Tigecycline (Tygacil)

The Pharmacy and Therapeutics Committee approved the addition tigecycline to the inpatient formulary with restriction to FDA-approved indications in March 2006. In 2010, a pooled analysis conducted by the FDA found an increased risk of all cause mortality in patients receiving tigecycline relative to comparator agents.¹ Subsequently, tigecycline labeling was updated to include this warning. ²

Given the increased risk for mortality with tigecycline, and potentially inferior efficacy, the following restrictions for tigecycline use are proposed:

Restriction:

1. All orders for tigecycline must be reviewed and approved by an infectious diseases (ID) service. The ordering physician is responsible for contacting an ID service. Only the loading dose and first maintenance dose will be dispensed pending ID response; therefore, the review must be initiated within 24 hours of the original order.
2. If tigecycline use is approved, ID will relay this information to the ordering physician as well as to the pharmacy. If tigecycline is thought to be inappropriate, ID will provide alternative recommendations and communicate these recommendations to the physician originating the tigecycline order.
3. ID may decide that a formal consultation is necessary for approval. In this instance, a formal ID consultation will be required for use of tigecycline.

Tigecycline Review

Tigecycline is a glycylcycline antibioitic, a class closely related to the tetracyclines. Tigecycline was developed to provide broad-spectrum coverage while overcoming two of the common resistance mechanisms associated with tetracycline antibiotics: drug efflux and ribosomal protection.

Tigecycline has activity against a number of Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis, and Gram-negative organisms, including ESBL-producing bacteria, Acinetobacter spp., and Stenotrophomonas spp. Of note, tigecycline does not have antipseudomonal activity. Tigecycline also possesses antianaerobic activity.

Due to the high volume of distribution, tigecycline achieves poor serum concentrations (approximately 0.6 mg/L). For this reason, tigecycline should not be used for endovascular infections, such as bacteremia or endocarditis.

Tigecycline is not indicated for use during pregnancy or in children under 8 years old as it may interfere with proper bone formation and cause permanent tooth discoloration. When considering use in these populations, all risks should be weighed against the potential benefits to the patient. Adverse reactions that were reported in >10% of patients in clinical trials with tigecycline include; nausea (29.5%), vomiting (19.7%), and diarrhea (12.7%).

The recommended dose of tigecycline is 100 mg IV bolus followed by 50 mg IV every 12 hours to be delivered over 30 to 60 minutes. Usual duration of therapy is 5 - 14 days, although actual duration should be dictated by the site and severity of infection and the patient's overall clinical status. For those with severe hepatic disease (Child-Pugh C), dose should be initiated at 100 mg IV bolus followed by 25 mg IV every 12 hours for the duration of therapy. Use in this population should be cautious, with frequent monitoring for treatment response and toxicity.

Tigecycline and risk of mortality

In 2010, a pooled analysis conducted by the FDA found an increased risk of all cause mortality in patients receiving tigecycline relative to comparator agents (Table 1).¹ Subsequently, tigecycline labeling was updated to include this warning.²

Subsequently, two meta-analyses were conducted assessing the efficacy and safety of tigecycline.^3,4 Both studies found a numerically higher rate of death with tigecycline relative to comparator agents but were unable to find a statistically significant overall increase in all-cause mortality (Cai et al., OR, 95%CI 1.47, 0.96-2.27; Tasina et al., 1.28, 0.97–1.69). These meta-analyses were limited because they only included 65%³ and 89%⁴ of the total subjects that the FDA pooled analysis included. In addition, selective reporting may have occurred as the number of deaths reported in some unpublished trials were lower than the number of deaths reported for the same studies according to the FDA pooled analysis.^1,4 The cause of this increased mortality is yet to be determined. Possible explanations offered by the FDA included progression of the underlying infection, patient related factors such as underlying co-morbidities or difference in complication rates, but there are concerns the difference in mortality may be related to the pharmacokinetic properties of the drug.¹ Tigecycline is a glycylcycline, a tetracycline like-class antibiotic and thus is a bacteriostatic agent (inhibits the growth of bacteria as opposed to killing the organisms). While tigecycline has excellent tissue penetration, it also has very low plasma concentrations, suggesting that it is not an ideal agent for treatment of bacteremia or other endovascular infections.² Despite these risks, tigecycline still has an important role, particularly as one of the few agents that may retain activity against multi-drug resistant organisms such as carbapenem-resistant Enterobacteriaceae and Vancomycin-resistant Enterococcus sp.The mortality difference was not statistically significant for each indication in Table 1; however, mortality in tigecycline treated patients was numerically greater in every infection, and pooled analysis reached statistical significance. In the study evaluating tigecycline for HAP, the subgroup of patients with VAP who received tigecycline had lower cure rates versus comparator; 47.9% vs. 70.1%.² Mortality was also greater in tigecycline treated VAP patients; 25/131 (19.1%) vs. 15/122 (12.3%). Particularly high mortality was seen among patients with VAP and associated bacteremia treated with tigecycline [9/18 (50.0%) vs. 1/13 (7.7%)].^1,2 As a result of the unacceptably low cure rate and excess mortality among VAP patients, tigecycline is not approved for HAP or VAP.

References

1. Food and Drug Administration. Drug Safety Announcement-Tigecycline.
2. Tygacil^® (tigecycline) Prescribing Information, Pfizer Pharmaceuticals Inc.
3. Cai Y, Wang R, Liang B, Bai N, Liu Y. Systematic review and meta-analysis of the effectiveness and safety of tigecycline for treatment of infectious disease. Antimicrob Agents Chemother. 2011 Mar;55(3):1162-72.
4. Tasina E, Haidich AB, Kokkali S, Arvanitidou M. Efficacy and safety of tigecycline for the treatment of infectious diseases: a meta-analysis. Lancet Infect Dis. 2011 Nov;11(11):834-44.

March 2012