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JAC Advance Access originally published online on April 4, 2006
Journal of Antimicrobial Chemotherapy 2006 57(6):1181-1188; doi:10.1093/jac/dkl107
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Treatment outcomes in patients receiving conventional amphotericin B therapy: a prospective multicentre study in Taiwan

Chien-Yuan Chen1, Ritesh N. Kumar2, Yin-Hsun Feng3, Chao-Hung Ho4, Jie-Yu You4, Chi-Chou Liao5, Chiung-Hui Tseng5, Panagiotis Mavros2, William C. Gerth2 and Yee-Chun Chen1,6,*

1 Department of Internal Medicine, National Taiwan University Hospital Taipei, Taiwan 2 Merck & Co. Whitehouse Station, NJ, USA 3 National Cheng Kung University Tainan, Taiwan 4 Veterans General Hospital Taipei, Taiwan 5 Chang Gung Memorial Hospital Tao-Yuan, Taiwan 6 Department of Medicine, National Taiwan University College of Medicine Taipei, Taiwan

*Correspondence address. Division of Infectious Diseases, Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan 100. Tel: +886-23123456 ext. 5054; Fax: +886-2-23971412; E-mail: ycc{at}ha.mc.ntu.edu.tw

Received 11 November 2005; returned 15 December 2005; revised 19 January 2006; accepted 7 March 2006


   Abstract
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 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 Transparency declarations
 References
 
Objectives: To evaluate treatment outcomes and healthcare resource use with conventional amphotericin B therapy for invasive fungal infections (IFIs).

Patients and methods: A prospective observational study in hospitalized adult patients receiving amphotericin B treatment was undertaken at four hospitals in Taiwan. Patients were observed from the start of therapy to hospital discharge.

Results: A total of 108 patients (October 2000 to April 2002) were included in the study. Proven or probable IFIs as defined by the EORTC/MSG criteria were the reasons for the initiation of amphotericin B in 35.2% of the sample. A total of 24.1% patients developed nephrotoxicity (NT) (defined as a 50% increase in the baseline serum creatinine and achieving a peak of at least 2.0 mg/dL). Treatment of proven/probable IFIs [odds ratio (OR) = 4.16, 95% confidence interval (CI) = 1.61–10.75] was a significant predictor of the development of NT. The in-hospital mortality rate was 38.0%. Proven/probable IFIs (OR = 6.93, 95% CI = 2.62–18.29) and the development of NT (OR = 3.68, 95% CI = 1.22–11.04) were independent predictors of in-hospital mortality. For patients alive at discharge, those with NT had a trend of longer hospital stay compared with patients who had not developed NT (mean, 49.3 ± 18.2 versus 29.3 ± 22.3 days, P = 0.069). For patients who died, those who had developed NT died sooner (15.5 ± 16.7 versus 33. 8 ± 26.9 days, P = 0.0004).

Conclusions: NT was associated with accelerated mortality and increased hospital stay for patients who survived. Using amphotericin B carefully or the use of antifungal agents with less potential for NT might improve patient outcomes.

Keywords: adverse effects , nephrotoxicity , medical resources , length of stay , mortality , invasive fungal infections


   Introduction
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 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Conclusions
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Invasive fungal infections (IFIs) are associated with significant morbidity and mortality despite advances in medical care.1–10 Conventional amphotericin B is the main therapeutic agent for the treatment of most IFIs due to its broad spectrum of activity.11,12 However, it can generate significant adverse effects (AEs) such as infusion-related events (fever, chills, nausea, vomiting), electrolyte abnormalities (hypokalaemia, hypomagnesaemia, hypernatraemia), metabolic acidosis and nephrotoxicity (NT).12–16 Amphotericin B was found to be the most nephrotoxic agent of currently available systemic antifungals based on a meta-analysis.15 An AE is associated with a significantly prolonged length of stay, increased economic burden and increased risk of death.17 The substantial impact of AEs to hospitals justifies the investment in efforts to prevent these events.18

The use of nephrotoxic agents, such as ciclosporin or tacrolimus, is common in allogeneic haematopoietic stem cell transplant recipients and has further exacerbated this problem.12 The frequent use of these agents should warrant clinicians to carefully monitor the use of amphotericin B in the treatment of IFIs.12,15 Furthermore, amphotericin B-related toxicity is a significant concern when amphotericin B is used for possible/suspected IFIs in empirical therapy or probable/definite IFIs in preemptive/definite therapy.7,11,19

Data regarding amphotericin B-related toxicity and treatment outcomes are limited in Asian populations. Therefore, we initiated a prospective study, collecting both routine and event-driven information among patients treated with amphotericin B. We identified the incidence of NT with amphotericin B treatment and the associated length of stay and mortality.


