Department of Microbiology, University of Leeds and The General Infirmary, Leeds LS2 9JT, UK
Sir,
The association between second- and third-generation cephalosporins and Clostridium difficile infection (CDI) is well described. By contrast, aminoglycosides, fluoroquinolones such as ciprofloxacin and ureidopenicillins with or without ß-lactamase inhibitors rarely cause C. difficile diarrhoea.13 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 piperacillintazobactam, 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.4
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 0.530 mg/L for tazobactam and piperacillin, with coefficient correlations >0.99. The limit for quantification of each compound was 0.5 µg/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 (6.255.4, mean 20.1 µg/g faeces); tazobactam was quantifiable in 4/12 samples (5.013.1, mean 7.6 µg/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 piperacillintazobactam before faecal sampling. There was no clear relationship between number of doses of piperacillintazobactam received and faecal antibiotic concentrations, i.e. no evidence for accumulation (Figure).
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Multiple retrospective studies have reported that ureidopenicillins with or without ß-lactamase inhibitors are uncommonly associated with CDI, particularly in comparison with cephalosporins.1,2 The only reported prospective comparison of such antibiotics found 3.6- and 7.4-fold excess relative risk of C. difficile colonization and symptomatic infection, respectively, in patients treated with cefotaxime compared with piperacillintazobactam.3 If it is believed that antibiotics that inhibit the anaerobic com-ponent of gut flora are more likely to create a niche for C. difficile, then ureidopenicillins, particularly when combined with ß-lactamase inhibitors, should theoretically be associated with CDI. While colonization resistance is an attractive theory, there is, however, controversy over the extent of the role played by gut anaerobes.5
The ureidopenicillins and tazobactam are excreted predominantly (5060% of dose) via the urinary tract.6 Only limited information is available about the gastrointestinal secretion of either compound, but it is believed that this is greater for piperacillin. While only 0.64% of a dose of [14C]tazobactam was found in faeces, epithelial concentrations were up to twice plasma levels.6 The only study to date that has reported faecal concentrations of piperacillin and tazobactam examined 20 patients being treated for intra-abdominal infections.4 The mean age of patients (51 years) was substantially younger than in the present study. Only six (30%) and four (20%) of the patients were found to have measurable faecal concentrations of piperacillin (1.2276 µg/g) and tazobactam (0.822.2 µg/g), respectively. These data were obtained using bioassays with limits of sensitivity (0.2 and 0.5 µg/g)4 similar to those in the present study.
We found marked inter-patient variation in the faecal concentrations of piperacillin and tazobactam was found. Piperacillin was more commonly present in faeces and in higher concentrations than tazobactam. In addition, there was no evidence for accumulation of either piperacillin or tazobactam (Figure). Thus, relatively poor and dissociated penetration of piperacillin and tazobactam into the gut lumen may explain why iv treatment with piperacillin tazobactam uncommonly leads to marked impairment of colonization resistance and hence increased risk of CDI.
Faecal flora studies have shown variable effects of piperacillin on the anaerobic large bowel flora,4,6 and this may relate to the inconsistent penetration of the antibiotic into this compartment. There are considerable difficulties inherent in the accurate quantification of gut flora, not least that the majority of anaerobic commensals are noncultivable. It is likely that the low propensity of ureidopenicillininhibitor antibiotics to induce CDI is due to several factors, including drug bioavailability, low pH, anaerobiasis and antibiotic binding to organic matter. In addition, the activity of ureidopenicillininhibitor antibiotics against C. difficile itself, including the UK epidemic strain (J. Freeman & M. H. Wilcox, unpublished data), reduces the likelihood that treatment with these antibiotics will provide selective pressure for gut bacterial overgrowth.
Acknowledgments
We thank Zakros Ltd for carrying out the antibiotic assays, Dr O. Corrado for permission to study his patients and Wyeth for providing financial support for the study.
Notes
* Corresponding author. Tel: +44-113-233-5595; Fax: +44-113-233-5649; E-mail: markwi{at}pathology.leeds.ac.uk
References
1 . de Lalla, F., Privitera, G., Ortisi, G., Rizzardini, G., Santoro, D., Pagano, A. et al. (1989). Third generation cephalosporins as a risk factor for Clostridium difficile-associated disease: a four-year survey in a general hospital. Journal of Antimicrobial Chemotherapy 23, 62331.[Abstract]
2 . Anand, A., Bashey, B., Mir, T. & Glatt, A. E. (1994). Epidemiology, clinical manifestations, and outcome of Clostridium difficile diarrhoea. American Journal of Gastroenterology 89, 51923.[ISI][Medline]
3 . Settle, C. D., Wilcox, M. H., Fawley, W. N., Corrado, O. J. & Hawkey, P. M. (1998). Prospective study of the risk of Clostridium difficile diarrhoea in elderly patients following treatment with cefotaxime or piperacillintazobactam. Alimentary Pharmacology and Therapeutics 12, 121723.[ISI][Medline]
4 . Nord, C. E., Brismar, B., Kasholm-Tengve, B. & Tunevall, G. (1993). Effect of piperacillintazobactam treatment on human bowel microflora. Journal of Antimicrobial Chemotherapy 31, Suppl. A, 615.
5 . Gorbach, S. L., Barza, M., Giuliano, M. & Jacobus, N. V. (1988). Colonization resistance of the human intestinal microflora: testing the hypothesis in normal volunteers. European Journal of Clinical Microbiology and Infectious Diseases 1, 98102.
6 . Sorgel, F. & Kinzig, M. (1993). The chemistry, pharmacokinetics and tissue distribution of piperacillin/tazobactam. Journal of Antimicrobial Chemotherapy 23, Suppl. A, 3960.