Continuous and 4 h infusion of amphotericin B: a comparative study involving high-risk haematology patients

A. Y. Peleg* and M. L. Woods

Infectious Diseases Unit, Department of Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia

Received 28 April 2004; returned 3 June 2004; revised 30 June 2004; accepted 19 July 2004


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives: To assess whether a continuous infusion of amphotericin B (CI-AmB) is less nephrotoxic than a 4 h infusion in haematology patients with fever and neutropenia, including bone-marrow transplant recipients. Efficacy was assessed as a secondary end-point.

Patients and methods: We conducted a retrospective cohort study over a 2 year period. A total of 1073 haematology admissions were reviewed (98.3% complete) and 81 admissions were eligible for study entry; 39 received CI-AmB and 42 a 4 h infusion of AmB.

Results: Renal impairment occurred significantly less frequently with CI-AmB compared with a 4 h infusion of AmB [10% versus 45%, respectively, odds ratio (OR) 0.14; 95% confidence interval (CI) 0.04–0.5, P<0.001]. The difference was maintained among allogeneic transplant recipients (P=0.007) and patients receiving concurrent nephrotoxic drugs (P<0.001). An AmB infusion rate of <0.08 mg/kg/h was associated with a significant reduction in renal impairment (P<0.001). A difference in survival was observed between the continuous and 4 h infusion of AmB (95% versus 79%, respectively, OR 5.1; 95% CI 1.02–25.1, P=0.03).

Conclusions: CI-AmB appears to be significantly less nephrotoxic than 4 h infusion AmB in haematology patients with fever and neutropenia—including high-risk bone-marrow transplant recipients—without increasing mortality. An AmB infusion rate of <0.08 mg/kg/h appears to be a safe threshold, associated with reduced renal impairment.

Keywords: neutropenia , fever of unknown origin , bone-marrow transplantation , nephrotoxicity , antifungal agents


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Empirical amphotericin B (AmB) in haematology patients with refractory fever and neutropenia is an important therapeutic intervention.1,2 It is aimed at preventing new fungal infections and treating clinically occult fungal disease during neutropenia.2,3 AmB, combined with the detergent deoxycholate, still forms the first line therapy for empirical treatment of opportunistic fungal infections, despite the development of newer, lipid formulations. It has a broad fungicidal spectrum, greater in vivo activity than liposomal AmB (liposomal-AmB),4 and is significantly less expensive than other available antifungal drugs. Unfortunately, given as a 4 h infusion, its use is limited by high rates of infusion reactions and dose-related nephrotoxicity, a complication now recognized to be associated with increased mortality5,6 and overall resource utilization.5 The alternative is a lipid-associated formulation of AmB, which is associated with fewer side effects, but is significantly more costly and has no overall efficacy advantage over conventional AmB.79

Continuous infusion amphotericin B (CI-AmB) has been shown to reduce the incidence of nephrotoxicity and infusion-related side effects, both in haematology patients and solid organ transplant recipients.1013 Comparative toxicity data in bone-marrow transplant recipients are lacking and overall efficacy data are still limited. This has led to a delayed acceptance of CI-AmB as the preferred form of administration. The current study aims to assess the nephrotoxicity and efficacy of CI-AmB compared with 4 h infusion AmB in haematology patients with fever and neutropenia, including bone-marrow transplant recipients, a group known to have poor tolerance to renal impairment14 and at high risk of invasive fungal infection.15


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
A retrospective cohort study was performed by assessing all haematology admissions during January 2001–January 2003 at the Royal Brisbane and Women's Hospital, a 900 bed tertiary referral centre with a bone-marrow transplant service. The institution's policy on AmB administration changed from a 4 h infusion to a 24 h continuous infusion in January 2002, enabling a comparison between the two groups. All patients who were given ≥48 h of AmB for refractory fever during neutropenia (neutrophil count <0.5 x 109 cells/L), or for possible, probable or proven fungal infection, were included in the study. Consecutive patient admissions were eligible for study entry as long as there was ≥1 month between admissions.

