Treatment of acute pharyngitis in children: an Italian intersociety consensus (SIPPS-SIP-SITIP-FIMP-SIAIP-SIMRI-FIMMG)

Abstract

Sore throat represents one of the main causes of antibiotic overprescription in children. Its management is still a matter of debate, with countries considering streptococcal pharyngotonsillitis a benign and self-limiting condition and others advocating for its antibiotic treatment to prevent suppurative complications and acute rheumatic fever. Italian paediatricians frequently prescribe antibiotics on a clinical basis regardless of microbiological results. Moreover, broad-spectrum antibiotics are inappropriately prescribed for this condition. In this regard, an intersociety consensus conference was issued to promote the judicious use of antibiotic therapy in paediatric outpatient settings. A systematic review of the literature was performed, and updated recommendations were developed according to the GRADE methodology. Antibiotic treatment with amoxicillin (50 mg/kg/day) for 10 days is recommended in all children with proven streptococcal pharyngitis. Benzathine-penicillin could be prescribed in children with impaired intestinal absorption or inability to tolerate enteral intake and in those at high risk of suppurative complications with low compliance to oral therapy. In children with suspected amoxicillin allergy, third-generation cefalosporins for five days are recommended in low-risk patients, and macrolides are recommended in high-risk ones. Candidates for tonsillectomy due to recurrent pharyngitis could be treated with amoxicillin-clavulanic acid, clindamycin, or combined therapy with amoxicillin plus rifampicin for four days, in an attempt to avoid surgery.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13052-024-01789-5.

Introduction

The management of acute pharyngotonsillitis in children is still a matter of debate, and current national and international guidelines recommend different diagnostic and treatment strategies [1–12]. Viral infections, including Adenovirus, Epstein-Barr virus, and Coxsackievirus, are the most common causes of acute pharyngitis [13]. Streptococcus pyogenes (Group A β-haemolytic streptococcus [GABHS]) is found in 1 out of 4 children with acute pharyngitis, although 10–21% of the children with microbiological GABHS evidence are carriers [14, 15]. Consequently, making an accurate diagnosis of streptococcal pharyngitis can be challenging due to the overlapping in the clinical picture between viral and bacterial illnesses [13]. This diagnostic conundrum leads to antibiotic overprescriptions. In particular, in Italy, acute pharyngitis is the second most common cause of antibiotic prescriptions among primary care paediatricians after upper respiratory tract infections [16, 17]. Streptococcal pharyngitis can lead to suppurative (i.e., peritonsillar/parapharyngeal abscess, otitis, sinusitis) or non-suppurative complications (i.e., acute rheumatic fever [ARF] and acute post-streptococcal glomerulonephritis [APSGN]). Mainly, two approaches can be identified worldwide: one advocating for the diagnosis and treatment of GABHS pharyngitis to prevent ARF; [1–8] the other supporting an unfavourable cost-benefit ratio of antibiotic treatment due to the low incidence of ARF in high-income countries and the benign and self-limiting nature of GABHS pharyngitis [9–12]. The guidelines from the Italian National Institute of Health Guidelines recommend that only children with clinical and microbiological evidence of GABHS pharyngitis should receive antibiotics [3]. However, in almost half of the cases, Italian paediatricians prescribe antibiotics in children solely on a clinical basis, disregarding microbiological results [18, 19]. Furthermore, nationwide surveys showed that broad-spectrum antibiotics are inappropriately prescribed in this context. Amoxicillin-clavulanic acid was prescribed in about 25% of Italian emergency units to treat acute pharyngitis in children, and third-generation cephalosporins were prescribed in about 28% of the cases in pediatric primary care [18, 19].

To promote appropriate antibiotic prescription and use in paediatric outpatient settings, an intersociety consensus document was developed providing updated recommendations for the treatment of acute pharyngitis in children and adolescents.

