NUZYRA (Page 5 of 7)
12.4 Microbiology
Mechanism of Action
Omadacycline is an aminomethylcycline antibacterial within the tetracycline class of antibacterial drugs. Omadacycline binds to the 30S ribosomal subunit and blocks protein synthesis. In general, omadacycline is considered bacteriostatic; however, omadacycline has demonstrated bactericidal activity against some isolates of S. pneumoniae and H. influenzae.
Resistance
The following in vitro data are available, but their clinical significance is unknown. Omadacycline was active in vitro against Gram-positive bacteria expressing ribosomal protection proteins (TetM) and tetracycline resistance active efflux pumps (TetK and TetL), and in Enterobactericeae expressing the TetB efflux pump. Additionally, omadacycline was active against some S. aureus , S. pneumoniae , and H. influenzae strains carrying macrolide resistance genes (ermA, B and/or C), or ciprofloxacin resistance genes (gyrA and parC) and beta-lactamase positive H. influenzae.
Interaction with Other Antimicrobials
In vitro studies have not demonstrated antagonism between omadacycline and other commonly used antibacterials (ampicillin, ceftazidime, ceftriaxone, imipenem, piperacillin/tazobactam, gentamicin, vancomycin, daptomycin, linezolid).
Antimicrobial Activity
Omadacycline has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1.1, 1.2)].
Community-Acquired Bacterial Pneumonia (CABP)
- Gram-positive bacteria
Streptococcus pneumoniae
Staphylococcus aureus (methicillin-susceptible isolates)
- Gram-negative bacteria
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
- Other microorganisms
Chlamydophila pneumoniae
Legionella pneumophila
Mycoplasma pneumoniae
Acute Bacterial Skin and Skin Structure Infections (ABSSSI)
- Gram-positive bacteria
Enterococcus faecalis
Staphylococcus aureus (methicillin-susceptible and -resistant isolates)
Staphylococcus lugdunensis
Streptococcus anginosus grp. (includes S. anginosus , S. intermedius , and S. constellatus)
Streptococcus pyogenes
- Gram-negative bacteria
Enterobacter cloacae
Klebsiella pneumoniae
The following in vitro data are available, but their clinical significance is unknown. At least 90% of isolates of the following bacteria exhibit an in-vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for NUZYRA against isolates of similar genus or organism group. However, the efficacy of NUZYRA in treating clinical infections due to these bacteria has not been established in adequate and well controlled clinical trials.
- Gram-positive bacteria
Enterococcus faecium (vancomycin-susceptible and -resistant isolates)
Streptococcus agalactiae
- Gram-negative bacteria
Enterobacter aerogenes
Escherichia coli
Citrobacter freundii
Citrobacter koseri
Klebsiella oxytocaMoraxella catarrhalis
Susceptibility Testing
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies with omadacycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterial drugs, oxytetracycline (adrenal and pituitary tumors), and minocycline (thyroid tumors).
Mutagenesis
Omadacycline was positive for clastogenicity and aneugenicity in an in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells and for mutagenicity in an in vitro forward mutation assay in mouse lymphoma cells. These effects were seen in the presence of metabolizing enzymes.
Omadacycline was negative in a chromosomal aberration test in Chinese hamster V79 cells and in vivo micronucleus assays administered intraperitoneally to ICR mice or intravenously to HanRcc: WIST rats.
Impairment of Fertility
Omadacycline administration to male rats in a fertility study caused reduced sperm counts and sperm motility at 20-mg/kg/day (approximately 1.3 times clinical systemic exposure, based on AUC in a separate study in rats at a similar dose), but had no effect on male fertility parameters. In general toxicity studies, inhibition of spermatogenesis occurred after administration of 45-mg/kg/day omadacycline (6 to 8 times the clinical AUC exposure) for 37 days or longer, but not at lower doses (15-mg/kg/day, ≤ 2 times clinical AUC exposure) or shorter treatment periods (4 weeks or less). In female rats, fertility was reduced at the 20-mg/kg/day dose (approximately equivalent to human exposures in a separate study in unmated females), characterized by reduced ovulation and increased embryonic loss when treatment occurred from before mating through early pregnancy.
13.2 Animal Toxicology and/or Pharmacology
Hyperpigmentation of the thyroid has been produced by members of the tetracycline class in the following species: in rats by omadacycline, oxytetracycline, doxycycline, tetracycline PO4, and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO4, and methacycline; in dogs by doxycycline and minocycline; in monkeys by omadacycline and minocycline.
Minocycline, tetracycline PO4, methacycline, doxycycline, tetracycline base, oxytetracycline HCl, and tetracycline HCl were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet.
Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline.
14 CLINICAL STUDIES
14.1 Community-Acquired Bacterial Pneumonia
A total of 774 adults with CABP were randomized in a multinational, double-blind, double-dummy trial (Trial 1, NCT #02531438) comparing NUZYRA to moxifloxacin. NUZYRA was administered 100-mg intravenously every 12 hours for two doses on Day 1, followed by 100-mg intravenously daily, or 300-mg orally, daily. Moxifloxacin 400-mg was administered intravenously or orally daily. Total treatment duration was 7-14 days. All enrolled patients were expected to require a minimum of at least 3 days of intravenous treatment. Efficacy and safety of an oral loading dose was not evaluated in CABP.
A total of 386 patients were randomized to NUZYRA and 388 patients were randomized to moxifloxacin. Patient demographic and baseline characteristics were balanced between the treatment groups. Patients were predominantly male (55%) and white (92%). Approximately 60% of patients in each group belonged to PORT Risk Class III, 26% were PORT Risk Class IV and 14.5% were PORT Risk Class II. The median age was 62 years, mean BMI was 27.34 kg/m2 , and approximately 47% of NUZYRA treated patients had CrCl <90 ml/min. Among NUZYRA-treated patients, common comorbid conditions included hypertension (49.5%), diabetes mellitus (16.3%), chronic lung disease (21.2%), atrial fibrillation (10.1%), and coronary artery disease (9.1%). The majority of sites were in Eastern Europe, which accounted for 82% of enrollment; 3 patients were enrolled in the US.
Clinical success at the early clinical response (ECR) timepoint, 72 to 120 hours after the first dose, was defined as survival with improvement in at least two of four symptoms (cough, sputum production, chest pain, dyspnea) without deterioration in any of these four symptoms in the intent to treat population (ITT), which consisted of all randomized patients.
Table 7 presents the clinical success rates at the ECR timepoint (ITT population).
| Endpoint | NUZYRA (%) | Moxifloxacin (%) | Treatment Difference(95% CI *) |
|---|---|---|---|
| * Clinical Success at the early clinical response (ECR) timepoint, 72 to 120 hours after the first dose, was defined as survival with improvement in at least two of four symptoms (cough, sputum production, chest pain, dyspnea) from baseline without deterioration in any of these symptoms, with no receipt of antibacterial treatment either as a rescue for CABP or as a treatment for other infections that may be effective for CABP, and no discontinuation of study treatment due to AE. | |||
| |||
| Clinical Success | 81.1% | 82.7% | -1.6 (-7.1, 3.8) |
Clinical response was also assessed by the investigator at the post therapy evaluation visit (PTE), 5 to 10 days after last dose of study drug and defined as survival and improvement in signs and symptoms of CABP, based on the clinician’s judgment, to the extent that further antibacterial therapy is not necessary. Table 8 presents the results of clinical response at the PTE visit for both the ITT population and the Clinically Evaluable (CE) population, which consisted of all ITT patients who had a diagnosis of CABP, received a minimum number of expected doses of study drug, did not have any protocol deviations that would affect the assessment of efficacy, and had investigator assessment at the PTE visit. Clinical response rates by most common baseline pathogen in the microbiological ITT (micro-ITT) population, defined as all randomized patients with a baseline pathogen are presented in Table 9.
| Endpoint | Population | NUZYRA n/N (%) | Moxifloxacin n/N (%) | Treatment Difference (95% CI †) |
|---|---|---|---|---|
| ||||
| Clinical Success at PTE | ITT | 338/386 (87.6) | 330/388 (85.1) | 2.5 (-2.4, 7.4) |
| Clinical Success at PTE | CE | 316/340 (92.9) | 312/345 (90.4) | 2.5 (-1.7, 6.8) |
| Pathogen | NUZYRA n/N (%) | Moxifloxacin n/N (%) |
|---|---|---|
| Streptococcus pneumoniae | 37/43 (86.0) | 31/34 (91.2) |
| Methicillin-susceptible Staphylococcus aureus ( MSSA) | 8/11 (72.7) | 8/10 (80.0) |
| Haemophilus influenzae | 26/32 (81.3) | 16/16 (100) |
| Haemophilus parainfluenzae | 15/18 (83.3) | 13/17 (76.5) |
| Klebsiella pneumoniae | 10/13 (76.9) | 11/13 (84.6) |
| Legionella pneumophila | 27/29 (93.1) | 27/28 (96.4) |
| Mycoplasma pneumoniae | 31/35 (88.6) | 25/29 (86.2) |
| Chlamydophila pneumoniae | 14/15 (93.3) | 13/14 (92.9) |
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