ORIGINAL PAPER

Antifungal step-down therapy based on hospital intravenous to oral switch policy and susceptibility testing in adult patients with candidaemia: a single centre experience
A. M. Bal,1 G. S. Shankland,2 G. Scott,3 T. Imtiaz,4 R. Macaulay,1 M. McGill1

Department of Microbiology, University Hospital Crosshouse, Kilmarnock, UK 2 Clinical Mycology Reference Laboratory, Southern General Hospital, Glasgow, UK 3 General Medicine, University Hospital Crosshouse, Kilmarnock, UK 4 Renal Medicine, University Hospital Crosshouse, Kilmarnock, UK Correspondence to: Dr Abhijit M. Bal, MBBS, MD, DNB, MNAMS, FRCP, FRCPath, Dip Med Mycol, Consultant & Honorary Senior Clinical Lecturer, Department of Microbiology, University Hospital Crosshouse, Kilmarnock KA2 0BE, UK Tel.: +44 1563 827 422 Fax: +44 1563 825 000 Email: abhijit.bal@nhs.net

SUMMARY Aims: Echinocandins are recommended for the treatment of candidaemia in moderately severe to severely ill patients. Step-down or de-escalation from echinocandin to uconazole is advised in patients who are clinically stable but data in relation to step-down therapy are sparse. Using our hospital intravenous to oral switch therapy (IVOST) policy to guide antifungal de-escalation in patients with candidaemia, we aimed to determine what proportion of patients are de-escalated to uconazole, the timescale to step-down, associated reduction in consumption of echinocandins and antifungal cost savings. Methodology: Patients with candidaemia were followed from April 2011 to March 2013. Results: A total of 37 episodes of candidaemia were documented during the study period. Twenty-seven patients were commenced on an echinocandin or voriconazole and 19 (70.3%) were de-escalated to uconazole based on the IVOST policy. The mean and median number of days to de-escalation of therapy was 4.6 and 5 days, respectively. One patient whose therapy was de-escalated relapsed. The overall 30 day crude mortality was 37.1%. The step-down approach led to signicant saving in antifungal drug cost of 1133.88 per candidaemic episode and 2208.08 per de-escalation. Conclusion: Implementation of IVOST policy led to streamlining of antifungal therapy.

Whats known
Antifungal step-down is advised by several international guidelines including the Infectious Diseases Society of America (IDSA) and the recent European Society for Clinical Microbiology and Infectious Diseases (ESCMID) guidance. In absence of any data, the timing of step-down is recommended between days 35 by the IDSA or day 10 by the ESCMID.

Whats new
Based on our hospital IVOST policy, we provide data in relation to the proportion of patients that were amenable for antifungal step-down and also the timing of step-down in these patients. Our nding suggests that step-down therapy can be considered by day ve in a vast majority of patients. This strategy may prevent emergence of echinocandin resistance and reduce cost.

Introduction
Disclosures AMB has lectured for Astellas and Pzer and has been on the advisory board of Pzer. AMB has attended educational meetings and major conferences sponsored by Astellas, Merck, and Pzer. Other authors have no conict of interest.

The management of candidaemia has evolved over the last few years as a result of availability of several new antifungal agents. The Infectious Diseases Society of America (IDSA) recommends initial echinocandin therapy in patients with moderately severe to severe illness (i.e. patients with haemodynamic instability), neutropenia, a history of recent azole exposure, and patients with a high risk of infection with Candida glabrata (e.g. patients with cancer or diabetes, and elderly patients) or Candida krusei. In patients who are commenced on an echinocandin, the IDSA recommends step-down therapy to uconazole, which is a cheaper option, when they are clinically stable and if the Candida species is likely to be susceptible to uconazole. Voriconazole is recommended if additional mould coverage is desirable. The IDSA recommends 35 days of therapy with an echinocandin before switching to oral uconazole, but recognises that there are no data to support the