Methods

A systematic review of the literature was conducted to issue recommendations regarding acute pharyngotonsillitis treatment. The review was performed according to the GRADE methodology and the PRISMA checklist (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) as reported in the Additional file 1 [20, 21]. The following databases Embase, Scopus, PubMed, and Cochrane were systematically screened with a date restriction from 2012 to April 2024. The following terms were combined as reported in Additional file 2: “child”, “pharyngitis”, “tonsillitis”, “sore throat”, “streptococcus pyogenes”. Randomized controlled trials, observational studies, and systematic reviews with or without meta-analysis on antibiotic therapy in children older than one month with acute pharyngotonsillitis were included. Not pertinent studies were excluded. (Figures A2.1 and A2.2 in the additional file 2). The quality assessment of evidence is provided in Additional File 3 and 4. The following outcomes were considered:

1. Persistence of symptoms on the third day and at the end of therapy (important outcome).

2. Complications: acute rheumatic fever [ARF], acute post-streptococcal glomerulonephritis [APSGN] within two months, peritonsillar abscess within two months (critical outcome).

3. Risk of recurrence within 28–42 days (important outcome).

Results

Question 1. Should Group A β-haemolytic streptococcus (GABHS) pharyngotonsillitis be treated with antibiotics?

Summary of evidence

One systematic review (SR) aiming to assess the benefit of antibiotics for sore throat in paediatric and adult patients in primary care was included [22]. The SR was of moderate methodological quality and included randomised controlled trials (RCTs) or quasi-RCTs. Twenty-seven studies with 12,835 cases of sore throat were included in the SR: 11 evaluated the antibiotic effect in GABHS-positive patients [23–33], one study included both GABHS-positive and negative patients and reported results separately [34], and 2 studies excluded GABHS-positive patients [35, 36]. The meta-analyses by Spinks et al. showed that antibiotics were more effective in reducing symptoms (sore throat, fever and headache) on day 3 in patients with a positive GABHS pharyngeal swab (15 studies, 3621 patients; relative risk [RR] = 0.58; 95% confidence interval [CI] 0.48 to 0.71; number needed to treat [NNT] = 6). The efficacy was lower in GABHS-negative cases (6 RCTs, 736 patients; RR = 0.78; 95% CI 0.63 to 0.97; NNT = 21). Similarly, at week 1, the RR was 0.29 (95% CI 0.12 to 0.70) in patients with GABHS pharyngotonsillitis (7 RCTs, 1117 patients) [22]. Compared with patients receiving placebo, those treated with antibiotics showed a reduced risk of developing acute otitis media (AOM) within 14 days (RR = 0.30; 95% CI 0.15 to 0.58) or peritonsillar abscess within 2 months (RR = 0.15; 95% CI 0.05 to 0.47). On the contrary, no risk reduction was showed considering acute sinusitis within 14 days (RR = 0.48; 95% CI 0.08 to 2.76 – not statistically significant). Concerning non-suppurative complications, in 14 studies, including 8,175 patients, antibiotics showed to reduce the ARF risk by more than two-thirds within two months (RR = 0.27; 95% CI 0.14 to 0.50). Conversely, the preventive effect of antibiotics on the risk of APSGN was not significant, and results were limited by the small number of cases (low-quality RCTs, 2 cases out of 5,147 patients).

Conclusion

In GABHS pharyngotonsillitis, antibiotic therapy is associated with reduction in acute symptoms by day 3, with a RR of 0.58 (95% CI 0.48 to 0.71; NNT = 6), and by day 7, with a RR of 0.29 (95% CI, 0.12 to 0.70). This therapeutic approach also significantly reduces the likelihood of developing suppurative complications, such as AOM and peritonsillar abscess, and ARF.

Recommendation

1. Antibiotic therapy is recommended in children with GABHS pharyngotonsillitis for a faster resolution of symptoms and a reduction in the risk of suppurative and non-suppurative complications (Quality of evidence high. Strong recommendation in favour of intervention).

Question 2. Should amoxicillin be considered the antibiotic of choice in the treatment of GABHS pharyngotonsillitis besides penicillin V?

Summary of evidence

Since penicillin V is not available in Italy, the panel decided to explore the available evidence on the use of amoxicillin in children with GABHS pharyngotonsillitis. Our analysis included 2 SRs [37, 38] and two RCTs [39, 40], comparing the efficacy and safety of several oral antibiotics, administered for 10 days or shorter, to penicillin V therapy for 10 days. The SRs were of high methodological quality, whereas the RCTs were of low to moderate quality [37–40].

