Tigecycline

Tigecycline is a glycylcycline, a class derived from the tetracyclines. It comes from minocycline, in the form of a 9-t-butylglycylamido derivative. Its role is to block the production of the proteins that the bacterium needs to live and multiply. To do this, it binds reversibly to the H34 helical region of the 30S subunit of the ribosome, the machine that assembles proteins. This binding prevents aminoacyl-tRNA from entering the ribosome’s A site, and synthesis stops.

Its affinity for the ribosome is about five times greater than that of the classic tetracyclines. This firmer anchoring allows it to bypass the two main mechanisms of tetracycline resistance: the efflux pumps that expel the antibiotic from the bacterium, such as tet(A), and ribosomal protection, such as tet(M). In practice, it is generally bacteriostatic: it blocks the multiplication of bacteria rather than destroying them directly.

Tigecycline is intended for adults aged 18 and over. It is indicated for complicated skin and soft-tissue infections, complicated intra-abdominal infections and community-acquired bacterial pneumonia. It is not indicated for diabetic foot infections, nor for hospital-acquired or ventilator-associated pneumonia. Its scope of prescription is therefore precise and limited.

Its use remains tightly controlled. It carries a boxed warning, the strongest form of alert: in a meta-analysis of the trials, all-cause mortality was higher with tigecycline than with the comparator treatments, at 4.0% versus 3.0%, a risk difference of 0.6%. It must be reserved for situations where no other appropriate option exists. It is a last-resort antibiotic, prescribed and administered in hospital.

Tigecycline is not taken by mouth. Its oral bioavailability is insufficient; it is given only by the intravenous route, as an infusion of 30 to 60 minutes every 12 hours. It is a medicine given by the care team, not a tablet that the patient manages themselves with or without food. Treatment takes place in a hospital setting, and its discontinuation is the doctor’s decision.

The usual protocol begins with a loading dose of 100 mg, followed by 50 mg every 12 hours. In severe hepatic impairment, at the Child-Pugh C stage, the maintenance dose is lowered to 25 mg every 12 hours. No adjustment is needed in renal impairment, because elimination does not occur mainly through the kidney.

Tigecycline stays in the body for a long time. Its half-life is about 27 hours after a single 100 mg dose, and lengthens to about 42 hours after repeated doses of 50 mg every 12 hours. It distributes widely into the tissues, with a large volume of distribution of 7 to 10 litres per kilogram. Pharmacokinetic comparisons with other hospital antibiotics confirm this prolonged half-life and large volume of distribution.

Its elimination occurs mainly through the bile, in unchanged form. This route explains the liver’s role in handling it, and justifies dose adjustment in severe hepatic impairment. The kidney, by contrast, plays little part, which removes the need to adjust the dose in renal impairment.

The most common adverse effects are digestive. In the trials, nausea occurred in 26% of patients, vomiting in 18% and diarrhoea in 12%. These disturbances are partly explained by the kinship with the tetracyclines, and they affect a significant share of those treated.

Other common effects have been reported: headache in 6% of patients, abdominal pain in 6%, and elevation of ALT, a liver transaminase also called SGPT, in 5%. Hypoproteinaemia affected 5% of treated patients versus 3% with the comparator, and an increase in blood urea 3% versus 1%.

Several parameters are monitored during treatment. A fall in fibrinogen, or hypofibrinogenaemia, has been reported: the label requires measuring coagulation parameters, including fibrinogen, before starting, then regularly during treatment. The liver is also given particular attention, with increases in total bilirubin, prothrombin time and transaminases, and isolated cases of significant liver dysfunction and hepatic failure.

Cases of acute pancreatitis, some of them fatal, have occurred with tigecycline: discontinuation is considered as soon as a suspicion arises. After marketing, symptomatic hypoglycaemia was observed, in diabetic as well as non-diabetic patients, and hypocalcaemia is among the effects reported at a frequency below 2% in the trials.

Tigecycline interacts with warfarin, an anticoagulant: concomitant use decreases its clearance by about 40% for R-warfarin and about 23% for S-warfarin. Prothrombin time, or another suitable anticoagulation test, must then be monitored. Like other antibacterials, it can also make oral contraceptives less effective.

A tetracycline class effect concerns forming tissues. Used during tooth development, that is during the second half of pregnancy, infancy and childhood up to 8 years of age, the molecule can permanently stain the teeth, in yellow-grey-brown shades, and reversibly slow bone growth. These effects rest on its binding to the calcium of forming tissues, which rules out its use in these situations.