Continuous and 4 h infusion AmB were given in 500 mL of 5% dextrose, and patients were given an additional 500 mL of normal saline over the 24 h period to reduce the risks of nephrotoxicity.16,17 Recommendations on AmB dosing were according to hospital protocol and that of published guidelines at the time:3,18 0.6 mg/kg/day for patients with refractory fever and neutropenia, and 1 mg/kg/day for suspected or proven aspergillosis. Early utilization of thoracic computed tomography scans was standard for patients with refractory fever and neutropenia;19 fungal antigen testing was not available at our institution. Triple lumen Hickman catheters were used for all haematology patients who required central venous access for intensive chemotherapy or bone-marrow transplantation. As a standard of care, all patients undergoing allogeneic transplantation were given fluconazole prophylaxis. Liposomal-AmB was indicated for patients with a doubling of baseline serum creatinine while on conventional amphotericin B, or patients with a baseline serum creatinine >140 µmol/L. This policy was unchanged throughout the study period. Hospital policy on first line therapy for invasive aspergillosis changed to voriconazole in 2003, after the defined study period, in accordance with the published literature.20

Definitions

Refractory fever was defined as a temperature of ≥38°C for 5 or more days despite broad-spectrum antibacterial therapy. Definitions of invasive fungal infection were based on international consensus guidelines.21 Patients at high risk of invasive fungal infection were defined as those who received chemotherapy for acute myeloid leukaemia and those who underwent allogeneic bone-marrow transplantation.15 A breakthrough fungal infection was defined as an infection that occurred at least 72 h after the initiation of empirical antifungal treatment.

Outcome measures

The primary outcome measure was the degree of renal impairment between the continuous and 4 h infusion AmB groups. Serum creatinine was measured daily and creatinine clearance (CrCl) was calculated by the Cockcroft–Gault formula.22 Renal impairment was defined as a doubling of baseline serum creatinine and is expressed as a creatinine ratio (peak serum creatinine during AmB administration:baseline serum creatinine). The relationship between AmB infusion rate and renal impairment was also analysed with the aim of determining a potentially safe infusion rate threshold. Infusion reactions were not assessed due to the retrospective nature of the study and the inaccuracy in documentation.

Efficacy was assessed as a secondary endpoint, and included mortality at 14 days after the initiation of AmB, absence of breakthrough fungal infections during administration of AmB or within 7 days after completion of treatment, and the successful treatment of any baseline fungal infection, if present. Secondary endpoint analysis was performed to assist in the generation of hypotheses for future studies.

Statistical analysis

Statistical comparison of groups was performed by the {chi}2 or Fisher exact test, as appropriate. Non-parametric data were evaluated using the Mann–Whitney rank sum test. The number of patients required for the study was assessed by a prior power calculation. Assuming a rate of renal impairment of 50% in the 4 h infusion group, as determined by a previous review at our institution and the published literature,7 and a rate of 15% in the CI-AmB group,11 a total of 36 patients in each arm would be required to achieve a power of 85% at a two-sided significance level of 5%. Multivariate logistic regression analysis was used to adjust for potential confounding variables with regard to renal impairment. All variables that achieved a P value of ≤0.50 on univariate analysis were considered for inclusion in the model.23 A Kaplan–Meier curve was evaluated for the time to develop renal impairment. To assist in the identification of a safe AmB infusion rate cutoff, a receiver operator curve (ROC) was performed. A cutoff with a high sensitivity and negative predictive value was thought to be optimal for the clinical purpose. Statistical data entry and analysis were performed using the Epi-Info software package, version 6 (CDC, Atlanta, GA, USA) and Intercooled Stata (Version 8, 2003, College Station, Texas, USA). All P values were two-tailed, and a P < 0.05 was considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
A total of 1073 admissions were reviewed for the time period, making up 98.3% of all haematology admissions. The remaining patient charts were unavailable for review. A total of 81 admissions from 77 patients were included in the study, 39 received CI-AmB and 42 received 4 h infusion AmB. Patient demographics and clinical characteristics are outlined in Table 1. There was no significant difference in the age, sex, mean daily dose, duration of therapy, length of neutropenia and use of concurrent nephrotoxic drugs between the continuous and 4 h infusion AmB groups. Importantly, both groups were composed of a large and similar proportion of patients at high risk of invasive fungal infection (77% CI-AmB versus 83% 4 h infusion AmB, P=0.5) despite a greater number of patients in the 4 h infusion AmB group having acute myeloid leukaemia. The number of proven baseline fungal infections was similar between the continuous and 4 h infusion AmB groups, with equal numbers of candidaemia (two patients with Candida krusei and one patient with Candida glabrata compared with one patient with Candida krusei and one patient with Candida tropicalis, respectively) and invasive aspergillosis (two patients versus three patients, respectively).