The SR by van Driel et al. included studies conducted on adult and paediatric outpatients [38]. Whereas, the SR by Altamimi et al. and the RCT by Li et al. were limited to the paediatric population [37, 40]. Details of the characteristics of the studies and results are provided in Tables A5.2 and A5.3 in the Additional file 5.

The SR by Altamimi et al. evaluated 20 RCTs, including 13,102 cases of GABHS pharyngotonsillits. Of these, only 3 studies assessed the complication rates [37].

Azithromycin (AZT) administered at 20 mg/kg was associated with lower rates of early treatment failure compared to the standard regimen with penicillin V (OR: 0.08; 95% CI: 0.01 to 0.64). Conversely, no statistically significant differences were observed among AZT administered at 10 mg/kg, clarithromycin, cefuroxime, or other antibiotics.

Regarding the risk of recurrence, the comparative analysis of various molecules yielded no statistically significant differences (OR = 0.95 [95% CI:0.83 to 1.08]). Three of the included studies reported complications related to GABHS infection [39–41]. The meta-analysis reported no risk difference (RD) in the development of ARF and/or APSGN between patients treated with antibiotics different from penicillin V and controls (OR = 0.53 [95% CI:0.17 to 1.64]) [39–41].

The SR by Van Driel et al. included 5,839 participants with confirmed GABHS infection, aged from 1 month to 80 years [38]. Most of the included studies were conducted within outpatient settings. Six studies compared penicillin with cephalosporins, six with macrolides, three with carbacephem, one with sulphonamides, one compared clindamycin with ampicillin, and one azithromycin with amoxicillin in children. They evaluated the efficacy in: (a) alleviating symptoms (pain, fever); (b) shortening the duration of the illness; (c) reducing clinical relapses (i.e., the resurgence of symptoms post-initial resolution); and (d) avoiding complications (suppurative complications, ARF, and APSGN). Furthermore, the incidence of adverse effects and the risk-benefit ratio associated with the diverse antibiotic regimens were also assessed [38].

Cephalosporins versus penicillin

No significant differences were reported about symptom resolution (2 to 15 days) for cephalosporins compared to penicillin (OR for lack of symptom resolution 0.79, 95%CI = 0.55 to 1.12; 5 studies; 2018 participants; low-quality evidence). The clinical recurrence was not significantly lower for cephalosporins compared to penicillin (OR = 0.55, 95% CI 0.30 to 0.99; NNT = 50; 4 studies; 1,386 participants; low-quality evidence). In the intention-to-treat subgroup analysis (855 children), the risk of treatment failure did not differ significantly (OR = 0.83, 95% CI = 0.40 to 1.73). No difference in the adverse event rates among groups was reported [38].

Macrolides versus penicillin

The difference in symptom resolution between macrolides and penicillin was not statistically significant across groups (OR = 1.11, 95%CI = 0.92 to 1.35; 6 studies; 1,728 participants; low-quality evidence). Similarly, the risk of clinical recurrence did not differ significantly (OR = 1.21, 95% CI 0.48 to 3.03; 6 studies; 802 participants; low-quality evidence) [38].

Azithromycin versus amoxicillin

Symptom resolution did not show a significant difference when comparing a single dose of Azithromycin (AZT) with a 10-day course of amoxicillin (OR = 0.76, 95% CI 0.55 to 1.05; 1 study; 673 participants; very low-quality evidence). No significant difference was observed considering recurrence rate (OR = 0.88, 95% CI = 0.43 to 1.82; 1 study; 422 participants; very low quality of evidence). However, adverse events were more frequently associated with AZT than amoxicillin treatment (OR = 2.67, 95%CI = 1.78 to 3.99; 1 study; 673 participants; very low quality of evidence) [38].

Kuroki et al. assessed the efficacy in GABHS eradication comparing a 3-days course of amoxicillin-clavulanate with amoxicillin given for 10 days in a low-quality RCT including 119 children (2–13 years, mean age 5.6 years) with proven GABHS pharyngotonsillitis [39].

