TETRACYCLINE HISTORY AND RESISTANCE
Tetracycline development began in the 1940s with the discovery of the natural product, chlortetracycline. One of the first agents termed “broad spectrum,” chlortetracycline became widely used in humans because of its activity against rickettsiae and other organisms with no therapeutic options prior to its discovery. Following identification of the 4-ring core structure, which coined the class name “tetracycline antibiotics” in the 1950s, the first of the semisynthetic agents, tetracycline, was introduced.1
Derived from chlortetracycline, tetracycline has a higher potency and stability and more favorable adverse effect profile.1-3
The second-generation semisynthetic compounds, doxycycline and minocycline, were developed via modification of the tetracycline core in the 1960s and 1970s, respectively.1
Shortly after the development of minocycline, resistance mechanisms to tetracyclines were identified: efflux pumps that eliminate drug molecules from within the cell and ribosomal protection mechanisms that reduce tetracycline-ribosomal binding. As with many other classes of antibiotics, resistance to tetracyclines increased over time; however, it was not until the early 2000s that minocycline was structurally modified to derive tigecycline.1
Although tigecycline offers a broad spectrum of activity that includes organisms resistant to tetracycline, its high rate of gastrointestinal toxicity, a US Food and Drug Administration (FDA) warning of increased mortality compared with other agents, and large volume of distribution preclude its use in many patients. These factors left the door open for novel tetracycline antibiotics with activity against organisms possessing tetracycline-resistance mechanisms and a more favorable adverse effect profile to come to market.
In 2018, 2 new tetracyclines, omadacycline and eravacycline, were approved by the FDA. Similar to tigecycline, these agents were designed to have activity specifically against tetracycline-resistant organisms. This article discusses omadacycline, a semisynthetic tetracycline derived from minocycline that has an aminomethyl group added to the C9 position of the tetracyclic core allowing it to overcome efflux systems and ribosomal protection mechanisms that confer resistance to older tetracyclines.4
It was approved by the FDA on October 2, 2018, for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSIs).
SPECTRUM OF ACTIVITY
Omadacycline is a broad-spectrum agent active against gram-positive organisms, including vancomycin-resistant Enterococcus
(VRE) and methicillin-resistant Staphylococcus aureus
; gram-negative organisms, including some extended-spectrum b-lactamase (ESBL)-producing Enterobacteriaceae and Acinetobacter baumannii
; atypicals; and anaerobes.4
It is not active against the “MP3” of Morganella morganii, Proteus mirabilis, Providencia
and Pseudomonas aeruginosa.
In an in vitro surveillance study, omadacycline had a minimum inhibitory concentration for 90% of the isolates (MIC90) of 0.5 μg/mL for S aureus
, 0.5 μg/mL for VRE, and ≤0.06 μg/mL for multidrug-resistant Streptococcus pneumoniae
compared with 8 μg/mL, 4 μg/mL, and 4 μg/mL, respectively, for doxycycline.5
The MIC90 of omadacycline was 4 mg/ mL for ESBL-producing Escherichia coli
and >4 μg/mL for ESBL-producing Klebsiella
spp compared with >8 μg/mL for each for doxycycline, and 0.25 μg/mL and 1 μg/mL, respectively, for tigecycline.6
Omadacycline also demonstrated activity against some strains of Acinetobacter baumannii
, although the MIC90 of 8 μg/mL indicates that it will be ineffective for some strains.7
The approved breakpoints for omadacycline are 4 μg/mL for Enterobacteriaceae, 0.5 μg/mL for S aureus
, 0.25 μg/mL for Enterococcus faecalis
, and 0.12 for Streptococcus anginosus
In an in vitro environment mimicking the gut microbiome, omadacycline and moxifloxacin were instilled to determine induction of a simulated Clostridium difficile
Moxifloxacin, a fluoroquinolone, was previously observed to induce CDI in an in vitro gut model.10
Fluoroquinolones carry a high risk of CDI, a reason for avoiding their use in some patients. It was observed in this study by Moura and colleagues that the environment in which moxifloxacin was instilled had spore germination and vegetative cell proliferation, while the environment in which omadacycline was instilled had no vegetative cell proliferation.9
This suggests that omadacycline may provide activity against C difficile
rather than increasing the risk for proliferation and development of CDI such as that seen with the fluoroquinolones.
