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Background Cariprazine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Aim This study aimed to evaluate the effects of erythromycin, a moderate cytochrome P450 (CYP)3A4 inhibitor, on the pharmacokinetics of cariprazine in male patients with schizophrenia, and to assess the influence of CYP2D6 phenotypes on cariprazine metabolism. Methods Forty-two patients received oral doses of 1.5 mg cariprazine alone for 28 days (to reach steady state), followed by a co-administration of cariprazine 1.5 mg daily with erythromycin 500 mg twice daily (BID) and Enterol 250 mg BID for 21 days, followed by a 14-day post-treatment period. Blood samples were collected at predefined time points and analysed for cariprazine, its two active metabolites: desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), and erythromycin using validated high performance liquid chromatography-tandem mass spectrometry methods. CYP2D6 phenotypes were determined by genotyping. The pharmacokinetic parameters were calculated using non-compartmental analysis. Results Erythromycin increased the area under the curve (AUC τ ) and peak concentration ( C max ) of Total cariprazine (cariprazine + DCAR + DDCAR) by about 40–50% but did not affect the time to peak concentration ( T max ). The CYP2D6 phenotypes had no substantial effect on the pharmacokinetics of cariprazine and its metabolites, either alone or in combination with erythromycin. Cariprazine was well tolerated and safe. Conclusion The findings suggest that co-administration of cariprazine with moderate CYP3A4 inhibitors may require dose adjustment or monitoring; however, pharmacogenetic testing for CYP2D6 is not necessary for optimising cariprazine therapy. Trial Registration Trial registration number (EudraCT Number): 2018-003721-28. Date of registration: 21-SEP-2018.

Recent demonstrations that long-term macrolide therapy can prevent exacerbations in chronic airways diseases have led to a dramatic increase in their use. However, little is known about the wider, potentially adverse impacts of these treatments. Substantial disruption of the upper airway commensal microbiota might reduce its contribution to host defense and local immune regulation, while increases in macrolide resistance carriage would represent a serious public health concern. Using samples from a randomized controlled trial, we show that low-dose erythromycin given over 48 weeks influences the composition of the oropharyngeal commensal microbiota. We report that macrolide therapy is associated with significant changes in the relative abundances of members of the Actinomyces genus and with significant increases in the carriage of transmissible macrolide resistance. Determining the clinical significance of these changes, relative to treatment benefit, now represents a research priority. Long-term macrolide therapy reduces rates of pulmonary exacerbation in bronchiectasis. However, little is known about the potential for macrolide therapy to alter the composition and function of the oropharyngeal commensal microbiota or to increase the carriage of transmissible antimicrobial resistance. We assessed the effect of long-term erythromycin on oropharyngeal microbiota composition and the carriage of transmissible macrolide resistance genes in 84 adults with bronchiectasis, enrolled in the Bronchiectasis and Low-dose Erythromycin Study (BLESS) 48-week placebo-controlled trial of twice-daily erythromycin ethylsuccinate (400 mg). Oropharyngeal microbiota composition and macrolide resistance gene carriage were determined by 16S rRNA gene amplicon sequencing and quantitative PCR, respectively. Long-term erythromycin treatment was associated with a significant increase in the relative abundance of oropharyngeal Haemophilus parainfluenzae ( P = 0.041) and with significant decreases in the relative abundances of Streptococcus pseudopneumoniae ( P = 0.024) and Actinomyces odontolyticus ( P = 0.027). Validation of the sequencing results by quantitative PCR confirmed a significant decrease in the abundance of Actinomyces spp. ( P = 0.046). Erythromycin treatment did not result in a significant increase in the number of subjects who carried erm (A), erm (B), erm (C), erm (F), mef (A/E), and msrA macrolide resistance genes. However, the abundance of erm (B) and mef (A/E) gene copies within carriers who had received erythromycin increased significantly ( P < 0.05). Our findings indicate that changes in oropharyngeal microbiota composition resulting from long-term erythromycin treatment are modest and are limited to a discrete group of taxa. Associated increases in levels of transmissible antibiotic resistance genes within the oropharyngeal microbiota highlight the potential for this microbial system to act as a reservoir for resistance. IMPORTANCE Recent demonstrations that long-term macrolide therapy can prevent exacerbations in chronic airways diseases have led to a dramatic increase in their use. However, little is known about the wider, potentially adverse impacts of these treatments. Substantial disruption of the upper airway commensal microbiota might reduce its contribution to host defense and local immune regulation, while increases in macrolide resistance carriage would represent a serious public health concern. Using samples from a randomized controlled trial, we show that low-dose erythromycin given over 48 weeks influences the composition of the oropharyngeal commensal microbiota. We report that macrolide therapy is associated with significant changes in the relative abundances of members of the Actinomyces genus and with significant increases in the carriage of transmissible macrolide resistance. Determining the clinical significance of these changes, relative to treatment benefit, now represents a research priority.

