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Omadacycline: a novel aminomethylcycline

Abstract Tetracyclines have come a long way since they became available almost seven decades ago, with numerous enhancements allowing new agents to overcome bacterial mechanisms of resistance. However, these enhancements come with toxicities and pharmacokinetic disadvantages such as the gastrointestinal side-effects and poor oral bioavailability seen with the glycylcylcines. Omadacycline, a new and improved tetracycline, has demonstrated a broad spectrum of in vitro activity, has oral and intravenous formulations, improved safety compared to glycylcyclines, as well as clinical efficacy and safety for two types of infections: acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This review will summarize salient points about its pharmacologic properties, available clinical efficacy, and safety data and omadacycline’s place in therapy.


Introduction
The tetracycline class of antibacterial agents was introduced for human use in the 1940s. 1 Demeclocycline, tetracycline, oxytetracycline, minocycline, and doxycycline remain available in the US for systematic use. Synthetic processes have allowed for modifications within the four core rings of tetracyclines and the development of several new tetracycline analogs, including tigecycline as a glycylcycline, eravacycline as a fluorocycline, and omadacycline as an aminomethylcycline. [2][3][4] Omadacycline (PTK0796, BAY 73-6944, MK-2764) is a first-in-class aminomethylcycline with broad-spectrum in vitro activity against Gram-positive aerobes, Gram-negative aerobes, anaerobes, and atypical bacteria. 4,5 Omadacycline retains antibacterial activity against strains expressing the two most common tetracycline resistance mechanisms, bacterial ribosomal protection proteins, and tetracyclinespecific efflux pumps. Both oral and intravenous (IV) formulations of omadacycline have been approved by the United States Food and Drug Administration (US FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). The recommended oral dosage of omadacycline in adults with ABSSSI is 450 mg orally once daily for Day 1 and 2 of therapy, followed by a maintenance dose of 300 mg orally once daily. The dosage of omadacycline in adults with CABP and ABSSSI is a loading dose of 200 mg by IV infusion over 60 minutes or 100 mg by IV infusion over 30 minutes twice on day 1, followed by a maintenance dose of 100 mg IV infusion over 30 minutes once daily or 300 mg orally once daily. The recommended treatment duration for omadacycline for both indications is 7-14 days.
This review provides an overview of the clinical microbiology, pharmacology, efficacy, and safety data of omadacycline. The current information will be provided as a foundation for understanding the clinical usefulness of the oral and IV dosage regimens of omadacycline for the treatment of ABSSSI and CABP in adults.

Mechanisms of action and resistance
Like all other tetracyclines, omadacycline is primarily a protein synthesis inhibitor, as confirmed by macromolecular synthesis experiments. 9 Protein synthesis inhibition is thought to occur from binding to the 30S ribosomal subunit. 9,10 Attachment to the 30S subunit blocks the acceptor site in the mRNA-ribosome complex, which prevents amino acid incorporation into the elongating peptide. 3 Because this interaction is reversible, tetracyclines are generally thought to be bacteriostatic agents: However, omadacycline has demonstrated in vitro bactericidal activity against Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. 7 Additionally, modest inhibition of peptidoglycan synthesis may be a resulting effect of protein synthesis. 9 Tetracycline resistance is thought to arise most commonly from organisms that encode for genes tet(K), tet(L), tet(A), and tet(B), which mediate efflux mechanisms, and from ribosomal protection genes tet(M), tet(O), and tet (S). 11,12 Other mechanisms of tetracycline resistance include drug degradation and mutations in rRNA binding sites. 3 The protein Tet(O) has been shown to protect the ribosome by promoting release of tetracycline from the 70S unit: Omadacycline demonstrated protein synthesis inhibition in both the presence and absence of Tet(O), however. 9 Additionally, omadacycline demonstrated protein synthesis inhibition in Staphylococcus aureus harboring efflux genes tet(K) and tet(M) in whole-cell assays. 9 Omadacycline could overcome ribosomal protection by higher affinity for the ribosome or by binding to the ribosome in a way that bypasses protection by proteins Tet(M) and Tet(O), however this is unclear at this point. Similarly, it is unknown how omadacycline overcomes efflux resistance. Intrinsic resistance to omadacycline in Pseudomonas aeruginosa and decreased susceptibility in Klebsiella pneumoniae have been described from overexpression of MexXY and AcrAB efflux pumps. 13 Microbiology A study by Pfaller et al 14 assessed the in vitro activity of omadacycline in 69,246 isolates collected in 2010 and 2011 from around the world. A concentration of ≤2 µg/ mL of omadacycline was able to inhibit growth in 99.9% of Staphylococcus aureus, 100% of methicillin susceptible Staphylococcus aureus (MSSA), 99.8% of methicillin resistant Staphylococcus aureus (MRSA), 100% of coagulase negative Staphylococcus, 100% of Enterococcus spp., including vancomycin susceptible and non-susceptible, and >99.9% of Enterococcus faecalis, including vancomycin susceptible and non-susceptible. A concentration of 0.5 µg/mL of omadacycline was able to inhibit 100% of Enterococcus faecium, including vancomycin susceptible and non-susceptible, 100% of other Enterococcus spp., 100% of Streptococcus pneumoniae, including penicillin susceptible or resistant, viridans group streptococci, and beta-hemolytic streptococci. Omadacycline also had activity against Enterobacteriaceae, notably Escherichia coli, Klebsiella aerogenes (formerly Enterobacter aerogenes), Klebsiella oxytoca, and Citrobacter spp.; also against Haemophilus influenzae, including beta-lactamase positive and negative, and Moraxella catarrhalis. The reported minimum inhibitory concentrations for 50% and 90% of isolates (MIC 50 /MIC 90 ) for omadacycline in select organisms in this study can be found in Table 1. The reader is encouraged to consult this publication for susceptibilities of other organisms.