   Patients and methods
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 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Conclusions
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This prospective observational study was conducted at four medical centres in Taiwan from October 2000 to April 2002. Each centre enrolled ~25 patients. Hospitalized adults, 18–80 years of age, receiving systemic amphotericin B treatment were followed from initiation of therapy through to hospital discharge. The demographic data included age, gender and weight. Clinical data were captured based on underlying medical condition, reason for starting amphotericin B, primary site of infection and whether the patient received prior amphotericin B therapy within the past 6 months. Laboratory data included the date of collection of the first positive fungal culture, identified fungal isolate, leucocyte count, absolute neutrophil count, serum creatinine, bilirubin and electrolytes. Minimum and maximum ranges of renal function during therapy were also determined.

The potential for AEs was determined by capturing information on the use of concurrent nephrotoxic agents (aminoglycosides, glycopeptides, non-steroid anti-inflammatory drugs, chemotherapy or immunosuppressants, contrast media and others). Pre-medication for prevention of adverse events included antihistamines, antiemetics, antipyretics, corticosteroids, meperidine (for severe rigors) and other agents. Resource utilization was determined in terms of the amphotericin B dose used and length of hospital stay from the start of amphotericin B therapy to discharge. Data elements collected reflect assessments and procedures performed under conditions of routine practice.

Definitions

IFI was defined based on the joint criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG)19 and determined at the initiation of therapy. Amphotericin B-related adverse events include anaphylaxis, fever, chills, nausea, vomiting, electrolyte abnormalities (hypokalaemia, hypomagnesaemia, hypernatraemia), metabolic acidosis, NT and others.12–16 NT was defined as a 50% increase in the baseline serum creatinine and achieving a peak of at least 2.0 mg/dL.20–22

Statistical analyses

The data collected were analysed using several different statistical tests to determine univariate and multivariate associations. Descriptive statistics were generated to gather information on the nature of the study sample. Categorical values were compared using {chi}2-test or Fisher's exact test. Relative risk and its 95% confidence interval (95% CI) were computed for each variable. Continuous variables were compared using independent-samples t-test. The Wald test statistic was used to determine the significance of the coefficients within the logistic and proportional hazard regression models.23,24 All statistical analyses were performed using SAS 8.0 for Windows. Results were considered statistically significant at P < 0.05. The logistic regression analysis was used to determine the association of patient/treatment characteristics with the development of NT and mortality. Univariate and multivariate associations of patient/treatment characteristics with NT and mortality were tested. For the multivariate analysis, only those characteristics that were significant at P < 0.20 in the univariate analysis were analysed. The results from the forward variable selection technique are reported. However, the same results were obtained from the backward and the stepwise selection technique. The proportional hazard regression model tested the univariate and multivariate association between patient/treatment characteristics with length of hospitalization. Separate models were tested for patients who were discharged alive and those that died in the hospital.


   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Discussion
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Patient characteristics and key outcomes

Among the 122 patients recruited, 14 were excluded from the analysis. One patient received a lipid formulation of amphotericin B, and 13 patients had no serum creatinine data to determine NT. The final sample size was 108. Three patients had received both a lipid formulation and amphotericin B. Only amphotericin B data from these patients were included in the analysis. In our final sample of patients, 14.8% had chronic renal disease at baseline (serum creatinine ≥ 1.5 mg/dL) and 24.1% developed NT after amphotericin B treatment (Table 1). The mean length of hospital stay after initiation of amphotericin B was 29.5 ± 23.5 days and the in-hospital mortality rate was 38.0%.


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  		Table 1. Factors associated with the development of nephrotoxicity in 108 patients receiving amphotericin B therapy: univariate analysis

 
The reasons for initiation of amphotericin B included proven/probable IFIs (35.2%) and possible/suspect IFIs (64.8%). Candida (27/34, 79.4%) was the leading documented pathogen, followed by Cryptococcus (11.8%), Aspergillus (5.9%) and others (2.9%). Lung was the most common site of infection (15.0%), followed by blood (5.4%), CNS (5.4%), paranasal sinuses (4.3%), liver (4.3%), bladder (4.3%), skin (3.2%), oesophagus (2.2%) and peritoneum (1.1%). Patients treated with proven/probable IFIs were more likely to have diabetes (21.1% versus 5.7%, P = 0.02), reported impaired renal function (34.2% versus 2.9%, P < 0.0001), chronic renal disease (31.6% versus 5.7%, P = 0.001), higher baseline serum creatinine level (1.68 ± 1.88 mg/dL versus 0.87 ± 0.39 mg/dL, P = 0.01) and other medical conditions (73.7% versus 18.6%, P < 0.0001) than those treated with possible/suspect IFIs. On the other hand, patients treated with possible/suspect IFIs were more likely to have leukaemia (84.3% versus 28.9%, P < 0.0001), neutropenia (71.2% versus 16.7%, P < 0.0001) and be treated for prevention of NT (24.3% versus 7.9%, P = 0.04).