The eradication rate of GABHS at 1–2 weeks after the end of treatment was 65.4% in the amoxicillin/clavulanate group and 85.4% in the amoxicillin group (p < 0.05). However, there was no statistically significant difference in clinical resolution, and clinical relapse/recurrence was rarely observed even in patients with subsequent GABHS isolation [39].

Li et al. evaluated the clinical impact of AZT (10 mg/kg once daily for 3 days), cefaclor (20 mg/kg/ day in 3 doses for 5 days) and amoxicillin (30 mg/kg/day in 3 doses for 10 days) in 256 children with proven GABHS pharyngotonsillitis with good adherence to therapy and clinical and microbiological assessments at the end of treatment (day 14) and at follow-up (day 30) [40]. Clinical success rate was 96.4% in children treated with AZT, 92.4% in those receiving cefaclor, and 91.0% in the amoxicillin group. However, no statistically significant difference was found among the 3 groups (AZT vs. cefaclor vs. amoxicillin) considering bacteriological eradication rate at the end of therapy (94.0%, 89.9% and 88.5%), and relapse rate (2.6%, 7.0% and 5.9%) [40].

Conclusion

The considered antibiotic regimens showed similar efficacy, and no relevant differences in the adverse event rates. No conclusion could be drawn for long-term complications since they were rarely reported. AZT at a dosage of 10 mg/kg/day was associated with an increased risk of recurrence and failure to eradicate GABHS. In contrast, AZT administration at 20 mg/kg/day was associated with increased clinical and microbiological success rate compared to a 10-day course of penicillin V. However, this higher dosage AZT regimen was associated with an increased incidence of adverse events, without a significant impact on recurrence risk. Notably, all studies were conducted in high-income countries, characterised by a low prevalence of streptococcal complications. Consequently, the applicability of these findings to regions with a high incidence of ARF is limited. Collectively, the research endorses the selection of amoxicillin as the preferred antibiotic drug for GABHS pharyngotonsillitis, when penicillin V is not available.

Recommendations

• 2.Amoxicillin is recommended as first-choice antibiotic drug in children with GABHS pharyngotonsillitis. (Quality of evidence high. Strong recommendation in favour of intervention).

Question 3. Should the duration of antibiotic therapy for GABHS pharyngotonsillitis be shorter than 10 days?

Summary of evidence

Most guidelines advocate for a 10-day treatment with penicillin V or amoxicillin for patients with GABHS pharyngotonsillitis; the exceptions are the 2018 NICE (National Institute for Health and Care Excellence) guidelines (5–10 days) and the 2021 German guidelines (5–7 days) [10, 12, 17]. A Cochrane systematic review did not find evidence of the efficacy of a 10-day antibiotic course in preventing suppurative and non-suppurative complications [22]. The primary outcome for most studies was the eradication rate of GABHS, while the difference in ARF incidence was not analyzed due to the low occurrence rate [22]. The SR by Altamimi et al. included a study comparing amoxicillin (25 mg/kg/dose twice a day) for 6 days to penicillin V for 10 days [37]. This study included 321 patients aged 3–15 years (mean age 5.9 years) of these 318 were evaluated in the safety analyses and 277 (86.3%) in the efficacy analyses. The patients were followed-up for one month after the end of therapy and the results showed that the efficacy and safety of 6-days course of amoxicillin (50 mg/kg/day twice a day) were not significantly different from those of 10-days course of penicillin V (45 mg/kg/day three times a day) for GABHS pharyngotonsillitis (efficacy odds ratio (OR) = 0.82; 95% CI 0.37 to 1.79) [37].

Conclusion

To date, only one study assessed a shorter duration of amoxicillin therapy compared to the standard regimen (penicillin V for 10 days), showing that it was equally effective for symptoms resolution. However, the latter results have not been reproduced, and no conclusion regarding long-term complications could be drawn due to a follow-up limited to 30 days. Therefore, the results do not provide sufficient evidence of efficacy and safety regarding critical outcomes such as the risk of suppurative and non-suppurative complications. Furthermore, the results cannot be generalised to settings with different ARF incidence rates. A therapy shorter than 10 days has been associated to a decreased risk of non-adherence to treatment.

Given the lack of robust evidence, the recommendation for a 10-day course of therapy is conservatively upheld, particularly in light of the increased risk of ARF in several Italian regions. Some authors suggested that the focus should be on minimising unnecessary prescriptions rather than on reducing the duration of antibiotic therapy [42].

