Kassem et al from Alexandria, Egypt (1996) compared the effectiveness of biweekly schedule of 1.2 million units of intramuscular Benzathine PenicillinG and four weekly schedules in the prevention of upper respiratory Group A beta- hemolytic streptococcal infections and rheumatic fever recurrences. The study was over 2 years and involved 360 subjects in a Randomized Clinical Trial (Kassem, Zaher, Shleib, El-Kholy, Madhour & Kaplan, 1996). In this study, 360 subjects with documented rheumatic fever were followed up over 2 years. Their age ranged from 4-20 years (mean age 11.4yrs+/- 4), ethnicity was Egyptian.
Group A beta-hemolytic streptococcal infection rate showed no difference between biweekly and four weekly schedule, with infection rates of 0.2% and 0.3% respectively, with a p value> 0.005. However, rheumatic fever recurrence rate in subjects on the biweekly schedule was half that in subjects on the four weekly schedule. Non-compliance resulted a four-fold increase in rheumatic fever recurrence rate. There was no significant difference in compliance between subjects of both study groups.
The p value> 0.5 indicated no significant difference in group A beta-hemolytic streptococcal infection rates, between the biweekly and four weekly prophylaxis schedule. However the significant difference in rheumatic fever recurrence rate, of the subjects on the biweekly schedule and those on the four weekly schedule indicated that the biweekly schedule reduced the sequelae of upper respiratory group A beta-hemolytic streptococcal infection.
The finding that rheumatic fever recurrence rate increased four-fold with non-compliance was consistent with the results of the study that intramuscular Benzathine Penicillin G injections reduce rheumatic fever recurrences. It is important to note that the authors have not elaborated on what criteria determined compliance, or the non-compliance figures for both groups, however it is assumed that non-compliance meant that the subjects did not complete the prophylaxis regime. Moreover, increased costs associated with the increased frequency of injections and compliance could be an issue with the pain and discomfort related to intramuscular Benzathine Penicillin G injections, with the biweekly schedule versus the four-weekly regime.
The second key study was aimed at finding out the effects of three versus four-weekly intramuscular Benzathine Penicillin G on streptococcal infection and recurrences of rheumatic fever. The study was conducted by Lue et al 91996), carried out in Taipei, Taiwan over a 12-year period in a Randomized Controlled Trial (RCT) and involved 249 subjects with rheumatic fever. Ethnicity of subjects was Taiwanese (Lue, Wu, Wang,Wu & Wu,1996).
Streptococcal infections and rheumatic fever recurrences were greater in the four-week (12.7 per 100 patient-years) versus three-week (7.5 per 100 patient-years) programme with a p value<0.01 indicating a significant difference between the two groups. Lower rates of rheumatic fever recurrences were observed in the three weekly programme. Recurrence rates per streptococcal infection showed no statistical difference (p value>0.3) between the three (13.6%) and four-weekly (15.5%) programmes. However, the rate of rheumatic fever recurrences as a result of prophylaxis failure was five times greater in the four-weekly (9.7%) than the three-weekly (3.0%) programme (p value=.015). Patient compliance was classified as complete if only one injection was missed in a year; partial, if two to three were missed; and drop out if four or more were missed in a year.
Lue et al (1996) found that three week prophylaxis treatment was more effective given that heart murmurs were significantly lessened in the three weekly (46%) versus four weekly (66%) programme, showing an increased risk of rheumatic fever recurrences in those receiving prophylaxis every four weeks. It is surprising to find that in this study non-compliance was higher in the four-week programme.
This can possibly be attributed to long intervals between rheumatic fever attacks (2-11 years) and possibly subject complacency with prophylaxis treatment. Lue et al (1996) found that three weekly prophylaxis treatments reduced streptococcal infections and rheumatic fever recurrences significantly in comparison to the four weekly one. This finding is similar to that of Kassem et al (1996) that the increased frequency of intramuscular Benzathine Penicillin G injections had a positive effect on reducing streptococcal infections and rheumatic fever recurrence rates.
The third study investigated plasma penicillin concentrations after increased doses of Benzathine Penicillin G for prevention of secondary rheumatic fever. This study was carried out by Currie, Burt & Kaplan (1994). The subjects were rural aboriginal communities in Arnhemland, Northern Territory, Australia with rheumatic fever. The study was over a 2-month period in a Randomized Clinical Trial (RCT) involving 25 subjects ( 15 are female), aged 16 to 49 years (mean, 29 years) and weight 40 to 90 kg ( mean 57kg). Written informed consent was obtained. Three different doses of Benzathine Penicillin G (1.2mu, 1.8mu, and 2.4mu) were given monthly.
The result showed that mean levels of penicillin in plasma for subjects with level>25ng/ml were not significantly different between the three dosage groups. Despite higher proportion of patients with plasma penicillin levels>25ng/ml, with higher than 1.2mu traditional Benzathine Penicillin G doses, figures did not reach statistical significance> three-week penicillin levels in 8 of 16 subjects showed inadequate levels (51.8ng/ml). This study provided some preliminary evidence that Benzathine Penicillin G doses greater than 1.2 mega units may prolong the duration of penicillin plasma levels during treatment against recurrent rheumatic fever.
Limitations to the success rate of increased doses of Benzathine Penicillin G in the secondary prevention of secondary rheumatic fever might be attributed to the possibility that some injections may have been given into adipose tissue rather than muscle, quality and storage of Benzathine Penicillin G may also have affected the results. A small sample size may have also affected figures not reaching statistical significance. There are also the practical difficulties associated with implementing such studies in rural outback communities, involving a lot of travel, associated costs, time and obtaining larger sample numbers.
In conclusion, rheumatic fever still prevail in some countries like New Zealand and this is thought to be linked to environmental factors such as socioeconomic status, overcrowding, poor nutrition, lack of access to appropriate medical care. Register based prevention programmes were set up to monitor and manage rheumatic fever in the community, however there needs to be some uniformity between registers and protection of data for continuity purposes. Intramuscular Benzyl Penicillin G (BPG) remains the drug of choice in reducing rheumatic fever and its recurrence rates. This is largely due to the fact that penicillin has proven its effectiveness, narrow antibacterial spectrum and is obtainable at low cost.
The three selected key studies further support the effectiveness of penicillin through is findings that it reduces rheumatic fever recurrence rates with increased frequency of injections, and that larger doses of Benzyl Penicillin G may play a role in prolonging the effectiveness of penicillin. However, with increased frequency of injections, compared to the traditional monthly regime, and the possibility of administering larger Benzyl Penicillin G doses, associates costs need to be considered.
Baker, M., chakraborty, M. (1996). Rheumatic fever in New Zealand in the 1990’s: still a cause for concern. The New Zealand Public Health Report, 3 (3), 17-19.
Baker, M., Goodyear, R. Howden-Chapman, P. (n.d). Chapter5: Household Crowding and Health. Retrieved March 18, 2006 http://www.stats.govt.nz/NR?rdonlyres/96EA48CC-FF7d-4540-A290-D866F6211B0E/0/Chapter5.pdf
Carapetis, J. R., Currie, B. J., Mathews, J. D. (2000). Cumulative incidence of rheumatic fever in an endemic region: a guide to the susceptibility of the population? Epidemiology ad Infection, 124 (2) 239-44.