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Tygacil

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Tygacil

Tygacil

CLINICAL PHARMACOLOGY

Mechanism of Action

Tigecycline is an antibacterial drug.

Pharmacodynamics

Cardiac Electrophysiology

No significant effect of a single intravenous dose of TYGACIL 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 after single and multiple intravenous doses based on pooled data from clinical pharmacology studies are summarized in Table 3. Intravenous infusions of tigecycline were administered over approximately 30 to 60 minutes.

Table 3: Mean (CV%) Pharmacokinetic Parameters of Tigecycline

  Single Dose
100 mg
(N=224)
Multiple Dosea
50 mg every 12h
(N=103)
Cmax (mcg/mL)b 1.45 (22%) 0.87 (27%)
Cmax (mcg/mL)c 0.90 (30%) 0.63 (15%)
AUC (mcg-h/mL) 5.19 (36%) --
AUC0-24h (mcg•h/mL) -- 4.70 (36%)
Cmin (mcg/mL) -- 0.13 (59%)
t½ (h) 27.1 (53%) 42.4 (83%)
CL (L/h) 21.8 (40%) 23.8 (33%)
CLr (mL/min) 38.0 (82%) 51.0 (58%)
Vss (L) 568 (43%) 639 (48%)
a100 mg initially, followed by 50 mg every 12 hours
b30-minute infusion c 60-minute infusion

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). 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.

Following the administration of tigecycline 100 mg followed by 50 mg every 12 hours to 33 healthy volunteers, the tigecycline AUC0-12h (134 mcg·h/mL) in alveolar cells was approximately 78-fold higher than the AUC0-12h in the serum, and the AUC0-12h (2.28 mcg·h/mL) in epithelial lining fluid was approximately 32% higher than the AUC0-12h in serum. The AUC012h (1.61 mcg·h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0-12h in the serum of 10 healthy subjects.

In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Concentrations at 4 hours after tigecycline administration were higher in gallbladder (38-fold, n=6), lung (3.7-fold, n=5), and colon (2.3-fold, n=6), and lower in synovial fluid (0.58-fold, n=5), and bone (0.35-fold, n=6) relative to serum. 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 and its metabolites. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.

Specific Populations

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). 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). Dosage adjustment is necessary in patients with severe hepatic impairment (Child Pugh C) [see Use in Specific Populations and DOSAGE AND ADMINISTRATION].

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 hours before hemodialysis, 4 ESRD patients receiving tigecycline 1 hour after hemodialysis, and 6 healthy control subjects. The pharmacokinetic profile of tigecycline was not significantly 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.

Geriatric Patients

No significant 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 Specific Populations].

Pediatric Patients

A single-dose safety, tolerability, and pharmacokinetic study of tigecycline in pediatric patients aged 8-16 years who recently recovered from infections was conducted. The doses administered were 0.5, 1, or 2 mg/kg. The study showed that for children aged 12-16 years (n = 16) a dosage of 50 mg twice daily would likely result in exposures comparable to those observed in adults with the approved dosing regimen. Large variability observed in children aged 8 to 11 years of age (n = 8) required additional study to determine the appropriate dosage.

A subsequent tigecycline dose-finding study was conducted in 8-11 year old patients with cIAI, cSSSI, or CABP. The doses of tigecycline studied were 0.75 mg/kg (n = 17), 1 mg/kg (n = 21), and 1.25 mg/kg (n=20). This study showed that for children aged 8-11 years, a 1.2 mg/kg dose would likely result in exposures comparable to those observed in adults resulting with the approved dosing regimen [see DOSAGE AND ADMINISTRATION].

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.

Drug Interactions

TYGACIL (100 mg followed by 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg, orally, every 24 hours) 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 of either drug is necessary when TYGACIL is administered with digoxin.

Concomitant administration of TYGACIL (100 mg followed by 50 mg every 12 hours) 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 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 P450 (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.

Microbiology

Mechanism of Action

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 to tigecycline. In general, tigecycline is considered bacteriostatic; however, TYGACIL has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila.

Mechanism(s) of Resistance

To date there has been no cross-resistance observed between tigecycline and other antibacterials. Tigecycline is not 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). 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 vitro studies have not demonstrated antagonism between tigecycline and other commonly used antibacterials.

Tigecycline has been shown to be active against most of the following bacteria, both in vitro and in clinical infections [see INDICATIONS AND USAGE].

