Departments of 1 Microbiology and 2 Elderly Medicine, Leeds Teaching Hospitals & University of Leeds, Old Medical School, Leeds LS1 3EX, UK
Received 15 March 2004; returned 10 April 2004; revised 16 April 2004; accepted 18 April 2004
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Abstract |
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Patients and methods: In 1999, piperacillintazobactam was added to the formulary in Elderly Medicine and its use promoted in preference to cefotaxime. Following review and feedback to clinicians of surveillance data, cefotaxime prescribing was actively restricted during 20002001. An audit of prescriber adherence to antibiotic policy was carried out by reviewing the records of 159 patients during FebruaryApril 2001. In December 2001, due to manufacturer production problems, supply of piperacillintazobactam was stopped. We performed standardized period prevalence surveillance (FebruaryApril) allowing comparisons of antibiotic utilization and CDD incidence during the 5 year study period (19982002).
Results: CDD incidence did not change significantly (P>0.1) during 19981999 despite a marked increase in piperacillintazobactam prescribing. However, when cefotaxime prescribing was curtailed in 2001, CDD rates decreased (in four of five wards) and overall by 52% (P=0.008). When piperacillintazobactam became unavailable in 2002, despite advice to the contrary cefotaxime prescribing rose five-fold, and CDD rates increased in four of five wards and by 232% (P<0.01) overall. Adherence to antibiotic policy introduced in 2000 was good (81% accordance); 94%, 88% and 73% of patients with cellulitis, urinary tract and respiratory tract infection, respectively, received appropriate antibiotics.
Conclusions: Long-term prescribing of piperacillintazobactam in Elderly Medicine in preference to cefotaxime is associated with reduced rates of CDD. However, unless cephalosporin prescribing is curtailed, the beneficial effects on CDD rates may be missed. This is one of few studies to document adverse effects due to loss of antibiotic supply.
Keywords: antibiotics , adverse events , elderly
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Introduction |
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Conversely, ureidopenicillins (with or without ß-lactamase inhibitors) appear to have low propensity to induce CDD.6,8,9 We previously compared in a prospective study the effects of empirical treatment of elderly inpatients with cefotaxime or piperacillintazobactam on C. difficile colonization and diarrhoea.9 We found a highly significant increased incidence of C. difficile colonization (26/34 versus 3/14, P=0.001) and diarrhoea (18/34 versus 1/14, P=0.006) in patients who received cefotaxime as opposed to piperacillintazobactam. In view of these findings, in 1999 we added piperacillintazobactam to the formulary in Elderly Medicine and promoted its use in preference to cefotaxime. The purpose of this study was to follow the effects of the new policy, of subsequent audit and reinforcements, and latterly to determine the effects of the loss of supply of piperacillintazobactam from the manufacturer on the long-term epidemiology of CDD in a large Elderly Medicine Unit.
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Methods |
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The Elderly Medicine Unit at the General Infirmary, Leeds (a university teaching hospital) consists of five wards. The wards have a similar design and layout each having five four-bedded bays with two to four beds in isolation rooms. We carried out retrospective surveillance of antibiotic usage and CDD incidence for the period September 1997October 1999 by interrogation of Microbiology, Infection Control and Pharmacy databases. Subsequently, we performed standardized period prevalence surveillance of antibiotic usage and CDD incidence for the same 3 months (FebruaryApril) in each of the years 20002002. Comparisons of antibiotic usage and CDD incidence during the study period 19982002 were confined to these same 3 months of each year.
CDD incidence
CDD cases were defined as Elderly Medicine inpatients with diarrhoeal stools. The faeces were cytotoxin positive without other obvious cause for their symptoms. Cytotoxin was detected by specific neutralization of cytopathic effects on Vero cell monolayers using C. difficile antitoxin. Hospital policy for the submission of faecal samples did not change during the study period. The routine laboratory specimen selection policy throughout the study period was to test diarrhoeal samples from inpatients only if C. difficile detection was requested. Patient admission data for each ward were used to calculate the number of CDD cases per 100 patients. The 2 test was used to determine the significance of observed changes in incidence of CDD.
