Tizoxim

Complicated Skin And Skin Structure Infections

Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of complicated skin and skin structure infections caused by susceptible isolates of Escherichia coli, 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 pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis.

Complicated Intra-Abdominal Infections

Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of complicated intra-abdominal infections caused by susceptible isolates of Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillinsusceptible and -resistant isolates), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.

Community-Acquired Bacterial Pneumonia

Tigecycline for injection is indicated in patients 18 years of age and older for the treatment of community-acquired bacterial pneumonia caused by susceptible isolates of Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae, and Legionella pneumophila.

Limitations Of Use

Tizoxim is not indicated for the treatment of diabetic foot infections. A clinical trial failed to demonstrate non-inferiority of Tizoxim for treatment of diabetic foot infections.

Tizoxim is not indicated for the treatment of hospital-acquired or ventilator-associated pneumonia. In a comparative clinical trial, greater mortality and decreased efficacy were reported in Tizoxim-treated patients.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tizoxim and other antibacterial drugs, Tizoxim should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. 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.

Appropriate specimens for bacteriological examination should be obtained in order to isolate and identify the causative organisms and to determine their susceptibility to tigecycline. Tizoxim may be initiated as empiric monotherapy before results of these tests are known.

Recommended Adult Dosage

The recommended dosage regimen for Tizoxim is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous infusions of Tizoxim should be administered over approximately 30 to 60 minutes every 12 hours.

The recommended duration of treatment with Tizoxim for complicated skin and skin structure infections or for complicated intra-abdominal infections is 5 to 14 days. The recommended duration of treatment with Tizoxim for community-acquired bacterial pneumonia is 7 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 progress.

Dosage In Patients With Hepatic Impairment

No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of Tizoxim should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response.

Dosage In Pediatric Patients

The safety and efficacy of the proposed pediatric dosing regimens have not been evaluated due to the observed increase in mortality associated with Tizoxim in adult patients. Avoid use of Tizoxim in pediatric patients unless no alternative antibacterial drugs are available. Under these circumstances, the following doses are suggested:

• Pediatric patients aged 8 to 11 years should receive 1.2 mg/kg of Tizoxim every 12 hours intravenously to a maximum dose of 50 mg of Tizoxim every 12 hours.
• Pediatric patients aged 12 to 17 years should receive 50 mg of Tizoxim every 12 hours.

The proposed pediatric doses of Tizoxim were chosen based on exposures observed in pharmacokinetic trials, which included small numbers of pediatric patients.

Preparation And Administration

Each vial of Tizoxim should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, or Lactated Ringer's Injection, USP to achieve a concentration of 10 mg/mL of tigecycline. (Note: Each vial contains a 6% overage. Thus, 5 mL of reconstituted solution is equivalent to 50 mg of the drug.) The vial should be gently swirled until the drug dissolves. Reconstituted solution must be transferred and further diluted for intravenous infusion. Withdraw 5 mL of the reconstituted solution from the vial and add to a 100 mL intravenous bag for infusion (for a 100 mg dose, reconstitute two vials; for a 50 mg dose, reconstitute one vial). The maximum concentration in the intravenous bag should be 1 mg/mL. The reconstituted solution should be yellow to orange in color; if not, the solution should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration (e.g., green or black) prior to administration. Once reconstituted, Tizoxim may be stored at room temperature (not to exceed 25ºC/77ºF) for up to 24 hours (up to 6 hours in the vial and the remaining time in the intravenous bag). If the storage conditions exceed 25ºC (77ºF) after reconstitution, tigecycline should be used immediately. Alternatively, Tizoxim mixed with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be stored refrigerated at 2° to 8°C (36° to 46°F) for up to 48 hours following immediate transfer of the reconstituted solution into the intravenous bag.

Tizoxim may be administered intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of Tizoxim with 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP or Lactated Ringer's Injection, USP. Injection should be made with an infusion solution compatible with tigecycline and with any other drug(s) administered via this common line.

Drug Compatibilities

Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer's Injection, USP. When administered through a Y-site, Tizoxim is compatible with the following drugs or diluents when used with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP: amikacin, dobutamine, dopamine HCl, gentamicin, haloperidol, Lactated Ringer's, lidocaine HCl, metoclopramide, morphine, norepinephrine, piperacillin/tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine HCl, theophylline, and tobramycin.

