Current treatment options for pneumonia caused by carbapenem-resistant Acinetobacter baumannii

Abstract

Purpose of review:

The purpose of this review is to briefly summarize the challenges associated with the treatment of pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB), discuss its carbapenem-resistance, and review the literature supporting the current treatment paradigm and therapeutic options.

Recent findings:

In a multicenter, randomized, and controlled trial the novel β-lactam-β-lactamase inhibitor sulbactam-durlobactam was compared to colistin, both in addition to imipenem-cilastatin. The drug met the prespecified criteria for non-inferiority for 28-day all-cause mortality while demonstrating higher clinical cure rates in the treatment of CRAB pneumonia. In an international, randomized, double-blind, placebo controlled trial colistin monotherapy was compared to colistin combined with meropenem. In this trial, combination therapy was not superior to monotherapy in the treatment of drug-resistant gram-negative organisms including CRAB pneumonia.

Summary:

CRAB pneumonia is a preeminent public health threat without an agreed upon first line treatment strategy. Historically, there have been drawbacks to available treatment modalities without a clear consensus on the first-line treatment regimen. CRAB pneumonia is a top priority for the continued development of antimicrobials, adjuvant therapies and refinement of current treatment strategies.

Introduction:

The Acinetobacter baumannii-calcoaceticus (ABC) complex is a group of clinically relevant gram-negative coccobacilli. Among the ABC complex, Acinetobacter baumannii is associated with the greatest burden of disease (1). It is one of six bacteria that combined to account for 73% of deaths attributable to antimicrobial resistance (AMR) in 2019 (2). Notably, hospital-acquired carbapenem-resistant Acinetobacter baumannii (CRAB) infections increased 78% during the COVID-19 pandemic (3). Both the CDC and the WHO have declared CRAB a top priority for the development of new antimicrobials (4,5). The Study Network of Acinetobacter baumannii as a Carbapenem-Resistant Pathogen (SNAP) published an international cohort of 842 hospitalized patients with CRAB infections, which provided insight into the burden of disease (6). 67% of the cohort was deemed to have an infection, 24% of whom died by day 30 underscoring the high mortality associated with CRAB infections (6).

CRAB is most commonly isolated from patients in intensive care units where hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are prevalent (7). In an international prevalence study of infections in the ICU, 64% of all infections were respiratory in origin and Acinetobacter species were responsible for 8% of all infections (8). In a large international, surveillance study of patients hospitalized with probable pneumonia from 2016 to 2019, Acinetobacter baumannii varied by region, accounting for 1.9%, 19% and 2.8% of isolates in Eastern Europe, Western Europe, and the United States respectively (9). VAP, in particular, is associated with high mortality and increased healthcare costs (8,10).

The presence of CRAB in the respiratory tract does not necessarily denote pneumonia. Microbial pathogenesis is the result of host damage from the host-microorganism interaction and can range from commensalism or colonization to disease (11). This interaction is occurring simultaneously with ever-changing immune function and microbial fitness (11). Antibiotics have the capacity to increase or decrease host damage by either augmenting or dampening the host immune response, depending on the current host-microorganism interaction (12). These possible scenarios make it difficult to weigh the benefit of antimicrobials for a particular patient. Likewise, this ambiguity complicates the interpretation of outcome data where it is not always clear whether host factors or antibiotic inefficacy are responsible for clinical nonresponse. Nevertheless, once the decision is made to treat CRAB pneumonia, there remains much to consider. This review focuses on relevant updates in the management of CRAB pneumonia, including recently published clinical trials and the 2023 Infectious Diseases Society of America (IDSA) guidance for the treatment of resistant gram-negative infections and novel therapeutics.

Carbapenem Resistance Mechanisms:

Carbapenem resistance mechanisms in Acinetobacter baumannii are vast and can be encoded on the chromosome or acquired via horizontal gene transmission or via natural transformation (3). The Ambler class D β-lactamase OXA-23(13) is the most common carbapenem resistance mechanism and has been disseminated worldwide (14). Resistance conferred via OXA-24/40 (15,16) is also common, though it has weaker activity against carbapenems and contributes to decreased susceptibility in conjunction with other mechanisms (3). Class B metallo-β-lactamases, porin channels and efflux pumps are less common mechanisms of carbapenem resistance (17). In the SENTRY antimicrobial surveillance program from 2020 through 2021, there were 788 Acinetobacter isolates in the US and 943 in Europe with 26% and 62% of isolates resistant to imipenem and/or meropenem in the US and Europe respectively (3). These isolates were sequenced for β-lactamase genes with 80.5% carrying bla_OXA-23-like and 16.6% carrying bla_OXA-24-like genes in Europe while 52.2% carried bla_OXA-23-like and 29.3% carried bla_OXA-24-like genes in the US (3).