Recommendation

• 3.Given the lack of robust evidence regarding the efficacy and safety of different therapy durations in reducing the risk of suppurative and non-suppurative complications, amoxicillin for 10 days is recommended in children with GABHS pharyngotonsillitis. The latter regimen is recommended also in regions with a low ARF incidence. (Quality of evidence very low. Weak recommendation in favour of intervention).

Question 4. In children allergic to penicillin, which antibiotics can be administered for the treatment of GABHS pharyngotonsillitis?

Summary of evidence

The prevalence of proven penicillin allergy is low, ranging from 0.7 to 1%, and the anaphylaxis prevalence is about 0.015 − 0.004%. Nonetheless, allergic reactions to penicillin are frequently suspected and lead to inappropriate antibiotics prescriptions [41, 43, 44].

A maculopapular rash, urticaria, and vomiting are common signs of both allergic reactions and infections, particularly viral ones. Pediatricians often need to decide whether these symptoms in patients treated with penicillin or amoxicillin are due to an allergic reaction. This assessment is crucial for deciding whether an alternative antibiotic is necessary, often without the support of an allergological consultation. To avoid inappropriate therapies, it is important to consider specific diagnostic criteria as stated by the the European Academy of Allergy & Clinical Immunology (EAACI) Position Paper [45]. The choice of the alternative antibiotic should be guided by the risk stratification for a severe reaction (2nd-3rd generation cephalosporins in low-risk patients, macrolide in high-risk patients) and its efficacy for a given disease [38, 40]. Macrolide-resistant GABHS strains are globally reported, with rates varying by region, reaching up to 18% in Italy in recent years. Therefore, local epidemiological data on macrolide-resistant GABHS prevalence should be considered when choosing the optimal management of penicilllin-allergic children [46].

Conclusions

In patients with GABHS pharyngotonsillitis and suspected penicillin allergy, who have not undewent an allergological work-up, the alternative antibiotic regimen (2nd-3rd generation cephalosporin or macrolides) should be prescribed based on the stratification of the risk for severe reactions and on local macrolide-resistant GABHS strains prevalence.

Recommendations

• 4a. In patients with GABHS pharyngotonsillitis with suspected amoxicillin allergy who have not uderwent an allergological work-up, the choice of alternative antibiotic (3rd generation cephalosporins or macrolides) must be based on careful risk stratification (Quality of the evidence very low. Opinion of the experts. Strong recommendation in favour of intervention).

• 4b. In patients with GABHS pharyngotonsillitis with suspected amoxicillin allergy and a low risk of an allergic reaction, a 3rd generation cephalosporin for 5 days should be recommended as an alternative therapy, restricting the use of macrolides to patients at high risk of severe allergic reactions (Quality of evidence very low. Weak recommendation in favour of intervention).

Question 5: Which antibiotic(s) should be recommended as first-choice therapy for relapsing GABHS pharyngotonsillitis despite several courses of amoxicillin?

The current medical consensus lacks a clear definition of relapsing pharyngotonsillitis. However, the 1981 “Paradise’s criteria” are often used and include having seven episodes in one year, five per year for two years, or three episodes per year for three years [47]. Considering that GABHS carriers can be misdiagnosed with relapsing GABHS pharyngotonsillitis due to other etiologies, an accurate diagnosis is crucial.

Tonsillectomy is the only treatment proven to significantly reduce the frequency of episodes. However, it may potentially result in postoperative complications, including hemorrhage, adverse effects from opioid analgesics, and an increased risk of infections [48]. As a result, antibiotics have been proposed as an alternative approach.