Antibiotic utilization
Antibiotic utilization on the study wards was determined by review of the Pharmacy database and was expressed as defined daily doses (DDDs) per month. The following DDDs were used to standardize the measurement of antibiotic usage: amoxicillin (1.5 g), ampicillin (2 g), cefotaxime (2 g), cefradine (2 g), ciprofloxacin [1 g by mouth, 800 mg intravenously (iv)], clarithromycin (500 mg by mouth, 1 g twice daily), erythromycin (2 g), and piperacillintazobactam (13.5 g).
Interventions
In 1999 we added piperacillintazobactam to the formulary in Elderly Medicine and promoted its use in preference to cefotaxime via educational meetings with physicians in training, consultant physicians, pharmacists and clinical microbiologists. At this time we did not formally restrict cefotaxime usage. Following review and feedback to clinicians of surveillance antimicrobial usage and CDD data, cefotaxime prescribing was actively restricted during 20002001 by its removal as a ward stock drug on the Elderly Medicine Unit. Written guidance was also issued to all prescribers including personal copies of the antimicrobial policy in the Elderly Medicine Unit. The policy stated that piperacillintazobactam was the drug of choice for cases of severe community-acquired or hospital-acquired pneumonia, or severe sepsis of unknown origin; cefotaxime was only indicated for suspected or proven cases of meningitis.
An audit of prescriber adherence to the antibiotic policy was carried out by reviewing the medical records of 159 patients admitted to the Elderly Medicine Unit during 1 February 200130 April 2001. These 159 cases were selected from a total of 769 consecutive admissions firstly on the basis of having received antibiotics during their inpatient stay, and secondly if the medical notes were available during the data collection period. The following data were recorded: patient age and sex; ward on which treatment was administered; reason for antibiotic prescription; choice of antibiotics, antibiotic dosages and routes of administration; and whether modifications were made to the antibiotic regimens. The results were fed back to clinicians.
In December 2001, Leeds General Infirmary was informed by the manufacturer (Wyeth Pharmaceuticals, Berks, UK) that, due to production problems supplies of piperacillintazobactam would be insufficient to meet the needs of the hospital. The manufacturer also withdrew piperacillin at this time. A decision was taken to conserve the limited supply of piperacillintazobactam for neutropenic patients with suspected sepsis on the Haematology Unit. At this time written guidance was therefore provided to prescribers on the Elderly Medicine Unit to use iv ciprofloxacin instead of piperacillintazobactam. Other aspects of the antimicrobial policy did not change.
Results
There was a marked increase in piperacillintazobactam prescribing (0200 DDDs per month) following its introduction into the formulary. At this time we did not remove cefotaxime as a ward stock antibiotic, and thus cefotaxime usage remained essentially unchanged (6266 DDDs per month). Usage of other antibiotics did not change markedly during this period (data not shown). CDD incidence did not change significantly (4.53.4 cases per 100 admissions, P > 0.1) comparing the same 3 months (FebruaryApril) of 1998 (pre-policy change) and 1999.
During 20002001, cefotaxime prescribing was actively restricted by its removal as a ward stock drug on the Elderly Medicine Unit. Written guidance was also issued to prescribers, included in the antimicrobial policy of the Elderly Medicine Unit. Cefotaxime usage decreased markedly in 2001 (by 83% compared with the same period in 2000) and piperacillintazobactam usage almost doubled (94% increase). Amoxicillin usage increased markedly in percentage terms (310%) but overall consumption in terms of DDDs per month (16) relative to piperacillintazobactam (199) and ciprofloxacin (220) was still modest. CDD rates decreased in four of five wards and overall by 52% (4.62.2 cases per 100 admissions, P=0.008) (Figure 1).
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In December 2001, following a shortage of piperacillintazobactam, there was a modest increase in ciprofloxacin usage (15%) compared with the same period in 2001. Despite recommendations to the contrary, cefotaxime prescribing increased markedly by 370% during 2002. CDD rates increased in four of five wards and by 232% overall (2.2 to 5.1 cases per 100 admissions, P < 0.01) (Figure 2). Figure 3 summarizes the piperacillintazobactam and cefotaxime prescribing rates and the corresponding CDD rates during the 5 year surveillance period.