timing of step-down (1) while the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) guidance advises 10 days of intravenous (IV) therapy followed by oral therapy (2). Initial aggressive therapy followed by step-down to uconazole leads to targeted prescribing, limits emergence of resistance and reduces cost. The need for antifungal stewardship is being increasingly recognised (3). De-escalation or stepdown therapy is vital to antimicrobial stewardship programs. Our hospitals have an IV to oral switch (IVOST) policy which was ratied by the Area Drug & Therapeutics Committee in November 2010 (Box 1). The IVOST policy, which is a key component of the Scottish Antimicrobial Prescribing Group good practice recommendations for hospital antimicrobial stewardship, was introduced following the publication of the Scottish Management of Antimicrobial Resistance Action Plan in 2008 by the Scottish government (4). The roll-out of the policy was accompanied by a pharmacy-led educational program for
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Box 1 NHS Ayrshire and Arran IVOST policy Area drug and therapeutics committee Guideline for intravenous antimicrobial to oral switch therapy in adults Specic indications for intravenous therapy

SIRS (i.e. 2 or more of the following: temperature >38 C or < 36 C, heart rate > 90 beats per minute, respiratory rate >20 per minute, white cell count > 12 or < 4 9 106/ml) Febrile with neutropenia Specic illnesses: e.g. meningitis, infective endocarditis and bone/joint infection may require prolonged IV treatment Oral route compromised: vomiting, nil by mouth, reduced gastrointestinal absorption, swallowing disorder, unconscious

If none of the above criteria is present, switch to oral therapy (check microbiology results). Suggested doses and IV to oral switches of antimicrobials:
Intravenous Oral

Amoxicillin Benzyl penicillin Clarithromycin Clindamycin Co-amoxiclav Flucloxacillin Meropenem, piperacillin-tazobactam, ciprooxacin, gentamicin

Metronidazole Vancomycin Caspofungin Micafungin

Amoxicillin 500 mg1 g three times a day Phenoxymethylpenicillin 500 mg1 g four times a day or amoxicillin 500 mg1 g three times a day For community acquired pneumonia: Doxycycline 200 mg day 1, then 100 mg once or twice daily Clindamycin 300450 mg three times a day Co-amoxiclav 625 mg three times a day Flucloxacillin 500 mg1 g four times a day If intra-abdominal sepsis, switch to: Co-amoxiclav 625 mg three times a day or ciprooxacin 500 mg twice daily plus metronidazole 400 mg three times a day Metronidazole 400 mg three times a day Contact microbiology/infectious diseases Fluconazole 200400 mg daily Fluconazole 200400 mg daily

Suggested doses may need adjusting for patients with renal/hepatic impairment. Contact Pharmacy for advice.

all clinical staff. Our objective was to evaluate our antimicrobial stewardship service in the context of antifungal step-down therapy. We aimed to nd out what proportion of patients are de-escalated to uconazole and the timescale at which de-escalation is undertaken based on the IVOST policy. We also estimated the savings in antifungal budget as a result of step-down therapy.

hospitals (10.8 per 100,000 acute occupied bed-days) (5).

Patients and isolates

Adult patients with candidaemia were followed from April 2011 to March 2013. Patients were identied using the laboratory information system and demographic data were collected. Blood cultures were processed using the BacT/Alert 3D system (bioMerieux, Marcy-ltoile, France) with 5 days incubation period. Positive blood culture bottles were subcultured to Sabourauds agar plates. All isolates were subjected to Germ tube (GT) test and GT negative isolates were identied with the help of API 20C Aux yeast identication system (bioMerieux). Antifungal susceptibility testing was carried out using the Sensititre YeastOne (YO10) colourimetric microdilution test (Trek Diagnostic Systems, Magellan Biosciences,

Methods
Setting
The study was undertaken at University Hospital Crosshouse and University Hospital Ayr (NHS Ayrshire and Arran), UK. The bed strength of the hospitals is approximately 1300. We have previously reported a high incidence of candidaemia in our
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Table 1 Interpretative criteria (lg/ml) for Candida species as per the manufacturers instructions

