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.

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.

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.

Comparison of phenoxymethylpenicillin, amoxicillin, and doxycycline for erythema migrans in general practice. A randomized controlled trial with a 1-year follow-up.

OBJECTIVES: To compare the three most commonly used antibiotics for erythema migrans (EM) in Norwegian primary care. METHODS: A randomized, parallel, controlled trial was carried out. Treatments were open to the patients, but blinded for the GPs and investigators. Patients eligible for inclusion were aged ≥18 years and clinically diagnosed with EM. Block randomization was processed in blocks of six. Patients were assigned to receive one of three antibiotic treatments for 14 days: phenoxymethylpenicillin (PCV), amoxicillin, or doxycycline. The primary outcome was the duration of EM in days in the three treatment groups. Patients kept a diary for the 14 days of treatment, in which they registered concomitant symptoms and side effects. The patients consulted their GP after 14 days of treatment and had a 1-year follow-up to monitor any development of disseminated Lyme borreliosis (LB). EMs with a duration of more than 14 days were followed until resolution. ClinicalTrials.govNCT01368341 and EU Clinical Trials Register 2010-023747-15. RESULTS: One hundred and eighty eight patients (PCV: n = 56, amoxicillin: n = 64, doxycycline: n = 68) were included by 44 Norwegian general practitioners (GPs) from June 2011 to November 2013. Follow-up was completed by December 2014. The median duration of EM was altogether 14 days (range 3-293). For the PCV group median duration was 14 days (range 5-91), for amoxicillin 13 days (range 4-179) and for doxycycline 14 days (range 3-293). The duration of EM did not differ significantly between the three antibiotic groups (p 0.277). None of the patients developed disseminated LB within the 1-year follow-up. CONCLUSIONS: We did not find 14 days of PCV, doxycycline, and amoxicillin treatments to differ in effectiveness or safety in the treatment of clinically diagnosed EM in primary care.

Does macrolide use confer risk of out-of-hospital cardiac arrest compared with penicillin V? A Danish national case-crossover and case-time-control study.

INTRODUCTION AND OBJECTIVES: Macrolides have been associated with proarrhythmic properties, but the evidence is conflicting. We evaluated the risk of out-of-hospital cardiac arrest (OHCA) associated with specific macrolides in a retrospective study. Associations between specific macrolides and OHCA were examined by conditional logistic regression analyses in case-crossover and case-time-control models, using penicillin-V treatment as the comparative reference. From nationwide registries, we identified all OHCAs in Denmark from 2001 to 2010 and use of antibiotics. ETHICS: The present study was approved by the Danish Data Protection Agency (Danish Data Protection Agency (ref.no. 2007-58-0015, local ref.no. GEH-2014-017, (I-Suite.nr. 02 735)). PARTICIPANTS: We identified 29 111 patients with an OHCA. Of these, 514 were in macrolide treatment ≤7 days before OHCA and 1237 in penicillin-V treatment. RESULTS: In the case-crossover analyses, overall macrolide use was not associated with OHCA with penicillin V as negative comparative reference (OR=0.90; 95% CI 0.73 to 1.10). Compared with penicillin-V treatment, specific macrolides were not associated with increased risk of OHCA: roxithromycin (OR=0.97; 95% CI 0.74 to 1.26), erythromycin (OR=0.68; 95% CI 0.44 to 1.06), clarithromycin (OR=0.95; 95% CI 0.61 to 1.48) and azithromycin (OR=0.85; 95% CI 0.57 to 1.27).Similar results were obtained using case-time-control models: overall macrolide use (OR=0.81; 95% CI 0.62 to 1.06) and specific macrolides (roxithromycin (OR=0.70; 95% CI 0.49 to 1.00), erythromycin (OR=0.67; 95% CI 0.38 to 1.18), clarithromycin (OR=0.75; 95% CI 0.41 to 1.39) or azithromycin (OR=1.17; 95% CI 0.70 to 1.95)). CONCLUSION: The risk of OHCA during treatment with macrolides was similar to that of penicillin V, suggesting no additional risk of OHCA associated with macrolides.

The Penicillin for the Emergency Department Outpatient treatment of CELLulitis (PEDOCELL) trial: update to the study protocol and detailed statistical analysis plan (SAP).

