Should tigecycline be considered for urinary tract infections? A pharmacokinetic re-evaluation

Sir, Recent debate over the use of tigecycline for urinary tract infection (UTI) treatment caused by multidrug-resistant (MDR) bacteria is based on concern of inadequate urine concentrations. First, a report of tigecycline effectiveness in a patient with recurrent UTI due to a presumed extended-spectrum β-lactamase (ESBL)-producing Escherichia coli isolate was published.1 The patient failed treatment with meropenem but the isolate from urine was reported susceptible to imipenem. The UTI was complicated by sepsis syndrome, renal abscesses, bilateral ureter catheters and possible pneumonia.1 A letter urging caution with the use of tigecycline for UTI treatment followed and summarized that only 15%–22% of tigecycline is excreted unchanged in urine.2 Although actual urine concentrations were not evaluated, the effect of renal impairment on tigecycline urinary excretion was discussed. The author asserted that ‘a 100 mg loading dose followed by 50 mg every 12 h does not ensure the ability to reach 1 to 2 mg/L in urine in a critically ill patient with chronic renal impairment’.2 To our knowledge, urinary concentration data have not been reported in patients with renal failure beyond poster presentations in 2003 (Forty-third Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract A-22) and 2004 (Fourteenth European Congress of Clinical Microbiology and Infectious Diseases, Abstract 902) and tigecycline has not been studied for UTI treatment besides case series.3 A follow-up letter suggested that use of a higher than recommended dose may be effective for MDR Klebsiella pneumoniae or Acinetobacter baumannii urosepsis.4 Moreover, the author provided ‘estimates’ of serum and urinary concentrations following 100, 200 and 400 mg loading doses, and 50 mg every 12 h, 100 mg every 12 h and 200 mg every 24 h maintenance doses, respectively.3,4 Urine concentration was assumed to be ∼0.3, 0.6 or 1.2 mg/L depending on the dosing schedule at an unstated time post-dose based on a serum concentration of 1.5, 3.0 or 6.0 mg/L, respectively.4 A linear relationship between dose and plasma/urine concentration was assumed and urine concentrations were calculated to be 20% of serum concentrations. Neither of these claims has a pharmacokinetic basis or considered varying dosing intervals. The assumption of linearity also contradicted a statement made in the letter about tigecycline kinetics resembling doxycycline's concentration-dependent kinetics at high doses.4 If one accepts that 15%–22% of tigecycline is excreted unchanged in the urine with standard dosing of 50 mg every 12 h, then the amount excreted would be 100 mg/day × 0.15–0.22 (i.e. 15–22 mg/day). Typical urine output is generally <2 L/day; thus, urinary concentrations should average 7.5–11 mg/L or greater. In a clinical pharmacology review, 14.8% of a 50 mg dose was claimed to be excreted as tigecycline epimer and 2.0% was claimed to be excreted as unchanged drug.5 The tigecycline epimer was described as pharmacologically inactive. However, tracing these data to the original published report revealed that the percentages were reversed.6 Unchanged tigecycline urine excretion of 14.8% rather than 2.0% is consistent with the low-end percentage excreted range reported in the literature. Average tigecycline urine concentrations are expected to exceed the MIC for Gram-negative isolates reported as susceptible by several-fold; however, there is concern over whether serum concentrations would also exceed the MIC in bacteraemic patients. Nothing has been published about the activity of tigecycline in urine and the extent that activity depends on urine pH or metal cation concentrations. Tigecycline should not be used for UTI when other therapies including aminoglycosides, carbapenems and colistin are options; however, in rare situations, tigecycline may be considered. Current data do not support the need for or safety of high-dose tigecycline as suggested by Cunha et al.3 and Cunha.4 No specific funding. None to declare.