Nephrotoxicity

The univariate analysis, depicted in Table 1, showed that patients treated for proven/probable IFIs had significantly greater odds for developing NT compared with patients treated for possible/suspected infections (OR = 4.36, 95% CI 1.72–11.05). Dose per treatment day (per mg increment) (OR = 1.04, 95% CI 1.01–1.08) and body weight (per kg increment) (OR = 1.05, 95% CI 1.00–1.09), also had a positive association with the development of NT. Surprisingly, patients using other nephrotoxic drugs had lower rates of NT compared with patients not using nephrotoxic drugs (OR = 0.72, 95% CI 0.53–0.97). Patients with leukaemia developed NT less often compared with patients with other conditions (OR = 0.29, 95% CI 0.11–0.71). Multivariate analysis revealed that only treatment for proven/probable IFIs (OR = 4.16, 95% CI 1.61–10.75) was significantly associated with NT.

In-hospital mortality

Variables described in Table 1 that were significant at P < 0.20 in the univariate analyses were included in the multivariate models as predictors of mortality and length of stay. Results comparing the development of NT and subsequent mortality showed that a higher percentage of patients who developed NT died (69%); compared with death rates among non-NT patients (28%) (OR = 5.77, 95% CI 2.21–15.11, P = 0.0004) (Figure 1). Other significant univariate associations demonstrated that patients treated for proven/probable IFIs (OR = 9.82, 95% CI 3.94–24.48, P < 0.0001), patients with renal impairment (OR = 5.78, 95% CI 1.70–19.64, P = 0.003) and those with chronic renal disease at baseline (OR = 6.52, 95% CI 1.94–21.94, P = 0.001) had significantly higher odds of dying. On the other hand, patients with neutropenia (OR = 0.31, 95% CI 0.13–0.72, P = 0.008) and leukaemia (OR = 0.19, 95% CI 0.08–0.44, P < 0.001) had lower odds of dying. Multivariate analysis showed that treatment for proven/probable IFI (OR = 6.93, 95% CI 2.62–18.29) and the development of NT (OR = 3.68, 95% CI 1.22–11.04) were independent positive predictors of in-hospital mortality.


Figure 1
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  		Figure 1. In-hospital mortality by nephrotoxicity for 108 patients who received amphotericin B therapy (P = 0.0004).

 
Length of hospital stay

The association of different parameters on the length of stay was conducted by dividing the sample based on those who died and those who were alive at discharge. Separating the study sample was essential to eliminate biased estimates in hospital length of stay due to mortality.

Patients discharged alive. Findings indicated that patients with NT discharged alive had a longer mean hospital stay after initiation of amphotericin B compared with patients without NT [mean, 49.3 ± 18.2 versus 29.3 ± 22.3 days, hazard ratio (HR) 0.50, P = 0.069] (Figure 2). For patients who were discharged alive, treatment of proven/probable IFIs (HR = 0.37, P = 0.0028) (Figure 3), higher dose per treatment day (HR = 0.97, P = 0.007), higher mean daily dose adjusted for weight (HR = 0.21, P = 0.003), and longer duration of treatment (HR = 0.96, P < 0.001) were significantly associated with a lower HR for leaving the hospital (implying a longer hospital stay). In the multivariate analysis, treatment of proven/probable IFI (HR = 0.50, 95% CI 0.26–0.98), duration of treatment (HR = 0.96, 95% CI 0.94–0.98) and immunosuppressant treatment (HR 0.14, 95% CI 0.03–0.67) were associated with a longer hospital stay.


Figure 2
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  		Figure 2. Mean length of hospital stay (from initiation of amphotericin B therapy to discharge) for 108 patients receiving amphotericin B therapy varied by nephrotoxicity (mean, 49.3 ± 18.2 versus 29.3 ± 22.3 days, P = 0.069; 15.5 ± 16.7 versus 33.8 ± 26.9 days, P = 0.0004).