View this table:
[in this window]
[in a new window]
 
Table 1. Demographic and clinical characteristics of the study population

 
Nephrotoxicity

Baseline serum creatinine and calculated CrCl were similar between the continuous and 4 h infusion AmB groups (Table 1). The median creatinine ratio (P < 0.001), percentage rise in serum creatinine (P < 0.001) and percentage reduction in CrCl (P < 0.001) during AmB treatment was significantly lower in patients given CI-AmB compared with 4 h infusion AmB (Table 2). Renal impairment, defined as a doubling of baseline serum creatinine, occurred significantly less frequently in the continuous compared with the 4 h infusion AmB group [10% and 45%, respectively, odds ratio (OR) 0.14; 95% confidence interval (CI) 0.04–0.5, P < 0.001].


View this table:
[in this window]
[in a new window]
 
Table 2. Renal toxicity in patients receiving continuous and 4 h infusion amphotericin B [values are expressed as median (range) unless otherwise specified]

 
The subgroup of patients who underwent allogeneic transplantation had similar results, with a median (range) creatinine ratio of 1.4 (1.1–2.2) in the CI-AmB group compared with 2.0 (1.3–4.0) in the 4 h infusion AmB group (P=0.005). Also, renal impairment was significantly less frequent with CI-AmB compared with 4 h infusion AmB (7% and 60%, respectively, OR 0.06; 95% CI 0.01–0.6, P=0.007). This significant difference in renal impairment was also maintained in the subgroup of patients who received concurrent nephrotoxic drugs (3% and 46%, respectively, OR 0.03; 95% CI 0.001–0.3, P < 0.001). No patient in the study required dialysis.

Multivariate logistic regression analysis (Table 3) confirmed that CI-AmB was the only variable to be significantly associated with renal impairment, with a protective effect (OR 0.16; 95% CI 0.05–0.5). The Kaplan–Meier analysis for renal impairment is shown in Figure 1, with a significant difference associated with CI-AmB (P < 0.001).


View this table:
[in this window]
[in a new window]
 
Table 3. Multivariate logistic regression analysis for variables associated with renal impairment

 


View larger version (14K):
[in this window]
[in a new window]
 
Figure 1. Kaplan–Meier analysis for time to develop renal impairment, showing a significant difference with CI-AmB compared with 4 h infusion AmB (P < 0.001).

 
A higher AmB infusion rate was significantly associated with renal impairment. Patients who developed renal impairment had a median infusion rate of 0.15 mg/kg/h compared with 0.04 mg/kg/h in the group with no renal impairment (P < 0.001). The relationship between the creatinine ratio and infusion rate is seen in Figure 2. After performing a ROC analysis (data not shown), 0.08 mg/kg/h was identified as the optimal safe infusion rate cutoff, with a sensitivity of 83% and a specificity of 62% with regard to the development of renal impairment. The negative predictive value of this cutoff was 90%. Using this threshold, we found that patients who had AmB infusion rates of ≥0.08 mg/kg/h were significantly more likely to develop renal impairment compared with patients with infusion rates of <0.08 mg/kg/h (OR 7.8; 95% CI 2.3–25.8, P < 0.001).



View larger version (10K):
[in this window]
[in a new window]
 
Figure 2. AmB infusion rate and creatinine ratio (Cr ratio). Renal impairment was defined as a Cr ratio of ≥2. After performing a ROC, 0.08 mg/kg/h was found to be the optimal safe infusion rate cutoff. Of patients who had renal impairment, 83% had an infusion rate of ≥0.08 mg/kg/h (sensitivity). Of patients with no renal impairment, 62% had an infusion rate of <0.08 mg/kg/h (specificity). Patients with infusion rates of ≥0.08 mg/kg/h were significantly more likely to develop renal impairment than patients with infusion rates <0.08 mg/kg/h (OR 7.8; 95% CI 2.3–25.8, P < 0.001).

