An overview of sulbactam‐durlobactam approval and implications in advancing therapeutics for hospital‐acquired and ventilator‐associated pneumonia by acinetobacter baumannii‐calcoaceticus complex: A narrative review

Abstract Purpose Infections caused by Acinetobacter baumannii, particularly those resistant to antibiotics such as carbapenem, have become a global health crisis with a significant mortality rate. Hospital‐acquired pneumonia (HAP) and ventilator‐associated pneumonia (VAP) resulting from the A. baumannii‐calcoaceticus (ABC) complex represent a major clinical challenge. This review aimed to understand the approval process, mechanism of action, therapeutic potential, and future implications of sulbactam‐durlobactam therapy (SUL‐DUR). Methods PubMed, Web of Science, EMBASE, Clinical trials. gov, ICTRP, and CENTRAL were searched for studies on SUL‐DUR for the treatment of hospital‐acquired pneumonia and ventilator‐associated pneumonia. Also, World Health Organization, U.S. Food and Drug Administration, and Centers for Disease Control and Prevention websites were searched for relevant information. Results SUL‐DUR, marketed as Xacduro, is a novel pharmaceutical combination that functions as a narrow‐spectrum parenterally administered antibiotic. Sulbactam acts as a β‐lactamase inhibitor, whereas durlobactam protects against degradation by A. baumannii enzymes. A phase 1 trial successfully established the safety and tolerability of SUL‐DUR in patients with normal and mild renal impairment. A phase 2 trial demonstrated the safety and tolerability of SUL‐DUR in a larger population with urinary tract infections. A phase 3 trial showed that SUL‐DUR was non‐inferior to colistin in terms of mortality in A. baumannii‐related VAP, HAP, and bacteremia. Conclusion The combination of sulbactam and durlobactam is a promising treatment option for HAP and VAP caused by ABC complex.


| INTRODUCTION
Antimicrobial resistance (AMR) is a global public health threat. 1,2global estimate from 2019 showed approximately 5 million deaths were associated with AMR, with a major burden in developing regions such as sub-Saharan Africa and South Asia. 3 Of total AMR-associated infections, lower respiratory tract infections accounted for approximately 1.5 million deaths, with Acinetobacter baumannii being one of the significant pathogens contributing to AMR-associated mortality.3 Specifically, carbapenem-resistant A.
baumannii infections (CRAB) were associated with approximately 50,000-100,000 deaths globally. 3Patients with CRAB have a significantly higher in-hospital and 30-day mortality rate. 4A metaanalysis revealed that patients having infections associated with CRAB are approximately twice as likely to die than those with carbapenem-susceptible A. baumannii infections. 5Also, CRAB infections can lead to significantly increased duration of intensive care unit stay. 4Various risk factors, such as chronic liver disease, chronic renal disease, hypertension, immunosuppressed state, and intubation, may lead to increased mortality. 6][9][10] The increasing prevalence of CRAB strains globally points towards a major limitation of existing therapeutic strategies.Furthermore, risk factors for the emergence of multidrug and extensive-drug resistant A. baumannii infections include previous exposure to carbapenem, tracheostomy, mechanical ventilation, and intensive care unit utilization. 11,12The COVID-19 pandemic further accelerated the rise of AMR, with CRAB being a significant contributor. 13,146][17] It presents a grave risk to patients in healthcare settings, particularly those reliant on ventilators, as highly resistant A. baumannii strains, including carbapenem-, multi-, and extensive-resistant strains, continue to spread.9][20] In addition to this, the increasing economic burden due to CRAB can be highly challenging, particularly for resource-poor countries. 12,21,22e current treatment options for CRAB primarily include the use of high-dose ampicillin-sulbactam in combination with at least one other agent. 23Often colistin, tigecycline, and minocycline are used in the treatment of CRAB as they are susceptible in the majority of cases. 24A meta-analysis of randomized controlled trials done on 377 patients revealed that almost 36.2%(95% CI = 23.3%-51.3%) of patients receiving colistin developed nephrotoxicity, and patients on colistin therapy are 2.4 times more likely to develop nephrotoxicity than comparators. 257][28] Newer drugs like cefiderocol have a limited role in HAP/VAP due to CRAB.4][35] One such breakthrough is the SUL-DUR, marketed as Xacduro, for managing HAP/VAP caused by CRAB.This review focuses on the mechanism of action, safety, efficacy, and future prospects of SUL-DUR.