BACKGROUND: Cellulitis is a painful, potentially serious, infectious process of the dermal and subdermal tissues and represents a significant disease burden. The statistical analysis plan (SAP) for the Penicillin for the Emergency Department Outpatient treatment of CELLulitis (PEDOCELL) trial is described here. The PEDOCELL trial is a multicentre, randomised, parallel-arm, double-blinded, non-inferiority clinical trial comparing the efficacy of flucloxacillin (monotherapy) with combination flucloxacillin/phenoxymethylpenicillin (dual therapy) for the outpatient treatment of cellulitis in the emergency department (ED) setting. To prevent outcome reporting bias, selective reporting and data-driven results, the a priori-defined, detailed SAP is presented here. METHODS/DESIGN: Patients will be randomised to either orally administered flucloxacillin 500 mg four times daily and placebo or orally administered 500 mg of flucloxacillin four times daily and phenoxymethylpenicillin 500 mg four times daily. The trial consists of a 7-day intervention period and a 2-week follow-up period. Study measurements will be taken at four specific time points: at patient enrolment, day 2-3 after enrolment and commencing treatment (early clinical response (ECR) visit), day 8-10 after enrolment (end-of-treatment (EOT) visit) and day 14-21 after enrolment (test-of-cure (TOC) visit). The primary outcome measure is investigator-determined clinical response measured at the TOC visit. The secondary outcomes are as follows: lesion size at ECR, clinical treatment failure at each follow-up visit, adherence and persistence of trial patients with orally administered antibiotic therapy at EOT, health-related quality of life (HRQoL) and pharmacoeconomic assessments. The plan for the presentation and comparison of baseline characteristics and outcomes is described in this paper. DISCUSSION: This trial aims to establish the non-inferiority of orally administered flucloxacillin monotherapy with orally administered flucloxacillin/phenoxymethylpenicillin dual therapy for the ED-directed outpatient treatment of cellulitis. In doing so, this trial will bridge a knowledge gap in this understudied and common condition and will be relevant to clinicians across several different disciplines. The SAP for the PEDOCELL trial was developed a priori in order to minimise analysis bias. TRIAL REGISTRATION: EU Clinical Trials Register (EudraCT number: 2016-001528-69). Registered on 5 April 2016. ClinicalTrials.gov, ID: NCT02922686 . Registered on 9 August 2016.

Interventions for the prevention of recurrent erysipelas and cellulitis.