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Discussion |
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We carried out policy reinforcement to prescribe piperacillintazobactam when broad spectrum therapy was required, together with active restriction of cefotaxime. We found that subsequent removal of cefotaxime as a ward stock drug was associated with a significant reduction in CDD incidence, and this was notably achieved on four of the five Elderly Medicine wards. Unfortunately, however, CDD rates increased again when piperacillintazobactam became unavailable because of manufacturing difficulties and thus, despite advice to the contrary, cefotaxime prescribing increased. Starr et al.15 speculated that selective pressure due to cephalosporin prescribing may increase the proportion of C. difficile-susceptible patients in a ward. In this setting, administration of narrow-spectrum antibiotics with otherwise relatively low propensities to select for C. difficile may subsequently induce symptomatic infection. In our Elderly Medicine unit, continued cefotaxime prescribing may have acted to maintain a relatively high proportion of CDD-susceptible patients. Guidelines for the treatment of community-acquired pneumonia, a common cause of hospital admission in the elderly, cite cephalosporins, including cefotaxime, as antibiotics of choice for severe as opposed to mildmoderate infections. Such guidelines have been implicated in the increased incidence of CDD.16 Misinterpretation of guidelines, in particular, defensive prescribing of broad spectrum antibiotics to patients in case of severe infection may increase the risk of CDD.17
We acknowledge that the prolonged surveillance period in the present study identified multiple fluctuations in antimicrobial prescribing and therefore it is not possible to ascribe cause and effect relationships between specific changes in antibiotic usage and CDD incidence. However, the consistency of effect that we observed associating increased ureidopenicillin and decreased cefotaxime usage with reductions in CDD rates is persuasive. It is extremely difficult to obtain robust data on the risk of the development of CDD associated with specific antibiotics.18 It is important to be certain that patients given the antibiotics under comparison had the same risk of acquiring C. difficile (or had the same likelihood of being colonized by the bacterium before receiving antibiotic treatment). Some parts of the hospital (for example geriatric units) will have a higher prevalence of environmental contamination, and some antibiotics may be more commonly prescribed in such settings. These issues are addressed within the present study. Furthermore, we have shown that some Elderly Medicine wards of similar design and patient mix have markedly different CDD incidences, for reasons that remain unknown.19,20 Many patients are exposed to multiple antibiotics, and indeed frequently receive combinations of antimicrobial agents. Also, duration of risk of CDD development after antibiotic exposure has not been clearly defined. While we cannot exclude a possible influence of polypharmacy or antibiotic duration, our longitudinal use of a fixed 3 month annual surveillance period, the same target clinical areas and antimicrobial prescribing expressed as DDDs minimize these likelihoods.
Our findings are also consistent with data from several other sources indicating that anti-pseudomonal penicillins such as piperacillin and ticarcillin have a low risk of inducing CDD.6,8,9 For example, Anand et al.8 observed 51 cases of CDD associated with the administration of 40 000 doses of third-generation cephalosporins; 21 000 doses of second-generation cephalosporins and 18 000 doses of first-generation cephalosporins were given, leading to 10 and five cases of CDD, respectively. By contrast, 62 000 doses of ticarcillinclavulanate were given but no cases of CDD were seen (P=0.0001). The reasons why anti-pseudomonal penicillins appear rarely to promote CDD compared with cephalosporins have not been clearly defined. Piperacillintazobactam is active against C. difficile, whereas most strains are relatively resistant to cefotaxime.21 Also, we have shown that piperacillin and tazobactam dissociate after administration, resulting in variable concentrations in human faeces and thus theoretically less disruption of bowel flora responsible for colonization resistance.22 Furthermore, recent data show that exposure of C. difficile to cefotaxime (and its active metabolite desacetylcefotaxime) in a human gut model results in marked production of toxin associated with germination.23 These effects were not seen with piperacillintazobactam.24
Antibiotic supply problems are not uncommon,25,26 but we believe that this is one of the first reports of specific adverse effects from such supply problems. It is notable also that a recent US report highlighted a similar relationship between piperacillintazobactam availability and CDD rates to that seen in the present study.27 However, in the former institution there was clearly an increasing incidence of CDD before antibiotic supply problems began. Infectious Diseases Society of America surveys of its members found that almost 90% had encountered shortages of one or more antimicrobial agents in 1999.25 Penicillin G (77%), meropenem (38%), ticarcillin with or without clavulanate (24%), cefazolin (20%), gentamicin (50%) and nafcillinoxacillin (13%) were the most commonly affected antibiotics. Whereas respondents believed that antibiotic shortages had affected thousands of patients, specific data were unavailable. Harbarth and colleagues26 carried out a 6 year retrospective study to examine the effecton antibiotic prescribing practice in a US hospitalof a recent shortage of penicillin G. Ampicillin replaced penicillin G in obstetrics for intrapartum prophylaxis of group B streptococcal disease, and a shift to broad-spectrum agents was noted in other patients considered potentially eligible for penicillin G treatment.