| METHODOLOGY
We searched PubMed, Web of Science, EMBASE, Clinical trials.gov, ICTRP, and CENTRAL for studies on SUL-DUR for the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia.
Keywords used were "sulbactam," "durlobactam," "acinetobacter," "pneumonia," "hospital acquired pneumonia," "ventilator associated pneumonia," "Xacduro," "carbapenem resistance," "antibiotic resistance," "clinical trial," "randomized."These keywords were either used alone or in combination with other keywords to obtain relevant results.Narrative reviews, systematic reviews, meta-analyses, and original studies relevant to the study objectives were included.Also, WHO, U.S. Food and Drug Administration (FDA), and CDC websites were searched for relevant information.Information was extracted from individual articles as relevant and was represented in the form of text, illustrations, and tables.All of this was under the supervision of the AA and AS.

| MECHANISM OF ACTION OF SULBACTAM-DURLOBACTAM
On May 23, 2023, the FDA approved Xacduro, a novel SUL-DUR pharmaceutical combination developed by Entasis Therapeutics. 36It is essential to ensure that sulbactam, a penicillin derivative, and durlobactam, a structurally non-β-lactam diazabicyclooctane (DBO) β-lactamase inhibitor, are used in combination.Together, they function as a narrow-spectrum antibiotic that can be administered parenterally. 371][42] However, sulbactam is susceptible to degradation by various β-lactamases. 37,43Hence, sulbactam has a limited therapeutic role as monotherapy.Durlobactam, on the other hand, is a specifically designed drug that acts as a highly adaptable inhibitor, displaying enhanced reactivity and superior binding to β-lactamases. 44,45This enhancement results from introducing a stronger bond between the 3rd and 4th carbon and adding a methyl group at the third position, distinguishing it from avibactam. 44This structural modification enables durlobactam to effectively shield sulbactam against enzymatic degradation, reinstating its efficacy against sulbactam-resistant ABC isolates expressing these β-lactamases. 45,46The DBO framework of durlobactam has been further altered, enhancing its capacity to inhibit a broad spectrum of class D β-lactamases and potently inhibiting class A and C β-lactamases. 39Furthermore, a systematic review reported that the SUL-DUR resistance was seen in only 2.3% of A. baumannii inections, 47 which is far less than cefoperazone/sulbactam (46.3%). 48This shows the potential of SUL-DUR in HAP/VAP.

