Rheumatic Fever Prophylaxis Using Benzathine Penicillin G (BPG): Two-week Versus Four-week Regimens: Comparison of Two Brands of BPG

Objective. This prospective study was aimed at answering two important questions: 1) Is a biweekly schedule of 1.2 million U intramuscular benzathine penicillin G (BPG) superior to a 4-week one in the prevention of upper respiratory Group A beta-hemolytic streptococcal (GABHS) infections and rheumatic fever (RF) recurrences? 2) Is there a difference in the bioavailability of BPG obtained from different manufacturers? Methodology. Three hundred sixty rheumatic patients aged 4 to 20 years were randomly assigned to either a biweekly (190 patients) or 4-week (160 patients) BPG prophylactic schedule and were followed-up monthly for 2 years by clinical examination, throat swab culture for GABHS and measurement of antistreptolysin O titer to detect GABHS infection and/or recurrences of RF (according to revised Jones' Criteria). Thereafter, 34 rheumatic subjects, aged 8 to 16 years were randomly assigned to receive a 4-week injection of 1.2 million U of either a locally manufactured BPG brand (22 patients) or an imported one (12 patients). Sera of all patients were tested for penicillin level by plate diffusion method on days 1, 2, 3, 4, 5, 6, 7, 14, 21, and 28 after the intramuscular injection of BPG. Results. The GABHS infection rate was found to be 0.2% and 0.3% for patients on the biweekly and 4-week BPG schedules, respectively, with no significant differences between them. However, the RF recurrence rate/patient/year for the 4-week schedule patients (0.12) was double that for the biweekly schedule ones (0.06). Estimation of the bioavailability of the two different brands of BPG demonstrated a difference in their pharmacokinetics and a decrease in the serum penicillin concentration below the minimum inhibitory concentration 3 weeks after the injection of either brand. Conclusion. Although a biweekly schedule may not be superior in preventing upper respiratory GABHS infection, it may play a role in preventing the sequelae of such infections. The short duration of penicillinemia explains the superiority of the 2-week schedule in RF prophylais. The difference in the pharmacokinetics of penicillin brands might contribute to the high recurrence rate of RF reported in Egypt.

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Rheumatic Fever Article Questioned

PEDIATRICS ◽

10.1542/peds.74.6.1133a ◽

1984 ◽

Vol 74 (6) ◽

pp. 1133-1134

Author(s):

SYLVIA P. GRIFFITHS

Keyword(s):

Rheumatic Fever ◽

Intramuscular Injection ◽

Group A Streptococcus ◽

Penicillin G ◽

Benzathine Penicillin ◽

Benzathine Penicillin G ◽

Group A

To the Editor.— The suggestion of Nordin1 that there may be a need to re-evaluate the current recommended prophylaxis for children with rheumatic fever is valid, particularly if carefully planned and controlled studies could be carried out. However, the author's contention that "It has been assumed that the levels of penicillin [following monthly intramuscular injection of 1.2 million units of benzathine penicillin G] are adequate to prevent reinfection with group A streptococcus, and hence to prevent recurrences of rheumatic fever" has always been qualified by others.

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A COMPARISON OF ORAL BENZATHINE PENICILLIN G AND SULFONAMIDES FOR THE PREVENTION OF STREPTOCOCCAL INFECTIONS AND RECURRENCES OF RHEUMATIC FEVER

PEDIATRICS ◽

10.1542/peds.15.5.509 ◽

1955 ◽

Vol 15 (5) ◽

pp. 509-515

Author(s):

Milton Markowitz ◽

Woodrow Hemphill

Keyword(s):

Rheumatic Fever ◽

Significant Rise ◽

Penicillin G ◽

Streptococcal Infections ◽

Benzathine Penicillin ◽

Number Of Patients ◽

Benzathine Penicillin G ◽

Daily Dose ◽

Group A ◽

Toxic Reactions

1. The incidence of recurrences of rheumatic fever and streptococcal infections in 82 rheumatic subjects receiving a 200,000 unit tablet of benzathine penicillin G daily was compared with that in 64 rheumatic patients on a standard daily dose of a triple sulfonamide preparation, while both groups were followed for an average period of 13 months. 2. A total of 9 recurrences of rheumatic fever was noted, 4 in the group treated with penicillin and 5 among patients on sulfonamides. 3. The incidence of streptococcal infections as determined by a significant rise in the antistreptolysin O titer was essentially the same in both groups. Group A streptococci were found in the throat in about the same number of patients in each group. 4. Toxic reactions of a mild nature were noted in 7 patients (11 per cent) receiving sulfonamides as compared to 2 patients (2.5 per cent) on oral penicillin. 5. A single daily dose of 200,000 units of benzathine penicillin G is as effective a prophylactic agent as the sulfonamides for the prevention of rheumatic fever. Its chief advantage is the lower incidence of toxic reactions.

