Frontiers in antibiotics最新文献

Background: Environmental coliform bacteria are frequently the cause of subclinical mastitis (SCM), a serious health issue in the dairy industry. Extended-spectrum β-lactamase (ESBL)-producing coliforms in livestock are a serious public health concern, particularly in environments where people and animals coexist. With an emphasis on their zoonotic and One Health implications, this study sought to evaluate the incidence of SCM and the occurrence of ESBL-producing coliforms in ruminants in Plateau State, Nigeria.

Methods: The California Mastitis Test (CMT) was used to screen 287 milk samples that were taken from cows, ewes, and does. Standard microbiological methods were used to identify the bacterial isolates from CMT-positive samples. The presence of resistance genes (bla _TEM and bla _CTX-M) was ascertained by PCR, and ESBL production was confirmed phenotypically. Phylogenetic analysis showed genetic diversity and possible horizontal gene transfer among isolates.

Results: Out of 287 milk samples, 79 (27.5%) had subclinical mastitis through the CMT, with a higher prevalence recorded in does 18(22.8%) while ewes and cows recorded 23(29.1%), and 38(48.1%) respectively. Of the 79 CMT-positive samples, the following isolates were identified: Citrobacter freundii (6.3%), Klebsiella pneumoniae (21.6%), K. oxytoca (2.5%), K. aerogenes (6.3%), and E. coli, being the most prevalent in cows (71%). Through PCR, 46 isolates expressed two important ESBL genes, bla _TEM and bla _CTX-M.

Conclusion: A possible zoonotic reservoir for antibiotic resistance in Nigeria is highlighted by the increased frequency of ESBL-producing coliforms in ruminants with SCM. These results highlight the necessity of implementing integrated One Health initiatives, such as public education, surveillance, and antimicrobial stewardship, in order to reduce the risk of resistant pathogen transmission from animals to people.

The development of medical countermeasures against pathogens of biodefense concern remains critical to protecting military and public health. This review compares data detailing antibacterial activity and efficacy for a selection of antibiotics evaluated against potential bacterial biothreat pathogens. The human safety and tolerability of these formulations were also considered. This review includes finafloxacin, levofloxacin, delafloxacin, omadacycline, gepotidacin, tebipenem and sulopenem. The selection criteria of these antibiotics were 1) the availability of an oral formulation, 2) the regulatory status (licensed by a regulatory authority or in an advanced stage of development) and 3) the availability of publicly available information on the biodefence pathogens of concern. We hope to highlight approved or advanced clinical candidates that have significant and unique potential in the biodefense space which may be deployed to protect both the public and warfighter against these bacterial infections.

Background: Rising antimicrobial resistance (AMR) necessitates innovative metrics, such as days of antibiotic spectrum coverage (DASC), to optimize antibiotic stewardship. This study evaluated antibiotic use in an Indian trauma center using DASC, defined daily doses (DDD), and the World Health Organization (WHO) Access, Watch, Reserve (AWaRe) classification.

Methods: This retrospective cohort study analyzed data from 1,812 adult inpatients (mean age: 35 years; 70% male; 80% with polytrauma) admitted to a 250-bed Level-1 Trauma Center at the All India Institute of Medical Sciences (AIIMS), India, from August to October 2022. We measured days of therapy (DOT), DDD, and DASC for 46 antibiotics across 12 pathogens [e.g., methicillin-susceptible Staphylococcus aureus (MSSA), carbapenem-resistant Enterobacteriaceae]. DASC scores were developed through expert consensus and local antibiogram data, and validated using Pearson's correlation with DOT (R = 0.43, p < 0.1) and DDD (R = 0.21). Differences in antibiotic usage between the ICU and ward were analyzed using a t-test in R software.

Results: Total antibiotic consumption was 81,064.6 g (3,142 DDD/1,000 patient-days). The Watch group antibiotics dominated usage (37%, 16,018.6 g), resulting in a low Access-to-Watch ratio (0.47). ICU settings showed higher DDD values (326 vs. 193/1,000 patient-days, p < 0.05) and DASC/DOT ratios (mean: 3; 95% CI: 2.73-4.01). Piperacillin-tazobactam accounted for the largest share of the Watch category use (5,952.9 g). DASC values (mean 4401.5, 95% CI: 3592-5211.1) showed a moderate correlation with DOT (R = 0.43, p < 0.1), offering spectrum-specific insights.

