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Ribosome hibernation is a commonly used strategy that protects ribosomes under unfavorable conditions and regulates developmental processes. Multiple ribosome-hibernation factors have been identified in all domains of life, but due to their structural diversity and the lack of a common inactivation mechanism, it is currently unknown how many different hibernation factors exist. Here, we show that the YqjD/ElaB/YgaM paralogs, initially discovered as membrane-bound ribosome binding proteins in E. coli, constitute an abundant class of ribosome-hibernating proteins, which are conserved across all proteobacteria and some other bacterial phyla. Our data demonstrate that they inhibit in vitro protein synthesis by interacting with the 50S ribosomal subunit. In vivo cross-linking combined with mass spectrometry revealed their specific interactions with proteins surrounding the ribosomal tunnel exit and even their penetration into the ribosomal tunnel. Thus, YqjD/ElaB/YgaM inhibit translation by blocking the ribosomal tunnel and thus mimic the activity of antimicrobial peptides and macrolide antibiotics.

Mycoplasma pneumoniae pneumonia (MPP) is the predominant community-acquired pneumonia (CAP) in children aged 5 years or older. In recent decades, the annual increase in drug resistance rates of macrolide antibiotics, particularly azithromycin (AZ), has led to complex clinical treatment strategies and substantial healthcare costs associated with MPP. Chinese medicine injections (CMIs), recognized as an effective supplementary therapy, are acknowledged by clinicians in China. It is necessary to explore the efficacy of azithromycin in combination with CMIs. Methods: Randomized controlled trials (RCTs) evaluating azithromycin in combination with seven types of CMIs for MPP in children were identified based on inclusion criteria and assessed using the revised Cochrane risk of bias tool (RoB 2.0). R 4.3.1 and STATA 15.0 were employed to generate ranking probabilities and perform network meta-analysis. Competing interventions were ranked using the surface under the cumulative ranking (SUCRA) probabilities. Results: A comprehensive analysis was performed on 155 RCTs involving 15,014 patients and 8 therapeutic strategies within this Bayesian network meta-analysis (BNMA). The results indicated that AZ combined with seven types of CMIs was more effective than azithromycin alone in overall outcomes. Notably, azithromycin combined with Chuanhuning injection (AZ + CHN) achieved the highest ranking in improving the clinical effectiveness rate (SUCRA, 80.89%); regarding secondary outcome measures, azithromycin combined with Yanhuning injection (AZ + YHN) had the highest probability of improving four different outcomes: disappearance time of cough (SUCRA, 80.01%), disappearance time of pulmonary rale (SUCRA, 87.77%), disappearance time of fever (SUCRA, 95.70%), and disappearance time of pulmonary shadows in X -ray (SUCRA, 97.34%); furthermore, azithromycin combined with Qingkailing injection (AZ + QKL) was more likely to reduce average hospitalization time (SUCRA, 94.60%). Conclusion: This study highlights the potential benefits of seven types of Chinese medicine injections as adjunctive therapy for Mycoplasma pneumoniae pneumonia in children. However, further support and validation of these findings are needed through high-quality randomized controlled trials with larger sample sizes and double-blind designs. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails/. [ABSTRACT FROM AUTHOR]

Sore throat represents one of the main causes of antibiotic overprescription in children. Its management is still a matter of debate, with countries considering streptococcal pharyngotonsillitis a benign and self-limiting condition and others advocating for its antibiotic treatment to prevent suppurative complications and acute rheumatic fever. Italian paediatricians frequently prescribe antibiotics on a clinical basis regardless of microbiological results. Moreover, broad-spectrum antibiotics are inappropriately prescribed for this condition. In this regard, an intersociety consensus conference was issued to promote the judicious use of antibiotic therapy in paediatric outpatient settings. A systematic review of the literature was performed, and updated recommendations were developed according to the GRADE methodology. Antibiotic treatment with amoxicillin (50 mg/kg/day) for 10 days is recommended in all children with proven streptococcal pharyngitis. Benzathine-penicillin could be prescribed in children with impaired intestinal absorption or inability to tolerate enteral intake and in those at high risk of suppurative complications with low compliance to oral therapy. In children with suspected amoxicillin allergy, third-generation cefalosporins for five days are recommended in low-risk patients, and macrolides are recommended in high-risk ones. Candidates for tonsillectomy due to recurrent pharyngitis could be treated with amoxicillin-clavulanic acid, clindamycin, or combined therapy with amoxicillin plus rifampicin for four days, in an attempt to avoid surgery. [ABSTRACT FROM AUTHOR]

Mycoplasma synoviae (MS) infection is a serious threat to poultry industry in China. Tilmicosin is a semisynthetic macrolide antibiotic used only in animals and has shown potential efficacy against MS, but there were no reported articles concerning the pharmacokinetics/pharmacodynamics (PK/PD) interactions of tilmicosin against MS in vitro and vivo. This study aimed to assess the antibacterial activity of tilmicosin against MS in vitro and in vivo using PK/PD model to provide maximal efficacy. The minimum inhibitory concentration (MIC) and killing rates of different drug concentrations were measured using the microdilution method in vitro. Then, tilmicosin was administered orally to the MS‐infected chickens at doses of 7.5 and 60 mg/kg, and the PK parameters of tilmicosin in joint dialysates were determined using high‐pressure liquid chromatography/tandem mass spectrometry (HPLC‐MS/MS) combined with the microdialysis technique. The antibacterial effect (△E) was calculated when the infected chickens were administered a single oral dose of tilmicosin at 4, 7.5, 15, 30, and 60 mg/kg b.w. The PK and PD data were fitted using the Sigmoid Emax model to evaluate the PK/PD interactions of tilmicosin against MS. The bactericidal activity of tilmicosin against MS was concentration dependent. Furthermore, the PK/PD index of AUC0–72h/MIC exhibited the most optimal fitting results (R2 =.98). The MS load decreased by 1, 2, and 3 Log10 CFU/mL, then AUC/MIC was determined as 13.99, 20.53, and 28.23 h, respectively, and the bactericidal effect can be achieved when the dose of MS‐infected chickens is at 31.64 mg/kg b.w. The findings of this study hold significant implications for optimizing the treatment regimen for MS infection. [ABSTRACT FROM AUTHOR]

Tylosin (TYL) is a macrolide antibiotic widely used in animal husbandry. Due to associated health risks, there is a demand for sensitive methods for mass screening of TYL in products of animal origin. This article describes the development of lateral flow immunoassays (LFIAs) for TYL detection using direct (anti-TYL antibodies conjugated with nanoparticles) and indirect antibody labeling (anti-species antibodies conjugated with nanoparticles and combined with native anti-TYL antibodies). The choice of LFIA conditions, such as concentrations of hapten–protein conjugates, specific antibodies, and gold nanoparticle (GNP) conjugates with antibodies, as well as incubation time of reagents and the concentration of detergent in the sample buffer, is presented. The achieved limits of TYL detection using LFIAs with indirect labeling were 0.8 ng/mL (visual) and 0.07 ng/mL (instrumental), compared to 4 ng/mL (visual) and 0.4 ng/mL (instrumental) for the case of direct labeling. The sensitivity of the LFIA using the indirect format was up to seven times higher, allowing the determination of the target analyte at low concentrations. TYL detection in ground meat using LFIA with indirect antibody labeling ranged from 76–119%. [ABSTRACT FROM AUTHOR]

Background Effective management of drug–food interactions is crucial for enhancing antibiotics' efficacy/safety. Adhering to PRISMA guidelines, we conducted a systematic review to assess the impact of dietary interventions on the bioavailability of 15 macrolides and 10 tetracyclines. Methods We included studies examining the influence of food, beverages, antacids, and mineral supplements on the pharmacokinetic parameters of orally administered macrolides and tetracyclines. We searched Medline (via PubMed), Embase and Cochrane Library databases up to December 2022. Risk of bias was assessed using Cochrane and NIH tools. Quantitative analyses were conducted if two or more comparable food-effect studies were available; otherwise, a qualitative summary was provided. Results We included 120 studies from 97 reports. Meta-analyses were conducted for 8 macrolides and 4 tetracyclines, with qualitative synthesis for 10 and 9, respectively. About 64% of the studies were open-label, crossover designs. Our assessment found that 37% of the studies had a high risk of bias, while only 6% had low risk. Food significantly affected 10 of 13 macrolides (77%) and 6 of 7 tetracyclines (86%). High positive effects on bioavailability were seen with extended-release azithromycin and clarithromycin, and erythromycin estolate. High negative impacts were observed with erythromycin propionate and stearate, azithromycin capsules, demeclocycline and omadacycline. Antacids and mineral supplements significantly decreased tetracyclines absorption. Milk and grapefruit juice showed variable impacts on absorption. Discussion Interactions depend on antibiotics' physicochemical characteristics, intervention type, drug formulation and potential patient factors. The quality of evidence was rated low due to outdated studies, methodological diversity and unequal data availability. [ABSTRACT FROM AUTHOR]

