CRAB-By No More?

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In 2017, the World Health Organization created a global priority pathogens list to promote the research and development of antibiotics for treating infections, prioritizing bacteria that pose the highest risk to human health, particularly multdrug-resistant organisms.¹ The list stratifies organisms into priority tiers from 1 to 3, (critical to medium, respectively), to delineate the risk to human health as well as the urgency of drug development. Carbapenem-resistant Acinetobacter baumannii (CRAB) is listed as a priority 1, critical pathogen. This categorization is well earned as infections caused by CRAB accounted for an estimated 57,700 of the 1.27 million global deaths that were attributed to drug-resistant bacteria in 2019, or roughly 4.5%.² As such, substantial effort has been invested in developing novel antibiotic treatment strategies in hopes of greater treatment success. This began with cefiderocol, which also has activity to other gram-negative organisms. More recently, 2 antibiotics have been introduced exclusively for the management of CRAB: sulbactam-durlobactam (Xacduro) and zosurabalpin. While the need for new therapies is a public health necessity, their specificity for just 1 organism does raise questions about the value of redundant therapeutics for this use, and how might they compete with or complement each other should zosurabalpin obtain FDA approval.

To understand the clinical need for new agents, it is important to recognize the current landscape of CRAB management. This is illustrated by the Infectious Diseases Society of America’s 2023 guidance recommendations, which suggest high-dose ampicillin-sulbactam (6 - 9 g of sulbactam daily) in combination with at least 1 additional agent, such as polymyxin B, minocycline, tigecycline, or cefiderocol monotherapy when available.³ Original recommendations for dual therapy were based on small studies, such as Makris et al, which demonstrated a more favorable clinical response in patients with CRAB infection when treated with ampicillin-sulbactam in combination with colistin vs colistin monotherapy, but had a limited sample size of 39 patients, with isolates at least intermediately susceptible to ampicillin-sulbactam with minimum inhibitory concentration less than 16 mg/L.⁴ There was also no observed difference in 30-day mortality rates between those treated with ampicillin-sulbactam plus colistin vs colistin monotherapy. Later on, in 2 randomized controlled trials examining meropenem plus colistin vs colistin monotherapy, both found no observable difference in 28- or 30-day mortality rates, and noted mortality rates of greater than 40% despite the dual therapy.^5,6

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With substantial mortality from CRAB infections even using 2 antimicrobials, it becomes clear why Acinetobacter baumannii is a high priority target for new antibiotic development. But because of the historically high mortality that comes with CRAB infection, it is unsurprising that the development of 2 new agents targeting CRAB infections has been met with cautious optimism and some concerns. The first major comment is that while early studies have shown promise, the agents’ efficacy is far from a proven fact. Secondly, given their substantial specificity toward CRAB, with no utility of treating infections caused by other bacteria, how will both therapeutics survive in a small, niche market?
Developed by Entasis Therapeutics, Xacduro received FDA approval in 2023 to treat hospital-acquired and ventilator-associated pneumonia due to CRAB. Sulbactam is an effective agent for susceptible strains of Acinetobacter baumannii. However, sulbactam can become inactivated by various β-lactamases harbored by CRAB, or through mutations of penicillin–binding proteins.^7,8 In addition to various additional mechanisms of resistance, a fact that makes CRAB particularly challenging to treat, is the presence of class D β-lactamases, which are usually not targets of other β-lactamase inhibitors (eg, vaborbactam, relebactam, and avibactam). Durlobactam, a novel diazabicyclooctane β-lactamase inhibitor, is a potent inhibitor of Acinetobacter-derived cephalosporinases and class D β-lactamases including carbapenemases (eg, OXA-23/40 and OXA-24), thereby restoring activity of sulbactam against CRAB. In a phase 3, randomized clinical trial, Kaye et al examined the efficacy and safety of sulbactam-durlobactam vs colistin, both in combination with imipenem-cilastatin.⁹ Sulbactam-durlobactam was found to be noninferior to colistin, in terms of 28-day mortality (19% vs 32%, respectively), and had a statistically significant lower risk of causing nephrotoxicity.⁹ Familiarity with the β-lactamase inhibitor class may increase clinician confidence in using the therapeutic, as well as these early reassuring numbers. However, Acinetobacter baumannii’s ability to readily develop antimicrobial resistance understandably creates concerns about how to sustainably use this therapeutic and extend its longevity before inevitable obsolescence.

Meanwhile, zosurabalpin belongs to a completely new antimicrobial class, the macrocyclic peptides (MCPs) developed by Roche. MCPs use a novel mechanism of action for treating gram-negative bacteria by targeting the LptB2FGC complex, which transports lipopolysaccharides (LPs) across a protein bridge that spans from the cytoplasmic membrane to the cell surface to assemble the LPs’ outer membrane, essential to gram-negative bacteria. Zosurabalpin is an Acinetobacter-specific MCP, and has shown to have good pharmacokinetic and safety profiles, as well as performing well in vivo efficacy in various mouse model infections, including sepsis and pneumonia caused by CRAB and pan-drug-resistant Acinetobacter.¹⁰ Preliminary data from unpublished ongoing phase 1 clinical trials has shown good safety and tolerability.11 Official statements from Roche, and current studies suggest that this intravenous therapy would optimally be for the treatment of hospital-acquired and ventilator-associated pneumonias caused by Acinetobacter, especially those with multidrug-resistant features.¹¹