Pharmacokinetics
The pharmacokinetics of omadacycline have mainly been established in healthy adult subjects and subjects from special populations (eg, patients with renal or hepatic impairment, the elderly). 6,[23][24][25][26][27][28][29][30] No clinically significant differences in the pharmacokinetics of omadacycline were observed based on age, gender, race, weight, renal impairment or end-stage renal disease (ESRD), and hepatic impairment. 6,26-28 A population pharmacokinetic model for describing oral and intravenous administration of omadacycline has been developed using pooled data from phase 1 studies in healthy subjects, one phase 1b study in patients with uncomplicated urinary tract infections, two phase 3 studies in patients with ABSSSIs, and a phase 3 study in patients with CABP. 31,32 Pharmacokinetic parameters of omadacycline following single and multiple oral and intravenous doses in healthy adult subjects are summarized in Table 2.
The exposure to omadacycline is similar between a 300-mg oral dose and a 100-mg intravenous dose of omadacycline in healthy fasted subjects ( Figure 1). 23 The ingestion of a high-fat non-dairy meal (800-1,000 calories; 50% calories from fat) 4 hours before administration of a single 300-mg oral dose of omadacycline did not substantially alter the rate (maximum plasma concentration, C max ) and extent of absorption (area under the plasma concentration-time curve, AUC). 29 Ingestion of a standard high-fat meal with and without dairy 2 hours before omadacycline administration, respectively, decreased C max by 42% and 40% and AUC by 63% and 59% compared to fasting conditions ( Figure 2). The C max and AUC were not substantially altered following ingestion of either a light non-fat (300-350 calories; ≤5% calories from fat) or a standard low-fat (800-1,000 calories; 30% calories from fat) meal 2 hours after omadacycline administration. 6,29,33 The volume of distribution of omadacycline at steadystate following IV administration of omadacycline in healthy subjects ranges from 168-288 L. 25,26,30,31 Plasma protein binding of omadacycline is approximately 21%, and is not concentration-dependent. 34 The mean (±SD) concentrations over time for unbound plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) following intravenous administration of multiple doses of omadacycline,  Figure 2 Mean±SD area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) of omadacycline following oral administration of a 300 mg oral dose under fasting condition (solid black bar), when a standard high-fat non-dairy meal was ingested 4 hours pre-dose (solid gray bar), when a standard high-fat non-dairy meal was ingested 2 hours pre-dose (crossed line bar), and when a standard high-fat meal including dairy was ingested 2 hours pre-dose (confetti bar). Note: Data from Tzanis et al. 29 eravacycline, and tigecycline to healthy subjects are shown in Figure 3. 29,35 The steady-state 24 hour AUC (AUC 0-24 ) of omadacycline in ELF was approximately 1.5-fold higher than the total plasma AUC 0-24 , and the AUC 0-24 in AM was 26-fold higher than total plasma AUC 0-24 . Although the pattern and time course of unbound plasma, ELF, and AM concentrations were similar among the three drugs, the magnitude of omadacycline concentrations was greater in all matrices compared to eravacycline and tigecycline. A phase 1 study assessed the pharmacokinetics of omadacycline in eight ESRD vs eight matched healthy subjects. 26 The following parameters were observed after an intravenous dose of omadacycline 100 mg before and after hemodialysis (HD) in ESRD subjects and in healthy subjects (pre-HD/post-HD/healthy subjects): AUC 0-∞ =10.20/10.30/9.76 µg•h/mL, C max =2.33/1.88/1.92 µg/mL, T max =0.59/0.58/0.58 h, V=194/ 214/204 L, CL=10.1/10.1/10.6 L/h, and t 1/2 =18.9/18.6/17.1 h. Based on these parameters, and tolerability and safety across ESRD and healthy subjects, omadacycline does not require dose adjustment in renal impairment or on HD days.