The ORACLE II trial compared the use of erythromycin and/or amoxicillin–clavulanate (co-amoxiclav) with that of placebo for women in spontaneous preterm labour and intact membranes, without overt signs of clinical infection, by use of a factorial randomised design. The aim of the present study—the ORACLE Children Study II—was to determine the long-term effects on children after exposure to antibiotics in this clinical situation. We assessed children at age 7 years born to the 4221 women who had completed the ORACLE II study and who were eligible for follow-up with a structured parental questionnaire to assess the child's health status. Functional impairment was defined as the presence of any level of functional impairment (severe, moderate, or mild) derived from the mark III Multi-Attribute Health Status classification system. Educational outcomes were assessed with national curriculum test results for children resident in England. Outcome was determined for 3196 (71%) eligible children. Overall, a greater proportion of children whose mothers had been prescribed erythromycin, with or without co-amoxiclav, had any functional impairment than did those whose mothers had received no erythromycin (658 [42·3%] of 1554 children vs 574 [38·3%] of 1498; odds ratio 1·18, 95% CI 1·02–1·37). Co-amoxiclav (with or without erythromycin) had no effect on the proportion of children with any functional impairment, compared with receipt of no co-amoxiclav (624 [40·7%] of 1523 vs 608 [40·0%] of 1520; 1·03, 0·89–1·19). No effects were seen with either antibiotic on the number of deaths, other medical conditions, behavioural patterns, or educational attainment. However, more children whose mothers had received erythromycin or co-amoxiclav developed cerebral palsy than did those born to mothers who received no erythromycin or no co-amoxiclav, respectively (erythromycin: 53 [3·3%] of 1611 vs 27 [1·7%] of 1562, 1·93, 1·21–3·09; co-amoxiclav: 50 [3·2%] of 1587 vs 30 [1·9%] of 1586, 1·69, 1·07–2·67). The number needed to harm with erythromycin was 64 (95% CI 37–209) and with co-amoxiclav 79 (42–591). The prescription of erythromycin for women in spontaneous preterm labour with intact membranes was associated with an increase in functional impairment among their children at 7 years of age. The risk of cerebral palsy was increased by either antibiotic, although the overall risk of this condition was low. UK Medical Research Council.

This is a protocol for PPROM-AZM Study, phase II, nonblinded, randomized controlled trial. Bronchopulmonary dysplasia (BPD) at a postmenstrual age of 36 weeks (BPD 36 ) is often observed in infants with preterm premature rupture of the membranes (pPROM). A regimen of ampicillin (ABPC) intravenous infusion for 2 days and subsequent amoxicillin (AMPC) oral administration for 5 days plus erythromycin (EM) intravenous infusion for 2 days followed by EM oral administration for 5 days is standard treatment for pPROM. However, the effect on the prevention of moderate/severe BPD 36 using the standard treatment has not been confirmed. Recently, it is reported that ampicillin/sulbactam (ABPC/SBT) plus azithromycin (AZM) was effective for the prevention of moderate/severe BPD 36 in pPROM patients with amniotic infection of Ureaplasma species. Therefore, our aim is to evaluate the occurrence rate of the composite outcome of “incidence rate of either moderate/severe BPD 36 or intrauterine fetal death, and infantile death at or less than 36 weeks 0 days” comparing subjects to receive ABPC/SBT for 14 days plus AZM for 14 days (intervention group) and those to receive ABPC/SBT for 14 days plus EM for 14 days (control group), in a total of 100 subjects (women with pPROM occurring at 22–27 weeks of gestation) in Japan. The recruit of subjects was started on April 2022, and collection in on-going. We also investigate the association between the detection of Ureaplasma species and occurrence of BPD 36 . In addition, information on any adverse events for the mother and fetus and serious adverse events for infants are collected during the observation period. We allocate patients at a rate of 1:1 considering two stratification factors: onset of pPROM (22–23 or 24–27 weeks) and presence/absence of a hospital policy for early neonatal administration of caffeine. Trial registration: The trial number in the Japan Registry of Clinical Trials is jRCTs031210631 .

