Recent study results show promising new modalities.
Hope. We could all use more of it these days, and the recently released topline results from the ATTACK study (NCT03894046) provide just that for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) infections.1 By any definition, treatment of CRAB infections represents a dire need for innovative therapeutics.
Current treatment decisions are motivated by desperation rather than clinical evidence, and the polymyxin class remains a cornerstone of recommended combinations.2 Thus, justifiable excitement has surrounded the preliminary results of the phase 3 ATTACK clinical trial evaluating the safety and efficacy of sulbactam-durlobactam (SUL-DUR) for treatment of patients with infections caused by CRAB.
In this study, patients with severe CRAB infections were randomized to receive imipenem-cilastatin plus SUL-DUR or imipenem-cilastatin plus colistin. Overall, 207 patients were enrolled from 95 trial sites across 17 countries. SUL-DUR met the primary end point of 28-day all-cause mortality showing noninferiority compared with colistin in a microbiologic-modified intent-to-treat population.1
Most notably, the 28-day mortality rates showed a statistical trend toward lower mortality among patients who received SUL-DUR at 19% (12/63) versus 32.3% (20/62) in the colistin arm (treatment difference, –13.2%; 95% CI, –30.0% to 3.5%). At the test-of-cure visit, rates of clinical cure were 61.9% and 40.3% for patients who received SUL-DUR and colistin, respectively (treatment difference, 21.6%; 95% CI, 2.9%-40.3%).
In a parallel, open-label arm of the study for patients who had either failed colistin or were infected by colistin-resistant CRAB, the mortality rate among 28 additional patients who received SUL-DUR was consistent with the main cohort (17.9%).
To add to the encouraging findings, the study met its primary safety objective, showing a statistically significant reduction in nephrotoxicity among patients who received at least 1 dose of SUL-DUR or colistin, reporting rates of 13.2% (12/91) and 37.6% (32/85), respectively (P=.0002). Collectively, the study provides an initial glimpse into a future of improving the outcomes of patients with CRAB infections should the agent be approved by the FDA.
These findings are the first to change the trajectory of a decade of disheartening clinical trial results for treatment of CRAB infections.
Motivated by observational cohort studies and numerous in vitro analyses demonstrating synergy of antibiotic combinations against CRAB,2 several randomized clinical trials have been now been conducted.
The first, by Durante-Mangoni et al, was a multicenter, open-label clinical trial that randomized critically ill patients to receive colistin alone or colistin plus rifampin for treatment of extensively drug-resistant (XDR) A baumannii infections.3 A total of 209 patients were included in the analysis; nearly 70% were diagnosed with ventilator-associated pneumonia (VAP), 20% with bloodstream infections, and 10% with hospital-acquired pneumonia (HAP). The primary outcome of the study was all-cause mortality at 30 days. Secondary outcomes included infection-related death at 30 days, microbiologic eradication, and development of colistin resistance. All-cause and infection-related mortality rates did not differ among patients who received colistin alone (42.9% and 26.6%, respectively) or colistin plus rifampin (43.3% and 21.2%, respectively). No patient developed colistin resistance in either arm; however, there was a statistically significant difference in rates of microbiologic eradication among patients who received combination therapy compared with monotherapy (60.6% vs 44.8%; P=.034). Results of a smaller, single-center randomized trial corroborated these observations.4
The findings were enough to justify trials of alternative combinations considering that colistin plus rifampin may not be the preferred combination agent due to high rates of resistance, drug-drug interactions, and known toxicity to patients. Thus, the combination of colistin plus fosfomycin was compared with colistin alone in a randomized, single-center trial in Thailand for patients with CRAB infections.5 In this study, 47 patients were enrolled into each arm of the open-label trial, which ultimately showed no difference in 28-day all-cause or infection-related mortality among patients who received colistin alone or with fosfomycin (Figure); however, the study was underpowered, and higher rates of microbiologic eradication were again documented for patients who received combination therapy.
