CRITICAL APPRAISAL OF ARTICLE ON HARM
Clinical question: Among patients with acute rheumatic fever, will long term penicillin
prophylaxis have adverse effects?
Population: patients with rheumatic fever taking penicillin as prophylaxis, 28 yrs old
Intervention: administration of penicillin
Outcome: harm, complications, or adverse reactions
Journal Title:
Allergic reactions to long term benzathine penicillin prophylaxis for rheumatic fever
Search terms: penicillin, prophylaxis, allergic reaction, rheumatic fever
Lancet. 1991 Jun 1;337(8753):1308-10.
Allergic reactions to long-term benzathine penicillin
prophylaxis for rheumatic fever. International Rheumatic
Fever Study Group.
1790 patients from 11 countries were enrolled in a prospective international
study to determine the incidence of allergic reactions to monthly intramuscular
benzathine penicillin (penicillin G benzathine) injections to prevent recurrences of
rheumatic fever. After 32,430 injections during 2736 patient years of observation, 57 of
the 1790 patients (3.2%) had an allergic reaction. 4 had anaphylaxis, an incidence of
0.2% (1.2/10,000 injections), all in patients over 12 years of age, and 1 patient died, a
fatality incidence of 0.05% (0.31/10,000 injections). These rates are similar to those
described for patients without rheumatic fever who receive short-term treatment with
parenteral penicillin. Rheumatic fever recurred in 8 of 1790 patients (0.45%) who
received benzathine penicillin prophylaxis compared with 11 of 96 (11.5%) who did not
comply with treatment. Life-threatening allergic reactions are rare in patients on longterm parenteral benzathine penicillin to prevent recurrences of rheumatic fever; the
long-term benefits of such prophylaxis by far outweigh the risk of a serious allergic
reaction.
PMID: 1674296 [PubMed - indexed for MEDLINE]
Critical Appraisal:

Relevance
Is the objective of the article similar to your dilemma?
Yes. The objective of the study is to determine the incidence of allergic
reactions to monthly intramuscular benzathine penicillin (penicillin G
benzathine) injections to prevent recurrences of rheumatic fever.
(Abstract, 1st paragraph, p1308)

Validity Guides
Were there clearly identified comparison groups?
Yes. The investigator only included patients ranging from 5 – 28 yrs old
who have history of rheumatic fever and received benzathine penicillin
prophylaxis. All patients enrolled in the study fulfilled the Jones criteria for
diagnosis of rheumatic fever and none had history of allergic reaction to
penicillin.
(Patients and Methods, 1st and 2nd paragraphs, p1309)
There were 1790 patients in total, 1500 had continued penicillin
prophylaxis while 290 patients dropped out of the study, either because they
moved, stopped prophylactic treatment for medical reasons other than allergy,
or did not comply with treatment. Of the 290, 96 patients did not comply with
prophylaxis.
(Results, 3rd paragraph, p1309)
Were the exposures and outcomes measured in the same way in the groups
compared?
Yes. The exposures and outcomes were measured in the same way in
the groups compared. Age, injection schedule, duration of previous prophylaxis,
and manufacturer of the penicillin used were recorded for all patients. After
entry to the study the date of each benzathine penicillin injection and any
subsequent signs and symptoms of a possible allergic reaction (hypotension,
dyspnoea, pruritus, urticaria, angioneurotic oedema, arthralgia, and
maculopapular rash) were recorded. Any allergic reaction was classified
according to its time of onset: immediate, or within 1 h of administration;
accelerated, after 1-72 h; and late, after more than 72 h.16 A record was also
kept of rheumatic fever recurrences among patients who received benzathine
penicillin prophylaxis and among those who did not comply with treatment.
(Patients and Methods, 2nd paragraph, p1309)
Was follow-up sufficiently long and complete?
Yes the follow up was sufficiently long to detect the outcome. Patients
with a history of rheumatic fever who received benzathine penicillin prophylaxis
were recruited in 1988-1990. Patients were followed prospectively for 6-24
months for a total of 2736 patient-years on prophylaxis.
(Patients and Methods, last paragraph, p1309)
During this period, of the 1790 patients who were enrolled, 194 patients
dropped out of the study, either because they moved, stopped prophylactic
treatment for medical reasons other than allergy, 96 did not comply with
treatment while the remaining 1500 continued with the treatment. The study
has 84 5 follow up.
(Results, last paragraph, p1309)
Is the temporal relationship between the exposure and outcome correct and
dose response gradient present?
The administration of penicillin was done before any event of allergic
reactions, anaphylaxis, or death. The patients received a uniform dose of
penicillin throughout the study. Hence, there was no dose response
relationship.
(Patients and Methods, 1st paragraph, p1309)
Overall, is the study valid?
Since almost all the validity guides are valid, the study can be
considered valid.

Results
What is the magnitude of the association between exposure and outcome?
Was the estimate of the risk precise?
Patients on penicillin prophylaxis have 1.14x more chances of having adverse
effects such as allergic reaction and anaphylaxis. With a confidence interval of 1.12 –
1.16, the prophylaxis has an associated risk of harm.
(Results, p1309)

Clinical Applicability
Are the study patients similar to my own?
Yes. Our patient is a 28 year old female with symptoms of acute rheumatic
fever who is on penicillin prophylaxis. Meanwhile, the subjects in this study are
men and women aged 5- 28years old who have history of rheumatic fever and
received benzathine penicillin prophylaxis.
(Patients and Methods,p1309)
Is our patient so different from those in the study that its results cannot
apply?
No, our patient is the same with the patients included in the study. The
age of our ARF patient (28 years old) falls within the range of the age of the
patients (between 5 and 28 years old). Subjects of the study are ARF patients
who had their penicillin prophylaxis. Therefore, this study can be applied to our
patient.
(Patients and Methods, p1309)
What is our patient’s risk of benefit and harm from the exposure?
The efficacy of antibiotic prophylaxis to prevent recurrences of rheumatic fever
has been known for over 50 years a major advance that has strikingly reduced
the morbidity and mortality from rheumatic fever.
(Introduction, p1308)
Penicillin can cause severe and even fatal allergic reactions, which led to
concern when long-acting depot penicillin became available in 1951. There
were also reported deaths in patients with a history of rheumatic fever treated
with penicillin.
However, the long term benefits of penicillin prophylaxis to prevent recurrent
rheumatic fever far outweigh the risk of a serious adverse reaction to penicillin.
(Discussion, last paragraph, p1310)
What alternative treatments are available?
In this article, Sulphadiazine was the alternative medication
recommended to patients who have positive skin tests results on penicillin
allergy.
Resolution to the Scenario
The patient will be advised to continue prophylactic treatment of
Penicillin for her acute rheumatic fever because it was established that the long
term benefits of penicillin prophylaxis to prevent recurrent rheumatic fever far
outweigh the risk of a serious adverse reaction to penicillin. It is however,
essential to look out for untoward reactions to penicillin and to have
resuscitation facilities available when patients are injected, and extra vigilance
may be necessary in patients with severe heart disease and a history of cardiac
decompensation.