Drug Incompatibilities

The following drugs should not be administered simultaneously through the same Y-site as Tizoxim: amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole and omeprazole.

Tizoxim is contraindicated for use in patients who have known hypersensitivity to tigecycline. Reactions have included anaphylactic reactions.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

All-Cause Mortality

An increase in all-cause mortality has been observed in a meta-analysis of Phase 3 and 4 clinical trials in Tizoxim-treated patients versus comparator-treated patients. In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving Tizoxim and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, the adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between Tizoxim and comparator-treated patients. An analysis of mortality in all trials conducted for approved indications (cSSSI, cIAI, and CABP), including post-market trials showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).

The cause of this mortality difference has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities. Tizoxim should be reserved for use in situations when alternative treatments are not suitable.

Mortality Imbalance And Lower Cure Rates In Hospital-Acquired Pneumonia

A trial of patients with hospital acquired, including ventilator-associated, pneumonia failed to demonstrate the efficacy of Tizoxim. In this trial, patients were randomized to receive Tizoxim (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received Tizoxim had lower cure rates (47.9% versus 70.1% for the clinically evaluable population).

In this trial, greater mortality was seen in patients with ventilator-associated pneumonia who received Tizoxim (25/131 [19.1%] versus 15/122 [12.3%] in comparator-treated patients). Particularly high mortality was seen among Tizoxim-treated patients with ventilator-associated pneumonia and bacteremia at baseline (9/18 [50.0%] versus 1/13 [7.7%] in comparator-treated patients).

Anaphylactic Reactions

Anaphylactic reactions have been reported with nearly all antibacterial agents, including Tizoxim, and may be life-threatening. Tizoxim is structurally similar to tetracycline-class antibiotics and should be avoided in patients with known hypersensitivity to tetracycline-class antibiotics.

Hepatic Adverse Effects

Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Hepatic dysfunction may occur after the drug has been discontinued.

Pancreatitis

Acute pancreatitis, including fatal cases, has occurred in association with tigecycline treatment. The diagnosis of acute pancreatitis should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Cases have been reported in patients without known risk factors for pancreatitis. Patients usually improve after tigecycline discontinuation. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis.

Fetal Harm

Tizoxim may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking tigecycline, the patient should be apprised of the potential hazard to the fetus. Results of animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline.

Tooth Discoloration

The use of Tizoxim during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellowgray-brown). Results of studies in rats with Tizoxim have shown bone discoloration. Tizoxim should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated.

Clostridium Difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Tizoxim, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Sepsis/Septic Shock In Patients With Intestinal Perforation

Monotherapy with tigecycline should be avoided in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1642), 6 patients treated with Tizoxim and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with Tizoxim had higher APACHE II scores (median = 13) versus the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established.

Tetracycline-Class Adverse Effects

Tizoxim is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia).

Development Of Drug-Resistant Bacteria

Prescribing Tizoxim in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of tigecycline. No mutagenic or clastogenic potential was found in a battery of tests, including 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 mouse micronucleus assay. Tigecycline did not affect mating or fertility in rats at exposures up to 5 times the human daily dose based on AUC (28 mcg·hr/mL at 12 mg/kg/day). In female rats, there were no compound-related effects on ovaries or estrous cycles at exposures up to 5 times the human daily dose based on AUC.

Use In Specific Populations

Pregnancy

Teratogenic Effects - Pregnancy Category D

Tigecycline was not teratogenic in the rat or rabbit. 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 reductions in fetal weights and an increased incidence of skeletal anomalies (delays in bone ossification) at exposures of 5 times and 1 times the human daily dose based on AUC in rats and rabbits, respectively (28 mcg·hr/mL and 6 mcg·hr/mL at 12 and 4 mg/kg/day). An increased incidence of fetal loss was observed at maternotoxic doses in the rabbits with exposure equivalent to human dose.

There are no adequate and well-controlled studies of tigecycline in pregnant women. Tizoxim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

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 nursing pups as a result of exposure via maternal milk.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tizoxim is administered to a nursing woman.

