Tigecycline is a novel intravenous (IV) antibiotic with a broad spectrum of antimicrobial activity, including activity against the drug-resistant bacteria methicillin-resistant Staphylococcus aureus. It is indicated for the treatment of a variety of complicated intraabdominal infections (cIAI) and complicated skin and skin structure infections (cSSSI). These include complicated appendicitis, infected burns, intra-abdominal abscesses, deep soft tissue infections, and infected ulcers. Tigecycline can be used as empiric monotherapy for both hospitaland community-acquired cSSSI and cIAI, is conveniently dosed (every 12 hours), and does not require dosage adjustment in patients with impaired renal function.
Mechanism of Action:1-7 Tigecycline (FIGURE), is the first glycylcycline antibiotic to be approved in the U.S. Glycylcyclines are tetracycline antibiotics containing a glycylamido moiety attached to the 9- position of a tetracycline ring; tigecycline is a direct analog of minocycline with a 9-glycylamide moiety. This substitution pattern imparts certain unique microbiologic properties to tigecycline and extends to antibacterial activity. Tigecycline 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, a mechanism similar to that of the tetracyclines. In general, tigecycline, like the tetracyclines, is considered bacteriostatic. Due to its unique structure, tigecycline is unaffected by the two major mechanisms of tetracycline resistance: ribosomal alteration and efflux. Thus, tigecycline demonstrates efficacy against more bacterial pathogens than the tetracyclines.
Tigecycline has been shown to be active both in vitro and in clinical infections versus many key pathogenic aerobic facultative gram-positive microorganisms, such as Enterococcus faecalis (vancomycin-susceptible isolates only), S. aureus (methicillin-susceptible and methicillinresistant isolates), and a variety of streptococci (Streptococcus agalactiae, Streptococcus anginosus, Streptococcus intermedius, Streptococcus constellatus, and Streptococcus pyogenes). Aerobic and facultative gram-negative bacteria susceptible to tigecycline are Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, and Klebsiella pneumoniae. Anaerobic microorganisms susceptible to tigecycline include a number of key pathogenic Bacteroides species (Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, and Bacteroides vulgatus), as well as Clostridium perfringens and Peptostreptococcus micros. To date, no cross-resistance has been reported between tigecycline and other antibiotics. In addition, tigecycline is not affected by resistance mechanisms, such as beta-lactamases (including extendedspectrum beta-lactamases), target site modifications, macrolide efflux pumps, or enzyme target changes (e.g. gyrase or topoisomerase). In vitro studies have not demonstrated antagonism between tigecycline and other commonly used antibacterial drugs.
Pharmacokinetics:1,8,9 Tigecycline is administered by IV infusion over about 30 to 60 minutes. Plasma protein binding ranges from approximately 71% to 89% at concentrations used in clinical studies (0.1 to 1.0 mcg/mL). The steady-state volume of distribution of tigecycline averages 500 to 700 L (7 to 9 L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the tissues. The area under the concentration-time curve (AUC)0-12h (134 mcg · hour/mL) in alveolar cells is approximately 78-fold higher than the AUC0-12h in the serum. The AUC0-12h (2.28 mcg · hour/mL) in epithelial lining fluid was roughly 32% higher than the AUC0-12h in serum. The AUC0-12h (1.61 mcg · hour/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0-12h in the serum of 10 healthy subjects.
In vivo and in vitro studies suggest that tigecycline is not extensively metabolized. Only trace amounts of metabolites, including a glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose), were detected in trials. Almost 60% of the tigecycline dose is eliminated by biliary/fecal excretion, and 33% is excreted in urine. Approximately 22% of the total dose is excreted as unchanged tigecycline in urine. Therefore, overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline and its metabolites. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.
The pharmacokinetics of tigecycline do not appear to be significantly altered in patients with mild hepatic impairment. However, the clearance of tigecycline is reduced by 25%, and the half-life is prolonged by 23% in patients with moderate hepatic impairment (Child Pugh class B). The clearance is reduced by 55%, and the half-life is prolonged by 43% in patients with severe hepatic impairment (Child Pugh class C). Therefore, no dosage adjustment is warranted in patients with mild to moderate hepatic impairment. Yet, in Child Pugh class C patients, the initial dose of tigecycline should be 100 mg, followed by a reduced maintenance dose of 25 mg every 12 hours. Patients in Child Pugh class C should be treated with caution and monitored for treatment response. The pharmacokinetic profile of tigecycline does not appear to be significantly altered in renal impairment, and tigecycline is not removed by hemodialysis. Thus, no dosage adjustment is necessary in patients with renal impairment or in patients undergoing hemodialysis.
In clinical trials to date, no significant differences in key pharmacokinetic parameters were observed based on age, gender, or race differences. The pharmacokinetics of tigecycline in patients younger than 18 years has not been established.
