20 December 2023

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Sulbactam co-packaged with durlobactam has been approved by the FDA

Sulbactam+durlobactam (Xacduro) has recently received the US Food and Drug Administration (FDA) approval and is now available in the US. This medication contains sulbactam co-packaged with durlobactam to offer a new treatment option for patients with infections caused by carbapenem-resistant Acinetobacter baumanniicalcoaceticus complex (CRAB). CRAB is estimated to be responsible globally for approximately 100,000 deaths, with high variation in infection and resistance rates across different global regions and countries.1 Resistance rates to carbapenems vary significantly, ranging from less than 5% to more than 60%. For instance, three European countries report a resistance rate of less than 1% and 21 countries, primarily Southern and Eastern European countries, have resistance rates exceeding 50%.2 Given this substantial variation of resistance rates across geographic regions, the need for a new effective drug against CRAB also varies greatly.

Sulbactam-durlobactam is a unique β-lactamase inhibitor (BLI) combination consisting of two BLIs: sulbactam is a well-established β-lactam-based drug used clinically as a BLI in combination with various penicillins and cephalosporins. It also has intrinsic antibacterial activity against a limited number of bacterial species, including Acinetobacter, achieved through inhibition of Penicillin-Binding-Protein (PBP)1 and PBP3. Sulbactam was often used as part of a combination regime in Acinetobacter infections. However, high resistance rates have been observed, primarily due to various class D β-lactamases, which are common in Acinetobacter and are key resistance mechanisms against β-lactam antibiotics, including carbapenems. This led to the mechanistically sound strategy of combining sulbactam, a BLI with direct activity in Acinetobacter, with the BLI durlobactam, a diazabicyclooctane (DBO), which exhibits greater activity against class D β-lactamases of the OXA enzyme family compared to other DBOs but has no intrinsic activity versus Acinetobacter. In short, durlobactam protects sulbactam from hydrolysis by these enzymes.

The global health impact of this new combination depends on factors such as the availability of this medication outside of the US and other currently planned countries, pricing that may restrict its use in regions with high CRAB infection rates, and the presence of rapid diagnostic infrastructure.

Clinical development of sulbactam+durlobactam

It is generally acknowledged that developing a pathogen-specific programme for critically ill patients focusing on resistant strains in a highly variable environment is a challenging endeavor. The FDA agreed to a streamlined development programme for treating patients with serious laboratory-confirmed CRAB infections. This expedited programme included one pivotal phase 3 trial in patients with mainly hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). Patients were treated with 1.0 g sulbactam and 1.0 g durlobactam IV infused over 3 hours every 6 hours in addition to imipenem as background therapy, or with the comparator drug colistin or polymyxin B plus imipenem. The primary efficacy analysis included 63 patients treated with the study antibiotic and 62 patients treated with the comparator. The study, designed as a non-inferiority trial with a 20% non-inferiority margin, was completed in less than two years. Results indicated that sulbactam-durlobactam demonstrated non-inferiority to colistin for the primary endpoint of 28-day all-cause mortality in CRAB infections when administered in combination with imipenem. Additionally, a small single-arm, open-label, non-randomised study included 28 patients treated with sulbactam-durlobactam who were infected with colistin-resistant Acinetobacter or were unable to participate in the main study for various reasons. The safety database included 180 patients who received sulbactam-durlobactam, and safety profiles were considered consistent with the pharmacologic class. Due to the limited number of patients, postmarketing safety monitoring was mandated by the FDA. While a streamlined program for targeted therapy expedites the marketing of the drug based on limited efficacy evidence, it leaves physicians without robust data to support clinical decision-making.

The clinical efficacy of the combination and its comparison with other standard of care therapies are based on limited data, with small patient numbers and a wide non-inferiority margin within a highly selected patient population. This limits the translation of study results to real-world value in terms of improved patient outcomes.

Several questions need to be addressed in the coming years

While this newly approved drug combination may provide an additional treatment option for this described patient group, several questions remain and need to be addressed in the coming years. The clinical efficacy of the combination and its comparison with other standard-of-care therapies are based on limited data, with small patient numbers and a wide non-inferiority margin within a highly selected patient population. This limits the translation of study results to real-world value in terms of improved patient outcomes. Experience with patients with more severe ventilator-associated disease at baseline and with specific patient groups is still missing. Similar issues have been observed with other recently approved antibiotics.3 A generally recognised clinical benefit of sulbactam-durlobactam compared to colistin is the lower incidence of nephrotoxicity. However, treatment-related adverse events leading to study drug discontinuation were similar between groups in the phase 3 trial.4 Clinical knowledge about this new drug combination needs to be gathered post-approval to evaluate its value through well-designed clinical trials in addition to studies within the regulatory framework. The global health impact of this new combination depends on factors such as the availability of this medication outside of the US and other currently planned countries, pricing that may restrict its use in regions with high CRAB infection rates, and the presence of rapid diagnostic infrastructure.

