Nadia Cheh-Oh

Background: To study a pharmacokinetics model of sulbactam and optimal dosing regimens to achieve a time above a minimal inhibitory concentration (fT > MIC) of 50%, 75%, and 100% in patients with Carbapenem-Resistant Acinetobacter baumannii (CRAB) infection. Methods: This prospective pharmacokinetic study was conducted on patients with pneumonia or bacteremia due to CRAB infection at Phramongkutklao Hospital in Bangkok, Thailand, from January 2021 to May 2023. The sulbactam administration protocol involved a daily dose of 9–12 g, adjusted according to renal function. Blood samples were also collected from the patients at different time points over a period of 7 days. Pharmacokinetic modeling was performed using NONMEM version 7.5.1, and a Monte Carlo simulation with Crystal Ball was used to determine the optimal sulbactam dose. Results: Overall, the 55 patients had 268 points of sulbactam concentration. The final model was a two-compartment model with first-order elimination and an objective function value (OFV) of 2377. Additionally, the estimated typical values of clearance (CL) were 3.17 L/h, the volume of the central compartment (V ₁ ) was 14.98 L, the volume of the peripheral compartment (V ₂ ) was 9.21 L, and the intercompartment clearance (Q) was 4.84 L/h. Creatinine clearance (CrCL) was the only significant covariate affecting apparent clearance and central compartment volume. A daily dose of 12 g was sufficient in patients with normal renal function. For pathogens with an MIC of 32 µg/mL, 4 g q8h extended infusion over 4 h achieved PTA > 80% for the 50% fT > MIC target in patients with CrCL 61–120 mL/min, while a 12 g/day continuous infusion achieved PTA > 90% for all fT > MIC targets. Conclusion: This study established a two-compartment model for sulbactam in CRAB infections, highlighting creatinine clearance as a key factor affecting clearance and central volume. Monte Carlo simulations indicated that higher doses, up to 12 g/day adjusted for renal function, may be necessary to meet pharmacodynamic targets in critically ill patients. These results offer a dosing framework to optimize the treatment of resistant A. baumannii infections when therapeutic drug monitoring is unavailable. Clinical trial number: Not applicable.

Background/Objective: Carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia has limited treatment options, and sulbactam MIC interpretation varies with the antimicrobial susceptibility testing (AST) method. This study compared sulbactam MICs determined using broth microdilution (BMD) and the E-test and examined their associations with 28-day mortality. Methods: This secondary analysis used data from a randomized controlled trial comparing colistin plus sulbactam at 9 g/day versus 12 g/day in adults with CRAB pneumonia. The sulbactam MICs of 134 isolates were determined using BMD and the E-test. The agreement between methods across MIC ranges and associations between MICs, dosing, and 28-day mortality were analyzed. Results: Sulbactam MICs determined using BMD were lower than those obtained with the E-test (MIC50/90: 32/128 µg/mL vs. 96/≥256 µg/mL). Overall, agreement between methods was limited and depended on MIC level, with better agreement at lower MICs and marked discrepancies at higher MICs, where the E-test frequently overestimated the MICs. Using the IDSA breakpoint (MIC ≤ 4 µg/mL), susceptibility was identified in 6% of isolates with BMD and 3% with the E-test. A significant survival benefit with high-dose sulbactam (12 g/day) was observed in patients with BMD-determined MICs ≥ 128 µg/mL (HR 0.27; 95% CI, 0.077–0.956; p = 0.042), whereas no mortality association was seen when MICs were categorized using the E-test results. Conclusions: AST method selection substantially affects sulbactam MIC interpretation in CRAB pneumonia. BMD shows stronger correlation with clinical outcomes than the E-test, particularly at high MIC levels. High-dose sulbactam may benefit patients with highly resistant isolates, underscoring the need for accurate and standardized AST methods.

Background/Objective: Carbapenem resistant Acinetobacter baumannii (CRAB) pneumonia has limited treatment options, and sulbactam MIC interpretation varies by antimicrobial susceptibility testing (AST) method. This study compared sulbactam MICs determined by broth microdilution (BMD) and E-test and examined their associations with 28-day mortality. Methods: This secondary analysis used data from a randomized controlled trial comparing colistin plus sulbactam at 9 g/day versus 12 g/day in adults with CRAB pneumonia. Sulbactam MICs of 134 isolates were determined by BMD and E-test. Agreement between methods across MIC ranges and associations between MICs, dosing, and 28-day mortality were analyzed. Results: Sulbactam MICs determined by BMD were lower than those obtained by E-test (MIC50/90: 32/128 µg/mL vs. 96/≥256 µg/mL). Overall agreement between methods was limited and depended on MIC level, with better agreement at lower MICs and marked discrepancies at higher MICs, where E-test frequently overestimated MICs. Using the IDSA breakpoint (MIC ≤4 µg/mL), susceptibility was identified in 6% of isolates by BMD and 3% by E-test. A significant survival benefit with high-dose sulbactam (12 g/day) was observed in patients with BMD-determined MICs ≥128 µg/mL (HR 0.27; 95% CI, 0.077–0.956; p=0.042), whereas no mortality association was seen when MICs were categorized using E-test results. Conclusions: AST method selection substantially affects sulbactam MIC interpretation in CRAB pneumonia. BMD shows stronger correlation with clinical outcomes than E-test, particularly at high MIC levels. High dose sulbactam may benefit patients with highly resistant isolates, underscoring the need for accurate and standardized AST methods.

Cheh-Oh N, et al. Infect Chemother. 2025 Feb;57:e9. https://doi.org/10.3947/ic.2024.0125

This retrospective study was conducted to evaluate the characteristics and outcomes of patients with ventilator-associated pneumonia (VAP) caused by Stenotrophomonas maltophilia (S. maltophilia), focusing on the impact of appropriate empirical antimicrobial treatment. Of the enrolled 240 patients with VAP due to S. maltophilia (median age: 45 years) in a tertiary-care hospital in southern Thailand between January 2010 and December 2021, 90% had medical comorbidities and 91% had previously received carbapenems. In addition, only 45% of the patients were initially admitted to the intensive care unit. Patients administered appropriate empirical antimicrobial treatment including colistin alone and colistin plus TMP-SMX or fluoroquinolone-based regimens had significantly lower 14-day, 30-day, and in-hospital mortalities, compared with those who did not receive appropriate empirical antimicrobial treatment (21% and 2% vs. 31%; 30% and 5% vs. 44%; and 30% and 12% vs. 53%, respectively). Thus, the use of appropriate empirical antimicrobial treatments led to a significantly reduced length of hospital stay, duration of ventilation, and hospital costs. The current study suggests that the use of appropriate empirical antimicrobial treatment based on susceptibility testing without considering pharmacokinetic properties and administration dosages improves the outcomes of patients with VAP due to S. maltophilia.