Is Streptococcus pyogenes a pathogen or passenger in uncomplicated acute sore throat? A systematic review and meta-analysis.

OBJECTIVES: The objective was to estimate the probability that finding a Streptococcus pyogenes (Group A Streptococcus) in a throat swab in a patient with a sore throat reflects the aetiology. We also investigated to what extent this is influenced by age, carrier rates of S. pyogenes and climate zone. METHODS: We conducted a comprehensive search of Medline and Scopus up until October 2023 for case-control studies reporting the prevalence of S. pyogenes in patients with a sore throat and healthy controls. We only included studies with separate data for children and adults. We used the positive and negative etiologic predictive values (P-EPV and N-EPV) to estimate the probability of a link between a sore throat and a finding of S. pyogenes. RESULTS: We included 15 studies in our meta-analysis. The overall P-EPV for children and adults were 63% (49-74%) and 92% (87-95%), respectively. The P-EPV rose to 83% (64-93%) for children and 94% (90-97%) for adults when only patients with 3-4 Centor criteria were included. The overall N-EPV was 97% (96-98%) for children and 96% (95-97%) for adults. CONCLUSION: Detecting S. pyogenes in adult patients with an uncomplicated acute sore throat is useful to rule in S. pyogenes as the likely aetiologic agent. The P-EPV significantly increased for children when those with 3-4 Centor criteria were selected. A negative throat swab is always useful for both children and adults to rule out S. pyogenes as the cause of sore throat.

Agreement between rapid antigen detection test and culture for group A streptococcus in patients recently treated for pharyngotonsillitis - a prospective observational study in primary care.

OBJECTIVE: The aim was to compare rapid antigen detection test (RADT) and throat culture for group A streptococci (GAS) among patients recently treated with penicillin V for GAS pharyngotonsillitis. DESIGN AND SETTING: The study was a secondary analysis within a randomized controlled trial comparing 5 versus 10 days of penicillin V for GAS pharyngotonsillitis. Patients were recruited at 17 primary health care centres in Sweden. SUBJECTS: We included 316 patients ≥ 6 years of age, having 3-4 Centor criteria, a positive RADT and a positive throat culture for GAS at inclusion, and also having a RADT and throat culture for GAS taken at a follow-up visit within 21 days. MAIN OUTCOME MEASURES: RADT and conventional throat culture for GAS. RESULTS: This prospective study showed 91% agreement between RADT and culture at follow-up within 21 days. Only 3/316 participants had negative RADT with a positive throat culture for GAS at follow-up, and 27/316 patients with positive RADT had a negative culture for GAS. Log rank test did not reveal any difference in the decline over time of positive tests between RADT and throat culture (p = 0.24). Agreement between RADT and throat culture for GAS at the follow-up was not associated with treatment duration, number of days from inclusion until follow-up, throat symptoms at follow-up, gender, or age. CONCLUSION: RADT and culture for GAS agreed to a high extent also after recent penicillin V treatment. RADT for GAS means a low risk for missing the presence of GAS.KEY POINTSTesting for group A streptococci (GAS) before antibiotic treatment can reduce antibiotic prescription for pharyngotonsillitis. It has been proposed that rapid antigen detection tests (RADT) for group A streptococci after recent penicillin V treatment may be falsely positive due to possible persisting antigens from non-viable bacteria.The decline of the presence of GAS was similar between RADT and conventional throat culture in patients who had recently completed penicillin V treatment for GAS pharyngotonsillitisRADT for GAS is useful in identifying the presence of GAS after recent penicillin V treatment.

Effects of penicillin V on the faecal microbiota in patients with pharyngotonsillitis-an observational study.

Background: The intestinal microbiota functions as a reservoir of antibiotic resistance. Objectives: To evaluate penicillin V (phenoxymethylpenicillin) effects on the faecal microbiota with focus on beta-lactam resistance. Methods: We included 31 primary care patients with group A streptococcal pharyngotonsillitis treated with penicillin V for 5 (800 mg × 4) or 10 days (1000 mg × 3). Twenty-nine patients contributed with three faecal swab samples each. The faecal specimens were collected at the start of penicillin V treatment, after the last dose and at follow-up 7-9 days after completed treatment. Samples were inoculated semiquantitatively on selective screening agar plates to study beta-lactam resistance, species shifts among Enterobacterales and enterococci, and colonization with Candida spp. and Clostridioides difficile. Representative colonies were identified using MALDI-TOF. Results were analysed by non-parametric statistical methods. Results: An increase in the proportion of patients colonized with ampicillin-resistant Enterobacterales, from 52% to 86% (P = 0.007), and Enterobacterales with decreased susceptibility to third-generation cephalosporins, from 32% to 52% (P = 0.034), was observed between the first and second samples. This increase was no longer significant at follow-up. New colonization with ampicillin-resistant Enterobacterales species and non-Enterobacterales Gram-negative species was observed, and persisted at follow-up. Conclusions: Following treatment with penicillin V, we observed decreased susceptibility to ampicillin and third-generation cephalosporins, and prolonged colonization with non-Escherichia coli Gram-negative species. These findings challenge the perception that penicillin V has limited ecological effect on the intestinal microbiota, and emphasizes the importance of avoiding even narrow-spectrum antimicrobials when possible.

