a Departments of General Internal Medicine, b Clinical Pharmacy and d Medical Microbiology, University Medical Center, Nijmegen, The Netherlands; c Pharmacy Department, Eemland Hospital, Amersfoort, The Netherlands
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Abstract |
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Introduction |
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Materials and methods |
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Assessment of therapy
Each course of fluconazole treatment was assessed by B. J. K. (infectious diseases specialist) and S. N. (pharmacist) on the basis of current guidelines employed in the hospitals and national and international recommendations. Recently published comprehensive guidelines were in press at the time of the evaluation,13,14 but there was agreement among experts on principles of antifungal treatment and several recommendations and reviews on the subject had been published in The Netherlands.9,15,16 Table I is a compilation of these and represents the guidelines applied to this evaluation.
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Laboratory investigations
Blood (at least 15 mL) was cultured aerobically using the Bactec 9240 (Becton-Dickinson, Woerden, The Netherlands) in hospital A and the BacT/Alert (Organon Teknika, Boxtel, The Netherlands) automated system in hospital B. In hospital A, Candida isolates were processed in the local specialist mycology laboratory. In hospital B, they were processed in the general microbiology laboratory.
Candida albicans was identified by germ tube and chlamydospore formation. Suspected Candida dubliniensis or germ tube negative isolates were further identified with the Auxacolor commercial yeast identification system (Bio-Rad, Marnes-La-Coquette, France). Yeast susceptibility testing was performed by broth dilution according to the NCCLS.18 Interpretative breakpoints for fluconazole were applied as proposed by Rex et al.19
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Results |
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On average, higher dosages were prescribed in hospital A compared with hospital B (Figure 1). The evaluation revealed least agreement with the dosage in cases of oesophageal candidosis, because of rather low dosages prescribed in both hospitals, contravening the guidelines. In hospital B in particular, prescribed dosages for all indications often tended to be lower than those recommended.
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Patients who died during treatment, or who were switched to another antifungal treatment, were excluded from the evaluation of duration of treatment (Figure 2). The mean duration of treatment for oesophageal candidosis and disseminated infection was considerably longer in hospital A than in hospital B (P = 0.03 and P = 0.006, respectively). The reviewers agreed with the duration of treatment in only 4050% of cases of oesophageal candidosis, mainly because the prescribed courses of treatment were considered to be too short. Also, for disseminated infections, duration of treatment was considered too short in 60% of cases in hospital B.
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Culture results were available in 75% of the cases. In 84 and 87% of these cases from hospitals A and B, respectively, the isolate was identified. In hospital A, C. albicans was found in 73% of the cases and Candida glabrata in 17%. In hospital B, C. albicans was isolated in 87% and C. glabrata in only 8% (Table II).
Susceptibility to antifungal agents was determined for 18 Candida isolates in hospital A and six isolates in hospital B. All isolates of C. albicans tested were susceptible to fluconazole (MIC 4 mg/L). Four of the 15 isolates of C. glabrata were resistant (MIC
64 mg/L), one isolate was susceptible dose dependent (MIC 16 mg/L), six were susceptible (MIC
8 mg/L) and for four isolates, susceptibility was not determined. In three patients with resistant C. glabrata isolates, treatment was changed to itraconazole after obtaining the in vitro susceptibility results, and in one patient, the dose of fluconazole was increased to 800 mg/day. The patient with the susceptible dose-dependent isolate first received higher doses of fluconazole and was later switched to amphotericin B. Of the four patients in whom the susceptibility of the isolate was not known, one was switched to itraconazole, one suffered from a urinary tract infection, which was successfully treated with a single dose of 400 mg fluconazole and two died as a result of other medical complications of their underlying disease within 2 and 40 days, respectively, after initiation of fluconazole treatment.
Superficial infections
The reviewers disagreed with the indication in 40% of the cases of presumed superficial candidosis in both hospitals. Reasons for disagreement were lack of culture results after failure of another antifungal treatment, or negative culture results. Seventeen patients in hospital A and six patients in hospital B had received prior antifungal therapy. Agreement with the prescribed dosage was 82% in hospital A and 56% in hospital B. In hospital A, disagreement was due to the administration of higher than recommended dosages, while in hospital B the prescribed dosages were too low. There was agreement with the duration of treatment for 82% of cases in both hospitals.
Oesophageal candidosis
Endoscopy was performed in 61% of patients with oesophageal candidosis in both hospitals. In hospital A, culture samples were taken in 75% of these, while in hospital B this was the case in only one patient.
