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Prophylaxis in patients with rheumatic fever: Every three or every four weeks?
EDITOR'S COLUMN
Prophylaxis in patients with rheumatic fever: Every three or every four weeks? Rheumatic fever is a recurrent disease, and recurrences are associated with more severe damage to organs that were injured during the initial attack, particularly the heart. Successful prevention of recurrent attacks of rheumatic fever was achieved a half century ago through the daily administration of antibiotic prophylaxis,a,2 In 1952, Stollerman and RusofP used a preparation of repository penicillin, benzathine penicillin G, and demonstrated that monthly intramuscular injections of this preparation were effective in preventing streptococcal infections and recurrences of rheumatic fever. A subsequent study by Wood et al. 4 compared the eff• of daily oral prophylaxis, either penicillin or sulfadiazine, with the efficacy of monthly parenteral benzathine penicillin G. The latter regimen proved to be far more effective in preventing recurrences of streptococcal infections and of rheumatic fever. On the basis of this and other confirmatory observations, the American Heart Association (AHA) recommended the use of 4-weekly (monthly) injections of 1.2 million units of long-acting benzathine penicillin G as an effective regimen for secondary prophylaxis of rheumatic fever. The efficacy of the monthly regimen for secondary prophylaxis, which many observers believe is responsible for the decline in the severity of rheumatic carditis observed over the past three decades, has remained unchallenged until recently. Both the A H A and the World Health Organization (WHO), in their most recent publications, 5,6 continue to recommend a single injection of benzathine penicillin G given at monthly intervals as the preferred form of prophylaxis for most patients. However, both agencies now add that in high-risk patients or situations, the dose may be given every 3 weeks. The additional recommendation is predicated on several observations. The first observation was the early and continued reporting of an unacceptably high recurrence rate of rheumatic fever in patients who are on the monthly prophylactic regimen, particularly in certain areas where the incidence of rheumatic fever is very high. 7-9 Other observations that led to this recommendation included plaarmacokinetic studies Reprint requests: Elia M. Ayoub, MD, Department of Pediatrics, Box J296, JHMHC, University of Florida, Gainesville, FL 32610.
indicating suboptimal levels of penicillin during the fourth week, and studies showing a decreased incidence of streptococcal infection and recurrences of rheumatic fever in patients placed on a 3-weekly versus a 4-weekly regimen of prophylaxis. The pharmacokinetic study by Ginsburg et ai. 1~ was among the first to draw attention to this problem. Their data revealed that penicillin was detected in the serum of 8 of 12 patients at 18 days and in none of 10 specimens obtained at 30 days after administration of 600,000 or 1,200,000 units of benzathine penicillin G. In a study reported in the current issue of THE JOURNAL,Kaplan et al? t determined penicillin concentrations in serum samples See related article, p. 146.
from 53 patients who had received 1,200,000 units of benzathine penicillin G. They found adequate levels of penicillin (>0.02/~g/ml) in 80% of the samples obtained at 21 days and in only 36% of samples obtained at 28 days. Only 44% of the 28-day samples had detectable levels of penicillin. On the other hand, Padmavati et al. 12 assayed serum penicillin levels in seven children, 28 days after administration of 1,200,000 units of benzathine penicillin G, and found concentrations greater than "the recommended minimum inhibitory concentrations of 0.03/ml" in all patients tested. These pharmacokinetic studies have drawn attention to the potential inadequacy of the 4-weekly regimen, but some facets of these studies could be questioned. The disparity between the penicillin levels in the studies by Ginsburg et al. and by Kaplan et al. was addressed by the latter authors, who suggested that storage of samples may have accounted for these differences. Other studies have raised the issue of differences in potency of the benzathine penicillin G preparations, questioning whether dose differences may account for the low levels seen at 3 to 4 weeks after administration of the penicillin. A focal issue appears to be the lack of consensus regarding the accepted serum minimal inhibitory concentration of penicillin for group A streptococci. The concentration chosen by Ginsburg et al. 1~ was 0.01 Izg/ml, Kaplan et al. 11 chose 0.02 #g/ml, and
89
90
Editor's column
