Glycylcyclines

Glycylcyclines are tetracycline derivatives with a glycylamido group that overcomes efflux and ribosomal protection resistance. Tigecycline is the original member. The group is often extended to include eravacycline (a fluorocycline) and omadacycline (an aminomethylcycline). They have very broad activity, including MRSA, vancomycin-resistant enterococci, ESBL producers, carbapenem-resistant Enterobacterales and Acinetobacter, but they are bacteriostatic and have pharmacokinetic limits.

Mechanism. Binding to the 30S ribosomal subunit with higher affinity than tetracyclines and steric hindrance of tet(M) protection, blocking protein synthesis.

Pharmacokinetics. Tigecycline and eravacycline are intravenous only. Tigecycline has a large volume of distribution (7 to 10 L/kg), so serum concentrations are low and bloodstream infection is poorly treated; half-life about 40 hours; biliary elimination; poor urinary excretion. Omadacycline is available orally and IV; oral absorption is reduced by food and cations.

Spectrum. Streptococci, MSSA, MRSA, VRE, Enterobacterales (including ESBL and many carbapenemase producers), Acinetobacter, Stenotrophomonas, anaerobes. Not active against Pseudomonas aeruginosa, Proteus, Providencia and Morganella.

• Tigecycline: licensed for complicated skin and soft tissue infection, complicated intra-abdominal infection and community-acquired pneumonia.
• Eravacycline: complicated intra-abdominal infection; more potent in vitro against Acinetobacter.
• Omadacycline: community pneumonia and acute bacterial skin infection; oral step-down.

Adult regimens.

• Tigecycline: 100 mg IV loading dose, then 50 mg every 12 hours. Severe hepatic impairment (Child-Pugh C): 100 mg, then 25 mg every 12 hours. Higher doses (200 mg loading, then 100 mg every 12 hours) are used off-label in severe carbapenem-resistant infection under specialist direction.
• Eravacycline: 1 mg/kg IV every 12 hours over 60 minutes (1.5 mg/kg with strong CYP3A inducers).
• Omadacycline: IV 200 mg on day 1 (or 100 mg twice), then 100 mg daily; oral 450 mg on days 1 and 2, then 300 mg daily for skin infection; 300 mg every 12 hours on day 1 then 300 mg daily for pneumonia.

Selection. Reserve agents where no better option exists: intra-abdominal or skin infection with multidrug-resistant organisms, usually combined with another active drug for carbapenem-resistant organisms. Tigecycline carries a boxed warning for increased all-cause mortality and is not used for bacteraemia, hospital-acquired or ventilator-associated pneumonia (as sole therapy), urinary infection or diabetic foot infection.

Contraindications. Hypersensitivity to tetracyclines; pregnancy; children under 8 years.

Serious effects. Nausea and vomiting (25 to 30 percent with tigecycline; slower infusion and antiemetics help); acute pancreatitis; hepatotoxicity (raised bilirubin and transaminases); hypofibrinogenaemia and prolonged coagulation times; C. difficile infection; photosensitivity.

Interactions. Warfarin (INR rise); oral contraceptive efficacy may fall; eravacycline levels fall with CYP3A inducers.

Monitoring. Liver tests, amylase or lipase if abdominal pain, fibrinogen and coagulation in prolonged use, and clinical response, since failure is more common than with comparators in some infections.

Special groups. Pregnancy: avoided. Breastfeeding: avoided or short course. Renal impairment: no adjustment for tigecycline or omadacycline. Hepatic impairment: tigecycline dose reduced in Child-Pugh C. Region: availability in East Africa is very limited.