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•High doses of amoxicillin cause dose-dependent toxicities.•Monitoring of amoxicillin trough plasma concentrations (ATPC) could avoid these toxicities.•ATPC is not a good tool alone because of high variability.•Low urinary pH and/or presence of amoxicillin cristalluria must alert the physician too. High doses of amoxicillin are recommended to treat severe infections such as endocarditis. Amoxicillin causes dose-dependent toxicities, in particular crystal nephropathy. Toxicity could be avoided by monitoring of amoxicillin trough plasma concentrations (ATPC). However, the relevance of ATPC testing in routine medical practice remains poorly studied. We conducted a prospective clinical trial in adults treated with high doses of discontinuous intravenous amoxicillin in a French university hospital. The primary outcome was the distribution of ATPCs over three days during the first week of treatment. Urine tests for amoxicillin crystalluria (AC), pH, and density were also performed. Seventy patients were included. Overall intra-class correlation (ICC) was 0.35 IC95% [0.21; 0.53] with the following pairwise concordances: D1-D4 (n= 55) 0.23 IC95% [-0.02; 0.47], D1-D7 (n= 47) 0.41 IC95% [0.19; 0.63], and D4-D7 (n= 50) 0.17 IC95% [-0.10; 0.43]. Inter-individual variability was also significant, with coefficients of variation being 0.87 at D1, 1.20 at D4, and 1.35 at D7. AC occurred in 32 patients (47.8%). Risk of AC increased when pH was below or equal to 6 (P = 0.002). ATPCs were higher in patients with AC and/or acute kidney injury. Variability in ATPC was high and ATPC cannot be considered as the only monitoring tool to adjust amoxicillin dosage. High ATPC, low urinary pH, and presence of AC can alert physicians to a potential iatrogenic effect and lead to the decision to hydrate the patient, alkalinize urine and decrease the dosage of amoxicillin. [Display omitted]

Background Antibiotic-induced disruption of the gut microbiome in the first 1000 days of life is linked to an increased risk of the development of immunological, metabolic, and neurobehavioral childhood-onset conditions. Supporting the recovery of the gut microbial community after it has been perturbed by antibiotics might be a promising strategy to reduce these risks. In this clinical study, the effect of a 6 weeks supplementation with synbiotics ( Bifidobacterium breve M-16 V, short chain galacto-oligosaccharides and long chain fructo-oligosaccharides) after antibiotic treatment on the recovery speed of the gut microbiota of toddlers will be studied. Methods/design A cohort of 126 Dutch toddlers aged 12 to 36 months old, who receive an amoxicillin or amoxicillin/clavulanic acid treatment, will be followed for 12 weeks. Participants will be randomized into an intervention group, who will consume the study product over a 6 weeks period starting at the last day of the antibiotic treatment or into a control group that will continue their usual eating pattern. Stool samples and their characteristics will be collected weekly by both groups. Stool samples will be analyzed for total microbiota and Bifidobacterium spp.. The differences in the proportion of Bifidobacterium out of total gut microbiota, composition of species belonging to Bifidobacterium, and beta diversity overtime will be compared between the two groups to study the effect of the intervention on the gut microbiota after perturbation. Furthermore, the effect of the treatment will also be studied in terms of the gut microbiota metabolic activity and stool characteristics. Additionally, food intake will be recorded to investigate whether diet, especially dietary fibers, may influence the gut microbiota as well. The findings may highlight a potential intervention strategy to support the recovery of the gut community after it has been perturbed by antibiotics in early life. Trial registration The TOBBI trial was approved by the board of Medical Ethics Review Committee NedMec in June 2022 and registered at  https://www.onderzoekmetmensen.nl/en/trial/20358 under the code NL75975.081.20, and at the World Health Organization at https://trialsearch.who.int/Trial2.aspx?TrialID=NL-OMON20358 under NTR-new: NL8996.

Patients treated with targeted temperature management (32 to 34°C) after cardiac arrest are at increased risk for early ventilator-associated pneumonia. In this multicenter trial, intravenous amoxicillin–clavulanate for 48 hours after cardiac arrest resulted in a lower incidence of early ventilator-associated pneumonia than placebo but did not affect ventilator-free days or mortality at day 28.

The WHO recommends oral amoxicillin for pneumonia with tachypnea, yet trial data show that withholding amoxicillin may be noninferior to using amoxicillin. In this double-blind trial, children 2 to 59 months of age in low-income communities in Pakistan were assigned to a 3-day course of placebo or amoxicillin. The noninferiority of placebo was not shown.

