On the Optimal Treatment of Metallo-Beta-Lactamase–Producing Enterobacterales Infections Using Aztreonam and Avibactam

To the editor—Thank you for the opportunity to respond to Tamma and colleagues’ commentary on the discussion of the REVISIT (Revisiting serious bacterial infection with innovation) study. First, to clarify, we agree with the 2024 Infectious Diseases Society of America guidance that in the absence of US Food and Drug Administration (FDA)–approved beta-lactam/beta-lactamase inhibitors with activity against metallo-beta-lactamase(MBL)-producing Enterobacterales, the preferred antibiotic options for New-Delhi metallo-beta-lactamase (NDM)-producing Enterobacterales (or other MBLs) include ceftazidime-avibactam plus aztreonam [1]. Fortunately, aztreonam/avibactam (ATM/AVI), which was developed through public–private partnership, has recently been approved by both the FDA and the European Medicines Agency for the treatment of infections caused by aerobic gram-negative bacteria where treatment options are limited. The pharmacokinetics–pharmacodynamics of ATM/AVI were evaluated in multiple in vivo and in vitro studies, and data are available from phase 1–3 studies and modeling [2]. The dosing regimen was optimized. This dosing regimen differs from that suggested for ceftazidime/avibactam + aztreonam by the hollow-fiber model and a Monte Carlo simulation [3, 4]. The latter studies advise the administration of 2 g aztreonam with ceftazidime/avibactam. Notably, the 2-gram dosing by prolonged or continuous infusion was found to be associated with elevations in liver enzymes, in some cases severe [5]. In contrast, the 1.5-g dosing of aztreonam in the ATM/AVI combination was not. Moreover, ATM/AVI dose regimens achieved high joint probability of target attainment (PTA) across renal function groups. In contrast, joint PTA with proposed ceftazidime/avibactam + aztreonam dose regimens for normal renal function was suboptimal (<85%) because of insufficient avibactam exposures when given 3 times daily, regardless of the ATM dose (2 g every 6 hours or every 8 hours) [6].