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Year : 2021  |  Volume : 10  |  Issue : 4  |  Page : 129-132

Safety and concerns of secondary prophylaxis for rheumatic heart disease with benzathine penicillin: A tertiary care cardiac centre experience

Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, Karnataka, India

Date of Submission04-Apr-2021
Date of Decision16-May-2021
Date of Acceptance17-May-2021
Date of Web Publication24-Dec-2021

Correspondence Address:
Dr. Arun B Shivashankarappa
MD, DM Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bannergatta Road, Jayanagar-9th Block, Bengaluru, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcpc.jcpc_23_21

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Background: Rheumatic Fever (RF) and Rheumatic heart disease (RHD) are common cardiovascular diseases in developing countries. Long-term Benzathine Penicillin G (BPG) injection is being used for secondary prophylaxis of RF/RHD. Although allergic reactions to BPG are rare, there is a lot of fear and hesitancy in administering it. Objective: The objective of this study is to assess the safety of injection BPG used for secondary prophylaxis of RHD. Methods: Patients who had received secondary prophylaxis to RHD at our institute's outpatient department from January 1, 2015 to December 31, 2020, were analysed retrospectively. Results: Among 25,819 injections of BPG given to 2878 patients, eight patients had adverse events. Five patients had anaphylaxis, two had urticaria, and one had vasovagal syncope. Incidence of adverse events was 0.03% of injections and 0.28% of patients. Majority of adverse events were seen in patients more than 18 years (7 out of 8). All were treated successfully and there was no mortality.
Conclusions: Life-threatening allergic reactions are very rare in patients on long-term intramuscular BPG for secondary prevention of RHD.

Keywords: Anaphylaxis, benzathine penicillin G, rheumatic heart disease, urticaria

How to cite this article:
Bhat P, Shivashankarappa AB, Krishnappa RB, Nanjappa MC. Safety and concerns of secondary prophylaxis for rheumatic heart disease with benzathine penicillin: A tertiary care cardiac centre experience. J Clin Prev Cardiol 2021;10:129-32

How to cite this URL:
Bhat P, Shivashankarappa AB, Krishnappa RB, Nanjappa MC. Safety and concerns of secondary prophylaxis for rheumatic heart disease with benzathine penicillin: A tertiary care cardiac centre experience. J Clin Prev Cardiol [serial online] 2021 [cited 2022 Dec 6];10:129-32. Available from: https://www.jcpconline.org/text.asp?2021/10/4/129/333701

  Introduction Top

The global burden of Rheumatic fever (RF) and Rheumatic heart disease (RHD) is significant and is predominantly found in people living in low socioeconomic status.[1] The overall estimated prevalence of RHD in India is about 1.5-2 per 1000 in all age groups, suggesting that there are about 2.0-2.5 million patients of RHD in the country.[2] The Indian Council of Medical Research initiated control and prevention of RF/RHD through hospital-based passive surveillance and implementation of secondary prophylaxis under the Jai Vigyan Mission Mode Project from 2000 to 2010.[3] Because of the impact of this disease on public health, and the proven efficacy of antibiotic prophylaxis, the World Health Organization has helped to establish programs for the prevention of RF in developing countries.[4]

Antibiotics are essential for secondary prophylaxis against RF and the development of RHD. Since the 1950s, RHD prophylaxis has been achieved through intramuscular injection of Benzathine Penicillin G (BPG).[5] The advantages of BPG include the need for once in 3 weekly injections and its unchallenged efficacy.[6],[7] Recurrence rate of RF with injection Benzathine Penicillin, oral Penicillin, and oral sulfadiazine was 0.4, 5.5 and 2.4, respectively, per 100 patient-years. in Irvington House study.[8] Although allergic reaction to Penicillin is rare, there is a lot of hesitancy in administering injection BPG. Skin testing is performed routinely before penicillin injection in most of the centres in India, although there are no published guidelines and recommendations.