Omadacycline is a substrate of P-gp. Administration of oral verapamil (P-gp inhibitor) 2 hours before a single 300 mg oral dose of omadacycline increased the AUC and C max of omadacycline by approximately 25% and 9%, respectively. 33 In healthy male volunteers receiving 300-mg oral [14C] omadacycline, 77.5% to 84.0% of the dose was recovered in the feces, approximately 14.4% (range=10.8%-17.4%) in the urine, with 95.5% of the administered radioactive dose recovered after 7 days. 37 Following intravenous administration of a 100-mg dose of omadacycline, 27% of the dose was recovered as unchanged omadacycline in the urine. 26 The systemic and renal clearance of omadacycline in healthy subjects following intravenous administration ranged from 8.8-11.8 L/h and 2.4-3.3 L/h, respectively. 26,27,30,31 The elimination t 1/2 is approximately 16-17 hours (range=11-25 hours). [23][24][25][26]30,31 Pharmacodynamics A limited number of pharmacokinetic-pharmacodynamic studies for older tetracyclines and tigecycline have identified correlations between 24 hour unbound area under the concentration-time curve to minimum inhibitory concentration (fAUC 0-24 /MIC) and efficacy. [38][39][40] Exposureresponse relationships for omadacycline have also been shown to correlate with fAUC 0-24 /MIC ratios. [41][42][43][44] Table 3 displays the magnitude of the plasma fAUC 0-24 /MIC ratio for omadacycline associated with net bacterial stasis as well as 1-and 2-log 10 colony forming unit (CFU) reductions from baseline for Streptococcus pneumoniae and Staphylococcus aureus in the neutropenic murine thigh and lung infection models, respectively. 41,42 Omadacycline was slightly more potent than tigecycline in both neutropenic and non-neutropenic, immunocompetent murine thigh infection model. The presence of neutrophils enhanced the in vivo efficacy of omadacycline by over 6-fold and by approximately 2-fold against single strains of Streptococcus pneumoniae and Klebsiella pneumoniae, respectively. 43 The total AUC 0-24 /MIC ratios for epithelial lining fluid (ELF) associated with bacterial stasis (14.18-17.80), 1-log 10 kill (6.00-200.64), and 2log 10 kill (17.26-47.27) were similar to corresponding plasma fAUC 0-24 /MIC values (Table 3), since the penetration of omadacycline into ELF approached 100% (range=72−102%) in mice. Lung surfactant does not have an effect on the in vitro activity of omadacycline. 45 Omadacycline has consistently demonstrated similar to or greater potency than minocycline, doxycycline, linezolid, and vancomycin for a wide range of mouse infections models and bacterial pathogens. 7 The post-antibiotic effect (PAE) of omadacycline has ranged from 2.2-3.3 hours for Streptococcus pneumoniae and Staphylococcus aureus. 46 The PAE of omadacycline for these pathogens, as well as for Escherichia coli (1.4 hours), were generally similar to those reported with tigecycline. A slightly longer PAE was observed with tigecycline (3.8-4.4 hours) compared to omadacycline (2.0-2.1 hours) for Enterococcus faecalis and Enterococcus faecium.