BACKGROUND: Erysipelas and cellulitis (hereafter referred to as 'cellulitis') are common bacterial skin infections usually affecting the lower extremities. Despite their burden of morbidity, the evidence for different prevention strategies is unclear. OBJECTIVES: To assess the beneficial and adverse effects of antibiotic prophylaxis or other prophylactic interventions for the prevention of recurrent episodes of cellulitis in adults aged over 16. SEARCH METHODS: We searched the following databases up to June 2016: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS. We also searched five trials registry databases, and checked reference lists of included studies and reviews for further references to relevant randomised controlled trials (RCTs). We searched two sets of dermatology conference proceedings, and BIOSIS Previews. SELECTION CRITERIA: Randomised controlled trials evaluating any therapy for the prevention of recurrent cellulitis. DATA COLLECTION AND ANALYSIS: Two authors independently carried out study selection, data extraction, assessment of risks of bias, and analyses. Our primary prespecified outcome was recurrence of cellulitis when on treatment and after treatment. Our secondary outcomes included incidence rate, time to next episode, hospitalisation, quality of life, development of resistance to antibiotics, adverse reactions and mortality. MAIN RESULTS: We included six trials, with a total of 573 evaluable participants, who were aged on average between 50 and 70. There were few previous episodes of cellulitis in those recruited to the trials, ranging between one and four episodes per study.Five of the six included trials assessed prevention with antibiotics in participants with cellulitis of the legs, and one assessed selenium in participants with cellulitis of the arms. Among the studies assessing antibiotics, one study evaluated oral erythromycin (n = 32) and four studies assessed penicillin (n = 481). Treatment duration varied from six to 18 months, and two studies continued to follow up participants after discontinuation of prophylaxis, with a follow-up period of up to one and a half to two years. Four studies were single-centre, and two were multicentre; they were conducted in five countries: the UK, Sweden, Tunisia, Israel, and Austria.Based on five trials, antibiotic prophylaxis (at the end of the treatment phase ('on prophylaxis')) decreased the risk of cellulitis recurrence by 69%, compared to no treatment or placebo (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.13 to 0.72; n = 513; P = 0.007), number needed to treat for an additional beneficial outcome (NNTB) six, (95% CI 5 to 15), and we rated the certainty of evidence for this outcome as moderate.Under prophylactic treatment and compared to no treatment or placebo, antibiotic prophylaxis reduced the incidence rate of cellulitis by 56% (RR 0.44, 95% CI 0.22 to 0.89; four studies; n = 473; P value = 0.02; moderate-certainty evidence) and significantly decreased the rate until the next episode of cellulitis (hazard ratio (HR) 0.51, 95% CI 0.34 to 0.78; three studies; n = 437; P = 0.002; moderate-certainty evidence).The protective effects of antibiotic did not last after prophylaxis had been stopped ('post-prophylaxis') for risk of cellulitis recurrence (RR 0.88, 95% CI 0.59 to 1.31; two studies; n = 287; P = 0.52), incidence rate of cellulitis (RR 0.94, 95% CI 0.65 to 1.36; two studies; n = 287; P = 0.74), and rate until next episode of cellulitis (HR 0.78, 95% CI 0.39 to 1.56; two studies; n = 287). Evidence was of low certainty.Effects are relevant mainly for people after at least two episodes of leg cellulitis occurring within a period up to three years.We found no significant differences in adverse effects or hospitalisation between antibiotic and no treatment or placebo; for adverse effects: RR 0.87, 95% CI 0.58 to 1.30; four studies; n = 469; P = 0.48; for hospitalisation: RR 0.77, 95% CI 0.37 to 1.57; three studies; n = 429; P = 0.47, with certainty of evidence rated low for these outcomes. The existing data did not allow us to fully explore its impact on length of hospital stay.The common adverse reactions were gastrointestinal symptoms, mainly nausea and diarrhoea; rash (severe cutaneous adverse reactions were not reported); and thrush. Three studies reported adverse effects that led to discontinuation of the assigned therapy. In one study (erythromycin), three participants reported abdominal pain and nausea, so their treatment was changed to penicillin. In another study, two participants treated with penicillin withdrew from treatment due to diarrhoea or nausea. In one study, around 10% of participants stopped treatment due to pain at the injection site (the active treatment group was given intramuscular injections of benzathine penicillin).None of the included studies assessed the development of antimicrobial resistance or quality-of-life measures.With regard to the risks of bias, two included studies were at low risk of bias and we judged three others as being at high risk of bias, mainly due to lack of blinding. AUTHORS' CONCLUSIONS: In terms of recurrence, incidence, and time to next episode, antibiotic is probably an effective preventive treatment for recurrent cellulitis of the lower limbs in those under prophylactic treatment, compared with placebo or no treatment (moderate-certainty evidence). However, these preventive effects of antibiotics appear to diminish after they are discontinued (low-certainty evidence). Treatment with antibiotic does not trigger any serious adverse events, and those associated are minor, such as nausea and rash (low-certainty evidence). The evidence is limited to people with at least two past episodes of leg cellulitis within a time frame of up to three years, and none of the studies investigated other common interventions such as lymphoedema reduction methods or proper skin care. Larger, high-quality studies are warranted, including long-term follow-up and other prophylactic measures.

Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice.

The early life microbiome plays important roles in host immunological and metabolic development. Because the incidence of type 1 diabetes (T1D) has been increasing substantially in recent decades, we hypothesized that early-life antibiotic use alters gut microbiota, which predisposes to disease. Using non-obese diabetic mice that are genetically susceptible to T1D, we examined the effects of exposure to either continuous low-dose antibiotics or pulsed therapeutic antibiotics (PAT) early in life, mimicking childhood exposures. We found that in mice receiving PAT, T1D incidence was significantly higher, and microbial community composition and structure differed compared with controls. In pre-diabetic male PAT mice, the intestinal lamina propria had lower Th17 and Treg proportions and intestinal SAA expression than in controls, suggesting key roles in transducing the altered microbiota signals. PAT affected microbial lipid metabolism and host cholesterol biosynthetic gene expression. These findings show that early-life antibiotic treatments alter the gut microbiota and its metabolic capacities, intestinal gene expression and T-cell populations, accelerating T1D onset in non-obese diabetic mice.

Oral fluoroquinolone use and serious arrhythmia: bi-national cohort study.