Ampicillin-sulbactam:

High-dose ampicillin-sulbactam is a first line option for the treatment of CRAB pneumonia. The anti-Acinetobacter activity of the drug is meditated by the sulbactam component; it has direct activity due to its inhibition of penicillin-binding proteins (PBPs), PBP1a/1b and PBP3 (17,18). Notably, CRAB resistance to sulbactam is common and is mediated by Acinetobacter baumannii-derived cephalosporinases (ADCs) and class D OXA enzymes (19,20). The rationale for using high-dose ampicillin-sulbactam is to overcome these resistance mechanisms and allow it to reach the PBP target (21).

In totality, the clinical data, including RCTs supports the use of ampicillin-sulbactam at high-doses. In a 2021 meta-analysis of 1835 patients with CRAB, multidrug resistant Acinetobacter baumannii (MDR-AB) and extensively drug resistant Acinetobacter baumannii (XDR-AB) from 18 studies, 11 evaluated the treatment of HAP or VAP and 6 others included patients with pneumonia (22). Ampicillin-sulbactam in combination with a second antibiotic had the highest-ranking efficacy in comparison to colistin-based, two-drug combinations and less nephrotoxicity was observed in sulbactam-containing regimens (22). A 2017 meta-analysis of 23 studies evaluating 15 treatments for CRAB pneumonia concluded that sulbactam was the top-performing treatment for survival benefit (23). In a small, open-label trial comparing colistin to colistin and high dose ampicillin/sulbactam, early clinical cure rates were 70% in the combination group versus 15.8% in the colistin alone group for the treatment of CRAB pneumonia (24). In contrast, a small clinical trial comparing colistin and meropenem with ampicillin-sulbactam and meropenem for CRAB VAP did not demonstrate a difference in clinical or microbiological cure (25). Likewise, a small single-center RCT demonstrated no difference in response rate or mortality between colistin and ampicillin-sulbactam in the treatment of MDR-AB VAP (26). Overall, the literature including a small, open label RCT supports high dose ampicillin-sulbactam as a first line treatment option for CRAB pneumonia. The IDSA recommends high-dose ampicillin-sulbactam as a component of combination therapy for the treatment of CRAB regardless of susceptibility while the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommends ampicillin-sulbactam for CRAB HAP or VAP that is susceptible to sulbactam (21,27).

Polymyxins:

Polymyxins, despite narrow therapeutic windows and significant nephrotoxicity, continue to be frequently used for XDR gram-negative infections including CRAB pneumonia (21,27). Existing evidence supports the use of ampicillin-sulbactam preferentially over the polymyxins. In a retrospective study of 98 patients with CRAB VAP, clinical cure rates were similar; however treatment with colistin was associated with an increased 30-day mortality and microbiologic failure was higher at 7 days (28). In an RCT interim analysis, 29 patients with MDR-AB VAP were randomly assigned to colistin plus levofloxacin or high-dose ampicillin-sulbactam plus levofloxacin; clinical response occurred in 27% of the colistin group and 83% of the ampicillin/sulbactam group while 14-day and 28-day mortality were significantly higher in the colistin group (29).

Several factors support using polymyxins for CRAB pneumonia in combination with a second CRAB-directed antibiotic rather than as monotherapy. First, polymyxins have been associated with the rapid acquisition of resistance (30,31). In one study, a 128-fold increase in minimum inhibitory concentration (MIC) was observed in the first 72 hours (17). Second, susceptibility to colistin has been over-reported, especially when using gradient tests (32). Thirdly, there is a significant overlap between therapeutic and nephrotoxic serum levels of polymyxin complicating appropriate dosing (33). Finally, concern exists over the ability of polymyxin to reach optimal therapeutic levels in pulmonary epithelial cells, a concern in the treatment of pneumonia (34–36). The IDSA recommends consideration of the polymyxins for CRAB infections with at least one other agent (21). ESCMID recommends consideration of polymyxin for CRAB infections where sulbactam resistance is present and polymyxin susceptibility is confirmed (27).

