Tigecycline

Tigecycline, a glycylcycline antibiotic, inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains.

In general, tigecycline is considered bacteriostatic. At 4 times the minimum inhibitory concentration (MIC), a 2-log reduction in colony counts was observed with tigecycline against Enterococcus spp., Staphylococcus aureus, and Escherichia coli.

Mechanism of resistance

Tigecycline is able to overcome the two major tetracycline resistance mechanisms, ribosomal protection and efflux. Cross-resistance between tigecycline and minocycline-resistant isolates among the Enterobacteriaceae due to multi-drug resistance (MDR) efflux pumps has been shown. There is no target-based cross-resistance between tigecycline and most classes of antibiotics.

Tigecycline is vulnerable to chromosomally-encoded multi-drug efflux pumps of Proteeae and Pseudomonas aeruginosa. Pathogens of the family Proteeae (Proteus spp., Providencia spp., and Morganella spp.) are generally less susceptible to tigecycline than other members of the Enterobacteriaceae. Decreased susceptibility in both groups has been attributed to the overexpression of the non-specific AcrAB multi-drug efflux pump. Decreased susceptibility in Acinetobacter baumannii has been attributed to the overexpression of the AdeABC efflux pump.

Breakpoints

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on

Antimicrobial Susceptibility Testing (EUCAST) are as follows:

Staphylococcus spp. S≤0.5 mg/L and R>0.5 mg/L
Streptococcus spp. other than S. pneumoniae S≤0.25 mg/L and R>0.5 mg/L
Enterococcus spp. S≤0.25 mg/L and R>0.5 mg/L
Enterobacteriaceae S≤1(^) mg/L and R>2 mg/L

^ Tigecycline has decreased in vitro activity against Proteus, Providencia, and Morganella spp.

For anaerobic bacteria there is clinical evidence of efficacy in polymicrobial intra-abdominal infections, but no correlation between MIC values, PK/PD data and clinical outcome. Therefore, no breakpoint for susceptibility is given. It should be noted that the MIC distributions for organisms of the genera Bacteroides and Clostridium are wide and may include values in excess of 2 mg/L tigecycline.

There is limited evidence of the clinical efficacy of tigecycline against enterococci. However, polymicrobial intra-abdominal infections have shown to respond to treatment with tigecycline in clinical trials.

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Pathogen

Commonly Susceptible Species:

Gram-positive Aerobes:

Enterococcus spp.†
Staphylococcus aureus*
Staphylococcus epidermidis
Staphylococcus haemolyticus
Streptococcus agalactiae*
Streptococcus anginosus group* (includes S. anginosus, S. intermedius and S. constellatus)
Streptococcus pyogenes*
Viridans group streptococci

Gram-negative Aerobes:

Citrobacter freundii*
Citrobacter koseri
Escherichia coli*
Klebsiella oxytoca*

Anaerobes:

Clostridium perfringens†
Peptostreptococcus spp.†
Prevotella spp.

Species for which acquired resistance may be a problem:

Gram-negative Aerobes:

Acinetobacter baumannii
Burkholderia cepacia
Enterobacter aerogenes
Enterobacter cloacae*
Klebsiella pneumoniae*
Morganella morganii
Proteus spp.
Providencia spp.
Serratia marcescens
Stenotrophomonas maltophilia

Anaerobes:

Bacteroides fragilis group†

Inherently resistant organisms:

Gram-negative Aerobes:

Pseudomonas aeruginosa

* denotes species against which it is considered that activity has been satisfactorily demonstrated in clinical studies.
^† see Breakpoints above.

Absorption

Tigecycline is administered intravenously and therefore has 100% bioavailability.

Distribution

The in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 mcg/ml). Animal and human pharmacokinetic studies have demonstrated that tigecycline readily distributes to tissues. In rats receiving single or multiple doses of 14^C-tigecycline, radioactivity was well distributed to most tissues, with the highest overall exposure observed in bone marrow, salivary glands, thyroid gland, spleen, and kidney. In humans, the steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating that tigecycline is extensively distributed beyond the plasma volume and concentrates into tissues.

No data are available on whether tigecycline can cross the blood-brain barrier in humans. In clinical pharmacology studies using the therapeutic dosage regimen of 100 mg followed by 50 mg q12h, serum tigecycline steady-state C_max was 866±233 ng/ml for 30-minute infusions and 634±97 ng/ml for 60-minute infusions. The steady-state AUC_0-12h was 2349±850 ng•h/ml.

Biotransformation

On average, it is estimated that less than 20% of tigecycline is metabolised before excretion. In healthy male volunteers, following the administration of 14^C-tigecycline, unchanged tigecycline was the primary ¹⁴C-labelled material recovered in urine and faeces, but a glucuronide, an N-acetyl metabolite and a tigecycline epimer were also present.

In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 by competitive inhibition. In addition, tigecycline did not show NADPH-dependency in the inhibition of CYP2C9, CYP2C19, CYP2D6 and CYP3A, suggesting the absence of mechanism-based inhibition of these CYP enzymes.