Conclusions: Excessive use of the Watch group antibiotics contributes significantly to AMR. However, DASC's novel, spectrum-focused approach offers a transformative tool for antibiotic stewardship, supporting targeted de-escalation and improved benchmarking. These findings underscore the urgent need for policy reforms to enforce adherence to the WHO AWaRe classification in Indian centers, potentially reducing AMR-related mortality (30% higher with resistant infections). Integrating DASC into global Antimicrobial stewardship (AMS) programs may redefine antibiotic prescribing practices and help mitigate the AMR crisis.

Background: Antibiotic resistance (ABR) to commonly used antibiotics is significant in sub-Saharan Africa (SSA). In SSA, Chad has one of the highest antimicrobial resistance (AMR) rates. The link between ABR and antibiotic consumption (ABC) is well-established. However, no ABC-related studies have been conducted in Chad recently. The purpose of this study is to examine the trajectory of ABC in Chad from 2017 to 2021, using the World Health Organization's (WHO) Access, Watch, and Reserve (AWaRe) antibiotic classification.

Methods: A descriptive retrospective study was conducted in N'Djamena, using antibiotic import and distribution data collected from the General Directorate of Pharmacy and four wholesale distributors of medicines. The defined daily doses (DDDs) and the mean relative change (MRC) were used to compute the results. Results were presented in terms of tables and graphs. The results were compared to the WHO's guidelines for ABC use via the AWaRe categorization.

Results: Between 2017 and 2021, an average ABC of 2.5 doses per inhabitant per year was observed, peaking in 2020 at 5.3 doses per inhabitant. In terms of DDD, the ten most commonly consumed antibiotics during the time, in descending order, were amoxicillin, ampicillin, sulfamethoxazole/trimethoprim, doxycycline, ciprofloxacin, phenoxymethyl-penicillin, erythromycin, ceftriaxone, azithromycin, and gentamicin. However, the MRC analysis detected an increase in benzathine benzyl penicillin, benzylpenicillin, ampicillin, amoxicillin+clavulanic acid, flucloxacillin, ceftriaxone, cefixime, cefpodoxime and cefalexin, cotrimoxazole, ciprofloxacin, levofloxacin, norfloxacin, ofloxacin, and azithromycin. Controversially, amoxicillin, cefotaxime, doxycycline, erythromycin, and moxifloxacin had a lower MRC from 2017 to 2021. Although 90% of the ABC are from the "Access" group, the "Watch" group has increased over time.

Conclusions: Our findings indicated a significant ABC in the Chadian population from 2017 to 2021, which may elucidate the country's elevated ABR. On average, 90% of ABC were categorized in the "Access" group, although utilization of the Watch group increased over time. This requires the prompt implementation of the monitoring system for ABC at all tiers in Chad.

Introduction: Antimicrobial resistance (AMR) can spread in microorganisms through the transfer of antimicrobial resistance genes (ARGs). Livestock husbandry is one of the pathways for AMR emergence and transmission. Chicken manure contains valuable nutrients for agricultural field fertilization and can be used as input material for biogas production by anaerobic digestion (AD). However, usually, chicken manure also contains quite high levels of ARGs. In this study, we investigated the presence and temporal dynamics of ARGs against different antibiotic classes in chicken manure and anaerobic digestate as a source of AMR spread.

Methods: To get an overview of the ARG profiles, we quantified the abundances of 374 ARGs by high-throughput (HT)-PCR. We studied eight selected ARGs (tetA, tetX, sul1, sul2, lnuF, emrD, aadA, and tnpA) using qPCR in chicken manure from different flocks and animal ages and in digestate from different AD time points.

Results: Chicken manure showed higher amounts of ARGs compared to digestate, which was characterized by a higher ARG diversity. We observed that the effect of chicken age differed between the flocks. ARG abundances in digestate from different time points and different treatment conditions did not exhibit major changes.