Context.--: Folate receptor-α (FRα, encoded by the FOLR1 gene) is overexpressed in several solid tumor types, including epithelial ovarian cancer (EOC), making it an attractive biomarker and target for FRα-based therapy in ovarian cancer. Objective.--: To describe the development, analytic verification, and clinical performance of the VENTANA FOLR1 Assay (Ventana Medical Systems Inc) in EOC. Design.--: We used industry standard studies to establish the analytic verification of the VENTANA FOLR1 Assay. Furthermore, the VENTANA FOLR1 Assay was used in the ImmunoGen Inc-sponsored SORAYA study to select patients for treatment with mirvetuximab soravtansine (MIRV) in platinum-resistant EOC. Results.--: The VENTANA FOLR1 Assay is highly reproducible, demonstrated by a greater than 98% overall percent agreement (OPA) for repeatability and intermediate precision studies, greater than 93% OPA for interreader and greater than 96% for intrareader studies, and greater than 90% OPA across all observations in the interlaboratory reproducibility study. The performance of the VENTANA FOLR1 Assay in the SORAYA study was evaluated by the overall staining acceptability rate, which was calculated using the number of patient specimens that were tested with the VENTANA FOLR1 Assay that had an evaluable result. In the SORAYA trial, data in patients who received MIRV demonstrated clinically meaningful efficacy, and the overall staining acceptability rate of the assay was 98.4%, demonstrating that the VENTANA FOLR1 Assay is safe and effective for selecting patients who may benefit from MIRV. Together, these data showed that the assay is highly reliable, consistently producing evaluable results in the clinical setting. Conclusions.--: The VENTANA FOLR1 Assay is a robust and reproducible assay for detecting FRα expression and identifying a patient population that derived clinically meaningful benefit from MIRV in the SORAYA study. [ABSTRACT FROM AUTHOR]

Background: Acute rhinosinusitis (ARS) is one of the most encountered conditions in primary care and otolaryngology clinics. However, little is known about how antibiotic prescription practices following a diagnosis of ARS compare to guidelines set forth by the American Academy of Otolaryngology in 2015. Objective: To investigate the epidemiology of ARS and the corresponding antibiotic prescribing practices by physicians and compare to published guidelines. Methods: Using the TriNetX Live database, we identified all patients diagnosed with ARS using the ICD10 code J01 between April 2015 and December 2022 across the state of Tennessee. After investigating the demographics of this cohort, we compared the first prescribed antibiotic within one day of ARS diagnosis to published guidelines. Antibiotics were grouped into their respective classes. Results: Of 81 310 patients diagnosed with ARS identified in the specified time frame, 66% were Female, 49% were African American, 44% were White, and the mean age was 47 ± 20 years. The six most common initial antibiotics prescribed for ARS were erythromycins/macrolides [14 609 (25.8%)], amoxicillin/clavulanate [14 322 (25.3%)], amoxicillin [9300 (16.4%)], third generation cephalosporins [7733 (13.6%)], quinolones [3648 (6.4%)] and tetracyclines [2235 (3.9%)]. Of this cohort, 56 719 patients (69.8%) of patients were prescribed an antibiotic within one day of diagnosis. Conclusion: Despite published guidelines recommending amoxicillin with or without clavulanic acid as first-line treatment for ARS, only 42.2% of prescribed antibiotics followed this guideline in our cohort. While accounting for patients with penicillin allergy, the second-most represented antibiotics were erythromycins/macrolides, which are specifically recommended against due to high rates of S. Pneumonia e resistance. Our results suggest that further investigation into the causes of erythromycin/macrolide prescriptions as first line treatment for ARS and practices at other institutions should be conducted. In addition, building awareness around published ARS guidelines for physicians may be useful in improving antibiotic stewardship in treatment of ARS. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the molecular epidemiological characteristics of hypervirulent Klebsiella pneumoniae (hvKp) in Yakeshi City, Hulunbuir, China, analyze the resistance of hvKp to commonly used antibiotics, explore independent risk factors for hvKp infection, and provide a research basis for anti-infection treatment. Methods: In total, 519 strains of K. pneumoniae, identified by the Inner Mongolia Forestry General Hospital from January 2020 to December 2022, were collected, and high-viscosity (HMV-Kp) and non-HMV-Kp strains were differentiated using string test. PCR and agarose gel electrophoresis were used to detect the rmpA, rmpA2, and iutA genes to identify hvKp strains. Sixty strains of hvKp were randomly selected for capsular serotyping by PCR and agarose gel electrophoresis. Sanger sequencing was used to sequence the housekeeping genes of 60 hvKp strains and perform ST analysis. A minimum spanning tree was drawn using capsule serotyping and ST typing. Significant differences in resistance to commonly used antibiotics between classical K. pneumoniae (cKp) and hvKp were analyzed by using the chi-squared test. Finally, the risk factors for hvKp infection were analyzed through binary logistic regression. Results: The HMV-Kp detection rate was 39.69%, versus 37.19% for hvKp. HMV-Kp accounted for 84.97% of all hvKp isolates. The hvKp detection rate was highest in the general surgery department. In capsule serotyping, K1 was the main subtype, accounting for 63.33% of all isolates (38/60), followed by K2 (16.67%, 10/60). Through ST typing, 18 subtypes were detected, with ST23 being the most common (50.00%), followed by ST86 (8.33%), and the remaining subtypes were scattered throughout the distribution. Compared with cKp, hvKp strains exhibited higher sensitivity to commonly used antibiotics, excluding furantoin. Male gender (odds ratio (OR) = 1.977), liver abscess (OR = 15.019), and the use of macrolide antibiotics in the past 3 months (OR = 5.473) were independent risk factors for hvKp infection. Conclusions: The hvKp detection rate in the local area was 37.19%, and a strong correlation was noted between hvKp and HMV-Kp strains. K1-ST23 was the dominant subtype in this study. Compared with cKp, hvKp strains were more sensitive to commonly used antibiotics. Male gender, liver abscess, suppuration or infection of other tissues and organs, and recent macrolide antibiotic use were risk factors for hvKp infection. [ABSTRACT FROM AUTHOR]

Background: A rebound in antibiotic consumption has been observed in the European community at the end of the COVID-19 pandemic. Here we evaluate the extent of this increase, when it exactly occurred, and how the seasonality in antibiotic use changed during the late-pandemic period. Methods: Data on community antibiotic consumption were available from the European Surveillance of Antimicrobial Consumption Network for 28 European countries between 2015 and 2022. Antibiotic consumption was expressed as defined daily doses per 1000 inhabitants per day (DID). The evolution in antibiotic use was investigated using non-linear changepoint mixed models for quarterly and yearly data. Results: An increase in overall antibiotic consumption was found in Europe between 2021 and 2022, mainly due to an increase in the consumption of penicillins, macrolides, lincosamides and streptogramins, and other β-lactam antibacterials. The analysis of quarterly data estimated a gradual increase in overall antibiotic consumption of 0.55 DID per quarter, as of the second quarter of 2020 and a decrease in seasonal variation of 1.64 DID between the first and second quarter of 2020. The changepoint analysis of yearly data estimated an increase of 3.33 DID in overall antibiotic consumption between 2021 and 2022. Conclusions: A gradual but significant rebound in the use of antibiotics was found in Europe, along with a decrease in its seasonal variation. The rapid rise in antibiotic consumption above pre-pandemic levels in several countries underlines the importance of continued antimicrobial stewardship. [ABSTRACT FROM AUTHOR]

The Yamaguchi reagent, based on 2,4,6-trichlorobenzoyl chloride (TCBC) and 4-dimethylaminopyridine (DMAP), is an efficient tool for conducting the intermolecular (esterification) reaction between an acid and an alcohol in the presence of a suitable base (Et3N or iPr2NEt) and solvent (THF, DCM, or toluene). The Yamaguchi protocol is renowned for its ability to efficiently produce a diverse array of functionalized esters, promoting high yields, regioselectivity, and easy handling under mild conditions with short reaction times. Here, the recent utilization of the Yamaguchi reagent was reviewed in the synthesis of various natural products such as macrolides, terpenoids, polyketides, peptides, and metabolites. [ABSTRACT FROM AUTHOR]