Agent

Susceptible

Susceptible (dose-dependent)

Intermediate

Resistant

Non-susceptible

Amphotericin Anidulafungin Caspofungin Fluconazole 5 Flucytosine Itraconazole Micafungin Posaconazole Voriconazole

2 2 8 4 0.125 2 1

>2 >2

1632 816 0.250.5 2

64 32 1 4 >2

West Sussex, UK) which is commercially marketed for this purpose and interpretation was based on manufacturers instructions (Table 1). Strains of C. krusei American Type Culture Collection (ATCC) 14243 and C. albicans ATCC 10231 were used for the purpose of quality control during susceptibility testing. Repeat cultures with identical species were regarded as single episodes if within 30 days of the rst positive culture.

Initial therapy
Caspofungin, micafungin, voriconazole and uconazole are included in our local antifungal formulary. Treatment for candidaemia is advised by microbiologists based on the IDSA recommendations. Standard dosages were used during the study: IV caspofungin 70 mg on day one followed by 50 or 70 mg daily depending upon body weight and 35 mg if dose reduction was necessary, IV micafungin 100 mg daily, oral voriconazole 400 mg twice daily for two doses followed by 200 mg twice daily, IV voriconazole 6 mg/kg twice daily for two doses followed by 4 mg/kg twice daily and oral or IV uconazole 200 800 mg daily. Removal of central vascular catheter (CVC) within 48 hours was advised if appropriate (6).

was considered appropriate for Candida parapsilosis irrespective of the SIRS parameters as this species is known to be less susceptible to echinocandins (2). We advised high-dose uconazole (800 mg daily in adult patients with dose adjustment where necessary, e.g. for weight or renal function) when de-escalating therapy in infections with C. glabrata with dosedependent susceptibility (S-DD) (8). IV uconazole was given if the decision to switch to oral uconazole was supported by the IVOST policy but the IV route was perceived to be benecial (e.g. patients with retained CVC). Overall clinical stability was assessed by the clinicians.

Appropriate therapy and minimum duration of treatment

Appropriate therapy was dened as therapy with an agent to which the isolated yeast was subsequently found to be susceptible or S-DD. To determine the reduction in consumption of dened daily dosages (DDDs) and cost savings, we estimated the minimum duration of treatment. This minimum duration was not used for clinical decision-making, i.e. patients were treated for longer duration where necessary but DDDs and cost were not calculated beyond the minimum duration so as not to overestimate savings. The estimated minimum duration was 14 days of therapy following the rst negative culture (1,2) or the last positive culture if follow-up negative cultures were not available (9).

De-escalation or step-down
The hospital IVOST policy recommends switching the route of administration of antimicrobials from the IV to oral (including echinocandins to uconazole) in patients who do not have evidence of systemic inammatory response syndrome (SIRS) (Box 1). SIRS is a dened term in clinical medicine (7). We applied our locally approved IVOST policy as a guide to step-down therapy. Where more than one reading was available for the SIRS parameters, the more abnormal value was recorded. In patients without evidence of SIRS over a 24 h period, therapy was switched to uconazole after identication and susceptibility testing, except that switch to uconazole

DDDs and cost

As per the World Health Organization Collaborating Centre for Drug Statistics Methodology, a DDD for caspofungin, micafungin, voriconazole (oral and parenteral) and uconazole (oral and parenteral) is 50, 100, 400 and 200 mg, respectively (10). Cost per DDD for caspofungin, micafungin, IV voriconazole, oral uconazole and IV uconazole was 327.67, 341, 154.28, 9.48 and 29.28, respectively, based on the British National Formulary published in
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March 2011 (11). For determining DDDs and cost and to avoid overestimation of savings, we limited our time frame to the number of days the patient received antifungal therapy or the estimated minimum duration of therapy whichever was less. Actual consumption of echinocandin and voriconazole DDDs was determined for this time frame while the projected echinocandin and voriconazole DDD consumption was the amount that would have been consumed had the initial therapy (i.e. without transition from echinocandin or voriconazole to uconazole) been continued during the time frame. DDDs for the step-down uconazole were also determined. Actual and projected costs for echinocandins and voriconazole and cost for step-down uconazole were calculated based on the DDDs. Savings were calculated by deducting the step-down cost from the difference between projected and actual cost.