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Letter to the Editor

PEDIATRICS ◽

10.1542/peds.70.3.507 ◽

1982 ◽

Vol 70 (3) ◽

pp. 507-507

Author(s):

Charles M. Ginsburg ◽

George H. McCracken

Keyword(s):

Rheumatic Fever ◽

American Heart Association ◽

American Heart ◽

Heart Association ◽

Penicillin G ◽

Group A Streptococci ◽

Benzathine Penicillin ◽

Benzathine Penicillin G ◽

Group A ◽

Penicillin Prophylaxis

Boxerbaum has implied that we have questioned the concept of penicillin prophylaxis for patients with rheumatic fever. We did not! Rather, we provided pharmacologic data demonstrating that the concentrations of penicillin in serum may be inadequate to prevent colonization or disease with group A streptococci or pneumococci 18 days or longer after administration of the doses of benzathine penicillin G that are recommended by the American Heart Association. In fact, Boxerbaum's data support our contention—group A streptococci were isolated from 8% of his patients who had received intramuscular benzathine penicillin.

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CONCENTRATION OF PENICILLIN IN THE SERUM FOLLOWING INTRAMUSCULAR ADMINISTRATION OF BENZATHINE PENICILLIN G TO CHILDREN WITH INACTIVE RHEUMATIC FEVER

PEDIATRICS ◽

10.1542/peds.21.2.233 ◽

1958 ◽

Vol 21 (2) ◽

pp. 233-242

Author(s):

Roswith I. Lade ◽

Antoni M. Diehl ◽

Irvin Snyder ◽

Tom R. Hamilton

Keyword(s):

Rheumatic Fever ◽

Positive Culture ◽

Significant Rise ◽

Penicillin G ◽

Benzathine Penicillin ◽

Beta Hemolytic Streptococcus ◽

Significant Difference ◽

Benzathine Penicillin G ◽

Group A ◽

Nose And Throat

Ninety-six children between the ages of 4 and 20 years with inactive rheumatic fever received 1,200,000 units of benzathine penicillin G every 28 days by intramuscular injection and were studied from the standpoint of effective and consistent concentrations of penicillin in the serum. The concentrations of penicillin in the serum could be determined with certainty in 81% of the specimens; concentrations ranged from 0.002 to 0.125 unit/ml. The mean concentration of penicillin reached in the serum of females was three times higher than in males. The concentration of penicillin in the serum of females increased with age and weight from the tenth to the seventeenth years. No such increase was observed in the sera of males in relation to age and weight. The differences in concentration of penicillin reached in the sera of the two sexes from 12 through 17 years of age were statistically significant (p less than 0.01). No significant difference in concentration of penicillin in the serum was found in comparing obese and thin girls of 10 through 15 years of age. The explanation for the differences between the two sexes is not apparent. During the period of the study, 491 swabs from the nose and throat yielded only one positive culture for beta hemolytic streptococcus of group A; this organism could not be typed and was not associated with an increase in the titer of antistreptolysin O. One other patient had a significant rise in antibody titer, but there was no antecedent positive culture for streptococcus. There were no recurrences of rheumatic fever.

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Three-Versus Four-week Administration of Benzathine Penicillin G: Effects on Incidence of Streptococcal Infections and Recurrences of Rheumatic Fever

PEDIATRICS ◽

10.1542/peds.97.6.984 ◽

1996 ◽

Vol 97 (6) ◽

pp. 984-988

Author(s):

Hung-Chi Lue ◽

Mei-Hwan Wu ◽

Jou-Kou Wang ◽

Fen-Fen Wu ◽

Yu-Nian Wu

Keyword(s):

