Efficacy of high doses of penicillin versus amoxicillin in the treatment of uncomplicated community acquired pneumonia in adults. A non-inferiority controlled clinical trial.

INTRODUCTION: Community-acquired pneumonia (CAP) is treated with penicillin in some northern European countries. OBJECTIVES: To evaluate whether high-dose penicillin V is as effective as high-dose amoxicillin for the treatment of non-severe CAP. DESIGN: Multicentre, parallel, double-blind, controlled, randomized clinical trial. SETTING: 31 primary care centers in Spain. PARTICIPANTS: Patients from 18 to 75 years of age with no significant associated comorbidity and with symptoms of lower respiratory tract infection and radiological confirmation of CAP were randomized to receive either penicillin V 1.6 million units, or amoxicillin 1000mg three times per day for 10 days. MAIN MEASUREMENTS: The main outcome was clinical cure at 14 days, and the primary hypothesis was that penicillin V would be non-inferior to amoxicillin with regard to this outcome, with a margin of 15% for the difference in proportions. EudraCT register 2012-003511-63. RESULTS: A total of 43 subjects (amoxicillin: 28; penicillin: 15) were randomized. Clinical cure was observed in 10 (90.9%) patients assigned to penicillin and in 25 (100%) patients assigned to amoxicillin with a difference of -9.1% (95% CI, -41.3% to 6.4%; p=.951) for non-inferiority. In the intention-to-treat analysis, amoxicillin was found to be 28.6% superior to penicillin (95% CI, 7.3-58.1%; p=.009 for superiority). The number of adverse events was similar in both groups. CONCLUSIONS: There was a trend favoring high-dose amoxicillin versus high-dose penicillin in adults with uncomplicated CAP. The main limitation of this trial was the low statistical power due to the low number of patients included.

A randomized controlled study of 5 and 10 days treatment with phenoxymethylpenicillin for pharyngotonsillitis caused by streptococcus group A - a protocol study.

BACKGROUND: In 2014 the Swedish government assigned to The Public Health Agency of Sweden to conduct studies to evaluate optimal use of existing antibiotic agents. The aim is to optimize drug use and dosing regimens to improve the clinical efficacy. The present study was selected following a structured prioritizing process by independent experts. METHODS: This phase IV study is a randomized, open-label, multicenter study with non-inferiority design regarding the therapeutic use of penicillin V with two parallel groups. The overall aim is to study if the total exposure with penicillin V can be reduced from 1000 mg three times daily for 10 days to 800 mg four times daily for 5 days when treating Streptococcus pyogenes (Lancefield group A) pharyngotonsillitis. Patients will be recruited from 17 primary health care centers in Sweden. Adult men and women, youth and children ≥6 years of age who consult for sore throat and is judged to have a pharyngotonsillitis, with 3-4 Centor criteria and a positive rapid test for group A streptococci, will be included in the study. The primary outcome is clinical cure 5-7 days after discontinuation of antibiotic treatment. Follow-up controls will be done by telephone after 1 and 3 months. Throat symptoms, potential relapses and complications will be monitored, as well as adverse events. Patients (n = 432) will be included during 2 years. DISCUSSION: In the era of increasing antimicrobial resistance and the shortage of new antimicrobial agents it is necessary to revisit optimal usage of old antibiotics. Old antimicrobial drugs are often associated with inadequate knowledge on pharmacokinetics and pharmacodynamics and lack of optimized dosing regimens based on randomized controlled clinical trials. If a shorter and more potent treatment regimen is shown to be equivalent with the normal 10 day regimen this can imply great advantages for both patients (adherence, adverse events, resistance) and the community (resistance, drug costs). TRIAL REGISTRATION: EudraCT number 2015-001752-30 . Protocol FoHM/Tonsillit2015 date 22 June 2015, version 2. Approved by MPA of Sweden 3 July 2015, Approved by Regional Ethical Review Board in Lund, 25 June 2015.

A systematic review of effectiveness of daily oral penicillin v prophylaxis in the prevention of pneumococcal infection in children with sickle cell anaemia.