The objective of this study is to assess the safety of BPG injection used for secondary prophylaxis of RHD.

  Methods Top

Patients who received secondary prophylaxis for RHD with intramuscular BPG at our institute outpatient division from January 1, 2015 to December 31, 2020, were evaluated retrospectively. Data were collected from the outpatient registry of secondary prophylaxis for RHD. This registry is maintained by the trained staff nurses who administer the injections. The patients with adverse events to injection BPG were analysed. The study was approved by the Institutional Ethics Committee.

  Results Top

Twenty five thousand eight hundred and nineteen injections of BPG were administered to 2,878 patients during the study period. All these injections were given by experienced nursing staff. All patients received Penidure brand. As BPG is available as lyophilized powder, it is reconstituted with 5 ml of sterile water. All patients received the test dose prior to each injection, which was given with 0.2 ml intradermal BPG. After an observation period of 30 minutes, full dose of BPG was administered deep intramuscular in the gluteal region at 90°, using 21 gauge needle, following which they were kept under observation for another 30 minutes.

The mean age of the total population was 31.54 ± 10.76 years. Female: Male ratio was 1.41:1. 383 patients (13.3%) were under 18 years and 2495 (86.7%) were above 18 years. Eight patients had adverse reactions, amounting to 0.03% of injections and 0.28% of patients. All these eight patients had received Penidure brand and no impurities were noted in any of them. Five patients had anaphylaxis, two had urticaria, and one had vasovagal syncope. Most of the adverse events occurred within 30 minutes. Five of them occurred with test dose and three with full dose, with test dose being well tolerated. Of five patients with anaphylaxis, three happened with test dose and two with full dose. In four patients, anaphylaxis occurred with first dose of BPG and in one patient, after 30 years of prophylaxis. One patient had life-threatening anaphylactic shock and cardiac arrest, requiring cardiopulmonary resuscitation, endotracheal intubation, and mechanical ventilation. However, she recovered within 24 hours. Remaining four patients with anaphylaxis were treated with hydrocortisone, antihistamine, and adrenaline and had rapid recovery. There was no mortality in any of these patients. Two patients had urticaria after the test dose, one after the first dose and another after 4 years of prophylaxis. They responded to antihistamines. One patient who developed vasovagal attack after full dose of injection responded promptly to atropine and IV fluids.

The majority of the adverse events occurred in patients >18 years (7 out of 8). All anaphylactic reactions were seen in females. In all patients, except the one with vasovagal syncope, injection BPG prophylaxis was stopped, and alternative antibiotics were started for secondary prophylaxis. Details of patients with adverse events and their management are given in [Table 1].
Table 1: Details of patients with adverse events to benzathine penicillin G and their management

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  Discussion Top

About 0.03% of injections had adverse reaction to BPG given for secondary prophylaxis of RHD at our institute. The observed incidence is very low, compared to that noted in the International RF Study Group (3.2%).[9]

Anaphylaxis is the most dreaded and worrisome reaction to penicillin. The reported incidence of serious reactions among patients without a history of RF ranges from 1 to 4/10,000 injections.[10] In our study, five had anaphylaxis among 2878 patients who received 25,819 injections, representing a frequency of 1.9/10,000 injections. This shows the rarity of serious allergic reactions to penicillin. The risk of such allergic reaction is further low in age group lesser than 18 years,[11] which was also shown in our study.

