Beyond resistance: assessing sulbactam-durlobactam’s role in today’s clinical landscape

KEYWORDS:

• SUL-DUR
• antimicrobial resistance
• carbapenem-resistant acinetobacter baumannii
• ventilator-associated bacterial pneumonia
• antibiotic resistance

1. Introduction

Infectious diseases represent an ever-growing challenge, and antimicrobial resistance (AMR) poses a significant threat to global health [1–3]. Carbapenem-resistant Acinetobacter baumannii (CRAB) represents a substantial public health concern due to its high resistance to last-line antibiotics [4]. A large multi-center study that involved whole-genome sequencing of 313 CRAB isolates across 47 countries, found integrative conjugative elements (ICE) clones in 62.6% of the isolates [4]. CRAB infections, that can be commonly seen in wounds and the respiratory tract, are associated with poor clinical outcomes, such as mortality, longer hospital stays, and increases intensive care unit (ICU) utilization compared to susceptible strains [5].

A study covering CRAB’s clinical and molecular epidemiology in U.S. hospitals highlighted its continued impact on vulnerable patient populations, with a notable 24% all-cause 30-day mortality among affected patients [6]. A recent UK study found that CRAB accounted for 51.9% of the carbapenem-resistant Gram-negative (CR-GN) isolates [7]. In Pakistan, an observational study conducted across three tertiary care hospitals identified Acinetobacter baumannii in 681 (41%) cases [8].

Sulbactam-durlobactam (SUL-DUR), a novel combination of β-lactamase inhibitors, has been developed for treating CRAB infections [9]. Sulbactam, structurally related to penicillin, possesses intrinsic activity against A. baumannii, while durlobactam protects sulbactam from degradation by A. baumannii-produced enzymes [9].

SUL-DUR was approved by The U.S. Food and Drug Administration (FDA) in May 2023 for treating hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) in patients aged 18 and older [10]. Because the World Health Organization (WHO) recognized CRAB infections as critical bacterial pathogens with a high threat level, this approval addresses a significant unmet medical need.

The development and approval of SUL-DUR against CRAB represents a significant advancement in antimicrobial therapy. However, a comprehensive discussion of its efficacy and limitations in the dynamic context of antibiotic resistance is still lacking. This editorial aims to address this gap, offering researchers and healthcare professionals a detailed examination of this new therapeutic option in the battle against AMR. It offers an in-depth view of SUL-DUR’s efficacy, potential limitations, and its strategic role in current antimicrobial regimens.

1.1. Current evidence

Several studies have documented the in vitro activity of SUL-DUR against CRAB strains. A notable global surveillance analysis from 2016 to 2021 demonstrated that this combination significantly reduced the maximum inhibitory concentration (MIC90) of sulbactam for 5032 ABC isolates from over 32 µg/mL to 2 µg/mL, rendering 98.3% of these isolates susceptible at 4 µg/mL or less, suggesting a preliminary breakpoint [11].

The efficacy of SUL-DUR has been assessed by five clinical trials in both phase II and III conducted across the United States, Australia, and Bulgaria. These trials include studies on plasma and intrapulmonary concentrations in healthy subjects, safety and pharmacokinetics in healthy subjects and those with renal impairment, and the efficacy and safety in treating complicated urinary tract infections and infections caused by CRAB in hospitalized adults.

In a phase 3 trial, conducted at 59 sites in 16 countries, SUL-DUR was assessed against colistin, both in combination with imipenem-cilastatin, for the treatment of CRAB [12]. The trial involved 181 patients, with 125 having laboratory-confirmed CRAB infection. SUL-DUR showed non-inferiority to colistin in 28-day all-cause mortality (19% vs. 32%) and had a significantly lower incidence of nephrotoxicity (13% vs. 38%). Simone Giuliano and colleagues raised concerns about attributing antimicrobial activity solely to SUL-DUR, given the concomitant use of imipenem as background therapy. They suggest potential synergies between SUL-DUR and imipenem, and advises further assessment of their interaction [13].

In a phase 2 randomized clinical trial, patients with complex urinary tract infections were randomly allocation using a 2:1 ratio to an active arm, receiving SUL-DUR or a control arm, receiving placebo, for seven days in conjunction with background therapy using imipenem-cilastatin. According to trial results, both treatments were well tolerated without serious adverse events, with its pharmacokinetic profile matching that seen among healthy individuals [14].

