FDA Adds Novel Antimicrobials to Arsenal

Pharmacy Practice in Focus: Health SystemsNovember 2019
Volume 8
Issue 6

Antimicrobial resistance continues to pose a significant health threat, necessitating new antibiotics with novel mechanisms to treat these complicated infections. However, between 2010 and 2018, newly approved antibiotics were primarily derived from previously established drug classes. This past summer, the FDA approved 2 new antibiotics.

Antimicrobial resistance continues to pose a significant health threat, necessitating new antibiotics with novel mechanisms to treat these complicated infections.

However, between 2010 and 2018, newly approved antibiotics were primarily derived from previously established drug classes. This past summer, the FDA approved 2 new antibiotics.

Lefamulin (Xenleta)

On August 19, 2019, the FDA approved lefamulin, a semisynthetic pleuromutilin that inhibits the 50S ribosomal subunit at the peptidyl transferase center and serves as the first intravenous (IV) and oral antibiotic with a novel mechanism of action in nearly 20 years.1,2 Indicated for the treatment of community-acquired bacterial pneumonia (CABP), lefamulin has a wide spectrum of activity but, notably, does not treat Acinetobacter baumannii, Enterococcus faecalis, Enterobacteriaceae, and Pseudomonas aeruginosa. Lefamulin offers predictable pharmacokinetics and achieves high concentrations in pulmonary epithelial lining fluid.2,3

In the LEAP 1 trial, patients with pneumonia were randomized to receive IV lefamulin 150 mg every 12 hours + IV moxifloxacin 400 mg or a placebo every 24 hours + linezolid (based on suspicion of methicillin- resistant Staphylococcus aureus) for 7 days. After 6 doses, patients could be transitioned to the respective oral formulation. The primary end point (early clinical response at 96 + 24 hours) occurred in 87.3% of patients taking lefamulin (n = 276) and 90.2% of those taking moxifloxacin (n = 275), indicating that lefamulin is noninferior to moxifloxacin in this setting (difference, —2.9%; 95% CI, –8.5 to 2.8; prespecified noninferiority margin, 12.5%).

Nausea, insomnia, injection site pain/phlebitis, alanine transaminase elevation, and diarrhea were the most commonly reported adverse effects (AEs). Prolonged QT intervals occurred rarely in both groups, but lefamulin should be avoided in patients with known QT prolongation and ventricular arrhythmias. Additionally, concomitant use of lefamulin with strong CYP3A4 inhibitors/ inducers should be avoided. Clostridium difficile— associated diarrhea was not reported in either group in the LEAP 1 trial. Lefamulin should be avoided in pregnant women because it has not been well studied in this population and may cause fetal harm.2 Recently, the LEAP 2 trial established that a 5-day course of oral lefamulin is noninferior to 7 days of oral moxifloxacin for CABP treatment.4 A phase 2 trial has also shown lefamulin to be effective for acute bacte- rial skin and skin structure infections compared with vancomycin.5

Imipenem/Cilastatin/Relebactam (Recarbrio)

On July 17, 2019, the FDA approved imipenem/cilastatin (IMI) + relebactam (REL), a carbapenem, renal dehydropeptidase inhibitor, and novel β-lactamase inhibitor, for adults with limited options for the management of complicated urinary tract infections (cUTIs) and intra-abdominal infections (cIAIs) secondary to susceptible gram-negative organisms. Adding relebactam protects imipenem from β-lactamases, including Klebsiella pneumoniae carbapenemase.6

In a phase 2 study, patients with cUTIs were randomized to REL 250 mg + IMI 500 mg, REL125mg+IMI500mg,orIMI500mg + a placebo every 6 hours. Patients could be transitioned to oral ciprofloxacin 500 mg every 12 hours after 96 hours of IV therapy, for a total treatment duration of up to 14 days. At baseline, 48.3% of patients presented with acute pyelonephritis and 10.9% had an imipenem nonsusceptible microorganism. At discontinuation of IV therapy, the primary outcome (proportion of microbiologically evaluable patients with favorable microbiological response at discontinuation of IV therapy) occurred in 98.6% of patients in the REL 125 mg + IMI arm, 95.5% in the REL 250 mg + IMI arm, and 98.7% of those receiving IMI + a placebo. Both dosing regimens were noninferior to IMI + a placebo.7