BACKGROUND: Children with sickle cell anaemia (SCA) are highly susceptible to infection caused by pneumococcal bacteria due to functional asplenia amongst other reasons. Pneumococcal infections are severe with high mortality among these children that the need for prophylactic penicillin therapy becomes necessary. The objective of this review is to look for evidence of the effectiveness of daily oral penicillin prophylaxis in the prevention of pneumococcal infection in children with SCA. METHODS: Electronic databases including genetic disorders group haemoglobinopathies trial register, Cochrane library, Pubmed, Turning Research Into Practice (TRIP) and Google were searched for relevant studies. Hand and grey literature searches were also done. Randomized controlled trials comparing oral penicillin prophylaxis for the prevention of pneumococcal infection in children with SCA with placebo or no treatment were searched for. RESULTS: Two trials were found to have met the inclusion criteria for the review. Results of the two included randomized controlled trials showed a significant reduction in the incidence of pneumococcal infection among children with SCA (and (0)-thallasaemia) receiving penicillin compared to the control group treated with placebo. The odds ratios for the two (Gaston et al and Falletta et al) studies were 0.37 (95% CI 0.16 to 0.86) and 0.5 (95% CI 0.1 to 2.71) respectively. CONCLUSION: There is strong evidence that daily oral penicillin prophylaxis greatly reduces the risk of pneumococcal infection in children with SCA under the age of three years and a moderately strong evidence that its, withdrawal at the age of five years did not result in any serious consequences.

Penicillin concentrations in oropharyngeal and frontal sinus tissue following enteral and intravenous administration measured by microdialysis in a porcine model.

BACKGROUND: Penicillin may be administered enterally or intravenously for the treatment of bacterial infections within the oropharynx and the frontal sinuses. We aimed to assess and compare penicillin concentrations in oropharyngeal and frontal sinus tissues following enteral and intravenous administration in a porcine model. METHOD: Twelve pigs were randomized to receive either enteral (0.8 g Penicillin V) or intravenous (1.2 g Penicillin G) penicillin. Microdialysis was used for sampling in oropharyngeal and frontal sinus tissues during a six-hour dosing interval. In addition, plasma samples were collected. The primary endpoints were time with drug concentration above the minimal inhibitory concentration (T>MIC) for two MIC targets: 0.125 (low target) and 0.5 (high target) µg/mL (covering Group A Streptococci, Fusobactarium necrophorum, Streptococcus pneumoniae and Hemophilus influenza) and attainment of these treatment targets for ≥50 % T>MIC. RESULTS: For both the low and high MIC targets, intravenous administration resulted in higher T>MIC in oropharyngeal and frontal sinus tissues compared to enteral administration. In oropharyngeal tissue, the treatment target (≥50 % T>MIC) was achieved for both the low target (96 %) and high target (68 %) when penicillin was administrated intravenously. In frontal sinus tissue, the treatment target was reached for the low target (70 %), but not the high target (35 %) when administered intravenously. None of the two tissues reached the treatment targets when penicillin was administered enterally. CONCLUSION: Intravenous administrated penicillin in standard dosage is superior to enteral administration of penicillin in standard dosage in achieving clinically important T>MIC as the majority of targets were achieved following intravenously administration, while none of the targets were achieved following enteral administration. These results support the general notion of higher tissue concentrations following intravenous compared to enteral administration.

The optimal antibiotic treatment duration for community-acquired pneumonia in adults diagnosed in general practice in Denmark (CAP-D): an open-label, pragmatic, randomised controlled trial.