CDD is expensive in terms of health resource utilization. During 19931996, the proportion of UK hospitals that had ward closures due to CDD increased from 5%16%.28 In a UK case-control study, estimated costs (in 1996) attributable to CDD were £4000 per case, 94% of which was due to an average 3 weeks per patient increased duration of hospital stay.29 It has recently been estimated that CDD accounts each year for >$1.1 billion in healthcare costs in the USA.30 The acquisition cost of piperacillintazobactam is relatively high compared with some other broad spectrum antibiotics, including cefotaxime. However, in a prospective study we calculated that the additional acquisition cost of piperacillintazobactam compared with cefotaxime was equivalent to
10% of the savings accrued from prevented CDD cases.9 It is therefore plausible that prescribing piperacillintazobactam in Elderly Medicine is cost effective. These considerations, of course, ignore the potential to avoid morbidity and the mortality associated with CDD particularly in the elderly.29,30
In conclusion, use of piperacillintazobactam in Elderly Medicine in preference to cefotaxime is associated with reduced rates of CDD. However, unless cefotaxime (cephalosporin) prescribing is curtailed, the beneficial effects on CDD rates may be missed. Such observations are likely to be due to the propensity of cefotaxime to induce CDD in both individual cases and patient populations.
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Footnotes |
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References |
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2 . Borriello, S. P. (1998). Pathogenesis of Clostridium difficile infection. Journal of Antimicrobial Chemotherapy 41, 139.[Abstract]
3 . Freeman, J. & Wilcox, M. H. (1999). Antibiotics and Clostridium difficile. Microbes and Infection 1, 37784.[CrossRef][ISI][Medline]
4 . Aronsson, B., Möllby, R. & Nord, C.-E. (1985). Antimicrobial agents and Clostridium difficile in acute enteric disease: epidemiological data from Sweden 1980-1982. Journal of Infectious Diseases 151, 47681.[ISI][Medline]
5 . Golledge, C. L., McKenzie, T. & Riley, T. V. (1989). Extended spectrum cephalosporins and Clostridium difficile. Journal of Antimicrobial Chemotherapy 23, 92931.[Abstract]
6 . de Lalla, F., Privitera, G., Ortisi, G. 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]
7
.
Wistrom, J., Norrby, S. R., Myhre, E. B. et al. (2001). Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study. Journal of Antimicrobial Chemotherapy 47, 4350.
8 . Anand, A., Bashey, B., Mir, T. et al. (1994). Epidemiology, clinical manifestations, and outcome of Clostridium difficile diarrhoea. American Journal of Gastroenterology 89, 51923.[ISI][Medline]
9 . 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 piperacillintazobactam. Alimentary Pharmacology and Therapeutics 12, 121723.[CrossRef][ISI][Medline]
10 . Samore, M. H., Venkataraman, L., DeGirolami, P. C. et al. (1996). Clinical and molecular epidemiology of sporadic and clustered cases of nosocomial Clostridium difficile diarrhea. American Journal of Medicine 100, 3240.[ISI][Medline]
11 . Lai, K. K., Melvin, Z. S., Menard, M. J. et al. (1997). Clostridium difficile associated diarrhea: epidemiology, risk factors, and infection control. Infection Control Hospital Epidemiology 18, 62832.[ISI]
12
.
Alfa, M. J., Du, T. & Beda, G. (1998). Survey of incidence of Clostridium difficile infection in Canadian hospitals and diagnostic approaches. Journal of Clinical Microbiology 36, 207680.