Padmavati et al? 2 selected 0.03 #g/ml. The mean serum concentration of penicillin at 28 days for the population studied by Kaplan et al. H was 0.02 ug/ml. Is this level inadequate? As reported by Ginsburg et al., ~~most strains of group A streptococci are inhibited by 0.01 fzg/ml of penicillin. Given the limited sensitivity of the disk agar method for assay of penicillin levels, it is possible that the use of a more sensitive method, such as high-performance liquid chromatography, could have shown that levels of 0.01 /zg/ml were present in the majority of the sera at 28 days. Another question that these studies engender is the relationship between serum levels of penicillin and protection against streptococcal pharyngitis. In previous studies, the presence of penicillin in the urine was found to correlate with protection against streptococcal infection and recurrence of rheumatic fever? 3 Ginsburg et al. 1~were able to detect penicillin in the" urine of 15 of 18 patients who had no detectable penicillin in the serum at 30 days. Kaplan et al. H did not test for penicillin in the urine of their patients. How relevant is this information? Does protection against streptococcal pharyngitis correlate best with serum levels, or does it correlate better with levels in tissue, or saliva, or urine? It may be that the serum penicillin level is only one of several factors influencing recurrence of rheumatic fever. Studies are needed to answer these questions. To supplement the pharmacokinetic studies, two recent clinical studies correlated the frequency of the administration of prophylaxis with the incidence of streptococcal infection and recurrence of rheumatic fever. 12,~4 Both studies found a higher rate of rheumatic fever recurrence in patients receiving prophylaxis at 4-weekly intervals in comparison with patients receiving prophylaxis every 3 weeks. These studies, which were performed in areas where the risk for rheumatic fever is high, emphasized the recommendation that prophylaxis with benzathine penicilli'n G be administered at 3-weekly rather than at 4-weekly intervals in high-risk areas. A major flaw in the design of the study by Padmavati et al. ~2is that the evaluation of the two prophylaxis regimens was retrospective and not concurrent. Thus the group of patients who received injections at 4-weekly intervals were seen during a period of 5 years, and the group of patients receiving the 3-weekly prophylaxis were seen during the following 5 years. Furthermore, it is not clear from the data presented whether Padmavati et al. documented a significant increase in the antistreptolysin O (ASO) titer between a specimen obtained before and one obtained during the recurrence. An elevated ASO titer can persist for a year or more after the acute attack in some patients with rheumatic fever. In contrast, the study by Hung-Chi et al. TM was a controlled, prospective study
The Journal of Pediatrics July 1989
involving two groups of patients. However, one group was seen in a cardiac clinic and the other in a rheumatic fever clinic. A curious observation appears in the results of this study. No recurrences were encountered among the group of patients followed in the cardiac clinic; all recurrences occurred in the patients seen in the rheumatic fever clinic. Despite these limitations, the studies mentioned above raise a reasonable concern about the adequacy of the monthly prophylaxis regimen in areas of high prevalence of rheumatic fever. Even then, is the adoption of a 3-weekly interval for prophylaxis the answer to this potential problem? Will additional pharmac0kinetic studies provide the answer, or will more extensive and better controlled prospective clinical studies be more appropriate? Regardless of which approach is used, other compelling questions, in addition to the questions raised above, should be considered before additional studies are undertaken: First, what will be the effect of a 3-weekly regimen on compliance? The only two proven recurrences in our practice over the past two decades occurred in the same patient, who was so scared by the pain associated with the injections of benzathine penicillin G that he invested a lot of effort in devising methods to avoid the injections. Second, is the low level or absence of penicillin during the fourth week the major cause for recurrences, or are other factors involved? Catanzaro et al.] 5 in their original studies on the primary prevention of rheumatic fever, noted that this complication was "prevented when penicillin therapy of streptococcal infection was delayed until nine days after the onset of illness" (pharyngitis). For penicillin tO be ineffective in preventing a recurrence of rheumatic fever when given at 4-weekly intervals, one has to invoke the probability that the observation described above does not apply to recurrent attacks. In addition, we must provide an answer to the question of why the majority of patients with rheumatic fever who are receiving prophylaxis and who acquire a pharyngitis, proved by culture, an ASO rise, or both, fail to show a recurrence of rheumatic fever. Third, what would be the added cost of a 3-weekly prophylaxis? Although the increased cost of the medication may not be substantial, as pointed out by Padmavati et al., ~2 one has to take into consideration the cost of administration of medication, added travel, increased work load on clinic personnel, and, not least, increased absenteeism of the patient from school. Finally, one wonders whether we are overlooking the obvious. What would happen if we simply increased the monthly dose of penicillin from 1.2 million to 1.8 million units? Would this obviate the problem of lower serum levels during the fourth week and reduce recurrence of rheumatic fever, albeit at th e price of more pain to the patient?