Table 2 Basic demographics and main ndings for all

37 patients with candidaemia

Demographics and treatment Numbers (%)

Results
Candida isolates and susceptibility
Thirty-eight Candida isolates were recovered from 37 patients (one patient had mixed infection with two Candida) during the study period with no repeat episodes. None of the patients was neutropenic. Twenty-eight (73.6%) of the 38 isolates were uconazole susceptible, nine (23.6%) were S-DD and one (2.6%) was resistant. Thirty-six (94.7%) isolates were voriconazole susceptible, one (2.6%) was S-DD and one (2.6%) was resistant. One (2.6%) isolate was echinocandin resistant. The quality control strains were within acceptable range. All treated patients were commenced on appropriate therapy as judged by the antifungal susceptibility test results. Overall 30-day crude mortality was 37.1%. Table 2 summarises the patient demographics and laboratory ndings.

Total number of adult patients Males/females Mean age Admission in intensive care unit Total number of Candida isolates Candida albicans Candida glabrata Candida parapsilosis Candida dubliniensis Candida guilliermondii Candida lusitaniae Alive at the time of detection of candidaemia Treated Initial treatment echinocandin Initial treatment voriconazole Initial treatment uconazole Step-down from echinocandin or voriconazole to uconazole Patients survived (day 30) Patients died (day 30)

37 14/23 66.1 10 (27%) 38 17 (44.7%) 11 (28.9%) 7 (18.4%) 1 (2.6%) 1 (2.6%) 1 (2.6%) 35 (94.5%) 35 (100%) 26 (74.2%) 1 (2.8%) 8 (22.8%) 19 (70.3%)* 22 13

*Including C. albicans (7), C. glabrata (7), C. parapsilosis (3), C. dubliniensis (1), C. guilliermondii (1) and C. lusitaniae (1) (one patient had mixed C. albicans and C. glabrata infection). Data not available for two patients who were lost to follow up.

Initial antifungal therapy

Thirty-ve out of 37 patients who were alive at the time candidaemia was detected were treated. Twentysix patients received an echinocandin as initial therapy, eight received uconazole and one patient in intensive care unit whose endotracheal aspirate grew Aspergillus fumigatus received voriconazole (Table 2). Of the 26 patients who received an echinocandin, 25 fullled at least one criterion for echinocandin therapy as per the IDSA guidance: 18 were elderly [dened as age 65 years as per the Ofce for National Statistics (12)] patients, eight had cancer, three patients were haemodynamically unstable, three had diabetes and one patient had recent uconazole therapy (some had multiple risk factors). Only one patient had no risk factor for initiating echinocandin,
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i.e. this patient should have got uconazole based on the IDSA guidance. Thus, our use of echinocandin as initial therapy was not disproportionate. Five out of eight patients appropriately received uconazole as they had no risk factor for echinocandin therapy based on the IDSA guidance but three patients who were given uconazole because they were clinically well were candidates for echinocandin therapy solely on account of their age. Twenty-two out of 37 patients with candidaemia had CVC: 10 had their lines removed within 48 h of detection of candidaemia (six started on echinocandin and one each on voriconazole and uconazole), 10 retained their lines for longer than 48 h (seven started on an echinocandin of which three had a subsequent positive blood culture from commencement of therapy) and two retained their CVC throughout the minimum duration of therapy (none received echinocandin). The estimated minimum duration of therapy ranged from 14 to 26 days.