To contextualize the potential of these 2 antimicrobials, it is helpful to assess them in comparison to cefiderocol. Cefiderocol was approved by the FDA in 2019 for hospital-acquired and ventilator-associated pneumonia caused by aerobic gram-negative bacteria with limited treatment options, including infections due to Acinetobacter baumannii. In the APEKS-NP trial (NCT03032380), lower 14-day, all-cause mortality rates were seen in patients who received cefiderocol compared with high-dose extended-infusion meropenem for gram-negative nosocomial pneumonia.¹² However, in a multicenter, phase 3, randomized clinical trial examining all-cause mortality rates in patients with nosocomial pneumonia, bloodstream infections, or complicated urinary tract infections caused by carbapenem-resistant gram-negative organisms, patients were randomly assigned to receive either cefiderocol or the best available therapy (primarily colitis-based regimens).¹³ Among the subgroup of patients with infections caused by CRAB, mortality rates were significantly higher among patients treated with cefiderocol vs best available therapy, 49% vs 18%, respectively. Although zosurabalpin remains far from reaching clinical practice, the results of preliminary phase 1 data bring reason to be optimistic about a potentially novel class of drugs for treatment of CRAB infections. As is often the case with many other new pharmaceuticals, the cost of these novel antibiotics, limited access, and evolving antimicrobial resistance may limit their widespread usage in clinical practice for a while (table).

In addition to a need for more clinical data, another common concern is the survivability of 2 niche antibiotics in a competitive pharmaceutical market. Two examples can be raised to demonstrate how this issue may play out. First, we can observe the coexistence of newer agents designed to target multidrug-resistant gram-negative bacteria: ceftolozane-tazobactam, ceftazidime-avibactam, and meropenem-vaborbactam. These agents obtained FDA approval close in time—2014, 2015, and 2017, respectively. While not identical, they share many common indications and target similar pathogens. All 3 have remained on the market because the need for such agents has not only persisted but grown. Another example may be seen with the development of new therapeutics for multidrug-resistant tuberculosis (MDR-TB), bedaquiline and pretomanid. Because MDR-TB treatment is necessary to promote global public health, therapies
directed toward it are of great interest and thrive in their niche. One could argue that the development of CRAB-specific therapeutics follows a similar logic as MDR-TB drug development and usage. Especially because CRAB often harbors resistance mechanisms that pose a unique treatment challenge to traditional antibiotics, this has delivered a scenario to think outside the box for new treatment strategies, culminating in the evolution of these niche therapeutics.
Despite attempts to define and optimize treatment for CRAB infections using the available antibiotic repertoire, such as β-lactams and polymyxins, patient outcomes remain poor and, at times, abysmal. Treatment options for CRAB must improve, and it is exciting to see progress with the advent of sulbactam-durlobactam and with zosurabalpin in clinical trials. While we should continue to be cautiously optimistic about the progress that is represented by these therapeutics, it is extremely important for infectious disease clinicians and pharmacists to advocate for policies that support antimicrobial drug research and development to ensure we have the tools to combat antimicrobial resistance far into the future.

References
1.WHO publishes list of bacteria for which new antibiotics are urgently needed. World Health Organization. News release. February 27, 2017. Accessed April 23, 2024. https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed

2.Murray CJL, Ikuta KS, Sharara F, et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet. 2022;399(10325):629-655. doi:10.1016/S0140-6736(21)02724-0

3.Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America 2023 guidance on the treatment of antimicrobial resistant gram-negative infections. Clin Infect Dis. Published online July 18, 2023. doi:10.1093/cid/ciad428

4.Makris D, Petinaki E, Tsolaki V, et al. Colistin versus colistin combined with ampicillin-sulbactam for multiresistant Acinetobacter baumannii ventilator-associated pneumonia treatment: an open-label prospective study. Indian J Crit Care Med. 2018;22(2):67-77. doi:10.4103/ijccm.IJCCM_302_17

5.Kaye KS, Marchaim D, Thamlikitkul V, et al. Colistin monotherapy versus combination therapy for carbapenem-resistant organisms. NEJM Evid. 2023;2(1):10.1056/evidoa2200131. doi:10.1056/EVIDoa2200131

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.Penwell WF, Shapiro AB, Giacobbe RA, et al. Molecular mechanisms of sulbactam antibacterial activity and resistance determinants in Acinetobacter baumannii. Antimicrob Agents Chemother. 2015;59(3):1680-1689. doi:10.1128/AAC.04808-14

8.Shields RK, Paterson DL, Tamma PD. Navigating available treatment options for carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex infections. Clin Infect Dis 2023;76(suppl 2):S179-S193. doi:10.1093/cid/ciad094

9.Kaye KS, Shorr AF, Wunderink RG, et al. Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK). Lancet Infect Dis. 2023;23(9):1072-1084. doi:10.1016/S1473-3099(23)00184-6

10.Zampaloni C, Mattei P, Bleicher K, et al. A novel antibiotic class targeting the lipopolysaccharide transporter. Nature. 2024;625(7995):566-571. doi:10.1038/s41586-023-06873-0

11.Guenther A, Millar L, Messer A, et al. 2126. Safety, tolerability, and pharmacokinetics (PK) in healthy participants following single dose administration of zosurabalpin, a novel pathogen-specific antibiotic for the treatment of serious Acinetobacter infections. Open Forum Infect Dis. 2023;10(suppl_2):ofad500.1749. doi:10.1093/ofid/ofad500.1749

12.Wunderink RG, Matsunaga Y, Ariyasu M, et al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2021;21(2):213-225. doi:10.1016/S1473-3099(20)30731-3

13.Bassetti M, Echols R, Matsunaga Y, et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2021;21(2):226-240. doi:10.1016/S1473-3099(20)30796-9