Omadacycline: A New Weapon in the Fight Against MRSA

OmadacyclineThose of us “of a certain age” have a life-long familiarity with the tetracycline antibiotics. First introduced in the 1940s, their broad spectrum of activity against a number of important community pathogens was a great asset. Tetracyclines were used to treat a wide range of both gram-positive and gram-negative bacteria, atypical organisms such as chlamydiae, mycoplasmas, and rickettsiae, and even some protozoan parasites.1 In retrospect, that asset became a liability, as the tetracyclines were used so frequently that community resistance among most of those same pathogens was fostered and ultimately limited the use of the class. Contributing to this development of resistance was broad low-level exposure of humans to tetracyclines because the drugs were widely used to treat infections in livestock that became foodstock.

Tetracyclines work by inhibiting bacterial protein synthesis. The drug prevents the attachment of aminoacyl-tRNA to the ribosomal acceptor (A) site; this mechanism is bacteriostatic, not bactericidal. The development of resistance to tetracycline may be due to bacterial acquisition of new genes, which code for efflux of tetracyclines or for a protein that protects bacterial ribosomes from the action of tetracyclines, or by mutations that alter the permeability of the outer membrane of the bacterial cells, change the regulation of those efflux systems, or alter the bacterial RNA itself.1 Despite their general loss of activity as broad-spectrum agents, tetracyclines developed a half-century or more ago still offer benefit in the treatment of severe acne, Lyme disease, some sexually transmitted diseases, traveler’s diarrhea, and rickettsial infections.

The most commonly used tetracyclines today are doxycycline, minocycline, tetracycline itself, and tigecycline. Persisting for decades has been the generalized clinical impression that tetracycline antibiotics are safe. Among the few adverse events noted are nausea and epigastric discomfort, especially if taken on an empty stomach. Additionally, if taken before the age of 8, tetracyclines are associated with permanent discoloration of the teeth. Tetracycline should not be used during pregnancy or breast-feeding. That’s a nicely compartmentalized list of concerns. But still . . . drugs developed in the 1940’s, against the superbugs (e.g., MRSA) of the 21st century? Can that safety be maintained while returning strength to the antibacterial action of a tetracycline? Enter omadacycline, the first “modernized” or “enhanced” tetracycline, which is, in fact, approved by the FDA for the treatment of ABSSSI.

Omadacycline is a novel aminomethylcycline. Edits were made on the tetracycline D-ring to protect it from both active efflux and ribosomal modifications (see above) that lead to resistance to most other tetracyclines.2 Omadacycline has been approved in the United States to treat ABSSI, as well as community-acquired bacterial pneumonia (CABP). Importantly, both IV and oral formulations of omadacycline are approve and available. Intravenous treatment can be initiated with a loading dose of 200 mg IV once or 100 mg IV twice on day 1, followed by 100 mg IV or 300 mg oral daily. For those patients with ABSSSI who in the clinician’s clinical judgment does not need IV therapy, oral treatment can be initiated with 450 mg oral on days 1 and 2, followed by 300 mg oral daily. This ability to transition treatment from IV to oral on the same drug offers smoother, safer, and more convenient de-escalation of treatment as infections respond to the antibiotic.

Switching from IV to oral therapy as soon as patients are showing improvement can reduce inpatient length of stay and decrease cost of care. While parenteral medications may be more bioavailable, some oral drugs produce serum levels comparable to those of the parenteral form. That is true of omadacycline, and switching to the same antibiotic reassures the clinician that the beneficial response is likely to continue.3,4

Omadacycline has reliable antimicrobial activity against tetracycline-resistant strains of not only MRSA, but also pneumococcus and VRE because the modifications to its structure bypass ribosomal protection and active tetracycline efflux in these pathogens.5 And importantly, in its development and with clinical monitoring to date, there have been no cases of C. diff-associated diarrhea attributable to omadacycline. Likewise, when considering alternatives for the management of ABSSSI, omadacycline is not significantly burdened by black box warnings, drug–drug interactions, or allergies.