BACKGROUND: Use of antibiotics is the main driver of antimicrobial resistance which is considered one of the biggest threats to human health. In Denmark, most antibiotics are prescribed in general practice. Acute lower respiratory tract infections, including community-acquired pneumonia (CAP), are among the most frequent indications for antibiotic prescribing. Phenoxymethylpenicillin is established as first-line treatment in general practice in Denmark. However, the treatment duration with phenoxymethylpenicillin is mostly based on traditions. Both 5 and 7 days of treatment is recommended in Danish guidelines, and when asking the general practitioners about what treatment duration, they prescribe the variation is even bigger. Several hospital-based studies have proven short course (≤ 6 days) antibiotic treatment non-inferior to long course (≥ 7 days) treatment of CAP. No evidence exists on the optimal treatment duration for CAP in non-hospitalised patients. This randomised controlled trial aim to investigate the optimal treatment duration with phenoxymethylpenicillin for CAP in adults diagnosed in general practice in Denmark. METHODS: This is an open-label, pragmatic, randomised controlled, five-arm DURATIONS trial. Participants will be recruited from at least 24 general practices in Denmark. Eligible participants are adults, with no pre-existing lung disease, presenting with symptoms of CAP, and in whom the general practitioner finds it relevant to treat with antibiotics. The study will compare treatment with phenoxymethylpenicillin 1.2 MIE q.i.d. in 3, 4, 5, 6, and 7 days. DISCUSSION: This study will provide evidence for the optimal antibiotic treatment duration of CAP in general practice and inform future guidelines on CAP in all countries using phenoxymethylpenicillin for the treatment of acute respiratory tract infections in adults. The results of this study might also be used to guide treatment recommendations in other countries using phenoxymethylpenicillin. Moreover, a (potential) reduction in antibiotic use might lower the development of antimicrobial resistance, increase patient treatment adherence, reduce risks of adverse events, and lower the economical exp TRIAL REGISTRATION: ClinicalTrials.gov: NCT06295120. Registered 28 February 2024.  The Scientific Ethics Committee for the North Denmark Region: N-20230039.

Towards pharmacokinetic boosting of phenoxymethylpenicillin (penicillin-V) using probenecid for the treatment of bacterial infections.

In the face of increasing antimicrobial tolerance and resistance there is a global obligation to optimise oral antimicrobial dosing strategies including narrow spectrum penicillins, such as penicillin-V. We conducted a randomised, crossover study in healthy volunteers to characterise the influence of probenecid on penicillin-V pharmacokinetics and estimate the pharmacodynamics against Streptococcus pneumoniae. Twenty participants took six doses of penicillin-V (250 mg, 500 mg or 750 mg four times daily) with and without probenecid. Total and free concentrations of penicillin-V and probenecid were measured at two timepoints. A pharmacokinetic model was developed, and the probability of target attainment (PTA) calculated. The mean difference (95% CI) between penicillin-V alone and in combination with probenecid for serum total and free penicillin-V concentrations was significantly different at both timepoints (total: 45 min 4.32 (3.20-5.32) mg/L p < 0.001, 180 min 2.2 (1.58-3.25) mg/L p < 0.001; free: 45 min 1.15 (0.88-1.42) mg/L p < 0.001, 180 min 0.5 (0.35-0.76) mg/L p < 0.001). There was no difference between the timepoints in probenecid concentrations. PTA analysis shows probenecid allows a fourfold increase in MIC cover. Addition of probenecid was safe and well tolerated. The data support further research into improved dosing structures for complex outpatient therapy and might also be used to address penicillin supply shortages.

Efficacy of high doses of oral penicillin versus amoxicillin in the treatment of adults with non-severe pneumonia attended in the community: study protocol for a randomised controlled trial.

