Clavulanic Acid

BackgroundNormal mammalian development and homeostasis are dependent upon the gut microbiota. Antibiotics, essential for the treatment and prophylaxis of bacterial infections, can have collateral effects on the gut microbiota composition, which can in turn have far-reaching and potentially deleterious consequences for the host. However, the magnitude and duration of such collateral effects appear to vary between individuals. Furthermore, the degree to which such perturbations affect the host response is currently unclear. We aimed to test the hypothesis that different human microbiomes have different responses to a commonly prescribed antibiotic and that these differences may impact the host response.MethodsGerm-free mice (n = 30) humanized with the microbiota of two unrelated donors (A and B) were subjected to a 7-day antibiotic challenge with amoxicillin-clavulanate ("co-amoxiclav"). Microbiome and colonic transcriptome analysis was performed, pre (day 0) and post antibiotics (day 8) and subsequently into recovery (days 11 and 18).ResultsUnique community profiles were evident depending upon the donor, with donor A recipient mice being dominated by Prevotella and Faecalibacterium and donor B recipient mice dominated by Bacteroides and Parabacteroides. Donor A mice underwent a marked destabilization of their microbiota following antibiotic treatment, while donor B mice maintained a more stable profile. Dramatic and overlapping alterations in the host transcriptome were apparent following antibiotic challenge in both groups. Despite this overlap, donor A mice experienced a more significant alteration in gene expression and uniquely showed correlations between host pathways and key microbial genera.ConclusionsGerm-free mice humanized by different donor microbiotas maintain distinct microbiome profiles, which respond in distinct ways to antibiotic challenge and evince host responses that parallel microbiome disequilibrium. These results suggest that inter-individual variation in the gut microbiota may contribute to personalized host responses following microbiota perturbation.

BackgroundDespite limited evidence of efficacy, antibiotic treatment is still frequently prescribed in dogs with uncomplicated acute diarrhea (AD).ObjectiveTo assess whether amoxicillin-clavulanic acid has a clinical benefit, an effect on the fecal microbiome, and the proportion of amoxicillin-resistant Escherichia coli in dogs with AD.AnimalsSixteen dogs with AD of MethodsProspective, placebo-controlled, double-blinded study. Clinical scores were compared between client-owned dogs randomly assigned to an antibiotic (AG) or a placebo (PG) group. The intestinal microbiome was analyzed using quantitative PCR assays. Amoxicillin-resistant fecal E. coli were assessed semiquantitatively with microbiological methods.ResultsThere was no difference in clinical recovery between treated dogs or controls (CADS index day 10: AG group median: 2 (range: 1-3; CI [1.4; 2.6]); PG group median: 1.6 (range: 1-3; CI [1.1; 2.4]); P > .99). All dogs gained normal clinical scores (CADS index ≤3) after 1 to 6 days (median 2 days) after presentation. There was no significant difference in the fecal dysbiosis index (during treatment: AG mean -2.6 (SD 3.0; CI [-5.1; 0.0]); PG mean -0.8 (SD 4.0; CI [-4.2; 2.5]; P > .99) or its bacterial taxa. The proportion of resistant fecal E. coli increased (to median: 100%; range: 35%-100%) during treatment with amoxicillin-clavulanic acid and was still increased (median: 10%; range 2%-67%) 3 weeks after treatment, both of which were significantly higher proportions than in the placebo group for both time points (during treatment AG median 100% versus PG median 0.2% (P Conclusions and clinical importanceOur study suggests that treatment with amoxicillin-clavulanic acid confers no clinical benefit to dogs with AD, but predisposes the development of amoxicillin-resistant E. coli, which persist for as long as 3 weeks after treatment. These findings support international guideline recommendations that dogs with diarrhea should not be treated with antimicrobials unless there are signs of sepsis.

Mycobacterium tuberculosis (Mtb) expresses a broad-spectrum β-lactamase (BlaC) that mediates resistance to one of the highly effective antibacterials, β-lactams. Nonetheless, β-lactams showed mycobactericidal activity in combination with β-lactamase inhibitor, clavulanate (Clav). However, the mechanistic aspects of how Mtb responds to β-lactams such as Amoxicillin in combination with Clav (referred as Augmentin [AG]) are not clear. Here, we identified cytoplasmic redox potential and intracellular redox sensor, WhiB4, as key determinants of mycobacterial resistance against AG. Using computer-based, biochemical, redox-biosensor, and genetic strategies, we uncovered a functional linkage between specific determinants of β-lactam resistance (e.g. β-lactamase) and redox potential in Mtb. We also describe the role of WhiB4 in coordinating the activity of β-lactamase in a redox-dependent manner to tolerate AG. Disruption of WhiB4 enhances AG tolerance, whereas overexpression potentiates AG activity against drug-resistant Mtb. Our findings suggest that AG can be exploited to diminish drug-resistance in Mtb through redox-based interventions.

ObjectivesThe aim of this study is to evaluate existing evidence on the effectiveness of amoxicillin and amoxicillin-clavulanate for community-acquired pneumonia in children and adults.DesignSystematic review and meta-analysis.Data sourcesPubMed, Cochrane Library, Web of Science and Ovid-MEDLINER were searched with no language restrictions through 16 July 2024.Eligibility criteriaWe included studies comparing the effectiveness of amoxicillin or amoxicillin-clavulanate versus other antibiotics or placebo.Data extraction and synthesisOnly randomised controlled trials comparing amoxicillin or amoxicillin-clavulanate with another antibiotic or placebo with a primary outcome of clinical resolution or clinical failure were eligible for our review. We used random-effects and fixed-effects logistic regression models to estimate the pooled treatment effect size. Heterogeneity of the studies was evaluated using the τ statistic. We performed an unplanned frequentist random-effects network meta-analysis for the indirect comparison between amoxicillin and amoxicillin-clavulanate. The revised Cochrane risk of bias tool for randomised trials was used to assess and categorise studies into low risk of bias, some concerns or high risk of bias.ResultsWe extracted data from 44 studies including 45 400 patients. We found no evidence of a differential effect on clinical resolution when comparing amoxicillin with other antibiotics (n=15 trials; pooled OR 0.88; 95% CI 0.56 to 1.38, where >1 favours amoxicillin) or amoxicillin-clavulanate with other antibiotics (n=17; OR 0.89; 95% CI 0.76 to 1.04). Similarly, evidence of difference in clinical failure between amoxicillin and other antibiotics was unclear and unable to rule out clinically important benefits or harms (n=8; OR 0.76; 95% CI 0.55 to 1.06, where 1 favours amoxicillin-clavulanate). Sixty-three per cent and 29% of amoxicillin and amoxicillin-clavulanate studies, respectively, had low risk of bias according to the Cochrane risk of bias tool for randomised trials.ConclusionsCurrent evidence is unclear as to whether amoxicillin or amoxicillin-clavulanate differs from other antibiotics, or from each other, in the treatment of community-acquired pneumonia, owing to the small number of trials and substantial heterogeneity in comparators used across study settings.Prospero registration numberCRD42024568554.