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.

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).

The Swedish model for prioritising research on the use of antibiotics: Aligning public funding with research gaps.

Due to the meagre development of new antibiotics, optimising the use of currently available antibiotics is important to reduce resistance pressures and to safeguard existing treatment options. The Public Health Agency of Sweden (PHAS) was tasked in 2014 to (1) develop a model for identifying and prioritising research gaps and (2) initiate studies to improve knowledge on how to optimise the use of existing antibiotics. A survey addressing knowledge-gaps and suggesting studies needed was distributed to a broad network of Swedish and European clinicians and experts. An independent reference group prioritised the proposals, applying predefined criteria focusing on public health relevance. The PHAS sponsored and led two multi-centre RCTs in cooperation with clinical researchers and took part in additional studies. A second survey and prioritization exercise following the same model was performed in 2019. The Swedish case study described in this paper provides an example of the role that the public sector can play in order to support the improved use of existing antibiotics. National and international institutions are well suited to perform systematic reviews of research priorities with a focus on public health concerns. The ultimate success of the model depends on political engagement, a close dialogue with healthcare professionals, collaboration between international sister-authorities responsible for public health in other countries, the availability of research funding, harmonisation of regulatory issues and regular revisions of clinical guidelines. The experience from the Swedish model illustrates opportunities for meeting clinical needs and filling knowledge gaps on existing off-patent antibiotics.

The clinical and microbiological efficacy of temocillin versus cefotaxime in adults with febrile urinary tract infection, and its effects on the intestinal microbiota: a randomised multicentre clinical trial in Sweden.

BACKGROUND: Use of third-generation cephalosporins, such as cefotaxime, is associated with an increased risk of selection for antimicrobial resistance, so alternative antibiotics need to be considered. The aim of the present study was to evaluate intestinal colonisation with third-generation cephalosporin-resistant pathogens following use of temocillin-an alternative antibiotic to cefotaxime that is potentially less prone to disturbing the intestinal microbiota-in empirical treatment of febrile urinary tract infection (UTI). METHODS: We did a randomised, multicentre, superiority, open-label phase 4 trial in patients who had been admitted to inpatient care in 12 Swedish hospitals with suspected or diagnosed febrile UTI (complicated or uncomplicated). To meet inclusion criteria, a patient was required to have at least one sign or symptom of pyelonephritis (ie, flank pain; costovertebral angle tenderness; and changes to urinary frequency or urgency or dysuria), a fever of 38·0°C or higher, and a positive urine dipstick (for nitrites, white blood cells, or both). Participants were also required to have an indication for intravenous antibiotic treatment. Participants were randomly assigned (1:1) to receive either 2 g temocillin or 1-2 g cefotaxime, by local investigators opening consecutive sealed randomisation envelopes that were generated centrally in advance. Both drugs were administered intravenously every 8 h. The trial was open label for investigators and patients, but those doing the microbiological analyses were masked to the groups. Participants were treated with antibiotics for 7-10 days (or up to 14 days if they had bacteraemia), at least 3 days of which were on the study drug; at day 4 and later, participants who were showing improvement could be given an oral antibiotic (ciprofloxacin, ceftibuten, cefixime, or co-trimoxazole). Patients not showing improvement were regarded as having treatment failures. Rectal swabs were collected at three timepoints: at baseline (before the first dose), after the last dose of study drug, and 7-10 days after treatment stopped. The composite primary outcome was colonisation with Enterobacterales with reduced susceptibility to third-generation cephalosporins, or colonisation with toxin-producing Clostridioides difficile, or both, to evaluate disturbance of the intestinal microbiota. The study is registered in the EU Clinical Trials Register (EudraCT 2015-003898-15). FINDINGS: Between May 20, 2016, and July 31, 2019, 207 patients were screened for eligibility, of whom 55 patients were excluded. 152 participants were randomly assigned to groups: 77 (51%) patients received temocillin, 75 (49%) patients received cefotaxime. The composite primary endpoint was met by 18 (26%) of 68 participants receiving temocillin versus 30 (48%) of 62 patients receiving cefotaxime (risk difference -22% [95% CI -42% to -3%]), showing superiority of temocillin versus cefotaxime (ie, less disturbance of the intestinal microbiota). 43 adverse events were reported in 40 (52%) of 77 patients in the temocillin group, versus 46 adverse events in 34 (45%) of 75 patients in the cefotaxime group. Most events were of mild to moderate severity. 21 (27%) patients in the temocillin and 17 (23%) patients in the cefotaxime group had an adverse event that was considered to be associated with the study drug. INTERPRETATION: Temocillin was found to be less selective than cefotaxime of Enterobacterales with reduced susceptibility to third-generation cephalosporins, and it could therefore be a favourable alternative in the empirical treatment of febrile UTI. Use of this antibiotic could reduce hospital transmission and health-care-associated infections by these pathogens. FUNDING: Public Health Agency of Sweden.

Evidence for action: a One Health learning platform on interventions to tackle antimicrobial resistance.

Improving evidence for action is crucial to tackle antimicrobial resistance. The number of interventions for antimicrobial resistance is increasing but current research has major limitations in terms of efforts, methods, scope, quality, and reporting. Moving the agenda forwards requires an improved understanding of the diversity of interventions, their feasibility and cost-benefit, the implementation factors that shape and underpin their effectiveness, and the ways in which individual interventions might interact synergistically or antagonistically to influence actions against antimicrobial resistance in different contexts. Within the efforts to strengthen the global governance of antimicrobial resistance, we advocate for the creation of an international One Health platform for online learning. The platform will synthesise the evidence for actions on antimicrobial resistance into a fully accessible database; generate new scientific insights into the design, implementation, evaluation, and reporting of the broad range of interventions relevant to addressing antimicrobial resistance; and ultimately contribute to the goal of building societal resilience to this central challenge of the 21st century.

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.