ObjectiveTo date, no randomised trials have compared the efficacy of vonoprazan and amoxicillin dual therapy with other standard regimens for Helicobacter pylori treatment. This study aimed to investigate the efficacy of the 7-day vonoprazan and low-dose amoxicillin dual therapy as a first-line H. pylori treatment, and compared this with vonoprazan-based triple therapy.DesignThis prospective, randomised clinical trial was performed at seven Japanese institutions. Patients with H. pylori–positive culture test and naive to treatment were randomly assigned in a 1:1 ratio to either VA-dual therapy (vonoprazan 20 mg+amoxicillin 750 mg twice/day) or VAC-triple therapy (vonoprazan 20 mg+amoxicillin 750 mg+clarithromycin 200 mg twice/day) for 7 days, with stratification by age, sex, H. pylori antimicrobial resistance and institution. Eradication success was evaluated by 13C-urea breath test at least 4 weeks after treatment.ResultsBetween October 2018 and June 2019, 629 subjects were screened and 335 were randomised. The eradication rates of VA-dual and VAC-triple therapies were 84.5% and 89.2% (p=0.203) by intention-to-treat analysis, respectively, and 87.1% and 90.2% (p=0.372) by per-protocol analysis, respectively. VA-dual was non-inferior to VAC-triple in the per-protocol analysis. The eradication rates in strains resistant to clarithromycin for VA-dual were significantly higher than those for VAC-triple (92.3% vs 76.2%; p=0.048). The incidence of adverse events was equal between groups.ConclusionThe 7-day vonoprazan and low-dose amoxicillin dual therapy provided acceptable H. pylori eradication rates and a similar effect to vonoprazan-based triple therapy in regions with high clarithromycin resistance.Trial registration numberUMIN000034140.

In children 6 to 23 months of age with otitis media, 5 days of antibiotic therapy was associated with less-favorable outcomes than standard 10-day treatment. The shorter course did not result in a lower rate of adverse events or of emergence of antimicrobial resistance. Next to the common cold, acute otitis media is the most frequently diagnosed illness in children in the United States 1 and the most commonly cited indication for antimicrobial treatment. 2 Concerns about the possible encouragement of antimicrobial resistance have led to recommendations by some clinicians that antimicrobial agents be withheld in large subgroups of children with acute otitis media, unless symptoms persist or worsen. 3 However, two trials lend support for routine antimicrobial treatment in young children, because affected participants younger than 3 years of age who received antimicrobial treatment for 7 or 10 days had more favorable outcomes than those who . . .

ObjectiveThe objective of this study was to assess the efficacy, safety and tolerability of vonoprazan, a novel potassium-competitive acid blocker, as a component of Helicobacter pylori eradication therapy.DesignA randomised, double-blind, multicentre, parallel-group study was conducted to verify the non-inferiority of vonoprazan 20 mg to lansoprazole 30 mg as part of first-line triple therapy (with amoxicillin 750 mg and clarithromycin 200 or 400 mg) in H pylori-positive patients with gastric or duodenal ulcer history. The first 50 patients failing first-line therapy with good compliance also received second-line vonoprazan-based triple therapy (with amoxicillin 750 mg and metronidazole 250 mg) as an open-label treatment.ResultsOf the 650 subjects randomly allocated to either first-line triple therapy, 641 subjects completed first-line therapy and 50 subjects completed second-line therapy. The first-line eradication rate (primary end point) was 92.6% (95% CI 89.2% to 95.2%) with vonoprazan versus 75.9% (95% CI 70.9% to 80.5%) with lansoprazole, with the difference being 16.7% (95% CI 11.2% to 22.1%) in favour of vonoprazan, thus confirming the non-inferiority of vonoprazan (p<0.0001). The second-line eradication rate (secondary end point) was also high (98.0%; 95% CI 89.4% to 99.9%) in those who received second-line therapy (n=50). Both first-line triple therapies were well tolerated with no notable differences. Second-line triple therapy was also well tolerated.ConclusionVonoprazan is effective as part of first-line triple therapy and as part of second-line triple therapy in H pylori-positive patients with a history of gastric or duodenal ulcer.Trial registration numberNCT01505127.

Broad-spectrum antibiotics for suspected early-onset neonatal sepsis (sEONS) may have pronounced effects on gut microbiome development and selection of antimicrobial resistance when administered in the first week of life, during the assembly phase of the neonatal microbiome. Here, 147 infants born at ≥36 weeks of gestational age, requiring broad-spectrum antibiotics for treatment of sEONS in their first week of life were randomized 1:1:1 to receive three commonly prescribed intravenous antibiotic combinations, namely penicillin + gentamicin, co-amoxiclav + gentamicin or amoxicillin + cefotaxime (ZEBRA study, Trial Register NL4882). Average antibiotic treatment duration was 48 hours. A subset of 80 non-antibiotic treated infants from a healthy birth cohort served as controls (MUIS study, Trial Register NL3821). Rectal swabs and/or faeces were collected before and immediately after treatment, and at 1, 4 and 12 months of life. Microbiota were characterized by 16S rRNA-based sequencing and a panel of 31 antimicrobial resistance genes was tested using targeted qPCR. Confirmatory shotgun metagenomic sequencing was executed on a subset of samples. The overall gut microbial community composition and antimicrobial resistance gene profile majorly shift directly following treatment (R 2  = 9.5%, adjusted p -value = 0.001 and R 2  = 7.5%, adjusted p -value = 0.001, respectively) and normalize over 12 months (R 2  = 1.1%, adjusted p -value = 0.03 and R 2  = 0.6%, adjusted p -value = 0.23, respectively). We find a decreased abundance of Bifidobacterium spp. and increased abundance of Klebsiella and Enterococcus spp. in the antibiotic treated infants compared to controls. Amoxicillin + cefotaxime shows the largest effects on both microbial community composition and antimicrobial resistance gene profile, whereas penicillin + gentamicin exhibits the least effects. These data suggest that the choice of empirical antibiotics is relevant for adverse ecological side-effects. Here, in a randomized trial of 147 infants receiving distinct antibiotic regimens for early-onset neonatal sepsis, Reyman et al. characterize the gut microbiome and resistance profiles, finding differential effects of antibiotic combinations on microbial community composition and antimicrobial resistance genes.

