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Update on New Antibiotics with Activity Against Multi-Drug Resistant Organisms

17 Nov 2020 4:47 PM | Anonymous

By: Jesse Smith, PharmD Candidate 2021, St. Louis College of Pharmacy at the University of Health Sciences and Pharmacy in St. Louis

Mentor: Bryan Lizza, PharmD, MS, BCCCP, Barnes-Jewish Hospital – St. Louis

Multi-Drug Resistance

In the United States, more than 2.8 million antibiotic-resistant infections occur annually, leading to more than 35,000 deaths.1 Despite recent initiatives in infection prevention and antibiotic conservation, multi-drug resistant organisms (MDROs) continue to be a global health crisis as mortality and morbidity from MDROs continue to rise.2 As a result of this need for new antibiotic therapy, advancements in antimicrobial development have led to several recently approved antibiotics. Pharmacists will play a vital role in ensuring appropriate use of these new novel agents as well as understanding their mechanisms of action and their important clinical features. The purpose of this article is to describe new antibiotics with activity towards MDROs and summarize important studies that led to their FDA approval.

(Click on tables below to view full size image.)



Clinical Trials

XenletaTM (lefamulin)6,7

The randomized double-blind phase 3 study Lefamulin Evaluation Against Pneumonia (LEAP 1) trial evaluated lefamulin’s ability to treat community-acquired bacterial pneumonia (CABP). The study compared the use of lefamulin at a dose of 150 mg intravenously every 12 hours to moxifloxacin at a dose of 400 mg intravenously every 24 hours for five to seven days. After taking six doses of intravenous therapy, patients in both groups could then be converted to oral formulations of their respective medication if improvement criteria were met. In addition, if methicillin-resistant Staphylococcus aureus (MRSA) was suspected, blinded linezolid was added to moxifloxacin and a placebo was added to lefamulin and the duration of treatment was extended to ten days. The study’s primary endpoint was early clinical response (ECR) 96 ± 24 hours after the first dose of the study drug defined as improvement in ≥2 CABP signs/symptoms, had no worsening in any CABP sign/symptom, and had not received a concomitant, nonstudy antibiotic for CABP. Lefamulin was shown to be non-inferior to moxifloxacin for ECR at a rate of 87.3% for lefamulin and 90.2% for moxifloxacin in treating CABP in the intention-to-treat analysis (95% confidence interval (CI), -8.5 to 2.8). In the subsequent double-blind, double-dummy, parallel-group randomized LEAP 2 clinical trial, oral lefamulin at a duration of five days compared to moxifloxacin at a duration of seven days was evaluated in treating CABP. The study found that ECR at 96 hours ± 24 hours after the first dose of study drug was 90.8% in the lefamulin group and 90.8% in the moxifloxacin group, meeting the noninferiority margin of 10%. Like LEAP 1, LEAP 2 demonstrated lefamulin to be non-inferior to moxifloxacin in treating CABP and both agents were deemed safe and generally well tolerated.

BaxdelaTM (delafloxacin)8

One of the major phase 3 trials that led to delafloxacin’s FDA approval was A Phase 3 Study to Compare Delafloxacin With Moxifloxacin for the Treatment of Adults With Community-Acquired Bacterial Pneumonia (DEFINE-CABP). This randomized, double-blind, comparator-controlled, multicenter, global study compared delafloxacin 300 mg intravenously, with an option to switch to 450 mg orally every 12 hours, to moxifloxacin at 400 mg intravenously daily, with an option to switch to 400 mg orally daily, in patients with CABP. The study’s primary end point was ECR, defined as improvement at 96 ±24 hours after the first dose of study drug. The study found that patients receiving delafloxacin demonstrated an ECR rate of 88.9% compared with 89% in the moxifloxacin group (95% CI, -4.4% to 4.1%). Overall, the authors concluded that delafloxacin was a viable and well tolerated treatment option as monotherapy for CABP in adults where broad spectrum coverage, including MRSA, is indicated.

FetrojaTM (Cefiderocol)9

The efficacy of cefiderocol was evaluated in the 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. The study compared cefiderocol 2 g over 1 hour intravenously every 8 hours or imipenem-cilastin 1 g/1g intravenously every 8 hours for 7-14 days in patients with complicated urinary tract infection, with or without pyelonephritis, or those with acute uncomplicated pyelonephritis. The primary efficacy endpoint for the study was the composite outcome of clinical response defined as the resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms and microbiological response defined as he bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less. The study showed that 73% of patients in the cefiderocol group versus 55% of patients in the imipenem-cilastin group achieved the primary efficacy (95% CI 8.23-28.92; p=0.0004). Thus, cefiderocol was deemed to be non-inferior to imipenem-cilastin in the treatment of complicated urinary tract infections.

The Future of Antibiotics

Although a steady number of novel antibiotics have received FDA approval over the past few years, providers continue to question if new medication approvals can keep up with evolving bacterial resistance. The World Health Organization (WHO) reports that as of September 1, 2019, there are 50 antibiotics and combinations (with a new therapeutic entity), and 10 biologicals in the clinical pipeline (Phase 1– 3) of which 32 target the WHO priority pathogens.2 A large barrier moving forward is whether pharmaceutical companies will allocate the necessary resources to develop new antibiotics as private investment funding continues to decrease.2 Regardless of the pace at which antibiotic therapy evolves, pharmacists will continue to play a key role in ensuring safe and effective use moving forward.

References

  1. CDC. Antibiotic resistance threats in the United States, 2019. Atlanta, GA:U.S. Department of Health and Human Services, CDC; 2019.
  2. WHO. 2019 Antibacterial agents in clinical development: an analysis of the antibacterial clinical development pipeline. Geneva: World Health Organization; 2019.
  3. Xenleta [package insert]. Dublin, Ireland: Nabriva Therapeutics Inc; 2019.
  4. Baxdela [package insert]. Lincolnshire, IL: Melinta Therapeutics Inc; 2017.
  5. Fetroja [package insert]. Florham Park, NJ: Shionogi Inc; 2019.
  6. File T, Goldberg L, Das A, et al. Efficacy and safety of intravenous-to-oral lefamulin, a pleuromutilin antibiotic, for the treatment of community-acquired bacterial pneumonia: the phase III lefamulin evaluation against pneumonia (LEAP 1) Trial. Clin Infect Dis. 2019;69(11):1856-1867.
  7. Alexander E, Goldberg L, Das A, et al. Oral lefamulin vs moxifloxacin for early clinical response among adults with community-acquired bacterial pneumonia: The LEAP 2 Randomized Clinical Trial. JAMA. 2019;322(17):1661-1671.
  8. Horcajada J, Salata R, Alvarez-Sala R, et al. A phase 3 Study to compare delafloxacin with moxifloxacin for the treatment of adults with community-acquired bacterial pneumonia (DEFINE-CABP). Open Forum Infect Dis. 2019;7(1):ofz514
  9. 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. The Lancet. 2018;18(12):1319-1328.


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