 
Efficacy

Survival at 14 days after the initiation of AmB was significantly different between the continuous and 4 h infusion AmB groups (95% and 79%, respectively, OR 5.1; 95% CI 1.02–25.1, P=0.03) (Table 4), although, mortality directly due to invasive fungal infection was not significantly different [one patient (2.6%) for CI-AmB versus two patients (4.8%) for 4 h infusion AmB, P=1.00]. The other causes of death in the CI-AmB group included a patient with relapsed leukaemia post-autologous bone-marrow transplantation. The other causes of death in the 4 h infusion AmB group included four patients with progressive primary disease (three with acute myeloid leukaemia and one with myeloma), two patients with acute leukaemia who died of non-fungal infective causes (Gram-negative sepsis and Stenotrophomonas maltophilia pneumonia, respectively) and one patient with lymphoma and Pseudomonas pneumonia.


View this table:
[in this window]
[in a new window]
 
Table 4. Measures of efficacy between continuous and 4 h infusion AmB

 
No significant difference was observed in cure rates of baseline fungal infections (P=1.00). The breakthrough fungal infections were equal between the groups (P=1.00) and included a Candida krusei fungaemia and a probable lung infection with Aspergillus flavus in the CI-AmB group, and a fungaemia with Trichosporon beigelii and an invasive sinus infection with Exserohilum rostratum in the 4 h infusion AmB group.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
This retrospective cohort study provides supportive evidence that CI-AmB is significantly less nephrotoxic than 4 h infusion AmB in haematology patients with fever and neutropenia. It is the first study to look at comparative data between continuous and 4 h infusion AmB in bone-marrow transplant recipients, a group who are often receiving concurrent nephrotoxic drugs and who are poorly tolerant to renal impairment.14

The reduction in renal impairment observed with CI-AmB (OR 0.16; 95% CI 0.05–0.5, P=0.003) is of clinical importance. Recent evidence shows that nephrotoxicity with AmB is associated with increased mortality, prolonged length of hospital stays and an increase in total costs.5,6,24 For example, Bates et al.5 showed that acute renal failure from AmB was associated with an OR of 6.6 for death (95% CI 4.5–9.7), a mean increase in length of stay of 8.2 days (P < 0.001) and a mean adjusted increase in total costs of $US 29 823 per patient (P < 0.001). The current study shows that patients who received CI-AmB, as compared with 4 h infusion AmB, were six times less likely to develop renal impairment (overall rate 10%). This significant difference in renal toxicity was maintained among allogeneic transplant recipients and patients receiving concurrent nephrotoxic drugs. Such data compare favourably with the rates of nephrotoxicity observed with previous CI-AmB trials11,25 and importantly with liposomal-AmB, a drug whose principal advantage is its superior safety profile over 4 h infusion AmB.26

Given the results of previous studies on CI-AmB1013 and the assumption that toxic reactions to AmB increase with more rapid infusions,27,28 we hypothesized that the rate of infusion of AmB may be the best predictor of renal toxicity. We found that an infusion rate of <0.08 mg/kg/h was associated with a significantly lower risk of renal impairment (P < 0.001). The importance of this finding relates to a commonly reported argument against CI-AmB. AmB is incompatible with other drugs and therefore requires a dedicated intravascular line or catheter lumen for a 24 h period. This can lead to practical issues with drug administration, especially in critically ill patients. Our data suggest that by using a safe infusion rate (<0.08 mg/kg/h), infusions over less than 24 h may be feasible, giving more time for other drugs to be administered. For example, a 60 mg AmB dose in a 60 kg patient (1.0 mg/kg) could be given over 15–20 h. Interestingly, the value of 0.08 mg/kg/h equates to an AmB dose of 1.92 mg/kg over 24 h, a value similar to the 2.0 mg/kg/day dose used by Imhof et al.25 in a dose escalation study of CI-AmB. This dose was shown to be feasible, safe and well tolerated in most patients.

Given the low rate of renal impairment with CI-AmB and the cheap drug acquisition cost, the pharmacoeconomic potential is substantial. At our institution, as a consequence of reduced renal impairment, the total pharmacy expenditure for liposomal-AmB decreased by $A 245 200 during the year CI-AmB was implemented. This is notable, given the indirect costs of reduced nephrotoxicity (reduced length of stay, decreased resource utilization) have not been estimated.

