Over prescription of antibiotics for adult pharyngitis is prevalent in developing countries but can be reduced using McIsaac modification of Centor scores: a cross-sectional study

Group A beta hemolytic Streptococcus (GABHS) is commonly implicated in bacterial pharyngitis [1]. Starting treatment with antibiotics for GABHS infection, within the first 24–48 hours of illness, when a bacterial cause is highly suspected, has been found to decrease duration of symptoms, such as sore throat, fever and adenopathy by approximately one day [2], and prevent complications of GABHS pharyngitis, particularly rheumatic fever and rheumatic heart disease [3]. However, the majority of pharyngitis cases in adults are of viral etiology [4]; only 5–15% of cases suffer from bacterial pathogens that require prompt antibiotic treatment [5, 6].

The World Health Organization (WHO) defines an appropriate prescription as “administration of the right drug indicated for the disease, in the right dose, through an appropriate route of administration, for the right duration” [7]. When these criteria are not fulfilled, the prescription is considered inappropriate. Inappropriate antibiotic prescriptions for treatment of pharyngitis have contributed to the emergence of resistant strains of oropharyngeal human flora [8] which in turn, have increased morbidity, mortality, and health-care costs [9]. Approximately three quarters of pharyngitis patients have received inappropriate antibiotic prescriptions, by receiving antibiotics for viral infections or otherwise not adhering to the WHO definition [10‐12].

First-line agents for treatment of bacterial pharyngitis include penicillin, ampicillin or amoxicillin.¹³ Alternative options include erythromycin (especially in patients with a non-life-threatening allergy to penicillin) and first-generation cephalosporins (CG) [1]. Both erythromycin and cephalosporins are also considered reasonable alternatives to penicillin in patients who fail to respond to penicillin or continue to become re-infected following penicillin therapy [13‐15]. As GABHS is the most important pathogen causing infection, fluoroquinolones, and sulfamethoxazole/trimethoprim that do not cover Gram-positive pathogens very well are not recommended. Although amoxicillin-clavulanate, clarithromycin, azithromycin and second-generation cephalosporins work very well against GABHS infection, they are considered third-line alternatives due to their broader spectrum of action and potential for causing resistance.

Throat swab and culture is the gold standard for diagnosis of pharyngitis. A rapid antigen detection test (RADT) can also give relatively specific diagnosis in a physician’s office. Although a WHO technical report states that there is less possibility of false-positive results with RADT, RADT kits vary in sensitivity, which ranges from 31–95%. Therefore, RADT cannot be substituted for standard blood agar cultures [3]. Because antibiotics treatment should occur fairly promptly, diagnosis of pharyngitis is often based on clinical symptoms; throat swabs are not always taken [16]. Thus to improve the diagnostic criteria, several scoring systems have been developed to predict, on a clinical basis, whether patients have bacterial or viral pharyngitis [17, 18].

Among the many devised clinical scores, the Centor criteria are reliable predictors of GABHS pharyngitis. They include evaluating patients for tonsillar exudates, tender anterior cervical lymphadenopathy or lymphadenitis, absence of cough, and history of fever (oral temperature greater than 38.3°C; 101°F) [19]. More recently, the Centor score was modified by incorporating patient's age, which allows the physician to place patients in low-, moderate-, or high-risk groups. The use of the McIsaac Modified Centor score has helped in decreasing inappropriate antibiotic use by almost 88% [18].