There was agreement with the indication to use fluconazole in 77% of the cases of oesophageal candidosis in both hospitals. Agreement with dosage was 62% in hospital A but only 39% in hospital B, largely because of low prescribed dosages. Also, the duration of treatment was judged too short in 46% of cases in hospital A and 61% in hospital B.
Disseminated infections
Of the 28 patients with disseminated candidosis in hospital A, 15 had positive blood cultures and 13 had negative blood cultures but were presumed to have disseminated infection on the basis of positive cultures from multiple, normally sterile, sites. Treatment of all cases with positive blood cultures was judged adequate, whereas of the cases with negative blood cultures, only six treatments were judged as definitely justified and three as probably justified. In the remaining four cases the indication was not justified, as the culture results were felt to reflect colonization rather than disseminated infection. The prescribed dosage was adequate in those cases in which the indication was thought to be justified, but inadequate if there was disagreement with the indication, in which cases the dose was judged too low for presumed systemic infection.
Of the 21 patients diagnosed with disseminated infections in hospital B, only two had positive blood cultures. Four patients had positive cultures of the catheter tip and the insertion site, and were presumed to have a catheter-related infection. Treatment of all of these six cases was considered justified. In 15 patients, presumed disseminated candidosis was diagnosed because of several positive culture results from other specimens. Treatment of seven of these cases was judged appropriate since positive cultures had been obtained from normally sterile sites and the clinical course was compatible with disseminated candidosis.13,20 In the remaining eight cases, the diagnosis of disseminated candidosis was considered inappropriate, since positive cultures were obtained from colonized surfaces only (e.g. bronchus or skin wound), without further clinical signs of invasive infection. Follow-up blood cultures during antifungal therapy were not performed routinely in either hospital.
Deep localized infections
In hospital A, the indication for treatment was considered appropriate in 93% of the cases of deep localized infection, dosage was adequate in 80% and the duration of treatment was adequate in 87% of the cases. In hospital B, the expert reviewers agreed with the indication in only 42% of the cases, mainly because of disagreement with the diagnosis pneumonia, which had been made on the basis of positive tracheal aspirates or sputum cultures without further signs of invasive infection. Dosage was considered adequate in 83% of the cases, but the duration of treatment was appropriate in only 50% of the cases.
Prophylaxis
Prophylactic use of fluconazole outside standard protocols accounted for only 11% of the indications in hospital A and 6% in hospital B. In these cases, the reviewers agreed with the prophylaxis in 100 and 80% of the cases in hospitals A and B, respectively.
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Discussion |
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In the non-university hospital (hospital B), the dosage and duration of treatment needs to be addressed. Especially for the treatment of oesophageal and disseminated candidosis, low dosages were prescribed for a rather short duration, which does not follow the current treatment guidelines.13
Another point of concern is the use of fluconazole in cases of colonization rather than true infection. This is the case in the patients diagnosed as suffering from Candida pneumonia, which is based solely on isolation of Candida from bronchial secretions.21 Also, in the case of presumed disseminated infections, diagnosis was based on positive cultures from sites indicative of colonization, leading to disagreement with the indication in this situation.
The study was performed in two different hospitals, a university and a non-university hospital. The most important differences detected were the lower dosages and the shorter duration of treatment prescribed in the non-university hospital. Another interesting difference was the lower prevalence of disseminated infections with positive blood cultures in the non-university hospital, which was probably due to a patient population that was less severely ill or the fact that blood cultures were less likely to be taken in this setting. Finally, the use of fluconazole in cases of colonization was more prevalent in the non-university hospital, as was reflected by the observation that Candida pneumonia was diagnosed six times during our study, whereas none of these diagnoses could be substantiated.
There are very few data in the literature to compare with the current study. An audit on antifungal drugs by Gutierrez et al.22 revealed that 58% of the regimens in their study were compliant with a predefined standard. Fluconazole was the drug most often used for non-approved indications, mostly for superficial infection in non-neutropenic patients. In only 20 of the 74 patients studied were microbiological results known.
Overall, in our drug use evaluation study, we could not detect major inappropriate use of fluconazole. However, it did highlight important issues, and areas for improvement could be identified. Discussion of these issues with the hospital staff and refinement of local guidelines should result in improved use. Direct feedback of the results of a comprehensive audit of prescribing habits is one of the most successful means of influencing physicians' performance, especially when feedback is supported by a chart review, as we did in our study.23,24
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Acknowledgments |
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Notes |
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Present address. Department of Medical Microbiology and Regional Laboratory for Public Health, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
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References |
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Received 30 August 2000; returned 18 December 2000; revised 5 February 2001; accepted 19 March 2001