Rapid Infusion of Amphotericin B: Is It Safe, Effective, and Wise? DAVIDJ. DRUT~!,M.D., fVewerk,NewJersey
he concept that amphotericin B might be adT ministered much more rapidly than the standard 4- to g-hour infusion period has been raised repeatedlyover the 35yearsthat this drug hasbeen in use.However,the exactdefinition of “rapid infusion” has never been established. Several recent atudiea have suggestedthat a-hour infusion regimens may be safe and reasonablywell tolerated [l-3]. However,becausethe three most recentprospectivestudies of this issuehaveevaluated4 hours asthe extendedinfusion period, and 1 hour [4,5]or 45minutes [S] asthe rapid infusion period,the definition of rapid infusion for the purposes of this commentary wilI be 1 hour or less. A 45-minute to l-hour infusion period for amphotericin B appears,on the surface,to be remarkably aggressive.However, such regimenswere explored from time to time in the early daysof amphotericin B usage and found, anecdotally, to be tolerable [7,8]. Twenty-one years ago,Fields and colleagues [9] evaluated16 amphotericin B infusions in three patients and found no differences in toxicity between 45-minute and B-hourinfusions.The clearest apparent limitation to the use of such aggressive infusions hasbeenpreexisting impaired renal function, under conditions where the patient is unable to clear a sudden load of potaaaium, presumably releasedfrom amphotericin B-damagedhost cells. Under such circumstances,hyperkalemia has resulted in life-threatening ventricular fibrillation
[101.
Whereasearlier studies seemedto indicate that only the occasionalpatient might tolerate rapid amphotericin B infusion, more recentstudieshavesuggestedthat the benefit canbe extendedto the larger patient population by meansof comprehensivepremedication and co-medicationregimensdirected at predictable side effects.Accordingly, although not From St. Michael’s Medical Center and Seton Hall University, School of Graduate Medical Education, Newark, New Jersey. Requests for reprints should be addressed to David J. Drutz, M.D., St.
Manukcript
submitted
June 2.1992.
and accepted
June 3,1992.
baaedon prospective,controlled studies,an empiric regimen of acetaminophen,diphenhydramine, hydrocortisone,and meperidinehasbecomea predictable concomitant to amphotericin B therapy in most institutions [11,12]. In addition, potassium supplementation, oral or intravenous,is employed routinely to offset the potassium loss that predictably accompaniesamphotericin B-induced distal renal tubular acidosis [13]. Although heparin, to prevent phlebitis, was originally a part of most amphotericin B infusion regimens,the use of central venouslines and control of the final concentration of amphotericin B in the i&sate, to 0.1 mg/mL, have lessenedthe apparent needfor this therapeutic adjunct [ll]. As noted, there have been three recent evaluations on the safety of 45-minute to l-hour amphotericin B infusion regimens(including the paper by Crux and colleaguesin this issueof the Journal) [P 61.The number of patients in each study was extremely smalk 12,20,and 25,respectively[4-6]. All three studiesexcludedpatientawith impaired renal function (creatinineclearancebelow 25mL/min [4] or below 40 mllmin [6]; or serum creatinine above 1.9 mg/dL [5]). Two included premeditation or comedication with diphenhydramine, acetaminophen, hydrocortisone, heparin, and meperidine [4,5].One omitted acetaminophenand heparin [6]. The latter study also utilized amphotericin B in a higher final concentration (0.25 mg/mL) then is usually recommended[6]. Outcomesof the three studieswere not identical, and there were differencesin protocol design that might haveaccountedfor the discrepancies.In the study by Oldfield and colleagues[4], the maintenancedoseof amphotericin B (0.29to 0.5 mg/kg/d) had already been reachedbefore the randomized, double-blind study commenced.No data wereprovided relative to the tolerance of the incremental dosesprecedingthe maintenancedose.The conclusion of this study was that the overall incidence of side effects (fever, acceleratedpulse, chills, and needfor supplemental meperidine administration) wasthe samein the l- and 4-hour infusion groups. However, the mean time to onset of the fever,
August1992 The AmericanJournalof Medlclno Volume93
119
RAPID INFUSION
OF AMPHOTERICIN
B / DRUTZ
