Nuzyra (Omadacycline) Approved for the Treatment of Community-Acquired Bacterial Pneumonia or Acute Bacterial Skin and Skin Structure Infections

March 2019, Vol 12, Tenth Annual Payers' Guide - Select Drug Profiles, Payers' Guide
Loretta Fala
Medical Writer
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Community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) are serious and potentially life-threatening infections. Bacteria can mutate, resulting in antibiotic-resistant infections, which is a major health concern that affects more than 2 million Americans and causes 23,000 deaths annually.1

In addition to their profound impact on patients, CABP and ABSSSI are associated with substantial healthcare costs.2,3 Pneumococcal pneumonia, caused by Streptococcus pneumoniae bacteria, affects approximately 900,000 people and leads to 400,000 hospitalizations annually in the United States.2 Similarly, more than 752,000 individuals with a diagnosis of primary ABSSSI were hospitalized in 2011, with an average hospital stay of 4.95 days.3

CABP is managed with antibiotics, supplemented by cough suppressants and fever and/or pain relief medications.4 ABSSSI are also managed with antibiotic agents, supplemented by wound care.5 Decisions regarding antibiotic selection are often guided by the bacterial strain causing the infection.5 New and effective antibacterial agents may improve outcomes for patients with CABP or ABSSSI.

Nuzyra New Once-Daily Option Approved for CABP or ABSSSI

On October 2, 2018, omadacycline (Nuzyra; Paratek Pharmaceuticals), an aminomethylcycline antibacterial within the tetracycline class, was approved by the US Food and Drug Administration (FDA) for the treatment of adults with CABP or with ABSSSI.6,7 Omadacycline was designed to combat resistance to tetracycline agents; it is a once-daily treatment available as an intravenous (IV) or an oral therapy. To reduce the incidence of drug-resistant bacteria and maintain the effectiveness of omadacycline and other antibacterial agents, omadacycline should only be used for the treatment of proved or strongly suspected cases of CABP or ABSSSI.7 As part of the FDA approval of omadacycline, postmarketing studies will be conducted in patients with CABP and in pediatric patients.6

“There continues to be a need for novel antibiotics with both IV and oral formulations, such as Nuzyra, to help physicians stay ahead of the evolving resistance landscape,” said Keith Kaye, MD, MPH, Director of Clinical Research, Division of Infectious Diseases, ­University of Michigan.6

Mechanism of Action

Omadacycline, an aminomethylcycline antibacterial within the tetracycline class, binds to the 30S ribosomal subunit and blocks protein synthesis. In vitro data have shown that omadacycline is active against Gram-positive bacteria that carry ribosomal protection genes (tet M) and efflux genes (tet K and tet L), and in Enterobacteriaceae that carry the tet B efflux gene. Omadacycline is also active against some Staphylococcus aureus, S pneumoniae, and Haemophilus influenzae strains that carry macrolide resistance genes or ciprofloxacin resistance genes and beta-­lactamase–positive H influenzae. The clinical significance of these in vitro data is unknown.7

Overall, omadacycline has shown in vitro activity against several bacteria, including Gram-positive, Gram-negative, and atypical pathogens. Moreover, it has shown efficacy for the treatment of CABP and ABSSSI.7

Dosing and Administration

Omadacycline is available in 2 formulations—as a 100-mg IV injection and as 150-mg oral tablets.7

For patients with CABP, the loading dose on day 1 is 200 mg by IV infusion over 60 minutes, or 100 mg by IV infusion over 30 minutes, given twice; the maintenance dose is 100 mg by IV infusion over 30 minutes once daily, or 300 mg orally once daily for a total of 7 to 14 days.7

For patients with ABSSSI, the loading dose on day 1 is 200 mg by IV infusion over 60 minutes; or 100 mg by IV infusion over 30 minutes, given twice; or, on days 1 and 2, 450 mg orally once daily. The maintenance dose is 100 mg by IV infusion over 30 minutes once daily, or 300 mg orally once daily, for a total duration of 7 to 14 days.7

Patients using oral omadacycline should fast for ≥4 hours before taking omadacycline tablets, with water; then no food or drink (except water) should be consumed for 2 hours, and no dairy products, antacids, or multivitamins for 4 hours.7