OBJECTIVE: To evaluate if oral fluoroquinolone use is associated with an increased risk of serious arrhythmia. DESIGN: Bi-national cohort study, linking register data on filled prescriptions, cases of serious arrhythmia, and patient characteristics. SETTING: Denmark, 1997-2011; Sweden, 2006-13. PARTICIPANTS: The study cohort was derived from a source population of all Danish and Swedish adults, aged 40 to 79 years. 909,656 courses of fluoroquinolone use (ciprofloxacin 82.6%, norfloxacin 12.1%, ofloxacin 3.2%, moxifloxacin 1.2%, and other fluoroquinolones 0.9%) and 909,656 courses of penicillin V use, matched 1:1 on propensity score, were included. MAIN OUTCOME MEASURE: The main outcome was risk of serious arrhythmia (fatal and non-fatal), comparing courses of fluoroquinolone use with courses of penicillin V use (an antibiotic with no pro-arrhythmic effect). The risk period of interest was current use, defined as days 0-7 of treatment. Subgroup analyses were conducted according to country, sex, age, underlying cardiovascular disease, concomitant use of drugs known to increase the risk of torsades de pointes, fluoroquinolone type, and levels of arrhythmia risk score. RESULTS: 144 cases of serious arrhythmia occurred during follow-up, 66 among current fluoroquinolone users (incidence rate 3.4 per 1000 person years) and 78 among current penicillin users (4.0 per 1000 person years); comparing oral fluoroquinolone treatment with penicillin V, the rate ratio was 0.85 (95% confidence interval 0.61 to 1.18). Compared with penicillin V, the absolute risk difference was -13 (95% confidence interval -35 to 16) cases of serious arrhythmia per 1,000,000 courses of fluoroquinolones. The risk of serious arrhythmia was not statistically significantly increased in any of the subgroups, including analyses by fluoroquinolone type. CONCLUSIONS: Contrary to previous reports, oral fluoroquinolone treatment was not associated with an increased risk of serious arrhythmia in the general adult populations of Denmark and Sweden. Given the statistical power of the study, even small increases in relative and absolute risk could be ruled out. Since ciprofloxacin was the most commonly used fluoroquinolone in our study, we cannot exclude that intraclass differences influence the risk of serious arrhythmia associated with other less frequently used fluoroquinolones.

Use of clarithromycin and roxithromycin and risk of cardiac death: cohort study.

OBJECTIVE: To assess the risk of cardiac death associated with the use of clarithromycin and roxithromycin. DESIGN: Cohort study. SETTING: Denmark, 1997-2011. PARTICIPANTS: Danish adults, 40-74 years of age, who received seven day treatment courses with clarithromycin (n = 160,297), roxithromycin (n = 588,988), and penicillin V (n = 4,355,309). MAIN OUTCOME MEASURES: The main outcome was risk of cardiac death associated with clarithromycin and roxithromycin, compared with penicillin V. Subgroup analyses were conducted according to sex, age, risk score, and concomitant use of drugs that inhibit the cytochrome P450 3A enzyme, which metabolises macrolides. RESULTS: A total of 285 cardiac deaths were observed. Compared with use of penicillin V (incidence rate 2.5 per 1000 person years), use of clarithromycin was associated with a significantly increased risk of cardiac death (5.3 per 1000 person years; adjusted rate ratio 1.76, 95% confidence interval 1.08 to 2.85) but use of roxithromycin was not (2.5 per 1000 person years; adjusted rate ratio 1.04, 0.72 to 1.51). The association with clarithromycin was most pronounced among women (adjusted rate ratios 2.83 (1.50 to 5.36) in women and 1.09 (0.51 to 2.35) in men). Compared with penicillin V, the adjusted absolute risk difference was 37 (95% confidence interval 4 to 90) cardiac deaths per 1 million courses with clarithromycin and 2 (-14 to 25) cardiac deaths per 1 million courses with roxithromycin. CONCLUSIONS: This large cohort study found a significantly increased risk of cardiac death associated with clarithromycin. No increased risk was seen with roxithromycin. Given the widespread use of clarithromycin, these findings call for confirmation in independent populations.

Oral flucloxacillin and phenoxymethylpenicillin versus flucloxacillin alone for the emergency department outpatient treatment of cellulitis: study protocol for a randomised controlled trial.