Four years later, the results of the highly anticipated AIDA trial (NCT01732250) were published.6 In this landmark open-label, multicenter study, patients were randomized to receive colistin alone or colistin in combination with dose-optimized meropenem for treatment of severe infections caused by carbapenem-resistant gram-negative pathogens. Clinical outcomes were assessed by 2 investigators who were blinded to the treatment arm. The primary outcome was clinical success at 14 days, defined as survival with improvement or stability in signs and symptoms of infection. In total, 198 patients were randomly assigned to receive colistin monotherapy and 208 patients to receive colistin plus meropenem. The main pathogen in the study was CRAB (77%), and common infection types included HAP/VAP (45%) or bacteremia (43%). No significant differences were observed for clinical success, survival, or microbiologic response among patients who received colistin monotherapy versus combination therapy. For patients infected with CRAB specifically, rates of clinical failure were 83% (125/151) and 81% (130/161) among those who received colistin alone or in combination with meropenem, respectively (P=.643). The corresponding rates of 28-day mortality following CRAB infection were 46% (70/151) and 52% (84/161), respectively (P=.404).
These findings are largely consistent with the recently completed OVERCOME (NCT01597973) study, which is the only randomized, double-blind, placebo-controlled trial to evaluate patients who received colistin alone versus colistin in combination with a carbapenem for the treatment of bacteremia or pneumonia due to XDR gram-negative pathogens.7 In total, 467 patients were enrolled and 425 were included in the modified intent-to-treat analysis. The most frequently isolated pathogens included XDR A baumannii (74%), carbapenem-resistant Enterobacterales (CRE; 16%), and XDR Pseudomonas aeruginosa (10%). The primary outcome of the study was 28-day all-cause mortality, which did not differ between patients who received colistin monotherapy or combination therapy across all pathogens (43% vs 37%; P=.21), including those specifically infected with XDR A baumannii (46% vs 42%; P=.50). Similarly, a composite definition of clinical failure did not unveil a benefit to treatment with colistin combination therapy, resulting in XDR A baumannii clinical failure rates of 70% and 64% among patients treated with colistin or colistin plus a carbapenem, respectively (P=.33). No differences in the rate of nephrotoxicity were reported between groups. These data strengthen findings from the AIDA trial and underscore the limited utility of combining colistin with a carbapenem specifically. In fact, post hoc analyses of both trials were unable to associate in vitro synergy to improved clinical outcomes.8,9
With the futility of combination therapy to treat CRAB infections shown in several randomized trials, the need for novel agents has never been greater. Cefiderocol was developed to overcome all known mechanisms of carbapenem resistance and was envisioned as a key addition to the antibiotic armamentarium against CRAB infections.10 Indeed, the CREDIBLE-CR study (NCT02714595) was developed with these very objectives in mind.
In this open-label, descriptive phase 3 trial, patients were randomly assigned 2:1 to receive cefiderocol or best-available therapy (BAT) for treatment of infections due to carbapenem-resistant gram-negative pathogens. Among 118 patients in the microbiologic intent-to-treat population, 56 were infected with CRAB. Overall, 83% of patients were treated with cefiderocol monotherapy compared with 26% who received monotherapy in the BAT arm, which was predominantly comprised of colistin-based combinations. Surprisingly, rates of death among patients infected with CRAB who were treated with cefiderocol (n=39) were numerically higher than those who received BAT (n=17) at the end-of-study visit (49% vs 18%, respectively). Patients assigned to the cefiderocol arm were more likely to be in the intensive care unit at the time of randomization and have ongoing septic shock than those in the BAT arm, which may explain in part, the imbalanced rates of death. Even with these factors in mind, cefiderocol was not more effectivethan BAT for CRAB infections.
Given the totality of discouraging results, clinicians will be eager to prioritize any treatment for CRAB infections associated with improved clinical outcomes. Nonetheless, it will be important to await presentation of the full results from the ATTACK trial to know how and where to place SUL-DUR within CRAB treatment algorithms. Presumably such data will form the basis of a new drug application to the FDA in 2022, marking the first antibacterial agent specifically developed to treat a single pathogen. In the interim, the results can be viewed as extremely positive.
Hospitals and other health care facilities currently challenged by frequent CRAB infections can find solace in knowing help is on the way. It’s also important to acknowledge that the overall landscape has improved over the past decade. Indeed, we still have much to learn about the role of cefiderocol in real-world settings, sulbactam in 2- or 3-drug combination regimens, eravacycline and other tetracyclines demonstrating in vitroactivity against CRAB, and bacteriophages as adjunctive therapy.2 In addition, several other antimicrobial agents are currently in development.11
As the data accumulate, future goals may shift toward marrying improved therapeutics with molecular diagnostics. As evidenced by the mechanism-focused approach to CRE infections,12 such paradigms are associated with improved outcomes for patients. For CRAB specifically, it is possible that certain AmpC or oxacillinase variants demonstrate differential responses to antimicrobial therapy, and thus, specific clones endemic in a region should inform local practice.
