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Dosage for malaria treatment
THE LANCET
Dosage for malaria treatment SIR—We write in response to mistakes by Kain and colleagues (Aug 31, p 621).1 By contrast with their suggestion, the most recent edition of Mandell, Douglas and Bennett’s principles and practice of infectious diseases2 makes clear that the recommended loading dose of quinidine gluconate for treatment of severe malaria is 10 mg/kg intravenously (iv), followed by 0·02 mg/kg of quinidine gluconate iv per minute, and that the loading dose of quinine dihydrochloride is 20 mg salt/kg iv followed by 10 mg salt/kg every 8 h (in table 2, p 464, Ch 34, by Jernigan and Pearson, which was reprinted with permission from The Medical Letter; and in table 4, p 2424 in Ch 253 by Krogstad). *Donald J Krogstad, Richard D Pearson, John E Bennett, Raphael Dolin, Gerald L Mandell *Department of Tropical Medicine, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA; University of Virginia Health Sciences Center Charlottesville, Virginia; Laboratory of Clnical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
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Kain KC, Gadd E, Gushulak B, McCarthy A, MacPherson D. Errors in treatment recommendations for severe malaria. Lancet 1996; 348: 621–22. Krogstad DJ. Plasmodium species (malaria). In: Mandell, Douglas and Bennett’s principles and practice of infectious diseases, 4th ed. New York: Churchill Livingstone, 1995: 2415–27.
SIR—Kain and colleagues’1 letter contains some errors of its own. The Medical Letter’s recommendation for parenteral treatment of malaria with quinidine is not what they say it is. For some years, to avoid possible confusion between base and salt dosages, we have specified use of quinidine gluconate (10 mg/kg loading dose, followed by 0·02 mg/kg per min). Mark Abramowicz The Medical Letter Inc, 1000 Main Street, New Rochelle, NY 10801-7537, USA
1
Kain KC, Gadd E, Gushnlak B, McCarthy A, MacPherson D. Errors in treatment recommendations for severe malaria. Lancet 1996; 348: 621–22.
SIR—Kain and colleagues’ letter,1 on behalf of the Committee to Advise on Tropical Medicine and Travel (CATMAT), Health and Welfare, Canada, contains an error in dosage and in citation of errors. The current recommendations as stated in The Medical Letter, in Mandell, Douglas and Bennett’s principles and practice of infectious diseases, 4th ed and in the Sanford Guide to Antimicrobial Therapy, 1996, each state “quinidine gluconate 10 mg/kg loading dose (in normal saline) slowly over 1–2 h, followed by continuous infusion of 0·02 mg/kg per min”, not base as Kain and co-workers say. The recommendation of 0·02 mg/kg per min requires an infusion pump. These are not generally available in most developing countries. The Sanford guide provides an alternative: quinidine gluconate iv continuous infusion. Alternative (infusion pump not available) 15 mg/kg iv over 4 h then 7·5 mg/kg iv over 4 h given every 8 h. The regimen of 10 mg/kg loading dose then 0·02 mg/kg per min provides 38·8 mg/kg quinidine gluconate (salt) for the first 24 h. This is the dose that was used by Miller et al.2 The regimen of 15 mg/kg loading dose then 7·5 mg/kg given every 8 h is equivalent, providing 37·5 mg/kg quinidine gluconate for the first 24 h. Phillips and co-workers used another regimen which provided 48 mg/kg quinidine gluconate (salt) during the first 24 h.3 The dosage regimen, “quinidine base 15 mg/kg loading dose (quinidine gluconate
Vol 348 • November 9, 1996
[salt] 24 mg/kg) by intravenous infusion over 4 h followed by quinidine base 7·5 mg/kg (quinidine gluconate [salt] 12 mg/kg) every 8 h infused over 4 h” recommended by Kain et al provides 60 mg/kg quinidine gluconate in the first 24 h. This is in excess by 25–60% of the dosages used in reported series. I agree that base/salt conversions of antimalarials create confusion and the committees should seek uniformity. In the meantime, the replacement of quinidine gluconate as an antiarrhythmic agent may have overtaken its use as an antimalarial agent.4 Jay P Sanford Sanford Guide to Antimicrobial Therapy, 5910 N Central Ex pressway, Dallas, TX 75206, USA
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Kain KC, Gadd E, Gushulak B, McCarthy A, MacPherson D. Errors in treatment recommendations for severe malaria. Lancet 1996; 348: 621–22. Miller KD, Greenberg AE, Campbell CC. Treatment of severe malaria in the United States with a continuous infusion of quinidine gluconate and exchange transfusions. N Engl J Med 1989; 321: 65–70. Phillips RE, Warrell DA, White NJ, et al. Intravenous quinidine for the treatment of severe falciparum malaria: clinical pharmacokinetic studies. N Engl J Med 1985; 312: 1273–78. Rosenthal PJ, Petersen C, Geertsma FR, Kohl S. Availability of intravenous quinidine for falciparum malaria. N Engl J Med 1996; 335: 138.