BACKGROUND: Streptococcus pneumoniae is the bacterial agent which most frequently causes pneumonia. In some Scandinavian countries, this infection is treated with penicillin V since the resistances of pneumococci to this antibiotic are low. Four reasons justify the undertaking of this study; firstly, the cut-off points which determine whether a pneumococcus is susceptible or resistant to penicillin have changed in 2008 and according to some studies published recently the pneumococcal resistances to penicillin in Spain have fallen drastically, with only 0.9% of the strains being resistant to oral penicillin (minimum inhibitory concentration>2 µg/ml); secondly, there is no correlation between pneumococcal infection by a strain resistant to penicillin and therapeutic failure in pneumonia; thirdly, the use of narrow-spectrum antibiotics is urgently needed because of the dearth of new antimicrobials and the link observed between consumption of broad-spectrum antibiotics and emergence and spread of antibacterial resistance; and fourthly, no clinical study comparing amoxicillin and penicillin V in pneumonia in adults has been published. Our aim is to determine whether high-dose penicillin V is as effective as high-dose amoxicillin for the treatment of uncomplicated community-acquired pneumonia. METHODS: We will perform a parallel group, randomised, double-blind, trial in primary healthcare centres in Spain. Patients aged 18 to 65 without significant associated comorbidity attending the physician with signs and symptoms of lower respiratory tract infection and radiological confirmation of the diagnosis of pneumonia will be randomly assigned to either penicillin V 1.6 million units thrice-daily during 10 days or amoxicillin 1,000 mg thrice-daily during 10 days. The main outcome will be clinical cure at 14 days, defined as absence of fever, resolution or improvement of cough, improvement of general wellbeing and resolution or reduction of crackles indicating that no other antimicrobial treatment will be necessary. Any clinical result other than the anterior will be considered as treatment failure. A total of 210 patients will be recruited to detect a non-inferiority margin of 15% between the two treatments with a minimum power of 80% considering an alpha error of 2.5% for a unilateral hypothesis and maximum possible losses of 15%. DISCUSSION: This pragmatic trial addresses the long-standing hypothesis that the administration of high doses of a narrow-spectrum antibiotic (penicillin V) in patients with non-severe pneumonia attended in the community is not less effective than high doses of amoxicillin (treatment currently recommended) in patients under the age of 65 years. TRIAL REGISTRATION: EudraCT number 2012-003511-63.

The feasibility of antibiotic dosing four times per day: a prospective observational study in primary health care.

OBJECTIVE: To investigate whether the increase in the number of doses of penicillin V from three times daily to four times daily for common infections, as recommended in the new Norwegian guidelines for antibiotic treatment in primary health care, would lead to reduced patient compliance. DESIGN: Prospective observational study. SETTING AND SUBJECTS: Six general practitioners included all patients who were prescribed systemic antibiotic treatment regardless of indication during a 10-month period. A total of 270 patients provided data for the study. METHODS: Telephone interview focusing on omitted antibiotic doses. RESULTS: Some 17% of patients had poor compliance, defined as failing to take 5% or more of total antibiotic doses. Neither level of poor compliance nor number of omitted doses differed significantly when the number of daily doses increased from three to four. There were significantly fewer omitted doses in the group given two doses per day when compared with three doses (p = 0.04) and four doses per day (p = 0.01). CONCLUSION: We found no difference in compliance or omitted doses between antibiotic regimens of three and four doses per day. The new Norwegian guidelines for antibiotic treatment in primary health care appear feasible with regard to patient compliance.

Once weekly azithromycin in secondary prevention of rheumatic fever.

Rheumatic fever and rheumatic heart disease (RHD) are still important problems in developing countries. Secondary prophylaxis which is the most cost-effective method in preventing recurrences of rheumatic fever is fraught with problems of drug compliance. The utility of 500 mg once weekly azithromycin (AZT), an orally effective long-acting antibiotic was evaluated against oral penicillin (phenoxy methyl penicillin 250 mg twice daily) in this study. Forty-eight consecutive patients (44% males, mean age 29.4 years) with established RHD were randomised into two groups-26 patients received AZT and 22 received oral penicillin. Patients were evaluated at randomisation, at 1 month, 3 months, and 6 months, clinically, serologically and by throat swab culture. End points were absence of streptococcal colonisation, infection or fever at the end of 6 months. During the study, 4 patients (15.4%) in the AZT group developed sore throat and fever, had positive throat culture and positive serology indicating streptococcal infection. None satisfied the criteria for rheumatic fever reactivation. None in the oral penicillin group developed streptococcal infection. In conclusion, weekly 500 mg of AZT is not effective in the prevention of streptococcal throat infection compared to oral penicillin therapy in adult patients with established RHD.

Antibiotic treatment of community-acquired pneumonia: A questionnaire survey in Danish general practice.