The new treatment option holds potential benefits for patients in countries with a high prevalence of CRAB, where such new antibiotics are approved and can be financially supported.

Sulbactam-durlobactam was specifically developed to address the challenge posed by the most resistant Acinetobacter strains, collectively referred to as CRAB. However, limited information is available regarding the real-world resistance situation of sulbactam-durlobactam and its potential for cross-resistance. Large surveillance studies, primarily designed to meet regulatory requirements, have demonstrated high susceptibility and very low resistance rates. Public health-oriented susceptibility studies reveal the expected multifactorial resistance mechanisms of sulbactam-durlobactam, namely alteration in PBPs, production of metallo-β-lactamases such as New Delhi Metallo-β-lactamases (NDM), the combination of multiple β-lactamases and expression of varying levels of β-lactamases. In “high-resistance countries” such as Greece, both the sulbactam-durlobactam MIC50 and MIC90 may exceed by one to three-fold the respective values of those strains reported in international studies.5 The variant of the PBP3 gene that likely confers resistance to sulbactam and the NDM β-lactamase, which durlobactam does not inhibit, may contribute to published higher resistance rates as soon as more independent susceptibility studies are completed.

Sulbactam-durlobactam was approved by the FDA for adult patients for the treatment of HABP/VABP, caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex. From my point of view, the new treatment option holds potential benefits for patients in countries with a high prevalence of CRAB, where such new antibiotics are approved and can be financially supported. Additionally, a well-equipped diagnostic infrastructure, stewardship measures, and surveillance and monitoring systems must be in place to prevent overuse, which could contribute to increasing antibiotic resistance. These requirements may not be met by countries with the highest need. Depending on the commercialisation and pricing strategy, this new drug combination may be out of reach for many countries with high medical needs.

References

  1. Antimicrobial Resistance Collaborators (2022) Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 399(10325):629-655.
  2. European Centre for Disease Prevention Control (ECDC) (2022) Antimicrobial resistance surveillance in Europe 2022 – 2020 data. [Accessed 11/12/2023]
  3. Mitra-Majumdar M, Powers JH III, Brown BL, Kesselheim AS (2022) Evidence at time of regulatory approval and cost of new antibiotics in 2016-19: cohort study of FDA approved drugs. BMJ Med. 1(1): e000227.
  4. Watkins RR, Du B, Isaacs R, Altarac D (2023) Sulbactam-Durlobactam: A step forward in treating carbapenem-resistant Acinetobacter baumannii (CRAB) infections. Clin Infect Dis. 76(Suppl 2): S210–S214.
  5. Petropoulou D, Siopi M, Vourli S, Pournaras S (2021) Activity of Sulbactam-Durlobactam and comparators against a national collection of carbapenem-resistant Acinetobacter baumannii isolates from Greece. Front Cell Infect Microbiol. 11: 814530.

Ursula Theuretzbacher is the founder of the Centre of Anti-Infective Agents (CEFAIA). She is an expert in antibacterial drug research and development (R&D) strategies and policies based on clinical and public health needs. Her broad therapeutic areas of expertise include early integration of pharmacokinetic/pharmacodynamic (PK/PD) concepts, optimization of dosing and usage approaches, public funding strategies for antibacterial R&D and initiatives to recover the global pipelines.

Previously, she was a work package leader or partner in several EU-funded international collaborative projects focused on antibacterial drug R&D and reviving of old antibiotics. Additionally, she has served as President of the International Society for Anti-Infective Pharmacology, as Founding President of the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) PK/PD of Anti-Infectives Study Group and as Executive Committee member of the International Society for Infectious Diseases (ISID).

Ursula was a member of the coordinating group of the WHO project Priority Pathogen List for R&D and is a leading scientist for the Clinical and Preclinical Pipeline analysis, and development of Target Product Profiles at WHO.

The author declares that they do not have any relationships or affiliations that could be construed as a potential conflict of interest.