Authors’ reply SIR—We appreciate this opportunity to respond to your correspondents. We restate that the aim of our communication was to call for clear, unambiguous, and uniform expression of antimalarial drug dosing recommendations and that all publications of malaria prevention and treatment guidelines be checked for systematically replicated errors caused by copying from one source to another or because of confusion between base/salt equivalence of these drugs. As Krogstad and colleagues point out, the dose of quinidine gluconate published in Mandell’s textbook and Sanford’s guide indicates the correct dose of salt to be used. However, their letter also highlights the inconsistent way in which malaria dosing information is conveyed to the user. Our experience is that untrained physicians are confused as to whether the dose of quinidine gluconate should be given as the salt or the base equivalent since neither are indicated in the text. The reader is expected to know that quinidine gluconate is a salt and that 10 mg/kg refers to salt and not to base equivalency of quinidine gluconate. This reportage is in contrast with other listed antimalarials for which the base, or salt, or both, doses are indicated, as in quinine hydrochloride 20 mg salt/kg or primaquine phosphate 15·3 mg base (26·5 mg phosphate salt). We have noted that even experienced physicians have difficulty in using many of the current guidelines because of variation in the way drug dosing is provided; sometimes as the salt, or the base, or both, or sometimes lacking either designation (salt or base) to aid the user. Such inconsistencies lead to confusion and treatment errors. Since clarity and consistency are important and because several different salts exist for many antimalarials, we suggest that uniform reference to the base equivalence will reduce confusion and help to avoid dosing errors. We are recommending that the dose of antimalarial drugs be expressed in base and that for an interim period the salt equivalency, clearly marked, follows in parentheses. We also recommend that manufacturers and distributors of these agents very clearly indicate in the labelling, packaging, and monographs the base concentration of the drugs, followed by the salt equivalency. It is precisely because of the base/salt confusion that we erred in our comments concerning The Medical Letter’s dose
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Dosage for malaria treatment SIR—We write in response to mistakes by Kain and colleagues (Aug 31, p 621).1 By contrast with their suggestion, the most recent edition of Mandell, Douglas and Bennett’s principles and practice of infectious diseases2 makes clear that the recommended loading dose of quinidine gluconate for treatment of severe malaria is 10 mg/kg intravenously (iv), followed by 0·02 mg/kg of quinidine gluconate iv per minute, and that the loading dose of quinine dihydrochloride is 20 mg salt/kg iv followed by 10 mg salt/kg every 8 h (in table 2, p 464, Ch 34, by Jernigan and Pearson, which was reprinted with permission from The Medical Letter; and in table 4, p 2424 in Ch 253 by Krogstad). *Donald J Krogstad, Richard D Pearson, John E Bennett, Raphael Dolin, Gerald L Mandell *Department of Tropical Medicine, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA; University of Virginia Health Sciences Center Charlottesville, Virginia; Laboratory of Clnical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
1
2
Kain KC, Gadd E, Gushulak B, McCarthy A, MacPherson D. Errors in treatment recommendations for severe malaria. Lancet 1996; 348: 621–22. Krogstad DJ. Plasmodium species (malaria). In: Mandell, Douglas and Bennett’s principles and practice of infectious diseases, 4th ed. New York: Churchill Livingstone, 1995: 2415–27.
SIR—Kain and colleagues’1 letter contains some errors of its own. The Medical Letter’s recommendation for parenteral treatment of malaria with quinidine is not what they say it is. For some years, to avoid possible confusion between base and salt dosages, we have specified use of quinidine gluconate (10 mg/kg loading dose, followed by 0·02 mg/kg per min). Mark Abramowicz The Medical Letter Inc, 1000 Main Street, New Rochelle, NY 10801-7537, USA
1
Kain KC, Gadd E, Gushnlak B, McCarthy A, MacPherson D. Errors in treatment recommendations for severe malaria. Lancet 1996; 348: 621–22.
