567. Therapeutic Drug Monitoring of Extended Infusion Ceftazidime-Avibactam-Aztreonam (CAZ-AVI-AZT) in Critically Ill Patients with Multidrug-Resistant (MDR) Gram-Negative Infections

TL;DR

This study examines drug levels in critically ill patients treated with a combination antibiotic to manage drug-resistant infections, finding suboptimal dosing and the need for better strategies.

Contribution

The study evaluates pharmacokinetic target attainment of extended infusion CAZ-AVI-AZT in critically ill patients with MDR Gram-negative infections.

Findings

78% of ceftazidime, 74% of avibactam, and 70% of aztreonam achieved 50% fT ≥ MIC.

Only 38% of ceftazidime, 35% of avibactam, and 42% of aztreonam achieved 100% fT ≥ MIC.

Clinical cure was achieved in 63% of patients, with no significant difference in success rates between those who attained targets and those who did not.

Abstract

Pharmacokinetic variability in critically ill patients complicates β-lactam dosing and increases the risk of treatment failure, particularly in infections caused by pathogens with elevated MICs. The combination of CAZ-AVI-AZT is used to treat complex infections caused by MDR Enterobacterales. This study evaluates pharmacokinetic/pharmacodynamic (PK/PD) target attainment of CAZ-AVI-AZT via extended infusions in critically ill patients.

Overall Target Attainment for CAZ-AVI-AZT at Peak Levels (50% fT)

Overall Target Attainment for CAZ-AVI-AZT at Peak Levels (50% fT)

Overall Target Attainment for CAZ-AVI-AZT at Trough Levels (100% fT)

Overall Target Attainment for CAZ-AVI-AZT at Trough Levels (100% fT)

A prospective, observational study was conducted at a tertiary care hospital in South India from Dec 2023 to Jun 2024, involving critically ill adult patients with confirmed/suspected MDR Enterobacterales infections who received ≥ 4 doses of CAZ-AVI-AZT administered via extended infusions (3-hour). Those with GFR < 15 mL/min and receiving dialysis were excluded. The E-strip stacking method was used to confirm that all isolates exhibited synergistic activity to CAZ-AVI-AZT. Clinical and microbiological cure at 30 days and at the end of therapy were also evaluated. PK/PD targets were 50% fT ≥ MIC and 100% fT ≥ MIC (50% free drug time above MIC and 100% free time above MIC, respectively).

Target Attainment Based on CAZ-AVI Susceptibility at Peak Level

Target Attainment Based on CAZ-AVI Susceptibility at Trough Level

Among 27 patients, the median age was 52 years (43, 61). The most common sources of infection were bacteraemia (37%), pneumonia (30%), UTI (22%), and IAI (11%). The most common pathogens isolated were K. pneumoniae (89%) and E. coli (11%). Median peaks/troughs (mcg/mL): CAZ 11.9/7.0, AVI 1.24/0.77, AZT 5.7/3.55.

50% fT ≥ MIC (of 8, 1, and 4 µg/mL, respectively) was achieved in 78%, 74%, and 70% of ceftazidime, avibactam, and aztreonam, respectively. 100% fT ≥ MIC was only attained in 38%, 35%, and 42% of ceftazidime, avibactam, and aztreonam, respectively. Only one patient had a microbiological failure, and clinical cure was achieved in 17 (63%) patients. Microbiological and clinical success rates did not vary between those who did or did not attain targets.

Our findings highlight suboptimal drug levels, variability, and lack of target attainment, stressing the need for dose optimization in this high-risk population.

All Authors: No reported disclosures

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