imipenem and meropenem between 1997 and 2023.

Figure 5. The resistance rates of P. aeruginosa to meropenem (a) and imipenem (b) during the years 1997 to 2023. Dashed lines represent 95% confidence intervals (CI: 0.2491–0.8040).

Table 2 shows mid-range resistance rates in P. aeruginosa isolates: imipenem (50%), meropenem (50%), ertapenem (73.3%), and doripenem (46.3%). Significant heterogeneity was present across all studies (I2 > 50%, P < 0.05), but no publication bias was detected (Figure 6, Table 2, Egger’s and Begg’s tests). Fewer than 10 articles investigated ertapenem and doripenem resistance, precluding further analysis.

Figure 6. Funnel plots of the meta-analysis for the resistance rate of P. aeruginosa isolates to carbapenems: imipenem (a), meropenem (b), ertapenem (c), and doripenem (d).

Discussion

Our analysis found substantial geographic difference in P. aeruginosa resistance to clinically important carbapenems (imipenem, meropenem, ertapenem, and doripenem), with reliably elevated resistance rates observed globally. Carbapenem-resistant P. aeruginosa (CRPA) has been downgraded in WHO Bacterial Priority Pathogens List (BPPL) from ‘critical’ to ‘high priority’ in the 2024 update, reflecting a potential global decrease in resistance observed in at least one WHO region and its relatively lower transmission compared to other carbapenem-resistant strains. These results are consistent with resistance patterns reported in the Global Burden of Disease Antimicrobial Resistance study [Reference Murray105].

Ertapenem was investigated due to its potential to reduce the use of imipenem, meropenem, and doripenem in antimicrobial stewardship programs without increasing resistance in Enterobacteriaceae and P. aeruginosa. However, despite ertapenem’s potential benefit in mitigating carbapenem resistance in P. aeruginosa, our study revealed a scarcity of research evaluating its antimicrobial activity. This may be due to some authors supporting ertapenem as an approach to decrease resistance to meropenem and imipenem [Reference Zequinão106].

Based on our evaluations, contributor characteristics, situations, sample types, antimicrobial susceptibility procedures, sample sizes, and study preference were highly heterogeneous. Geographical differences in P. aeruginosa antibiotic resistance frequencies likely come from differing antibiotic prescribing and consumption patterns across populations. Therefore, the important CRPA burden in high-income areas, particularly Central/Eastern Europe and Central Asia, demands urgent continued investment in targeted antimicrobial development [Reference Murray105, Reference Aguilar107, Reference Burke108]. Furthermore, its high mortality rate among immunocompromised individuals and in healthcare settings necessitates ongoing innovative research and development to mitigate its impact. The WHO BPPL guides global surveillance by prioritizing critical threats [109, 110].

ß-Lactams are broad-spectrum antibiotics often used empirically for sepsis, with carbapenems possessing a particularly broad antimicrobial spectrum [Reference Umemura111]. Carbapenem use in patients with extended-spectrum ß-lactamase-producing pathogen infections is linked to lower mortality, according to studies. Carbapenems are the preferred first-line antibiotics for sepsis, but their increasing global use poses a serious public health threat [Reference Umemura111]. This threat requires that the WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS) should continue monitoring CRPA for emerging resistance and intervention effectiveness [109].

The substantial heterogeneity and varying sample sizes across included studies may have influenced our analysis. The relative weight was calculated for each study and reported in the present study to overcome this problem. This study was limited by its restriction to English-language sources, potentially excluding relevant research. Furthermore, the meta-analysis, constrained by fewer than ten articles on P. aeruginosa antimicrobial resistance to ertapenem and doripenem, lacked statistical power and precluded definitive conclusions.

This meta-analysis was limited by the variation in breakpoints and methods used to define antimicrobial susceptibility and resistance across different studies. CLSI recommended standard-specific zone diameter and MIC breakpoints for imipenem and meropenem in P. aeruginosa antibiotic susceptibility testing in 2011 (M100-S21) and 2022 (M100-Ed32) [112, 113]. The meta-analysis included studies from 1997 to 2023. Studies prior to 2011 and 2022 used different antimicrobial susceptibility testing guidelines (non-M100-S21, M100-Ed32), resulting in variations in breakpoints and thresholds for susceptible and resistant strain determination.