 

Figure 3
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  		Figure 3. In-hospital mortality, mean length of hospital stay (LOS) and nephrotoxicity varied by classification of invasive fungal infections (IFI) (P < 0.001, P < 0.001, P = 0.003 and P = 0.002, respectively).

 
Patients dying in hospital. For patients who died in the hospital: reported impaired renal function (HR = 3.65, P < 0.001); chronic renal disease at baseline (HR = 4.09, P < 0.001); development of NT (HR = 3.17, P = 0.0004); other medical conditions (HR = 3.12, P = 0.006); treatment of proven/probable IFIs (HR = 4.13, P < 0.001); and age (HR = 1.03, P = 0.009) were associated with a high HR implying early death, and, therefore, a reduced length of hospital stay. The presence of neutropenia (HR = 0.36, P < 0.001) and leukaemia (HR = 0.34, P = 0.009) resulted in a lower HR and a longer length of stay for patients dying in the hospital. In the multivariate analysis, NT (HR = 2.42, 95% CI = 1.25–4.68) and treatment of proven/probable IFIs (HR = 3.61, 95% CI = 1.77–7.36) were associated with reduced lengths of hospital stay due to mortality. As expected, the duration of treatment (HR = 0.94, 95% CI = 0.91–0.97) was associated with greater lengths of stay.

Adverse effects and medical resource use

Eighty-three patients (76.9%) reported experiencing at least one adverse event including NT. An additional 14.1 medications, 11.2 laboratory tests, 2.3 consultations and 0.2 imaging procedures were ordered for patients receiving amphotericin B due to monitoring or treatment of amphotericin B-related AEs.


   Discussion
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 Patients and methods
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Conclusions
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The incidence of NT varies in the literature because of differences in study design, definition of NT, patient population, dose and duration of amphotericin B therapy and prevention of amphotericin B toxicity (Table 2).15,20–22,25–35 The results of this multicentre, prospective observational study contributes to a better understanding of the treatment outcomes associated with amphotericin B therapy in Taiwan and demonstrates that the incidence of NT was higher or equal to those in Western countries using similar definitions.20–22,34,35 Our study also showed that patients treated for proven/probable IFIs had higher lengths of stay (for patients discharged alive), increased NT and higher mortality rates compared with patients treated for possible/suspected IFIs. Similar to a previous study, this demonstrates that the impact of delay in initiation of therapeutic agents is substantial.7 Early intervention is strongly recommended rather than waiting for microbiological or histopathological confirmation; especially, when safer alternatives are available.36,37 Our study results validate the need for policy and clinical decision makers to further understand that patients at risk of NT, or who have impaired renal function may be candidates to receive better tolerated systemic antifungal agents. Prevention of NT may not only reduce mortality, but also reduce hospital stay for patients discharged alive.


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  		Table 2. Variation of frequencies of amphotericin B-related nephrotoxicity by definition, patient population, study design and intervention

 
The results of this study are consistent with published studies,20–22,25 and demonstrate that when NT occurs, not only does the overall mortality rate increase but the length of hospital stay also increases for patients discharged alive. The adverse outcomes associated with amphotericin B treatment can significantly increase the overall treatment costs.17,18,21 Studies have shown that with amphotericin B treatment it is essential to consider additional treatment cost drivers besides the acquisition cost of the medication, such as cost of NT, additional hospital stay, and resources that were used to monitor and treat drug-related AEs.12,17,18,21,22 In an era of global budget control, estimating the true cost of amphotericin B and other systemic antifungal agents should take into consideration the following costs: (i) drug acquisition costs; (ii) associated costs of preparing and administering the drug; (iii) cost of monitoring and treating AEs; (iv) increased length of hospital stay due to treatment; and (v) costs associated with mortality. A case-control study conducted before the introduction of new antifungal agents demonstrated that nosocomial infection due to Candida albicans was associated with additional direct medical costs up to $6584 ± 11 467, which was higher than that due to Staphylococcus aureus ($3294 ± 10 401) and Pseudomonas aeruginosa ($1202 ± 17 962).38

NT is clearly shown to be a major limitation of the clinical usefulness of amphotericin B.39,40 The significant risk factors of amphotericin B-related NT included prior use of amphotericin B, impaired renal function, and daily dose per treatment day.15,20,25,26,34,35,39,40 It was also observed that patients treated for proven/probable IFIs had worse renal function at baseline compared with patients treated empirically.20,26,39 Prior to the availability of new antifungal agents, patients with inferior renal function and proven/probable IFIs were still treated with amphotericin B, a drug that has NT. This led to higher mortality rates in this group and a greater length of hospitalization for patients that were ultimately discharged from the hospital alive. The risk of developing NT is an important factor to be considered before start of the antifungal therapy.12,20,38