Real-world studies on SUL-DUR’s effectiveness are limited. Noor Zaidan reported in her case study [15] that a patient suffering from extensive CRAB infection and septic shock was effectively treated using combination therapy comprising cefiderocol and SUL-DUR. This therapy combination resulted in rapid improvement within 72 hours, as evidenced by reduced respiratory secretions, resolved fevers, and discontinuance of vasopressor medications. Over 14 days of treatment, the patient’s respiratory function improved significantly, leading to reduced ventilatory support needs and eventually being released for rehabilitation with no adverse reactions from medications prescribed. However, due to the concurrent administration of cefiderocol and SUL-DUR, its exact role in eliminating bacteria is still uncertain. The authors of the case report believe durlobactam may have played a pivotal role by protecting sulbactam while simultaneously increasing cefiderocol’s effectiveness.

Recently, a study conducted a physical compatibility assessment between SUL-DUR and 95 intravenous drugs under simulated Y-site administration. Results demonstrated its compatibility with 86 of them, allowing pharmacists and nurses to safely coordinate IV medication administration [16].

1.2. Other agents

Beyond sulbactam-durlobactam, zosurabalpin emerges as a novel candidate with significant anti-CRAB potential. This new antibotic showed potent in vitro and in vivo efficacy against drug-resistant Acinetobacter strains. Its development underscores the ongoing search for innovative solutions to combat multidrug-resistant pathogens, including CRAB [17]. Other treatment options for CRAB infections include colistin and cefiderocol. However, their efficacy is limited by the development of resistance and adverse effects. The search for new treatments continues, highlighting the urgent need for innovative solutions to combat CRAB infections effectively [18].

2. Expert opinion

The advent of SUL-DUR represents a pivotal moment in the fight against CRAB infections. The evidence presented in this editorial demonstrates that SUL-DUR is a promising therapeutic agent, particularly in light of its efficacy, lower nephrotoxicity compared to colistin, and potential for synergistic effects with other antimicrobials. However, the full potential and limitations of SUL-DUR in clinical practice require careful consideration.

Firstly, the issue of resistance development to SUL-DUR must be addressed. This issue is an ongoing challenge, and the possibility of CRAB developing resistance to SUL-DUR cannot be dismissed. Future studies should focus on monitoring resistance patterns and understanding the mechanisms by which CRAB might develop resistance to SUL-DUR. It is crucial to establish surveillance programs to track the emergence of SUL-DUR resistance and to develop strategies to mitigate this risk.

Secondly, while SUL-DUR shows promise, its clinical implications are yet to be fully understood in diverse patient populations and settings. The current evidence is based on controlled clinical trial environments, which might not fully represent real-world scenarios. For instance, the effectiveness of SUL-DUR in patients with multiple comorbidities, varying degrees of renal impairment, or those who are immunocompromised remains to be thoroughly evaluated. Future studies should aim to assess the efficacy and safety of SUL-DUR in these broader patient populations.

Thirdly, the economic implications of introducing SUL-DUR into the healthcare market, particularly in comparison to existing treatment options, warrant thorough assessment to guarantee its affordability and long-term sustainability within healthcare systems. As of now, there appears to be a notable gap in the literature regarding cost-effectiveness studies of SUL-DUR. This omission is critical, as the financial burden of new treatments can significantly influence their adoption and accessibility, especially in resource-limited settings. Therefore, comprehensive economic analyses are essential to evaluate the overall value of SUL-DUR, taking into account not only the drug costs but also the potential savings from reduced hospital stays, decreased incidence of side effects, and improved patient outcomes.

Furthermore, in light of the growing threat posed by CRAB infections and the potential of SUL-DUR as an effective treatment option, it is imperative to emphasize the development and widespread adoption of commercialized drug susceptibility testing products. Such advancements are crucial for enabling laboratories to conduct timely and accurate drug susceptibility testing (DST) once SUL-DUR becomes commercially available for clinical use. The inclusion of automated drug susceptibility systems, alongside established methods such as the disk-diffusion method and Etest, would significantly enhance the ability of laboratories to report bacterial responses to SUL-DUR accurately. This strategic approach will support the rational use of SUL-DUR in clinical settings, potentially delaying the emergence of drug resistance.

In my opinion, SUL-DUR represents an enormous leap forward, yet its use must be implemented carefully to preserve its efficacy. Stewardship programs should be put in place to ensure appropriate dosing of SUL-DUR to minimize resistance development risks, and physicians must receive education on its indications, dosing schedules and potential interactions for maximum benefit in clinical practice.

3. Conclusion

SUL-DUR holds promising future perspectives to the antimicrobial arsenal against CRAB infections. Nonetheless, continued research and vigilance are of upmost importance. Studies focusing on resistance monitoring, effectiveness in diverse patient populations, and potential synergistic combinations with other antimicrobials are crucial. Furthermore, careful stewardship and clinician education will be paramount in maximizing the clinical utility of SUL-DUR while safeguarding its effectiveness for future generations.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.