Bad Bugs, New Drugs: A Discussion of Selected New Therapeutics From IDWeek 2022

IDWeek 2022 was an exciting time for infectious disease professionals across the globe, marking the first live gathering of this event in 3 years. The expo was brimming with highly anticipated events, including multiple esteemed keynote speakers and (just as importantly) the IDBugBowl trivia competition.

Several abstracts for new therapeutics were presented at a Thursday session. Two in particular are highlighted below, including a new β-lactam/β-lactamase inhibitor (BLIBLI) showing success with urinary tract infections (UTIs) and a novel approach to Clostridioides difficile infection (CDI) that may reduce the rate of recurrence.

CERTAIN-1

With 19% of Enterobacterales and 13% of Pseudomonas health care–associated infections being multidrug resistant,¹ encountering durable microbes while treating UTIs is now a common clinical scenario. However, Venatorx Pharmaceuticals may offer a potential carbapenem-sparing frontline option.

Paul McGovern, MD, presented details on a promising investigational BLBLI combination called cefepime-taniborbactam (FTB). He discussed data from CERTAIN-1 (NCT03840148),² a phase 3 randomized control trial that seeks to “rescue” cefepime from emerging gram-negative resistance with the addition of taniborbactam. This novel β-lactamase inhibitor demonstrates activity against bugs expressing serine and metallo-β-lactamases, which are an increasingly prevalent global threat.³

To date, there has been difficulty in substituting cephalosporins and penicillins for carbapenems alone in the treatment of extended-spectrum β-lactamase gram negative infections,⁴ leaving clinicians obligated at times to reach for those “bigger guns.”

CERTAIN-1 focused on adult patients hospitalized with complicated UTI (cUTI) and acute pyelonephritis (AP), with urine cultures encompassing both sensitive and resistant gram-negatives. In a head to head comparison of FTB against meropenem (MEM), FTB met the prespecified noninferiority margin of –15%. Even further, a prespecified test for superiority was met for the primary end point, which was a composite of microbiologic as well as clinical test of cure (TOC). Microbiologic response was classified as a reduction of urine culture colony-forming units (CFU)/ mL from 105 to 103 or less, whereas clinical response required the clearance of symptoms or return to premorbid baseline.

A total of 661 patients were randomly assigned, with 66% (436) included in the final micro intention-to-treat population. Inclusion in the population required urine culture with gram-negative pathogens at more than 105 CFU/mL that were sensitive to both antimicrobial treatment arms, and no more than 2 microorganisms identified in that same culture. Patients included in the study were randomly assigned 2:1, receiving either FTB 2.5 g IV every 8 hours or MEM 1 g IV every 8 hours for 7 to 14 days (ultimately depending on presence of bacteremia, at the investigators’ discretion). Approximately 43% of patients were treated for AP, with the rest being treated for cUTI. Notably, approximately 24% of the included population met systemic inflammatory response syndrome criteria at time of inclusion and about 13% had bacteremia.

FTB performed well; at the initial TOC visit on days 19 to 23, composite success was 70.6% for FTB and 58% for MEM. This 12% difference is statistically significant but was mainly driven by microbiologic success, with nonsignificant differences in clinical TOC. However, at the late follow-up visit on days 28 to 35, the 12% composite difference was still present, now being driven by a 10% difference in clinical response favoring FTB. Although microbiologic TOC does not always align with clinical outcomes,⁵ it was encouraging to see concordance in this trial.

McGovern finished the presentation by discussing safety through treatment-emergent adverse events. Serious adverse events occurred in 2.0% and 1.8% of patients in each respective group. With similar safety profiles overall, FTB showed superiority over MEM in treatment of cUTI and AP, demonstrating a much-needed option to avoid carbapenems in selected clinical scenarios.

RI-CODIFY 2

Stubborn gram-positive infections were not forgotten at IDWeek2022. Pablo C. Okhuyson, MD, presented data from Ri-CoDIFy 2 (NCT03595566), a phase 3 double-blind study comparing the efficacy and safety of ridinilazole (RDZ) with vancomycin (VAN) for the treatment of CDI.

Ridinilazole, developed by Summit Therapeutics, is a narrow-spectrum bis-benzimidazole that has bactericidal activity against C difficile. This novel compound’s activity is thought to be related to the disruption of bacterial cell division⁶ via binding to the DNA minor groove. Notably, RDZ selectively targets C difficile, thereby sparing the rest of the gut microbiota.¹

Inclusion criteria were 3-fold: Patients had to demonstrate signs and symptoms of CDI, have CDI confirmed via positive free toxin test, and have 1 CDI episode or less in the past month or 3 episodes or less in the past 12 months. The primary end point for superiority relative to VAN was sustained clinical response (SCR), defined as a clinical response and no recurrence of CDI through 30 days past the end of treatment (EOT) date.

There were also multiple interesting secondary end points, including: proportion of patients experiencing a clinical response, proportion of patients experiencing recurrence, proportion of patients experiencing an SCR over 90 days past EOT, change in abundance of gut microbiota from baseline to EOT, and safety of RDZ. After inclusion, participants were randomly assigned 1:1 to receive either 200 mg of oral RDZ twice a day for 10 days or 125 mg of oral VAN once a day for 10 days.

