Antimicrobial resistance among Gram-negative (GN) bacteria is an urgent global challenge. Infections caused by metallo-β-lactamase (MBL)–producing Enterobacterales and Stenotrophomonas maltophilia are of particular concern due to limited treatment options and high mortality. At an industry-sponsored symposium at the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Global 2026, infectious disease experts discussed emerging treatment strategies to improve outcomes, with a focus on the β-lactam/β-lactamase inhibitor combination, aztreonam-avibactam (ATM/AVI).
Disease burden
Resistance to β-lactam antibiotics in GN bacteria is primarily mediated by β-lactamase production, which includes serine-β-lactamases (SBLs; Ambler classes A, C and D) and MBLs (Ambler class B). Among these, class A (eg, KPC), class D (eg, OXA-48-like) and class B enzymes (eg, IMP, NDM, and VIM) are key drivers of carbapenem resistance. [Clin Infect Dis 2019;69:S521-S528]
“Global surveillance data indicate that MBLs, particularly NDM, are increasingly prevalent among carbapenem-resistant GN bacteria, which is concerning given the limited therapeutic options available,” noted Dr Subramanian Swaminathan of Gleneagles Global Hospital, Chennai, India. [J Glob Antimicrob Resist 2024;37:168-175]
MBL-producing Enterobacterales are associated with substantial mortality. A matched case-control study in intensive care unit (ICU) patients found significantly higher in-hospital mortality with GN NDM-1 producers vs non-NDM controls (55.3 vs 14.7 percent; adjusted odds ratio [aOR], 11.29; p<0.001). Similarly, prospective cohort studies in tertiary-care settings have reported increased all-cause mortality with VIM-producing (14-day mortality: 23.9 vs 15.8 percent; p=0.2) and IMP-producing (30-day mortality: 12.5 vs 5.1 percent; p=0.349) infections vs corresponding controls with no VIM-productions and non–carbapenemase-producing Enterobacteriaceae. [PLoS One 2015;10:e0123337; Antimicrob Agents Chemother 2009; 53:1868-1873; J Antimicrob Chemother 2020;75:697-708]
S. maltophilia is an intrinsically resistant GN pathogen, with resistance to antibiotic classes including aminoglycosides and carbapenems, partly mediated by a chromosomally encoded MBL (L1). It is associated with mortality rates of 21–69 percent, with higher risk in immunocompromized individuals, those with haematological malignancies, and in the setting of ICU admission or mechanical ventilation, indwelling catheters, and prior or inappropriate antibiotic therapy. [Antimicrob Agents Chemother 2020;64:e01433- e01420; Clin Microbiol Rev 2012;25:2-41; Infect Dis (Lond) 2024;56:335-347]
Identifying high-risk patients
Risk of MBL infections is driven by patient- and healthcare-associated factors. “Common risk factors include ICU admission, prior antimicrobial use, healthcare exposure, dialysis and comorbidities,” remarked Dr Paula Ramirez of La Fe University and Polytechnic Hospital, Valencia, Spain. “Local epidemiology and patient microbiology data, including prior colonization or surveillance cultures, further refine risk assessment, particularly in settings with high colonization pressure.” [Antibiotics (Basel) 2022;11:144; Crit Care 2012;16:142]
Treatment considerations
Given the limited therapeutic options available, treatment of MBL-producing Enterobacterales should be guided by local epidemiology, susceptibility patterns, and prior antibiotic exposure. [Antibiotics (Basel) 2022;11:144; Curr Infect Dis Rep 2026;28:3]
“While antimicrobial spectrum remains critical, pharmacokinetics [PK], pharmacodynamics [PD] and safety are equally important,” said Ramirez. In critically ill patients, pathophysiological alterations can significantly affect drug exposure, making PK/PD optimization essential to ensure adequate concentrations at the infection site. [J Intensive Med 2024;4:287-298]
