Tigecycline is a broad-spectrum antibacterial and the first glycylcycline to be marketed in the UK. It is active against certain resistant bacteria, including meticillin-resistant Staphylococcus aureus (MRSA) and bacteria that produce extended-spectrum β-lactamase (ESBL). Tigecycline is licensed for intravenous treatment of adults with complicated skin and soft tissue infections, and complicated intra-abdominal infections. We review tigecycline and assess its place for these infections.[1]

Skin and Soft Tissue Infections

Infections of the skin and soft tissue range from simple abscesses and superficial cellulitis to deeper, complicated conditions such as diabetic foot infection, gas gangrene, and necrotizing fasciitis. Infections are described as complicated when they involve deeper skin structures, such as fascia or muscle layers; when they require surgical intervention; or when significant co-morbidities are present (e.g., diabetes mellitus, immunosuppression). Common causes of soft tissue infections include Gram-positive bacteria (e.g., Streptococcus pyogenes, Staphylococcus aureus, Streptococcus agalactiae). Empirical treatment options for these infections typically reflect the involvement of such organisms and may include combinations of benzylpenicillin and flucloxacillin. For patients who are penicillin-allergic, a macrolide antibacterial is an alternative. Other treatment options include co-amoxiclav, clindamycin, or piperacillin in combination with tazobactam. When infections are caused by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin or linezolid may be used. For infections involving an extended-spectrum beta-lactamase (ESBL)-producing organism, a carbapenem is indicated.[2]

Tigecycline: Spectrum of Activity and Resistance Patterns

Tigecycline is a broad-spectrum antibacterial agent with primarily bacteriostatic activity against many clinically relevant pathogens. Unlike tetracyclines, it is not affected by common resistance mechanisms such as ribosomal protection proteins (e.g., Tet[M]) or active efflux pumps (e.g., Tet[A]–[E] in Enterobacteriaceae or Tet[K] in staphylococci). Tigecycline is more effective against Gram-positive cocci than against Gram-negative bacilli. It covers a wide range of Gram-positive species, including Staphylococcus aureus (including MRSA), Streptococcus agalactiae, Streptococcus pyogenes, penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant enterococci. Among Gram-negative bacteria, susceptibility varies, with Escherichia coli, Klebsiella oxytoca, and Klebsiella pneumoniae being susceptible. Tigecycline is also active against Bacteroides fragilis and ESBL-producing Gram-negative organisms. However, Pseudomonas aeruginosa is intrinsically resistant to tigecycline, and species such as Proteus, Morganella, and Providencia are generally less susceptible compared to other Enterobacteriaceae. Acquired resistance has been reported in a few organisms, including Klebsiella pneumoniae, Enterobacter aerogenes, and Enterobacter cloacae.

Licensed dose and Pharmacokinetics

Tigecycline is administered via intravenous infusion. The recommended dosage for adults (aged 18 years or older) is an initial 100 mg, followed by 50 mg every 12 hours. The duration of treatment ranges from 5 to 14 days, depending on the site and severity of the infection, as well as the patient’s response. After intravenous administration, tigecycline is highly protein-bound (71–89%) and widely distributed to most tissues. It achieves high concentrations in bile, the gall bladder, the colon, and the lungs. In contrast, serum concentrations are relatively low (around 0.6–0.7 mg/L), which may limit its effectiveness in cases of bacteraemia. Tigecycline does not penetrate well into the cerebrospinal fluid, making it unsuitable for treating meningitis. Studies using radioactive tracers suggest that tigecycline concentrates in bone, although its bioavailability at this site is not confirmed. Less than 20% of the drug is metabolized before excretion, which primarily occurs via the bile.[3]

Clinical Efficacy

Four double-blind, randomized controlled trials have assessed the effectiveness of intravenous tigecycline in its licensed indications. These trials were published as two pooled analyses (each involving two studies). The studies aimed to determine whether tigecycline was non-inferior to other active therapies, although this methodology was not clearly stated in the study titles or abstracts.

Complicated Intra-Abdominal Infection

In the first pooled analysis, 1,658 patients requiring surgery for complicated intra-abdominal infections received either tigecycline (100 mg initially, followed by 50 mg every 12 hours) or imipenem/cilastatin (imipenem dose 200–500 mg intravenously every 6 hours, adjusted for weight and creatinine clearance). Patients were stratified at randomization based on illness severity. The primary outcome measures were clinical responses in two pre-specified subgroups: Microbiologically-modified intention-to-treat (m-mITT): 76% of total randomized patients who received at least one      dose of study drug, had clinical evidence of a complicated intra-abdominal infection, and had a known bacterial cause at baseline.