Although amoxicillin–clavulanate is the recommended first-line empirical oral antibiotic treatment for non-severe exacerbations in children with bronchiectasis, azithromycin is also often prescribed for its convenient once-daily dosing. No randomised controlled trials involving acute exacerbations in children with bronchiectasis have been published to our knowledge. We hypothesised that azithromycin is non-inferior to amoxicillin-clavulanate for resolving exacerbations in children with bronchiectasis. We did this parallel-group, double-dummy, double-blind, non-inferiority randomised controlled trial in three Australian and one New Zealand hospital between April, 2012, and August, 2016. We enrolled children aged 1–19 years with radiographically proven bronchiectasis unrelated to cystic fibrosis. At the start of an exacerbation, children were randomly assigned to oral suspensions of either amoxicillin–clavulanate (22·5 mg/kg, twice daily) and placebo or azithromycin (5 mg/kg per day) and placebo for 21 days. We used permuted block randomisation (stratified by age, site, and cause) with concealed allocation. The primary outcome was resolution of exacerbation (defined as a return to baseline) by 21 days in the per-protocol population, with a non-inferiority margin of −20%. We assessed several secondary outcomes including duration of exacerbation, time to next exacerbation, laboratory, respiratory, and quality-of-life measurements, and microbiology. This trial was registered with the Australian/New Zealand Registry (ACTRN12612000010897). We screened 604 children and enrolled 236. 179 children had an exacerbation and were assigned to treatment: 97 to amoxicillin–clavulanate, 82 to azithromycin). By day 21, 61 (84%) of 73 exacerbations had resolved in the azithromycin group versus 73 (84%) of 87 in the amoxicillin–clavulanate group. The risk difference showed non-inferiority (−0·3%, 95% CI −11·8 to 11·1). Exacerbations were significantly shorter in the amoxicillin–clavulanate group than in the azithromycin group (median 10 days [IQR 6–15] vs 14 days [8–16]; p=0·014). Adverse events were attributed to the trial medication in 17 (21%) of 82 children in the azithromycin group versus 23 (24%) of 97 in the amoxicillin–clavulanate group (relative risk 0·9, 95% CI 0·5 to 1·5). By 21 days of treatment, azithromycin is non-inferior to amoxicillin–clavulanate for resolving exacerbations in children with non-severe bronchiectasis. In some patients, such as those with penicillin hypersensitivity or those likely to have poor adherence, azithromycin provides another option for treating exacerbations, but must be balanced with risk of treatment failure (within a 20% margin), longer exacerbation duration, and the risk of inducing macrolide resistance. Australian National Health and Medical Research Council.

AbstractObjectiveTo assess the efficacy of three months of antibiotic treatment compared with placebo in patients with chronic low back pain, previous disc herniation, and vertebral endplate changes (Modic changes).DesignDouble blind, parallel group, placebo controlled, multicentre trial.SettingHospital outpatient clinics at six hospitals in Norway.Participants180 patients with chronic low back pain, previous disc herniation, and type 1 (n=118) or type 2 (n=62) Modic changes enrolled from June 2015 to September 2017.InterventionsPatients were randomised to three months of oral treatment with either 750 mg amoxicillin or placebo three times daily. The allocation sequence was concealed by using a computer generated number on the prescription.Main outcome measuresThe primary outcome was the Roland-Morris Disability Questionnaire (RMDQ) score (range 0-24) at one year follow-up in the intention to treat population. The minimal clinically important between group difference in mean RMDQ score was predefined as 4.ResultsIn the primary analysis of the total cohort at one year, the difference in the mean RMDQ score between the amoxicillin group and the placebo group was −1.6 (95% confidence interval −3.1 to 0.0, P=0.04). In the secondary analysis, the difference in the mean RMDQ score between the groups was −2.3 (−4.2 to−0.4, P=0.02) for patients with type 1 Modic changes and −0.1 (−2.7 to 2.6, P=0.95) for patients with type 2 Modic changes. Fifty patients (56%) in the amoxicillin group experienced at least one drug related adverse event compared with 31 (34%) in the placebo group.ConclusionsIn this study on patients with chronic low back pain and Modic changes at the level of a previous disc herniation, three months of treatment with amoxicillin did not provide a clinically important benefit compared with placebo. Secondary analyses and sensitivity analyses supported this finding. Therefore, our results do not support the use of antibiotic treatment for chronic low back pain and Modic changes.Trial registrationClinicalTrials.gov NCT02323412.