Pediatric Use

Use in patients under 18 years of age is not recommended. Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of the increased mortality observed in Tizoxim-treated adult patients in clinical trials, pediatric trials of Tizoxim to evaluate the safety and efficacy of Tizoxim were not conducted.

In situations where there are no other alternative antibacterial drugs, dosing has been proposed for pediatric patients 8 to 17 years of age based on data from pediatric pharmacokinetic studies.

Because of effects on tooth development, use in patients under 8 years of age is not recommended.

Geriatric Use

Of the total number of subjects who received Tizoxim in Phase 3 clinical studies (n=2514), 664 were 65 and over, while 288 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events of some older individuals cannot be ruled out.

No significant difference in tigecycline exposure was observed between healthy elderly subjects and younger subjects following a single 100 mg dose of tigecycline.

Hepatic Impairment

No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of tigecycline should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response.

The following serious adverse reactions are described elsewhere in the labeling:

• All-Cause Mortality
• Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia
• Anaphylaxis [WARNINGS AND PRECAUTIONS]
• Hepatic Adverse Effects [WARNINGS AND PRECAUTIONS]
• Pancreatitis [WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials, 2514 patients were treated with Tizoxim. Tizoxim was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of adverse reactions through test of cure reported in ≥2% of patients in these trials.

Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in ≥ 2% of Patients Treated in Clinical Studies

In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving Tizoxim and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between Tizoxim and comparator-treated patients (see Table 2). The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities.

Table 2. Patients with Outcome of Death by Infection Type

Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRSA or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DFI with and without osteomyelitis).

An analysis of mortality in all trials conducted for approved indications -cSSSI, cIAI, and CABP, including post-market trials (one in cSSSI and two in cIAI) -showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).

In comparative clinical studies, infection-related serious adverse reactions were more frequently reported for subjects treated with Tizoxim (7%) versus comparators (6%). Serious adverse reactions of sepsis/septic shock were more frequently reported for subjects treated with Tizoxim (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established.

The most common adverse reactions were nausea and vomiting which generally occurred during the first 1 – 2 days of therapy. The majority of cases of nausea and vomiting associated with Tizoxim and comparators were either mild or moderate in severity. In patients treated with Tizoxim, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe).

In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for Tizoxim and 9% for vancomycin/aztreonam; vomiting incidence was 20% for Tizoxim and 4% for vancomycin/aztreonam. In patients treated for complicated intraabdominal infections (cIAI), nausea incidence was 25% for Tizoxim and 21% for imipenem/cilastatin; vomiting incidence was 20% for Tizoxim and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for Tizoxim and 8% for levofloxacin; vomiting incidence was 16% for Tizoxim and 6% for levofloxacin.

Discontinuation from Tizoxim was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea (<1%).

The following adverse reactions were reported (<2%) in patients receiving Tizoxim in clinical studies:

Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis

Cardiovascular System: thrombophlebitis

Digestive System: anorexia, jaundice, abnormal stools

Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia

Special Senses: taste perversion

Hemic and Lymphatic System: prolonged activated partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia

Skin and Appendages: pruritus

Urogenital System: vaginal moniliasis, vaginitis, leukorrhea

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Tizoxim. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.

• anaphylactic reactions
• acute pancreatitis
• hepatic cholestasis, and jaundice
• severe skin reactions, including Stevens-Johnson Syndrome
• symptomatic hypoglycemia in patients with and without diabetes mellitus

No specific information is available on the treatment of overdosage with tigecycline. Intravenous administration of Tizoxim at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. Tigecycline is not removed in significant quantities by hemodialysis.

Cardiac Electrophysiology

No significant effect of a single intravenous dose of Tizoxim 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.

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

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 AUC_0-12h (134 mcg·h/mL) in alveolar cells was approximately 78-fold higher than the AUC_0-12h in the serum, and the AUC_0-12h (2.28 mcg·h/mL) in epithelial lining fluid was approximately 32% higher than the AUC_0-12h in serum. The AUC_012h(1.61 mcg·h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC_0-12h 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.

Elimination

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.

Tigecycline is a substrate of P-glycoprotein (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.

Excretion

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.