Another phase 2 study randomized patients with cIAIs to receive REL 250 mg+ IMI 500 mg, REL 125 mg+ IMI 500mg, or IMI 500 mg + a placebo every 6 hours for 4 to 14 days based on clinicians’ judgment. At baseline, 13% of patients had imipenem-resistant gram-negative infections. The primary end point (proportion of microbiologically evaluable patients with favorable clinical response at discontinuation of IV therapy) occurred in 96.3% of REL 250 mg + IMI and 98.8% of REL 125 mg + IMI patients. Both were noninferior to IMI alone (98.2%; P <0.001), making this new agent a potential alternative for patients with limited antibiotic options because of resistance patterns. Pharmacokinetic/pharmacodynamic simulations established that REL 250 mg + IMI 500 mg every 6 hours covers more than 90% of carbapenem-resistant organisms.8 The recently published RESTORE-IMI 1 trial supports the findings of both phase 2 studies in cUTI and cIAI populations, as well as hospital-acquired/ventilator-associated pneumonia.9

The most commonly reported AEs included diarrhea, nausea, headache, vomiting, and aspartate aminotransferase/alanine aminotransferase elevation. This agent carries drug interaction warnings with concurrent use of ganciclovir, which should not be used concomitantly because of an increased risk of seizures, and valproic acid, because imipenem/cilastatin may decrease valproic acid concentrations. Imipenem/cilastatin + relebactam will require renal dose adjustments, and C difficil—-associated diarrhea has been reported with its use.10

New antimicrobials should be used judiciously to avoid further emergence of antibiotic resistance and reserved for patients without other options. Currently, lefamulin is approved only for the treatment of CABP, but it has potential for use in other infectious diseases. The use of imipenem/cilastatin + relebactam may also be extrapolated to other infectious diseases in the future and serve a key role in treating multidrug-resistant gram-negative infections.


  • Nabriva Therapeutics receives U.S. FDA approval of Xenleta (lefamulin) to treat commu- nity-acquired bacteria pneumonia (CABP) [news release]. Dublin, Ireland: Nabriva; August 19, 2019. investors.nabriva.com/news-releases/news-release-details/nabriva-therapeutics-re- ceives-us-fda-approval-xenletatm. Accessed September 4, 2019.
  • File TM Jr, Goldberg L, Das A, et al. Efficacy and safety of IV-to-oral lefamulin, a pleu- romutilin antibiotic, for treatment of community-acquired bacterial pneumonia: the phase 3 LEAP 1 trial [published online February 4, 2019]. Clin Infect Dis. 2019. doi: 10.1093/cid/ ciz090.
  • Veve MP, Wagner JL. Lefamulin: review of a promising novel pleuromutilin antibiotic. Pharmacotherapy. 2018;38(9):935-946. doi: 10.1002/phar.2166.
  • Alexander E, Goldberg L, Das A, et al. LB6. Oral lefamulin is safe and effective in the treatment of adults with community-acquired bacterial pneumonia (CABP): results of lefam- ulin evaluation against pneumonia (LEAP 2) study. Open Forum Infect Dis. 2018;5(suppl 1):S761. doi: 10.1093/ofid/ofy229.2180.
  • Prince WT, Ivezic-Schoenfeld Z, Lell C, et al. Phase II clinical study of BC-3781, a pleuromutilin antibiotic, in treatment of patients with acute bacterial skin and skin structure infec- tions. Antimicrob Agents Chemother. 2013;57(5):2087-2094. doi: 10.1128/AAC.02106-12.
  • FDA approves Merck’s Recarbrio (imipenem, cilastatin, and relebactam) for the treatment of adults with complicated urinary tract and complicated intra-abdominal bacterial infections where limited or no alternative treatment options are available [news release]. Kenilworth, NJ: Merck; July 17, 2019. mrknewsroom.com/news-release/ prescription-medicine-news/fda-approves-mercks-recarbrio-imipenem-cilastatin-and-releba. Accessed September 4, 2019.
  • Sims M, Mariyanovski V, Mcleroth P, et al. Prospective, randomized, double-blind, phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebact- am with imipenem/cilastatin alone in patients with complicated urinary tract infections. J Antimicrob Chemother. 2017;72(9):2616-2626. doi: 10.1093/jac/dkx139.
  • Lucasti C, Vasile L, Sandesc D, et al. Phase 2, dose-ranging study of relebactam with imi- penem-cilastatin in subjects with complicated intra-abdominal infection. Antimicrob Agents Chemother. 2016;60(10):6234-6243. doi: 10.1128/AAC.00633-16.
  • Motsch J, Murta de Oliveira C, Stus V, et al. RESTORE-IMI 1: a multicenter, randomized, double-blind trial comparing efficacy and safety of imipenem/relebactam vs colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections [published online August 10, 2019]. Clin Infect Dis. doi: 10.1093/cid/ciz530.
  • Recarbrio [prescribing information]. Whitehouse Station, NJ: Merck & Co, Inc; 2019. merck.com/product/usa/pi_circulars/r/recarbrio/recarbrio_pi.pdf. Accessed October 17, 2019.

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit sidp.org.

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