tachycardia, and chills was significantly shorter in the l-hour group [4]. In the study by Ellis and colleagues[6], a 1-mg test doseof amphotericin B was followed immediately by 7 days of treatment with a maintenance doseof 0.5 mg/kg; there wereno interval incremental doses,and therefore,no opportunity to develop stepwisetolerance(“tachyphylaxis”) to side effects. In this randomized, double-blind study, the mean time to onsetof chills wasshorterfor the 45-minute infusion group. In addition, accelerated pulse, chills, and supplemental meperidine requirements were significantly more common in the 45-minute group. Finally, nauseaand vomiting werea particular problem in the 45-minute group. Tolerance to many of the aforementionedside effectsdeveloped over the first 5 days of therapy. The authors concluded that rapid infusion of amphotericin B could not be recommended,at least during the first 5 to 7 days of therapy [6]. Finally, in the current study by Crux and colleagues[5], a 1-mg test doseof amphotericin B was followed in 4 to 6 hoursby a 5-mgincremental dose, and subsequentlyby daily dosageincreasesto a desired maintenance dose of 0.5 to 1.0 n&g/d. Thus, the evaluation period in this nonrandomixed study encompassedthe entire interim dosageregimen. The authors concluded that rapid infusions are safe and have no more toxicity than more prolonged infusions [5]. A cautious conclusion from these three studies might be that 45-minute to l-hour infusions of amphotericin B are safe, provided that extensive premeditation and co-medication for side effects are utilized and provided that there is a period of incremental increasesof daily dosagebeyond the initial test dosein order to achieveside-effect tolerance,an apparent matter of 5 to 7 days. However,it should be noted that all three authors were cautious about recommending aggressiveinfusion regimens for all patients. Oldfield et al [4] pointed out the needfor a larger study, with electrocardiographic monitoring. Cruz and co-workers [5] considered the approachto be experimental and to be conducted only under controlled circumstances. None of these studies was designedin such a way that therapeutic efficacy could be assessed.In none of the rapid infusion studies published to date has efficacy been as rigorously assessedas safety. Clearly, much larger and more comprehensive studies are neededbefore l-hour (or less) amphotericin B infusions can be recommendedfor general use.However,it is clearthat somepatients do tolerate aggressivetherapy, and thesethree studiespro-
120
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Journal
of Medlclne
Volume
93
vide reassuranceof short-term safety under those circumstances. It is possible, should rapid infusion regimens grow in popularity, that additional toxic propensities of amphotericin B may emerge.Recentstudies suggestthat amphotericin B has a direct constricting effect on vascularsmooth muscle 1141;this may accountnot only for impaired renal perfusion with reduced glomerular filtration rate (amply recognized), but also for cardiovascular side effects, which haveheretoforebeenuncommon (e.g.,malignant hypertension [15]). Although not of apparent major significance,transient blood pressureabnormalities were noted in two of the studies discussed above [4,6], and one of the patients in the Crux study experiencedatrial fibrillation (l-hour infusion) [5]. Not only should rapid infusion [9] regimens be proscribed in patients with renal failure (and uncontrolled potassium concentrations),but also in those with a history of cardiovascular disease. Based on data available in the literature, plue personalexperienceand communicationswith othersin the field, I believethat amphotericin B should not be routinely administered in lessthan 2 hours. In addition, the more commonly accepted4- to 6hour regimen is preferred and should be employed whenthere is no tactical reasonfor rapid amphotericin B infusion. Although amphotericin B plasma levels may be transiently higher in patients who receivethe drug by rapid infusion [9], the poor apparent relationship among peak plasma levels, in vitro susceptibility of fungi (testing is not standardized), and clinical outcome militate against using rapid infusion asa strategyto treat putatively more resistant fungi.
REFERENCES 1. Cteary JD, Weisdorf D. fletcher CV. Effect of infuslon rate on amphotericin B-associated febrile reactions. Drug lntell Clin Pharm 1988; 22: 76972. 2. Spltzer TR, Creger RJ, Fox RM, Lazarus HM. Rapid infusion amphotericin B: effective and well-tolerated therapy for neutropenic fever. Fharmatherapeutica 1939; 5: 305-11. 3. Aming M, Dresen B. Aul C. Schneider W. Influence of infusion time on the acute toxicity of amphotericin B: results of a randomized double-blind study. Recent Results Cancer Res 1991; 121: 34742. 4.Oktfiald EC, Garst PD, Hostettler C, Whii M, Samuelson D. Randomii, doubleblind trial of l-versus 4-hour amphotericin B infusion durations. Antimicrab Agents Chemother 1990; 34: 14024 5. Cruz JM. Peacock JE Jr, Loomer L, eta/. Rapid intravenous infusion of amphotericin B: a pilot study. Am J Med 1992; 93: 123-30. 6. Ellis ME. Al-Hokail AA, Clink HM, et a/. Double-blind randomii study of tha effect of infusion rates on toxicity of amphotericin 6. Antimicrob Agents Chemother 1992; 36: 172-9. 7. Seabury JH. Dascomb HE. Experience with amphotericin B. Ann NY Acad Sci 1960; 89: 202-20.