Antifungal transitioning
Nineteen (70.3%) out of 27 patients who were started on an echinocandin or on voriconazole were stepped down to uconazole based on the IVOST

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policy within the dened time frame of therapy. Eighteen patients were correctly de-escalated as per the SIRS criteria while one patient was stepped down even though the patient did not full the criteria because bacterial sepsis was also thought to contribute towards the illness. This patient survived for more than 30 days without suffering a relapse. The patient on voriconazole was stepped down to uconazole because on reassessment, the patient was thought to have been transiently colonised with A. fumigatus. Eight patients who stepped down to uconazole got some or all of the uconazole through IV rather than oral route based on individual circumstances (e.g. retained CVC, refusal to take oral medicines) although they were candidates for oral therapy and were appropriately stepped down to uconazole (Table 3). Two patients who received oral uconazole subsequently got IV uconazole because of frequent vomiting or suspected CVC related infection following delay in CVC removal. Of the eight patients whose therapy was not de-escalated to uconazole, four died early in therapy, two patients had suspected prosthetic cardiac device related infection, and in two cases we did not advise step-down because of trailing effect or resistance to uconazole. One patient with C. glabrata [minimum inhibitory concentration (MIC) for uconazole 16 lg/ml] infection following cancer surgery whose therapy was switched after 4 days from IV micafungin to IV followed by oral uconazole (400 mg) continued to improve clinically until the 10th day of uconazole therapy at which point he developed aspiration pneumonitis. The 400 mg dose was used because the patient weighed approximately 40 kg and a dose of 800 mg would have far exceeded the maximum dose that is recommended for the treatment of candidaemia caused by C. glabrata with uconazole MIC of 1632 lg/ml (8). This patient had a relapse of candidaemia with C. glabrata with identical susceptibility prole. The transition to uconazole in this patient was appropriately guided by the IVOST policy. Micafungin was reintroduced but the patient succumbed to the illness 2 days later. Fluconazole blood level at the time of relapse was 28.4 lg/ml. Other than this patient, there were no relapses during the study period at day 30 (n = 37), 90 (n = 34), 180 (n = 29) or at 1 year (n = 20). Overall, 14 (six with C. glabrata, four with C. albicans, two with C. parapsilosis, and one each with C. lusitaniae and C. dubliniensis infection) out of the 19 patients who were de-escalated to uconazole were alive at day 30, four (two with C. albicans, one patient with C. glabrata who relapsed, and one patient with C. guilliermondii) died by day 30 and one (C. parapsilosis infection) was lost to follow up.

The mean and median number of days to switch to uconazole (oral or IV) from the day of detection of Candida in bloodstream was 4.6 and 5 days, respectively (range 39 days) counting from the commencement of therapy and 2.05 and 2 days from the day of interpretation of susceptibility. The median duration of IV therapy was 7 days.

DDDs and cost of therapy

Table 3 details the projected and actual DDDs for echinocandins and voriconazole and the step-down DDDs for uconazole for all 19 patients. If these 19 patients whose therapy was de-escalated to uconazole continued their therapy on echinocandin or voriconazole, the total DDD consumption for these agents was projected to be 313.6 (caspofungin 167.9, micafungin 117, voriconazole 28.7) compared with 114.6 (caspofungin 64.9, micafungin 35, voriconazole 14.7) that were actually consumed thus saving 199 (caspofungin 103, micafungin 82, voriconazole 14) DDDs. We were therefore able to save 63,871.93 on echinocandins and voriconazole. However, we also consumed an additional 371.5 DDDs of uconazole (oral 235, IV 136.5) as a result of the step-down which amounted to 6224.52. Thus, our true antifungal cost savings amounted to 57,647.41 with an average of 1558.03 per candidaemia episode (n = 37). In four patients, extraneous factors might have led to exaggeration of savings: three with retained CVC beyond 48 h that led to persistently positive blood cultures leading to prolongation of the projected duration of therapy and one patient who was given an echinocandin but should have received uconazole. Excluding these patients from analysis, we consumed 149.4 (caspofungin 67.4, micafungin 68, voriconazole 14) fewer DDDs (Table 3) amounting to 47,432.87 in echinocandin and voriconazole saving with a true cost savings of 41,953.67 after deducting the expenditure on step-down uconazole. This translates into an average minimum saving per candidaemia episode of 1133.88 with all 37 candidaemic episodes in the denominator and 2208.08 per de-escalation (n = 19).