Data from the Nepalese RF/RHD prevention and control programme registry showed that 65 patients (1.4%) among 77,300 injections of BPG given to 4,712 patients, had allergic reactions. Five had anaphylaxis, an incidence of 0.1% (0.7/10,000 injections), 60 had minor allergy, an incidence of 1.3%.[12]

In our study, all the anaphylaxis and urticaria were seen in females. This kind of female preponderance in allergy to penicillin was also reported in a study by Stephanie Albin.[13]

Five of our patients had allergic reaction to test dose, and full dose was abandoned in them. Thus, skin testing with BPG might further reduce the already low risk of a fatal reaction in patients with RHD. Patients with a positive skin test could receive an alternative prophylactic drug, such as Erythromycin. In our study, it was noted that three patients had no reaction to test dose, but developed full reaction after full dose. Hence, negative skin testing does not rule out allergic reaction. Although most of the allergic reactions occur with first dose, they can even occur in patients who had previously well-tolerated injection BPG.[14] This was observed even in our study in three patients. Sometimes reactions can occur when there is a change in brand and batch, because of the possible differences in quality of the drug with different manufacturers and batches. Hence, it is necessary to note the brand name and batch number. Furthermore, it is safer to give test dose to all patients before each dose.

  Conclusions Top

Life-threatening adverse reactions to long-term intramuscular BPG are very rare in patients on secondary prophylaxis of RHD. Hence, there should not be any hesitancy in administering BPG prophylaxis, as the benefit is far more than the risk.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of Group A streptococcal diseases. Lancet Infect Dis 2005;5:685-94.  Back to cited text no. 1
Kumar RK, Tandon R. Rheumatic fever and rheumatic heart disease: The last 50 years. Indian J Med Res 2013;137:643-58.  Back to cited text no. 2
[PUBMED]  [Full text]  
Jai Vigyan Mission mode project on community control of RHD. Non-communicable diseases Indian Council Med Res Annu Rep. 2007–08.63-64.  Back to cited text no. 3
Strasser T, Dondog N, El Kholy A, Gharagozloo R, Kalbian VV, Ogunbi O, et al. The community control of rheumatic fever and rheumatic heart disease: Report of a WHO international cooperative project. Bull World Health Organ 1981;59:285-94.  Back to cited text no. 4
Stollerman GH, Rusoff JH. Prophylaxis against group A streptococcal infections in rheumatic fever patients; use of new repository penicillin preparation. J Am Med Assoc 1952;150:1571-5.  Back to cited text no. 5
World Health Organization. Rheumatic Fever and Rheumatic Heart Disease: Report of a WHO Expert Consultation. WHO Technical Report Series No. 923. Geneva: World Health Organization; 2004 .  Back to cited text no. 6
Chandrashekhar YS, Narula J. Rheumatic Fever. In: Willerson J.T., Wellens H.J.J., Cohn J.N., Holmes D.R. (eds) Cardiovascular Medicine. Springer, London 2007.   Back to cited text no. 7
Feinstein AR, Spagnuolo M, Wood HF, Taranta A, Tursky E, Kleinberg E. Rheumatic fever in children and adolescents. A long-term epidemiologic study of subsequent prophylaxis, streptococcal infections, and clinical sequelae. VI. Clinical features of streptococcal infections and rheumatic recurrences. Ann Intern Med 1964;60:l568-86.  Back to cited text no. 8
Allergic reactions to long-term benzathine penicillin prophylaxis for rheumatic fever. International Rheumatic Fever Study Group. Lancet 1991;337:1308-10.  Back to cited text no. 9
Enffmeyer JE. Penicillin allergy. Clin Rev Allergy 1986;4:171-86.  Back to cited text no. 10
Sullivan TJ. Pathogenesis and management of allergic reactions to penicillin and other beta-lactam antibiotics. Pediatr Infect Dis 1982;1:344-50.  Back to cited text no. 11
Regmi P, Upadhyaya A. Allergic reaction to long – Term BPG injection for secondary prevention of acute rheumatic fever and recommendations for skin testing. Nepalese Heart J 2013;8:16-8.  Back to cited text no. 12
Albin S, Agarwal S. Prevalence and characteristics of reported penicillin allergy in an urban outpatient adult population. Allergy Asthma Proc 2014;35:489-94.  Back to cited text no. 13
Bhattacharya S. The facts about penicillin allergy: A review. J Adv Pharm Technol Res 2010;1:11-7.  Back to cited text no. 14
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