| SAFETY AND TOLERABILITY OF SULBACTAM-DURLOBACTAM
SUL-DUR is primarily cleared renally, which makes it essential to evaluate its safety and tolerability in the setting of renal impairment.
To understand this further, a phase 1, open-label, nonrandomized study involving 34 participants was conducted at three clinical sites in the United States of America between September 2017 and September 2018. 49This study assessed the safety of SUL-DUR in participants with normal, mild, moderate, and severe renal impairment (RI) and those with end-stage renal disease (ESRD).Safety assessment was done based on the occurrence of adverse events (AEs), vitals, physical examination, electrocardiogram, and laboratory evaluation. 49In this study, patients with normal renal function and mild RI did not report any adverse effects.Dizziness, fall, foot fracture, infusion site extravasation, and nausea were reported in participants with moderate RI. 49Participants with severe RI reported epistaxis and mucosal dryness. 49Also, along with viral upper respiratory tract infection, nausea was reported in subjects with end-stage renal disease. 49Out of 9AEs, six were of mild severity, three were moderately severe, and none of the AEs led to patient discontinuation.However, this trial pointed out the need to adjust dosing in patients with moderate to severe RI and those with ESRD.
To establish evidence for tolerability of SUL-DUR, a multicenter phase 2 study was conducted from January to May 2018 among 80 hospitalized adults with complicated urinary tract infections, including pyelonephritis. 50In this study, SUL-DUR was given intravenously in the background of imipenem-cilastatin therapy for 7 to 14 days.A higher rate of AEs (37.7% vs. 29.6%)was observed in the intervention group than in the comparator group.Also, AEs attributable to drug use were higher (22.6% vs. 14.8%) in the intervention group than in the comparator group.AEs included headache, phlebitis, nausea, vomiting, abdominal pain, diarrhea, dyspepsia, gastritis, duodenitis, bronchitis, conjunctivitis, infusion site reaction, vulvovaginal candidiasis, increase in blood glucose and creatinine concentration, elevation of blood pressure and alanine aminotransferase. 50Though two patients discontinued intervention due to AEs, no serious AEs and deaths were reported. 50Despite the demonstrated safety, the trial did not include HAP/VAP patients with ABC complex, limiting the applicability of the study's findings.
To compare the safety profile of SUL-DUR with existing treatment strategies, a phase 3 trial evaluated the safety profile of SUL-DUR in 80 and 81 patients on SUL-DUR and colistin, respectively. 51 this study, the occurrence of any treatment-emergent adverse event (TEAE) was lower (88% vs. 94%) in the intervention group than comparator group.Specifically, drug-related TEAEs (12% vs. 30%), serious AEs (40% vs. 49%), and TEAEs (11% vs. 16%) leading to discontinuation, allergic/hypersensitivity reactions (34% vs. 44%), and clostridium difficile infections (1% vs. 7%) were lower in the intervention group than comparator group.Since SUL-DUR is cleared really, nephrotoxicity was the primary safety endpoint, which was assessed based on the RIFLE classification for acute kidney injury. 51,52The incidence of nephrotoxicity was significantly lower (13% vs. 38%, p < 0.001) in the intervention group than in the control group. 51[51]