Although the current study was not sufficiently powered to conclude on clinical efficacy, the results are encouraging and should stimulate further comparative trials to investigate this important area. Interestingly, a survival advantage was detected with CI-AmB, a finding observed in a previous study by Eriksson et al.11 We observed an increased mortality in the 4 h infusion AmB group, primarily due to relapsed disease and bacterial infection, factors that would not be influenced by the use of AmB. A study with a larger sample size is required to further elucidate this secondary endpoint.

The major limitations of this study are its retrospective nature and its use of historical controls. Retrospective cohort studies have the inherent limitation of potential selection bias. This issue was addressed by performing a nearly complete (98.3%) review of the cohorts involved. The two groups were evenly matched in important demographic characteristics, except for the number of patients with acute myeloid leukaemia. This difference in underlying disease, and its potential affect on renal impairment, was adjusted for by a multivariate logistic regression analysis. The limitations of using historical control data have been minimized by the use of clear inclusion criteria and an objective definition for the primary outcome. Unmeasured confounders, such as adherence to nephroprotective measures, can be problematic and may lead to potential bias. Increased staff motivation due to greater awareness of the adverse outcomes of AmB-associated nephrotoxicity may have influenced the results in favour of CI-AmB. The data came from a single institution and therefore may not be generalizable to other settings.

This study provides supportive evidence that CI-AmB is a less nephrotoxic alternative than 4 h infusion amphotericin B in haematology patients with fever and neutropenia. The infusion rate appears to be the most important predictor of renal impairment, with a potentially safe threshold of <0.08 mg/kg/h. Mortality was not increased with CI-AmB, and as a consequence of reduced toxicity, the requirement for a more costly lipid preparation is reduced. A comparative, prospective trial with a lipid preparation of amphotericin B is warranted.


    Acknowledgements
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
We thank the Haematology Unit, Infectious Diseases Unit and the medical records department at the Royal Brisbane and Women's Hospital for their assistance with chart retrieval. We also thank Dr Charles Denaro and Dr Monica Slavin for reviewing the manuscript, and Kerry Watson and Micheal Bailey for statistical advice. Financial support and conflicts of interest: none.


    Footnotes
 
* Correspondence address. Infectious Diseases Unit, The Alfred Hospital, Prahran, Melbourne, Victoria, 3181, Australia. Tel: +61-3-9276-2000; Fax: +61-3-9276-2431; orEmail: antonpeleg{at}iprimus.com.au


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
1 . Pizzo, P. A., Robichaud, K. J., Gill, F. A. et al. (1982). Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. American Journal of Medicine 72, 101–11.[ISI][Medline]

2 . Empiric antifungal therapy in febrile granulocytopenic patients. EORTC International Antimicrobial Therapy Cooperative Group (1989). American Journal of Medicine 86, 668–72.[ISI][Medline]

3 . Hughes, W. T., Armstrong, D., Bodey, G. P. et al. (1997). 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Infectious Diseases Society of America. Clinical Infectious Diseases 25, 551–73.[ISI][Medline]

4 . Pahls, S. & Schaffner, A. (1994). Comparison of the activity of free and liposomal amphotericin B in vitro and in a model of systemic and localized murine candidiasis. Journal of Infectious Diseases 169, 1057–61.[ISI][Medline]

5 . Bates, D. W., Su, L., Yu, D. T. et al. (2001). Mortality and costs of acute renal failure associated with amphotericin B therapy. Clinical Infectious Diseases 32, 686–93.[CrossRef][ISI][Medline]

6 . Harbarth, S., Burke, J. P., Lloyd, J. F. et al. (2002). Clinical and economic outcomes of conventional amphotericin B-associated nephrotoxicity. Clinical Infectious Diseases 35, e120–7.[CrossRef][ISI][Medline]

7 . White, M. H., Bowden, R. A., Sandler, E. S. et al. (1998). Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia. Clinical Infectious Diseases 27, 296–302.[ISI][Medline]

8 . Walsh, T. J., Finberg, R. W., Arndt, C. et al. (1999). Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. New England Journal of Medicine 340, 764–71.[Abstract/Free Full Text]

9 . Cagnoni, P. J. (2002). Liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients. Journal of Antimicrobial Chemotherapy 49, Suppl. 1, 81–6.[Abstract/Free Full Text]