Dose justification for intravenous, intravenous-to-oral, and oral dosing regimens of omadacycline for treatment of ABSSSI and CABP were based on population pharmacokinetics of healthy subjects and patients, simulated

Clinical efficacy Skin and skin structure infections
Noel et al 48 investigated the efficacy of omadacycline vs linezolid for the treatment of complicated skin and skin structure infections (CSSSI) in hospitalized patients in a randomized, controlled, evaluator-blinded phase 2, noninferiority trial in the US between 2007 and 2008. Subjects were randomized to receive intravenous treatment for CSSSI with either omadacycline 100 mg every 24 hours or linezolid 600 mg every 12 hours with an option to add aztreonam 2 g every 12 hours in cases of investigatorsuspected or documented gram-negative pathogens. Based on the investigator's judgment at hospital discharge, subjects could transition to oral therapy (two omadacycline 100 mg tablets daily, or one linezolid 600 mg tablet twice daily), at which point only the investigators remained blinded to study medication. Subjects were included if ≥18 years of age with one of the following: a wound infection, a major abscess, an infected ulcer in a lower extremity, or cellulitis. Subjects were excluded if they had infections potentially involving bone or if these were resolved with surgery alone. If the lower limit of the 95% confidence interval (95% CI) of the treatment difference was higher than −20%, omadacycline was considered non-inferior to linezolid. There were 118 subjects randomized to omadacycline and 116 to linezolid with the following disposition: 94.1% (111/118) vs 93.1% (108/116) subjects in the safety (primary endpoint) population and intention-to-treat (ITT) populations who received ≥1 dose of study medication; 75.7% (84/111) vs 72.2% (78/108) in the ITT population who had a baseline pathogen (the modified ITT population, MITT); 90.1% (100/111) vs 81.5% (88/108) clinically evaluable (CE), which were subjects in the ITT population who had a defined infection, received ≥5 days of treatment, had all defined clinical evaluations, and didn't receive antibiotics outside the study; 77% (77/100) vs 71.5% (63/88) were microbiologically evaluable (ME), which included subjects in the CE population with a baseline pathogen. 48 The higher proportions of subjects in the omadacycline arm cascading from the MITT to the ME population were due to a higher number of subjects in the linezolid group who completed treatment, but were lost to follow-up and didn't have a test-of-cure visit.
O'Riordan et al 49 conducted a phase 3, double-blind, double-dummy, randomized clinical trial that assessed the non-inferiority of omadacycline compared to linezolid for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in hospitalized subjects from Europe, the Americas, and South Africa between 2015 and 2016. This was known as the OASIS-1 study (Omadacycline in Acute Skin and Skin Structure Infections Study). Subjects randomly received a 7-14day treatment course of either omadacycline 100 mg intravenously every 12 hours for two doses, then every 24 hours, with an optional switch to oral 300 mg every 24 hours ≥3 days later or linezolid 600 mg intravenously every 12 hours, with an optional switch to oral 600 mg every 12 hours ≥3 days later. Subjects included were ≥18 years of age, with a skin infection, which included wound infections, cellulitis, or erysipelas, and major abscesses (restricted to ≤30% of randomized subjects). Skin infections had to show a contiguous surface area of ≥75 cm 2 , defined edema, erythema or induration, and inflammatory response. Subjects who used ≥1 dose of potentially effective systemic or topical antibiotic treatment within 72 hours prior to the first dose of study medication, were expected to require long-term treatment for chronic skin infections, or had significant liver or renal insufficiency or immunocompromise, were disallowed into the study.
The primary efficacy endpoint was early clinical response in the modified intention-to-treat population (MITT), which comprised randomized subjects without only gram-negative organisms at baseline. 49 This primary endpoint was assessed 48-72 hours after treatment initiation with study medication, and defined as survival with a decrease of ≥20% in lesion size. Secondary efficacy endpoints included: Investigator-assessed clinical response (survival with resolution or improvement in signs and symptoms without need for further treatment) at the endof-treatment (EOT) and at the post-treatment evaluation (PTE) visit (7-14 days after the last dose of study medication) in both the MITT and the clinical per-protocol (cPP) populations; and microbiologic response at EOT and PTE visits in the microbiologic MITT and per-protocol (mMITT and mPP) populations. Diagnostic assays such as Gram stain, culture, and blood samples were collected for testing as appropriate. Safety data, including adverse events (AEs), clinical laboratories, vital signs, and electrocardiography were also obtained. For both primary and secondary endpoints, non-inferiority was met if the lower limit of the 95% confidence interval for the difference between groups was higher than −10 percentage points.
There were 655 subjects randomized (ITT population), 329 to receive omadacycline and 326 to receive linezolid: 645 received ≥1 dose of study medication (safety population), and 627 subjects in the MITT population (316 omadacycline, 311 linezolid). 49 Baseline demographics and clinical characteristics were similar between treatment arms, including the median lesion area in the MITT group (299.5 cm 2 omadacycline, 315 cm 2 linezolid) and mean duration of treatment (4.4 days intravenous with 5.5 days oral omadacycline vs 4.4 intravenous with 5.4 oral linezolid). Based on the baseline pathogen associated with ABSSSI in the mMITT population, infections were gram-positive monomicrobial in 71.9%, gram-positive polymicrobial in 12.7%, and mixed gram-positive and gram-negative in 15.4% of subjects. These included the following organisms for the omadacycline vs linezolid arms: Staphylococcus aureus in 68.4% vs 66.5%, methicillin-resistant S. aureus (MRSA) in 30.3% vs 22.0%, Streptococcus anginosis group in 20.6% vs 16.3%, gram-positive anaerobes in 7.0% vs 6.6%, gram-negative aerobes in 12.3% vs 10.1%, and gram-negative anaerobes in 7.5% vs 5.7% of subjects. The proportions of subjects with a switch from intravenous to oral therapy (88.5% vs 87.9%) and ≥80% adherence (99.1% vs 98.8%) were similar between treatment omadacycline and linezolid, respectively.