| EFFICACY OF SULBACTAM-DURLOBACTAM
A phase 3 study was necessary to compare the effectiveness of SUL-DUR with existing therapies.Hence, a phase 3 trial of SUL-DUR was done in two parts-the first part included a randomized cohort of 181 patients and the second part included an observational cohort of 26 patients. 51This trial compared the efficacy profile of SUL-DUR with colistin, in the background of imipenem-cilastatin therapy given for antibiotic coverage for other causative agents.In the randomized cohort, 91 patients received SUL-DUR as intervention therapy and 86 patients received colistin as comparator therapy. 51SUL-DUR was given as an intravenous infusion over 3 h every 6 h for 7 to 14 days.Of 91 participants receiving SUL-DUR, 24 did not complete treatment, and finally, 63 were included for primary efficacy analysis at Day 28.For the colistin group, 31 did not complete treatment, and 62 were included for primary efficacy analysis at Day 28.The 28-day allcause mortality was 12 (19.0%) of 63 in the intervention group and 20 (32.3%) in the comparator group. 51This proved the noninferiority of SUL-DUR to colistin in HAP/VAP/bacteremia caused by A. baumanii.On adjustment for randomization stratification, the treatment difference was −13.8%, consistent across various subgroups. 51Also, the clinical improvement at the therapeutic end point (75% vs. 45%; treatment difference = 29%, 11.4 to 47.4), cure rate (62% vs. 40%; treatment difference = 22%, 2.9 to 40.3), and sustained clinical cure (43% vs. 31%; treatment difference = 12%, −6.2 to 30.6) was higher in the intervention group than control group. 51In addition, microbiological outcomes such as response at therapeutic end point (86% vs. 61%; treatment difference = 24%, 7.9 to 40.9), at test of cure (68% vs. 42%; treatment difference = 26%, 7.9 to 44.7) and sustained response at late follow up (48% vs. 40%; treatment difference = 7%, −11.7 to 26.3) was higher in the intervention group than control group. 51All these findings provide quality evidence on the non-inferiority of SUL-DUR to colistin and advocate for successful use in HAP/VAP and bacteremia due to A. baumanii.However, the use of imipenem-cilastatin in all patients as a background therapy may lead to exaggeration of the actual efficacy of SUL-DUR.This use of background therapy such as imipenem-cilastatin with SUL-DUR raises important concerns about whether these drugs should always be used in conjunction.
Hence, a more appropriate study design is mandated for the accurate determination of SUL-DUR efficacy, which may be limited due to practical considerations of benefit and harm to the patient.
Though this may be difficult to achieve using randomized study design, prospective or retrospective studies may help address this issue.
T A B L E 1 Clinical trials on Xacduro.
Parameter O'Donnell et al. 49 Sagan et al. 50aye et al. 51 1).Findings from the phase 1 study showed SUL-DUR as a safe and tolerable therapeutic option in healthy subjects or those with mild RI. 49 However, due to adverse events reported in patients with moderate to severe RI and ESRD, dosing needed to be adjusted. 49To further understand the safety and explore the efficacy profile, a Phase 2 study was conducted. 50Though it was established that the safety and efficacy profile of SUL-DUR is similar to colistin, there is a slightly increased incidence of adverse events in the SUL-DUR group as compared to the control group. 50A phase 3 ATTACK trial was conducted to generate quality evidence.This trial showed a lower incidence of adverse events in the SUL-DUR group, putting rest to safety concerns of the phase 2 trial. 50,51Also, the clinical and microbiological assessment showed promising evidence for the efficacy of SUL-DUR and established non-inferiority of SUL-DUR to colistin. 51Based on the evidence from the clinical trials, the FDA approved SUL-DUR for use in the treatment of HAP/VAP caused by susceptible isolates of A. baumannii-calcoaceticus complex, for patients aged ≥18 years. 36In the process, the FDA granted SUL-DUR fast track, priority review, and generating antibiotic incentives now (Table 2) designations. 36

| INDICATION, CONTRAINDICATION, WARNING, AND PRECAUTIONS FOR SULBACTAM-DURLOBACTAM USE
Each carton of SUL-DUR contains sulbactam in one clear, single-dose vial, 1 g/vial; and durlobactam in two amber, single-dose vials, 0.5 g/vial each (Figure 2).Each vial should be reconstituted with sterile water and then injected into an infusion bag for therapeutic use.The standard dosage is 1 g of sulbactam and 1 g of durlobactam given via intravenous infusion over 3 h every 6 h in patients with creatinine clearance (crCL) of 45 to 129 ml/minute. 53SUL-DUR is contraindicated in patients with a known history of severe hypersensitivity to SUL-DUR or any betalactam antibiotics.Hence, caution should be maintained and detailed drug and allergy history should be taken into account.5][56] In addition, judicious use of SUL-DUR is essential to reduce the chances of AMR.Hence, it should be indicated only in case of an established diagnosis or strong suspicion.Also, clinicians should understand the possible interaction between organic anion transporter 1 (OAT1) inhibitors and SUL-DUR leading to increased sulbactam concentration, as reported with other beta-lactam antibiotics. 57In addition, clinicians should be vigilant as a significant proportion of patients can have adverse reactions.

| SULBACTAM-DURLOBACTAM WITH OTHER FIRST-LINE ANTIBIOTICS FOR ACINETOBACTER INFECTIONS
Though there is no clear consensus on the management of HAP/VAP due to CRAB, the Infectious Disease Society of America has specifically stated recommendations for the management of moderate to severe HAP/VAP. 23,30A combination therapy of high-dose ampicillin-sulbactam and another agent, irrespective of antimicrobial susceptibility is the recommended approach. 23,58Alternatively, polymyxin B/tetracycline/cefiderocol derivatives can be used in conjunction with another agent. 23However, cefiderocol is usually reserved for refractory CRAB infections. 23High-dose, extendedinfusion meropenem or imipenem-cilastatin, rifamycins, and nebulized antibiotics are not recommended. 23

Designation FDA definition
Fast Track a A process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.The purpose is to get important new drugs to the patient earlier.