Volume 115 Number 1
Editor's column
Until these questions are answered, we should follow the r e c o m m e n d a t i o n of the A H A and W H O and continue to provide prophylaxis at m o n t h l y intervals in this country and in other countries where the risk for r h e u m a t i c fever, despite the recent resurgence, remains relatively low. However, adoption of t h e 3-weekly regimen in high-risk areas is still an open question. Better-designed prospective studies may provide the answer to this question, and its final adoption awaits a more definitive evaluation.
Elia M. Ayoub, MD Department o f Pediatrics University o f Florida Gainesville, FL 32610 Chairman, Task Force on Rheumatic Fever and Rheumatic Heart Disease State o f Florida Cardiac Disease in the Young Council American Heart Association, Florida Affiliate REFERENCES I. Thomas CB, France R. A preliminary report of the prophylactic use of sulfonamide in patients susceptible to rheumatic fever. Bull Johns Hopkins Hosp 1939;64:67. 2. Coburn AF, Moore LV. The prophylactic use of sulfanilamide in streptococcal respiratory infections with special reference to rheumatic fever. J Clin Invest 1939;18:147. 3. Stollerman GH, Rusoff JH. Prophylaxis against group A streptococcal infections in rheumatic fever patients: use of a new repository penicillin preparation. JAMA 1952;150: 1571. 4. Wood HF, Feinstein AR, Taranta A, et al. Rheumatic fever in children and adolescents: a long-term epidemiologic study of subsequent prophylaxis, streptococcal infections, and clinical sequelae, llI. Comparative effectiveness of three prophylaxis regimens in preventing streptococcal infections and
5.
6.
7.
8.
9. 10.
11.
12.
13. 14.
15.
91
rheumatic fever recurrences. Ann Intern Med 1964;60(Suppl 5, pt 2):31. Dajani AS, Bisno AL, Chung K J, et al. Prevention of rheumatic fever: a statement for health professionals by the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascualr Disease in the Young, the American Heart Association. Circulation 1988;78:1082. WHO Study Group. Rheumatic fever and rheumatic heart disease. WHO Technical Report Series No. 764. Geneva: World Health Organization, 1988. Sanyal SL, Berry AM, Duggal S, et al. Sequelae of the initial attack of acute rheumatic fever in children from north India: a prospective 5-year follow-up study. Circulation 1982; 65:375. Majeed HA, Shaltout A, Yousof AM. Recurrences of acute rheumatic fever: a prospective study of 79 episodes. Am J Dis Child 1984;138:341. Padmavati S. Rheumatic fever and rheumatic heart disease in developing countries. Bull WHO 1978;56:543. Ginsburg CM, McCracken GH, Zweighaft TC. Serum penicillin concentration after intramuscular administration of benzathine penicillin G in children. Pediatrics 1982;69:452. Kaplan EL, Berrios X, Speth J, Siefferman T, Giuzman B, Quesny F. Pharmacokinetics of benzathine penicillin G: serum levels during the 28 days after intramuscular injection of 1,200,000 units. J PEDIATR 1989;115:t46-50. Padmavati S, Gupta V, Prakash K, et al. Penicillin for rheumatic fever prophylaxis: 3-weekly or 4-weekly schedule. J Assoc Physicians India 1987;35:753. Markowitz M. Eradication of rheumatic fever: an unfulfilled hope. Circulation 1970;41:1077. Hung-Chi L, Mei-Hwan W, Kue-Hsiung H. Rheumatic fever recurrences: controlled study of 3-week versus 4-week benzathine penicillin prevention programs. J PED1ATR t986; 108:299. Catanzaro F J, Stetson CA, Jorris A J, et al. The rolc of the streptococcus in the pathogenesis of rheumatic fever. Am J Med I954;17:749.
