Prolonged vs. Short-Term Infusion of Imipenem/Cilastatin for Multidrug-Resistant Gram-Negative Bacilli Severe Pneumonia: A Randomized Controlled Trial Evaluating Efficacy, Safety, and Cost-Effectiveness

Abstract

Background : Multidrug-resistant Gram-negative bacilli (MDR-GNB) severe pneumonia poses significant therapeutic challenges due to limited antibiotic efficacy and high mortality. Prolonging the infusion time of β -lactams like imipenem/cilastatin may enhance pharmacodynamic target attainment, but clinical evidence is lacking. This trial compared prolonged versus short-term infusion of imipenem/cilastatin in critically ill patients with MDR-GNB pneumonia. Methods : In this prospective, randomized, open-label, blinded endpoint (PROBE) trial conducted at a provincial tertiary hospital in China, 82 adults with severe pneumonia (IDSA/ATS 2016 criteria) and confirmed MDR-GNB infections were randomly assigned to receive imipenem/cilastatin 1 g every 8 hours administered either as: 3-hour prolonged infusion (intervention group, n = 41) via infusion pump; 30-minute intermittent infusion (control group, n = 41) through standard gravity flow. Both groups received equivalent total daily doses (3 g/day) of imipenem/cilastatin, administered at identical drug concentrations (1 g/100 mL normal saline). The intervention group received 3-hour prolonged infusions via a pump, while the control group utilized 30-minute intermittent gravity infusions. The primary outcome was clinical response rate (resolution of systemic inflammation + radiological improvement) at day 8. Secondary outcomes included microbial eradication kinetics, 90-day survival, safety, and cost-effectiveness. Statistical analyses included univariate comparisons (chi-square/t-tests/Mann-Whitney U), Kaplan-Meier survival analysis with log-rank test, and multivariable Cox regression, performed using R 4.4.3/SPSS 27.0. Results : The prolonged infusion group achieved higher clinical response rates at day 8 (82.9% vs. 58.5%; P = 0.015) and reduced secondary fungal infections (7.3% vs. 29.3%, P = 0.010). Accelerated microbial eradication was observed with prolonged infusion (median 6.0 vs. 7.0 days, P = 0.004). Kaplan-Meier analysis demonstrated superior 90-day survival (95.1% vs. 68.3%, log-rank P = 0.02), with prolonged infusion independently protective in multivariable Cox regression (adjusted HR = 0.08, 95% CI: 0.01 - 0.51; P = 0.008). Safety profiles were comparable, with no significant differences in nephrotoxicity, hepatic injury, or seizures (P > 0.05). Pharmacoeconomic analysis revealed equivalent direct medication costs between groups. Conclusion : Prolonged infusion of imipenem/cilastatin improves clinical outcomes and survival in MDR-GNB severe pneumonia without increasing toxicity or costs. These findings support adopting prolonged infusion as a standard-of-care strategy. Future studies should validate these results in broader populations and optimize dosing regimens using pharmacokinetic-pharmacodynamic modeling.