Introduction: Although long-term macrolide antibiotics could reduce the recurrent exacerbation of chronic obstructive pulmonary disease (COPD), the side effect of bacterial resistance and the impact on the microbiota remain concerning. We investigated the influence of long-term erythromycin treatment on the airway and gut microbiota in mice with emphysema and patients with COPD. Methods: We conducted 16S rRNA gene sequencing to explore the effect of erythromycin treatment on the lung and gut microbiota in mice with emphysema. Liquid chromatography-mass spectrometry was used for lung metabolomics. A randomized controlled trial was performed to investigate the effect of 48-week erythromycin treatment on the airway and gut microbiota in COPD patients. Results: The mouse lung and gut microbiota were disrupted after cigarette smoke exposure. Erythromycin treatment depleted harmful bacteria and altered lung metabolism. Erythromycin treatment did not alter airway or gut microbial diversity in COPD patients. It reduced the abundance of pathogens, such as Burkholderia, in the airway of COPD patients and increased levels of symbiotic bacteria, such as Prevotella and Veillonella. The proportions of Blautia, Ruminococcus, and Lachnospiraceae in the gut were increased in COPD patients after erythromycin treatment. The time to the first exacerbation following treatment was significantly longer in the erythromycin treatment group than in the COPD group. Conclusion: Long-term erythromycin treatment reduces airway and gut microbe abundance in COPD patients but does not affect microbial diversity and restores microbiota balance in COPD patients by reducing the abundance of pathogenic bacteria.

This study aims to compare real-world clinical response, safety, and institutional medication efficiency of intravenous (IV) azithromycin (AZI) versus erythromycin lactobionate (ERY) in hospitalized children with pneumonia (MPP). A retrospective cohort of 1,049 children with PCR- or serology-confirmed MPP was assembled (AZI: = 672; ERY: = 377). Propensity scores were estimated using prespecified baseline confounders (sex, age, severity phenotype, concomitant antibacterial agents, antiviral co-treatment). A 1:1 nearest-neighbor propensity score matching (PSM) without replacement cohort was built (364 matched pairs per arm). The primary endpoint was a three-level composite ordinal outcome (cure, improvement, ineffective) hierarchically assigned at 72 ± 12 h after IV macrolide initiation, without assuming that missing domains imply success. Two sensitivity cohorts tested missingness assumptions. Secondary endpoints included LOS, macrolide duration, and corticosteroid escalation, interpreted as adaptive process nodes. Sparse safety used bias-reduced likelihood inference. Institutional drug efficiency was evaluated by decomposing macrolide costs into dispensed, consumed, and wastage-related avoidable cost signals. Before matching, ordinal response distributions differed modestly ( = 0.040). After PSM, composite ordinal outcomes were similar (paired ordinal = 0.599), with comparable cure rates (33.8% vs. 32.7%). A treatment × age interaction signal was observed ( _interaction=0.008). In smaller strata (<80 per arm), ORs for a higher ordinal grade with ERY vs. AZI were 0.75 (<8 years; = 0.096) and 2.19 (≥8 years; = 0.029). In the adjusted full cohort, ERY showed higher odds of mostly mild adverse events (adjusted OR 6.52, = 0.006), driven by skin reactions (adjusted OR 17.90, = 0.021) with wide CIs from sparse precision. Institutional macrolide costs were substantially higher with ERY (both < 0.001). Duration was longer with ERY ( < 0.001), while LOS and escalation rates were similar post-match. IV AZI and IV ERY showed comparable overall clinical response in hospitalized pediatric MPP. The age interaction is a response-heterogeneity signal requiring confirmation, not causal proof of efficacy reversal. ERY carried higher odds of mostly mild adverse events, longer duration, and greater institutional macrolide cost burden. These results support future work on resistance-informed, sequence-aware, and child-appropriate formulation stewardship to improve interpretability, safety precision, and institutional antibiotic sustainability.

Macrolides and ketolides comprise a family of clinically important antibiotics that inhibit protein synthesis by binding within the exit tunnel of the bacterial ribosome. While these antibiotics are known to interrupt translation at specific sequence motifs, with ketolides predominantly stalling at Arg/Lys-X-Arg/Lys motifs and macrolides displaying a broader specificity, a structural basis for their context-specific action has been lacking. Here, we present structures of ribosomes arrested during the synthesis of an Arg-Leu-Arg sequence by the macrolide erythromycin (ERY) and the ketolide telithromycin (TEL). Together with deep mutagenesis and molecular dynamics simulations, the structures reveal how ERY and TEL interplay with the Arg-Leu-Arg motif to induce translational arrest and illuminate the basis for the less stringent sequence-specific action of ERY over TEL. Because programmed stalling at the Arg/Lys-X-Arg/Lys motifs is used to activate expression of antibiotic resistance genes, our study also provides important insights for future development of improved macrolide antibiotics. Macrolides and ketolides antibiotics selectively interfere with the translation of a specific subset of proteins. Here the authors show how the macrolide erythromycin and the ketolide telithromycin interplay with the nascent polypeptide chain to arrest translation.