Generating Antibiotic Incentives Now b
It creates incentives for the development of antibacterial and antifungal drug products that treat serious or life-threatening infections.

Priority Review c
To act on an application within 6 months (compared to 10 months under standard review).It will direct overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.

RECOMMENDATIONS
Despite the promising potential, It is essential to recognize that the studies on sulbactam and durlobactam for treating HAP and VAP have certain limitations.The phase 2 trial also had certain limitations as it did not add substantial evidence regarding the efficacy of SUL-DUR.Also, the trial did not include HAP/VAP patients with ABC complex, limiting the applicability of the study's findings.The phase 3 trial only studied 28 days all-cause mortality and reporting of severe adverse events up to a maximum of 44 days.However, this shorter follow-up may not be sufficient to account for long-term renal impairment secondary to intervention.Also, there is a paucity of studies or trials involving individuals with comorbidities such as cardiovascular disease, high blood pressure, diabetes, osteoarthritis, hypercholesterolemia, dyslipidemia, and other conditions.The low representation of women and various racial and ethnic groups does not help in establishing the generalizability of the study's findings.Also, the study did not include pregnant women and cancer patients, which can limit the applicability of the study's findings to vulnerable populations.Another aspect is considering the effect of alcohol on the efficacy of sulbactam.Furthermore, the different genetic strains may respond differently to SUL-DUR, which needs to be accounted for.
More trials are needed to address allergic or hypersensitivity reactions, as individuals administered sulbactam and durlobactam in the ATTACK trial exhibited a higher frequency of these reactions compared to the control group (Figure 3).Also, additional experi-
SUL-DUR approval comes as a welcome addition to managing cases, especially in the setting of carbapenem resistance.This in combination with antibiotic coverage for other causative organisms, adds a new dimension to the management of HAP/VAP.However, it is very early to establish the combination of SUL-DUR with other established treatment T A B L E 2 FDA approval designation of Xacduro.
modalities.Further studies are warranted to compare the safety and efficacy of SUL-DUR with existing therapeutic modalities.In addition, the cost of procuring antibiotics is a major concern for effective management, particularly in resource-poor countries.SUL-DUR is priced at approximately 510 US dollars per carton, taking it to approximately 14,280 US dollars for 1 week of treatment, which is unaffordable for most.59Further studies are required to shed light on cost-effective management strategies for CRAB infections.

F I G U R E 2
Drug profile of Xacduro.[Created with Biorender.com].F I G U R E 3 Recommendations for further research.[Created with Biorender.com].
mentation and testing are necessary to determine the optimal dosage of medication for individuals with severe renal insufficiency and endstage renal disease.A comprehensive study should investigate the effects of sulbactam and durlobactam treatment on individuals who frequently consume alcohol, as evidence suggests that alcohol consumption may interfere with the efficacy of sulbactam.Furthermore, it would be beneficial for the study to include subjects who engage in smoking and alcohol consumption.This would allow for a comprehensive evaluation of the combined impact of these factors on a patient's physical well-being during treatment.10| CONCLUSIONThe increasing prevalence of Acinetobacter infections, particularly in healthcare settings and among ventilator-dependent patients, presents a significant global health concern.Established antibiotic treatments have faced formidable challenges due to the emergence of drug-resistant A. baumanii strains, especially carbapenem-resistant varieties.The advent of sulbactam-sulbactam combination therapy represents a promising breakthrough in the fight against CRAB infections, including those resistant to a wide range of drugs, such as multidrug-resistant and extensively drug-resistant strains.However, further research and careful consideration of specific patient populations is essential to fully realize this innovative treatment's potential.