Co-administration of ATM and a β-lactam/β-lactamase inhibitor combination has historically been used in the absence of effective alternatives. Because cephalosporins are hydrolyzed by MBLs, they are not used in this context. Nevertheless, the co-administration strategy is limited by nonaligned PK/PD targets, the need for coordinated infusions, logistical complexity, lack of standardized susceptibility testing, and limited randomized clinical trial evidence. [Infect Chemother 2026;58:82-90; Chem Rev 2021;121:7957-8094; Infect Dis Ther 2024;13:2423-2447]
ATM/AVI: Active against MBL producers
MBLs hydrolyze nearly all β-lactams except monobactams such as ATM. However, co-produced SBLs can inactivate ATM. AVI inhibits these enzymes, restoring ATM activity. The ATM/AVI combination is therefore active against MBL-producing pathogens, including Enterobacterales co-producing ESBLs, OXA-48-like enzymes, or KPC, as well as S. maltophilia. [Antimicrob Agents Chemother 2020;64:e01433-e01420; Antimicrob Agents Chemother 2015;59:4239-4248]
ATM/AVI is approved for treatment of complicated intra-abdominal infection (cIAI) and hospital-acquired pneumonia (HAP; including ventilator-associated pneumonia [VAP]) with limited or no alternative treatment options. [European Medicines Agency. Emblaveo Summary of Product Characteristics]
Optimized PK/PD
ATM/AVI demonstrates low protein binding and no significant hepatic metabolism (hence, low potential for drug-drug interactions). Both components are primarily renally eliminated and exhibit linear PK, with a half-life of approximately 2–3 hours. [Emblaveo Hong Kong Prescribing Information, August 2025]
Dose optimization is driven by PK/ PD principles, particularly achievement of a joint probability of target attainment (PTA) for both components. ATM’s efficacy is associated with time above minimum inhibitory concentration (MIC) (ie, 60 percent fT >MICATM-AVI of 8 mg/L), while AVI’s activity depends on time above a defined threshold (ie, 50 percent fT >CT of 2.5 mg/L). [Antimicrob Agents Chemother 2025;69:e0195024]
“The recommended ATM/AVI regimen — 2 g/0.67 g loading dose followed by 3-hour infusions every 6 hours in a fixed 3:1 ratio — is designed to achieve optimal PK/PD target attainment from the first dose, which is particularly relevant in critically ill patients,” noted Professor Garyfallia Poulakou of the National and Kapodistrian University of Athens, Greece. “Modelling demonstrates a joint PTA >90 percent across most renal function strata, including patients with augmented renal clearance, and across infection types.” [Emblaveo Hong Kong Prescribing Information, August 2025; Antimicrob Agents Chemother 2025;69:e0195024]
Key clinical trials
In the phase III REVISIT trial, 422 patients with cIAI or HAP/VAP caused by GN bacteria (including MBL producers) were randomized to receive ATM/AVI (plus metronidazole for cIAI) or meropenem with/ without colistin. Clinical cure rates were comparable between groups, with similar 28-day mortality. (Figure) [Lancet Infect Dis 2025;25:218-230]
In a subgroup of patients with Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥8, ATM/ AVI demonstrated comparable efficacy across infection types, with numerically higher response rates vs comparator therapy. [Open Forum Infect Dis 2025;12:ofae631.312]
The phase III ASSEMBLE trial evaluated ATM/AVI (n=12) vs best available therapy (n=3) in MBL-producing infections. Noting the very small comparator group, clinical cure rates were 42 vs 0 percent, with favourable microbiological responses of 50 vs 0 percent. [JAC Antimicrob Resist 2025;7:dlaf131]
Conclusions
Multidrug-resistant MBL-producing GN infections, including Enterobacterales and S. maltophilia, are associated with high mortality and have limited treatment options. ATM/AVI provides targeted activity through inhibition of co-produced β-lactamases and PK/PD-optimized exposure, achieving high PTA. Emerging clinical evidence supports its role in treating these serious infections.
This special report is supported by an education grant from the industry.