A Cochrane review by Ng et al. on antibiotic therapy in recurrent pharyngotonsillitis could not draw any conclusions as none of the RCTs met the inclusion criteria [49]. A SR by Munck et al. in 2018 compared the efficacy of several antibiotics to oral penicillin in reducing pharyngotonsillitis incidence [50]. Efficacy was assessed considering three different clinical scenarios in children and adults: patients with relapsing pharyngotonsillitis without ongoing infection (Q1), those with ongoing infection (Q2), and those with recurrence within four weeks post-antibiotic therapy (Q3) [50]. Three RCTs were included in the SR for Q1, two for Q2, and none for Q3. Lildholdt et al. found no significant difference in the reduction of relapses between azithromycin and a placebo [51]. Two studies by Brook et al. in 1989 demonstrated the superiority of clindamycin and amoxicillin/clavulanic acid over oral penicillin in symptom resolution and eradication of beta-lactamase-producing bacteria, suggesting that they may play a role in the relapse pathogenesis (RR = 0.15, CI 95% 0.04–0.56, p = 0.005 for clindamycin; RR = 0.19, CI 95% 0.05–0.75, p = 0.018 for amoxicillin/clavulanic acid) [52, 53]. However, these RCTs had a high risk of bias and significant heterogeneity in patients’ age, number of episodes per year, and antibiotic treatments. The SR concluded that penicillin might be inadequate for relapsing pharyngotonsillitis treatment. Whereas, amoxicillin/clavulanic acid or clindamycin, which are effective against beta-lactamase-producing bacteria, could prevent further relapses, although current evidence supporting their efficacy is limited [50]. Similarly, in 2024 a SR by Hung et al. assessed the efficacy of different antibiotics for the eradication of GABHS in asymptomatic carriers [54]. Three RCTs, published between 1985 and 1991, were included. Negativization of pharyngeal swab culture was used to evaluate the eradication in all these studies [55–57]. Brook et al. included both children and young adults (age range 8–24 years) [55], the remaining studies were restricted to the pediatric population [56, 57]. The combined antibiotic regimen based on a single dose of intramuscular penicillin G followed by 4 days of oral rifampicin was assessed in 2 studies, and the eradication ranged between 68% [95% CI: 49–88%] and 93% [95% CI: 79–100%] at 3 weeks post-treatment [56, 57]. Penicillin monotherapy, either intramuscular or oral, and oral erythromycin reported eradication rates comparable to no treatment: 30% (95% CI 1.6–58%), 14% (95% CI 0–33%), 43%(95% CI 17–69%), and 23% (95% CI 0.2–46%) [54]. On the contrary, the 10-day clindamycin regimen, evaluated in 2 studies, was the most efficacious strategy achieving eradication in 93% (95% CI 81–100%) of cases at 10 days and in 100% (95% CI 79–100%) at 3 weeks after treatment [54]. However, Hung et al. advised caution in the widespread use of clindamycin due to the increasing resistance of GABHS to macrolides and clindamycin [54].

Conclusion

Given the evidence, it’s not possible to recommend a specific antibiotic therapy for recurrent GABHS pharyngotonsillitis. If avoiding tonsillectomy is a priority, amoxicillin-clavulanate, clindamycin, or a combination therapy with amoxicillin plus rifampicin might be considered as alternatives. However, these recommendations are issued with the caveat that the evidence supporting their use is currently limited.

Recommendation

• 5.In the case of relapsing GABHS tonsillitis, antibiotic therapy should be recommended only in patients candidated to tonsillectomy, as an attempt to avoid surgery. In these cases, amoxicillin-clavulanic acid, clindamycin, or a combination of amoxicillin plus rifampicin in the last 4 days of treatment should be prescribed. (Quality of evidence low. Weak recommendation).

Question 6: which is the appropriate dosage of Amoxicillin in the treatment of GABHS pharyngotonsillitis?

In the management of acute GABHS pharyngotonsillitis, amoxicillin dosage for children under 40 kg varies from 40 to 90 mg/kg/day, not exceeding 3 g/day, and is typically divided into two or three doses. A good-quality RCT, including 517 children aged 2–12 years with confirmed GABHS pharyngotonsillitis, compared the efficacy and safety of a standard amoxicillin regimen of 40 mg/kg/day in 3 doses with a twice-daily regimen (45 mg/kg/day divided in 2 doses) [58]. A positive clinical response in over 96% of patients at the end of treatment (Day 11) was registered in both groups, with successful bacteriological responses in more than 94% of patients, showing that a twice-daily regimen was as effective and as well tolerated as the standard one [58]. Nakao et al. showed that a single daily dose of amoxicillin, ranging from 40 to 50 mg/kg/day for ten days, was as effective as multiple daily doses in children with streptococcal pharyngotonsillitis older than three years [59].