10 . Chabot, G. G., Pazdur, R., Valeriote, F. A. et al. (1989). Pharmacokinetics and toxicity of continuous infusion amphotericin B in cancer patients. Journal of Pharmaceutical Science 78, 307–10.[ISI]

11 . Eriksson, U., Seifert, B. & Schaffner, A. (2001). Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. British Medical Journal 322, 579–82.[Abstract/Free Full Text]

12 . Furrer, K., Schaffner, A., Vavricka, S. R. et al. (2002). Nephrotoxicity of cyclosporine A and amphotericin B-deoxycholate as continuous infusion in allogenic stem cell transplantation. Swiss Medical Weekly 132, 316–20.[ISI][Medline]

13 . Speich, R., Dutly, A., Naef, R. et al. (2002). Tolerability, safety and efficacy of conventional amphotericin B administered by 24-hour infusion to lung transplant recipients. Swiss Medical Weekly 132, 455–8.[ISI][Medline]

14 . Zager, R. A., O'Quigley, J., Zager, B. K. et al. (1989). Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients. American Journal of Kidney Diseases 13, 210–6.[ISI][Medline]

15 . Prentice, H. G., Kibbler, C. C. & Prentice, A. G. (2000). Towards a targeted, risk-based, antifungal strategy in neutropenic patients. British Journal of Haematology 110, 273–84.[CrossRef][ISI][Medline]

16 . Mayer, J., Doubek, M., Doubek, J. et al. (2002). Reduced nephrotoxicity of conventional amphotericin B therapy after minimal nephroprotective measures: animal experiments and clinical study. Journal of Infectious Diseases 186, 379–88.[CrossRef][ISI][Medline]

17 . Heidemann, H. T., Gerkens, J. F., Spickard, W. A. et al. (1983). Amphotericin B nephrotoxicity in humans decreased by salt repletion. American Journal of Medicine 75, 476–81.[ISI][Medline]

18 . Stevens, D. A., Kan, V. L., Judson, M. A. et al. (2000). Practice guidelines for diseases caused by Aspergillus. Infectious Diseases Society of America. Clinical Infectious Diseases 30, 696–709.[CrossRef][ISI][Medline]

19 . Caillot, D., Casasnovas, O., Bernard, A. et al. (1997). Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. Journal of Clinical Oncology 15, 139–47.[Abstract]

20 . Herbrecht, R., Denning, D. W., Patterson, T. F. et al. (2002). Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. New England Journal of Medicine 347, 408–15.[Abstract/Free Full Text]

21 . Ascioglu, S., Rex, J. H., de Pauw, B. et al. (2002). Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clinical Infectious Diseases 34, 7–14.[CrossRef][ISI][Medline]

22 . Cockcroft, D. W. & Gault, M. H. (1976). Prediction of creatinine clearance from serum creatinine. Nephron 16, 31–41.[ISI][Medline]

23 . Dales, L. G. & Ury, H. K. (1978). An improper use of statistical significance testing in studying covariables. International Journal of Epidemiology 7, 373–5.[Abstract]

24 . Cagnoni, P. J., Walsh, T. J., Prendergast, M. M. et al. (2000). Pharmacoeconomic analysis of liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients. Journal of Clinical Oncology 18, 2476–83.[Abstract/Free Full Text]

25 . Imhof, A., Walter, R. B. & Schaffner, A. (2003). Continuous infusion of escalated doses of amphotericin B deoxycholate: an open-label observational study. Clinical Infectious Diseases 36, 943–51.[CrossRef][ISI][Medline]

26 . Ostrosky-Zeichner, L., Marr, K. A., Rex, J. H. et al. (2003). Amphotericin B: time for a new "gold standard". Clinical Infectious Diseases 37, 415–25.[CrossRef][ISI][Medline]

27 . Oldfield, E. C., 3rd, Garst, P. D., Hostettler, C. et al. (1990). Randomized, double-blind trial of 1- versus 4-hour amphotericin B infusion durations. Antimicrobial Agents and Chemotherapy 34, 1402–6.[ISI][Medline]

28 . Ellis, M. E., al-Hokail, A. A., Clink, H. M. et al. (1992). Double-blind randomized study of the effect of infusion rates on toxicity of amphotericin B. Antimicrobial Agents and Chemotherapy 36, 172–9.[Abstract]