Faecal concentrations of piperacillin and tazobactam in elderly patients.

Abstract

Sir, The association between secondand third-generation cephalosporins and Clostridium difficile infection (CDI) is well described. By contrast, aminoglycosides, fluoroquinolones such as ciprofloxacin and ureidopenicillins with or without -lactamase inhibitors rarely cause C. difficile diarrhoea. Poor anti-anaerobic activity by aminoglycosides and fluoroquinolones, and hence preservation of gut flora resistance to C. difficile colonization, could explain in part the low risk of CDI associated with these antimicrobials. However, this explanation is not applicable to combinations such as piperacillin–tazobactam, which are active in vitro against aerobic and anaerobic gut flora. The low propensity to induce CDI may be related to poor gut concentration of an antibiotic, but little is known about piperacillin and tazobactam penetration into the colon. We are aware of only one other pertinent study, in which elderly patients with intra-abdominal sepsis were investigated. Faecal drug concentrations were measured in 13 consecutive elderly medical patients receiving treatment (4.5 g iv tds; piperacillin:tazobactam ratio 8:1) for suspected or proven infection to determine whether poor gut drug accumulation may explain the low propensity of this combination to induce CDI. Faecal specimens (n 17) were frozen at –20°C on the day of collection and then transported on dry ice for assay. Concentrations of piperacillin and tazobactam were measured blind by high-performance liquid chromatography (HPLC) (Zacron Ltd, London, UK). Briefly, tissue homogenate proteins were precipitated with 3.5% v/v hydrochloric acid in acetonitrile. Drug extraction from the supernatant was achieved with 10% v/v chlorobutane in ethyl acetate. The extract was reconstituted into a mobile phase consisting of 0.05 M phosphate buffer/water/acetonitrile (50%/45%/5% v/v, pH 6) and injected on to a C18 reverse phase column. Components were eluted with a phosphate buffer/acetonitrile gradient, and monitored at an absorbance of 210 nm. The assay is linear over the concentration range 0.5–30 mg/L for tazobactam and piperacillin, with coefficient correlations 0.99. The limit for quantification of each compound was 0.5 g/g faeces (the concentration of the lowest standard). Patients were followed to determine whether they developed CDI after antibiotic administration (diarrhoea and a cytotoxin-positive faecal sample). The mean and median age of patients (11 females) was 85 years. Piperacillin was detectable in 15/17 specimens, versus 12/17 for tazobactam. Piperacillin was above the limit of sensitivity in 12/15 specimens (6.2–55.4, mean 20.1 g/g faeces); tazobactam was quantifiable in 4/12 samples (5.0–13.1, mean 7.6 g/g). In the only four samples that had quantifiable concentrations of both piperacillin and tazobactam, the ratios of piperacillin to tazobactam were 1.8, 6.4, 7.6 and 11.1. Of four faecal specimens collected from one patient, two had quantifiable concentrations of piperacillin and none had measurable levels of tazobactam. Patients received between two and 13 doses of piperacillin–tazobactam before faecal sampling. There was no clear relationship between number of doses of piperacillin–tazobactam received and faecal antibiotic concentrations, i.e. no evidence for accumulation (Figure). Three of the patients from whom specimens were collected developed CDI in the 2 weeks following administration of piperacillin–tazobactam, although because of earlier antibiotic use it was not possible to be certain of the agent causing diarrhoea. Interestingly, tazobactam was not measurable in any of the six faecal samples from these patients. In patient 1 four faecal specimens were available