Tygacil

Tygacil Mechanism of Action

tigecycline

Manufacturer:

Pfizer
Full Prescribing Info
Action
Antibacterial.
Microbiology: Tigecycline, a glycylcycline, 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 2 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.
Tigecycline has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections:
Aerobic and Facultative Gram-Positive Microorganisms: Enterococcus faecalis (vancomycin-susceptible isolates only); Staphylococcus aureus (methicillin-susceptible and -resistant isolates); Streptococcus agalactiae; Streptococcus anginosus group (includes S. anginosus, S. intermedius and S. constellatus); Streptococcus pneumoniae (penicillin-susceptible isolates); Streptococcus pyogenes.
Aerobic and Facultative Gram-Negative Microorganisms: Citrobacter freundii, Enterobacter cloacae, Escherichia coli (include ESBL, producing isolates), Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis.
Anaerobic Microorganisms: Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, Peptostreptococcus micros.
Other Microorganism: Chlamydia pneumoniae, Mycoplasma pneumoniae.
The following in vitro data are available, but their clinical significance is unknown. At least 90% of these microorganisms exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for tigecycline. However, the safety and effectiveness of tigecycline in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials:
Aerobic Gram-Positive Microorganisms: Enterococcus avium, Enterococcus casseliflavus, Enterococcus faecalis (vancomycin-resistant isolates), Enterococcus faecium (vancomycin-susceptible and -resistant isolates), Enterococcus gallinarum, Listeria monocytogenes, Staphylococcus epidermidis (methicillin-susceptible and -resistant isolates), Staphylococcus haemolyticus, Streptococcus pneumonia (penicillin-resistant isolates).
Aerobic Gram-Negative Microorganisms: Acinetobacter calcoaceticus/baumannii complex, Aeromonas hydrophila, Citrobacter koseri, Enterobacter aerogenes, Haemophilus parainfluenzae, Neisseria meningitidis, Pasteurella multocida, Serratia marcescens, Stenotrophomonas maltophilia.
Anaerobic Microorganisms: Bacteroides distasonis, Bacteroides ovatus, Peptostreptococcus, Porphyromonas and Prevotella spp.
Other Microorganisms: Mycobacterium abscessus, Mycobacterium chelonae and Mycobacterium fortuitum.
Susceptibility Testing: When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (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 in testing medium that is fresh (<12 hrs 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 tigecycline 15 mcg 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-mcg tigecycline disk should be interpreted according to the criteria in Table 1.


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A 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-mcg tigecycline disk, the criteria provided in Table 2 should be used to test quality control strains.


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Pharmacokinetics: The mean pharmacokinetic parameters of tigecycline after single and multiple IV doses are summarized in Table 3. IV infusions of tigecycline were administered over approximately 30-60 min (see Table 3).