RAPID INFUSlON OF AMPHOTERICIN B / DRUTZ 9. Utz JP. Bennett JE. Brand&s MW, Butler WT. Hill GJ. Amphotericin B toxicity. Ann Intern Med 1964; 61: X34-64. S.Ftelds BT. Bates JH. Abernathy RS. Effect of rapid intravenous infusion on serum concentrattons of amphotericin B. Appl Microbiil 1971; 22: 6157. lO.Craven PC, Gremillii DH. Risk factors of ventricular fibrillation during rapid amphotericin B infusion. Antimicrob Agents Chemother 1985: 27: 66%
12. Grasela TH. Goodwin SD, Walawander MK. Cramer RL, Fuhs DW, Moriarty VP. Prospective surveillance of intravenous amphotericin B use patterns. Pharmacotherapy 1990: 10: 341-6. 13. Gallis HA, Drew RH, pickard WW. Amphotericin B: SO years of dinical experience. Rev Infect Dis 1990; 12: 30649. 14. Sawaya BP, Weihprecht H. Campbell WR. et al. Direct vasoconstnctiin as a possible cause for amphotericin B-induced nephrotoxiddty in rats. J Clin Invest
71.
1991; 87: 2097-107. 15. Dukes CS, Perfect JR. Amphotericin B-induced malig!nant hypertensive scdes [letter]. J Infect Dis 1990; 161: 588.
11. Clements
JS, Peacock JE. Amphotericin ty. Am J Med 1990; 88: !i-22N-7N.
B revisited:
reassessme
nt of toxici-
Augusll992
The American Journal ol Medlclne
Volume 93
epi-
121
he concept that amphotericin B might be adT ministered much more rapidly than the standard 4- to g-hour infusion period has been raised repeatedlyover the 35yearsthat this drug hasbeen in use.However,the exactdefinition of “rapid infusion” has never been established. Several recent atudiea have suggestedthat a-hour infusion regimens may be safe and reasonablywell tolerated [l-3]. However,becausethe three most recentprospectivestudies of this issuehaveevaluated4 hours asthe extendedinfusion period, and 1 hour [4,5]or 45minutes [S] asthe rapid infusion period,the definition of rapid infusion for the purposes of this commentary wilI be 1 hour or less. A 45-minute to l-hour infusion period for amphotericin B appears,on the surface,to be remarkably aggressive.However, such regimenswere explored from time to time in the early daysof amphotericin B usage and found, anecdotally, to be tolerable [7,8]. Twenty-one years ago,Fields and colleagues [9] evaluated16 amphotericin B infusions in three patients and found no differences in toxicity between 45-minute and B-hourinfusions.The clearest apparent limitation to the use of such aggressive infusions hasbeenpreexisting impaired renal function, under conditions where the patient is unable to clear a sudden load of potaaaium, presumably releasedfrom amphotericin B-damagedhost cells. Under such circumstances,hyperkalemia has resulted in life-threatening ventricular fibrillation
[101.
Whereasearlier studies seemedto indicate that only the occasionalpatient might tolerate rapid amphotericin B infusion, more recentstudieshavesuggestedthat the benefit canbe extendedto the larger patient population by meansof comprehensivepremedication and co-medicationregimensdirected at predictable side effects.Accordingly, although not From St. Michael’s Medical Center and Seton Hall University, School of Graduate Medical Education, Newark, New Jersey. Requests for reprints should be addressed to David J. Drutz, M.D., St.