In this study of subjects with ABSSSI, omadacycline demonstrated non-inferiority to linezolid with respect to the primary endpoint of early clinical response: 84.8% vs 85.5%, respectively, a difference of −0.7 percentage points (95% CI=−6.3-4.9). 49 The efficacy of omadacycline was also non-inferior or similar to linezolid in secondary endpoints across different populations, including early and later clinical responses in the MITT, cPP, different skin infection types, and mMITT. Based on ABSSSI pathogens isolated at baseline, early and later clinical responses were also similar between treatments. Clinical response rates at the PTE visits were also similar for subjects with monomicrobial gram-positive (87.8% vs 84.8%), polymicrobial gram-positive (74.2% vs 81.5%), and polymicrobial mixed infections (80.5% vs 75.9%) for omadacycline vs linezolid, respectively. In subjects with bacteremia, the investigator-assessed clinical responses at PTE were 82% (9/11) vs 100% (9/9) for omadacycline vs linezolid, respectively. Given the small sample of subjects with bacteremia, it is unwise to draw interpretations about performance of either drug in subjects with bacteremia. Primary and select secondary endpoints from this study are summarized in Table 4.
A second phase 3, randomized, double-blind, noninferiority clinical trial in multiple centers across the US evaluated the efficacy and safety of oral-only treatment of ABSSSI with omadacycline compared to linezolid. 50,63 In this trial, known as the OASIS-2 study, 735 subjects were randomized to receive a 7-14-day treatment with either omadacycline 450 mg orally daily for 2 days, then 300 mg orally daily or linezolid 600 mg orally twice daily.    Similar to OASIS-1, subjects ≥18 years of age with qualifying ABSSSI were included, and enrollment was limited for subjects with major abscesses (≤30%), but some (≤25%) subjects were allowed to participate if they had received a short-acting antibiotic within the previous 72 hours to study medication. Also similar to OASIS-1, the primary endpoint was early clinical response in the MITT population based on survival with lesion size reduction (≥20%), which was evaluated 48-72 hours after the initial dose of study medication. Secondary endpoints included the investigator-assessed clinical success at the EOT and PTE visits in different populations. Results from the OASIS-2 study are only available in abstract form, and have not been published in a peer-reviewed manner as of this writing.
In the OASIS-2 study, there were 360 subjects who received omadacycline and 360 subjects who received linezolid in the MITT population, with a mean duration of treatment of 8.2 days and 8.0 days, respectively. 50 Baseline characteristics for omadacycline vs linezolid were relatively similar: A majority of males in each arm (65.8% vs 59.9%); with a mean age of 42.8 vs 44.5 years; a mean lesion area of 422 cm 2 (range=75-2,601 cm 2 ) vs 396 cm 2 (range=75-2,243 cm 2 ); and similar proportions in the types of ABSSSI, which included 58.3% vs 59.4% wound infections, 23.9% vs 23.3% cellulitis and erysipelas, and 17.8% vs 17.2% major abscesses, respectively. The proportions of subjects that met the primary endpoint were 87.5% vs 82.5% for omadacycline vs linezolid and a treatment difference of 5 percentage points (95% CI= −0.2-10.3) established non-inferiority. Secondary endpoints of investigator-assessed clinical success at PTE were 84.2% vs 80.8% in the MITT population (3.3 percentage points difference; 95% CI=-2.2-9.0) and 97.9% vs 95.5% in the CE (cPP) population (2.3 percentage points difference; 95% CI=−0.5-5.8), both for omadacycline vs linezolid, respectively. A summary of primary and secondary endpoints for the OASIS-2 study are presented in Table 4.

