New Antibiotics Treat Select Resistant Infections

On November 14, 2019, the FDA approved cefiderocol (Fetroja) for the treatment of complicated urinary tract infections (cUTIs) and pyelonephritis in adult patients who have limited or no alternative treatment options.¹

Cefiderocol, a siderophore cephalosporin, penetrates the outer cell membrane of gram-negative bacteria by binding to ferric iron, which allows uptake into the periplasmic space via iron transporters.² Cefiderocol can also passively diffuse through bacterial porin channels and is stable against many β-lactamases, including select extended-spectrum β-lactamases (ESBLs) and carbapenemases.³ It has demonstrated broad in vitro activity against gram-negative organisms including Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia.⁴ Two major phase 3 trials that investigated cefiderocol for multiple indications are APEKS-NP (NCT03032380) and CREDIBLE-CR (NCT02714595).^5,6

APEKS-NP was a double-blind, international, multicenter, noninferiority, randomized trial that evaluated cefiderocol for the treatment of hospital-acquired pneumonia caused by gram-negative organisms.⁶ Patients received intravenous (IV) cefiderocol 2 g every 8 hours (infused over 3 hours) or IV meropenem 2 g every 8 hours (infused over 3 hours) for 7 to 14 days while hospitalized. In the cefiderocol group, patients also received linezolid for a minimum of 5 days to provide activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Among 291 randomized patients, the rates of the primary outcome, 14-day all-cause mortality, were 12.4% (n = 18 of 145) for cefiderocol versus 11.6% (n = 17 of 146) for high-dose meropenem (difference, 0.8%; 95% CI, —6.6 to 8.2).²

CREDIBLE-CR was an international, multicenter, parallel-group, prospective, randomized clinical trial. It enrolled patients with bloodstream infections, nosocomial pneumonia, or sepsis and cUTI caused by carbapenem-resistant gram-negative organisms, including A baumannii, K pneumoniae, P aeruginosa, S maltophilia, E coli, or other species of Enterobacterales. Patients were randomized to receive either IV cefiderocol 2 g every 8 hours (infused over 3 hours), with an additional antibiotic if deemed necessary or the best alternative therapy (BAT), a combination of up to 3 antibiotics, intravenously for 7 to 14 days.⁵ Overall, the clinical cure rates at test of cure were 52.5% (n = 42 of 80) versus 50% (n = 19 of 38) in the cefiderocol and BAT groups, respectively.⁶ All-cause mortality by the end of the study, day 49, was 33.7% (n = 34 of 101) in the cefiderocol group versus 18.4% (n = 9 of 49) in the BAT group.⁶ The reason for the increased rates of mortality in the cefiderocol group is unknown. However, the largest rates of mortality were in the subgroup with nosocomial pneumonia, which the APEKS-NP trial investigated more thoroughly, with no mortality difference observed.⁶

Fosfomycin was first approved in the 1960s and has recently under gone significant revival because of its activity against increasingly common multidrug-resistant (MDR) uropathogenic gram-negative bacteria.⁷ Fosfomycin inhibits cell wall synthesis by inactivation of the enzyme MurA, which is responsible for the first step of peptidoglycan synthesis.⁸ During in vitro studies, fosfomycin has demonstrated a broad spectrum of activity against MDR pathogens, including carbapenem-resistant Enterobacterales (CRE), ESBL-producing Enterobacterales, MRSA, and vancomycin-resistant enterococci.⁹ Fosfomycin has approved susceptibility breakpoints only for E coli and Enterococcus faecalis, which may be a barrier to its clinical use.¹⁰

Fosfomycin has been used extensively in Asia and Europe in both IV and oral formulations for a wide variety of infections.¹¹ Although only the oral formulation is available in the United States, an IV formulation is in development. In October 2018, Nabriva Therapeutics submitted a new drug application (NDA) to the FDA for Contepo, IV fosfomycin (formerly ZTI-01).¹² The FDA issued a complete response letter on April 30, 2019, citing concerns with “facility inspections and manufacturing deficiencies at one of Nabriva’s contract manufacturers.”¹² After further investigation, Nabriva resubmitted the NDA in December 2019, and the FDA has set a Prescription Drug User Fee Act date of June 19, 2020.¹³