Mycoplasma pneumoniae pneumonia (MPP) is the predominant communityacquired pneumonia (CAP) in children aged 5 years or older. In recent decades, the annual increase in drug resistance rates of macrolide antibiotics, particularly azithromycin (AZ), has led to complex clinical treatment strategies and substantial healthcare costs associated with MPP. Chinese medicine injections (CMIs), recognized as an effective supplementary therapy, are acknowledged by clinicians in China. It is necessary to explore the efficacy of azithromycin in combination with CMIs. Methods: Randomized controlled trials (RCTs) evaluating azithromycin in combination with seven types of CMIs for MPP in children were identified based on inclusion criteria and assessed using the revised Cochrane risk of bias tool (RoB 2.0). R 4.3.1 and STATA 15.0 were employed to generate ranking probabilities and perform network meta-analysis. Competing interventions were ranked using the surface under the cumulative ranking (SUCRA) probabilities. Results: A comprehensive analysis was performed on 155 RCTs involving 15,014 patients and 8 therapeutic strategies within this Bayesian network meta-analysis (BNMA). The results indicated that AZ combined with seven types of CMIs was more effective than azithromycin alone in overall outcomes. Notably, azithromycin combined with Chuanhuning injection (AZ + CHN) achieved the highest ranking in improving the clinical effectiveness rate (SUCRA, 80.89%); regarding secondary outcome measures, azithromycin combined with Yanhuning injection (AZ + YHN) had the highest probability of improving four different outcomes: disappearance time of cough (SUCRA, 80.01%), disappearance time of pulmonary rale (SUCRA, 87.77%), disappearance time of fever (SUCRA, 95.70%), and disappearance time of pulmonary shadows in X-ray (SUCRA, 97.34%); furthermore, azithromycin combined with Qingkailing injection (AZ + QKL) was more likely to reduce average hospitalization time (SUCRA, 94.60%). Conclusion: This study highlights the potential benefits of seven types of Chinese medicine injections as adjunctive therapy for Mycoplasma pneumoniae pneumonia in children. However, further support and validation of these findings are needed through high-quality randomized controlled trials with larger sample sizes and double-blind designs. [ABSTRACT FROM AUTHOR]

Asthma and cardiovascular disease (CVD) often co-exist. When a patient has both conditions, management requires an approach that addresses the unique challenges of each condition separately, while also considering their potential interactions. However, specific guidance on the management of asthma in patients with CVD and on the management of CVD in patients with asthma is still lacking. Nevertheless, health care providers need to adopt a comprehensive approach that includes both respiratory and CVD health. The management of CVD in patients with asthma requires a delicate balance between controlling respiratory symptoms and minimising potential cardiovascular (CV) risks. In the absence of specific guidelines for the management of patients with both conditions, the most prudent approach would be to follow established guidelines for each condition independently. Careful selection of asthma medications is essential to avoid exacerbation of CV symptoms. In addition, optimal management of CV risk factors is essential. However, close monitoring of these patients is important as there is evidence that some asthma medications may have adverse effects on CVD and, conversely, that some CVD medications may worsen asthma symptoms. On the other hand, there is also increasing evidence of the potential beneficial effects of asthma medications on CVD and, conversely, that some CVD medications may reduce the severity of asthma symptoms. We aim to elucidate the potential risks and benefits associated with the use of asthma medications in patients with CVD, and the potential pulmonary risks and benefits for patients with asthma who are prescribed CVD medications. [ABSTRACT FROM AUTHOR]

Acute Generalized Exanthematous Pustulosis (AGEP) is a rare and severe cutaneous adverse reaction characterized by the abrupt onset of widespread sterile pustules on an erythematous base. This is associated with medications, including antiepileptic drugs, phenytoin, and antibiotics such as beta-lactams and macrolides. This is a rare case where a macrolide antibiotic is reported to induce AGEP in an epileptic patient who was on phenytoin therapy. The patient, at the age of 25, was taking phenytoin for the past two years to subside epileptic symptoms. In this period, he has never reported any complications related to AGEP. Including macrolide antibiotics in his prescription aggravated the symptoms of AGEP within a few days. The primary course of action involved immediate withdrawal of both the drugs i.e. phenytoin and macrolide antibiotic, and symptomatic treatment. [ABSTRACT FROM AUTHOR]

Microorganisms inhabiting hostile Arctic environments express a variety of functional phenotypes, some of clinical interest, such as haemolytic ability and antimicrobial resistance. We studied haemolytic bacterial isolates from Arctic habitats, assessing their minimum inhibitory concentration (MIC) against antimicrobials. We then performed whole genome sequencing and analysed them for features conferring antimicrobial resistance. MIC data showed that Micromonospora spp. belong to 33% non‐wild type (NWT) for erythromycin and penicillin and 22% NWT for tetracycline. Both Pseudomonas spp. belong to 43% NWT for nalidixic acid and streptomycin and 29% NWT for colistin. Finally, the Pedobacter isolate was in 80% NWT for antimicrobials tested. Whole‐genome sequencing analyses revealed that fluoroquinolones, tetracyclines, macrolides and penams were the most frequent drug classes against which genotypic resistance was found. Additionally, resistance genes to heavy metals and disinfectants were identified. Our research demonstrates the presence of antimicrobial resistance in bacteria from Arctic habitats and highlights the importance of conservation efforts in these environments, where anthropogenic influence is becoming more evident. Furthermore, our data suggest the possible presence of novel resistance mechanisms, which could pose a threat if the responsible genes are transferable between species or become widespread due to environmental stress and alterations brought about by climate change. [ABSTRACT FROM AUTHOR]

Background Over the years, reports have associated fluoroquinolones (FQ) with seizures. The incidence and whether FQ compared to non-epileptogenic antibiotic are associated with increased risk of seizures has yet to be examined. Methods A retrospective observational study of hospitalized patients treated with FQ (ofloxacin, ciprofloxacin, levofloxacin, moxifloxacin) or macrolides (MA: azithromycin or roxithromycin) between January 2009 and January 2021 in a large tertiary academic medical centre. The outcome was the occurrence of a seizure during treatment. The Naranjo scale was used to assess causality between FQ treatment and seizures. Comparative analysis was conducted using propensity score matching to correct for possible bias due to non-random selection, followed by inverse probability weighting (IPW) to estimate the difference in seizure risk between FQ and MA. Results Overall, 52 722 patients were treated with FQ during a total of 178 982 days. Mean age was 65 (±19) years and 47% were females. Thirty-three patients (0.06%) experienced a seizure, yielding an incidence of 1:5422 treatment days. Causality was deemed probable and possible among 9/33 and 24/33, respectively. The MA group composed of 8522 patients treated during 17 954 treatment days. Mean age was 65 (±21) years, 49% were females. Six (0.07%) patients experienced each a single seizure. IPW estimated OR for seizures among the FQ versus MA group was 1.44 (95%CI 0.59–3.5, P  = 0.42). Discussion The incidence of FQ associated seizures among hospitalized patients is low and the risk did not significantly exceed that under macrolides. Our results provide evidence for clinicians and decision-makers when balancing fluoroquinolones risks and benefits. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine the epidemiological characteristics of Helicobacter pylori (H. pylori) infection at the genotype level in patients presenting with dyspeptic complaints, and to show the distribution of virulence factors, importance of intrafamilial transmission, as well as the distribution of resistance to macrolide and quinolone antibiotics. Methods: The study comprised 110 patients with dyspeptic complaints who were admitted to our hospital between January 13, 2015, and December 31, 2016. Through histopathology, culture, and glmMpolymerase chain reaction (PCR) techniques, we detected H. pylori. The vacA, cagA, and cagE genes were determined in patients with positive PCR results were positive. Results: H. pylori strains and clinical results were not found to be significantly correlated in the study. Both genetic variants A2142G and A2143G were discovered to be present in the individuals. Eight patients had clarithromycin resistance (34.7%). All patients with a positive A2142G mutation and 55% of patients with a positive A2143G mutation were found to have clarithromycin resistance. Levofloxacin resistance was present in only one (4.3%) patient who could produce H. pylori in culture. Conclusion: Approximately 1/3 of the children with dyspeptic complaints were positive for H. pylori infection. The most common genotype was observed to be vacAs2. Even individuals with at least one of the genetic mutations A2142G and A2143G have the potential for antibiotic resistance. High resistance was found against clarithromycin in the standard triple therapy regimen used in children for treating H. pylori infection. [ABSTRACT FROM AUTHOR]

Epothilones are 16‐membered macrolides that act as microtubule‐targeting agents to tackle cancer. Many synthetic analogues have been investigated for their activity, yet often based on macrolide structures. A notable exception is Ixabepilone, an azalide whose metabolic stability and pharmacokinetics are significantly improved. Exploiting the amide‐triazole bioisosterism, in this work we report the synthesis of the first generation of epothilones lacking the macrolide or azalide structure, with the ester or amide linkage replaced by a triazole unit. Together with the synthesis of this new analogue, computational and biological evaluations have been performed too. [ABSTRACT FROM AUTHOR]

