e1-06: Tetracycline Derivatives

Tigecycline, a glycylcycline tetracycline derivative, is available as a parenteral antibacterial for the treatment of nosocomial infection. It is active against most gram-positive bacteria, including methicillin-resistant staphylococci, VRE, and many multidrug-resistant aerobic gram-negative bacilli, including Acinetobacter, Enterobacter, Citrobacter, and ESBL-producing E coli and Klebsiella. However, tigecycline has little to no activity against Pseudomonas and only modest activity versus Proteus spp. In addition, tigecycline demonstrates excellent anaerobic activity against B fragilis and gram-positive anaerobes. A loading dose of 100 mg is administered intravenously with maintenance at 50 mg every 12 hours. The medication distributes into deep compartments with a large volume of distribution and low serum levels. Considering the low achievable serum levels associated with tigecycline, this agent should not be used in bacteremic and septic patients. The medication is primarily eliminated via biliary/fecal excretion with a half-life of 30–40 hours. Dose adjustment to 25 mg every 12 hours is recommended in Child-Pugh class C liver disease. Tigecycline has a similar adverse effect profile as the tetracyclines; upper gastrointestinal side effects are particularly common. While approved for complicated skin and soft-tissue infection and intra-abdominal infection, the spectrum of activity of tigecycline has resulted in its use in the treatment of certain resistant gram-negative pathogens, including ESBL-producing organisms. Tigecycline has been associated with increased mortality in ventilator-associated pneumonia when compared with imipenem. Consequently, its use in sepsis and ventilator-associated pneumonia is not recommended. Tigecycline has a boxed warning highlighting its increased all-cause mortality. Tigecycline is also not indicated for treatment of diabetic foot infection or hospital-acquired pneumonia.

Omadacycline is an aminomethylcycline tetracycline derivative, approved for treatment of bacterial community-acquired pneumonia and acute skin and skin structure infections. Available as both a tablet and in an intravenous formulation, omadacycline has activity against S aureus, S pneumoniae, viridans group streptococci, E coli, H influenzae, M catarrhalis, atypical bacteria (eg, Mycoplasma pneumoniae, Legionella pneumophilia, nontuberculous Mycobacteria), and anaerobes. Omadacycline is also active against the biothreat pathogens Bacillus anthracis and Yersinia pestis. Similar to tigecycline, omadacycline also retains activity against resistant bacteria, such as MRSA, VRE, and ESBL-producing Enterobacteriaceae. In clinical trials, omadacycline was noninferior to linezolid for the treatment of bacterial skin and skin structure infections and noninferior to moxifloxacin for the treatment of community-acquired pneumonia. Omadacycline has a warning for higher rates of mortality (2%) compared to moxifloxacin (1%) in the treatment of community-acquired pneumonia; it is recommended that high-risk patients (eg, older than 65 years with comorbidities) be monitored while receiving omadacycline for this indication. The adverse effects of omadacycline are similar to other medications in the tetracycline class. Treatment with omadacycline requires a fixed loading dose following by a fixed, once-daily maintenance dose. If administered orally, it is recommended that patients fast for at least 4 hours prior to and 2 hours after taking omadacycline and that administration is separated by at least 4 hours from multivalent cations (eg, milk, antacids, multivitamins). One potential benefit of omadacycline over other antibacterials with similar spectrum of activity is that omadacycline does not appreciably induce C difficile proliferation.

Eravacycline is a fluorocycline antibiotic with a similar structure as tigecycline. Eravacycline is available only as an intravenous solution for the treatment of complicated intra-abdominal infections. Eravacycline has activity against S aureus, Enterococcus, Enterobacteriaceae, and anaerobes. Similar to tigecycline and omadacycline, eravacycline also has activity against MRSA, VRE, ESBL-producing Enterobacteriaceae, and carbapenem-resistant E coli and K pneumoniae. Compared to tigecycline, eravacycline shows more potent in vitro activity against multidrug-resistant gram-negative bacteria. Eravacycline was evaluated in two phase 3 trials for the treatment of complicated intra-abdominal infections, where it showed noninferiority to meropenem and ertapenem. Eravacycline was also evaluated for the treatment of complicated urinary tract infections, where it failed to show efficacy compared to more standard therapy. Similar to tigecycline and omadacycline, the most common side effects that patients experience with eravacycline are nausea and vomiting. Eravacycline is dosed based on weight (1 mg/kg) twice daily.