Clinical course of pharyngotonsillitis with group A streptococcus treated with different penicillin V strategies, divided in groups of Centor Score 3 and 4: a prospective study in primary care.

BACKGROUND: Sore throat is a common reason for prescribing antibiotics in primary care, and 10 days of treatment is recommended for patients with pharyngotonsillitis with group A streptococcus (GAS). Our group recently showed that penicillin V (PcV) four times daily for 5 days was non-inferior in clinical outcome to PcV three times daily for 10 days. This study compares duration, intensity of symptoms, and side effects in patients with a Centor Score (CS) of 3 or 4 respectively, after treatment with PcV for 5 or 10 days and evaluates whether all patients with pharyngotonsillitis with a CS of 3 or 4 should be treated for 5 days or if severity of symptoms or CS suggest a longer treatment period. METHOD: Data on symptoms and recovery from patient diaries from 433 patients included in a RCT comparing PcV 800 mg × 4 for 5 days or PcV 1 g × 3 for 10 days was used. Patients six years and older with CS-3 or CS-4 and positive rapid antigen detection test for GAS-infection were grouped based on CS and randomized treatment. Comparisons for categorical variables were made with Pearson's chi-squared test or Fisher's exact test. Continuous variables were compared with the Mann-Whitney U test. RESULTS: Patients with CS-3 as well as patients with CS-4 who received PcV 800 mg × 4 for 5 days self-reported that they recovered earlier compared to patients with CS-3 or CS-4 who received treatment with PcV 1 g × 3 for 10 days. In addition, the throat pain as single symptom was relieved 1 day earlier in patients with CS-4 and 5 days of treatment compared to patients with CS-4 and 10 days of treatment. No differences in side effects between the groups were found. CONCLUSION: Intense treatment with PcV four times a day for 5 days seems clinically beneficial and strengthens the suggestion that the 4-dose regimen with 800 mg PcV for 5 days may be the future treatment strategy for GAS positive pharyngotonsillitis irrespectively of CS-3 or CS-4. Trail registration ClinicalTrials.gov ID: NCT02712307 (3 April 2016).

Does C-reactive protein predict time to recovery and benefit from oseltamivir treatment in primary care patients with influenza-like illness? A randomized controlled trial secondary analysis.

OBJECTIVE: Recovery time and treatment effect of oseltamivir in influenza-like illness (ILI) differs between patient groups. A point-of-care test to better predict ILI duration and identify patients who are most likely to benefit from oseltamivir treatment would aid prescribing decisions in primary care. This study aimed to investigate whether a C-reactive protein (CRP) concentration of ≥30 mg/L can predict (1) ILI disease duration, and (2) which patients are most likely to benefit from oseltamivir treatment. DESIGN: Secondary analysis of randomized controlled trial data. SETTING: Primary care in Lithuania, Sweden and Norway during three consecutive influenza seasons 2016-2018. SUBJECTS: A total of 277 ILI patients aged one year or older and symptom duration of ≤72 h. MAIN OUTCOME MEASURES: Capillary blood CRP concentration at baseline, and ILI recovery time defined as having 'returned to usual daily activity' with residual symptoms minimally interfering. RESULTS: At baseline, 20% (55/277) had CRP concentrations ≥30mg/L (range 0-210). CRP concentration ≥30 mg/L was not associated with recovery time (adjusted hazards ratio (HR) 0.80: 95% CI 0.50-1.3; p = 0.33). Interaction analysis of CRP concentration ≥30 mg/L and oseltamivir treatment did not identify which patients benefit more from oseltamivir treatment (adjusted HR 0.69: 95% CI 0.37-1.3; p = 0.23). CONCLUSION: There was no association between CRP concentration of ≥30 mg/L and recovery time from ILI. Furthermore, CRP could not predict which ILI patients benefit more from oseltamivir treatment. Hence, we do not recommend CRP testing for predicting ILI recovery time or identifying patients who will receive particular benefit from oseltamivir treatment.Key PointsPredicting disease course of influenza-like illness (ILI), and identifying which patients benefit from oseltamivir treatment is a challenge for physicians.• There was no association between CRP concentration at baseline and recovery time in patients consulting with ILI in primary care.• There was no association between CRP concentration at baseline and benefit from oseltamivir treatment.• We, therefore, do not recommend CRP testing for predicting recovery time or in decision-making concerning oseltamivir prescribing in ILI patients.