Studies of the liposomal formulation of amphotericin B,27,28,30 caspofungin32,41 and voriconazole,31,33 have reported significant decreases in the rate of NT, and should be considered as first-line therapy for life-threatening IFIs in patients who have pre-existing renal dysfunction or a high probability of developing severe renal impairment.11,12,16,20 This is particularly important in countries like Taiwan, where overall healthcare costs and utilization have already significantly increased based on the provision of universal health insurance.42

The financial impact of new antifungal agents is a concern in Taiwan. In 1995, national health insurance was introduced to cover all citizens in Taiwan. This programme was proposed to assure access to healthcare at a reasonable cost. However, healthcare expenditures grew despite the control mechanisms.42 Due to cost-containment pressures, amphotericin B is still widely used to treat IFIs; however, such use must be accompanied by strategies to reduce amphotericin B-related NT (Table 3).


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  		Table 3. Strategies to prevent or reduce amphotericin B-related nephrotoxicity

 
Strategies to reduce amphotericin B-related NT involve extensive patient monitoring and increased utilization of healthcare resources.34,35,39,43–47 Implementation of these strategies further exacerbates treatment costs associated with amphotericin B therapy. Studies have shown that there are circumstances in which amphotericin B can be used with an acceptable risk–benefit ratio.12,34,35 However, these studies have increasingly raised difficult questions regarding how much toxicity is required before a patient is considered, ‘intolerable’ to amphotericin B, and, an ideal candidate to receive alternative antifungal therapies.

Fluconazole is an alternative agent for IFIs.5,8,48–51 Fluconazole is a fungistatic drug with narrow spectrum, and also has the potential to produce drug–drug interactions with certain medications.48,49 Besides, the susceptibility to fluconazole of certain strains of Candida, especially Candida non-albicans is questionable.48 Therefore, alternative agents with less toxicity and a broader spectrum of activity may provide better effectiveness and survival rates.31–33,41,48,52,53

There were several limitations to this study. The first limitation was that clinical practice at the four study sites was not standardized. In addition, not all observed NT may be attributable to amphotericin B alone. However, we did control for important factors such as underlying diseases, medical conditions and concurrent nephrotoxic medication use that may impact the development of NT. Our study adopted an observational study design and showed that patient characteristics between the proven/probable and possible/suspected infections group were different. However, an observational study design is closer to actual clinical practice and the results provide a good indication of amphotericin B-related outcomes within a real group of Taiwanese patients. Finally, this study possessed a comparatively small sample size. However, it must be noted that most studies that have been conducted to evaluate the effectiveness of treatment for IFIs have low enrolment rates due to the challenge involved in recruiting high-risk patients, who are susceptible to numerous infections and have a high risk of mortality.


   Conclusions
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
Transparency declarations
 References
 
In Taiwan, amphotericin B is used to treat critically ill patients with IFIs. However, in this study NT occurred in 24.1% of the patients treated with amphotericin B. NT was a strong independent predictor of in-hospital mortality and resulted in increased length of stay for patients who survived. Patients receiving amphotericin B for possible/suspected IFIs had better outcomes than those receiving amphotericin B for proven/probable IFIs. Therefore, patient outcomes could be improved, in future, by early aggressive antifungal treatment, and replacing the use of amphotericin B with other safer antifungal agents in patients with a high risk of NT. Finally, the total cost of antifungal treatment should not be limited to drug costs alone, but the overall cost of healthcare must be taken into consideration in the era of global cost-containment.


   Transparency declarations
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References
 
Y.-C. C. has received lecture fees from Merck and Pfizer. R. N. K., P. M. and W. C. G. are employees of Merck. The other authors declare that they have no conflict of interest.


   Acknowledgements
 
This study was presented in part at the Fortieth Annual Meeting of the Infectious Diseases Society of America, Denver, CO, USA, November, 2002, Abstract no. 364. We thank Dr Calvin Kunin for critical review and useful comments. We thank Shideh Khorahsheh from the Syreon Corporation for project management support. This work was supported in part by a grant from Merck & Co., Inc., Whitehouse Station, NJ, USA. The funding agency was not involved in the data collection process.


   References
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 Abstract
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 Patients and methods
 Results
 Discussion
 Conclusions
 Transparency declarations
 References
 
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