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Pharmacology: Pharmacodynamics: Mechanism of action: 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. Tigecycline carries a glycylamido moiety attached to the 9-position of minocycline. The substitution pattern is not present in any naturally occurring or semisynthetic tetracycline and imparts certain microbiologic properties that transcend any known tetracycline-derivative in vitro or in vivo activity. In addition, tigecycline is able to overcome the two major tetracycline resistance mechanisms, ribosomal protection and efflux. Accordingly, tigecycline has demonstrated in vitro and in vivo activity against a broad spectrum of bacterial pathogens. There has been no cross resistance observed between tigecycline and other antibiotics. In in vitro studies, no antagonism has been observed between tigecycline and other commonly used antibiotics. 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. However, tigecycline has shown some bactericidal activity, and a 3-log reduction was observed against Neisseria gonorrhoeae. Tigecycline has also demonstrated bactericidal activity against common respiratory strains of Streptococcus pneumoniae, Haemophilus influenzae, and Legionella pneumophila.
Susceptibility Test Methods: Dilution Techniques: Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure based on dilution methods (broth, agar, or microdilution) or equivalent using standardized inoculum and concentrations of tigecycline. For broth dilution tests for aerobic organisms, MICs must be determined using testing medium that is fresh (<12 hours old). The MIC values should be interpreted according to the criteria provided in Table 1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 μg tigecycline to test the susceptibility of microorganisms to tigecycline. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for tigecycline. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 μg tigecycline disk should be interpreted according to the criteria in Table 1. (See Table 1.)
Click on icon to see table/diagram/imageA report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable; other therapy should be selected.
Quality Control: As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standard tigecycline powder should provide the MIC values provided in Table 2. For the diffusion technique using the 15 μg tigecycline disk, laboratories should use the criteria provided in Table 2 to test quality control strains. (See Table 2.)
Click on icon to see table/diagram/imageThe 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. The information as follows provides only approximate guidance on the probability as to whether the microorganism will be susceptible to tigecycline or not.
Susceptible: Gram-positive aerobes: Enterococcus avium, Enterococcus casseliflavus, Enterococcus faecalis (vancomycin-resistant strains), Enterococcus faecalis* (includes vancomycin-susceptible strains), Enterococcus faecium (vancomycin-susceptible and -resistant isolates), Enterococcus gallinarum, Listeria monocytogenes, Staphylococcus aureus* (includes methicillin-susceptible and -resistant strains), Staphylococcus epidermidis (methicillin-susceptible and -resistant isolates), Staphylococcus haemolyticus, Streptococcus agalactiae*, Streptococcus anginosus* (includes S. anginosus, S. intermedius, S. constellatus), Streptococcus pneumoniae* (penicillin-susceptible isolates), Streptococcus pyogenes*, Viridans group streptococci.
Gram-negative aerobes: Acinetobacter baumanniiǂ, Aeromonas hydrophila, Citrobacter freundii*, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae*, Escherichia coli* (including extended spectrum beta lactamase-producing strains), Haemophilus influenzae (ampicillin-resistant), Haemophilus parainfluenzae, Klebsiella oxytoca*, Klebsiella pneumoniae* (including extended spectrum beta lactamase-producing strains), Legionella pneumophila*, Pasteurella multocida, Serratia marcescens, Stenotrophomonas maltophilia.
Anaerobic bacteria: Bacteroides fragilis*, Bacteroides distasonis, Bacteroides thetaiotaomicron*, Bacteroides uniformis*, Bacteroides vulgatus*, Clostridium perfringens*, Peptostreptococcus spp., Peptostreptococcus micros*, Porphyromonas spp., Prevotella spp.
Atypical bacteria: Mycobacterium abscessus, Mycobacterium fortuitum.
* Clinical efficacy has been demonstrated for susceptible isolates in the approved clinical indications.
ǂ There have been reports of the development of tigecycline resistance in Acinetobacter infections seen during the course of standard treatment. Such resistance appears to be attributable to an MDR efflux pump mechanism. While monitoring for relapse of infection is important for all infected patients, more frequent monitoring in this case is suggested. If relapse is suspected, blood and other specimens should be obtained and cultured for the presence of bacteria. All bacterial isolates should be identified and tested for susceptibility to tigecycline and other appropriate antimicrobials.
Resistant: Gram-negative aerobes: Pseudomonas aeruginosa.
Anaerobic bacteria: No naturally-occurring species have been found to be inherently resistant to tigecycline.