BACKGROUND: Oral flucloxacillin, either alone or in combination with phenoxymethylpenicillin, is a commonly prescribed antibiotic for the treatment of cellulitis, particularly in Ireland and the United Kingdom. This study aims to establish the non-inferiority of oral monotherapy (flucloxacillin alone) to dual therapy (flucloxacillin and phenoxymethylpenicillin) for the outpatient treatment of cellulitis in adults. METHODS/DESIGN: This study is a multicentre, randomised, double-blind, placebo-controlled trial of adults who present to the emergency department (ED) with cellulitis that is deemed treatable on an outpatient basis with oral antibiotics. After fulfilling specified inclusion and exclusion criteria, informed consent will be taken. Patients will be given a treatment pack containing 7 days of treatment with flucloxacillin 500 mg four times daily and placebo or flucloxacillin 500 mg four times daily and phenoxymethylpenicillin 500 mg four times daily. The primary outcome measure under study is the proportion of patients in each group in which there is greater than or equal to a 50% reduction in the area of diameter of infection from the area measured at enrolment at the end-of-treatment visit (7 to 10 days). Secondary endpoints include a health-related quality of life measurement as rated by the SF-36 score and the Extremity Soft Tissue Infection Score (not validated), compliance and adverse events. Patients will be followed up by telephone call at 3 days, end-of-treatment visit (EOT) at 7 to 10 days and test-of-cure (TOC) visit at 30 days. To achieve 90% power, a sample size of 172 patients per treatment arm is needed. This assumes a treatment success rate of 85% with oral flucloxacillin and phenoxymethylpenicillin, an equivalence threshold Δ = 12.5% and an α = 0.025. Non-inferiority will be assessed using a one-sided confidence interval on the difference of proportions between the two groups. Standard analysis including per-protocol and intention-to-treat will be performed. DISCUSSION: This trial aims to establish the non-inferiority of flucloxacillin monotherapy to dual therapy in the treatment of uncomplicated cellulitis among ED patients. In doing so, this trial will bridge a knowledge gap in this understudied and common condition and will be relevant to clinicians across several different disciplines.

Use of azithromycin and death from cardiovascular causes.

BACKGROUND: Azithromycin use is associated with an increased risk of death from cardiovascular causes among patients at high baseline risk. Whether azithromycin confers a similar risk in the unselected general population is unknown. METHODS: We conducted a nationwide historical cohort study involving Danish adults (18 to 64 years of age), linking registry data on filled prescriptions, causes of death, and patient characteristics for the period from 1997 through 2010. We estimated rate ratios for death from cardiovascular causes, comparing 1,102,050 episodes of azithromycin use with no use of antibiotic agents (matched in a 1:1 ratio according to propensity score, for a total of 2,204,100 episodes) and comparing 1,102,419 episodes of azithromycin use with 7,364,292 episodes of penicillin V use (an antibiotic with similar indications; analysis was conducted with adjustment for propensity score). RESULTS: The risk of death from cardiovascular causes was significantly increased with current use of azithromycin (defined as a 5-day treatment episode), as compared with no use of antibiotics (rate ratio, 2.85; 95% confidence interval [CI], 1.13 to 7.24). The analysis relative to an antibiotic comparator included 17 deaths from cardiovascular causes during current azithromycin use (crude rate, 1.1 per 1000 person-years) and 146 during current penicillin V use (crude rate, 1.5 per 1000 person-years). With adjustment for propensity scores, current azithromycin use was not associated with an increased risk of cardiovascular death, as compared with penicillin V (rate ratio, 0.93; 95% CI, 0.56 to 1.55). The adjusted absolute risk difference for current use of azithromycin, as compared with penicillin V, was -1 cardiovascular death (95% CI, -9 to 11) per 1 million treatment episodes. CONCLUSIONS: Azithromycin use was not associated with an increased risk of death from cardiovascular causes in a general population of young and middle-aged adults. (Funded by the Danish Medical Research Council.).

Evaluation of the sensitizing potential of antibiotics in vitro using the human cell lines THP-1 and MUTZ-LC and primary monocyte-derived dendritic cells.

Since the 7th amendment to the EU cosmetics directive foresees a complete ban on animal testing, alternative in vitro methods have been established to evaluate the sensitizing potential of small molecular weight compounds. To find out whether these novel in vitro assays are also capable to predict the sensitizing potential of small molecular weight drugs, model compounds such as beta-lactams and sulfonamides - which are the most frequent cause of adverse drug reactions - were co-incubated with THP-1, MUTZ-LC, or primary monocyte-derived dendritic cells for 48 h and subsequent expression of selected marker genes (IL-8, IL-1ß, CES1, NQO1, GCLM, PIR and TRIM16) was studied by real time PCR. Benzylpenicillin and phenoxymethylpenicillin were recognized as sensitizing compounds because they are capable to induce the mRNA expression of these genes in moDCs and, except for IL-8, in THP-1 cells but not in MUTZ-LC. Ampicillin stimulated the expression of some marker genes in moDCs and THP-1 cells. SMX did not affect the expression of these genes in THP-1, however, in moDCs, at least PIR was enhanced and there was an increase of the release of IL-8. These data reveal that novel in vitro DC based assays might play a role in the evaluation of the allergenic potential of novel drug compounds, but these systems seem to lack the ability to detect the sensitizing potential of prohaptens that require metabolic activation prior to sensitization and moDCs seem to be superior with regard to the sensitivity compared with THP-1 and MUTZ-3 cell lines.