Indian Society of Critical Care Medicine Guidelines on Evidence-based Recommendations for the Treatment of Carbapenem-resistant Enterobacterales, Carbapenem-resistant Acinetobacter baumannii, and Carbapenem-resistant Pseudomonas aeruginosa in Critically Ill Patients: A GRADE-guided Approach.

Abstract

Background: Carbapenem-resistant Enterobacterales (CRE), Acinetobacter baumannii (CRAB), and Pseudomonas aeruginosa (CRPA) are major antimicrobial resistance (AMR) threats in Indian intensive care units, with mortality rates often exceeding 40-70%. Despite the clinical burden, there is a lack of standardized treatment guidelines. This study aimed to develop Grading of Recommendations Assessment, Development and Evaluation (GRADE)-based recommendations for managing carbapenem-resistant gram-negative (CRGN) infections in critically ill patients.

Methodology: A systematic review was conducted following the GRADE framework. PubMed was searched through October 2024 for studies comparing polymyxin B/colistin with alternative regimens for CRE, CRAB, and CRPA, and sulbactam-based therapy vs comparators for CRAB. Meta-analyses were performed using RevMan. Evidence of certainty was graded, and recommendations were formulated through structured expert consensus. Outcomes included clinical cure, microbiological eradication, mortality, and adverse events (AEs).

Results: Fifty-two studies were included: 36 evaluating polymyxin/colistin and 16 evaluating sulbactam. For CRE, β-lactam/β-lactamase inhibitor (BL/BLI) combinations achieved higher cure rates (58.7 vs 48.9%), fewer AEs (10.3 vs 13.3%), and trends toward reduced mortality compared with polymyxin-based regimens, leading to a strong recommendation for non-polymyxin therapy (very low certainty). For CRAB, sulbactam-based regimens, particularly sulbactam-durlobactam, showed superior cure rates (61.9 vs 39.7%) and reduced nephrotoxicity (13 vs 38%), supporting a strong recommendation (very low certainty). For CRPA, efficacy appeared comparable, but polymyxin therapy caused higher toxicity (42.1 vs 17.9%), resulting in a weak recommendation for non-polymyxin options (very low certainty).

Conclusion: These findings provide GRADE-based treatment recommendations for carbapenem-resistant infections in Indian ICUs. Non-polymyxin regimens are preferred for CRE and CRPA, while sulbactam-based therapy is favored for CRAB. This shift away from polymyxin use may improve outcomes and reduce toxicity, though robust randomized trials are urgently needed.