Manukcript
submitted
June 2.1992.
and accepted
June 3,1992.
baaedon prospective,controlled studies,an empiric regimen of acetaminophen,diphenhydramine, hydrocortisone,and meperidinehasbecomea predictable concomitant to amphotericin B therapy in most institutions [11,12]. In addition, potassium supplementation, oral or intravenous,is employed routinely to offset the potassium loss that predictably accompaniesamphotericin B-induced distal renal tubular acidosis [13]. Although heparin, to prevent phlebitis, was originally a part of most amphotericin B infusion regimens,the use of central venouslines and control of the final concentration of amphotericin B in the i&sate, to 0.1 mg/mL, have lessenedthe apparent needfor this therapeutic adjunct [ll]. As noted, there have been three recent evaluations on the safety of 45-minute to l-hour amphotericin B infusion regimens(including the paper by Crux and colleaguesin this issueof the Journal) [P 61.The number of patients in each study was extremely smalk 12,20,and 25,respectively[4-6]. All three studiesexcludedpatientawith impaired renal function (creatinineclearancebelow 25mL/min [4] or below 40 mllmin [6]; or serum creatinine above 1.9 mg/dL [5]). Two included premeditation or comedication with diphenhydramine, acetaminophen, hydrocortisone, heparin, and meperidine [4,5].One omitted acetaminophenand heparin [6]. The latter study also utilized amphotericin B in a higher final concentration (0.25 mg/mL) then is usually recommended[6]. Outcomesof the three studieswere not identical, and there were differencesin protocol design that might haveaccountedfor the discrepancies.In the study by Oldfield and colleagues[4], the maintenancedoseof amphotericin B (0.29to 0.5 mg/kg/d) had already been reachedbefore the randomized, double-blind study commenced.No data wereprovided relative to the tolerance of the incremental dosesprecedingthe maintenancedose.The conclusion of this study was that the overall incidence of side effects (fever, acceleratedpulse, chills, and needfor supplemental meperidine administration) wasthe samein the l- and 4-hour infusion groups. However, the mean time to onset of the fever,
August1992 The AmericanJournalof Medlclno Volume93
119
RAPID INFUSION
OF AMPHOTERICIN
B / DRUTZ
tachycardia, and chills was significantly shorter in the l-hour group [4]. In the study by Ellis and colleagues[6], a 1-mg test doseof amphotericin B was followed immediately by 7 days of treatment with a maintenance doseof 0.5 mg/kg; there wereno interval incremental doses,and therefore,no opportunity to develop stepwisetolerance(“tachyphylaxis”) to side effects. In this randomized, double-blind study, the mean time to onsetof chills wasshorterfor the 45-minute infusion group. In addition, accelerated pulse, chills, and supplemental meperidine requirements were significantly more common in the 45-minute group. Finally, nauseaand vomiting werea particular problem in the 45-minute group. Tolerance to many of the aforementionedside effectsdeveloped over the first 5 days of therapy. The authors concluded that rapid infusion of amphotericin B could not be recommended,at least during the first 5 to 7 days of therapy [6]. Finally, in the current study by Crux and colleagues[5], a 1-mg test doseof amphotericin B was followed in 4 to 6 hoursby a 5-mgincremental dose, and subsequentlyby daily dosageincreasesto a desired maintenance dose of 0.5 to 1.0 n&g/d. Thus, the evaluation period in this nonrandomixed study encompassedthe entire interim dosageregimen. The authors concluded that rapid infusions are safe and have no more toxicity than more prolonged infusions [5]. A cautious conclusion from these three studies might be that 45-minute to l-hour infusions of amphotericin B are safe, provided that extensive premeditation and co-medication for side effects are utilized and provided that there is a period of incremental increasesof daily dosagebeyond the initial test dosein order to achieveside-effect tolerance,an apparent matter of 5 to 7 days. However,it should be noted that all three authors were cautious about recommending aggressiveinfusion regimens for all patients. Oldfield et al [4] pointed out the needfor a larger study, with electrocardiographic monitoring. Cruz and co-workers [5] considered the approachto be experimental and to be conducted only under controlled circumstances. None of these studies was designedin such a way that therapeutic efficacy could be assessed.In none of the rapid infusion studies published to date has efficacy been as rigorously assessedas safety. Clearly, much larger and more comprehensive studies are neededbefore l-hour (or less) amphotericin B infusions can be recommendedfor general use.However,it is clearthat somepatients do tolerate aggressivetherapy, and thesethree studiespro-
