Is It Time to Give Amphotericin Round-the-Clock?
Abstract & Commentary
Synopsis: Compared to the standard practice of administering amphotericin B over a 4-hour period, infusing amphotericin B over the entire 24-hour period was associated with fewer infusion-related side effects and lesser nephrotoxicity.
Source: Eriksson U, et al. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: Randomised controlled trial. BMJ. 2001;322:579-582.
Since its introduction into clinical practice more than 40 years ago, amphotericin B has remained an invaluable antifungal agent whose use has been limited chiefly by immediate and delayed side effects. Among the troublesome immediate, infusion-related adverse effects, fever, shaking chills, nausea, and vomiting are well known.
Eriksson and colleagues at Zurich University Hospital enrolled patients in a trial comparing 2 amphotericin B infusion times, 4 hours (termed "rapid") and 24 hours ("continuous"). Patients qualified for the study if they had refractory fever or strongly suspected or proven invasive fungal infection. Of the 80 patients enrolled in the trial, more than 90% were severely neutropenic as a result of treatment for acute leukemia or lymphoma. Half of the patients received rapid amphotericin B infusions, while the other half were infused continuously over the entire 24 hours of each day of treatment. Maximum daily doses ranged from 0.4 to 1.2 mg/kg in the rapid group, and 0.5 to 1.5 mg/kg in the continuous group. Median maximum daily doses were virtually identical in the 2 groups, 0.95 mg/kg and 0.96 mg/kg, respectively. Study patients were treated for a minimum of 3 days to a maximum of 89 days; those in the continuous treatment group were treated somewhat longer than those in the rapid group (median length of therapy 16 and 12 days, respectively). Therapy with concomitant nephrotoxic medications, such as aminoglycosides and vancomycin, was similar in both groups. Patients were monitored for fever (antipyretics were prohibited), chills, rigors, vomiting, and such laboratory analytes as serum creatinine, electrolytes, magnesium, and C-reactive protein.
Febrile and other reactions to amphotericin B infusions occurred significantly less often in the continuous-infusion group (see Table). Moreover, patients receiving continuous infusion required drugs to suppress fever and chills (eg, meperidine, acetaminophen, and corticosteroids) less often than those in the 4-hour infusion group.
| Table: Infusion-Related Side Effects | ||
|
Infusion Rate
|
||
|
Rapid
|
Continuous
|
|
|
(n=40)
|
(n=40)
|
|
| Reactions on day 1 | ||
| Fever |
21 (53)
|
10 (25)
|
| Chills |
21 (53)
|
5 (13)
|
| Vomiting |
14 (35)
|
4 (10)
|
| Headache |
4 (10)
|
0
|
| Overall reactions | ||
| Chills |
25 (63)
|
8 (20)
|
| Vomiting |
24 (60)
|
11 (28)
|
| Values are numbers (percentages) of patients | ||
Continuous infusion patients experienced lesser increases of serum creatinine—and had correspondingly greater calculated creatinine clearances—during and at the end of treatment. Hypokalemia was less frequent in the continuous infusion group, but the difference was not statistically significant. Although proven or probable fungal infection was more frequent in the continuous infusion group, mortality both during and after amphotericin B treatment was diminished.
Eriksson et al conclude that continuous infusion of amphotericin B may be at least as effective as daily 4-hour infusions, and is associated with decreased rates of nephrotoxicity and infusion-related side effects.
Comment by Jerry D. Smilack, MD
The implications of this study are extremely important. Clinicians’ reluctance to institute amphotericin B therapy is chiefly related to infusion-related side effects and concern over the potential of nephrotoxicity. Indeed, these are the driving forces behind the increasing use of liposomal amphotericin B products that have become available in the past few years. Eriksson et al have demonstrated that daily administration of amphotericin B over a 24-hour period can result in marked reduction of chills, fever, and gastrointestinal side effects, with the additional benefit of reduced nephrotoxicity.
What are the limitations of this study? The most important limitation is that it was performed almost exclusively in a strictly defined group of patients, those with hematological or solid tumor malignancies, almost all of whom were severely neutropenic. Granted, the number of patients in each of the randomized groups was respectable, but not huge. Whether similar results would be obtained in non-neutropenic, general medical, and surgical patients is open to conjecture and requires investigation. Another small point relates to Eriksson et al’s definition of fever (core temperature ³ 39.3° C [102.7° F]); whether a lower threshold definition would alter the results is not known. Also unclear was how Eriksson et al differentiated fever induced by amphotericin B from fever associated with suspected or proven fungal infection. One final point that was somewhat vague in the study: although Eriksson et al stated the maximum daily and cumulative doses of amphotericin B, doses used to initiate therapy were not mentioned. One must presume they were similar in both groups of patients.
Will continuous (24-hour) dosing become the method of choice? Will it obviate clinicians’ tendency to go directly to liposomal amphotericin B? The questions are not moot insofar as medical costs are concerned. Amphotericin B deoxycholate is inexpensive (average wholesale price [AWP] of a 50-mg daily dose is $11.64), while the liposomal preparations strain hospital budgets (AWP of a 350-mg dose [5 mg/kg for a 70 kg patient] ranges from $653.31 for amphotericin B cholesteryl complex to $1318.80 for amphotericin B liposomal).
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