Is C-reactive protein associated with influenza A or B in primary care patients with influenza-like illness? A cross-sectional study.

OBJECTIVE: Identifying influenza A or B as cause of influenza-like illness (ILI) is a challenge due to non-specific symptoms. An accurate, cheap and easy to use biomarker might enhance targeting influenza-specific management in primary care. The aim of this study was to investigate if C-reactive protein (CRP) is associated with influenza A or B, confirmed with PCR testing, in patients presenting with ILI. DESIGN: Cross-sectional study. SETTING: Primary care in Lithuania, Norway and Sweden. SUBJECTS: A total of 277 patients at least 1 year of age consulting primary care with ILI during seasonal influenza epidemics. MAIN OUTCOME MEASURES: Capillary blood CRP analysed as a point-of-care test and detection of influenza A or B on nasopharyngeal swabs in adults, and nasal and pharyngeal swabs in children using PCR. RESULTS: The prevalence of positive tests for influenza A among patients was 44% (121/277) and the prevalence of influenza B was 21% (58/277). Patients with influenza A infection could not be identified based on CRP concentration. However, increasing CRP concentration in steps of 10 mg/L was associated with a significantly lower risk for influenza B with an adjusted odds ratio of 0.42 (0.25-0.70; p<.001). Signs of more severe symptoms like shortness of breath, sweats or chills and dizziness were associated with higher CRP. CONCLUSIONS: There was no association between CRP and influenza A. Increased concentration of CRP was associated with a lower risk for having influenza B, a finding that lacks clinical usefulness. Hence, CRP testing should be avoided in ILI, unless bacterial pneumonia is suspected. Key points Identifying influenza A or B as cause of influenza-like illness (ILI) is a challenge due to non-specific symptoms. There was no association between concentration of CRP and influenza A. Increased concentration of CRP was associated with a lower risk for having influenza B, a finding that lacks clinical usefulness. A consequence is that CRP testing should be avoided in ILI, unless bacterial pneumonia or similar is suspected.

Penicillin V four times daily for five days versus three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci: randomised controlled, open label, non-inferiority study.

OBJECTIVE: To determine whether total exposure to penicillin V can be reduced while maintaining adequate clinical efficacy when treating pharyngotonsillitis caused by group A streptococci. DESIGN: Open label, randomised controlled non-inferiority study. SETTING: 17 primary healthcare centres in Sweden between September 2015 and February 2018. PARTICIPANTS: Patients aged 6 years and over with pharyngotonsillitis caused by group A streptococci and three or four Centor criteria (fever ≥38.5°C, tender lymph nodes, coatings of the tonsils, and absence of cough). INTERVENTIONS: Penicillin V 800 mg four times daily for five days (total 16 g) compared with the current recommended dose of 1000 mg three times daily for 10 days (total 30 g). MAIN OUTCOME MEASURES: Primary outcome was clinical cure five to seven days after the end of antibiotic treatment. The non-inferiority margin was prespecified to 10 percentage points. Secondary outcomes were bacteriological eradication, time to relief of symptoms, frequency of relapses, complications and new tonsillitis, and patterns of adverse events. RESULTS: Patients (n=433) were randomly allocated to the five day (n=215) or 10 day (n=218) regimen. Clinical cure in the per protocol population was 89.6% (n=181/202) in the five day group and 93.3% (n=182/195) in the 10 day group (95% confidence interval -9.7 to 2.2). Bacteriological eradication was 80.4% (n=156/194) in the five day group and 90.7% (n=165/182) in the 10 day group. Eight and seven patients had relapses, no patients and four patients had complications, and six and 13 patients had new tonsillitis in the five day and 10 day groups, respectively. Time to relief of symptoms was shorter in the five day group. Adverse events were mainly diarrhoea, nausea, and vulvovaginal disorders; the 10 day group had higher incidence and longer duration of adverse events. CONCLUSIONS: Penicillin V four times daily for five days was non-inferior in clinical outcome to penicillin V three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci. The number of relapses and complications did not differ between the two intervention groups. Five day treatment with penicillin V four times daily might be an alternative to the currently recommended 10 day regimen. TRIAL REGISTRATION: EudraCT 2015-001752-30; ClinicalTrials.gov NCT02712307.