120
Aujust
1992
The Amerken
Journal
of Medlclne
Volume
93
vide reassuranceof short-term safety under those circumstances. It is possible, should rapid infusion regimens grow in popularity, that additional toxic propensities of amphotericin B may emerge.Recentstudies suggestthat amphotericin B has a direct constricting effect on vascularsmooth muscle 1141;this may accountnot only for impaired renal perfusion with reduced glomerular filtration rate (amply recognized), but also for cardiovascular side effects, which haveheretoforebeenuncommon (e.g.,malignant hypertension [15]). Although not of apparent major significance,transient blood pressureabnormalities were noted in two of the studies discussed above [4,6], and one of the patients in the Crux study experiencedatrial fibrillation (l-hour infusion) [5]. Not only should rapid infusion [9] regimens be proscribed in patients with renal failure (and uncontrolled potassium concentrations),but also in those with a history of cardiovascular disease. Based on data available in the literature, plue personalexperienceand communicationswith othersin the field, I believethat amphotericin B should not be routinely administered in lessthan 2 hours. In addition, the more commonly accepted4- to 6hour regimen is preferred and should be employed whenthere is no tactical reasonfor rapid amphotericin B infusion. Although amphotericin B plasma levels may be transiently higher in patients who receivethe drug by rapid infusion [9], the poor apparent relationship among peak plasma levels, in vitro susceptibility of fungi (testing is not standardized), and clinical outcome militate against using rapid infusion asa strategyto treat putatively more resistant fungi.
REFERENCES 1. Cteary JD, Weisdorf D. fletcher CV. Effect of infuslon rate on amphotericin B-associated febrile reactions. Drug lntell Clin Pharm 1988; 22: 76972. 2. Spltzer TR, Creger RJ, Fox RM, Lazarus HM. Rapid infusion amphotericin B: effective and well-tolerated therapy for neutropenic fever. Fharmatherapeutica 1939; 5: 305-11. 3. Aming M, Dresen B. Aul C. Schneider W. Influence of infusion time on the acute toxicity of amphotericin B: results of a randomized double-blind study. Recent Results Cancer Res 1991; 121: 34742. 4.Oktfiald EC, Garst PD, Hostettler C, Whii M, Samuelson D. Randomii, doubleblind trial of l-versus 4-hour amphotericin B infusion durations. Antimicrab Agents Chemother 1990; 34: 14024 5. Cruz JM. Peacock JE Jr, Loomer L, eta/. Rapid intravenous infusion of amphotericin B: a pilot study. Am J Med 1992; 93: 123-30. 6. Ellis ME. Al-Hokail AA, Clink HM, et a/. Double-blind randomii study of tha effect of infusion rates on toxicity of amphotericin 6. Antimicrob Agents Chemother 1992; 36: 172-9. 7. Seabury JH. Dascomb HE. Experience with amphotericin B. Ann NY Acad Sci 1960; 89: 202-20.
RAPID INFUSlON OF AMPHOTERICIN B / DRUTZ 9. Utz JP. Bennett JE. Brand&s MW, Butler WT. Hill GJ. Amphotericin B toxicity. Ann Intern Med 1964; 61: X34-64. S.Ftelds BT. Bates JH. Abernathy RS. Effect of rapid intravenous infusion on serum concentrattons of amphotericin B. Appl Microbiil 1971; 22: 6157. lO.Craven PC, Gremillii DH. Risk factors of ventricular fibrillation during rapid amphotericin B infusion. Antimicrob Agents Chemother 1985: 27: 66%
12. Grasela TH. Goodwin SD, Walawander MK. Cramer RL, Fuhs DW, Moriarty VP. Prospective surveillance of intravenous amphotericin B use patterns. Pharmacotherapy 1990: 10: 341-6. 13. Gallis HA, Drew RH, pickard WW. Amphotericin B: SO years of dinical experience. Rev Infect Dis 1990; 12: 30649. 14. Sawaya BP, Weihprecht H. Campbell WR. et al. Direct vasoconstnctiin as a possible cause for amphotericin B-induced nephrotoxiddty in rats. J Clin Invest
71.
1991; 87: 2097-107. 15. Dukes CS, Perfect JR. Amphotericin B-induced malig!nant hypertensive scdes [letter]. J Infect Dis 1990; 161: 588.
11. Clements
JS, Peacock JE. Amphotericin ty. Am J Med 1990; 88: !i-22N-7N.
B revisited:
reassessme
nt of toxici-
Augusll992
The American Journal ol Medlclne
Volume 93
epi-
121