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Distribution: The in vitro plasma protein-binding of tigecycline ranges from approximately 71-89% at concentrations observed in clinical studies (0.1-1 mcg/mL). In humans, the steady-state volume of distribution of tigecycline averaged 500-700 L (7-9 L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the human tissues.
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 hrs. In a bronchoalveolar lavage study, the tigecycline AUC0-12 hrs (134 mcg·hr/mL) in alveolar cells was approximately 77.5-fold higher than the AUC0-12 hrs in the serum of these subjects, and the AUC0-12hrs (2.28 mcg·hr/mL) in epithelial lining fluid was approximately 32% higher than the AUC0-12hrs in serum. In a skin blister study, the AUC0-12hrs (1.61 mcg·hr/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0-12hrs 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 hrs 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=5). 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. Approximately 22% of the total dose is excreted as unchanged tigecycline 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.
Special Populations: Use in Patients with Hepatic Impairment: In a study comparing 10 patients with mild hepatic impairment (Child-Pugh A), 10 patients with moderate hepatic impairment (Child-Pugh B) and 5 patients 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 patients with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25% and the half-life of tigecycline was prolonged by 23% in patients 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 patients with severe hepatic impairment (Child-Pugh C).
Based on the pharmacokinetic profile of tigecycline, no dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child-Pugh A and Child-Pugh B). However, in patients with severe hepatic impairment (Child-Pugh C), the dose of Tygacil should be reduced to 100 mg followed by 25 mg every 12 hrs. Patients with severe hepatic impairment (Child-Pugh C) should be treated with caution and monitored for treatment response. (See Precautions and Dosage & Administration.)
Use in Patients with Renal Impairment: A single-dose study compared 6 subjects with severe renal impairment (creatinine clearance ≤30 mL/min), 4 end-stage renal disease (ESRD) patients receiving tigecycline 2 hrs before hemodialysis, 4 ESRD patients receiving tigecycline 1 hr after hemodialysis and 6 healthy control subjects. The pharmacokinetic profile of tigecycline was not altered in any of the renally impaired patient groups, nor was tigecycline removed by hemodialysis. No dosage adjustment of Tygacil is necessary in patients with renal impairment or in patients undergoing hemodialysis. (See Dosage & Administration.)
Pediatric Use: The pharmacokinetics of tigecycline in patients <18 years have not been established. (See Use in children under Precautions.)
Geriatric Use: 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 Tygacil. Therefore, no dosage adjustment is necessary based on age. (See Use in the elderly under Precautions.)
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/hr) and men (22.8±8.7 L/hr). 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/hr), Black subjects (23±7.8 L/hr), Hispanic subjects (24.3±6.5 L/hr), White subjects (22.1±8.9 L/hr) and "other" subjects (25±4.8 L/hr). Therefore, no dosage adjustment is necessary based on race.
Drug-Drug Interactions: Tygacil (100 mg followed by 50 mg every 12 hrs) and digoxin (0.5 mg followed by 0.25 mg orally every 24 hrs) were co-administered to healthy subjects in a drug interaction study. Tigecycline slightly decreased the Cmax of digoxin by 13% but did not affect the AUC or clearance of digoxin. This small change in Cmax did not affect 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 is necessary when Tygacil is administered with digoxin.
Concomitant administration of Tygacil (100 mg followed by 50 mg every 12 hrs) and warfarin (25-mg single dose) to healthy subjects 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 increased international normalized ratio (INR). In addition, warfarin did not affect the pharmacokinetic profile of tigecycline. However, prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin.
In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome P-450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6 and 3A4. Therefore, Tygacil 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.
Toxicology: Animal Toxicology: Decreased erythrocytes, reticulocytes, leukocytes and platelets, in association with bone marrow hypocellularity, have been seen with tigecycline at exposures of 8.1 and 9.8 times the human daily dose based on AUC in rats and dogs, respectively. These alterations were shown to be reversible after 2 weeks of dosing.
Bolus IV 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 AUC in rats and dogs, respectively.
No evidence of photosensitivity was observed in rats following administration of tigecycline.
Clinical Studies: Complicated Skin and Skin Structure Infections: Tygacil was evaluated in adults for the treatment of complicated skin and skin structure infections (cSSSI) in 2 randomized, double-blind, active-controlled, multinational, multicenter studies. These studies compared Tygacil (100 mg IV initial dose followed by 50 mg every 12 hrs) with vancomycin (1 g IV every 12 hrs)/aztreonam (2 g IV every 12 hrs) for 5-14 days. Patients 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 clinically modified intent-to-treat (c-mITT) patients (see Table 4).


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Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients with complicated skin and skin structure infections are presented in Table 5. (See Table 5.)


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Complicated Intra-Abdominal Infections: Tygacil was evaluated in adults for the treatment of complicated intra-abdominal infections (cIAI) in 2 randomized, double-blind, active-controlled, multinational, multicenter studies. These studies compared tigecycline (100 mg IV initial dose followed by 50 mg every 12 hrs) with imipenem/cilastatin (500 mg IV every 6 hrs) for 5-14 days. Patients with complicated diagnoses including appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of 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 microbiologically evaluable (ME) and the microbiologic modified intent-to-treat (m-mITT) patients (see Table 6).


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Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 7.


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