The Summary of Product Characteristics (SPC) provided by the European and Italian Medicines Agencies recommend a dosage of 50 mg/kg/day divided in 2 doses for the treatment of streptococcal pharyngotonsillitis [60, 61].

Conclusion

Amoxicillin administered at 50 mg/kg/day in two doses is as effective and as well-tolerated as 40 mg/kg/day given three times a day for treating acute GABHS pharyngotonsillitis. It is thus reasonable to conclude that a twice-daily regimen may be associated to enhanced adherence to treatment.

Recommendation

• 6.In children with GABHS pharyngotonsillitis, a daily dose of amoxicillin (50 mg/kg/day) divided into 2 administrations may be recommended to improve treatment adherence. (Quality of evidence low. Weak recommendation in favour of intervention.)

Question 7: May parenteral antibiotics, specifically intramuscular benzathine-penicillin, be recommended as treatment alternative to oral amoxicillin in selected GABHS pharyngotonsillitis patients?

Parenteral antibiotic therapy is usually considered in children with low adherence to oral treatment. A RCT conducted in Ghana, including 99 paediatric patients, compared the efficacy of amoxicillin and benzathine-penicillin in the treatment of GABHS pharyngitis [62]. Treatment failure rate was higher in those treated with amoxicillin than in the penicillin group (18.9% vs. 6.4%, respectively [p ≥ 0.05]). However, amoxicillin was administered as a single daily dose [62]. In a recent retrospective, multicenter study conducted in Israel, involving 242,366 pediatric patients enrolled over a decade (2010–2019), treatment with amoxicillin or penicillin V was associated with a significantly lower risk of streptococcal complications (OR = 0.68, 95% CI 0.52–0.89; P < 0.01) and reduced rates of medical re-evaluation compared to benzathine penicillin treatment [63]. Given the overlapping efficacy, oral treatment with amoxicillin should be preferred to parenteral antibiotics because it is less invasive and stressful for the child. Furthermore, benzathine-penicillin must be administered by trained healthcare workers, it can be painful and has an overall higher cost than oral amoxicillin.

Conclusion

Benzatin-penicillin antibiotic therapy should be limited to patients with reduced gastrointestinal absorption, inability to take oral therapies or poor adherence to oral amoxicillin.

Recommendations

• 7a. In children with GABHS pharyngotonsillitis, benzathine-penicillin therapy should only be recommended for subjects with reduced gastrointestinal absorption or inability to take oral therapies. (High quality of evidence. Weak recommendation in favour of intervention)

• 7b. In children with GABHS pharyngotonsillitis, benzathine-penicillin therapy may be recommended in case of poor adherence to oral amoxicillin, especially in patients at high risk of suppurative complications (such as in cases of primary or secondary immunodeficiency). (Very low quality of evidence, expert opinion. Weak recommendation in favour of intervention)

Question 8. Is it recommended to treat non-streptococcal bacterial pharyngotonsillitis (Fusobacterium spp., other anaerobes, Staphylococcus aureus, etc.) with antibiotic therapy?

Pharyngotonsillitis often leads to antibiotic prescriptions, regardless of proven GABHS infection, especially if the patient is febrile. However, antibiotic therapy is highly controversial in non-streptococcal bacterial pharyngotonsillitis. In this regard, 2 high-quality SRs of RCTs with meta-analysis were retrieved [22, 64]. The SR by Spinks et al. included studies evaluating the benefits of antibiotics for sore throats in children and/or adult patients [22]. Of these, one study reported outcome differences between GABHS-positive and negative patients [34] and two studies specifically excluded GABHS-positive patients [35, 36]. In GABHS-negative patients, antibiotics were not effective in reducing symptoms by day 3 (RR = 0.78; 95% CI 0.63–0.97 – NNT = 21 [15 RCTs, high quality, 3,621 patients]) and day 7 (RR = 0.73; CI 95% 0.50 to 1.07. Not statistically significant [5 RCTs, high quality, 541 patients]) [22]. Concerning the risk of suppurative complications, only one study reported a significant reduction in the incidence of acute otitis media within 14 days (RR = 0.06 [CI 95% from 0.1 to 03]) [36]. The SR by Spurling et al. assessed the clinical benefits, bacterial resistance, and patient satisfaction with delayed/no use of antibiotics for upper respiratory tract infections (fever, sore throat, cough, etc.) in primary care patients and emergency departments [64]. Specifically, four studies evaluated ‘sore throat’ in children [28, 65–67]. Of these, only Little et al. included patients without GABHS infection [67]. The clinical outcomes were heterogeneous, and in most cases, no significant difference was observed between delayed antibiotic therapy, immediate antibiotic administration, or no antibiotic therapy [64]. Due to insufficient data, it was not possible to aggregate study data for the comparison between delayed antibiotic administration and no antibiotic therapy.

Conclusions

In patients without comorbidities, non-GABHS pharyngotonsillitis has limited clinical significance. The study findings showed that the disease is generally self-limiting and that antibiotic therapy does not significantly reduce the duration of symptoms or the risk of complications. Therefore, a microbiological test to identify the aetiological agent is not recommended.

Recommendations

• 8a. Antibiotic therapy is not recommended in patients without comorbidities with pharyngotonsillitis and a culture and/or molecular test positive for bacteria other than GABHS. (Quality of evidence moderate. Strong recommendation against intervention)

• 8b. If antibiotic therapy for pharyngotonsillitis with a culture and/or molecular test positive for bacteria other than GABHS is considered appropriate, infectious disease counseling is recommended. (Quality of evidence very low. Expert opinion. Strong recommendation in favour of intervention)

Discussion

Acute pharyngitis is a common condition among children, with 288.6 million episodes of streptococcal pharyngitis occurring globally each year [68]. It has been estimated that in 2020 sore throat led to 8.6 million courses of antibiotics in children (5–14 years) [69]. In this context, broad-spectrum antibiotics are frequently prescribed in the Italian pediatric outpatient setting [18, 19]. This consensus document aims to guide healthcare providers in the judicious use of antibiotics for acute pharyngotonsillitis in children and adolescents. Antibiotic treatment with amoxicillin (50 mg/kg/day administered in 2 divided doses) for 10 days is recommended in all children with confirmed streptococcal pharyngitis. Intramuscular benzathine-penicillin could be considered in children with impaired intestinal absorption. Similarly, it represents a valid therapeutic option in those at high risk for suppurative complications, such as immunodeficient children, with low compliance to oral therapy. In children with a suspected amoxicillin allergy, the risk of severe allergic reaction should be evaluated according to the EAACI (European Academy of Allergy & Clinical Immunology) position paper [45]. Macrolides could be prescribed as an alternative therapy in high-risk patients and third-generation cefalosporins for five days in low-risk ones. Data regarding the treatment of recurrent streptococcal pharyngitis are lacking. However, in children candidates to tonsillectomy, antibiotics could be prescribed as an attempt to avoid surgery. In the latter case, amoxicillin-clavulanic acid, clindamycin, or a combined therapy with amoxicillin plus 4-days rifampicin should be used. The panel recommends against antibiotic treatment in previously healthy patients with acute pharyngotonsillitis and evidence of non-GABHS bacterial infection. However, antibiotic therapy could be considered in children with underlying conditions, in which case a consultation with an infectious disease specialist is warranted.

Abbreviations

AOM

Acute otitis media

ARF

Acute rheumatic fever

APSGN

Acute post-streptococcal glomerulonephritis

AZT

Azithromycin

CI

Confidence interval

GABHS

Group A β-haemolytic streptococcus

GL

Guideline

NNT

Number needed to treat

OR

Odds ratio

SPC

Summary of Product Characteristics

SR

Systematic review

RCT

Randomized controlled trial

RD

Risk difference

RR

Relative risk

Authors’ contributions

All authors contributed to the study conception and design. The literature search, data analysis and first drafting of the manuscript were performed by MCV, GS, MB, RP and EC. All co-authors contributed to the review, critically reviewed the revised manuscript. All authors read and approved the final manuscript.

Funding

The authors declare no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

All the data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

All authors declare no relevant financial or non-financial interests.