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Pharmacokinetics of Rheumatic Fever Prophylaxis Regimens V
THAMLIKlTKULt,
S
KOBWANTHAN~,
S
PRUKSACHATVUTHl1 AND
R LERTLUKNlTHl1
'Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; 2Department of Preventive and Social Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
The pharmacokinetics ofbenzathine penicillin G (1200000 IV given intramuscularly), penicillin V (250 mg given orally twice daily), erythromycin stearate (250 mg given orally twice daily) and roxithromycin (150 mg given orally once daily) were investigated. The drugs were given prophylactically to prevent the recurrence of rheumatic fever to 20 patients attending a rheumatic fever clinic in a study of crossover design. Serum antibiotic concentrations were determined by microbiological assay at intervals of up to 28 days after intramuscular injection and immediately before and 1 - 2 h after the fifth oral dose. The concentrations of penicillin G in all serum samples obtained on day 28 after parenteral benzathine penicillin G administration were greater than 0.01 mg/dl. Most patients had no detectable penicillin V or erythromycin in blood samples drawn immediately before the fifth dose. The concentration of roxithromycin at 24 h after the dose was greater than 1.2 mg/dl in all patients. Based on the pharmacokinetic profiles, it is suggested that 1200 000 IV benzathine penicillin G given every 4 weeks is an appropriate regimen for preventing the recurrence ofrheumatic fever in Thai adults. Roxithromycin
20
l ' Thuml ikitkul, S Kolnvunllum ak u n, ,"l Prulcscu.h ulvuth i PI a l.
Phu rmacuk inut ir:» of rhuum al ic: f(~\I~1' prophvlactics
had much better pharmacokinetics than penicillin V and erythromycin stearate, and is probably the best alternative regimen to intramuscular penicillin G. KEY WORDS: BENZATHINE PENICILLING; PENICILLIN V; ERYTHROMYCIN STEARATE; ROXITHROMYCIN;
ANTIBIOTICS; RHEUMATIC FEVER;
PROPHYLAXIS
INTRODUCTION pharmacokinetics of these prophylactic regimens, which are currently being used, and of roxithromycin, a long-acting macrolide antibiotic, as a potential alternative regimen.
Rheumatic fever and rheumatic heart diseases are still the leading causes of disability and death in patients with cardiovascular conditions from developing countries.'> Several antibiotic regimens have been shown to be effective in preventing the recurrence of rheumatic fever and reducing the related morbidity and mortality.v' The prophylactic regimens include 1200000 IV benzathine penicillin G injected every 4 weeks or 250 mg penicillin V given orally twice daily. For patients who are allergic to penicillin, 250 mg erythromycin or 500 mg sulphadiazine given twice daily is recommended." Over the past decade, there have been several pharmacokinetic studies and clinical studies which suggest that benzathine penicillin G should be given every 3 weeks instead of every 4 weeks because the serum concentration of penicillin G is very low during week 4 and because the rate of recurrence of rheumatic fever is higher in the patients receiving the 4week regimen." - 9 A recent World Health Organization study group re-emphasized the recommendation that benzathine penicillin G should be given every 3 weeks to patients living in areas where the risk of recurrence of rheumatic fever is high. ' ° In Siriraj Hospital, two secondary prophylactic regimens, the 4-weekly benzathine penicillin G injection and oral penicillin V given orally twice daily, have been used for decades. The objective of the present study was to determine the
PATIENTS AND METHODS PATIENTS A total of 20 adult patients who had had a prior episode of rheumatic fever or rheumatic heart disease and had been attending the rheumatic fever clinic at Siriraj Hospital were recruited for the study. The patients, 10 males and 10 females, had a mean age of 29 years and a mean body weight of 50.5 kg. No organic heart disease was present in six patients but six had mitral stenosis, five had mitral stenosis plus mitral regurgitation and three had mitral regurgitation. In 19 patients, the cardiac status was functional class I and in one patient functional class II of the classification system of the New York Heart Association." The mean duration of rheumatic fever prophylaxis was 8.1 years: 12 patients had fully complied with the benzathine penicillin G prophylaxis (missing on average only one injection per year); the other eight patients had partially complied to the prophylaxis regimen (missing more than one injection per year). The subjects were informed about the study objectives and procedures, and all agreed to participate. They were instructed to avoid taking other
21
\' Tlunnlik S /\0/)\\ S Pruksachutvuthi et al. i t k u l ,
u n t b
a n o k u n ,
Pharmacok inutir:s of rhuum at ir: Iever prophylactics
were inoculated onto a paper disc 6 mm in diameter and the assay plates were incubated at 35°C overnight. The lower detection limits of the assay were 0.015, 0.02, 0.03 and 1 mg/ dl, respectively, for penicillin G, penicillin V, erythromycin and roxithromycin.
medication, especially antibiotics, during the study period.