The OPTIC Study: CABP

The OPTIC clinical trial was a randomized, double-blind, double-dummy study of 774 adults with CABP who were randomized in a 1:1 ratio to receive omadacycline or moxifloxacin for 7 to 14 days; patients received 100 mg omadacycline intravenously every 12 hours for 2 doses on day 1, followed by 100 mg intravenously daily, with the option to switch to oral 300 mg daily after 3 days of IV therapy; or 400 mg moxifloxacin intravenously, with the option to switch to oral therapy after 3 days of IV therapy.7,8 The efficacy and safety of an oral-only dosing of omadacycline were not evaluated in patients with CABP.7

At the early clinical response evaluation, omadacycline was noninferior to moxifloxacin—81.1% versus 82.7%, respectively (Table 1). At the posttherapy evaluation, omadacycline showed clinical improvement similar to moxifloxacin—87.6% versus 85.1%, respectively (Table 1).7,8 Omadacycline was effective across a broad spectrum of bacteria that cause pneumonia, including S aureus, S pneumoniae, H influenzae and Haemophilus parainfluenzae, Legionella pneumophila, Mycoplasma pneumoniae, Chla­mydophila pneumoniae, Klebsiella pneumoniae, and others.7

Table 1

The 2 OASIS Studies: ABSSSI

Omadacycline was compared with linezolid in 2 double-blind, double-dummy studies in patients with cellulitis, major abscess, or wound infections; the treatment ­duration was 7 to 14 days.7,9,10 OASIS-1 included 655 patients (mean age, 47 years) who were randomized in a 1:1 ratio to omadacycline 100 mg intravenously every 12 hours for 2 doses, followed by 100 mg intravenously every 24 hours, with the option to switch to 300 mg orally every 24 hours after 3 days of IV therapy; or to linezolid 600 mg intravenously every 12 hours, with the option to switch to 600 mg orally every 12 hours after 3 days of IV therapy.7,9

OASIS-2 included 735 patients; of these, 368 patients received oral omadacycline 450 mg once daily on days 1 and 2, followed by 300 mg once daily; and 367 patients received oral linezolid 600 mg every 12 hours.7,10

In the pooled analysis of the OASIS trials, omadacycline was noninferior to linezolid at the early clinical response evaluation (Table 2). At the posttherapy evaluation, treatment with omadacycline led to a similar rate of clinical improvement as linezolid. Overall, omadacycline demonstrated a high clinical response rate in most common types of ABSSSI, including those caused by S aureus (methicillin susceptible and resistant), Strepto­coc­cus anginosus, Streptococcus pyogenes, Enterococcus faecalis, Enterobacter cloacae, and K pneumoniae.7

Table 2

Adverse Reactions

The most common (≥2%) adverse events in patients with CABP who received omadacycline were increased alanine aminotransferase (ALT) levels (3.7%), hypertension (3.4%), elevated gamma-glutamyl transferase levels (2.6%), insomnia (2.6%), vomiting (2.6%), constipation (2.4%), nausea (2.4%), increased aspartate aminotransferase (AST) levels (2.1%), and headache (2.1%).

The serious adverse events rate was 6% with omadacycline versus 6.7% with moxifloxacin. Overall, 21 patients with CABP in the omadacycline arm and 27 patients in the moxifloxacin arm discontinued treatment because of adverse events.7

The most common (≥2%) adverse reactions with omadacycline in the 2 pooled ABSSSI studies were nausea (21.9%), vomiting (11.4%), infusion-site reactions (5.2%), increased ALT levels (4.1%), increased AST levels (3.6%), headache (3.3%), and diarrhea (3.2%). Of note, in the OASIS-1 study, which used IV to oral dosing of omadacycline, the nausea rate was 12% and vomiting was 5%; in OASIS-2, which used an oral loading dose of omadacycline, nausea was 30%, and vomiting was 17%. In each study, 1 patient discontinued omadacycline because of nausea and vomiting.

The rate of serious events was 2.3% with omadacycline versus 1.9% with linezolid. Overall, 1 patient died in the omadacycline arm versus 3 patients in the linezolid arm.7

Contraindications

Omadacycline is contraindicated in patients with a known hypersensitivity to tetracycline antibacterial drugs, including omadacycline, or to any of the excipients in omadacycline.7

Drug Interactions

Patients who receive anticoagulant therapy may require a reduced anticoagulant dosage while taking omadacycline, because tetracyclines can depress plasma prothombin activity. Antacids that contain aluminum, calcium, magnesium, bismuth subsalicylate, and iron can impair the absorption of tetracyclines, including omadacycline.7

