Turning the Tide Against Carbapenem-resistant Acinetobacter baumannii : Advancing Care With Sulbactam–Durlobactam

Acinetobacter baumannii is a Gram-negative opportunistic pathogen that presents significant challenges in healthcare settings, particularly in intensive care units (ICUs) and long-term acute care hospitals (LTACHs). It is among the leading nosocomial pathogens associated with ventilator-associated pneumonia (VAP), ranking as the 10th most frequently reported pathogen in ICUs, where it accounted for 3.2% of cases. In LTACHs, it plays an even more prominent role, ranking 4th and contributing to 6.6% of VAP cases [1]. The World Health Organization (WHO) has designated carbapenem-resistant A. baumannii (CRAB) as a critical priority pathogen due to its extensive antimicrobial resistance, the limited treatment options, and global health impact [2–4]. This paper explores the clinical and epidemiological aspects of A. baumannii, the challenges posed by existing therapies, and the emergence of sulbactam–durlobactam (SUL/DUR) as a promising therapeutic option. The global epidemiology of A. baumannii reflects its position as a leading cause of nosocomial infections and a critical public health challenge due to its rapid acquisition of multidrug resistance (MDR). CRAB is particularly concerning, with its prevalence intensifying in several regions globally. The Mediterranean region remains a significant hotspot, where over 90% of clinical isolates demonstrate carbapenem resistance [5]. Indeed, similar data are reported from various parts of the world as can be seen in Figure 1. Global percentage of resistance to carbapenems (R%) of A. baumannii between 2009 and 2018. Adapted from Ma and McClean [5]. Global percentage of resistance to carbapenems (R%) of A. baumannii. The intensity of pink shading indicates estimated carbapenem resistance levels worldwide between 2009 and 2018. Regions shown in green reflect a lack of reliable surveillance or published data. Figure reproduced from [5]. In the United States, surveillance data of healthcare-associated infections from 2015 to 2017 highlight the disproportionate burden of carbapenem resistance among Acinetobacter spp., with carbapenem resistance identified in 41.3% to 52.8% of isolates in patients in ICUs and in 75.4% to 76.9% of isolates from patients in LTACHs [1]. In comparison, Pseudomonas aeruginosa exhibited carbapenem resistance ranging from 19.7% to 26.3% in isolates from ICU patients and 35.9% to 61.4% in isolates from LTACH patients, while Enterobacterales demonstrated carbapenem resistance rates of 3.5% to 7.2% in ICUs and 9.4% to 13.7% in LTACHs [1]. Additional data from the JMI Laboratories’ SENTRY Antimicrobial Surveillance Program (2014–2021) reinforce these findings, showing that 36.5% of Acinetobacter baumannii–calcoaceticus species complex (ACB) isolates were meropenem-resistant [6]. Given these high resistance rates, CRAB infections pose a substantial clinical burden, causing an estimated 8500 infections and 700 deaths [7]. A broader global perspective underscores the growing crisis. Recent modeling by Oldenkamp et al [8], expanding surveillance efforts across multiple regions, found CRAB present in 87% of countries, impacting 99% of the global population. This widespread prevalence disproportionately affects low- and middle-income regions, where healthcare inequities amplify the devastating effects of rising resistance. Figure 1 provides a striking visualization of these trends, mapping key resistance hotspots across the Mediterranean, the Middle East, and Southeast Asia while also highlighting emerging areas of concern, including sub-Saharan Africa. CRAB infections are associated with significantly higher mortality rates compared with infections caused by carbapenem-susceptible A. baumannii (CSAB). A systematic review of 16 studies comparing outcomes between CRAB and CSAB infections reported a 2.22-fold increase in mortality among patients with CRAB infections, with the highest risk observed in individuals with severe underlying conditions or those receiving inappropriate initial treatments [9]. Global mortality data reveal substantial regional differences. A multicenter study found that 30-day mortality among CRAB-infected patients was highest in South-Central America (49%), followed by the United States (25%), China (20%), the Middle East (18%), and Australia–Singapore (6%) [10]. Among infection types, bloodstream infections (BSIs) had the highest 30-day mortality (42%), followed by respiratory infections (23%), wound infections (11%), and urinary tract infections (UTI; 11%). Several studies have identified key risk factors for mortality after infection due to CRAB. A retrospective cohort study of CRAB infections in ICUs reported a 90-day mortality rate of 30.3%, with higher mortality observed among patients with BSIs and severe comorbidities [11]. Independent risk factors for increased mortality included diabetes, immunocompromised status, high sequential organ failure assessment scores, vasopressor use, and pneumonia as the primary source of bacteremia [12]. A different analysis of 164 patients with CRAB BSIs demonstrated a 30-day mortality rate of 55%, with ST191 identified as the most prevalent strain. Inappropriate empirical therapy was a significant factor associated with mortality [13]. A retrospective cohort study involving 196 patients in a tertiary care teaching hospital reported an in-hospital mortality rate of 58.7%. Predictors of mortality included invasive mechanical ventilation, effective antibiotic treatment lasting ≤6 days, age >58 years, and the absence of coinfection [14]. A U.S. cohort study of 4599 inpatients with Acinetobacter infections found that 13.6% died during admission. However, among patients specifically infected with CRAB, the inpatient mortality rate was notably higher at 24.7%, nearly 3 times that of non-CRAB infections (8.5%) [15]. These findings underscore the critical need for early and appropriate therapeutic interventions, particularly in cases of carbapenem-resistant strains. Beyond its clinical consequences, CRAB infections impose a substantial economic burden on healthcare systems. In the U.S., CRAB infections cost an estimated $281 million annually [7]. A U.S.-based study by Nelson et al [16] estimated the cost of an MDR A. baumannii healthcare-associated infection to range from $33 510 to $129,917, depending on the methodology used. In China, patients with CRAB infections incurred $7277 in additional hospital costs and a 15.8-day increase in hospital length of stay compared with those with CSAB infections [17]. Finally, in Europe, the European Centre for Disease Prevention and Control (ECDC) estimated 56 960 CRAB infections in EU/EEA hospitals in 2019, leading to 2749 attributable deaths and 92 991 disability-adjusted life years [18]. Acinetobacter baumannii demonstrates remarkable adaptability in its resistance mechanisms, making it a significant challenge in clinical management. One of its primary resistance mechanisms is the production of OXA-type carbapenemases, including OXA-23, OXA-24/40, and OXA-58. Among these, OXA-23 is particularly widespread and is the most common mechanism of carbapenem resistance [10]. Molecular studies have shown that OXA-23 exhibits conformational flexibility near its active site, enabling it to hydrolyze a broad spectrum of β-lactam antibiotics with enhanced catalytic efficiency [19]. Despite its clinical importance, OXA-23 is often underrepresented in commercial molecular diagnostic assays such as BCID2, Verigene, CarbaR, and Carba5, which primarily target carbapenemases like KPC, NDM, and OXA-48 [20]. This omission frequently results in the under detection of OXA-23-producing strains and delays in identifying CRAB. Recent advancements, including the NG-Test DetecTool OXA-23 and RESIST ACINETO assays (currently lacking FDA clearance), have demonstrated high sensitivity and specificity for detecting OXA-23 directly from blood cultures, addressing this gap in diagnostic capability [21–23]. Genome sequencing and in silico analyses have enabled the identification of extended-spectrum β-lactamases (ESBLs) such as blaPER, blaVEB, and blaGES in Acinetobacter spp., of which blaPER is most common [24]. The blaPER in Acinetobacter spp. has been documented from diverse geographic regions, highlighting its global distribution [24]. Of particular concern, the expression of PER-type ESBLs in A. baumannii can compromise the activity of newer agents such as cefiderocol. In addition to carbapenemases and ESBLs, antimicrobial resistance in A. baumannii is also mediated by chromosomal class C β-lactamases, known as Acinetobacter-derived cephalosporinases (ADCs). These enzymes confer intrinsic resistance to penicillins and first- and second-generation cephalosporins [24]. Structural variation in ADCs primarily occurs in the Ω-loop region near the cephalosporin binding site, where a common alanine duplication (Adup) has been observed that leads to hydrolysis of third-generation cephalosporins such as cefotaxime and ceftazdime [25]. Three Adup variants of ADC have also demonstrated increased catalytic efficiency against cefiderocol, leading to increases in cefiderocol MIC values. However, most isolates with these ADC variants still demonstrate cefiderocol MICs ≤4 µg/mL [25]. Resistance in A. baumannii is further driven by intrinsic mechanisms such as efflux pumps, porin alterations, and chromosomally encoded enzymes such as OXA-51 and AmpC β-lactamases (Figure 2). Resistance mechanisms of Acinetobacter baumannii to antimicrobial agents. Various resistance mechanisms of Acinetobacter baumannii to antimicrobial agents are shown, including the mechanism of action of sulbactam and