Simple Summary: The restoration of HLA-class-I expression in lung cancer cells may reverse immune evasion, enhance cytotoxic T-cell activity, and improve immune checkpoint inhibitors' therapeutic efficacy. In the current study, we provide experimental evidence that autophagy blockage either at the late stage (chloroquine and bafilomycin) or early stage of the autophagic process (ULK1 inhibitors and MAP1LC3A silencing) can up-regulate the expression of HLA-class-I molecules in the A549 and H1299 NSCLC cell lines and their CD133+ stem cells. This upregulation enhances the cytotoxic activity of activated CD8+ T-cells, in particular after pre-incubation with anti-PD-L1 monoclonal antibodies. The restoration of HLA-class-I-mediated antigen presentation with autophagy blockers in lung cancer is a promising avenue that urgently requires further exploration in clinical trials. Background/Objectives: Immune checkpoint inhibitors have an established role in non-small cell lung cancer (NSCLC) therapy. The loss of HLA-class-I expression allows cancer cell evasion from immune surveillance, disease progression, and failure of immunotherapy. The restoration of HLA-class-I expression may prove to be a game-changer in current immunotherapy strategies. Autophagic activity has been recently postulated to repress HLA-class-I expression in cancer cells. Methods: NSCLC cell lines (A549 and H1299) underwent late-stage (chloroquine and bafilomycin) and early-stage autophagy blockage (ULK1 inhibitors and MAP1LC3A silencing). The HLA-class-I expression was assessed with flow cytometry, a Western blot, and RT-PCR. NSCLC tissues were examined for MAP1LC3A and HLA-class-I expression using double immunohistochemistry. CD8+ T-cell cytotoxicity was examined in cancer cells pre-incubated with chloroquine and anti-PD-L1 monoclonal antibodies (Moabs); Results: A striking increase in HLA-class-I expression following incubation with chloroquine, bafilomycin, and IFNγ was noted in A549 and H1299 cancer cells, respectively. This effect was further confirmed in CD133+ cancer stem cells. HLA-class-I, β2-microglobulin, and TAP1 mRNA levels remained stable. Prolonged exposure to chloroquine further enhanced HLA-class-I expression. Similar results were noted following exposure to a ULK1 and a PIKfyve inhibitor. Permanent silencing of the MAP1LC3A gene resulted in enhanced HLA-class-I expression. In immunohistochemistry experiments, double LC3A+/HLA-class-I expression was seldom. Pre-incubation of H1299 cancer cells with chloroquine and anti-PD-L1 MoAbs increased the mean % of apoptotic/necrotic cells from 2.5% to 18.4%; Conclusions: Autophagy blockers acting either at late or early stages of the autophagic process may restore HLA-class-I-mediated antigen presentation, eventually leading to enhanced immunotherapy efficacy. [ABSTRACT FROM AUTHOR]

Previous studies evaluating the risk of spontaneous abortions following exposure to macrolides reported controversial results. The goal of the current study was to examine the risk for spontaneous abortions following exposure to macrolides during pregnancy. We conducted a population‐based retrospective cohort study by linking three computerized databases: Clalit Health Services drug dispensation database, Soroka Medical Center (SMC) birth database, and SMC hospitalizations database. Multivariate time‐varying Cox regressions were performed and adjusted for suspected confounders and known risk factors for spontaneous abortions. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated. A secondary analysis was performed to assess the association between exposure to macrolides in terms of the defined daily dose dispensed and spontaneous abortions. The study cohort included 65,457 pregnancies that ended at Soroka Medical Center between 2004 and 2009, of which 6508 (9.9%) resulted in a spontaneous abortion. A total of 825 (1.26%) pregnancies were exposed to macrolides during the exposure period. Exposure to macrolides was not associated with spontaneous abortions as a group (adjusted HR 1.00 95% CI 0.77‐1.31) or as specific medications. There was no evidence of a dose‐response relationship between exposure to macrolides and spontaneous abortions. In conclusion, this population‐based retrospective cohort study did not detect an increased risk for spontaneous abortion following exposure to macrolides during the first trimester of pregnancy. [ABSTRACT FROM AUTHOR]

Background: The strategies to control scabies in highly endemic populations include individual case/household management and mass drug administration (MDA). We used a decision-analytic model to compare ivermectin-based MDA and individual case/household management (referred to as "usual care") for control of scabies in Ethiopia at different prevalence thresholds for commencing MDA. Methods: A decision-analytic model was based on a repeated population survey conducted in Northern Ethiopia in 2018-2020, which aimed to evaluate the secondary impact of single-dose ivermectin MDA for the control of onchocerciasis on scabies prevalence. The model estimates the number of scabies cases and costs of two treatment strategies (MDA and usual care) based on their effectiveness, population size, scabies prevalence, compliance with MDA, medication cost, and other parameters. Results: In the base-case analysis with a population of 100,000 and scabies prevalence of 15%, the MDA strategy was both more effective and less costly than usual care. The probability of MDA being cost-effective at the current costeffectiveness threshold (equivalent to the cost of usual care) was 85%. One-way sensitivity analyses showed that the MDA strategy remained dominant (less costly and more effective) in 22 out of 26 scenarios. MDA was not cost-effective at scabies prevalence <10%, MDA effectiveness <85% and population size <5,000. An increase in the cost of ivermectin from 0 (donated) to 0.54 US$/dose resulted in a decrease in the probability of MDA being cost-effective from 85% to 17%. At 0.25 US$/dose, the MDA strategy was no longer cost-effective. Conclusions: The model provides robust estimates of the costs and outcomes of MDA and usual care and can be used by decision-makers for planning and implementing scabies control programmes. Results of our analysis suggest that single-dose ivermectin MDA is cost-effective in scabies control and can be initiated at a scabies prevalence >10%. [ABSTRACT FROM AUTHOR]

Background: Mycoplasma genitalium (MG) is an emerging sexually transmitted infection, often harboring resistance-associated mutations to azithromycin (AZM). Global surveillance has been mandated to tackle the burden caused by MG, yet no data are available for Austria. Thus, we aimed to investigate the prevalence of MG, disease characteristics, and treatment outcomes at the largest Austrian HIV—and STI clinic. Methods: All MG test results at the Medical University of Vienna from 02/2019 to 03/2022 were evaluated. Azithromycin resistance testing was implemented in 03/2021. Results: Among 2671 MG tests, 199 distinct and mostly asymptomatic (68%; 135/199) MG infections were identified, affecting 10% (178/1775) of all individuals. This study included 83% (1479/1775) men, 53% (940/1775) men who have sex with men (MSM), 31% (540/1754) HIV+, and 15% (267/1775) who were using HIV pre-exposure prophylaxis (PrEP). In logistic regression analysis, 'MSM' (aOR 2.55 (95% CI 1.65–3.92)), 'use of PrEP' (aOR 2.29 (95% CI 1.58–3.32)), and 'history of syphilis' (aOR 1.57 (95% CI 1.01–2.24) were independent predictors for MG infections. Eighty-nine percent (178/199) received treatment: 11% (21/178) doxycycline (2 weeks), 52% (92/178) AZM (5 days), and 37% (65/178) moxifloxacin (7–10 days) and 60% (106/178) had follow-up data available showing negative tests in 63% (5/8), 76% (44/58) and 85% (34/40), respectively. AZM resistance analysis was available for 57% (114/199)) and detected in 68% (78/114). Resistance-guided therapy achieved a cure in 87% (53/61), yet, empiric AZM-treatment (prior to 03/2021) cleared 68% (26/38). Conclusions: Mycoplasma genitalium was readily detected in this Austrian observational study, affected predominantly MSM and often presented as asymptomatic disease. We observed a worryingly high prevalence of AZM resistance mutations; however, empiric AZM treatment cleared twice as many MG infections as expected. [ABSTRACT FROM AUTHOR]

Introduction: Chronic obstructive pulmonary disease (COPD) is a common syndrome associated with smoking and environmental exposures coupled with genetic susceptibility. Recent major advancements in the treatment of COPD patients have become available. Areas covered: New data on the role of classic bronchodilators, including short-acting and long-acting beta2-agonists and anti-muscarinic antagonists, in the treatment of COPD patients are discussed. Data promoting a more targeted approach to inhaled and systemic corticosteroid use in COPD are reviewed. Phosphodiesterase (PDE) inhibitors, including the recently approved PDE 3/4 inhibitor inhaled ensifentrine, are noted. Selective use of antibiotics can play a role in complex COPD patients. COPD patients with evidence of asthma-COPD overlap syndrome and type-two lymphocytic inflammatory-mediated airway constriction appear to respond to biologics, particularly the anti-IL-4/IL-3 antagonist monoclonal antibody, dupilumab. Expert opinion: New therapeutic options have made the approach and treatment of the COPD patient much more complicated. These options tend to be very expensive. Attention to identifying the endotype and phenotype will help direct the pharmacotherapy. [ABSTRACT FROM AUTHOR]