Omadacycline had been studied in 3 phase 3 trials to date: the OASIS 1 and 2 trials for ABSSSIs, and the OPTIC trial for CABP. The OASIS 1 study compared intravenous to oral omadacycline with linezolid for 7 to 14 days for the treatment of ABSSSIs due to gram-positive pathogens in 627 adults. The number of patients with an abscess was capped at 30%, as the primary treatment for these patients is incision and drainage for source control. The primary endpoint was early clinical response, defined as ≥20% reduction in lesion size without receipt of another antimicrobial for ABSSSIs, at 48 to 72 hours of therapy. Omadacycline demonstrated noninferiority with a success rate of 84.8% compared with 85.5% with linezolid, a difference of –0.7% (95% CI, –6.3% to 4.9%). Omadacycline also demonstrated a clinical success rate, defined as sufficient resolution of infection according to the investigator’s analysis at the posttreatment evaluation, of 86.1% compared with 83.6% with linezolid.11
The OASIS 2 study mirrored the OASIS 1 design, but compared oral-only omadacycline with linezolid in 720 adults, with up to 25% of randomized patients permitted to receive 1 dose of a short-acting antibiotic prior to the study drug. Omadacycline again demonstrated noninferiority in early clinical response compared with linezolid (87.5% vs. 82.5%) with a difference of 5.0% (95% CI, –0.2% to 10.3%). The clinical success rate at the posttreatment evaluation was 84.2% with omadacycline versus 80.8% with linezolid.11
Omadacycline received FDA approval for ABSSSIs at an indicated dose of 200 mg intravenously (IV) once or 100 mg IV every 12 hours on day 1, followed by a maintenance regimen of 100 mg IV once daily. It may also be dosed as an oral regimen of 450 mg once daily on days 1 and 2, followed by a maintenance regimen of 300 mg once daily.12
The OPTIC trial compared omadacycline with moxifloxacin for the treatment of CABP for 7 to 14 days in 774 adults. Patients enrolled required hospitalization for moderate to severe infection that was radiographically confirmed without empyema or abscess and no evidence of septic shock. The primary endpoint was early clinical success, defined as at least 1 level of improvement on a scale of absent, mild, moderate, or severe in at least 2 CABP symptoms (cough, sputum production, pleuritic chest pain, dyspnea) without worsening of any other CABP symptoms, at 72 to 120 hours after the first dose of study drug. Omadacycline demonstrated noninferiority in early clinical success with a rate of 81.1% compared with 82.7% of patients who received moxifloxacin, a difference of –1.6% (95% CI, –7.1% to 3.8%). At the posttreatment evaluation 5 to 10 days after the last dose of the study drug, the clinical success rate according to the investigator’s analysis was 87.6% with omadacycline compared with 85.1% with moxifloxacin.11
The FDA granted omadacycline approval for CABP at an indicated dose of 200 mg IV once or 100 mg IV every 12 hours on day 1, followed by a maintenance dose of 100 mg IV once daily or 300 mg orally once daily.12
Following a single 100-mg IV dose, omadacycline achieved a maximum concentration (Cmax) of 1507 ng/mL and an area under the curve (AUC) of 9358 h*ng/mL. The mean steady-state Cmax with intravenous administration is 2120 ng/mL, and AUC is 12,140 h*ng/mL. Omadacycline is 34.5% bioavailable, explaining its oral dosing at 300 mg, which achieved a Cmax of 548 ng/mL and AUC of 9399 h*ng/mL following a single dose. The mean steady-state Cmax with oral administration of 300-mg tablets is 952 ng/mL and AUC is 11,156 h*ng/mL, comparable to the 100-mg intravenous dose. There is a significant food effect with oral administration. When administered 2 hours after a high-fat, nondairy meal, Cmax and AUC were reduced by 40% and 59%, respectively. As with other tetracyclines, concurrent administration with multivalent cations such as calcium should be avoided with the oral formulation.12
The mean volume of distribution with intravenous administration is 190 L, and protein binding is estimated to be 20%.12 Omadacycline had a steady-state 24-hour mean epithelial fluid lining concentration of 0.41 mg/L and mean alveolar macrophage concentration of 11.06 mg/L, indicating sufficient lung concentrations.13 Omadacycline is not metabolized and does not induce or inhibit CYP450 enzymes. It has a half-life of approximately 15 hours and is eliminated mainly in the feces (81%) unchanged, with 14% renal elimination following oral administration. Dosage adjustment is not required for renal or hepatic impairment.12
ADVERSE REACTIONS, WARNINGS, AND PRECAUTIONS
Warnings and precautions associated with omadacycline use are consistent with those reported for older tetracyclines, including tooth discoloration and inhibition of bone growth in children, as well as hypersensitivity. Additionally, omadacycline carries a labeled warning for a mortality imbalance in patients with CABP: 2% with omadacycline versus 1% with moxifloxacin. All deaths occurred in patients over 65 years, most of whom had multiple comorbidities.12
Adverse events most commonly observed in clinical studies were transaminase elevation, headache, and infusion-site reactions.11 Although nausea, vomiting, and diarrhea occurred among patients receiving omadacycline, its structural modification may reduce the incidence of these events compared with that of tigecycline.4,11
Within 1 hour of dosing omadacycline 100 mg IV, a mean increase in heart rate of 17 bpm was observed, although no symptoms or QTc changes were found.13
PLACE IN THERAPY
Although omadacycline shows some activity against resistant bacteria, the in vitro and clinical data for multidrug-resistant organisms are limited at this time. Omadacycline presents an alternative agent for patients with multiple antimicrobial allergies that limit therapeutic options and as an alternative to fluoroquinolones. With its broad-spectrum activity, omadacycline may be particularly useful in treating CABP in such patients where coverage of gram-positive, gram-negative, and atypical organisms is necessary in situations where cultures cannot be obtained.