Rheumatic Fever ◽

Color Doppler ◽

Clinic Visit ◽

Penicillin G ◽

Controlled Study ◽

Streptococcal Infections ◽

Benzathine Penicillin ◽

Acute Phase Reactants ◽

Weight Percentage ◽

Benzathine Penicillin G

Objective. To investigate the effects of 3-week versus 4-week administration of benzathine penicillin G (BPG) on the incidence of Group A streptococcal infections and the recurrences of rheumatic fever (RF). Study Design. We started, in 1979, randomly allocating all patients with RF to a 3-week or 4-week BPG prophylaxis program. They were examined at the RF clinic, every 3 to 6 months, and at any time they did not feel well. During 1979 to 1989, throat cultures and sera for antistreptolysin O and streptozyme titers were obtained at each clinic visit. Chest radiographs, electrocardiogram, color Doppler echocardiograms, and acute phase reactants were obtained. Subjects. Two hundred forty-nine patients fulfilled the revised Jones criteria and were followed until December 1991: 124 in the 3-week and 125 in the 4-week program. Their age, sex, weight, percentage with history of RF, severity of cardiac involvement, follow-up duration, and compliance to program were comparable. Eight hundred eighty throat cultures were collected in the 3-week program and 770 were collected in the 4-week program. Six hundred sixteen and 627 sera were determined in each program for antistreptolysin O, and 582 and 592 sera for streptozyme titers. Results. True streptococcal infections occurred in both programs: 39 infections in the 3-week program, and 59 infections in the 4-week program (7.5 vs 12.7 per 100 patient-years). Four infections with no antibody response occurred in the 3-week program, and three such infections in the 4-week program. Nine RF recurrences occurred in 8 patients in the 3-week program, and 16 recurrences in 16 patients in the 4-week program. Prophylaxis failure occurred in 2 of 124 patients in the 3-week program, and in 10 of 125 patients in the 4-week program (0.25 vs 1.29 per 100 patient-years). The overall recurrences/infections rate in each program was comparable, 13.6% vs 15.5%, but the recurrences/infections rate due to prophylaxis failure was higher in the 4-week program than in the 3-week program, 3.0% versus 9.7%. Conclusions. This 12-year prospective and controlled study documented that streptococcal infections and RF recurrences occurred more often in the 4-week program than in the 3-week program. The risk of prophylaxis failure was fivefold greater in the 4-week program than in the 3-week program.

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Recurrence of Rheumatic Fever During Prophylaxis with Monthly Benzathine Penicillin G

PEDIATRICS ◽

10.1542/peds.73.4.530 ◽

1984 ◽

Vol 73 (4) ◽

pp. 530-531

Author(s):

James D. Nordin

Keyword(s):

Rheumatic Fever ◽

Penicillin G ◽

Benzathine Penicillin ◽

Real Risk ◽

Benzathine Penicillin G ◽

The Subject

A 9-year-old girl had apparent recurrence of rheumatic fever while receiving monthly benzathine penicillin injections. A review of pharmacokinetc studies on the subject suggests that this is a real risk. A need for review of the current recommendations for rheumatic fever prophylaxis is suggested.

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Allergic Reactions in Rheumatic Fever Patients on Long-term Benzathine Penicillin G: The Role of Skin Testing for Penicillin Allergy

PEDIATRICS ◽

10.1542/peds.97.6.981 ◽

1996 ◽

Vol 97 (6) ◽

pp. 981-983

Author(s):

Milton Markowitz ◽

Hung-Chi Lue

Keyword(s):

Developing Countries ◽

Rheumatic Fever ◽

The United States ◽

World Health ◽

Penicillin G ◽

Allergic Reactions ◽

Benzathine Penicillin ◽

Benzathine Penicillin G ◽

The Impact

An injection of 1.2 million U benzathine penicillin G (BPG) every 3 or 4 weeks has proven by far to be the most effective method to prevent recurrences of acute rheumatic fever.1-3 The efficacy of this method of prophylaxis was first demonstrated more than 40 years ago, and since its introduction, it has played a major role in reducing the morbidity and mortality from rheumatic fever.4 Rheumatic fever causes 25% to 40% of all cardiovascular diseases in developing countries.5 Because of the impact of this disease on public health, the World Health Organization (WHO) has helped establish programs for prevention of recurrent attacks of rheumatic fever in many developing countries.6 WHO recommends BPG as the prophylactic drug of choice. One of the problems encountered has been the high drop-out rates among patients enrolled in these programs. Among the reasons for discontinuing prophylaxis is the fear of an allergic reaction.7 The initial study using BPG for the prevention of recurrences of rheumatic fever in children and adolescents reported only 5 (1.2%) mild allergic reactions among 410 patients receiving monthly injections.1 Since then, although rheumatic fever prevention in the United States (U.S.) has consisted almost exclusively of using BPG, there been very few documented reports of serious allergic reactions in rheumatic fever patients on long-term prophylaxis. The only fatalities reported in the American literature occurred in four adults with advanced rheumatic heart disease.8,9 The salutary experience with BPG in the U.S. contrasts sharply with the numerous anecdotal reports of fatal allergic reactions to BPG in many developing countries.

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