Community-acquired bacterial pneumonia
Stets et al 51 conducted a phase 3, double-blind, doubledummy, randomized clinical trial that assessed the noninferiority of omadacycline compared to moxifloxacin for the treatment of community-acquired bacterial pneumonia (CABP) in hospitalized subjects from Europe, the Americas, Africa, and Asia between 2015 and 2017. This was known as the OPTIC study (Omadacycline for Pneumonia Treatment in the Community). The 7-14-day treatment consisted of either omadacycline 100 mg intravenously every 12 hours for two doses, then every 24 hours, with an optional switch to oral 300 mg every 24 hours ≥3 days later, or moxifloxacin 400 mg intravenously every 24 hours, with an optional switch to oral 400 mg every 24 hours ≥3 days later. Subjects included were as follow: ≥18 years of age; with ≥3 symptoms of cough, purulent sputum, dyspnea, or pleuritic chest pain; with ≥2 abnormal vital signs; ≥1 clinical sign or laboratory associated with CABP; radiologic confirmation of pneumonia; classified as Pneumonia Severity Index (PSI) risk class II (in ≤15% of randomized subjects), III or IV; had not received ≥1 doses of potentially effective antibiotic treatment 72 hours prior to the first dose of study medication (except for one dose of a short-acting antibiotic in ≤25% of subjects); and did not have hospital-acquired pneumonia or empyema, significant liver or renal insufficiency, or immunocompromise. The primary efficacy endpoint was early clinical response in the intent-to-treat (ITT) population, defined as survival with improvement of ≥1 levels compared to baseline in ≥2 symptoms of CABP and no worsening of ≥1 levels in other symptoms of CABP, without rescue antibiotic therapy. 51 This primary efficacy endpoint was assessed 72-120 hours after the first dose of study medication, based on the investigator's assessment of symptoms of CABP on a 4-point scale (absent, mild, moderate, severe). Secondary efficacy endpoints included: Investigator-assessed clinical response (survival with resolution or improvement in signs and symptoms without need for further treatment) at the end-of-treatment (EOT) and at the post-treatment evaluation (PTE) visit (5-10 days after the last dose of study medication) in both the ITT and the clinical per-protocol (cPP) populations; and microbiologic response at EOT and PTE visits in the microbiologic and per-protocol ITT (mITT and mPP) populations. Diagnostic assays such as sputum or other specimens from the lower respiratory tract, blood, and urine were collected for staining, culture, or antigen/serologic testing as appropriate. Safety data, including adverse events (AEs), clinical laboratories, vital signs, and electrocardiography were also obtained. For both primary and secondary endpoints, non-inferiority was met if the lower limit of the 95% confidence interval for the difference between groups was higher than −10 percentage points.
In this study of subjects with CABP, omadacycline demonstrated non-inferiority to moxifloxacin with respect to the primary endpoint of early clinical response: 81.1% vs 82.7%, respectively, a difference of −1.6 percentage points (95% CI=−7.1-3.8). 51 The efficacy of omadacycline was also non-inferior or similar to moxifloxacin in secondary endpoints across different populations including early and later clinical responses in the ITT, cPP, different PSI risk classes, and mITT. Based on CABP pathogens isolated at baseline, early and later clinical responses were similar between treatments. In subjects with bacteremia, the investigatorassessed clinical responses at PTE were 73% (11/15) vs 83% (15/18) for omadacycline and moxifloxacin, respectively. Given the small sample of subjects with bacteremia and missing values reported by the investigators, it is unwise to draw interpretations about performance of either drug in subjects with bacteremia. Primary and select secondary endpoints from this study are summarized in Table 5.
At this time, the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) do not offer susceptibility test interpretive criteria or "breakpoints" for omadacycline, but upcoming updates should provide these criteria in the future. 52,53 However, based on the studies presented above, the US FDA has identified omadacycline breakpoints for a limited number of microorganisms causative of ABSSSI and CABP in minimum inhibitory concentrations and disk diffusion methods (Table 6). 54

Clinical safety
A phase 2 clinical trial assessed safety of omadacycline compared to linezolid as a primary endpoint. 48 The mean ±standard deviation duration of exposure to omadacycline was 10.0±3.91 days and it was 9.6±4.36 days to linezolid, and 4.3-days was the mean duration of intravenous exposure in each treatment group. One or more treatment-emergent adverse events (TEAE) occurred in 41.6% (46/111) of subjects receiving omadacycline, and in 50.9% (55/108) of those receiving linezolid. Adverse events (AE) considered related to either treatment were 21.6% (24/111) in the omadacycline and 30.6% (33/108) in the linezolid groups. There was one serious AE (SAE) in the omadacycline and two in the linezolid groups. Discontinuations due to AE occurred in one subject treated with omadacycline (AE deemed unrelated to the study medication) and in two subjects receiving linezolid (heartburn and pruritic rash, both possibly related to the study medication). The most common AEs in both groups were gastrointestinal in nature. Safety endpoints, including lab abnormalities from this phase 2 study, are summarized in Table 7. In the OASIS-1 study, TEAE occurred in 48.3% (156/ 323) of subjects on omadacycline vs 45.7% (147/322) on linezolid. 49 The AE deemed related to either treatment by blinded investigators occurred in 18.0% (58/323) vs 18.3% (59/322) of subjects on omadacycline vs linezolid, respectively. Serious AE occurred in 3.7% (12/323) of subjects on omadacycline and 2.5% (8/322) on linezolid, and AE leading to treatment discontinuation occurred in 1.9% (6/ 323) vs 2.2% (7/322) of subjects, respectively. There was one death reported in the omadacycline arm due to opiate overdose, and two in the linezolid arm considered unrelated to study medication (one cardiac arrest and one cardiac failure). Similar to the phase 2 study, the most common AE were gastrointestinal in nature (nausea and vomiting), all of which were mild-to-moderate and transient, except for severe vomiting in one subject on linezolid; gastrointestinal AE led to discontinuation of study medications in one subject in each group. There were no significant changes in vital signs, electrocardiogram, or laboratories reported in this phase 3 study. Safety endpoints from the OASIS-1 study are summarized in Table 7.