The emergence of inactivation enzyme-encoding genes tet(X), blaEBR, and estT challenges the effectiveness of tetracyclines, β-lactams, and macrolides. This study aims to explore the concurrence and polymorphism of their variants in Empedobacter sp. strains from food-producing animals and surrounding environments. A total of eight tet(X) variants, seven blaEBR variants, and seven estT variants were detected in tet(X)-positive Empedobacter sp. strains (6.7%) from chickens, sewage, and soil, including 31 Empedobacter stercoris and 6 novel species of Taxon 1. All of them were resistant to tigecycline, tetracycline, colistin, and ciprofloxacin, and 16.2% were resistant to meropenem, florfenicol, and cefotaxime. The MIC90 of tylosin, tilmicosin, and tildipirosin was 128 mg/L, 16 mg/L, and 8 mg/L, respectively. Cloning expression confirmed that tet(X6) and the novel variants tet(X23), tet(X24), tet(X25), tet(X26), and tet(X26.2) conferred high-level tigecycline resistance, while all of the others exhibited relatively low-level activities or were inactivated. The bacterial relationship was diverse, but the genetic environments of tet(X) and blaEBR were more conserved than estT. An ISCR2-mediated tet(X6) transposition structure, homologous to those of Acinetobacter sp., Proteus sp., and Providencia sp., was also identified in Taxon 1. Therefore, the tet(X)-positive Empedobacter sp. strains may be ignored and pose a serious threat to food safety and public health. [ABSTRACT FROM AUTHOR]

The strasseriolide macrolides show promising in vitro and in vivo activities against P. falciparum and T. cruzi, the parasites causing malaria and Chagas disease, respectively. However, the as yet poor understanding of structure/activity relationships and the fact that one family member proved systemically toxic for unknown reasons render a more detailed assessment of these potential lead compounds difficult. To help overcome these issues, a collective total synthesis was devised. The key steps consisted of a ring closing alkyne metathesis (RCAM) reaction to forge a common macrocyclic intermediate followed by a hydroxy‐directed ruthenium catalyzed trans‐hydrostannation of the propargyl alcohol site thus formed. The resulting alkenyltin derivative served as the central node of the synthesis blueprint, which could be elaborated into the natural products themselves as well as into a set of non‐natural analogues according to the concept of diverted total synthesis. The recorded biological data confirmed the potency of the compounds and showed the lack of any noticeable cytotoxicity. The "northern" allylic alcohol subunit was recognized as an integral part of the pharmacophore, yet it provides opportunities for chemical modification. [ABSTRACT FROM AUTHOR]

Tilmicosin (TMC), a semi‐synthetic macrolide antibiotic, is widely used in veterinary medicine due to its broad‐spectrum, bacteriostatic properties. Frequently administered in various birds species, it is likely used off‐label in geese as well. The study sought to investigate TMC's pharmacokinetics, tissue residues, in geese through in vivo experiments. The study involved longitudinal open studies on 15 healthy adult males, with three phases separated by one‐month washout periods. Geese were administered TMC through intravenous (IV, 5 mg/kg), subcutaneous (SC, 10 mg/kg), and oral (PO, 25 mg/kg for five consecutive days) routes, with blood samples drawn at specific intervals. Tissue samples were also collected for subsequent analysis at pre‐assigned times. TMC in goose plasma was quantified by a fully validated HPLC method. Plasma concentrations were quantified up to 4 hr for the PO and IV routes, and up to 10 hr in the SC route. Significant variations in bioavailability were observed between SC (87%) and PO (4%) routes. The body extraction ratio was low at 0.03, suggesting minimal ability of the liver and kidneys to eliminate TMC. Multiple oral doses showed no plasma accumulation, but tissue data revealed extensive distribution and prolonged residence, up to 120 h, suggesting a sustained therapeutic effect despite the brief plasma half‐life. Regarding the multiple PO doses, provisional withdrawal times of 6, 7.5, and 8 days were suggested for the liver, muscles, and kidneys, respectively, according to the MRL set for these matrices in chickens by EMA. In conclusion, while the practical oral administration is discouraged at the population level, SC administration of TMC may be appropriate for geese, albeit impractical for flock therapy. [ABSTRACT FROM AUTHOR]

Gardnerella vaginalis is a Gram-variable bacillus capable of causing bacterial vaginosis, a condition prevalent in reproductive-age women, this bacterium is present in almost 100% of cases and is also considered a gateway to various sexually transmitted infections. This organism exhibits high pathogenicity linked to virulence and resistance genes acquired throughout evolution, showcasing elevated resistance to a broad spectrum of drug classes. This study conducted comparative genomic analyses to identify these genes and correlate their presence with positive Darwinian selection. Additionally, new drug targets were selected through docking and molecular modeling, guided by the heightened antimicrobial resistance exhibited by this microbial species. The available genomes of G. vaginalis were analyzed, and the orthologous genes were delineated and positively selected, whereby 29 groups were found. Of these genes, one of great importance was predicted, Mef(A), which is related to resistance to the macrolide group of antibiotics, which are one of the main choices for the treatment of sexually transmitted infections. Additionally, two potential protein candidates were selected as drug targets. These proteins were linked with a natural compound each and are considered good potential drug targets. The analyses in this study contribute to analyzing the evolution of the species and how resistance genes are related to their permanence as a potential pathogen. [ABSTRACT FROM AUTHOR]

Streptococcus pyogenes, commonly known as Group A Streptococcus (GAS), is a significant human pathogen responsible for a wide range of diseases, from mild pharyngitis to severe conditions such as necrotizing fasciitis and toxic shock syndrome. The increasing antibiotic resistance, especially against macrolide antibiotics, poses a challenge to the effective treatment of these infections. This paper reviews the current state and mechanisms of antibiotic resistance in S. pyogenes. Furthermore, molecular targets for developing anti-virulence agents, which aim to attenuate virulence rather than killing it outright, are explored. This review specifically focuses on virulence regulators, proteins that coordinate the expression of multiple virulence factors in response to environmental signals, playing a crucial role in the pathogen's ability to cause disease. Key regulatory systems, such as RopB, Mga, CovRS, and the c-di-AMP signaling system, are discussed for their roles in modulating virulence gene expression. Additionally, potential molecular target sites for the development of anti-virulence agents are suggested. By concentrating on these regulatory pathways, it is proposed that anti-virulence strategies could enhance the effectiveness of existing antibiotics and reduce the selective pressure that drives the development of resistance. [ABSTRACT FROM AUTHOR]

Mycobacterium abscessus (MABS) displays differential subspecies susceptibility to macrolides. Thus, identifying MABS's subspecies (M. abscessus, M. bolletii and M. massiliense) is a clinical necessity for guiding treatment decisions. We aimed to assess the potential of Machine Learning (ML)‐based classifiers coupled to Matrix‐Assisted Laser Desorption/Ionization Time‐of‐Flight (MALDI‐TOF) MS to identify MABS subspecies. Two spectral databases were created by using 40 confirmed MABS strains. Spectra were obtained by using MALDI‐TOF MS from strains cultivated on solid (Columbia Blood Agar, CBA) or liquid (MGIT®) media for 1 to 13 days. Each database was divided into a dataset for ML‐based pipeline development and a dataset to assess the performance. An in‐house programme was developed to identify discriminant peaks specific to each subspecies. The peak‐based approach successfully distinguished M. massiliense from the other subspecies for strains grown on CBA. The ML approach achieved 100% accuracy for subspecies identification on CBA, falling to 77.5% on MGIT®. This study validates the usefulness of ML, in particular the Random Forest algorithm, to discriminate MABS subspecies by MALDI‐TOF MS. However, identification in MGIT®, a medium largely used in mycobacteriology laboratories, is not yet reliable and should be a development priority. [ABSTRACT FROM AUTHOR]

Tylosin tartrate, a macrolide antibiotic, is one of a class of emerging contaminants that have been detected in natural bodies of water since they are not easily removed by conventional treatment processes. In this study, the direct and indirect photodegradation of tylosin tartrate was analyzed to understand the role of reactive oxygen species and organic matter that may be present in surface waters. While direct photolysis caused negligible degradation (k = (9.4 ± 1.8) × 10−5 s−1), the addition of 0.4 M hydrogen peroxide (k = (2.18 ± 0.01) × 10−4 s−1) or usage of the photo-Fenton process (k = (2.96 ± 0.02) × 10−4 s−1) resulted in greater degradation. The degradation was maximized by combining tylosin tartrate with an experimentally determined optimal concentration of humic acid (15 mg/L), which readily produced singlet oxygen and increased the overall degradation (k = 1.31 ± 0.05) × 10−3 s−1) by means of indirect photolysis. Absolute pseudo-first-order bimolecular reaction rate constants for tylosin tartrate were measured with singlet oxygen [(4.7936 ± 0.0001) × 105 M−1 s−1] and hydroxyl radical [(5.2693 ± 0.0002) × 109 M−1 s−1] using competition kinetics, and when combined with data on concentration of the reactive oxygen species, showed that the hydroxyl radical makes a contribution to the degradation that is approximately eleven orders of magnitude greater than singlet oxygen. [ABSTRACT FROM AUTHOR]

