Case Commentary: Uncertainty in Evaluating Treatment Outcomes in Carbapenem-Resistant Acinetobacter baumannii Infections

ABSTRACT

Carbapenem-resistant Acinetobacter baumannii (CRAB) infections are challenging to treat and associated with poor clinical outcomes. In this issue, sulbactam-durlobactam, a novel β-lactam-β-lactamase inhibitor, was used with cefiderocol to successfully treat CRAB pneumonia. While this report and in vitro data are encouraging, determining the impact of treatment regimens on clinical outcomes after CRAB infections is not straightforward. Therefore, careful evaluation in pathogen-directed randomized controlled trials is needed to determine the optimal treatment of CRAB infections.

INTRODUCTION

Infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) are notoriously difficult to treat, both because of the limited therapeutic options available for this pathogen as well as the vulnerable patient population most likely to be infected (1, 2). According to U.S. national surveillance data, >40% of the Acinetobacter cultures identified in patients with ventilator-associated pneumonia in the intensive care unit (ICU) are resistant to carbapenems (3). Most CRAB isolates are also either extremely drug resistant (only susceptible to polymyxins, tigecycline, and aminoglycosides) or pan-drug resistant, making treatment extremely challenging (2, 4). Patients with CRAB have at least double the odds of dying compared to patients with carbapenem-susceptible A. baumannii (5). In this issue of Antimicrob Agents Chemother, Zaidan et al. present a case of a 55-year-old female who developed nosocomial pneumonia caused by Pseudomonas aeruginosa and highly resistant A. baumannii. Combination therapy of cefiderocol and sulbactam-durlobactam was associated with a sustained clinical response.

Sulbactam-durlobactam, a novel β-lactam-β-lactamase inhibitor (BL-BLI), has the potential to be a much-needed addition to the currently available therapeutics with activity against CRAB. As alluded to in the clinical challenge question proposed by Zaiden et al., many of the recently developed novel BL-BLIs targeting carbapenem-resistant Gram-negative pathogens, including meropenem-vaborbactam, ceftazidime-avibactam, ceftolozane-tazobactam, and imipenem-relebactam, do not have activity against CRAB (6). In the United States, sulbactam is currently only used in fixed combination with ampicillin. In addition to β-lactamase inhibition, sulbactam also has direct activity against A. baumannii by binding to the penicillin-binding proteins of Acinetobacter spp. (7, 8). Unfortunately, sulbactam is degraded by many commonly acquired β-lactamases, resulting in high MICs against most CRAB (7–9). Durlobactam, a non-β-lactam β-lactamase inhibitor, can inhibit Ambler class A, C, and D β-lactamases (including OXA-type carbapenemases) and help restore the activity of sulbactam (7, 9). In a study of 1,722 diverse A. baumannii-calcoaceticus complex isolates, adding durlobactam decreased the MIC₉₀ by 32-fold compared to sulbactam alone (8). Sulbactam-durlobactam also has demonstrated in vitro activity specifically against CRAB, with <4% of 246 CRAB isolates found to have an MIC of >4 mg/liter for sulbactam, the proposed clinical breakpoint for resistance (9, 10). Notably, durlobactam does not inhibit metallo-β-lactamases (MBLs), and this may limit its usefulness in treating cases of extremely drug-resistant A. baumannii in countries where the prevalence of MBLs is high (11, 12).

Clinically, sulbactam-durlobactam was well tolerated in a phase 2 study, including patients with complicated urinary tract infections (cUTI) and acute pyelonephritis. All patients were treated with imipenem-cilastatin and randomized to receive sulbactam-durlobactam or placebo. Similar efficacy was observed in the two treatment arms, but since all patients received imipenem-cilastatin, this was expected (13). ATTACk (Acinetobacter Treatment Trial Against Colistin), a pathogen-focused phase 3 randomized trial, is currently recruiting patients with hospital-acquired or ventilator-associated bacterial pneumonia or bacteremia caused by A. baumannii-calcoaceticus complex (ABC) and will provide critical information about the efficacy of sulbactam-durlobactam for treating serious A. baumannii infections (registered at ClinicalTrials.gov under the identifier NCT03894046). Patients in this study will be randomized to receive either combination therapy with sulbactam-durlobactam and imipenem-cilastatin or combination therapy with colistin and imipenem-cilastatin. The primary efficacy endpoint is 28-day all-cause mortality, and the primary safety endpoint is the incidence of nephrotoxicity. There is an arm of this study (part B) which will analyze patients with ABC isolates resistant to polymyxins, all of whom will receive sulbactam-durlobactam and imipenem-cilastatin (https://clinicaltrials.gov/ct2/show/study/NCT03894046).

The case presented by Zaidan et al. is an example of real-world use of sulbactam-durlobactam for serious CRAB infections. The case also illustrates challenges in determining the contribution of antibacterial treatment regimens to ultimate clinical outcomes after CRAB infections. These challenges are related to several factors. First, patients at risk for CRAB colonization and infection tend to have multiple chronic and acute medical issues. These noninfectious comorbid conditions themselves are also associated with poor clinical outcomes and all-cause mortality. Second, differentiating between infection and colonization is quite difficult in the setting of nosocomial pneumonia. Third, as in the case exemplified here, CRAB is often part of a polymicrobial process. The relative contribution of CRAB versus other bacteria is generally impossible to determine. Fourth, in real-world settings, treatment of CRAB infections is often characterized by the use of multiple antibacterial agents and frequent switches in therapy. In the case described, cefiderocol was given as a second agent. Cefiderocol has good in vitro activity against CRAB (4). However, in CREDIBLE-CR, an open-label, multicenter, phase 3 study comparing cefiderocol to the best available therapy for patients with a carbapenem-resistant Gram-negative pathogens, mortality was higher in patients with A. baumannii infections treated with cefiderocol than the best available therapy (14). These results led to the U.S. Food and Drug Administration (FDA) requiring a warning on the prescribing information (https://www.fetroja.com/using-fetroja). Based on two large randomized controlled trials (AIDA and OVERCOME), one question which is definitively answered is that adding a carbapenem to colistin is not beneficial in the treatment of CRAB infections (15, 16). While some encouraging in vitro data exist, clinical data similarly do not support using fosfomycin, rifamycins, or glycopeptides in combination regimens for CRAB infections.

In summary, CRAB infections are associated with a high burden of morbidity and mortality, and limited treatment options exist. Evaluating existing and novel treatment options for CRAB infections is challenging, and the translation of in vitro findings to clinical use is not straightforward. Nonetheless, the AIDA and OVERCOME trials have provided a roadmap to conclusively answer important questions in the management of CRAB infections. Furthermore, the development of novel agents with anti-CRAB activity is an important and encouraging step. Similar to outstanding questions in the evaluation and treatment of other bacterial diseases, diagnostic issues remain of paramount importance. Rapid diagnostics are increasingly being used and developed. However, these generally do not address the question of distinguishing infection versus colonization. Diagnostics based on evaluating the host response may assist in this determination (17, 18). Novel diagnostics, treatment options, and robust clinical trials to determine their efficacy will hopefully usher in the dawn of a new era in CRAB infections with less questions and more answers.

The views expressed in this article do not necessarily reflect the views of the journal or of ASM.