durlobactam. These include antibiotic-modifying enzymes, efflux pumps, porin alterations, and drug target modifications, along with the antibiotic classes affected by each mechanism. Abbreviations: AMEs, aminoglycoside modifying enzymes; ESBLs, extended-spectrum β-lactamases; LPS, lipopolysaccharide; PBP, penicillin binding protein. Efflux systems, including AdeABC, actively expel antibiotics, reducing concentrations inside the bacterial cell and limiting activity. Modifications to cell wall porins further restrict antibiotic entry, while enzyme degradation by ADCs hydrolyze cephalosporins, diminishing the effectiveness of β-lactam antibiotics [26]. Alterations in penicillin-binding proteins (PBPs), particularly PBP3, also play a critical role in resistance by reducing the binding affinity of β-lactams, including novel agents like cefiderocol [27, 28]. The genomic plasticity of A. baumannii exacerbates its resistance profile, enabling the acquisition and dissemination of resistance genes through mobile genetic elements such as transposons and plasmids. High-risk clones, including ST1 and ST2, amplify this problem by spreading resistance determinants via horizontal gene transfer and homologous recombination [2]. Rapid and accurate detection of resistance genes is critical for effective clinical management. Recent innovations in diagnostic tools have shown promise in addressing this need. For instance, a 15-μL recombinase polymerase amplification (RPA) assay demonstrated high sensitivity and specificity in detecting blaOXA-23 and blaOXA-51 genes, offering a rapid and cost-effective alternative to traditional PCR and qPCR methods. The RPA assay detected resistance in 90% of A. baumannii isolates within 18 minutes, demonstrating its potential as a fast molecular diagnostic tool [29]. However, because the assay was tested on bacterial isolates rather than directly from clinical specimens, its suitability as a point-of-care test remains uncertain. An increasingly studied feature of A. baumannii isolates is its propensity to have heteroresistance to important antibiotics, defined as the presence of a resistant subpopulation within an otherwise susceptible bacterial community. Heteroresistance is not detected by routine antimicrobial susceptibility testing (AST) performed in clinical laboratories [30] and may lead to treatment failure by enabling regrowth of resistant cells during therapy [31]. Heteroresistance is most commonly reported with colistin, a last-resort option for multidrug-resistant Acinetobacter infections but has also been described with newer and repurposed agents including cefiderocol and tigecycline [32, 33]. Additional studies are needed to better understand the clinical importance of heteroresistance in A. baumannii. These findings highlight the urgent need for comprehensive surveillance systems, robust diagnostic tools, and innovative therapeutic strategies to combat A. baumannii resistance. Targeted diagnostics, such as rapid immunochromatographic assays, combined with novel therapeutic agents that circumvent conventional resistance in the clinical and public health impact of this and addressing the resistance mechanisms in A. baumannii is to its and The treatment of CRAB infections remains a significant challenge due to the extensive resistance mechanisms and the limited of effective therapeutic in and with clinical outcomes and mortality rates highlighting the need for of for CRAB Abbreviations: percentage of the drug remains the under the to bloodstream under the to of for CRAB Abbreviations: percentage of the drug remains the under the to bloodstream under the to of the and for CRAB Abbreviations: bloodstream CRAB, carbapenem-resistant Acinetobacter carbapenem-resistant carbapenem-resistant bacterial healthcare-associated urinary tract ventilator-associated ventilator-associated bacterial A. baumannii. of the and for CRAB Abbreviations: bloodstream CRAB, carbapenem-resistant Acinetobacter carbapenem-resistant carbapenem-resistant bacterial healthcare-associated urinary tract ventilator-associated ventilator-associated bacterial A. baumannii. including and are still frequently to severe CRAB infections in regions, particularly in These agents demonstrate broad activity against MDR but clinical is limited by and the emergence of strains involving such as or have shown rates compared with the remains and treatment outcomes depending on resistance and to The and has the susceptible for the of these agents to in pneumonia and which often in drug studies have demonstrated that to bacterial in infection even at the highest further role in the treatment of CRAB pneumonia Given these on particularly as be with and alternative agents be The compared the of to therapy for pneumonia and BSIs caused by Gram-negative of which were due to A. baumannii. 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