Streptococcal infections may contribute to psoriasis development, and antistreptococcal treatments are considered potential therapies, but their effectiveness remains uncertain due to limited systematic evidence. Our objective was to analyze antistreptococcal therapies' effectiveness in improving psoriasis. We conducted a systematic review following PRISMA guidelines, evaluating antistreptococcal treatment efficacy in psoriasis patients from PubMed, Scopus, and Embase databases until August 14, 2022. Eligible studies included psoriasis patients undergoing antistreptococcal therapy, regardless of demographics or psoriasis type. 50 studies (1778 patients) were analyzed, with penicillins/aminopenicillins as the most studied antibiotics (21 studies), showing mixed outcomes, some reporting significant improvement in guttate psoriasis, while others showed no significant difference. Rifampin demonstrated positive results in most of ten studies, and macrolides showed varying effectiveness in two studies. Tonsillectomy in 14 studies (409 patients) mainly focusing on guttate and chronic plaque psoriasis showed positive outcomes, indicating improved symptoms and quality of life. Limitations include heterogeneous studies, sampling bias, and quality of evidence. This systematic review reveals limited and varied evidence for systemic antibiotic therapy efficacy in psoriasis treatment, while tonsillectomy emerges as a potentially beneficial antistreptococcal option, urging further well-designed, controlled studies with larger sample sizes and standardized protocols for better comparisons. [ABSTRACT FROM AUTHOR]

Staphylococcus hyicus is a significant pathogen in swine, primarily causing exudative epidermitis. Addressing S. hyicus infections requires both the characterization of virulence and antimicrobial resistance (AMR) in farm-recovered isolates. This study aimed to characterize the virulence, AMR, and biofilm formation of S. hyicus isolates from Spanish swine farms. A total of 49 isolates were analyzed, originating from animals with cutaneous, reproductive, and systemic clinical signs. Half of the isolates (49.0%) were positive for at least one virulence factor (VF) gene, with SHETA being the most frequent (28.6%). A high frequency of multidrug resistant (MDR) isolates was observed (83.7%), with significant resistance to commonly used antimicrobials, including lincosamides (83.7%), pleuromutilins (81.6%), penicillins (75.5%), and tetracyclines (73.5%). All isolates exhibited robust in vitro biofilm formation capacity (DC = 15.6 ± 7.0). Significant associations were found between VFs, biofilm formation, and AMR patterns, highlighting the link between the resistance to lincosamides and pleuromutilins (p < 0.001; Φ = 0.57) and macrolides (p < 0.001; Φ = 0.48), and the association of AMR with the ExhC and ExhD VF genes. These findings underscore the need for targeted diagnostics to improve management and therapeutic strategies to mitigate the impact of S. hyicus on swine production. [ABSTRACT FROM AUTHOR]

In recent years, the widespread application of antibiotics has raised global concerns, posing a severe threat to ecological health. In this study, the occurrence, source, and ecological risks of 39 antibiotics belonging to 5 classes in mangrove sediments from Lianzhou Bay, China, were assessed. The total concentrations of the antibiotics (∑39 antibiotics) ranged from 65.45 to 202.24 ng/g dry weight (dw), with an average of 142.73 ± 36.76 ng/g dw. The concentrations of these five classes of antibiotics were as follows: Sulfonamides (SAs) > Tetracyclines (TCs) > Fluoroquinolones (QUs) > Penicillin (PCs) > Macrolides (MLs). The spatial distribution of antibiotics varied as high tidal zone > middle tidal zone > low tidal zone. The total organic carbon (TOC), pH, nitrate (NO3−-N), and nitrite (NO2−-N) of the sediment significantly influenced the distribution of antibiotics (p < 0.05). A source analysis identified untreated sewage from aquaculture as the primary source of antibiotics in the local mangrove. A risk assessment revealed that ciprofloxacin, norfloxacin, ofloxacin of QUs, and tetracycline of TCs exhibited medium risks to algae in certain sampling sites, while other antibiotics exhibited low or no risks to all organisms. Nevertheless, the total risk of all the detected antibiotics to algae was medium in 95% of the sites. The overall ecological risk level of antibiotics in the middle tidal zone was slightly lower than in the high tidal zone and the lowest in the low tidal zone. In summary, the experimental results provided insights into the fate and transport behaviors of antibiotics in mangrove sediments from Lianzhou Bay. [ABSTRACT FROM AUTHOR]

Rationale: Macrolides are critical antibiotics featuring a macrocyclic lactone core with deoxy sugars. Understanding their gas‐phase fragmentation is challenging but essential for improving structural elucidation in mass spectrometry, which has implications for drug discovery and development. Methods: We used electrospray ionization collision‐induced dissociation tandem mass spectrometry (ESI‐CID‐MS) combined with quantum chemical calculations to investigate the fragmentation pathways of erythromycin A and roxithromycin. This approach helps elucidate the preferred fragmentation routes influenced by protonation sites. Results: Macrolides showed similar fragmentation patterns, including sequential losses of saccharide or amino sugar units and dehydration from the macrocycle core. Multiple competitive pathways were observed, influenced by protonation sites. Computational studies confirmed the most favorable protonation sites and their impact on fragmentation, providing insights into key diagnostic product ions. Subsequent fragments involved rearrangement pathways such as alkene formation and cleavages via remote hydrogen transfers and pericyclic reactions. Conclusions: Our integrated approach offers a comprehensive understanding of macrolide fragmentation, enhancing structural elucidation and potential applications in drug development. This study advances mass spectrometry analysis of macrolides, contributing to pharmaceutical research by integrating orthogonal annotation methods and fragmentation studies. [ABSTRACT FROM AUTHOR]

This study presents the synthesis and characterization of a new zinc-based coordination polymer, {[Zn(BPMEDA)I]2+·2I3−}n (zinc-CP), utilizing Zn(II) ions and the N,N′-bis(2-pyridylmethyl)-1,2-ethylenediamine tetrahydrochloride dihydrate (BPMEDA) ligand. Powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), single-crystal X-ray diffraction (SCXRD), energy-dispersive X-ray spectroscopy (EDAX), scanning electron microscopy (SEM), and elemental mapping confirmed zinc-CP's structural integrity and composition. Furthermore, we assessed the stability of our crystal at different pH levels and evaluated its water stability by immersing the crystal in water over several days. The photoluminescence detection capability of zinc-CP was investigated with nine different antibiotics, revealing that the macrolide antibiotics, roxithromycin (RXM) and azithromycin (AZM), exhibited the highest limits of detection (LOD). Additionally, the photocatalytic degradation phenomenon of zinc-CP was assessed for the same antibiotics, demonstrating remarkable degradation rates of 97.59% for sulfadiazine (SDZ) and 94.52% for RXM. These findings demonstrate zinc-CP's potential as a sensitive sensor and photocatalyst for environmental pharmaceutical contaminants. Zinc-CP can identify and degrade pharmaceutical pollutants like antibiotics, indicating its potential for environmental cleanup. Zinc-CP's sensitive detection and catalytic breakdown make it a promising material for controlling pharmaceutical waste in water and other ecosystems in an environmentally responsible manner. [ABSTRACT FROM AUTHOR]

Macrolide antibiotic azithromycin is widely used in clinical practice to treat respiratory tract infections and inflammatory diseases. However, its mechanism of action is not fully understood. Given the involvement of the CD27 pathway in the pathophysiology of various T-lymphocyte-mediated inflammatory, autoimmune, and lymphoproliferative diseases, we examined the impact of AZM on CD27 regulation and potential consequences on CD4+ and CD8+ T-cell phenotypes. Using cellular immunology approaches on healthy donors' peripheral blood mononuclear cells, we demonstrate AZM-mediated downregulation of surface CD27 expression as well as its extracellular release as soluble CD27. Notably, AZM-exposed CD27high (hi) cells were defective in their ability to expand compared to CD27intermediate (Int) and CD27low (lo) subsets. The defective CD27hi subset expansion was found to be associated with impaired cell proliferation and cell division. At the molecular level, the CD27hi subset exhibited lower mTOR activity than other subsets. Functionally, AZM treatment resulted in marked depletion of helper CD4+ (Th1) and cytotoxic CD8+ T-lymphocyte (Tc1)-associated CXCR3+CD27hi effector cells and inhibition of inflammatory cytokine IFN-g production. These findings provide mechanistic insights on immunomodulatory features of AZM on T-lymphocyte by altering the CD27 pathway. From a clinical perspective, this study also sheds light on potential clinical benefits observed in patients on prophylactic AZM regimens against various respiratory diseases and opens avenues for future adjunct therapy against Th1- and Tc1-dominated inflammatory and autoimmune diseases. [ABSTRACT FROM AUTHOR]