Facultative Gram-positive bacteria

Enterococcus faecalis (vancomycin-susceptible isolates)
Staphylococcus aureus
(methicillin-susceptible and -resistant isolates)
Streptococcus agalactiae

Streptococcus anginosus
grp. (includes S. anginosus, S. intermedius, and S. constellatus)
Streptococcus pneumoniae
(penicillin-susceptible isolates)
Streptococcus pyogenes

Facultative Gram-negative bacteria

Citrobacter freundii
Enterobacter cloacae

Escherichia coli

Haemophilus influenzae
(beta-lactamase negative isolates)
Klebsiella oxytoca

Klebsiella pneumoniae

Legionella pneumophila

Anaerobic bacteria

Bacteroides fragilis
Bacteroides thetaiotaomicron

Bacteroides uniformis

Bacteroides vulgatus

Clostridium perfringens

Peptostreptococcus micros

At least 90% of the following bacteria exhibit in vitro minimum inhibitory concentrations (MICs) that are at concentrations that are achievable using the prescribed dosing regimens. However, the clinical significance of this is unknown because the safety and effectiveness of tigecycline in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Facultative Gram-positive bacteria

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

Facultative Gram-negative bacteria

Acinetobacter baumannii*
Aeromonas hydrophila

Citrobacter koseri

Enterobacter aerogenes

Haemophilus influenzae
(ampicillin-resistant)
Haemophilus parainfluenzae

Pasteurella multocida

Serratia marcescens

Stenotrophomonas maltophilia

Anaerobic bacteria

Bacteroides distasonis
Bacteroides ovatus

Peptostreptococcus
spp.
Porphyromonas
spp.
Prevotella
spp.

Other bacteria

Mycobacterium abscessus
Mycobacterium fortuitum

*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.

Susceptibility Test Methods

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)1,3,4 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 ( < 12h old). The MIC values should be interpreted according to the criteria provided in Table 4.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The standardized procedure2,4 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 mcg tigecycline to test the susceptibility of bacteria 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 4.

Anaerobic Techniques

Anaerobic susceptibility testing with tigecycline should be done by the agar dilution method3 since quality control parameters for broth-dilution are not established.

Table 4: Susceptibility Test Result Interpretive Criteria for Tigecycline

Pathogen Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in mm)
S I R S I R
Staphylococcus aureus (including methicillin-resistant isolates) ≤ 0.5a - - ≥ 19 - -
Streptococcus spp. other than S. pneumoniae ≤ 0.25a - - ≥ 19 - -
Streptococcus pneumoniae ≤ 0.06a - - ≥ 19 - -
Enterococcus faecalis (vancomycin-susceptible isolates) ≤ 0.25a - - ≥ 19 - -
Enterobacteriaceaeb ≤ 2 4 ≥ 8 ≥ 19 15-18 ≤ 14
Haemophilus influenzae ≤ 0.25a - - ≥ 19 - -
Anaerobesc ≤ 4 8 ≥ 16 n/a n/a n/a
aThe current absence of resistant isolates precludes defining any results other than “Susceptible.” Isolates yielding MIC results suggestive of “Nonsusceptible” category should be submitted to reference laboratory for further testing.
bTigecycline has decreased in vitro activity against Morganella spp., Proteus spp. and Providencia spp.
cAgar dilution

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.1,2,3,4 Standard tigecycline powder should provide the MIC values provided in Table 5. For the diffusion technique using the 15 mcg tigecycline disk the criteria provided in Table 5 should be achieved.

Table 5: Acceptable Quality Control Ranges for Susceptibility Testing

QC organism Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in mm)
Staphylococcus aureus ATCC 25923 Not Applicable 20-25
Staphylococcus aureus ATCC 29213 0.03-0.25 Not Applicable
Escherichia coli ATCC 25922 0.03-0.25 20-27
Enterococcus faecalis ATCC 29212 0.03-0.12 Not Applicable
Streptococcus pneumoniae ATCC 49619 0.016-0.12 23-29
Haemophilus influenzae ATCC 49247 0.06-0.5 23-31
Bacteroides fragilisaATCC 25285 0.12-1 Not Applicable
Bacteroides thetaiotaomicrona ATCC 29741 0.5-2 Not Applicable
Eubacterium lentuma ATCC 43055 0.06-0.5 Not Applicable
Clostridium difficilea ATCC 70057 0.12-1 Not Applicable
ATCC = American Type Culture Collection
aAgar dilution

Animal Toxicology and/or Pharmacology

In two week studies, decreased erythrocytes, reticulocytes, leukocytes, and platelets, in association with bone marrow hypocellularity, have been seen with tigecycline at exposures of 8 times and 10 times the human daily dose based on AUC in rats and dogs, (AUC of approximately 50 and 60 mcg·hr/mL at doses of 30 and 12 mg/kg/day) respectively. These alterations were shown to be reversible after two weeks of dosing.