The studies in our analysis exclusively used phenotypic methods for antibiotic susceptibility evaluation. These methods encompass classical culture-dependent techniques (disk diffusion assay, gradient diffusion method) yielding results in 18–48 h and automated microdilution systems providing faster results (6–24 h post-isolation). Fast bacterial identification and antibiotic susceptibility testing are crucial to combatting drug resistance, but traditional culture-based methods are time-consuming. Necessity often compels physicians to prescribe antibiotics empirically, contributing to inappropriate use, increased mortality and costs, and the spread of antibiotic resistance [Reference Li, Yang and Zhao114]. To expedite patient treatment and outcomes, continuous development of rapid antibiotic susceptibility and microorganism identification methods is crucial. Traditional methods like broth microdilution and disk diffusion remain essential in clinical practice to ensure accurate results that align with EUCAST and CLSI standards or to validate new methods [Reference Benkova, Soukup and Marek115].

Combating antibiotic resistance in P. aeruginosa and other pathogens necessitates coordinated global efforts, continuous monitoring, and responsive control programs. Developing new anti-Pseudomonas therapeutics is a key challenge in pharmaceutical science, alongside the pursuit of rapid diagnostic methods. Intensively studied methods for supporting the human immune system include preventative vaccines, therapeutic antibodies, and the development of antimicrobial peptides [Reference Dorotkiewicz-Jach116]. Antimicrobial agents encompass novel antibiotics, ß-lactamase and efflux pump inhibitors, quorum-dissolving molecules, and antibacterial nanoparticles. Developing alternative therapies like phage and photodynamic therapies, which employ mechanisms distinct from traditional antibiotics, is crucial.

In conclusion, the findings of the present study indicate that the overall resistance to carbapenems in clinical isolates of P. aeruginosa is relatively high and prevalent throughout the world. Moreover, time trend analysis showed that the resistance to meropenem has increased from the year 1997 to 2023. The increasing resistance of P. aeruginosa to carbapenems, as the last-resort antibiotics, is considered a global threat. Therefore, it requires new treatment approaches to fight against antimicrobial resistance and reduce the treatment failure. Moreover, applying the national and international surveillance programmes is necessary to control the emergence and spreading of carbapenem-resistant strains.

Data availability statement

The datasets supporting this study are included in the article, and excess information is available from the corresponding author upon request.

Author contribution

M.H.A.: Conceptualization, Formal analysis, Methodology, Resources, Supervision, Funding acquisition, Writing–review & editing. Z.F.A.: Data curation, Formal analysis, Methodology, Investigation, Writing – original draft. S.B.: Conceptualization, Formal analysis, Methodology.

Competing interests

The authors declare that they have no competing interests.

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Figure 0

Figure 1. Flow chart of the literature search, systematic review and study selection.

Figure 1

Table 1. Studies included in meta-analysis after final evaluation

Figure 2

Figure 2. Forest plot of the meta-analysis of resistance rate of P. aeruginosa to imipenem.

Figure 3

Figure 3. Forest plot of the meta-analysis of resistance rate of P. aeruginosa to meropenem.

Figure 4

Figure 4. Forest plots of the meta-analysis of resistance rate to ertapenem (a) and doripenem (b) for P. aeruginosa.

Figure 5

Table 2. Meta-analysis results for resistance rate of Pseudomonas aeruginosa in included studies

Figure 6

Figure 5. The resistance rates of P. aeruginosa to meropenem (a) and imipenem (b) during the years 1997 to 2023. Dashed lines represent 95% confidence intervals (CI: 0.2491–0.8040).

Figure 7

Figure 6. Funnel plots of the meta-analysis for the resistance rate of P. aeruginosa isolates to carbapenems: imipenem (a), meropenem (b), ertapenem (c), and doripenem (d).