Treatment of Recurrent Urosepsis with Tigecycline: a Pharmacological Perspective

In the February 2008 issue of Journal of Clinical Microbiology, Krueger et al. reported the successful use of tigecycline in a 25-year-old female with septic shock and multiorgan failure caused by an extended-spectrum β-lactamase (ESBL)-producing Escherichia coli strain originating from the right renal pelvis (3).

Based on this case, the authors concluded that tigecycline may be a useful treatment option for serious urinary tract infections (UTIs) caused by multidrug-resistant (MDR) pathogens; however, I believe that several issues would have to be considered before using tigecycline in this indication.

Tigecycline susceptibility is unaffected by the presence of β-lactamases (4), and several authors have confirmed the in vitro activity of tigecycline against ESBL-producing Enterobacteriaceae.

Badal et al. (1) have found that 110 genitourinary isolates of ESBL-producing Enterobacteriaceae were susceptible to tigecycline, with a MIC₉₀ of 2 mg/liter, and Bouchillon et al. (2) have demonstrated between 2004 and 2006 that tigecycline was effective against 669 isolates of ESBL-producing Enterobacteriaceae with a MIC₅₀ and MIC₉₀ of 0.5 and 2 mg/liter, respectively. However, most of these in vitro results do not have support from clinical studies and physicians should strongly consider the tigecycline pharmacological profile before its use in patients with severe infections due to MDR pathogens, especially in UTIs.

When given at the standard clinical dose of 100 mg followed by 50 mg every 12 h, tigecycline is extensively distributed into the tissues, as shown by its high volume of distribution (8 liter/kg) (4) The major component of tigecycline systemic clearance in humans might be biliary secretion, gastrointestinal secretion across the gut walls, or both. Renal excretion represents only a minor elimination pathway (4). The renal clearance of tigecycline (0.03 liter/h/kg) accounts for 10 to 15% of tigecycline's total systemic clearance (ranging from 0.2 to 0.3 liter/h/kg), and only 15% to 22% of the administered dose is recovered unchanged in urine (6). Studies have shown that tigecycline dosage does not have to be adjusted in patients with renal impairment; however, systemic clearence of tigecycline is reduced 20% in patients with severe renal impairment or end-stage renal diseases (6).

It would seem logical that if the drug is to be successfully employed for UTIs due to ESBL-producing Enterobacteriaceae infections, its concentration in the urine should exceed the MIC (≅1 to 2 mg/liter). The authors do not detail the tigecycline MIC of the E. coli strain isolated, but therapy with tigecycline as a 100-mg loading dose followed by 50 mg every 12 h does not ensure the ability to reach 1 to 2 mg/liter in urine in a critically ill patient with chronic renal impairment. Related to this point, Reid et al. have published an example of rapid development of tigecycline resistance in an Acinetobacter baumannii with a initial MIC of 1.5 mg/liter after 2 weeks of therapy with tigecycline due to a UTI (5). The resistant isolate may have been selected by a sustained exposure to a subinhibitory concentration of tigecycline in the urine of the patient.

Also, in a patient in whom urosepsis is suspected, an antibiotic with a high serum concentration should be used. Tigecycline produces, after the recommended dose, relatively low mean-steady-state serum concentrations of 0.4 to 0.6 mg/liter, which is lower than the MIC₉₀ of the most of the ESBL-producing-Enterobacteriaceae (4).

We know that tigecycline's pharmacological and microbiological profiles, which include MDR pathogens, encourage physicians’ use of the drug in other infections in addition to the approved ones—complicated skin and skin structure infections and intra-abdominal infections.

In this context, I agree with Krueger et al. that tigecycline is a very good option to reduce carbapenem use, especially in selected infections, including unlabeled indications. We analyzed during the first months after its launch, the tigecycline prescriptions for 113 patients in 12 institutions in Argentina. Twenty-five patients (22%) received tigecycline for approved indications, and 88 (78%) received it for “off-label” indications. The most frequent “off-label” use was ventilator-associated pneumonia (63 patients), and no UTIs were registered (Curcio et al., unpublished data).

Related to the patient reported, the episode of systemic inflammatory response syndrome, described after the successful treatment with meropenem, which was considered secondary to the urinary source, did not have clinical or microbiological documentation: that is, the recurrent urosepsis was not confirmed. Therefore, the clinical success obtained with the tigecycline therapy in this episode could be reached because another possible infection (nosocomial pneumonia?) was treated. Anyway, still assuming the case as a recurrent prolepsis, I consider that tigecycline was not used appropriately in this patient.

To our knowledge, the incapacity of tigecycline to reach the primary focus of infection could be the main reason to avoid its use in UTIs, still more so in bacteremic patients.

On the other hand, the use of tigecycline for treating patients with UTIs can have consequences not only in terms of clinical outcomes but also in terms of epidemiological collateral damage (i.e., selection of a tigecycline-resistant isolate, as has been reported by Reid et al. [5]).

In Argentina, some physicians consider tigecycline as a possibility to treat all microbiologically documented severe infections caused by MDR bacteria. As infectious disease physicians, we have the obligation to share with our colleagues the concepts related to the site concentrations, pharmacodynamics parameters, clinical outcomes, and need for further investigations of tigecycline and the rest of the antibiotics in order to improve the clinical outcomes of our patients.