13 . Karlstrom, O., Fryklund, B., Tullus, K. et al. (1998). A prospective nationwide study of Clostridium difficile-associated diarrhea in Sweden. The Swedish C. difficile Study Group. Clinical Infectious Diseases 26, 1415.[ISI][Medline]
14
.
Stone, S., Kibbler, C., How, A. et al. (2000). Feedback is necessary in strategies to reduce hospital acquired infection. British Medical Journal 321, 3023.
15 . Starr, J. M., Rogers, T. R. & Impallomeni, M. (1997). Hospital-acquired Clostridium difficile diarrhoea and herd immunity. Lancet 349, 4268.[CrossRef][ISI][Medline]
16
.
Impallomeni, M., Galletly, N. P., Wort, S. J. et al. (1995). Increased risk of diarrhoea caused by C. difficile in elderly patients receiving cefotaxime. British Medical Journal 311, 13456.
17
.
Wilcox, M. H. (2000). Respiratory antibiotic use and Clostridium difficile infectionis it the drugs or is it the doctors. Thorax 55, 6334.
18
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Wilcox, M. H. (2001). Clarithromycin and risk of Clostridium difficile-associated diarrhoea. Journal of Antimicrobial Chemotherapy 47, 3589.
19 . Fawley, W. N. & Wilcox, M. H. (2001). Molecular epidemiology of endemic Clostridium difficile infection. Epidemiology and Infection 126, 34350.[CrossRef][ISI][Medline]
20 . Wilcox, M. H., Fawley, W. N., Wigglesworth, N. et al. (2003). Comparison of the effect of detergent versus hypochlorite cleaning on environmental contamination and incidence of Clostridium difficile infection. Journal of Hospital Infection 54, 10914.[CrossRef][ISI][Medline]
21
.
Freeman, J. & Wilcox, M. H. (2001). Antibiotic activity against genotypically distinct and indistinguishable Clostridium difficile isolates. Journal of Antimicrobial Chemotherapy 47, 2446.
22
.
Wilcox, M. H., Brown, A. & Freeman, J. (2001). Faecal concentrations of piperacillin and tazobactam in elderly patients. Journal of Antimicrobial Chemotherapy 48, 1556.
23
.
Freeman, J., O'Neill, F. J. & Wilcox, M. H. (2003). Effects of cefotaxime and desacetylcefotaxime upon Clostridium difficile proliferation and toxin production in a triple-stage chemostat model of the human gut. Journal of Antimicrobial Chemotherapy 52, 96102.
24 . Wilcox, M. H., Baines, S., Freeman, J. et al. (2003). Piperacillintazobactam does not induce Clostridium difficile toxin production in a human gut model. Programs and Abstracts of the Forty-third Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2003. Abstract K728. American Society for Microbiology, Washington, DC, USA.
25 . Strausbaugh, L. J., Jernigan, D. B. & Liedtke, L. A. (2001). National shortages of antimicrobial agents: results of 2 surveys from the IDSA Emerging Infections Network. Clinical Infectious Diseases 33, 1495501.[CrossRef][ISI][Medline]
26 . Harbarth, S., Gundlapalli, A. V., Stockdale, W. et al. (2003). Shortage of penicillin G: impact on antibiotic prescribing at a US tertiary care centre. International Journal of Antimicrobial Agents 21, 4847.[CrossRef][ISI][Medline]
27
.
Alston, W. K. & Ahern, J. A. (2004). Increase in the rate of nosocomial Clostridium difficile-associated diarrhoea during shortages of piperacillintazobactam and piperacillin. Journal of Antimicrobial Chemotherapy 53, 54950.
28 . Wilcox, M. H. & Smyth, E. T. (1998). Incidence and impact of Clostridium difficile infection in the UK, 1993-1996. Journal of Hospital Infection 39, 1817.[ISI][Medline]
29 . Wilcox, M. H., Cunnliffe, J. G., Trundle, C. et al. (1996). Financial burden of hospital-acquired Clostridium difficile infection. Journal of Hospital Infection 34, 2330.[ISI][Medline]
30 . Kyne, L., Hamel, M. B., Polavaram, R. et al. (2002). Health care costs and mortality associated with nosocomial diarrhoea due to Clostridium difficile. Clinical Infectious Diseases 34, 34653.[CrossRef][ISI][Medline]