Antibiotics are used to fight pathogens but also target commensal bacteria, disturbing the composition of gut microbiota and causing dysbiosis and disease 1 . Despite this well-known collateral damage, the activity spectrum of different antibiotic classes on gut bacteria remains poorly characterized. Here we characterize further 144 antibiotics from a previous screen of more than 1,000 drugs on 38 representative human gut microbiome species 2 . Antibiotic classes exhibited distinct inhibition spectra, including generation dependence for quinolones and phylogeny independence for β-lactams. Macrolides and tetracyclines, both prototypic bacteriostatic protein synthesis inhibitors, inhibited nearly all commensals tested but also killed several species. Killed bacteria were more readily eliminated from in vitro communities than those inhibited. This species-specific killing activity challenges the long-standing distinction between bactericidal and bacteriostatic antibiotic classes and provides a possible explanation for the strong effect of macrolides on animal 3 – 5 and human 6 , 7 gut microbiomes. To mitigate this collateral damage of macrolides and tetracyclines, we screened for drugs that specifically antagonized the antibiotic activity against abundant Bacteroides species but not against relevant pathogens. Such antidotes selectively protected Bacteroides species from erythromycin treatment in human-stool-derived communities and gnotobiotic mice. These findings illluminate the activity spectra of antibiotics in commensal bacteria and suggest strategies to circumvent their adverse effects on the gut microbiota. This study systematically profiles the activity of several classes of antibiotics on gut commensal bacteria and identifies drugs that mitigate their collateral damage on commensal bacteria without compromising their efficacy against pathogens.

Purpose Netupitant is a new highly selective neurokinin-1 receptor antagonist being studied for the prevention of nausea and vomiting in patients undergoing chemotherapy. In vitro studies suggest that netupitant inhibits the cytochrome P-450 isoenzyme 3A4 (CYP3A4). Because netupitant may be used with a variety of drugs, which may be substrates of CYP3A4, two studies were designed to establish the potential risk for drug–drug interaction with three different CYP3A4 substrates: midazolam, erythromycin, and dexamethasone. Methods Both trials were three-period crossover studies performed in healthy subjects. In the first study, 20 subjects received netupitant and either midazolam or erythromycin. In the second study, 25 subjects received netupitant and dexamethasone. Serial blood samples were collected over the course of the two studies and pharmacokinetic parameters were determined for all analytes. Results Netupitant, by inhibiting the CYP3A4, increased the C max and AUC inf of midazolam by 40 and 144 %, respectively, and the C max and AUC inf of erythromycin by 30 %. Netupitant was shown to increase the exposure to dexamethasone in a dose-dependent manner with the mean increase in AUC and C max by 72 and 11 %, respectively, on day 1 and by 138 and 75 %, respectively, on day 4 when co-administered with 300 mg of netupitant. Conclusions The results of these studies suggest that netupitant is a moderate inhibitor of CYP3A4 and therefore, co-administration with drugs that are substrates of CYP3A4 may require dose adjustments. Treatments were well tolerated in both studies.

We investigated the efficacy and cost-effectiveness of five antimicrobial regimens for mild to moderate facial acne and whether propionibacterial antibiotic resistance affects treatment response. In this randomised, observer-masked trial, 649 community participants were allocated one of five antibacterial regimens. Primary outcomes were patients' self-assessed improvement and reduction in inflamed lesions at 18 weeks. Analyses were by intention to treat. Moderate or greater improvement at 18 weeks was reported in 72 (55%) of 131 participants assigned oral oxytetracycline plus topical placebo, 70 (54%) of 130 assigned oral minocycline plus topical placebo, 78 (60%) of 130 assigned topical benzoyl peroxide plus oral placebo, 84 (66%) of 127 assigned topical erythromycin and benzoyl peroxide in a combined formulation plus oral placebo, and 82 (63%) of 131 assigned topical erythromycin and benzoyl peroxide separately plus oral placebo. Most improvement occurred in the first 6 weeks. Treatment differences for the proportion of people with at least moderate improvement were: minocycline versus oxytetracycline –1·2% (unadjusted 95% CI –13·3 to 10·9); combined erythromycin and benzoyl peroxide versus oxytetracycline 11·1% (–0·7 to 22·9) and versus minocycline 12·3% (0·4 to 24·2); erythromycin and benzoyl peroxide separately versus combined formulation –3·5% (–15·2 to 8·2); benzoyl peroxide versus oxytetracycline 5·0% (–7·0 to 17·0), versus minocycline 6·2% (–5·8 to 18·2), and versus combined formulation –6·1% (–17·9 to 5·7). Benzoyl peroxide was the most cost-effective treatment. Efficacy of both tetracyclines was reduced by pre-existing tetracycline resistance. Topical benzoyl peroxide and benzoyl peroxide/erythromycin combinations are similar in efficacy to oral oxytetracycline and minocycline and are not affected by propionibacterial antibiotic resistance.