Elimination

The recovery of the total radioactivity in faeces and urine following administration of 14^C-tigecycline indicates that 59% of the dose is eliminated by biliary/faecal excretion, and 33% is excreted in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.

The total clearance of tigecycline is 24 L/h after intravenous infusion. Renal clearance is approximately 13% of total clearance. Tigecycline shows a polyexponential elimination from serum with a mean terminal elimination half-life after multiple doses of 42 hours although high interindividual variability exists.

In vitro studies using Caco-2 cells indicate that tigecycline does not inhibit digoxin flux, suggesting that tigecycline is not a P-glycoprotein (P-gp) inhibitor. This in vitro information is consistent with the lack of effect of tigecycline on digoxin clearance noted in the in vivo drug interaction study described above.

Tigecycline is a substrate of P-gp based on an in vitro study using a cell line overexpressing P-gp. The potential contribution of P-gp-mediated transport to the in vivo disposition of tigecycline is not known. Co-administration of P-gp inhibitors (e.g. ketoconazole or cyclosporine) or P-gp inducers (e.g. rifampicin) could affect the pharmacokinetics of tigecycline.

Special populations

Hepatic impairment

The single-dose pharmacokinetic disposition of tigecycline was not altered in patients with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25% and 55% and the half-life of tigecycline was prolonged by 23% and 43% in patients with moderate or severe hepatic impairment (Child Pugh B and C), respectively.

Renal impairment

The single dose pharmacokinetic disposition of tigecycline was not altered in patients with renal insufficiency (creatinine clearance 30 ml/min, n=6). In severe renal impairment, AUC was 30% higher than in subjects with normal renal function.

Elderly

No overall differences in pharmacokinetics were observed between healthy elderly subjects and younger subjects.

Paediatric population

Tigecycline pharmacokinetics was investigated in two studies. The first study enrolled children aged 8-16 years (n=24) who received single doses of tigecycline (0.5, 1, or 2 mg/kg, up to a maximum dose of 50 mg, 100 mg, and 150 mg, respectively) administered intravenously over 30 minutes. The second study was performed in children aged 8 to 11 years who received multiple doses of tigecycline (0.75, 1, or 1.25 mg/kg up to a maximum dose of 50 mg) every 12 hours administered intravenously over 30 minutes. No loading dose was administered in these studies. Pharmacokinetic parameters are summarised in the table below.

Dose Normalized to 1 mg/kg Mean ± SD Tigecycline C_max and AUC in Children:

* single dose AUC_0-∞, multiple dose AUC_0-12h

The target AUC_0-12h in adults after the recommended dose of 100 mg loading and 50 mg every 12 hours, was approximately 2500 ng•h/mL.

Population PK analysis of both studies identified body weight as a covariate of tigecycline clearance in children aged 8 years and older. A dosing regimen of 1.2 mg/kg of tigecycline every 12 hours (to a maximum dose of 50 mg every 12 hours) for children aged 8 to <12 years and of 50 mg every 12 hours for adolescents aged 12 to <18 years would likely result in exposures comparable to those observed in adults treated with the approved dosing regimen.

Higher C_max values than in adult patients were observed in several children in these studies. As a consequence, care should be paid to the rate of infusion of tigecycline in children and adolescents.

Gender

There were no clinically relevant differences in the clearance of tigecycline between men and women. AUC was estimated to be 20% higher in females than in males.

Race

There were no differences in the clearance of tigecycline based on race.

Weight

Clearance, weight-normalised clearance, and AUC were not appreciably different among patients with different body weights, including those weighing ≥125 kg. AUC was 24% lower in patients weighing ≥125 kg. No data is available for patients weighing 140 kg and more.

In repeated dose toxicity studies in rats and dogs, lymphoid depletion/atrophy of lymph nodes, spleen and thymus, decreased erythrocytes, reticulocytes, leukocytes, and platelets, in association with bone marrow hypocellularity, and adverse renal and gastrointestinal effects have been seen with tigecycline at exposures of 8 and 10 times the human daily dose based on AUC in rats and dogs, respectively. These alterations were shown to be reversible after two weeks of dosing.

Bone discolouring was observed in rats which was not reversible after two weeks of dosing.

Results of animal studies indicate that tigecycline crosses the placenta and is found in foetal tissues. In reproduction toxicity studies, decreased foetal weights in rats and rabbits (with associated delays in ossification) and foetal loss in rabbits have been observed with tigecycline. Tigecycline was not teratogenic in the rat or rabbit. Tigecycline did not affect mating or fertility in rats at exposures up to 4.7 times the human daily dose based on AUC. In female rats, there were no compound-related effects on ovaries or oestrus cycles at exposures up to 4.7 times the human daily dose based on AUC.

Results from animal studies using ¹⁴C-labelled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in the nursing pups as a result of exposure via maternal milk.

Lifetime studies in animals to evaluate the carcinogenic potential of tigecycline have not been performed, but short-term genotoxicity studies of tigecycline were negative.

Bolus intravenous administration of tigecycline has been associated with a histamine response in animal studies. These effects were observed at exposures of 14 and 3 times the human daily dose based on the AUC in rats and dogs respectively.

No evidence of photosensitivity was observed in rats following administration of tigecycline.