Tetracycline derivatives:

Minocycline, tigecycline and eravacycline are durable to common tetracycline resistance mechanisms (37,38) and have in vitro activity against ABC complex. Minocycline, in particular, has robust in vitro activity with 85.7% of CRAB isolates susceptible in one international surveillance study (39). Unlike ampicillin/sulbactam, sulbactam/durlobactam and polymyxins, there are no RCTs to guide tetracycline use for the treatment of CRAB pneumonia. However, the totality of observational data does support tetracycline use in combination with another CRAB active antibiotic. Of the tetracyclines, minocycline has the most robust evidence for its use. In the largest observational study examining its efficacy for MDR-AB infections, 55 patients, 58% of whom had a respiratory infection, received either minocycline monotherapy (n=3) or minocycline in combination with additional antimicrobials (n=52) with 73% of these patients achieving clinical success (40). Interpretation of this retrospective, single-center study is complicated by the diversity of antibiotics used in combination therapy and the conservative 100 mg dose of minocycline administered (41). In fact, in vitro pharmacodynamic modeling supports high dose minocycline at doses of 350 mg daily (17); though safety and efficacy of this approach has yet to be borne out in clinical trials.

The effectiveness of tigecycline for pneumonia has been called into question by observational and meta-analyses where an increase in mortality has been observed, including in patients with CRAB pneumonia (42–45). While subsequent, non-randomized studies have suggested that high dose tigecycline may mitigate this effect (46,47), these studies were conducted with combination therapy making it difficult to assess tigecycline monotherapy. Additionally, there is a lack of clarity around the definition of tigecycline-susceptible CRAB as there are no published MIC breakpoints. Importantly, tigecycline susceptibility should not be extrapolated from minocycline breakpoints. Given these limitations, tigecycline is considered a second line tetracycline in the treatment of CRAB pneumonia.

Clinical data evaluating eravacycline for the treatment of CRAB pneumonia is scant. In the only comparative study, 93 patients were included in a retrospective cohort that compared eravacycline with best previously available therapy; 30-day mortality was 33% in the eravacycline group versus 15% (P = 0.048) in the control group and microbiologic cure rates were lower with eravacycline (48).

The IDSA recommends either high-dose minocycline or tigecycline in combination with at least one other agent for the treatment of CRAB infections with a preference for minocycline (21). ESCMID recommends high-dose tigecycline for patients with sulbactam-resistant CRAB infections (27).

Cefiderocol:

Cefiderocol, was approved for the treatment of bacterial HAP and VAP in 2020. The drug was developed to overcome various mechanisms of AMR. It contains a siderophore component that binds to iron, facilitates bacterial cell wall entry, and may offer protection from porin channels, efflux pumps and inactivation by carbapenemases (49,50). However, downregulation of iron receptors by bacteria plays a role in disabling this mechanism of entry (49,50). While surveillance studies have demonstrated excellent in vitro activity (51,52) against ABC complex, clinical data have been discouraging. In an open-label RCT of 152 patients with carbapenem-resistant gram-negative infections, 54 of whom had CRAB infections, 36 of which were pneumonia, mortality rates were 49% and 18% in the cefiderocol group and best available treatment group respectively (53). In a retrospective study of 124 patient with CRAB infections, 35 of whom had VAP, patients who received cefiderocol-containing regimens were compared to patients who received colistin-based regimens (54). While mortality was higher in the group who received colistin (55.8% versus 34%), the group who received cefiderocol experienced higher rates of microbiological failure (17.4% versus 6.8%) with half of these patients developing resistance post-treatment (54). Overall, the data does not support cefiderocol being used as a first line therapy for CRAB pneumonia. The IDSA recommends only using cefiderocol to treat CRAB infections refractory to other agents and only in combination with other CRAB-directed antibiotics (21). ESCMID recommends against using cefiderocol for CRAB infections (27).

Carbapenems:

Despite meropenem and/or imipenem-cilastatin by definition having elevated MICs to CRAB, carbapenems inclusion in combination regimens were previously justified by studies demonstrating in vitro synergy with colistin (55–57). However, the futility of adding meropenem to colistin has been confirmed by two clinical trials. In the AIDA trial, 406 patients, 312 of whom had CRAB and 43% of whom had pneumonia, were randomized to colistin versus colistin with meropenem (58). Combination therapy was not superior to monotherapy (58). In the OVERCOME trial, patients with pneumonia (70%) and/or bacteremia, 78% of whom had CRAB infections, were randomized to colistin and meropenem or colistin and placebo; there were no differences in mortality, clinical failure or microbiological cure (59). It is therefore unlikely that adding meropenem to colistin in the treatment of CRAB pneumonia will benefit patients. However, the role of imipenem-cilastatin in combination with sulbactam-durlobactam, as was administered in the ATTACK trial, needs to be further clarified. The IDSA recommends against treatment with meropenem or imipenem/cilastatin for CRAB infections (21). ESCMID strongly recommends against the use of the combination of polymyxins and meropenem for the treatment of CRAB; however they recommend considering meropenem when the MIC < 8 mg/L (27). Of note, both of these recommendations were published prior to the publication of the ATTACK trial.

