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The new england journal of medicine

Editorials

Omadacycline — The Newest

Henry F. Chambers, M.D.

Omadacycline was the second of the context of the growing threat of drug-resistant tetracycline class to be approved by the Food and bacterial pathogens (carbapenem-resistant gram- Drug Administration (FDA) in 2018. Results of negative pathogens most especially) and the two phase 3, double-blind, randomized clinical urgent need for new agents active against them, trials of the drug, one involving acute bacterial one must ask: So what? skin and skin-structure infections and the other Omadacycline has few advantages over the community-acquired bacterial pneumonia, are numerous agents already available for the treat- now reported in the Journal.1,2 Each trial was ment of acute bacterial skin and skin-structure designed and executed according to FDA guid- infections. The benefit, if any, of its activity ance.3,4 The primary efficacy end point in each against susceptible gram-negative organisms was was early clinical response, at 48 to 72 hours for untested because patients with a sole gram-nega- acute bacterial skin and skin-structure infec- tive pathogen at baseline were excluded from tions and at 72 to 120 hours for community- analysis. In addition, , the comparator acquired bacterial pneumonia, in an intention- agent, which lacks such activity, performed as to-treat population. Each was a noninferiority well overall, and there were too few patients trial with a noninferiority margin of 10 percent- with mixed infection for a meaningful analysis. age points and 90% and 80% power, respectively, The oral formulation of omadacycline may offer for the comparison of omadacycline with linezo­ an advantage in certain circumstances — for lid for acute bacterial skin and skin-structure example, it could be given instead of linezolid as infections and the comparison of omadacycline treatment for the occasional patient receiving with for community-acquired bac- monoamine oxidase inhibitor or antiserotonergic terial pneumonia. Previous antibacterial therapy antidepressant therapy. was an exclusion criterion in the trial involving A similar analysis pertains to community- acute bacterial skin and skin-structure infections acquired bacterial pneumonia, for which there and was limited to 25% of the patients in the are several effective treatment options, although trial involving community-acquired bacterial pneu- omadacycline may offer some advantages. In addi- monia, which gives confidence in the conclu- tion to having activity against typical bacterial re- sions that omadacycline had a meaningful treat- spiratory pathogens, omadacycline is active against ment effect and that it was similar in efficacy to the atypical organisms Legionella pneumophila, standard-of-care agents for these infections. Mycoplasma pneumoniae, and pneumoniae, Both trials checked all the boxes required of whereas beta-lactams are not. Omadacycline is a a high-quality, interventional ,5 and single-agent alternative, either parenteral or oral, the results enabled FDA approval of omadacy- to empirical beta-lactam– combination cline for the treatment of acute bacterial skin therapy or a respiratory fluoroquinolone for and skin-structure infections and community- community-acquired bacterial pneumonia. Fluoro­ acquired bacterial pneumonia. Yet within the quinolones, rightly or wrongly, have increasingly