STUDY DESIGN The study was of a crossover design. All subjects received 1200 000 IU benzathine penicillin injected intramuscularly, 250 mg penicillin V given orally twice daily, 250 mg erythromycin stearate given orally twice daily and 150 mg roxithromycin given orally once daily. All subjects were given benzathine penicillin G as the initial regimen and, after a wash-out period of 1 week, the oral regimens were given in random order. Benzathine penicillin G was given only once during the study period and each oral regimen was given for five doses with a 3-day wash-out period between regimens. Blood samples were drawn at 1 h after injection of1200 000 IU benzathine penicillin G and on days 7, 14, 21 and 28 afterinjection; blood samples were not obtained on day 21 from two patients and on day 28 from four subjects. For the subjects taking oral drugs, the blood samples were obtained immediately before the fifth dose (trough concentration) and 1 - 2 h after the fifth dose (peak concentration). The serum was separated by centrifuging the clotted blood sample at 2500 rpm for 10 min and the serum samples stored at -70° C for a maximum of 3 months before assay.
STATISTICAL ANALYSIS Descriptive statistics were used to analyse the data.
RESULTS The serum concentrations of penicillin G 1 h after injection and on days 7, 14, 21 and 28 after injection for all subjects were detectable at all times, and 86% of the subjects had concentrations greater than 0.02 mg/dl on day 28 (Fig. 1). The peak and trough serum concentrations of penicillin V, erythromycin and roxithromycin (Table 1) indicate that most patients receiving penicillin V or erythromycin had undetectable trough concentrations, whereas those receiving roxithromycin had satisfactory values.
DISCUSSION A crossover study design was employed to eliminate the effects of biological differences between the patients. All of the patients had a history of documented rheumatic fever or rheumatic heart disease; therefore, the results of the study should represent the pharmacokinetics of prophylactic regimens for the target population. The pharmacokinetics of benzathine penicillin G and oral penicillin V were studied because they are the conventional regimens recommended by the World Health Organization'? and are widely used in Thailand. Erythromycin was included in the study because of the clinicians' preference for this drug over sulphadiazine
ANTIBIOTIC CONCENTRATION DETERMINATION The antibiotic concentrations were determined by microbiological assay;" the test organism was Micrococcus luteus ATCC 9341. The standard samples of benzyl penicillin sodium, penicillin V and erythromycin were supplied as powders by the Government Pharmaceutical Organization, Thailand, and roxithromycin was obtained from Roussel Co., Thailand, and the diluent used was drugfree normal human serum. Test serum (20 Ill)
22
\' Thcnnlikitkul. ,
!OllrJIU}
(!{
lnlcrnutiouul ,\lee/jeu} Heseu/'I:h I !I!I:!: :W: 20 - :W
Pharmacokinetics of Rheumatic Fever Prophylaxis Regimens V
THAMLIKlTKULt,
S
KOBWANTHAN~,
S
PRUKSACHATVUTHl1 AND
R LERTLUKNlTHl1
'Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; 2Department of Preventive and Social Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
The pharmacokinetics ofbenzathine penicillin G (1200000 IV given intramuscularly), penicillin V (250 mg given orally twice daily), erythromycin stearate (250 mg given orally twice daily) and roxithromycin (150 mg given orally once daily) were investigated. The drugs were given prophylactically to prevent the recurrence of rheumatic fever to 20 patients attending a rheumatic fever clinic in a study of crossover design. Serum antibiotic concentrations were determined by microbiological assay at intervals of up to 28 days after intramuscular injection and immediately before and 1 - 2 h after the fifth oral dose. The concentrations of penicillin G in all serum samples obtained on day 28 after parenteral benzathine penicillin G administration were greater than 0.01 mg/dl. Most patients had no detectable penicillin V or erythromycin in blood samples drawn immediately before the fifth dose. The concentration of roxithromycin at 24 h after the dose was greater than 1.2 mg/dl in all patients. Based on the pharmacokinetic profiles, it is suggested that 1200 000 IV benzathine penicillin G given every 4 weeks is an appropriate regimen for preventing the recurrence ofrheumatic fever in Thai adults. Roxithromycin
20
l ' Thuml ikitkul, S Kolnvunllum ak u n, ,"l Prulcscu.h ulvuth i PI a l.
Phu rmacuk inut ir:» of rhuum al ic: f(~\I~1' prophvlactics
had much better pharmacokinetics than penicillin V and erythromycin stearate, and is probably the best alternative regimen to intramuscular penicillin G. KEY WORDS: BENZATHINE PENICILLING; PENICILLIN V; ERYTHROMYCIN STEARATE; ROXITHROMYCIN;
ANTIBIOTICS; RHEUMATIC FEVER;
PROPHYLAXIS
INTRODUCTION pharmacokinetics of these prophylactic regimens, which are currently being used, and of roxithromycin, a long-acting macrolide antibiotic, as a potential alternative regimen.