Ideally, the next wave of CRAB treatment options will finally retire the use of colistin and older polymyxin derivatives in clinical practice. As evidenced by the ATTACK study, reducing rates of nephrotoxicity is an important objective for new therapeutics. Taken together, the vision of successfully treating CRAB infections is within sight, and the topline findings from the ATTACK study show that hope is certainly on the horizon.
1. Entasis Therapeutics announces positive topline results for sulbactam-durlobactam (SUL-DUR) from phase 3 ATTACK trial. News release. Entasis Therapeutics Holdings Inc. October 18, 2021. Accessed November 2, 2021. https://investors.entasistx.com/news-releases/news-release-details/entasis-therapeutics-announces-positive-topline-results
2. Abdul-Mutakabbir JC, Griffith NC, Shields RK, Tverdek FP, Escobar ZK. Contemporary perspective on the treatment of Acinetobacter baumannii infections: insights from the Society of Infectious Diseases pharmacists. Published online October 14, 2021. Infect Dis Ther. doi:10.1007/s40121-021-00541-4
3. Durante-Mangoni E, Signoriello G, Andini R, et al. Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized clinical trial. Clin Infect Dis. 2013;57(3):349-358. doi:10.1093/cid/cit253
4. Aydemir H, Akduman D, Piskin N, et al. Colistin vs. the combination of colistin and rifampicin for the treatment of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia. Epidemiol Infect. 2013;141(6):1214-1222. doi:10.1017/S095026881200194X
5. Sirijatuphat R, Thamlikitkul V. Preliminary study of colistin versus colistin plus fosfomycin for treatment of carbapenem-resistant Acinetobacter baumannii infections. Antimicrob Agents Chemother. 2014;58(9):5598-5601. doi:10.1128/AAC.02435-13
6. Paul M, Daikos GL, Durante-Mangoni E, et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis. 2018;18(4):391-400. doi:10.1016/S1473-3099(18)30099-9
7. Kaye KS, Marchaim D, Thamlikitkul V, et al. Results from the OVERCOME trial: colistin monotherapy versus combination therapy for the treatment of pneumonia or bloodstream infection due to extensively drug resistant gram-negative bacilli. Presented at: 31st European Congress of Clinical Microbiology & Infectious Diseases; July 9-12, 2021; virtual. Accessed November 2, 2021. https://eacademy.escmid.org/escmid/2021/eccmid-2021/332468/keith.s.kaye.results.from.the.overcome.trial.colistin.monotherapy.versus.html?f=listing%3D1%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D2029%2Alabel%3D22317%2Amarker%3D1333
8. Nutman A, Lellouche J, Temkin E, et al; AIDA Study Group. Colistin plus meropenem for carbapenem-resistant gram-negative infections: in vitro synergism is not associated with better clinical outcomes. Clin Microbiol Infect. 2020;26(9):1185-1191. doi:10.1016/j.cmi.2020.03.035
9. Pogue JM, Rybak MJ, Stamper K, et al. The impact of in vitro synergy between colistin and meropenem on clinical outcomes in invasive carbapenem-resistant gram-negative infections: a report from the OVERCOME trial. Presented at: IDWeek 2021; September 29-October 3, 2021; virtual.
10. McCreary EK, Heil EL, Tamma PD. New perspectives on antimicrobial agents: cefiderocol. Antimicrob Agents Chemother. 2021;65(8):e0217120. doi:10.1128/AAC.02171-20
11. Isler B, Doi Y, Bonomo RA, Paterson DL. New treatment options against carbapenem-resistant Acinetobacter baumannii infections. Antimicrob Agents Chemother. 2018;63(1):e01110-e01118. doi:10.1128/AAC.01110-18
12. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America guidance on the treatment of extended-spectrum β-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). Clin Infect Dis. 2021;72(7):e169-e183. doi:10.1093/cid/ciaa1478