Sulbactam-durlobactam:

Sulbactam-durlobactam is a novel bactericidal β-lactam-β-lactamase inhibitor recently approved by the Food and Drug Administration (FDA) for the treatment of HAP and VAP secondary to ABC. Sulbactam has activity against Acinetobacter by binding to PBP-1 and PBP-3 but is subject to degradation from both class D OXA enzymes and ADCs. Durlobactam offers potent inhibition of class D β-lactamases (60). Importantly, in vitro durlobactam has been shown to restore sulbactam’s activity against CRAB (60–62).

Clinical efficacy of sulbactam-durlobactam for the treatment of CRAB pneumonia was demonstrated by the ATTACK trial, a multicenter, non-inferiority RCT that compared colistin to sulbactam-durlobactam both with background imipenem-cilastatin (63). The microbiologically modified intention-to-treat population included 128 patients, 125 of whom had HAP, VAP or ventilated pneumonia (63). After 3 withdrawals of consent, 125 of the participants were assessed for the primary endpoint of 28-day all-cause mortality, which 19% of the sulbactam-durlobactam group and 32% of the colistin group met thereby achieving the pre-specified criteria for non-inferiority (63). The sulbactam-durlobactam group had higher clinical cure rates, more favorable microbiological outcomes, and less nephrotoxicity (63). The concomitant imipenem-cilastatin therapy must be considered. It was continued during the entire course of therapy, even in patients with monomicrobial infections. Thus, it is not entirely clear that the positive results are from sulbactam-durlobactam alone or from synergistic effects of the combination. There were shortcomings in this study, including a lack of representation of patients in North America and the exclusion of patients with underlying lung disease; however, these results indicate sulbactam-durlobactam is a promising new first-line treatment option. Clarifying the necessity of imipenem-cilastatin in addition to sulbactam-durlobactam should be a focus of future research. Of note, sulbactam-durlobactam was unavailable for inclusion in the 2023 IDSA guidelines or the 2022 ESCMID MDR gram-negative guidelines (21,27).

Therapeutic Approach with Combination Therapy:

While in vitro studies have demonstrated synergy between various agents for the treatment of Acinetobacter baumannii (24,27,64–67) several clinical studies, including RCTs have failed to show a consistent benefit (18,24,58,68,69). A key exception is a trial comparing colistin versus colistin combined with high-dose ampicillin-sulbactam in the treatment of VAP, which found combination therapy was associated with a favorable clinical response (70). Despite this equivocal data the IDSA recommends at least two active antibiotics for the treatment of CRAB infections including high-dose ampicillin-sulbactam as one of the agents regardless of susceptibility (21). This treatment approach is based on a dearth of clinical trials demonstrating the efficacy of any single antibiotic in the treatment of CRAB, the organism’s ability to rapidly acquire resistance, and the large bacterial burdens associated with infection (21). Similarly, ESCMID recommends combination therapy including two in vitro active antibiotics in the management of severe and high-risk CRAB infections (27).

Conclusion:

CRAB and its manifestations as a pulmonary pathogen remain a preeminent public health challenge. Despite the recent FDA approval of the promising sulbactam-durlobactam, there continues to be a high priority for the development of other novel antimicrobials, adjuvant treatment modalities and clarification of the first-line treatment strategy. Short-term research priorities include clarifying the role of imipenem-cilastatin, if any, in the positive results of the ATTACK trial. While combination therapy continues to be the standard in the treatment of CRAB pneumonia, further research to clarify the most effective combination therapy is needed.

Key points:

• CRAB pneumonia is an urgent public health threat that requires ongoing basic and clinical research

• Carbapenem resistance is most often conferred by class D β-lactamases OXA-23 or OXA-24/40

• Treatment with the combination of at least two antimicrobials in the treatment of CRAB pneumonia is a recommended approach by the IDSA for all CRAB infections and by ESCMID for severe, complicated infections

• Sulbactam-durlobactam should be included in first-line treatment regimens where available