The double-blind, multicenter, parallelgroup, randomized, phase 2/3 ZEUS trial (NCT02753946) evaluated the efficacy and safety of ZTI-01 versus piperacillintazobactam. Patients hospitalized for cUTI including acute pyelonephritis were randomized to receive IV fosfomycin 6 g every 8 hours or IV piperacillintazobactam 4.5 g every 8 hours, both infused over 60 minutes, for a 7-day course. Patients with concomitant bacteremia could receive up to a 14-day course, and there was no transition to oral antibiotics.⁸ Of 465 randomized patients, 233 and 231 were treated with fosfomycin and piperacillin-tazobactam, respectively. The primary objective of the study was overall response, a combination of clinical cure and microbiologic eradication. Success rates were 64.7% (n = 119 of 184) and 54.5% (n = 97 of 178) for fosfomycin and piperacillin-tazobactam, respectively (difference, 10.2%; 95% CI, —0.4 to 20.8; noninferiority mar gin, 15%). In the subgroup with cUTI, overall success rates were 61.2% (n = 52) with fosfomycin and 41.7% with piperacillin-tazobactam (n = 35), resulting in a 19.5% difference. In the subgroup with pyelonephritis, overall success rates were 67.7% (n = 67) with fosfomycin and 66% with piperacillintazobactam (n = 62).⁸

Diarrhea, nausea, and vomiting were common adverse effects of IV fosfomycin in the ZEUS trial. Notably, IV fosfomycin also had a higher incidence of hypokalemia (6.4% vs 1.3%, respectively) and increased alanine aminotransferase levels (8.6% vs 2.6%) compared with piperacillin-tazobactam. Overall, IV fosfomycin showed a favorable adverse effect profile.⁸

Conclusion

Cefiderocol and IV fosfomycin represent exciting new options for the treatment of select resistant gram-negative infections.^14,15 Cefiderocol may be a useful agent for the treatment of resistant infections caused by non-Enterobacterales gram-negative organisms such as P aeruginosa and S maltophilia. As a non—β-lactam antibiotic, fosfomycin may play a role in the treatment of ESBL or CRE infections when β-lactam monotherapy is not optimal. Further clinical outcomes data will help better define their niche treatment areas and roles.

Deepika Sivakumar, PharmD, is PGY1 pharmacy resident at Detroit Receiving Hospital in Michigan.Elizabeth B. Hirsch, PharmD, RPh is an assistant professor in the Department of Experimental and Clinical Pharmacology at the University of Minnesota College of Pharmacy in Minneapolis.Brandon Dionne, PharmD, BCPS-AQ ID, BCIDP, AAHIVP, is an assistant clinical professor at Northeastern University School of Pharmacy.

REFERENCES

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• Shionogi reports positive results from cefiderocol phase III study in adults with pneumonia caused by gram-negative pathogens. News release. Shionogi Inc. October 2, 2019. Accessed March 5, 2020. https://www.shionogi.com/shionogi-reports-positive-results-from-cefiderocol-phase-iii-study-in-adults-with-pneumonia-caused-by-gram-negative-pathogens
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• Kaye KS, Rice LB, Dane AL, et al. Fosfomycin for injection (ZTI-01) versus piperacillin-tazobactam for the treatment of complicated urinary tract infection including acute pyelonephritis: ZEUS, a phase 2/3 randomized trial. Clin Infect Dis. 2019;69(12):2045-2056. doi:10.1093/cid/ciz181
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• Nabriva Therapeutics receives FDA acknowledgement of new drug application resubmission for intravenous Contepo (fosfomycin) for injection. News release. Nabriva Therapeutics. January 8, 2019. Accessed March 9, 2020. https://www.investors.nabriva.com/news-releases/news-release-details/nabriva-therapeutics-receives-fda-acknowledgement-new-drug
• Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018;18(12):1319-1328. doi:10.1016/S1473-3099(18)30554-1
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