Our 24-month study used metagenomics to investigate antimicrobial resistance (AMR) abundance in raw sewage from wastewater treatment works (WWTWs) in two municipalities in Gauteng Province, South Africa. At the AMR class level, data showed similar trends at all WWTWs, showing that aminoglycoside, beta-lactam, sulfonamide and tetracycline resistance was most abundant. AMR abundance differences were shown between municipalities, where Tshwane Metropolitan Municipality (TMM) WWTWs showed overall higher abundance of AMR compared to Ekurhuleni Metropolitan Municipality (EMM) WWTWs. Also, within each municipality, there were differing trends in AMR abundance. Notably, within TMM, certain AMR classes (macrolides and macrolides_streptogramin B) were in higher abundance at a WWTW serving an urban high-income area, while other AMR classes (aminoglycosides) were in higher abundance at a WWTW serving a semi-urban low income area. At the AMR gene level, all WWTWs samples showed the most abundance for the sul1 gene (encoding sulfonamide resistance). Following this, the next 14 most abundant genes encoded resistance to sulfonamides, aminoglycosides, macrolides, tetracyclines and beta-lactams. Notably, within TMM, some macrolide-encoding resistance genes (mefC, msrE, mphG and mphE) were in highest abundance at a WWTW serving an urban high-income area; while sul1, sul2 and tetC genes were in highest abundance at a WWTW serving a semi-urban low income area. Differential abundance analysis of AMR genes at WWTWs, following stratification of data by season, showed some notable variance in six AMR genes, of which blaKPC-2 and blaKPC-34 genes showed the highest prevalence of seasonal abundance differences when comparing data within a WWTW. The general trend was to see higher abundances of AMR genes in colder seasons, when comparing seasonal data within a WWTW. Our study investigated wastewater samples in only one province of South Africa, from WWTWs located within close proximity to one another. We would require a more widespread investigation at WWTWs distributed across all regions/provinces of South Africa, in order to describe a more comprehensive profile of AMR abundance across the country. [ABSTRACT FROM AUTHOR]

The most prevalent cause of dementia is Alzheimer's disease. Cognitive decline and accelerating memory loss characterize it. Alzheimer's disease advances sequentially, starting with preclinical stages, followed by mild cognitive and/or behavioral impairment, and ultimately leading to Alzheimer's disease dementia. In recent years, healthcare providers have been advised to make an earlier diagnosis of Alzheimer's, prior to individuals developing Alzheimer's disease dementia. Regrettably, the identification of early-stage Alzheimer's disease in clinical settings can be arduous due to the tendency of patients and healthcare providers to disregard symptoms as typical signs of aging. Therefore, accurate and prompt diagnosis of Alzheimer's disease is essential in order to facilitate the development of disease-modifying and secondary preventive therapies prior to the onset of symptoms. There has been a notable shift in the goal of the diagnosis process, transitioning from merely confirming the presence of symptomatic AD to recognizing the illness in its early, asymptomatic phases. Understanding the evolution of disease-modifying therapies and putting effective diagnostic and therapeutic management into practice requires an understanding of this concept. The outcomes of this study will enhance indepth knowledge of the current status of Alzheimer's disease's diagnosis and treatment, justifying the necessity for the quest for potential novel biomarkers that can contribute to determining the stage of the disease, particularly in its earliest stages. Interestingly, latest clinical trial status on pharmacological agents, the nonpharmacological treatments such as behavior modification, exercise, and cognitive training as well as alternative approach on phytochemicals as neuroprotective agents have been covered in detailed. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions Patients with inflammatory bowel disease (IBD) have an increased risk of Clostridioides difficile infection (CDI) compared with those without IBD, which is worsened with antibiotic usage. While prior studies have shown a correlation between CDI development and certain classes of antibiotics, the IBD population has not been well represented. This study evaluates the rates of CDI with outpatient antibiotic use in patients with IBD.We conducted a retrospective cohort study composed of patients with IBD and compared the incidence of CDI in patients who received an outpatient prescription for antibiotics (6694 patients) against those without prescriptions (6025 patients) from 2014 to 2020 at our institution. We compared CDI rates based on nine antibiotic classes: penicillins, cephalosporins, sulfonamides, tetracyclines, macrolides, quinolones, clindamycin, metronidazole, and nitrofurantoin.The risk of CDI was low (0.7%) but significantly higher for those with antibiotic exposure (0.9% vs 0.5%, P = 0.005) and had a positive correlation with a smoking history. The increased risk of CDI in the IBD population was attributable to the clindamycin and metronidazole classes (odds ratio = 4.7, 95% confidence interval: 1.9–11.9, P = 0.001; odds ratio = 3.6, 95% confidence interval: 2.1–6.2, P < 0.0001, respectively).The use of clindamycin or metronidazole prescribed in an outpatient setting was associated with a statistically significant increased risk of CDI in patients with IBD. Although the association between clindamycin and CDI is a well‐established and common finding, the association between metronidazole and CDI is unique in this study. [ABSTRACT FROM AUTHOR]

Background Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. Methods COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. Results The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (−0.56 log10 copies/mL; 95% confidence interval [CI], −1.05 to −.06; P =.027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI,.55 to.94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI,.36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. Conclusions In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. Clinical Trials Registration NCT04510194. [ABSTRACT FROM AUTHOR]

Background Growing evidence indicates antimicrobial resistance disproportionately affects individuals living in socially vulnerable areas. This study evaluated the association between the CDC/ATSDR Social Vulnerability Index (SVI) and Streptococcus pneumoniae (SP) antimicrobial resistance (AMR) in the United States. Methods Adult patients ≥18 years with 30-day nonduplicate SP isolates from ambulatory/hospital settings from January 2011 to December 2022 with zip codes of residence were evaluated across 177 facilities in the BD Insights Research Database. Isolates were identified as SP AMR if they were non-susceptible to ≥1 antibiotic class (macrolide, tetracycline, extended-spectrum cephalosporins, or penicillin). Associations between SP AMR and SVI score (overall and themes) were evaluated using generalized estimating equations with repeated measurements within county to account for within-cluster correlations. Results Of 8008 unique SP isolates from 574 US counties across 39 states, the overall proportion of AMR was 49.9%. A significant association between socioeconomic status (SES) theme and SP AMR was detected with higher SES theme SVI score (indicating greater social vulnerability) associated with greater risk of AMR. On average, a decile increase of SES, indicating greater vulnerability, was associated with a 1.28% increased risk of AMR (95% confidence interval [CI],.61%, 1.95%; P =.0002). A decile increase of household characteristic score was associated with a 0.81% increased risk in SP AMR (95% CI,.13%, 1.49%; P =.0197). There was no association between racial/ethnic minority status, housing type and transportation theme, or overall SVI score and SP AMR. Conclusions SES and household characteristics were the SVI themes most associated with SP AMR. [ABSTRACT FROM AUTHOR]

Antibiotic contamination poses a significant global concern due to its far-reaching impact on public health and the environment. This comprehensive review delves into the prevalence of various antibiotic classes in environmental pollution and their interactions with natural ecosystems. Fluoroquinolones, macrolides, tetracyclines, and sulphonamides have emerged as prevalent contaminants in environmental matrices worldwide. The concentrations of these antibiotics vary across diverse environments, influenced by production practices, consumer behaviours, and socio-economic factors. Low- and low-middle-income countries face unique challenges in managing antibiotic contamination, with dominant mechanisms like hydrolysis, sorption, and biodegradation leading to the formation of toxic byproducts. Ecotoxicity reports reveal the detrimental effects of these byproducts on aquatic and terrestrial ecosystems, further emphasizing the gravity of the issue. Notably, monitoring the antibiotic parent compound alone may be inadequate for framing effective control and management strategies for antibiotic pollution. This review underscores the imperative of a comprehensive, multi-sectoral approach to address environmental antibiotic contamination and combat antimicrobial resistance. It also advocates for the development and implementation of tailored national action plans that consider specific environmental conditions and factors. Thus, an approach is crucial for safeguarding both public health and the delicate balance of our natural ecosystems. [ABSTRACT FROM AUTHOR]

Gram-positive enterococciare opportunistic and resistant to many antibiotics. This study aimed to investigate the presence of Enterococcus spp. in our community and whether these isolates are resistant to the macrolides class of antibiotics. Fifty isolates from 112 clinical samples were recognized as Enterococcus spp. and confirmed using Vitek-2 system. The current study found that 50/112 (44.6%) represented the total isolates, 38/50 (76%) of which were Enterococcus faecalis, while 12/50 (24%) were Enterococcus faecium, twenty (40%) isolates from root canals and 30 (60%) isolates from urine were isolated. The sensitivity of the enterococcal isolates to various macrolides (erythromycin, azithromycin and clarithromycin) antibiotics was determined by using the disk diffusion approach. Later, the minimum inhibitory concentrations (MICs) for erythromycin and the most resistant drug among this group were investigated using the agar dilution technique. And then molecular detection for mef gene was done using two specific primers via PCR technique. The current findings revealed high resistance rates to macrolide antibiotics which were reported in 21/50 (42%) of total isolates and at significant levels of MIC values for most isolates (57%). And as for the PCR results, it was negative for mef gene in all tested isolates. [ABSTRACT FROM AUTHOR]