Clinical Profile:10-13 Tigecycline is indicated for the treatment of cSSSI and cIAI caused by susceptible strains of the bacteria in patients 18 years of age and older. Tigecycline was evaluated in adults for the treatment of cSSSI in two randomized, double-blind, active-controlled, multinational, and multicenter studies (Studies 300 and 305). Patients enrolled in these trials had wound infections and cellulitis (≥10 cm, requiring surgery/drainage or with complicated underlying disease), major abscesses, infected ulcers, or burns. The causative pathogens were E. coli, E. faecalis (vancomycin-susceptible isolates only), S. aureus (methicillin-susceptible and methicillinresistant isolates), S. agalactiae, S. anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), S. pyogenes, or B. fragilis. These studies compared tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) with vancomycin (1 g IV every 12 hours)/aztreonam (2 g IV every 12 hours) for five to 14 days. The primary efficacy end point was the clinical response at the test of cure (TOC) visit in the coprimary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) patients. Clinical cure rates were 86.5% and 79.7% for the CE and c-mITT patients receiving tigecycline, respectively, compared with rates of 88.6% and 81.9% for the CE and c-mITT patients receiving vancomycin/aztreonam, respectively.
Tigecycline was evaluated in adults for the treatment of cIAI in two randomized, double-blind, activecontrolled, multinational, and multicenter studies. Patients in these studies were diagnosed with appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine, and peritonitis caused by C. freundii, E. cloacae, E. coli, K. oxytoca, K. pneumoniae, E. faecalis (vancomycin-susceptible isolates only), S. aureus (methicillin-susceptible isolates only), S. anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), B. fragilis, B. thetaiotaomicron, B. uniformis, B. vulgatus, C. perfringens, and P. micros. Tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) was compared with imipenem/cilastatin (500 mg IV every six hours) for five to 14 days. The primary efficacy end point was the clinical response at the TOC visit for the coprimary populations of the microbiologically evaluable and the microbiologic modified intent-to-treat patients. Clinical cure rates were 86.1% and 80.2% for the CE and c-mITT patients receiving tigecycline, respectively, compared to rates of 86.2% and 81.5% for the CE and c-mITT patients receiving imipenem/cilastatin, respectively.
Tigecycline should be used only to treat infections that are proven to be, or strongly suspected to be, caused by susceptible bacteria. Failure to do so may result in treatment failures and promotion of tigecycline resistance. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Adverse Reactions:1,10-13 In the phase III trials cited above, more than 1,400 patients were treated with tigecycline. The drug was relatively well tolerated in these studies and displayed an adverse-reaction profile similar to that of the tetracyclines. The most commonly reported adverse effects included nausea and vomiting; these generally occurred within the first two days of therapy. Other less common adverse effects included photosensitivity, pseudotumor cerebri, pancreatitis, and antianabolic action. Tigecycline was discontinued because of treatment-emergent adverse events in 5% of patients, compared to 4.7% for all comparators (5.3% for vancomycin/aztreonam and 4.4% for imipenem/cilastatin). Notably, treatment with tigecycline, like all antibiotics, may promote the overgrowth of nonsusceptible organisms and the emergence of secondary complications, such as pseudomembranous colitis. Permanent tooth discoloration may occur if tigecycline is used during tooth development, i.e., during the last half of pregnancy, infancy, and until the age of 8 years. Therefore, use is not recommended in this population unless other drugs are not likely to be effective or are contraindicated. Tigecycline may cause fetal harm when administered to pregnant women and is classified in pregnancy category D.
Drug Interactions:1,10-13 In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following six cytochrome P450 (CYP450) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Thus, tigecycline is not expected to alter the metabolism of drugs metabolized by these enzymes. In addition, because tigecycline is not extensively metabolized, clearance of tigecycline is not expected to be affected by drugs that inhibit or induce the activity of these CYP450 isoforms.
In controlled drug-interaction studies, tigecycline (100 mg followed by 50 mg every 12 hours) decreased the Cmax of digoxin (0.5 mg followed by 0.25 mg orally every 24 hours) by 13% but did not affect the AUC or clearance of digoxin. This modest change in Cmax did not impact the steady-state pharmacodynamic effects of digoxin as measured by changes in ECG intervals. In addition, digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore, no dosage adjustment of either drug is necessary when tigecycline is administered with digoxin.
In another study, concomitant administration of tigecycline (100 mg followed by 50 mg every 12 hours) and warfarin (25-mg single dose) resulted in a decrease in clearance of R-warfarin and S-warfarin by 40% and 23%, an increase in Cmax by 38% and 43%, and an increase in AUC by 68% and 29%, respectively. Tigecycline did not significantly alter the effects of warfarin on the international normalized ratio (INR). In addition, warfarin did not affect the pharmacokinetic profile of tigecycline. However, prothrombin time or another suitable anticoagulation test is necessary if tigecycline is administered with warfarin.
Dosage and Administration:1 Tigecycline is supplied in a single-dose 5-mL glass vial containing 50 mg of lyophilized powder for reconstitution and injection. The manufacturer’s literature should be consulted regarding the preparation, handling, and storage of this product. The recommended dosage regimen for tigecycline is an initial dose of 100 mg, followed by 50 mg every 12 hours. IV infusions should be administered over approximately 30 to 60 minutes every 12 hours. The recommended duration of treatment for cSSSI or cIAI is five to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patient’s clinical and bacteriological response.
No dosage adjustment of tigecycline is necessary based on age, gender, or race or in patients with renal impairment or who are undergoing hemodialysis. Also, no dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh classes A and B). However, in patients with severe hepatic impairment (Child Pugh class C), the initial dose of tigecycline should be 100 mg, followed by a reduced maintenance dose of 25 mg every 12 hours. Patients in Child Pugh class C should be treated with caution and monitored for treatment response.
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