Several guidelines have been published on diagnosis and treatment of streptococcal pharyngitis in adults; however, not all are in agreement. The American College of Physicians’ (ACP) guideline endorsed by Centre for Disease Control (CDC), American Academy of Family Physicians and the American Society of Internal Medicine, recommend that patients with low Centor scores of 0 or 1 (i.e., low risk for streptococcal pharyngitis) do not require any testing or treatment with antibiotics. For patients with Centor scores of 2 or, 3, the guidelines suggest using a RADT, which would give a sensitivity of > 80% for accurate diagnosis of GABHS infection, and prescribing antibiotics to patients with positive tests [20, 21]. Empirical treatment with antibiotics is recommended for patients with Centor scores of 3 or 4 [22]. However, practice guidelines issued by the American Heart Association [23], American Academy of Pediatrics [24], and Infectious Diseases Society of America (IDSA) [25] recommend microbiologic confirmation by throat culture or RADT to diagnose all adults with pharyngitis prior to antibiotic prescribing, regardless of their Centor scores. IDSA and others are of the opinion that if prestigious organizations like AAFP and CDC endorse the option of not culturing at all for any given score, it would be unlikely that physicians would opt for either RADT or culture [26].

These concerns were addressed by McIsaac who pointed out that missed infections are not due solely to score approaches, as physicians do not obtain a throat swab for every case of sore throat [27]. Therefore, treatment decisions based on clinical judgment would already miss 50% of GABHS infections, while 20–40% of the larger number of non-GABHS sore throat presentations would be identified as needing antibiotics [19, 28].

Table 1 shows the demographics of the study population. Of the 137 patients, the average age of the study population was 26 years old while the median age was 23 years. There were more males than females who presented with symptoms of pharyngitis (66% male vs 34% females). Thirty patients each with scores 0, 1, 2 and 3, and 17 patients with score 4 were evaluated for bacterial pharyngitis (N= 137); of these patients, only 6 were GABHS+ but 135 were treated with antibiotics. Thus, the prevalence of bacterial pharyngitis in our population was 43.8 per 1000 population. Penicillin was the most frequently prescribed antibiotic class (34.1%). Within this class, the majority of prescriptions were for amoxicillin-clavulanate (26.6%), a broad-spectrum penicillin. Approximately 15% of the prescriptions were for cephalosporins (14.8%), with the third-generation cephalosporins accounting for 9.6% of the usage, second-generation cephalosporins accounting for 3.7%, and first-generation cephalosporins accounting for 1.4% of total antibiotic usage. Macrolides (31.1%), quinolones (14.8%), sulfonamide (3.0%), tetracyclines (2.2%) were also prescribed for patients.

Antibiotics were prescribed inappropriately to adult pharyngitis patients; we saw no association between antibiotic use and culture confirmation results (P = 0.75). When cross tabulated, of the patients who were given antibiotics, only 4% patients were GABHS+; 96% of patients were GABHS– (Table 2).

A total of 135 patients received antibiotics, but only 15/135 (11.1%) received appropriate antibiotics; 120/135 (88.9%) who received inappropriate antibiotics, not recommended by current guidelines. Table 3 shows the breakdown of the antibiotics received by the patients. Only 8/135 (5.8%) of the patients received first-line agents for treatment of pharyngitis; most patients received second-line agents (7/135; 5.2%) and third-line agents (120/135; 88.9%). Of the inappropriate antibiotics prescribed, macrolides (42/135; 31.1%) were prescribed most, including erythromycin for non-penicillin allergic patients, clarithromycin and roxithromycin; followed by broad-spectrum penicillin; amoxicillin-clavulanate (36/135; 26.7%), the third-generation cephalosporin cefixime (13/135; 9.6%) and fluoroquinolones (20/135; 14.8%).

Antibiotics were prescribed by brand names to 96.2% of patients. Irrespective of which class of antibiotic was prescribed, only 45% (61/135) of patients were prescribed antibiotics at appropriate doses and durations, whereas 55% (74/135) received prescriptions for inappropriate doses and/or durations.

Table 4 shows an even distribution of patients in each of the 4 score groups (30 in each group), except for group 4 (17 patients). The McIsaac score system was found to be 100% sensitive and 68.7% specific, giving a positive predictive value (PPV) of 12.7% and a negative predictive value (NPV) of 100%.