Two phase 3 trials called the Omadacycline in Acute Skin and Skin Structure Infections Studies (OASIS) studies evaluated the safety and efficacy of omadacycline in the treatment of adults with ABSSSI.6,7 Both OASIS-1 and OASIS-2 were randomized, double-blind, double-dummy, noninferiority studies. The primary FDA endpoint for both studies was early clinical response (ECR) at 48–72 hours after treatment initiation and the post-treatment evaluation (PTE). Both studies also assessed bacteriological response at the end of treatment and at the follow-up visit. OASIS-1 randomized patients with ABSSSI to IV omadacycline or IV linezolid, with the option to transition to oral formulations after three or more days. OASIS-2 considered only oral omadacycline vs oral linezolid. The overall data showed that omadacycline was noninferior to linezolid. Both IV and oral formulations were effective across study populations, regardless of ABSSSI type and baseline pathogen. We looked at a subset of IV drug abusers in the OASIS studies and found that S. aureus was the most commonly isolated pathogen in IVDU and non-IVDU patients, and that about 50% of S. aureus pathogens in the population were MRSA. In these cohorts, omadacycline showed similar efficacy and safety, compared with linezolid, in IVDU and non-IVDU patients.8

Omadacycline is a potentially powerful and very useful weapon for emergency physicians in the management of ABSSSI. While it would not be appropriate to use in less severe cases that can usually be managed with trimethoprim-sulfa or clindamycin (though the latter has a troublesome association with C. diff), it is an excellent choice for patients who first need IV therapy, who have multiple comorbidities, concerns for the adverse effects of fluoroquinolones, a history of C. Diff, or allergies to other antibiotics. When the agent is initiated parenterally, the ultimate switch to the same agent orally is easy to make, connecting that positive ECR with a good final outcome.

1. Chopra I, Roberts M. Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance. Microbiol Mol Biol Rev. 2001;65(2):232-260. doi:10.1128/MMBR.65.2.232-260.2001
2. Draper MP, Weir S, Macone A, et al. Mechanism of action of the novel aminomethylcycline antibiotic omadacycline. Antimicrob Agents Chemother. 2014;58(3):1279-1283. doi:10.1128/AAC.01066-13
3. Kaasch AJ, Fätkenheuer G, Prinz-Langenohl R, et al. Early oral switch therapy in low-risk Staphylococcus aureus bloodstream infection (SABATO): study protocol for a randomized controlled trial. Trials. 2015;16:450. doi:10.1186/s13063-015-0973-x
4. Houfi AE, Javed N, Solem CT, et al. Early-switch/early-discharge opportunities for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections: proof of concept in the United Arab Emirates. Infect Drug Resist. 2015;8:173. doi:10.2147/IDR.S78786
5. Macone AB, Caruso BK, Leahy RG, et al. In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline. Antimicrob Agents Chemother. 2014;58(2):1127-1135. doi:10.1128/AAC.01242-13
6. O’Riordan W, Green S, Overcash JS, et al. Omadacycline for Acute Bacterial Skin and Skin-Structure Infections. N Engl J Med. 2019;380(6):528-538. doi:10.1056/NEJMoa1800170
7. O’Riordan W, Cardenas C, Shin E, et al. Once-daily oral omadacycline versus twice-daily oral linezolid for acute bacterial skin and skin structure infections (OASIS-2): a phase 3, double-blind, multicentre, randomised, controlled, non-inferiority trial. Lancet Infect Dis. 2019;19(10):1080-1090. doi:10.1016/S1473-3099(19)30275-0
8. SAEM Annual Meeting Abstracts. Acad Emerg Med. 2019;26(S1):S9-S304. See Pollack et al, Abstract 88. doi:10.1111/acem.13756

Dr. Charles Pollack

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