Prophylaxis in patients with rheumatic fever: Every three or every four weeks? Rheumatic fever is a recurrent disease, and recurrences are associated with more severe damage to organs that were injured during the initial attack, particularly the heart. Successful prevention of recurrent attacks of rheumatic fever was achieved a half century ago through the daily administration of antibiotic prophylaxis,a,2 In 1952, Stollerman and RusofP used a preparation of repository penicillin, benzathine penicillin G, and demonstrated that monthly intramuscular injections of this preparation were effective in preventing streptococcal infections and recurrences of rheumatic fever. A subsequent study by Wood et al. 4 compared the eff• of daily oral prophylaxis, either penicillin or sulfadiazine, with the efficacy of monthly parenteral benzathine penicillin G. The latter regimen proved to be far more effective in preventing recurrences of streptococcal infections and of rheumatic fever. On the basis of this and other confirmatory observations, the American Heart Association (AHA) recommended the use of 4-weekly (monthly) injections of 1.2 million units of long-acting benzathine penicillin G as an effective regimen for secondary prophylaxis of rheumatic fever. The efficacy of the monthly regimen for secondary prophylaxis, which many observers believe is responsible for the decline in the severity of rheumatic carditis observed over the past three decades, has remained unchallenged until recently. Both the A H A and the World Health Organization (WHO), in their most recent publications, 5,6 continue to recommend a single injection of benzathine penicillin G given at monthly intervals as the preferred form of prophylaxis for most patients. However, both agencies now add that in high-risk patients or situations, the dose may be given every 3 weeks. The additional recommendation is predicated on several observations. The first observation was the early and continued reporting of an unacceptably high recurrence rate of rheumatic fever in patients who are on the monthly prophylactic regimen, particularly in certain areas where the incidence of rheumatic fever is very high. 7-9 Other observations that led to this recommendation included plaarmacokinetic studies Reprint requests: Elia M. Ayoub, MD, Department of Pediatrics, Box J296, JHMHC, University of Florida, Gainesville, FL 32610.
indicating suboptimal levels of penicillin during the fourth week, and studies showing a decreased incidence of streptococcal infection and recurrences of rheumatic fever in patients placed on a 3-weekly versus a 4-weekly regimen of prophylaxis. The pharmacokinetic study by Ginsburg et ai. 1~ was among the first to draw attention to this problem. Their data revealed that penicillin was detected in the serum of 8 of 12 patients at 18 days and in none of 10 specimens obtained at 30 days after administration of 600,000 or 1,200,000 units of benzathine penicillin G. In a study reported in the current issue of THE JOURNAL,Kaplan et al? t determined penicillin concentrations in serum samples See related article, p. 146.
from 53 patients who had received 1,200,000 units of benzathine penicillin G. They found adequate levels of penicillin (>0.02/~g/ml) in 80% of the samples obtained at 21 days and in only 36% of samples obtained at 28 days. Only 44% of the 28-day samples had detectable levels of penicillin. On the other hand, Padmavati et al. 12 assayed serum penicillin levels in seven children, 28 days after administration of 1,200,000 units of benzathine penicillin G, and found concentrations greater than "the recommended minimum inhibitory concentrations of 0.03/ml" in all patients tested. These pharmacokinetic studies have drawn attention to the potential inadequacy of the 4-weekly regimen, but some facets of these studies could be questioned. The disparity between the penicillin levels in the studies by Ginsburg et al. and by Kaplan et al. was addressed by the latter authors, who suggested that storage of samples may have accounted for these differences. Other studies have raised the issue of differences in potency of the benzathine penicillin G preparations, questioning whether dose differences may account for the low levels seen at 3 to 4 weeks after administration of the penicillin. A focal issue appears to be the lack of consensus regarding the accepted serum minimal inhibitory concentration of penicillin for group A streptococci. The concentration chosen by Ginsburg et al. 1~ was 0.01 Izg/ml, Kaplan et al. 11 chose 0.02 #g/ml, and
89
90
Editor's column