The proportion of patients experiencing an SCR with RDZ was higher than those who received VAN (73% vs 70.7%; P = .4672), but did not meet significance or the threshold for superiority. This numerical difference may have been driven by a reduction in recurrent CDI (rCDI). The apparent advantage of RDZ was found with recurrence; the rate of rCDI was lower for RDZ than for VAN (8.1% vs 17.3%; P = .0002). This translated to a relative risk reduction of rCDI for RDZ of 53%.

The proportion of patients receiving RDZ who experienced a clinical response at EOT plus 2 days was less than the proportion who received VAN (86.5% vs 92.3%), but did not meet the predetermined threshold for inferiority. Notably, 1 specific subgroup analysis of patients who were not receiving antibiotics when they developed CDI showed that RDZ had a higher SCR (77.6% vs 72.6%), similarly driven by a 60% relative reduction in rCDI (P = .0005).

One especially interesting focus of this study was to analyze participant gut microbiota at baseline and EOT. Gut microbiota appear to be a critical factor in preventing recurrence of CDI. One mechanism is thought to occur through the production of secondary bile acids, which inhibit the growth of C difficile.⁷ In this study, both groups had similar microbiome richness at baseline. However, the VAN group had significantly decreased microbiome diversity and abundance at EOT whereas the patients receiving RDZ had relative preservation of their microbiome.

More specifically, the VAN group saw an increase in pathogenic bacteria from the proteobacteria phylum, such as Escherichia coli and Klebsiella species. Although both groups had similar production of inhibitory secondary bile acids at baseline, at EOT the VAN group saw a significant decrease in relative abundance of secondary bile acids, which continued through day 40. Production of secondary bile acids was associated with clinical response and reduced CDI recurrence. All told, this was a strong signal that RDZ may be superior at preserving the protective gut microbiome, and offers a mechanistic reason for the lower rates of rCDI seen in this study’s data.

Overall, RDZ did not demonstrate superiority over VAN in the treatment of CDI, but it did reduce the rates of rCDI and, importantly, preserve the patients’ gut microbiome. More studies on RDZ are needed before it is ready for market. In light of the focus on preserving the gut microbiome with antibiotic use and its importance in preventing rCDI, future studies comparing RDZ with fidaxomicin would be especially intriguing.

SUMMARY

On the heels of CERTAIN-1, Venatorx Pharmaceuticals will be assembling a new drug application package in early 2023 for FTB, with hopes of the agent being available to clinicians in 2024.

Summit Therapeutics expects to conduct at least 1 additional clinical trial of RDZ before achieving full market approval from the FDA.⁸ Cefepime-taniborbactam may represent a safe and effective carbapenem-sparing agent in cUTI and AP, whereas ridinilazole may play an important role in treating CDI.

Since Boucher et al’s 2009 update to the Infectious Diseases Society of America report Bad Bugs, No Drugs,⁹ we have made only modest inroads into an otherwise stagnating field of antibiotic discovery. IDWeek2022 highlighted several promising therapeutics in the pipeline that will hopefully become useful tools for clinicians in the near future.

References

1. US Department of Health and Human Services. Antibiotic Resistance Threats in the United States, 2013. Centers for Disease Control and Prevention; 2013.
2. McGovern PC, Wagenlehner F, Gasink L. CERTAIN-1: a phase 3 study of cefepime-taniborbactam efficacy and safety in the treatment of complicated urinary tract infections (cUTI), including acute pyelonephritis (AP). Paper [or Abstract] presented at: IDWeek 2022; October 19-23, 2022; Washington, DC.
3. Bush K. Alarming β-lactamase-mediated resistance in multidrug-resistant Enterobacteriaceae. Curr Opin Microbiol. 2010;13(5):558-564. doi:10.1016/j.mib.2010.09.006
4. Harris PNA, Tambyah PA, Lye DC, et al; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN). Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA. 2018;320(10):984-994. doi:10.1001/jama.2018.12163
5. Timsit JF, de Kraker MEA, Sommer H, et al; COMBACTE-NET consortium. Appropriate endpoints for evaluation of new antibiotic therapies for severe infections: a perspective from COMBACTE’s STAT-Net. Intensive Care Med. 2017;43(7):1002-1012. doi:10.1007/s00134-017-4802-4
6. Cho JC, Crotty MP, Pardo J. Ridinilazole: a novel antimicrobial for Clostridium difficile infection. Ann Gastroenterol. 2019;32(2):134-140. doi:10.20524/aog.2018.0336
7. Allegretti JR, Kearney S, Li N, et al. Recurrent Clostridium difficile infection associates with distinct bile acid and microbiome profiles. Aliment Pharmacol Ther. 2016;43(11):1142-1153. doi:10.1111/apt.13616
8. Summit Therapeutics provides update on ridinilazole. News release. Summit Therapeutics Inc. July 14, 2022. Accessed October 26, 2022. https://www.globenewswire.com/en/news-release/2022/07/14/2479712/0/en/Summit-Therapeutics-Provides-Update-on-Ridinilazole.html
9. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! an update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(1):1-12. doi:10.1086/595011