Increase in the rate of nosocomial Clostridium difficile-associated diarrhoea during shortages of piperacillin–tazobactam and piperacillin

W. Kemper Alston1,* and John W. Ahern2

1 Infectious Diseases Unit, Department of Medicine, University of Vermont College of Medicine, Burlington, VT; 2 Pharmacotherapy Department, Fletcher Allen Health Care, Burlington, VT, USA

Keywords: colitis, antibiotics, formulary

Sir,

Shortages of antibiotics have become frequent occurrences in the USA. During recent years, hospitals have experienced problems obtaining a wide variety of antimicrobials and vaccines.1 While the potential impact on the management of infectious diseases is apparent, adverse clinical outcomes associated with antibiotic shortages have not been reported. This may be in part because the redundancy of the modern antimicrobial formulary typically allows substitution when treating individual patients. Whether the alterations in prescribing practices created by these shortages have had more subtle effects remains to be seen.

Antibiotic exposure is the most important risk factor for Clostridium difficile-associated diarrhoea (CDAD).2 Changes in antibiotic utilization created by restriction policies and the intentional manipulation of formularies have been associated with both the occurrence and control of CDAD outbreaks.35

During 2002, our hospital experienced an outbreak of CDAD simultaneously with a shortage of piperacillin–tazobactam and the commercial unavailability of piperacillin. When the supply of piperacillin–tazobactam improved and usage returned to baseline, the rates of CDAD fell. We hypothesize that this unintentional change in our formulary, and the impact it had on antibiotic utilization, was a significant factor in this outbreak.

Fletcher Allen Health Care (FAHC) is an academic medical centre that serves as the teaching hospital for the University of Vermont College of Medicine (Burlington, VT, USA). During 2002 there was an average daily inpatient census of 369 patients. There were three infection-control practitioners, and an active antibiotic control programme managed by one of four infectious disease specialists and an infectious disease pharmacist. Piperacillin became unavailable in January 2002. A shortage of piperacillin–tazobactam began in March, and the supply was exhausted by June 2002 (Figure 1a). The utilization of antibiotics changed during this shortage. In particular, the use of ceftriaxone and cefotetan was at the highest ever for this hospital (Figure 1b).



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Figure 1. (a) Increase in the rate of CDAD (circles) coincident with shortages of piperacillin–tazobactam (white bars) and piperacillin (black bars). (b) Utilization of ceftriaxone (white bars) and cefotetan (black bars) in relation to the rate of CDAD (circles). (c) Utilization of clindamycin (black bars) and metronidazole (white bars) in relation to the rate of CDAD (circles). (d) Utilization of ampicillin–sulbactam (black bars) and levofloxacin (white bars) in relation to the rate of CDAD (circles).

 
Between January 2000 and March 2002, the rate of nosocomial CDAD (defined as a positive toxin assay beyond day 2 of hospitalization) at FAHC averaged 92 cases per 100 000 patient-days. For the period April to June 2002 there was an abrupt increase to 211 cases per 100 000 patient days (P < 0.001, Poisson distribution; Figure 1a). There were no changes in isolation policies, hand hygiene products, diagnostic testing methodology or algorithms, or surveillance protocols that could explain this increase. Genotype analysis was not performed because the diagnoses were based on toxin assays. No other increases in specific bacterial infections were recognized. In response, additional infection control education was provided to staff. Ampicillin–sulbactam was added to the hospital formulary. An educational memo was sent to house officers encouraging the use of levofloxacin over ceftriaxone for community-acquired pneumonia, ampicillin–sulbactam over cefotetan for intra-abdominal infection, and metronidazole instead of clindamycin for anaerobic infections, where appropriate. As a result, the usage of ceftriaxone, cefotetan and clindamycin declined, while the prescribing of levofloxacin, metronidazole and ampicillin–sulbactam increased (Figure 1). The rate of CDAD gradually fell over the next 12 months, during which time the piperacillin–tazobactam shortage resolved.

We believe that the shortage of piperacillin–tazobactam and piperacillin during 2002, and the changes in antibiotic utilization it triggered, was a significant factor in this CDAD outbreak. It is possible that the alternative antibiotics used during the shortage are associated with higher rates of CDAD. There are published reports describing a low risk of CDAD with piperacillin–tazobactam and ticarcillin–clavulanate.5,6 Although the apparent temporal relationship between these two events does not establish causation, and may be attributable to coincidence, we feel that the data presented are compelling evidence that antibiotic shortages had an important impact on the rate of CDAD in our hospital.

Footnotes

* Correspondence address. Infectious Diseases Unit, Burgess 302, MCHV Campus, Fletcher Allen Health Care, 111 Colchester Avenue, Burlington, VT 05401, USA. Tel: +1-802-847-4835; Fax: +1-802-847-5322; E-mail: wallace.alston{at}vtmednet.org Back

References

1 . Strausbaugh, L. J., Jernigan, D. B., Liedtke, L. A. et al. (2001). National shortages of antimicrobial agents: results of 2 surveys from the Infectious Diseases Society of America Emerging Infections Network. Clinical Infectious Diseases 33, 1495–501.[CrossRef][ISI][Medline]

2 . Gerding, D. N., Johnson, S., Peterson, L. R. et al. (1995). Clostridium difficile-associated diarrhea and colitis. Infection Control and Hospital Epidemiology 16, 459–77.[ISI][Medline]

3 . Ho, M., Yang, D., Wyle, F. A. et al. (1996). Increased incidence of Clostridium difficile-associated diarrhea following decreased restriction of antibiotic use. Clinical Infectious Diseases 23, Suppl. 1, S102–6.[ISI][Medline]

4 . McNulty, C., Logan, M., Donald, I. P. et al. (1997). Successful control of Clostridium difficile infection in an elderly care unit through use of a restrictive antibiotic policy. Journal of Antimicrobial Chemotherapy 40, 707–11.[Abstract]

5 . Settle, C. D., Wilcox, M. H., Fawley, W. N. et al. (1998). Prospective study of the risk of Clostridium difficile diarrhoea in elderly patients following treatment with cefotaxime or piperacillin–tazobactam. Alimentary Pharmacology and Therapeutics 12, 1217–23.[CrossRef][ISI][Medline]

6 . Anand, A., Bashey, B., Mir, T. et al. (1994). Epidemiology, clinical manifestations, and outcome of Clostridium difficile-associated diarrhea. American Journal of Gastroenterology 89, 519–23.[ISI][Medline]