BACKGROUND: Discrepancies exist in Danish guidelines for the treatment of bacterial community-acquired pneumonia (CAP). This study aimed to investigate how general practitioners (GPs) treat adults with CAP and explore associations between GP characteristics and treatment duration. METHODS: In autumn 2020, GPs in the North Denmark Region were asked to complete an electronic questionnaire on antibiotic prescribing for CAP. Information about GP gender, age, experience and type of practice was obtained. Multivariable logistic regression was used to analyse the association between GP characteristics and treatment duration. RESULTS: A total of 298 GPs were invited to participate of whom 108 completed the survey. Penicillin V was used as first line treatment for CAP by all participants. Treatment duration varied from 5 (54.6%) to 10 days (8.3%). A 5-day course of penicillin was less likely to be prescribed by male GPs (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.13-0.94) and more likely to be prescribed by GPs with 5-9 years of experience in general practice (OR 5.03, 95% CI 1.09-23.21) compared to those with 10-19 years of experience. CONCLUSION: Variation in antibiotic treatment of CAP emphasises the importance of generating solid evidence about the optimal duration regarding both effectiveness and safety.

Primary subacute osteomyelitis of the talus in children: a case series and review.

Subacute haematogenous osteomyelitis of the talus in children is a rare condition. All previously reported cases have been managed by hospital admission with surgical debridement and antibiotics or by intravenous antibiotic therapy followed by oral antibiotics. This case series documents the management of the condition at our institution and reviews the current published literature. We conclude that with appropriate patient selection, primary subacute haematogenous osteomyelitis of the paediatric talus can be managed on an out-patient basis with oral antibiotic therapy.

[Update on current care guidelines: antimicrobials in acute dentistry]. / Hammasperäiset äkilliset infektiot ja mikrobilääkkeet.

In most cases, acute oral infections originate from the dentition. The use of antimicrobials is secondary to appropriate dental care and does not allow postponing the elimination of the infection source. Medically compromised patients are more susceptible to odontogenic infection complications and antimicrobials have a more important role in their treatment. In the treatment of dental abscesses, a pre-operative 2 g single-dose of amoxicillin is recommended for all patients. An additional five to seven-day course of penicillin V or amoxicillin, in combination with metronidazole or clavulanic acid, should be considered, especially in the treatment of medically compromised patients.

Maternal antibiotic administration during a critical developmental window has enduring neurobehavioural effects in offspring mice.

Rates of perinatal maternal antibiotic use have increased in recent years linked to prophylactic antibiotic use following Caesarean section delivery. This antibiotic use is necessary and beneficial in the short-term; however, long-term consequences on brain and behaviour have not been studied in detail. Here, we endeavoured to determine whether maternal administration of antibiotics during a critical window of development in early life has lasting effects on brain and behaviour in offspring mice. To this end we studied two different antibiotic preparations (single administration of Phenoxymethylpenicillin at 31 mg/kg/day; and a cocktail consisting of, ampicillin 1 mg/mL; vancomycin 0.5 mg/mL; metronidazole 1 mg/mL; ciprofloxacin 0.2 mg/mL and imipenem 0.25 mg/mL). It was observed that early life exposure to maternal antibiotics led to persistent alterations in anxiety, sociability and cognitive behaviours. These effects in general were greater in animals treated with the broad-spectrum antibiotic cocktail compared to a single antibiotic with the exception of deficits in social recognition which were more robustly observed in Penicillin V exposed animals. Given the prevalence of maternal antibiotic use, our findings have potentially significant translational relevance, particularly considering the implications on infant health during this critical period and into later life.

GPs' antibiotic prescription patterns for respiratory tract infections--still room for improvement.

OBJECTIVE: Inappropriate use of antibiotics is associated with increased antibiotic resistance in the community. About 90% of all antibiotic prescriptions in Norway are issued by general practitioners and in 60% issued for respiratory tract infections. The article describes and analyses antibiotic prescription patterns by general practitioners in Vestfold, Norway. DESIGN: Prospective cohort study. SUBJECTS: A total of 145 list-holding general practitioners in Vestfold, Norway in February to March 2003. METHODS: Merging of two electronic administrative data sets: antibiotic prescriptions dispensed in pharmacies and general practitioners' electronic bills from the National Insurance Agency. MAIN OUTCOME MEASURES: Proportion and type of antibiotic prescribed for different respiratory tract infectious diagnoses. RESULTS: We found large variations among general practitioners' antibiotic prescription habits. In 27% of consultations with RTI diagnoses, an antibiotic was prescribed; 37% were for Penicillin V and 28% for a macrolide. Quinolones and cephalosporins were only rarely prescribed. In a logistic regression analysis the following factors were independently associated with antibiotic prescription rate: type of infection, type of contact, being a general practitioner specialist, and years since medical exam. In another logistic regression analysis the following factors were independently associated with broad-spectrum antibiotic prescription: type of infection, age of patient, type of contact, being a specialist, length of list, and being a high prescriber of antibiotics. CONCLUSION: The variation in proportion of total antibiotic prescribing and broad-spectrum prescription for respiratory tract infections is high, and reveals potentials to change general practitioners' prescription behaviour, in order to maintain the positive situation in Norway as to antibiotic resistance.