Dosage and administration
The US FDA-approved dosage and duration of therapy of omadacycline for the treatments of adult patients with ABSSSI and CABP caused by susceptible microorganisms are listed in Table 8. 1 A loading dose for both intravenous and oral routes of administration is recommended because the long elimination half-life of omadacycline allows for once daily dosing. No dose adjustments are required for patients with renal or hepatic impairment.
Omadacycline for injection is available as sterile lyophilized powder in single-dose vials containing 100 mg of omadacycline (equivalent to 131 mg omadacycline tosylate). 6 Each vial is reconstituted with sterile water and subsequently further diluted in 100 mL of normal saline or 5% dextrose. The intravenous dose of 200 mg should be administered as an infusion over 60 minutes whereas the 100 mg dose can be administered as a 30 minute intravenous infusion. Intravenous omadacycline should be administered through a dedicated intravenous line or through a Y-site. Omadacycline for injection should not be administered through the same intravenous line or with solutions containing multivalent cations (eg, calcium, magnesium). No further information is available about the compatibility of omadacycline with other intravenous solutions or drugs.
Omadacycline for oral administration is available as tablets containing 150 mg of omadacycline (equivalent to 196 mg omadacycline tosylate). 6 The systematic exposure (eg, AUC) is similar between 300 mg oral dose and a 100 mg intravenous dose of omadacycline. 23 Oral tablets of omadacycline should be administered in a fasting state (ie, no food or beverages (other than water) for at least 4 hours before and 2 hours after dosing). 6,29 Similar to other tetracyclines, no dairy products, antacids, or multivitamins should be administered for 4 hours after oral dosing of omadacycline. This precaution is highlighted by the observed decrease in AUC and C max when administered with a meal that contained dairy. 29 Other warnings and precautions include permanent tooth discoloration, enamel hypoplasia, bone growth inhibition in the fetus, and up to 8 years of age, hypersensitivity reactions, the potential for Clostridium difficile-associated diarrhea, photosensitivity, and other warnings associated with the tetracycline class of antibiotics, including crossing the placenta and excretion in human milk, which may pose a risk to the fetus and children. 6

Place of omadacycline in therapy
Omadacycline has broad-spectrum in vitro activity, allowing monotherapy for commonly encountered communityacquired infections including ABSSSI and CABP. Pharmacokinetic and pharmacodynamic characteristics have established an initial loading dose followed by once daily maintenance dose regimens for both the intravenous and oral formulations of omadacycline. No adjustment in dose is required in patients with renal or liver impairment, and the potential of drug-drug interactions with cytochrome isoenzymes and transporters appears to be minimal. The bioequivalent oral doses of omadacycline allows empiric outpatient therapy in patients with elevated risk for polymicrobial infections caused by staphylococci (including methicillin-resistant isolates), streptococci (including penicillin-and macrolide-resistant isolates), and multiple Gram-negative organisms or have contraindications to first-line antimicrobial agents. Intravenous administration of omadacycline allows patients in the emergency room or admitted to the hospital to receive effective empiric antibiotic therapy as well as a shorter length of stay because of the potential for intravenous to oral sequential therapy with the same antibiotic. The incidence of adverse events has been low, and the common adverse reactions (≥2% of patients) are gastrointestinal, elevations in liver transaminases, and infusion site reactions with intravenous administration. While the use of linezolid as a comparator was endorsed by regulatory agencies in the US and Europe, it is possible that other strategies (eg, narrow spectrum beta-lactam, trimethoprimsulfamethoxazole, or older tetracyclines) may be more appropriate based on local standard of care or local antimicrobial susceptibilities. The role of omadacycline is limited by the data currently available from clinical trials. [48][49][50][51] The challenge is to appropriately use omadacycline to optimize clinical outcomes, minimize adverse events, improve healthcare efficiency, and reduce overall healthcare costs among patients with ABSSSI and CABP. In both phase 2 and 3 clinical trials, omadacycline demonstrated efficacy and safety for the treatment of ABSSSI. [48][49][50] Oral omadacycline may allow treatment as monotherapy in the ambulatory care setting as well as sequential therapy after intravenous omadacycline or switch therapy following other broad spectrum intravenous antibiotics. Current susceptibility patterns of microorganisms, patient allergies, low potential of serious adverse events (including nephrotoxicity), and drug-drug interactions, lack of significant risks for causing Clostridium difficile infection or QTc prolongation, oral and intravenous formulations, and cost will all be part of the decisions on whether to use omadacycline to treat ABSSSI. Omadacycline will need to establish its niche among the numerous antibiotic choices available to treat adult patients with ABSSSI. 