Resistance: To date there has been no cross-resistance observed between tigecycline and other antibacterial drugs. Tigecycline is less affected by the two major tetracycline resistance mechanisms, ribosomal protection and efflux. Additionally, tigecycline is not affected by resistance mechanisms such as beta-lactamases (including extended spectrum beta-lactamases), target-site modifications, macrolide efflux pumps or enzyme target changes (e.g., gyrase/topoisomerases). However, some ESBL-producing isolates may confer resistance to tigecycline via other resistance mechanisms. Tigecycline resistance in some bacteria (e.g., Acinetobacter calcoaceticus-Acinetobacter baumannii complex) is associated with multi-drug resistant (MDR) efflux pumps.
Interaction with Other Antimicrobials: In in vitro studies, no antagonism has been observed between tigecycline and any other commonly used antibiotic class.
Clinical trial data on Efficacy: Complicated Skin and Skin Structure Infections (cSSSI): Tigecycline was evaluated in adults for the treatment of (cSSSI) in two randomized, double-blind, active-controlled, multinational, multicenter studies. 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 5 to 14 days. Subjects with complicated deep soft tissue infections, including wound infections and cellulitis (≥10 cm, requiring surgery/drainage or with complicated, underlying disease), major abscesses, infected ulcers, and burns were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) subjects. (See Table 3.)
Click on icon to see table/diagram/imageClinical cure rates at TOC by pathogen in the microbiologically evaluable (ME) subjects with cSSSI are presented in the Table 4. (See Table 4.)
Click on icon to see table/diagram/imageComplicated Intra-abdominal Infections (cIAI): Tigecycline was evaluated in adults for the treatment of cIAI in two randomized, double-blind, active-controlled, multinational, multicenter studies. These studies compared tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg IV every 6 hours) for 5 to 14 days. Subjects with complicated diagnoses including appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of the intestine, and peritonitis were enrolled in the studies. The primary efficacy endpoint was the clinical response at the TOC visit for the co-primary populations of the ME and the microbiologic modified intent-to-treat (m-mITT) subjects. (See Table 5.)
Click on icon to see table/diagram/imageClinical cure rates at TOC by pathogen in the ME subjects with cIAI are presented in Table 6. (See Table 6.)
Click on icon to see table/diagram/imageMethicillin-Resistant Staphylococcus aureus (MRSA): Tigecycline was evaluated in adults for the treatment of various serious infections (cIAI, cSSSI, and other infections) due to MRSA in Study 307.
Study 307 was a randomized, double-blind, active-controlled, multinational, multicenter study evaluating tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) and vancomycin (1 g IV every 12 hours) for the treatment of infections due to MRSA. Subjects with cIAI, cSSSI, and other infections were enrolled in this study. The primary efficacy endpoint was the clinical response at the TOC visit for the co-primary populations of the ME and the m-mITT subjects. For clinical cure rates see Table 7 for MRSA. (See Table 7.)
Click on icon to see table/diagram/imageCardiac Electrophysiology: No significant effect of a single intravenous dose of tigecycline 50 mg or 200 mg on QTc interval was detected in a randomized, placebo- and active-controlled four-arm crossover thorough QTc study of 46 healthy subjects.
Pharmacokinetics: The mean pharmacokinetic parameters of tigecycline for the recommended dosage regimen after single and multiple intravenous doses are summarized in Table 8.
Intravenous infusions of tigecycline should be administered over approximately 30 to 60 minutes. (See Table 8.)
Click on icon to see table/diagram/imageAbsorption: 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 μg/mL). Animal and human pharmacokinetic studies have demonstrated that tigecycline readily distributes to tissues. In rats receiving single or multiple doses of 14C-tigecycline, radioactivity was well distributed to most tissues, with the highest overall exposure observed in bone, bone marrow, thyroid gland, kidney, spleen, and salivary gland. In humans, the steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the tissues of humans.
Two studies examined the steady-state pharmacokinetic profile of tigecycline in specific tissues or fluids of healthy subjects receiving tigecycline 100 mg followed by 50 mg every 12 hours. In a bronchoalveolar lavage study, the tigecycline AUC0-12h (134 μg·h/mL) in alveolar cells was approximately 77.5-fold higher than the AUC0-12h in the serum of these subjects, and the AUC0-12h (2.28 μg·h/mL) in epithelial lining fluid was approximately 32% higher than the AUC0-12h in serum. In a skin blister study, the AUC0-12h (1.61 μg·h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0-12h in the serum of these subjects.