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 two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 300 and 305). These studies compared TYGACIL (100 mg intravenous initial dose followed by 50 mg every 12 hours) with vancomycin (1 g intravenous every 12 hours)/aztreonam (2 g intravenous every 12 hours) for 5 to 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 clinical modified intent-to-treat (c-mITT) patients. See Table 6. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 7.

Table 6: Clinical Cure Rates from Two Studies in Complicated Skin and Skin Structure Infections after 5 to 14 Days of Therapy

  TYGACILa
n/N (%)
Vancomycin/Aztreonamb
n/N (%)
Study 300
  CE 165/199 (82.9) 163/198 (82.3)
  c-mITT 209/277 (75.5) 200/260 (76.9)
Study 305
  CE 200/223 (89.7) 201/213 (94.4)
c-mITT 220/261 (84.3) 225/259 (86.9)
a100 mg initially, followed by 50 mg every 12 hours
bVancomycin (1 g every 12 hours)/Aztreonam (2 g every 12 hours)

Table 7: Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Skin and Skin Structure Infectionsa

Pathogen TYGACIL
n/N (%)
Vancomycin/Aztreonam
n/N (%)
Escherichia coli 29/36 (80.6) 26/30 (86.7)
Enterobacter cloacae 10/12 (83.3) 15/15 (100)
Enterococcus faecalis (vancomycin-susceptible only) 15/21 (71.4) 19/24 (79.2)
Klebsiella pneumoniae 12/14 (85.7) 15/16 (93.8)
Methicillin-susceptible Staphylococcus aureus (MSSA) 124/137 (90.5) 113/120 (94.2)
Methicillin-resistant Staphylococcus aureus (MRSA) 79/95 (83.2) 46/57 (80.7)
Streptococcus agalactiae 8/8 (100) 11/14 (78.6)
Streptococcus anginosus grp.b 17/21 (81.0) 9/10 (90.0)
Streptococcus pyogenes 31/32 (96.9) 24/27 (88.9)
Bacteroides fragilis 7/9 (77.8) 4/5 (80.0)
aTwo cSSSI pivotal studies and two Resistant Pathogen studies
bIncludes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus

Complicated Intra-abdominal Infections

TYGACIL was evaluated in adults for the treatment of complicated intra-abdominal infections (cIAI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 301 and 306). These studies compared TYGACIL (100 mg intravenous initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg intravenous every 6 hours) for 5 to 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 8. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 9.

Table 8: Clinical Cure Rates from Two Studies in Complicated Intra-abdominal Infections after 5 to 14 Days of Therapy

  TYGACILa
n/N (%)
Imipenem/Cilastatinb
n/N (%)
Study 301
  ME 199/247 (80.6) 210/255 (82.4)
  m-mITT 227/309 (73.5) 244/312 (78.2)
Study 306
  ME 242/265 (91.3) 232/258 (89.9)
  m-mlTT 279/322 (86.6) 270/319 (84.6)
a100 mg initially, followed by 50 mg every 12 hours
bImipenem/Cilastatin (500 mg every 6 hours)

Table 9: Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Complicated Intra-abdominal Infectionsa

Pathogen TYGACIL
n/N (%)
Imipenem/Cilastatin
n/N (%)
Citrobacter freundii 12/16 (75.0) 3/4 (75.0)
Enterobacter cloacae 15/17 (88.2) 16/17 (94.1)
Escherichia coli 284/336 (84.5) 297/342 (86.8)
Klebsiella oxytoca 19/20 (95.0) 17/19 (89.5)
Klebsiella pneumoniae 42/47 (89.4) 46/53 (86.8)
Enterococcus faecalis 29/38 (76.3) 35/47 (74.5)
Methicillin-susceptible Staphylococcus aureus (MSSA) 26/28 (92.9) 22/24 (91.7)
Methicillin-resistant Staphylococcus aureus (MRSA) 16/18 (88.9) 1/3 (33.3)
Streptococcus anginosus grp.b 101/119 (84.9) 60/79 (75.9)
Bacteroides fragilis 68/88 (77.3) 59/73 (80.8)
Bacteroides thetaiotaomicron 36/41 (87.8) 31/36 (86.1)
Bacteroides uniformis 12/17 (70.6) 14/16 (87.5)
Bacteroides vulgatus 14/16 (87.5) 4/6 (66.7)
Clostridium perfringens 18/19 (94.7) 20/22 (90.9)
Peptostreptococcus micros 13/17 (76.5) 8/11 (72.7)
aTwo cIAI pivotal studies and two Resistant Pathogen studies
bIncludes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus

Community-Acquired Bacterial Pneumonia

TYGACIL was evaluated in adults for the treatment of community-acquired bacterial pneumonia (CABP) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 308 and 313). These studies compared TYGACIL (100 mg intravenous initial dose followed by 50 mg every 12 hours) with levofloxacin (500 mg intravenous every 12 or 24 hours). In one study (Study 308), after at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms. Total therapy was 7 to 14 days. Patients with community-acquired bacterial pneumonia who required hospitalization and intravenous therapy 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) patients. See Table 10. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 11.

Table 10: Clinical Cure Rates from Two Studies in Community-Acquired Bacterial Pneumonia after 7 to 14 Days of Total Therapy

  TYGACILa
n/N (%)
Levofloxacinb
n/N (%)
95% CIc
Study 308d
  CE 125/138 (90.6) 136/156 (87.2) (-4.4, 11.2)
  c-mITT 149/191 (78) 158/203 (77.8) (-8.5, 8.9)
Study 313
  CE 128/144 (88.9) 116/136 (85.3) (-5.0, 12.2)
  c-mITT 170/203 (83.7) 163/200 (81.5) (-5.6, 10.1)
a100 mg initially, followed by 50 mg every 12 hours
bLevofloxacin (500 mg intravenous every 12 or 24 hours)
c95% confidence interval for the treatment difference
dAfter at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms in Study 308.

Table 11: Clinical Cure Rates By Infecting Pathogen in Microbiologically Evaluable Patients with Community-Acquired Bacterial Pneumoniaa

Pathogen TYGACIL
n/N (%)
Levofloxacin
n/N(%)
Haemophilus influenzae 14/17 (82.4) 13/16 (81.3)
Legionella pneumophila 10/10 (100.0) 6/6 (100.0)
Streptococcus pneumoniae (penicillin-susceptible only)b 44/46 (95.7) 39/44 (88.6)
aTwo CABP studies
bIncludes cases of concurrent bacteremia [cure rates of 20/22 (90.9%) versus 13/18 (72.2%) for TYGACIL and levofloxacin respectively]

To further evaluate the treatment effect of tigecycline, a post-hoc analysis was conducted in CABP patients with a higher risk of mortality, for whom the treatment effect of antibiotics is supported by historical evidence. The higher-risk group included CABP patients from the two studies with any of the following factors:

  • Age ≥ 50 years
  • PSI score ≥ 3
  • Streptococcus pneumoniae bacteremia

The results of this analysis are shown in Table 12. Age ≥ 50 was the most common risk factor in the higher-risk group.

Table 12: Post-hoc Analysis of Clinical Cure Rates in Patients with Community-Acquired Bacterial Pneumonia Based on Risk of Mortalitya

  TYGACIL
n/N (%)
Levofloxacin
n/N (%)
95% CIb
Study 308c      
  CE      
    Higher risk      
     Yes 93/103 (90.3) 84/102 (82.4) (-2.3, 18.2)
     No 32/35 (91.4) 52/54 (96.3) (-20.8, 7.1)
  c-mITT      
   Higher risk      
     Yes 111/142 (78.2) 100/134 (74.6) (-6.9, 14)
     No 38/49 (77.6) 58/69 (84.1) (-22.8, 8.7)
Study 313      
  CE      
    Higher risk      
     Yes 95/107 (88.8) 68/85 (80) (-2.2, 20.3)
     No 33/37 (89.2) 48/51 (94.1) (-21.1, 8.6)
  c-mITT      
    Higher risk      
     Yes 112/134 (83.6) 93/120 (77.5) (-4.2, 16.4)
     No 58/69 (84.1) 70/80 (87.5) (-16.2, 8.8)
aPatients at higher risk of death include patients with any one of the following: ≥ 50 year of age; PSI score ≥ 3; or bacteremia due to Streptococcus pneumoniae
b95% confidence interval for the treatment difference
cAfter at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms in Study 308.

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition. CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

3. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard -Eight Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012.

4. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement. CLSI document M100-S23. CLSI document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013.

Last reviewed on RxList: 10/10/2013
This monograph has been modified to include the generic and brand name in many instances.

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