Appropriate antibiotic prescribing for the general dentist.

While it is important for dental providers to keep current with published antibiotic guidelines (which may represent standards of care), there remains some controversy as to the evidence base for the efficacy of these recommendations. When antibiotics are indicated, their appropriate prescription remains an important challenge for dental and medical professionals alike.

Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers.

BACKGROUND: Enhanced methods of drug monitoring are required to support the individualisation of antibiotic dosing. We report the first-in-human evaluation of real-time phenoxymethylpenicillin monitoring using a minimally invasive microneedle-based ß-lactam biosensor in healthy volunteers. METHODS: This first-in-human, proof-of-concept study was done at the National Institute of Health Research/Wellcome Trust Imperial Clinical Research Facility (Imperial College London, London, UK). The study was approved by London-Harrow Regional Ethics Committee. Volunteers were identified through emails sent to a healthy volunteer database from the Imperial College Clinical Research Facility. Volunteers, who had to be older than 18 years, were excluded if they had evidence of active infection, allergies to penicillin, were at high risk of skin infection, or presented with anaemia during screening. Participants wore a solid microneedle ß-lactam biosensor for up to 6 h while being dosed at steady state with oral phenoxymethylpenicillin (five 500 mg doses every 6 h). On arrival at the study centre, two microneedle sensors were applied to the participant's forearm. Blood samples (via cannula, at -30, 0, 10, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240 min) and extracellular fluid (ECF; via microdialysis, every 15 min) pharmacokinetic (PK) samples were taken during one dosing interval. Phenoxymethylpenicillin concentration data obtained from the microneedles were calibrated using locally estimated scatter plot smoothing and compared with free-blood and microdialysis (gold standard) data. Phenoxymethylpenicillin PK for each method was evaluated using non-compartmental analysis. Area under the concentration-time curve (AUC), maximum concentration, and time to maximum concentration were compared. Bias and limits of agreement were investigated with Bland-Altman plots. Microneedle biosensor limits of detection were estimated. The study was registered with ClinicalTrials.gov, number NCT03847610. FINDINGS: Ten healthy volunteers participated in the study. Mean age was 42 years (SD 14). Seven (70%) were men. Microdialysis and microneedle results were similar for phenoxymethylpenicillin ECF maximum concentration (0·74 mg/L vs 0·64 mg/L; 95% CI -0·24 to 0·44; p=0·53), time to maximum concentration (1·18 h vs 1·10 h; -0·52 to 0·67; p=0·79), and AUC (1·54 mg × h/L vs 1·67 mg × h/L; -1·10 to 0·85; p=0·79). In total, 440 time points were compared with mean difference between measurements -0·16 mg/L (95% CI -1·30 to 0·82). Mean phenoxymethylpenicillin AUCs for free serum and microneedle PK were similar (1·77 mg × h/L [SD 0·59] vs 1·67 mg × h/L [1·00]; -0·77 to 0·97; p=0·81). Median coefficient of variation between sensors within individuals was 7% (IQR 4-17). Limit of detection for the microneedles was estimated at 0·17 mg/L. INTERPRETATION: This study is proof-of-concept of real-time, microneedle sensing of penicillin in vivo. Future work will explore microneedle use in patient populations, their role in data generation to inform dosing recommendations, and their incorporation into closed-loop control systems for automated drug delivery. FUNDING: National Institute for Health Research Imperial Biomedical Research Centre, Mérieux Foundation.

The Effect of Flucloxacillin on Warfarin Anticoagulation: A Swedish Register-Based Nationwide Cohort Study.

