Revisiting Cotrimoxazole for Carbapenem-Resistant Klebsiella Pneumoniae Urinary Tract Infections

Dear Editor,

The rapid surge of Carbapenem resistance is reshaping urinary tract infection (UTI) management in India.¹ With Carbapenem-resistant Klebsiella pneumoniae (CR-Kp), classified among critical priority pathogens by both the World Health Organization (WHO) and the Indian Priority Pathogen List (IPPL), the therapeutic window has narrowed, often leaving reliance on last-line parenteral agents.^2,3 In this context, renewed evaluation of older antimicrobials with preserved activity is clinically relevant.

We report the antibiotic sensitivity pattern of urinary K. pneumoniae isolates in our centre. Out of a total of 6,744 isolates, K. pneumoniae accounted for 25.7% (308/1196) in 2023, 33.6% (381/1132) in 2024, and 24.6% (1089/4416) in 2025. CR-Kp was demonstrated in a declining trend: 82.1% (253/308; 95% CI: 77.8-86.4) in 2023, 78.2% (298/381; 95% CI: 74.1-82.3) in 2024, and 57.3% (624/1089; 95% CI: 54.3-60.3) in 2025 (p <0.001 for trend). These findings are broadly consistent with Indian Antimicrobial Resistance Surveillance Network (AMRSN) data, which report low carbapenem susceptibility among urinary K. pneumoniae isolates nationally, highlighting the ongoing therapeutic challenge. The observed decline at our center may be influenced by multiple factors, including changes in antimicrobial use, infection prevention practices, and surveillance; however, causality cannot be inferred in the absence of formal time-series or controlled analyses.

Concurrently, cotrimoxazole susceptibility among CR-Kp isolates increased from 9% (23/253; 95% CI: 5.5–12.5) in 2023 to 11.07% (33/298; 95% CI: 7.5–14.6) in 2024, and 28.8% (180/624; 95% CI: 25.3–32.3) in 2025 (p <0.001 for trend) [Figure 1]. This finding is noteworthy, as these isolates were resistant to most of the first-line oral agents, leaving few non-parenteral therapeutic alternatives.

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Figure 1: Trends in prevalence of Klebsiella pneumoniae, carbapenem-resistant Klebsiella pneumoniae (CRKp), and cotrimoxazole susceptibility among CR-Kp urinary isolates from 2023 to 2025.

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Our findings are consistent with previously published literature. Data from the CRACKLE study⁴ demonstrated that ∼29% of CRE remained susceptible to trimethoprim-sulfamethoxazole, underscoring its potential role in select infections. Similarly, surveillance studies from the Middle East and South Asia have reported cotrimoxazole susceptibility rates ranging from 25–35% among CR-Kp isolates, particularly from urinary sources.^5,6 Bahrami et al. reported cotrimoxazole susceptibility in nearly 30.6% of CR-Kp isolates, emphasizing that resistance to carbapenems does not necessarily translate to resistance against folate pathway inhibitors.⁵ These findings align with our observations and support the reproducibility of this susceptibility pattern across different geographical regions.

Current IDSA 2025 guidelines recognize trimethoprim-sulfamethoxazole as a preferred oral treatment option for carbapenem-resistant Enterobacterales UTIs when susceptibility is demonstrated, supporting its role as a carbapenem-sparing agent. Cotrimoxazole also possesses favorable pharmacokinetic properties, including excellent oral bioavailability and high urinary concentrations, making it well-suited for UTI management.^7,8 However, prospective clinical trials are needed to confirm efficacy and safety before widespread clinical use.

In routine clinical practice, UTIs caused by CR-Kp frequently prompt escalation to newer β-lactam/β-lactamase inhibitor combinations or last-line agents such as colistin or cefiderocol, even in patients without systemic illness. Susceptibility-guided use of cotrimoxazole may provide an effective oral alternative, reducing hospital stay, limiting intravenous antibiotic exposure, and preserving newer agents.

To conclude, our study demonstrates a declining trend in carbapenem resistance and a concurrent increase in cotrimoxazole-susceptibility among CR-Kp urinary isolates. These findings support consideration of cotrimoxazole as a potential oral option in selected patients when susceptibility is documented, while highlighting the need for clinical outcome data. Continued surveillance and prospective clinical studies are warranted to further define its role in the management of UTIs caused by CR-Kp.