Furthermore, even when antibiotics are used, physicians are prescribing broader class agents for treatment, such as amoxicillin/clavulanate or macrolides, rather than using the simple narrow-spectrum agents such as penicillin or amoxicillin/ampicillin; even when the antibiotic choice was appropriate, doses and durations of those antibiotics mostly were not. Although benzathine penicillin is recommended by the WHO, we did not see its usage in our study. Our investigation did not interrogate physicians’ motives; however, we speculate that they preferred the ease and lower cost of oral antibiotics to benzathine penicillin, which costs more and requires intramuscular injection.

Although our findings are similar to those of other studies conducted in western countries, the enormity of the problem seems to be much larger in Pakistan due to the large numbers of patients seeking medical attention for pharyngitis [32, 33]. Many factors could have contributed to inappropriate prescribing of antibiotics for pharyngitis. Quality of health care is constrained by costs in developing countries like Pakistan. Therefore, for a common ailment like sore throat, a costly throat swab and culture is not a routine practice. Furthermore, RADT is not an option in our setting because of its unavailability and high cost. Finally, patients generally expect to get the maximum benefit from a physician visit so that they do not have to pay the cost of the next visit. As a result, physicians are burdened with patients’ expectation of providing all care during the patient’s first and only visit. The results of our study would be generalizable to other low income countries such as India, Afghanistan and Bangladesh.

Our study showed that it would be useful for clinicians in Pakistan to use the McIsaac Modified Centor score as it is not costly, and is sensitive and specific enough to reduce unnecessary antibiotic prescriptions. Based on our study, we recommend that the score-only approach would save antibiotics prescriptions for most patients, as most adult patients with pharyngitis had scores of 0, 1 or 2. Although without a RADT test option, more antibiotics would be prescribed for patients with a score of 3 or 4, this percentage is better than the percentage of patients getting inappropriate antibiotics without clinical score-based screening at all. This modified Centor clinical prediction rule holds more importance in our setting because RADT is not widely available in our country; given their high cost and varied sensitivity (31–95%) of the different RADT kits, their use will be limited [3]. During the course of our study, we saw that affordability of RADT testing was the major concern in this setting, which resulted in almost 99% of patients being prescribed antibiotics. Following a score approach would significantly reduce unnecessary antibiotics prescriptions.

Our study implies that, as with developed countries, clinicians in low socioeconomic countries need further education on appropriate antibiotics to use for GABHS infection, particularly the proper dose and duration of those antibiotics and possible repercussions of inappropriately prescribed antibiotics. Education should emphasize the higher prevalence of viral etiology, use of the McIsaac modified Centor scoring system, and published guidelines on treatment of pharyngitis [8, 14]. This is particularly important as India and Pakistan have been found to be among the initial sites of extremely resistant organisms such as Escherichia coli and Klebsiella pneumonia with the carbapenem-resistance gene blaNDM-1, [34] which may have resulted from uncontrolled and excessive use of antibiotics in these countries. Inappropriate use of antibiotics in developing regions has consequences for everyone; microbes have no country. Sensitivity to this issue needs to be renewed by creating awareness that should be well supported by data.

This study has several limitations. This patient sample was very small with representation of few selected settings where the influx of patients is from lower- and middle-class families. A larger sample with patients from different areas of Karachi in future studies would offer better-supported conclusions about city-wide prescribing practices, and about the prevalence of GABHS infection in adults. The McIsaac–Centor score has been validated for use in industrialized countries, where prevalence of rheumatic heart disease is < 1 per 1000 population, compared to >10 per 1000 in Pakistan /Asia [35]. Thus, using the McIsaac modified score as a routine clinical tool may also mean that more cases of rheumatic fever are being prevented, given the higher prevalence of rheumatic fever in Pakistan compared to the industrialized nations.

In Pakistan, antibiotics are prescribed for most cases of adult pharyngitis when in fact, the majority of the cultures are negative for bacterial infection. Furthermore, it was alarming for us to discover the high use of second generation macrolides and cephalosporins rather than the recommended narrower spectrum agents. McIsaac modification of Centor score directly related to culture results. We therefore highly recommend its use to help family physicians evaluate appropriate use of antibiotics.