Rheumatic fever and rheumatic heart diseases are still the leading causes of disability and death in patients with cardiovascular conditions from developing countries.'> Several antibiotic regimens have been shown to be effective in preventing the recurrence of rheumatic fever and reducing the related morbidity and mortality.v' The prophylactic regimens include 1200000 IV benzathine penicillin G injected every 4 weeks or 250 mg penicillin V given orally twice daily. For patients who are allergic to penicillin, 250 mg erythromycin or 500 mg sulphadiazine given twice daily is recommended." Over the past decade, there have been several pharmacokinetic studies and clinical studies which suggest that benzathine penicillin G should be given every 3 weeks instead of every 4 weeks because the serum concentration of penicillin G is very low during week 4 and because the rate of recurrence of rheumatic fever is higher in the patients receiving the 4week regimen." - 9 A recent World Health Organization study group re-emphasized the recommendation that benzathine penicillin G should be given every 3 weeks to patients living in areas where the risk of recurrence of rheumatic fever is high. ' ° In Siriraj Hospital, two secondary prophylactic regimens, the 4-weekly benzathine penicillin G injection and oral penicillin V given orally twice daily, have been used for decades. The objective of the present study was to determine the
PATIENTS AND METHODS PATIENTS A total of 20 adult patients who had had a prior episode of rheumatic fever or rheumatic heart disease and had been attending the rheumatic fever clinic at Siriraj Hospital were recruited for the study. The patients, 10 males and 10 females, had a mean age of 29 years and a mean body weight of 50.5 kg. No organic heart disease was present in six patients but six had mitral stenosis, five had mitral stenosis plus mitral regurgitation and three had mitral regurgitation. In 19 patients, the cardiac status was functional class I and in one patient functional class II of the classification system of the New York Heart Association." The mean duration of rheumatic fever prophylaxis was 8.1 years: 12 patients had fully complied with the benzathine penicillin G prophylaxis (missing on average only one injection per year); the other eight patients had partially complied to the prophylaxis regimen (missing more than one injection per year). The subjects were informed about the study objectives and procedures, and all agreed to participate. They were instructed to avoid taking other
21
\' Tlunnlik S /\0/)\\ S Pruksachutvuthi et al. i t k u l ,
u n t b
a n o k u n ,
Pharmacok inutir:s of rhuum at ir: Iever prophylactics
were inoculated onto a paper disc 6 mm in diameter and the assay plates were incubated at 35°C overnight. The lower detection limits of the assay were 0.015, 0.02, 0.03 and 1 mg/ dl, respectively, for penicillin G, penicillin V, erythromycin and roxithromycin.
medication, especially antibiotics, during the study period.
STUDY DESIGN The study was of a crossover design. All subjects received 1200 000 IU benzathine penicillin injected intramuscularly, 250 mg penicillin V given orally twice daily, 250 mg erythromycin stearate given orally twice daily and 150 mg roxithromycin given orally once daily. All subjects were given benzathine penicillin G as the initial regimen and, after a wash-out period of 1 week, the oral regimens were given in random order. Benzathine penicillin G was given only once during the study period and each oral regimen was given for five doses with a 3-day wash-out period between regimens. Blood samples were drawn at 1 h after injection of1200 000 IU benzathine penicillin G and on days 7, 14, 21 and 28 afterinjection; blood samples were not obtained on day 21 from two patients and on day 28 from four subjects. For the subjects taking oral drugs, the blood samples were obtained immediately before the fifth dose (trough concentration) and 1 - 2 h after the fifth dose (peak concentration). The serum was separated by centrifuging the clotted blood sample at 2500 rpm for 10 min and the serum samples stored at -70° C for a maximum of 3 months before assay.
STATISTICAL ANALYSIS Descriptive statistics were used to analyse the data.
RESULTS The serum concentrations of penicillin G 1 h after injection and on days 7, 14, 21 and 28 after injection for all subjects were detectable at all times, and 86% of the subjects had concentrations greater than 0.02 mg/dl on day 28 (Fig. 1). The peak and trough serum concentrations of penicillin V, erythromycin and roxithromycin (Table 1) indicate that most patients receiving penicillin V or erythromycin had undetectable trough concentrations, whereas those receiving roxithromycin had satisfactory values.
DISCUSSION A crossover study design was employed to eliminate the effects of biological differences between the patients. All of the patients had a history of documented rheumatic fever or rheumatic heart disease; therefore, the results of the study should represent the pharmacokinetics of prophylactic regimens for the target population. The pharmacokinetics of benzathine penicillin G and oral penicillin V were studied because they are the conventional regimens recommended by the World Health Organization'? and are widely used in Thailand. Erythromycin was included in the study because of the clinicians' preference for this drug over sulphadiazine
ANTIBIOTIC CONCENTRATION DETERMINATION The antibiotic concentrations were determined by microbiological assay;" the test organism was Micrococcus luteus ATCC 9341. The standard samples of benzyl penicillin sodium, penicillin V and erythromycin were supplied as powders by the Government Pharmaceutical Organization, Thailand, and roxithromycin was obtained from Roussel Co., Thailand, and the diluent used was drugfree normal human serum. Test serum (20 Ill)
22
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