Infections caused by antimicrobial-resistant Escherichia coli are the leading cause of death attributed to antimicrobial resistance (AMR) worldwide, and the known AMR mechanisms involve a range of functional proteins. Here, we employed a pangenome wide association study (GWAS) approach on over 1,000 E. coli isolates from sick dogs collected across the US and Canada and identified a strong statistical association (empirical P < 0.01) of AMR, involving a range of antibiotics to a group 1 capsular (CPS) gene cluster. This cluster included genes under relaxed selection pressure, had several loci missing, and had pseudogenes for other key loci. Furthermore, this cluster is widespread in E. coli and Klebsiella clinical isolates across multiple host species. Earlier studies demonstrated that the octameric CPS polysaccharide export protein Wza can transmit macrolide antibiotics into the E. coli periplasm. We suggest that the CPS in question, and its highly divergent Wza, functions as an antibiotic trap, preventing antimicrobial penetration. We also highlight the high diversity of lineages circulating in dogs across all regions studied, the overlap with human lineages, and regional prevalence of resistance to multiple antimicrobial classes. [ABSTRACT FROM AUTHOR]

In this Account, we summarize the development of a new strategy for streamlined synthesis of tetrahydropyran-embedded macrolactones and its successful implementation to a 13-step synthesis of (–)-exiguolide and an 11-step synthesis of (+)-neopeltolide. 1 Introduction 2 Development of Macrocyclization/Transannular Pyran Cyclization Strategy 3 Total Synthesis of (–)-Exiguolide 4 Total Synthesis of (+)-Neopeltolide 5 Conclusions [ABSTRACT FROM AUTHOR]

Systematic reviews have reported conflicting evidence on whether macrolide antibiotics reduce rates of chronic lung disease of prematurity (CLD) in at-risk preterm infants born at less than 30 weeks' gestation, including in those colonised with pulmonary Ureaplasma spp. Since an adequately powered trial has been lacking, we aimed to assess if the macrolide azithromycin improved survival without the development of physiologically defined moderate or severe CLD in preterm infants. AZTEC was a multicentre, double-blind, randomised, placebo-controlled trial conducted in 28 tertiary neonatal intensive care units in the UK. Infants were eligible if they were born at less than 30 weeks' gestation and had received at least 2 h of either non-invasive (continuous positive airway pressure or humidified high flow nasal cannula therapy) or invasive respiratory support (via endotracheal tube) within 72 h of birth. Eligible infants were randomly allocated in a 1:1 ratio using random permuted blocks of four to receive either intravenous azithromycin at 20 mg/kg per day for 3 days followed by 10 mg/kg for 7 days, or to placebo. Allocation was stratified by centre and gestational age at birth (<28 weeks vs ≥28 weeks). Azithromycin and placebo vials were encased in tamper-evident custom cardboard cartons to ensure masking for clinicians, parents, and the research team. The primary outcome was survival without development of physiologically defined moderate or severe CLD at 36 weeks' postmenstrual age. Outcomes and safety were analysed on an intention-to-treat basis (all randomly allocated infants, regardless of any post-randomisation events). The study was registered with ISRCRN (11650227) and is closed. Infants were recruited between Oct 9, 2019, and March 22, 2022. 799 (53·1%) of 1505 eligible infants underwent random allocation; three infants were withdrawn, including consent to use their data, leaving 796 infants for analysis. Survival without moderate or severe CLD occurred in 166 (42%) of 394 infants in the intervention group and 179 (45%) of 402 in the placebo group (three-level adjusted OR [aOR] 0·84, 95% CI 0·55–1·29, p=0·43). Pulmonary Ureaplasma spp colonisation did not influence treatment effect. Overall, seven serious adverse events were reported for the azithromycin group (five graded as severe, two as moderate), and six serious adverse events were reported in the placebo group (two severe, two moderate, and two mild), as assessed by the local principal investigators. Since prophylactic use of azithromycin did not improve survival without development of physiologically-defined CLD, regardless of Ureaplasma spp colonisation, it cannot be recommended in clinical practice. UK National Institute for Health and Care Research. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the bacterial characteristics of pneumococcal isolates obtained from a tertiary care hospital in Japan. We analyzed the antimicrobial susceptibility, possession of macrolide resistance genes, pneumococcal serogroup/serotype, and sequence type (ST) of pneumococcal isolates from patients aged 15 years or older between 2011 and 2020 at Nagasaki University Hospital. Of the 73 isolates analyzed, 86.3% showed resistance to macrolides, and 28.8%, 46.6%, and 11.0% harbored mefA, ermB, and both, respectively. Of the isolates possessing ermB, 97.6% showed high levels of macrolide resistance [minimal inhibitory concentration (MIC) range, > 16 µg/mL]. Solithromycin (MIC range, 0.03-0.25 µg/mL), regardless of the presence of macrolide resistance genes, and lascufloxacin (MIC range, 0.06-0.5 µg/mL) showed potent in vitro activity against pneumococci. Serotype 19A was the most prevalent (six isolates), followed by serotypes 10A, 15A, and 15B/C (five isolates each). Four serotypes (11A, 19A, 22F, and 23B) and five STs (36, 99, 433, 558, and 3111) were significantly correlated with the presence of macrolide resistance genes. All four isolates with serotype 11A/ST99 and three isolates with serotype 19A/ST3111 harbored both mefA and ermB. No macrolide resistance genes were detected in either of the two isolates with serotype 22F/ST433, while all ten isolates with serogroup 15 (serotypes 15A and 15B/C, five isolates each) possessed ermB alone. Our study revealed the bacterial characteristics of the pneumococcal isolates obtained from our hospital. In vitro activity of solithromycin and lascufloxacin against these isolates was confirmed. [ABSTRACT FROM AUTHOR]

Purpose: Infection with carbapenem-resistant Acinetobacter baumannii (CRAB) is a tough nut to crack. Carrimycin is a novel recombinant macrolide antibiotic, and has good anti-infection effects in vivo. At present, it is rarely reported for treatment of CRAB infection. We present a case where a patient with COVID-19 complicated by CRAB infection was successfully treated with a combination therapy including carrimycin, offering clinical insights and experience. Patients and Methods: The patient infected with CRAB was cured by carrimycin combined with tigecycline and amikacin ultimately. We analyzed and summarized the therapeutic regimen and disease feature to provide reference for clinical treatment. Results: The patient was admitted to emergency observation wards with fever and was diagnosed with COVID-19 pneumonia. During the treatment, his condition worsened. He had a fever, cough, and expectoration. After 3 days of empirical treatment with meropenem, tested positive for A. baumannii infection by the next-generation sequencing, and CRAB was detected in blood and sputum culture. Then, he was administered with tigecycline and amikacin immediately for 5 days, however the therapeutic effect was not significant. The patient still remained in a high inflammatory response. Ultimately, the treatment regimen was changed to carrimycin combined with tigecycline and amikacin for 7 days, and then carrimycin combined with tigecycline for 10 days, the patient's clinical condition gradually improved. The patient received carrimycin monotherapy for 7 days, then discharged. Conclusion: Carrimycin may be a bright alternative for CRAB infection as one of the drugs in combination therapy, especially in a patient with hyperinflammatory response. [ABSTRACT FROM AUTHOR]

Published data on the molecular mechanisms underlying antimicrobial resistance in Group B Streptococcus (GBS) isolates from Saudi Arabia are lacking. Here, we aimed to determine the genetic basis of resistance to relevant antibiotics in a collection of GBS clinical isolates (n = 204) recovered from colonized adults or infected patients and expressing serotypes Ia, Ib, II, III, V, and VI. Initial susceptibility testing revealed resistance to tetracycline (76.47%, n = 156/204), erythromycin (36.76%, n = 75/204), clindamycin (25.49%, n = 52/204), levofloxacin (6.37%, n = 13/204), and gentamicin (2.45%, n = 5/204). Primers designed for the detection of known resistance determinants in GBS identified the presence of erm(A), erm(B), mef(A), and/or lsa(C) genes at the origin of resistance to macrolides and/or clindamycin. Of these, erm(B) and erm(A) were associated with the cMLSB (n = 46) and iMLSB (n = 28) phenotypes, respectively, while mef(A) was linked to the M phenotype (n = 1) and lsa(C) was present in isolates with the L phenotype (n = 8). Resistance to tetracycline was mainly mediated by tet(M) alone (n = 112) or in combination with tet(O) (n = 10); the remaining isolates carried tet(O) (n = 29), tet(L) (n = 2), or both (n = 3). Isolates resistant to gentamicin (n = 5) carried aac(6′)-Ie-aph(2′)-Ia, and those exhibiting resistance to levofloxacin (n = 13) had alterations in GyrA and/or ParC. Most isolates with the erm gene (93.24%, n = 69/74) also had the tet gene and were therefore resistant to erythromycin, clindamycin, and tetracycline. Overall, there were no clear associations between serotypes and resistance genotypes except for the presence of erm(B) in serotype Ib isolates. Dissemination of antibiotic resistance genes across different serotypes represents a public health concern that requires further surveillance and appropriate antibiotic use in clinical practice. [ABSTRACT FROM AUTHOR]