Padmavati et al? 2 selected 0.03 #g/ml. The mean serum concentration of penicillin at 28 days for the population studied by Kaplan et al. H was 0.02 ug/ml. Is this level inadequate? As reported by Ginsburg et al., ~~most strains of group A streptococci are inhibited by 0.01 fzg/ml of penicillin. Given the limited sensitivity of the disk agar method for assay of penicillin levels, it is possible that the use of a more sensitive method, such as high-performance liquid chromatography, could have shown that levels of 0.01 /zg/ml were present in the majority of the sera at 28 days. Another question that these studies engender is the relationship between serum levels of penicillin and protection against streptococcal pharyngitis. In previous studies, the presence of penicillin in the urine was found to correlate with protection against streptococcal infection and recurrence of rheumatic fever? 3 Ginsburg et al. 1~were able to detect penicillin in the" urine of 15 of 18 patients who had no detectable penicillin in the serum at 30 days. Kaplan et al. H did not test for penicillin in the urine of their patients. How relevant is this information? Does protection against streptococcal pharyngitis correlate best with serum levels, or does it correlate better with levels in tissue, or saliva, or urine? It may be that the serum penicillin level is only one of several factors influencing recurrence of rheumatic fever. Studies are needed to answer these questions. To supplement the pharmacokinetic studies, two recent clinical studies correlated the frequency of the administration of prophylaxis with the incidence of streptococcal infection and recurrence of rheumatic fever. 12,~4 Both studies found a higher rate of rheumatic fever recurrence in patients receiving prophylaxis at 4-weekly intervals in comparison with patients receiving prophylaxis every 3 weeks. These studies, which were performed in areas where the risk for rheumatic fever is high, emphasized the recommendation that prophylaxis with benzathine penicilli'n G be administered at 3-weekly rather than at 4-weekly intervals in high-risk areas. A major flaw in the design of the study by Padmavati et al. ~2is that the evaluation of the two prophylaxis regimens was retrospective and not concurrent. Thus the group of patients who received injections at 4-weekly intervals were seen during a period of 5 years, and the group of patients receiving the 3-weekly prophylaxis were seen during the following 5 years. Furthermore, it is not clear from the data presented whether Padmavati et al. documented a significant increase in the antistreptolysin O (ASO) titer between a specimen obtained before and one obtained during the recurrence. An elevated ASO titer can persist for a year or more after the acute attack in some patients with rheumatic fever. In contrast, the study by Hung-Chi et al. TM was a controlled, prospective study
The Journal of Pediatrics July 1989
involving two groups of patients. However, one group was seen in a cardiac clinic and the other in a rheumatic fever clinic. A curious observation appears in the results of this study. No recurrences were encountered among the group of patients followed in the cardiac clinic; all recurrences occurred in the patients seen in the rheumatic fever clinic. Despite these limitations, the studies mentioned above raise a reasonable concern about the adequacy of the monthly prophylaxis regimen in areas of high prevalence of rheumatic fever. Even then, is the adoption of a 3-weekly interval for prophylaxis the answer to this potential problem? Will additional pharmac0kinetic studies provide the answer, or will more extensive and better controlled prospective clinical studies be more appropriate? Regardless of which approach is used, other compelling questions, in addition to the questions raised above, should be considered before additional studies are undertaken: First, what will be the effect of a 3-weekly regimen on compliance? The only two proven recurrences in our practice over the past two decades occurred in the same patient, who was so scared by the pain associated with the injections of benzathine penicillin G that he invested a lot of effort in devising methods to avoid the injections. Second, is the low level or absence of penicillin during the fourth week the major cause for recurrences, or are other factors involved? Catanzaro et al.] 5 in their original studies on the primary prevention of rheumatic fever, noted that this complication was "prevented when penicillin therapy of streptococcal infection was delayed until nine days after the onset of illness" (pharyngitis). For penicillin tO be ineffective in preventing a recurrence of rheumatic fever when given at 4-weekly intervals, one has to invoke the probability that the observation described above does not apply to recurrent attacks. In addition, we must provide an answer to the question of why the majority of patients with rheumatic fever who are receiving prophylaxis and who acquire a pharyngitis, proved by culture, an ASO rise, or both, fail to show a recurrence of rheumatic fever. Third, what would be the added cost of a 3-weekly prophylaxis? Although the increased cost of the medication may not be substantial, as pointed out by Padmavati et al., ~2 one has to take into consideration the cost of administration of medication, added travel, increased work load on clinic personnel, and, not least, increased absenteeism of the patient from school. Finally, one wonders whether we are overlooking the obvious. What would happen if we simply increased the monthly dose of penicillin from 1.2 million to 1.8 million units? Would this obviate the problem of lower serum levels during the fourth week and reduce recurrence of rheumatic fever, albeit at th e price of more pain to the patient?