55,56 Omadacycline can be considered as an alternative therapy choice for adult patients with CABP when current first-line agents such as fluoroquinolones or the combination of a beta-lactam plus a macrolide are not treatment options because of hypersensitivity, adverse effect profile, or concerns about resistant pathogens. 57 Low protein binding and high concentrations of omadacycline in the epithelial lining fluid and alveolar macrophages provide pharmacokinetic advantages for this antibiotic to be effective in the treatment of lower respiratory tract infections caused by susceptible microorganisms. The increasing resistance and safety concerns with fluoroquinolones makes omadacycline a reasonable alternative for intravenous and oral monotherapy for inpatient and ambulatory care settings. 58 Despite the approval by regulatory agencies to use moxifloxacin as a comparator in the phase 3 study, local standards of care and local antimicrobial susceptibility should guide antimicrobial therapy. Because of insufficient clinical data to assess the observed mortality imbalance in the phase 3 clinical trial (OPTIC) comparing omadacycline to moxifloxacin, the US FDA has required a postmarketing commitment of Paratek Pharmaceuticals to conduct another active-controlled safety and efficacy study in adults with CABP. 59 In addition, an activecontrolled safety study in children between 8 and 17 years old with CABP will also be conducted as part of the pediatric assessment requirement of a new drug application to US FDA. 9 These additional studies will further define the potential roles of omadacycline for the treatment of adult and pediatric patients with CABP.
Ongoing clinical trials with omadacycline include phase-2 studies for the treatment of uncomplicated urinary tract infections and acute pyelonephritis. 60,61 Paratek Pharmaceuticals also has a cooperative research agreement with the US Army Medical Research Institute of Infectious Diseases to study omadacycline against biodefense pathogens, including Yersinia pestis (plague) and Bacillus anthracis (anthrax). 17,62 Omadacycline has not be evaluated for the treatment of infections caused by multiple-drug-resistant Gram-negative infections, and clinical trials are required to define the role of omadacycline against pathogens such as carbapenam-resistant Enterobacteriaceae and Acinetobacter spp. 55 When deciding how to approach antimicrobial therapy, cost is always a concern, particularly with new agents. A 3-year budget impact model to evaluate omadacycline use for the treatment of CABP in the US showed that, although an initial treatment acquisition cost would be incurred ($20,643), the impact from transitioning from intravenous to oral treatment on the 3-year cost decreased by reducing 1 day of hospital stay ($2,384), provided cost-savings by reducing 2 days of hospital stay ($15,875), and provided a substantial cumulative cost-saving by shifting inpatient care to the outpatient management ($112,843). 64 Similar hypothetical models of patients with ABSSSI also showed significant costsavings by reducing hospital stay and shifting inpatient to outpatient care or from avoiding inpatient admission for intravenous antibiotic administration. 65,66 Hence, in theory, the upfront costs of implementing omadacycline use for CABP and ABSSSI could be offset by decreased hospital stay or avoidance in the US.

Conclusion
Three phase 3 clinical trials have established the novel aminomethylcycline, omadacycline, as an effective and safe antibiotic for the treatment of ABSSSI and CABP. The oral and intravenous formulations will allow monotherapy to be used in both the outpatient and inpatient settings. No dosage adjustment in renal or hepatic impairment, minimal chances of major drug-drug interactions, and a low incidence of adverse effects are positive features of this new tetracycline analog. While omadacycline retains antibacterial activity against bacterial strains expressing the two most common tetracycline resistance mechanisms (ie, bacterial ribosomal protection proteins and tetracycline-specific efflux pumps), further microbiological evidence and clinical efficacy against multidrugresistant pathogens are still needed. Omadacycline will need to establish its place among the available antibiotic choices for the treatment of community-acquired infections.

Disclosure
Dr Rodvold is a consultant for Paratek Pharmaceuticals, Inc. and reports personal fees from Paratek Pharmaceuticals, outside the submitted work. The authors report no other conflicts of interest in this work.