In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Tissue concentrations at 4 hours after tigecycline administration were measured in the following tissue and fluid samples: gallbladder, lung, colon, synovial fluid, and bone. Tigecycline attained higher concentrations in tissues versus serum in gallbladder (38-fold, n=6), lung (3.7-fold, n=5), and colon (2.3-fold, n=6). The concentration of tigecycline in these tissues after multiple doses has not been studied.
Metabolism: Tigecycline is not extensively metabolized. In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. In healthy male volunteers receiving 14C-tigecycline, tigecycline was the primary 14C-labeled material recovered in urine and feces, but a glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) were also present.
Elimination: The recovery of total radioactivity in feces and urine following administration of 14C-tigecycline indicates that 59% of the dose is eliminated by biliary/fecal 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.
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.
Special Populations: Hepatic insufficiency: In a study comparing 10 subjects with mild hepatic impairment (Child Pugh A), 10 subjects with moderate hepatic impairment (Child Pugh B), and 5 subjects with severe hepatic impairment (Child Pugh C) to 23 age and weight matched healthy control subjects, the single-dose pharmacokinetic disposition of tigecycline was not altered in subjects with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25% and the half-life of tigecycline was prolonged by 23% in subjects with moderate hepatic impairment (Child Pugh B). In addition, systemic clearance of tigecycline was reduced by 55%, and the half-life of tigecycline was prolonged by 43% in subjects with severe hepatic impairment (Child Pugh C).
Based on the pharmacokinetic profile of tigecycline, no dosage adjustment is warranted in subjects with mild to moderate hepatic impairment (Child Plug A and Child Pugh B). However, in subjects with severe hepatic impairment (Child Pugh C), the dose of tigecycline should be reduced to 100 mg followed by 25 mg every 12 hours. Subjects with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response (see Dosage & Administration).
Renal insufficiency: A single-dose study compared 6 subjects with severe renal impairment (creatinine clearance ClCr ≤30 mL/min), 4 end stage renal disease subjects receiving tigecycline 2 hours before hemodialysis, 4 end stage renal disease subjects receiving tigecycline after hemodialysis, and 6 healthy control subjects. The pharmacokinetic profile of tigecycline was not altered in any of the renally-impaired subject groups, nor was tigecycline removed by hemodialysis. No dosage adjustment of tigecycline is necessary in subjects with renal impairment or in subjects undergoing hemodialysis (see Dosage & Administration).
Elderly: No overall differences in pharmacokinetics were observed between healthy elderly subjects (n=15, age 65-75; n=13, age >75 and younger subjects (n=18) receiving a single, 100 mg dose of tigecycline. Therefore, no dosage adjustment is necessary based on age.
Children: The pharmacokinetics of tigecycline in patients less than 18 years of age have not been established.
Gender: In a pooled analysis of 38 women and 298 men participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance between women (20.7 ± 6.5 L/h) and men (22.8 ± 8.7 L/h). Therefore, no dosage adjustment is necessary based on gender.
Race: In a pooled analysis of 73 Asian subjects, 53 black subjects, 15 Hispanic subjects, 190 White subjects, and 3 subjects classified as "other" participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance among the Asian subjects (28.8 ± 8.8 L/h), Black subjects (23.0 ± 7.8 L/h), Hispanic subjects (24.3 ± 6.5 L/h), white subjects (22.1 ± 8.9 L/h), and "other" subjects (25.0 ± 4.8 L/h). Therefore, no dosage adjustment is necessary based on race.
Toxicology: Preclinical safety data: Carcinogenicity: Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of tigecycline.
Mutagenicity: No mutagenic or clastogenic potential was found in a battery of tests, including an in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, in vitro forward mutation assay in CHO cells (HGRPT locus), in vitro forward mutation assays in mouse lymphoma cells, and in vivo micronucleus assay.
Reproduction toxicity: 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 estrus cycles at exposures up to 4.7 times the human daily dose based on AUC.
In preclinical safety studies, 14C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with slight reductions in fetal weights and an increased incidence of minor skeletal anomalies (delays in bone ossification) at exposures of 4.7 times and 1.1 times the human daily dose based on AUC in rats and rabbits, respectively.
Results from animal studies using 14C-labeled 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 the maternal milk.
Other: Decreased erythrocytes, reticulocytes, leukocytes and platelets, in association with bone marrow hypocellularity, have been seen with tigecycline at exposures of 8.1 times and 9.8 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.
Bolus intravenous administration of tigecycline has been associated with a histamine response in preclinical studies. These effects were observed at exposures of 14.3 and 2.8 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.