Volume 115 Number 1
Editor's column
Until these questions are answered, we should follow the r e c o m m e n d a t i o n of the A H A and W H O and continue to provide prophylaxis at m o n t h l y intervals in this country and in other countries where the risk for r h e u m a t i c fever, despite the recent resurgence, remains relatively low. However, adoption of t h e 3-weekly regimen in high-risk areas is still an open question. Better-designed prospective studies may provide the answer to this question, and its final adoption awaits a more definitive evaluation.
Elia M. Ayoub, MD Department o f Pediatrics University o f Florida Gainesville, FL 32610 Chairman, Task Force on Rheumatic Fever and Rheumatic Heart Disease State o f Florida Cardiac Disease in the Young Council American Heart Association, Florida Affiliate REFERENCES I. Thomas CB, France R. A preliminary report of the prophylactic use of sulfonamide in patients susceptible to rheumatic fever. Bull Johns Hopkins Hosp 1939;64:67. 2. Coburn AF, Moore LV. The prophylactic use of sulfanilamide in streptococcal respiratory infections with special reference to rheumatic fever. J Clin Invest 1939;18:147. 3. Stollerman GH, Rusoff JH. Prophylaxis against group A streptococcal infections in rheumatic fever patients: use of a new repository penicillin preparation. JAMA 1952;150: 1571. 4. Wood HF, Feinstein AR, Taranta A, et al. Rheumatic fever in children and adolescents: a long-term epidemiologic study of subsequent prophylaxis, streptococcal infections, and clinical sequelae, llI. Comparative effectiveness of three prophylaxis regimens in preventing streptococcal infections and
5.
6.
7.
8.
9. 10.
11.
12.
13. 14.
15.
91
rheumatic fever recurrences. Ann Intern Med 1964;60(Suppl 5, pt 2):31. Dajani AS, Bisno AL, Chung K J, et al. Prevention of rheumatic fever: a statement for health professionals by the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascualr Disease in the Young, the American Heart Association. Circulation 1988;78:1082. WHO Study Group. Rheumatic fever and rheumatic heart disease. WHO Technical Report Series No. 764. Geneva: World Health Organization, 1988. Sanyal SL, Berry AM, Duggal S, et al. Sequelae of the initial attack of acute rheumatic fever in children from north India: a prospective 5-year follow-up study. Circulation 1982; 65:375. Majeed HA, Shaltout A, Yousof AM. Recurrences of acute rheumatic fever: a prospective study of 79 episodes. Am J Dis Child 1984;138:341. Padmavati S. Rheumatic fever and rheumatic heart disease in developing countries. Bull WHO 1978;56:543. Ginsburg CM, McCracken GH, Zweighaft TC. Serum penicillin concentration after intramuscular administration of benzathine penicillin G in children. Pediatrics 1982;69:452. Kaplan EL, Berrios X, Speth J, Siefferman T, Giuzman B, Quesny F. Pharmacokinetics of benzathine penicillin G: serum levels during the 28 days after intramuscular injection of 1,200,000 units. J PEDIATR 1989;115:t46-50. Padmavati S, Gupta V, Prakash K, et al. Penicillin for rheumatic fever prophylaxis: 3-weekly or 4-weekly schedule. J Assoc Physicians India 1987;35:753. Markowitz M. Eradication of rheumatic fever: an unfulfilled hope. Circulation 1970;41:1077. Hung-Chi L, Mei-Hwan W, Kue-Hsiung H. Rheumatic fever recurrences: controlled study of 3-week versus 4-week benzathine penicillin prevention programs. J PED1ATR t986; 108:299. Catanzaro F J, Stetson CA, Jorris A J, et al. The rolc of the streptococcus in the pathogenesis of rheumatic fever. Am J Med I954;17:749.