588 n engl j med 380;6 nejm.org February 7, 2019 The New England Journal of Medicine Downloaded from nejm.org by GIUSEPPE GIOCOLI on February 15, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved. Editorials fallen from favor because of rare adverse events, ity as a predictor of in vivo efficacy, the MIC including tendinopathies, neuropathic effects, breakpoints vary according to species and can- and, more recently, aortic dissection. When the not be generalized, and the MICs for drug-resis- use of omadacycline for the treatment of com- tant strains often are higher than those for munity-acquired bacterial pneumonia is consid- susceptible strains.6,9 ered, it is important to remember that patients These considerations notwithstanding, omada- with hemodynamic instability, septic shock, cycline is the latest candidate with at least some clinically significant immunologic deficiency, or promise for the treatment of infections caused infection with a suspected drug-resistant patho- by carbapenem-resistant Enterobacteriaceae and gen (e.g., fluoroquinolone-resistant Klebsiella pneu- species of acinetobacter. Well designed clinical moniae) were excluded from the trial. In addition, trials of omadacycline for the treatment of infec- there was an imbalance in mortality: eight tions caused by multiple-drug–resistant gram- deaths in the omadacycline group as compared negative pathogens are needed to determine its with four in the moxifloxacin group. The rea- real value as an antibacterial agent. sons for this imbalance are unclear, but death Disclosure forms provided by the author are available with the occurred disproportionately among patients full text of this editorial at NEJM.org. with a Pneumonia Severity Index risk class of IV From the Division of Infectious Diseases, Zuckerberg San Fran- (classes range from I to IV, with higher classes cisco General Hospital, University of California, San Francisco, indicating a higher risk of death). San Francisco. So what is the role of omadacycline for treat- 1. O’Riordan W, Green S, Overcash JS, et al. Omadacycline for ment of infections caused by multiple-drug–­ acute bacterial skin and skin-structure infections. N Engl J Med resistant pathogens? It is a question desperately 2019;​380:​528-38. 2. Stets R, Popescu M, Gonong JR, et al. Omadacycline for in need of an answer. Omadacycline does not community-acquired bacterial pneumonia. N Engl J Med 2019;​ have cross-resistance with beta-lactam antibiot- 380:​517-27. ics, , polymyxins, and fluoroqui- 3. Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research. Guid- nolones and is active against organisms express- ance for industry — acute bacterial skin and skin structure in- ing tetracycline efflux and ribosomal protection fections: ​developing drugs for treatment. October 2013 (https:// genes. It is many times more active than doxycy- www.fda​ .gov/​ downloads/​ Drugs/​ Guidances/​ ucm071185​ .pdf).​ 4. Department of Health and Human Services, Food and Drug cline and against Enterobacteriaceae Administration Center for Drug Evaluation and Research. Guid- and Acinetobacter baumannii, with minimum inhibi- ance for industry — community-acquired bacterial pneumonia:​ tory concentrations (MICs) less than or equal to developing drugs for treatment — draft guidance. January 2014 6 (https://www.fda​ .gov/​ downloads/​ drugs/​ guidances/​ ucm123686​ ​ 4 μg per milliliter for 90% of strains, the FDA .pdf). breakpoint MIC for susceptibility of K. pneu- 5. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: moniae to omadacycline. Two other advanced- updated guidelines for reporting parallel group randomised trials. PLoS Med 2010;7(3):​ e1000251.​ spectrum — and erava- 6. Pfaller MA, Huband MD, Shortridge D, Flamm RK. Surveil- cycline, the latter of which was recently approved lance of omadacycline activity tested against clinical isolates by the FDA for the treatment of intraabdominal from the United States and Europe as part of the 2016 SENTRY antimicrobial surveillance program. Antimicrob Agents Che- infections — have similar properties. Results mother 2018;62(4):​ e02327-e17.​ with tigecycline in the treatment of carbapenem- 7. Isler B, Doi Y, Bonomo RA, Paterson DL. New treatment op- resistant gram-negative infections have been tions against carbapenem-resistant Acinetobacter baumannii 7,8 infections. Antimicrob Agents Chemother 2018;​63(1):​e01110-18. disappointing. The FDA label warns of higher 8. Shankar C, Nabarro LEB, Anandan S, Veeraraghavan B. Mi- all-cause mortality with tigecycline than with nocycline and tigecycline: what is their role in the treatment of comparators in clinical trials and specifically carbapenem-resistant gram-negative organisms? Microb Drug Resist 2017;​23:​437-46. states that it is not indicated for the treatment of 9. Livermore DM, Mushtaq S, Warner M, Woodford N. In vitro hospital-acquired pneumonia. failed activity of eravacycline against carbapenem-resistant Enterobac- in phase 3 trials evaluating its use in compli- teriaceae and Acinetobacter baumannii. Antimicrob Agents Che- mother 2016;​60:​3840-4. cated urinary tract infections, a stated limitation DOI: 10.1056/NEJMe1900188 of use in the label. With respect to in vitro activ- Copyright © 2019 Massachusetts Medical Society.

n engl j med 380;6 nejm.org February 7, 2019 589 The New England Journal of Medicine Downloaded from nejm.org by GIUSEPPE GIOCOLI on February 15, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved.