A Single Dose of Intravenous Penicillin as an Adjunct to Oral Penicillin in the Treatment of Acute Tonsillitis, Peritonsillar Phlegmon, and Peritonsillar Abscess

Background Tonsillar infections are highly prevalent and are associated with substantial morbidity, including severe sore throat, dysphagia, and general malaise. The disease spectrum ranges from acute tonsillitis (AT) through peritonsillar phlegmon (PP) to peritonsillar abscess (PTA), and clinical data suggest that these conditions often represent a continuum in which inadequate treatment may lead to disease progression. Traditionally, Group A streptococci have been considered the primary pathogen. However, our previous studies have demonstrated that Fusobacterium necrophorum and Streptococcus dysgalactiae also play important roles in moderate to severe tonsillar infections. The predominant pathogens are susceptible to beta-lactam antibiotics, and in Denmark both oral phenoxymethylpenicillin (PMP) and intravenous benzylpenicillin (BP) are commonly used. However, PMP exhibits considerable interindividual variability in bioavailability, which may result in insufficient antibiotic exposure. The efficacy of beta-lactam antibiotics depends on the duration that drug concentrations remain above the minimum inhibitory concentration (T\>MIC), and experimental data from our research group have shown that intravenous BP provides more stable and adequate tissue exposure than oral PMP. In clinical practice, rapid symptomatic improvement is often observed following intravenous BP administration, but this has not been investigated in randomized studies. We hypothesize that a single initial intravenous dose of BP, administered in addition to standard oral PMP therapy, may result in more rapid symptom relief without the need for hospitalization. Treatment effects will be assessed using disease-specific Patient-Reported Outcome Measures (PROMs), namely the STAT-10 and PTAAT-12 questionnaires, both developed by our research group. The project addresses an important clinical and pharmacological knowledge gap and has the potential to optimize treatment, reduce disease burden, and strengthen outpatient management of tonsillar infections. Objectives * To investigate the effects of a single dose of intravenous penicillin as an adjunct to oral penicillin therapy in patients with AT, PP, and PTA, respectively. * To define the minimal clinically important difference (MCID) for the STAT-10 score and the PTAAT-12 score. Study Design This is an investigator-initiated, randomized, double-blind, placebo-controlled, parallel-group trial in which patients with AT, PP, or PTA are randomized 1:1 to receive either a single dose of intravenous benzylpenicillin (2 MIU) or placebo (isotonic saline) in addition to standard oral phenoxymethylpenicillin therapy. Patients will be enrolled into three groups (AT Group, PP Group, and PTA Group), which will be analyzed separately. Inclusion Criteria Adults (≥18 years of age) with clinically diagnosed acute tonsillitis (AT Group), peritonsillar phlegmon (PP Group), or peritonsillar abscess treated with incision and drainage (PTA Group). Perspectives The study has the potential to improve the clinical management of patients with AT, PP, and PTA by providing evidence on whether an initial intravenous dose of penicillin enhances treatment outcomes. Timeline * Anticipated start of patient recruitment: October 2026. * Anticipated primary completion: December 2028. * Anticipated study completion (last participant\'s 12-month follow-up): December 2029.