Discussion
This is the rst report of a policy-guided antifungal de-escalation in patients with candidaemia. Step-down antifungal therapy is supported by various guidelines (1,2). The 30-day crude mortality rate of 37.1% in candidaemic patients in this study compares favourably to our previously published data (crude mortality 48.3% in our centre (P = not signicant) (13). However, mortality in patients with candidaemia continues to be high similar to that in other studies (14,15).
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Table 3 Showing the details of DDDs for the 19 patients whose therapy was de-escalated from echinocandin (ECH)

[caspofungin (CAS) or micafungin (MCF)] or intravenous (IV) voriconazole (VOR) to oral (O) or IV uconazole (FLC)
No. Initial therapy Projected DDD (ECH or VOR) Actual DDD (ECH or VOR) Step-down therapy DDD

1 2 4 5 6 7 11 12 13 18 19 22 23 24 25 28 29 35 36 Total

CAS CAS CAS MCF CAS CAS MCF CAS CAS CAS CAS MCF MCF MCF CAS MCF VOR MCF MCF ECH or VOR

17.4 21 11.4 14 28 12.4 10 19.6 16.4 8.4 18.9 16 15 17 14.4 14 28.7 16 15 313.6

9.4 12.6 3.4 8 8.4 3.4 3 7 6.4 4.4 3.5 4 5 3 6.4 4 14.7 5 3 114.6

FLC FLC FLC FLC FLC FLC FLC FLC FLC FLC FLC FLC FLC FLC FLC FLC FLC FLC FLC FLC

O IV O O O O, IV O, IV O IV IV IV, O IV, O O IV, O O IV, O IV O O (O+IV)

8 12 14 12 28 4, 3.5 4,10 18 20 8 30, 8 2, 22 20 7, 7 8 8,14 36 44 24 371.5

Patient 1, 6, 24: Retained central vascular catheter for > 48 h with subsequent positive blood cultures (patient 1 also de-escalated without meeting IVOST criteria). Patient 4: Should not have received ECH.

Antifungal de-escalation at day 10 has been carried out in randomised control trial settings (16). The ESCMID guidelines recommend an oral switch after 10 days of IV therapy (but this does not necessarily preclude switching from echinocandin to IV uconazole rst before switching to oral uconazole) (2) while the IDSA recommends an initial 35 days of echinocandin therapy followed by a switch to oral uconazole once the patient is clinically stable (but provides no guidance on how to assess clinical stability) and if the isolated Candida is likely to be susceptible (1). Our IVOST policy based on SIRS criteria provides a more objective assessment of patients clinical condition and this was reinforced by antifungal susceptibility testing rather than relying on the likelihood of susceptibility to uconazole as recommended by the IDSA. SIRS parameters have been used in the follow up of patients with candidaemia. Wisplinghoff and colleagues (17) noted that roughly 20% of patients had a resolution of SIRS on therapy, which is lower than what we observed, but this may be because of the fact that only half of their patients were commenced on appropriate treatment unlike in our centre where almost all patients were treated appropriately within 24 h. Moreover, it would
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appear that uconazole, which is fungistatic, was used as initial treatment in their patients while a vast majority of our patients got initial fungicidal therapy with an echinocandin. Additionally, we perceived signicant benets from determining antifungal susceptibility testing such as detecting an echinocandinresistant C. albicans early (18). Recent ndings have highlighted the emergence of echinocandin resistance in Candida (19). Timely de-escalation to uconazole may limit the development of resistance to echinocandin by reducing unnecessary exposure. Currently, only 38% of microbiology laboratories in the UK carry out antifungal susceptibility (20). We were able to de-escalate therapy in 70.3% of patients at a median of day 5 but several patients got IV uconazole rather than oral because of other factors. This compares favourably with 39% de-escalation achieved without an active clinical assessment program (21). In a non-compulsory stewardship program, Lopez-Medrano et al. (22) recommended a change in therapy in 29% of patients, most of which were switches from IV to oral formulation of the same agent or discontinuation of therapy with only 6% recommendations to substitute to uconazole (probably because most patients had mould infections). Further,