SIR—Kain and colleagues’ letter,1 on behalf of the Committee to Advise on Tropical Medicine and Travel (CATMAT), Health and Welfare, Canada, contains an error in dosage and in citation of errors. The current recommendations as stated in The Medical Letter, in Mandell, Douglas and Bennett’s principles and practice of infectious diseases, 4th ed and in the Sanford Guide to Antimicrobial Therapy, 1996, each state “quinidine gluconate 10 mg/kg loading dose (in normal saline) slowly over 1–2 h, followed by continuous infusion of 0·02 mg/kg per min”, not base as Kain and co-workers say. The recommendation of 0·02 mg/kg per min requires an infusion pump. These are not generally available in most developing countries. The Sanford guide provides an alternative: quinidine gluconate iv continuous infusion. Alternative (infusion pump not available) 15 mg/kg iv over 4 h then 7·5 mg/kg iv over 4 h given every 8 h. The regimen of 10 mg/kg loading dose then 0·02 mg/kg per min provides 38·8 mg/kg quinidine gluconate (salt) for the first 24 h. This is the dose that was used by Miller et al.2 The regimen of 15 mg/kg loading dose then 7·5 mg/kg given every 8 h is equivalent, providing 37·5 mg/kg quinidine gluconate for the first 24 h. Phillips and co-workers used another regimen which provided 48 mg/kg quinidine gluconate (salt) during the first 24 h.3 The dosage regimen, “quinidine base 15 mg/kg loading dose (quinidine gluconate
Vol 348 • November 9, 1996
[salt] 24 mg/kg) by intravenous infusion over 4 h followed by quinidine base 7·5 mg/kg (quinidine gluconate [salt] 12 mg/kg) every 8 h infused over 4 h” recommended by Kain et al provides 60 mg/kg quinidine gluconate in the first 24 h. This is in excess by 25–60% of the dosages used in reported series. I agree that base/salt conversions of antimalarials create confusion and the committees should seek uniformity. In the meantime, the replacement of quinidine gluconate as an antiarrhythmic agent may have overtaken its use as an antimalarial agent.4 Jay P Sanford Sanford Guide to Antimicrobial Therapy, 5910 N Central Ex pressway, Dallas, TX 75206, USA
1
2
3
4
Kain KC, Gadd E, Gushulak B, McCarthy A, MacPherson D. Errors in treatment recommendations for severe malaria. Lancet 1996; 348: 621–22. Miller KD, Greenberg AE, Campbell CC. Treatment of severe malaria in the United States with a continuous infusion of quinidine gluconate and exchange transfusions. N Engl J Med 1989; 321: 65–70. Phillips RE, Warrell DA, White NJ, et al. Intravenous quinidine for the treatment of severe falciparum malaria: clinical pharmacokinetic studies. N Engl J Med 1985; 312: 1273–78. Rosenthal PJ, Petersen C, Geertsma FR, Kohl S. Availability of intravenous quinidine for falciparum malaria. N Engl J Med 1996; 335: 138.
Authors’ reply SIR—We appreciate this opportunity to respond to your correspondents. We restate that the aim of our communication was to call for clear, unambiguous, and uniform expression of antimalarial drug dosing recommendations and that all publications of malaria prevention and treatment guidelines be checked for systematically replicated errors caused by copying from one source to another or because of confusion between base/salt equivalence of these drugs. As Krogstad and colleagues point out, the dose of quinidine gluconate published in Mandell’s textbook and Sanford’s guide indicates the correct dose of salt to be used. However, their letter also highlights the inconsistent way in which malaria dosing information is conveyed to the user. Our experience is that untrained physicians are confused as to whether the dose of quinidine gluconate should be given as the salt or the base equivalent since neither are indicated in the text. The reader is expected to know that quinidine gluconate is a salt and that 10 mg/kg refers to salt and not to base equivalency of quinidine gluconate. This reportage is in contrast with other listed antimalarials for which the base, or salt, or both, doses are indicated, as in quinine hydrochloride 20 mg salt/kg or primaquine phosphate 15·3 mg base (26·5 mg phosphate salt). We have noted that even experienced physicians have difficulty in using many of the current guidelines because of variation in the way drug dosing is provided; sometimes as the salt, or the base, or both, or sometimes lacking either designation (salt or base) to aid the user. Such inconsistencies lead to confusion and treatment errors. Since clarity and consistency are important and because several different salts exist for many antimalarials, we suggest that uniform reference to the base equivalence will reduce confusion and help to avoid dosing errors. We are recommending that the dose of antimalarial drugs be expressed in base and that for an interim period the salt equivalency, clearly marked, follows in parentheses. We also recommend that manufacturers and distributors of these agents very clearly indicate in the labelling, packaging, and monographs the base concentration of the drugs, followed by the salt equivalency. It is precisely because of the base/salt confusion that we erred in our comments concerning The Medical Letter’s dose
1311