Use in Specific Populations

Data on the presence of omadacycline in human milk are not available; because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, breastfeeding is not recommended during treatment with omadacycline and for 4 days after the last dose. Women of reproductive potential should use contraception while taking omadacycline.7

In the CABP clinical trial, patients aged ≥65 years who received omadacycline or moxifloxacin showed a numerically lower clinical success rate at the early clinical response evaluation compared with younger patients.7

After a single 100-mg IV dose of omadacycline, no significant differences in drug exposure were observed between older and younger patients.7

No dose adjustment of omadacycline is required in patients with mild, moderate, or severe hepatic insufficiency or in those with mild, moderate, or severe renal impairment, including patients with end-stage renal disease who are receiving hemodialysis.7

Warnings and Precautions

In the CABP clinical trial, the mortality rate was 2% in patients who received omadacycline compared with 1% in those who received moxifloxacin; the cause of the mortality imbalance has not been established. Patients with CABP, particularly those at high risk, should be closely monitored for clinical response to therapy.7

The use of omadacycline therapy during the second and third trimester of pregnancy, in infants, and in children aged up to 8 years may inhibit bone growth. Omad­acycline use during the last half of pregnancy, in infants, and in children through age 8 years may cause permanent discoloration of the teeth and hypoplasia of the tooth enamel.7

Although no patients who received omadacycline in the 2 OASIS studies or in the OPTIC study had Clostridium difficile–associated diarrhea, C difficile–associated diarrhea ranging from mild diarrhea to fatal colitis, can occur with nearly all antibacterial agents, including ­omadacycline; patients who have diarrhea after omadacycline therapy should be evaluated.7

Conclusion

The FDA approval of omadacycline, a new tetracycline antibiotic, provides a novel antibacterial treatment option for patients with CABP or ABSSSI. Omadacycline is available in 2 once-daily formulations—as an IV infusion and as oral tablets. In clinical trials that included nearly 2000 patients, omadacycline was effective against a broad spectrum of Gram-positive, Gram-negative, atypical, and drug-resistant bacterial strains.

References

  1. Centers for Disease Control and Prevention. Antibiotic/antimicrobial resistance (AR/AMR). Updated September 10, 2018. www.cdc.gov/drugresistance/index.html. Accessed October 26, 2018.
  2. Centers for Disease Control and Prevention. Pneumococcal disease: fast facts. Updated January 23, 2018. www.cdc.gov/pneumococcal/about/facts.html. Accessed November 5, 2018.
  3. Kaye KS, Patel DA, Stephens JM, et al. Rising United States hospital admissions for acute bacterial skin and skin structure infections: recent trends and economic impact. PLoS One. 2015;10:e0143276.
  4. Mayo Clinic. Pneumonia. March 13, 2018. www.mayoclinic.org/diseases­conditions/pneumonia/diagnosis-treatment/drc-20354210. Accessed November 5, 2018.
  5. Mayo Clinic. Staph infections. December 6, 2017. www.mayoclinic.org/diseases-conditions/staph-infections/diagnosis-treatment/drc-20356227. Accessed November 5, 2018.
  6. Drugs.com. FDA approves Nuzyra (omadacycline) for community-acquired bacterial pneumonia and acute skin and skin structure infections. October 2, 2018. www.drugs.com/newdrugs/fda-approves-nuzyra-omadacycline-community­acquired-bacterial-pneumonia-acute-skin-skin-structure-4836.html. Accessed October 26, 2018.
  7. Nuzyra (omadacycline) for injection, for intravenous use/tablets, for oral use [prescribing information]. Boston, MA: Paratek Pharmaceuticals; December 2018.
  8. Stets R, Popescu M, Gonong JR, et al. Omadacycline for community-­acquired bacterial pneumonia. N Engl J Med. 2019;380:517-527.
  9. O’Riordan WA, Green S, Overcash JS, et al. A phase 3 randomized, double-­blind, multi-center study to compare the safety and efficacy of oral and IV ­omadacycline to linezolid for treating adult subjects with ABSSSI (the OASIS study). Presented at the European Congress of Clinical Microbiology and Infectious Diseases; April 22-25, 2017; Vienna, Austria.
  10. O’Riordan WA, Cardenas C, Sirbu A, et al. A phase-3 randomized, double-­blind, multi-centre study to compare the safety and efficacy of oral omadacycline to oral linezolid for treating adult subjects with ABSSSI (OASIS-2 study). Presented at the European Congress of Clinical Microbiology and Infectious Diseases; April 21-24, 2018; Madrid, Spain.
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