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we demonstrated signicant cost savings in antifungal drug budget but we acknowledge that even in the absence of a specic IVOST policy, random de-escalation would still take place. Also, a thorough analysis of cost efcacy would need to take into account reagent cost, labour cost and hospital length of stay (LOS). Nevertheless, our lowest estimate of average saving of 1133.88 per candidaemia episode is signicant. It is important to highlight that one patient in our study who was switched to uconazole died after suffering a bout of aspiration pneumonia followed by a relapse of C. glabrata infection. On a weight basis, this patient received a high dose of uconazole (400 mg) following step-down from micafungin. The relapse was on the 10th day of the uconazole therapy until which time the patient continued to improve clinically and thus a lack of steady-state concentration is unlikely to have contributed towards relapse. The 400 mg dose has been used when de-escalating therapy even in patients with normal body weight (16) and this dose is expected to attain the desired area under the curve/MIC ratio of 25 for an isolate with MIC 16 lg/ml because uconazole dosages are identical to the area under the curve (23). High-dose uconazole has been successfully used to treat infection with C. glabrata with MIC in the S-DD range (8). However, the more recent ESCMID guidance published after this case discourages the use of uconazole for C. glabrata irrespective of the MIC although there is no evidence base to this recommendation (2). In fact, a recent study found similar mortality in patients treated with echinocandins or uconazole (24). Voriconazole may be a suitable option for step-down therapy in patients with C. glabrata infection (1). There are limitations to our data. Our CVC removal rate within 48 h was low although its inuence on the DDD usage was limited. Our estimate of savings is of antifungal drug budget only and excludes the costs associated with delivery of this service. We did not collect information on hospital LOS or associated costs because comparing our data with non-protocol based de-escalation would necessitate a randomised study with appropriate control groups. Our objective was not to determine the

overall cost efcacy of the program but only to evaluate our current service and identify areas of improvement. We successfully de-escalated a majority of patients relatively early during the course of therapy. Our work lends support to the suggested duration (35 days) of initial echinocandin therapy prior to step-down in the IDSA guidance although the actual switch to oral therapy was achieved at a median of 7 days as therapy was often switched to IV uconazole (1). We also highlight the possibility of failure as a result of step-down uconazole in C. glabrata although only one out of seven patients with C. glabrata whose therapy was de-escalated to uconazole relapsed. This is particularly relevant when a majority of hospitals in the UK use uconazole as initial therapy even in critically ill patients (13) and is a further argument in favour of our practice of starting with echinocandins in a majority of patients followed by an early switch to uconazole on the basis of clinical and microbiological ndings.

Acknowledgements
The work was classied as a service improvement project by the local Clinical Governance group. The work had the support of the Healthcare Quality, Governance & Standards Unit. Policy approved by the Antimicrobial Management Team and ratied by the Area Drug and Therapeutics Committee was evaluated as part of our service improvement strategy. University College London and British Society for Medical Mycology kindly agreed to provide grants for antifungal susceptibility testing. We are grateful to Dr Elizabeth Johnson, Director, Mycology Reference Laboratory, Bristol, for carrying out the assay for serum uconazole level.

Author contributions
AMB, GS and MM were involved in concept and design of the study and drafting the article. TI, GS and RM collected the data and TI and GS helped with analysis of the data. All authors critically revised the manuscript.

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Paper received March 2013, accepted June 2013

2013 John Wiley & Sons Ltd Int J Clin Pract, January 2014, 68, 1, 2027