Dr. Heaney is a PGY2 resident in Infectious Diseases Pharmacy at Temple University School of Pharmacy in Philadelphia, Pennsylvania. She completed her PharmD at the University of the Sciences Philadelphia College of Pharmacy and a PGY1 residency at Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania.
- Nelson ML, Levy SB. The history of the tetracyclines. Ann N Y Acad Sci. 2011;1241:17-32. doi: 10.1111/j.1749-6632.2011.06354.x.
- McCorry RL, Weaver JA. Tetracycline. Lancet. 1955;268(6874):1102-1105.
- Wood WS, Kipnis GP, Spies HW, Dowling HF, Lepper MH, Jackson GG. Tetracycline therapy: clinical and laboratory observations on one hundred eighty-four patients treated with tetracycline. AMA Arch Intern Med. 1954;94(3):351-363.
- Barber KE, Bell AM, Wingler MJB, Wagner JL, Stover KR. Omadacycline enters the ring: a new antimicrobial contender. Pharmacotherapy. 2018;38(12):1194-1204. doi: 10.1002/phar.2185.
- 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.
- Pfaller MA, Rhomberg PR, Huband MD, Flamm RK. Activity of omadacycline tested against Enterobacteriaceae causing urinary tract infections from a global surveillance program (2014). Diagn Microbiol Infect Dis. 2018;91(2):179-183. doi: 10.1016/j.diagmicrobio.2018.01.019.
- Pfaller MA, Huband MD, Shortridge D, Flamm RK. Surveillance of omadacycline activity tested against clinical isolates from the United States and Europe as part of the 2016 SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother. 2018;62(4). doi: 10.1128/AAC.02327-17.
- US Food and Drug Administration. Omadacycline injection and oral products FDA identified breakpoints. FDA website. www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm622612.htm. Updated October 5, 2018. Accessed January 4, 2019.
- Moura IB, Buckley AM, Ewin D, et al. Omadacycline gut microbiome exposure does not induce Clostridium difficile proliferation or toxin production in a model that simulates the proximal, medial and distal human colon [published online November 19, 2018]. Antimicrob Agents Chemother. doi: 10.1128/AAC.01581-18.
- Omadacycline p-toluenesulfonate tablets and injection for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) briefing document for: Antimicrobial Drugs Advisory Committee (AMDAC). FDA website. www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm615849.pdf. Accessed December 21, 2018.
- Omadacycline [package insert]. Boston, MA: Paratek Pharmaceuticals Inc.; 2018. www.accessdata.fda.gov/drugsatfda_docs/label/2018/209816_209817lbl.pdf. Accessed January 4, 2019.
- Gotfried MH, Horn K, Garrity-Ryan L, et al. Comparison of omadacycline and tigecycline pharmacokinetics in the plasma, epithelial lining fluid, and alveolar cells of healthy adult subjects. Antimicrob Agents Chemother. 2017;61(9). doi: 10.1128/AAC.01135-17.
- Villano S, Tanaka SK. Omadacycilne, an aminomethylcycline antibiotic, has no effect on QT/QTc intervals in healthy subjects. Poster presented at: 26th European Congress of Clinical Microbiology and Infectious Diseases; April 9-12, 2016; Amsterdam, Netherlands. Omadacycilne, an aminomethylcycline antibiotic, has no effect on QT/QTc intervals in healthy subjects.