Microbiologically evaluable (ME): 62% of total randomized patients who received the study drug for at least 5 days, did not receive concomitant antibacterials, had an outcome assessment within 12–42 days after the first dose, and had a pre-therapy intra-abdominal culture with at least one causative bacterium susceptible to both study regimens. Non-inferiority was assumed if the absolute response rate for tigecycline was no more than 15% below that for imipenem/cilastatin (i.e., the lower limit of the 2-sided 95% confidence interval [CI] was ?15%). The main pathogens isolated were E. coli, Streptococcus anginosus, Bacteroides spp., Klebsiella spp., and P. aeruginosa. At the test-of-cure visit (12–42 days after therapy), tigecycline was non-inferior to imipenem/cilastatin for both the m-mITT group (difference ?1.3%, 95% CI ?5.8 to +3.2) and ME groups (difference 0.0%, 95% CI ?4.5% to +4.4%). However, interpretation of these results is challenging because data were only reported for subgroups of randomized patients, with no overall intention-to-treat assessment. Additionally, few patients were severely ill, immunocompromised, or had bacteraemia. The product summary advises caution when treating such patients.

Complicated Skin and Soft Tissue Infection

In the second pooled analysis, 1,129 patients with complicated skin or skin-structure infections were randomized to receive tigecycline (100 mg initially, followed by 50 mg twice daily) or a combination of intravenous vancomycin (1 g twice daily) and intravenous aztreonam (2 g twice daily) for up to 14 days. Approximately 62–63% of patients in each group had deep soft tissue infections, of whom 58–59% had cellulitis and 26–29% required surgery or drainage. Few patients with comorbid factors (e.g., diabetes [20%], peripheral vascular disease [7%], or bacteraemia [3%]) were enrolled. Patients with severe underlying disease (e.g., immunocompromised individuals), decubitus foot ulcers, or infections requiring more than 14 days of therapy (e.g., necrotizing fasciitis) were excluded. Therefore, extrapolating these data to such patients is inappropriate, and the product summary advises caution when treating them.

The primary outcome measures were clinical responses for the clinical modified intent-to-treat population (c-mITT, 94% of total) and the clinically evaluable population (CE, 74% of total). The objective was to show whether tigecycline was non-inferior to vancomycin plus aztreonam within a margin of 15% in absolute response at the test-of-cure assessment. The predominant pathogens were methicillin-susceptible and methicillin-resistant S. aureus, with Streptococcus spp., enterococci, and E. coli also present. At the test-of-cure assessment (12–92 days after the last dose), tigecycline was non-inferior to vancomycin plus aztreonam for both the c-mITT (difference ?2.1%, 95% CI ?7.1 to +2.8%) and CE (difference ?2.1%, 95% CI ?6.8% to +2.7%) populations.

Conclusion

Tigecycline is a glycylcycline antibacterial structurally related to minocycline. It is licensed for the treatment of adults with complicated skin and soft tissue, or intra-abdominal infections. The drug is active against multiple resistant bacteria and so appears to be a useful addition to the antibacterials available to treat such infections. However, evidence to support use of the drug in its licensed indications is weak. Trial evidence suggests that the drug is non-inferior to both vancomycin plus aztreonam in patients with complicated skin and soft tissue infections, and imipenem plus cilastatin in patients with complicated intra-abdominal infections. However, use of a relatively large non-inferiority margin in both analyses, together with use of a lower than standard dose of imipenem/cilastatin in some patients, make interpretation of these studies difficult. Furthermore, key limitations in study design and analysis prevent results being extrapolated to patients with certain severe illnesses or co-morbidities. On current evidence, it would seem appropriate to restrict use of tigecycline to infections that have failed to respond to current standard treatments or where there is known resistance to such therapies.

References

[1] Fritsche TR, et al. In vitro activity of tigecycline (GAR-936) tested against 11,859 recent clinical isolates associated with community-acquired respiratory tract and Gram-positive cutaneous infections. Diagn Microbiol Infect Dis 2004; 49: 201–9.

[2] Rodvold KA, et al. Serum, tissue and body fluid concentrations of tigecycline after a single 100mg dose. J Antimicrob Chemother 2006; 58: 1221–9.

[3] Muralidharan G, et al. Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents Chemother 2005; 49: 220–9