BACKGROUND: Data indicate that codispensing flucloxacillin to patients already on warfarin may result in decreased warfarin efficacy. OBJECTIVES: This article investigates the effect of flucloxacillin on warfarin anticoagulation. PATIENTS AND METHODS: In a retrospective cohort study of warfarin users, using three nationwide registers we included 5,848 patients receiving 10 days flucloxacillin treatment and 201 with ≥30 days treatment. To assess the potential for confounding by indication, we also identified 21,430 individuals initiating phenoxymethylpenicillin. International normalized ratio (INR) values and warfarin doses were calculated day-by-day and proportion of patients with a subtherapeutic INR week-by-week during cotreatment. RESULTS: Following initiation of flucloxacillin with a planned treatment duration of 10 days and ≥30 days, the mean INR decreased from 2.36 (95% confidence interval [CI] 2.34; 2.37) to 2.20 (95% CI 2.19; 2.21) and from 2.24 (95% CI 2.16; 2.32) to 1.96 (95% CI 1.89; 2.02), respectively. Consequently, for individuals with 10 days treatment the proportion of patients with a subtherapeutic INR of < 2 increased from 22% in the week preceding flucloxacillin initiation to 35% in the third week after initiation of flucloxacillin. In patients with 30 days treatment, the proportion increased from 34 to 63% by week 6. In individuals initiating phenoxymethylpenicillin, INR levels did not decrease. CONCLUSION: One in three patients with 10 days flucloxacillin and almost two in three patients initiating long-term treatment, was exposed to a subsequent subtherapeutic anticoagulant effect. To avoid unnecessary thromboembolic complications, the initiation of flucloxacillin should be accompanied by closer INR monitoring which may be especially important among individuals with lengthy treatments.

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.

Pharmacodynamic analysis and clinical trial of amoxicillin sprinkle administered once daily for 7 days compared to penicillin V potassium administered four times daily for 10 days in the treatment of tonsillopharyngitis due to Streptococcus pyogenes in children.

An a priori pharmacokinetic/pharmacodynamic (PK/PD) target of 40% daily time above the MIC (T >MIC; based on the MIC(90) of 0.06 microg/ml for Streptococcus pyogenes reported in the literature) was shown to be achievable in a phase 1 study of 23 children with a once-daily (QD) modified-release, multiparticulate formulation of amoxicillin (amoxicillin sprinkle). The daily T >MIC achieved with the QD amoxicillin sprinkle formulation was comparable to that achieved with a four-times-daily (QID) penicillin VK suspension. An investigator-blinded, randomized, parallel-group, multicenter study involving 579 children 6 months to 12 years old with acute streptococcal tonsillopharyngitis was then undertaken. Children were randomly assigned 1:1 to receive either the amoxicillin sprinkle (475 mg for ages 6 months to 4 years, 775 mg for ages 5 to 12 years) QD for 7 days or 10 mg/kg of body weight of penicillin VK QID for 10 days (up to the maximum dose of 250 mg QID). Unexpectedly, the rates of bacteriological eradication at the test of cure were 65.3% (132/202) for the amoxicillin sprinkle and 68.0% (132/194) for penicillin VK (95% confidence interval, -12.0% to 6.6%). Thus, neither antibiotic regimen met the minimum criterion of > or =85% eradication ordinarily required by the U.S. FDA for first-line treatment of tonsillopharyngitis due to S. pyogenes. The results of subgroup analyses across demographic characteristics and current infection characteristics and by age/weight categories were consistent with the primary-efficacy result. The clinical cure rates for amoxicillin sprinkle and penicillin VK were 86.1% (216/251) and 91.9% (204/222), respectively (95% confidence interval, -11.6% to -0.4%). The results of a post hoc PD analysis suggested that a requirement for 60% daily T >MIC(90) more accurately predicted the observed high failure rates for bacteriologic eradication with the amoxicillin sprinkle and penicillin VK suspension studied. Based on the association between longer treatment courses and maximal bacterial eradication rates reported in the literature, an alternative composite PK/PD target taking into consideration the duration of therapy, or total T >MIC, was considered and provides an alternative explanation for the observed failure rate of amoxicillin sprinkle.