Conclusion: The flocks' variability had no relevant effect on ARG abundances in chicken manure, likely due to similar growth conditions. However, manure ARG content increased with the age of the chickens. In our experimental batch setup, AD was more effective in reducing AMR microorganisms than reducing ARGs. Further investigations on process optimization or the application of pre-treatment methods could enhance ARG reduction. Notably, pre-mixing chicken manure with material from a biogas plant prior to processing resulted in a lower ARG load compared to untreated chicken manure.

Background: Antibiotic-resistant bacteria are becoming a significant global concern. To combat the spread of resistance or reverse multidrug resistance, developing novel antimicrobials and/or resistance modulators is essential. This study aimed to evaluate the synergistic effects of the methanolic extract of Pandanus fascicularis fruits (MEPFF) in combination with azithromycin against multidrug-resistant bacteria.

Methods: Phytochemical analysis along with the determination of total phenolic content (TPC), total flavonoid content (TFC), and total antioxidant capacity (TAC) of MEPFF, was performed using standard procedure. The extract's DPPH free radical scavenging activity was assessed to evaluate its potential antioxidant activity. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of MEPFF against Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa were determined, followed by an analysis of the synergistic effect with azithromycin, as well as the activity of azithromycin alone. Subsequently, the drug-likeness, antibacterial activity, and toxicological properties were analyzed using in silico tools.

Results: The quantitative investigation found terpenoids, flavonoids, tannins, phenolics, saponins, cardiac glycosides, and alkaloids in MEPFF. The TFC, TPC, and TAC of MEPFF were found at 183 ± 9.54 mg QE, 248.33 ± 11.06 mg GAE, and 95.33 ± 8.33 mg AAE/gm extract. The extract showed significant antioxidant activity in the DPPH experiment, with an IC50 value of 12.13±0.53 µg/ml. Azithromycin and the extract together have far greater antibacterial action against all four bacterial strains. The minimal inhibitory concentration (MIC) is 3.67 ± 1.15 to 5.83 ± 0.76 mg/mL, while the minimum bactericidal concentration (MBC) is 4.33 ± 1.26 to 7.33 ± 1.04 mg/mL. In silico studies revealed that pandamarilactone-1, nonpandamarilactone-B, and thiamine had the best docking energy (-9.9, -8.9, and -8.5 kcal/mol), suggesting most active compounds against MPh-II protein.

Conclusion: The extract enhances antibiotic therapy and suggests that the aforesaid synergistic drug-herb combinations may treat MDR bacterial infections.

Tuberculosis drug trials are primarily designed to identify antibiotic regimens with the strongest potency to kill Mycobacterium tuberculosis. However, microbiologic cure is not synonymous with improved health and recovery. Beyond antimicrobial efficacy, parameters such as morbidity and mortality related to lung function, cardiovascular health, and cancer should be prioritized. This narrative review emphasizes the critical need to emphasize clinical outcomes as much, if not more, than microbiological endpoints. We examine the underlying pathophysiological mechanisms and determinants of non-microbiological outcomes in tuberculosis, providing a synthesis of current knowledge. While there is growing evidence for some biomarkers to risk stratify TB patients for risk of all-cause mortality, relapse, or lung damage, no evidence was found on TB-associated cancer or cardiovascular disease. In addition to monitoring microbiologic outcomes, clinical trials and treatment cohorts need to capture patient-centered health dimensions more broadly. Finally, we highlight key research gaps and opportunities to evaluate non-microbiological biomarkers, aiming to improve patient monitoring and enable stratified approaches to tuberculosis management.

Introduction: Infections are a major driver of broad-spectrum antibiotic use. This wide use of antibiotics contributes to the emergence of antimicrobial resistance globally that poses a threat to human and animal health. Infections continue to be a major cause of death among pregnant women and neonates. Therefore, this study aimed to assess the burden of extended-spectrum beta-lactamase (ESBL)-producing E. coli and K. pneumoniae carriage among neonates and their surroundings admitted to a referral hospital in Northeast Tanzania.

Methodology: The burden of ESBL-producing E. coli and K. pneumoniae in a neonatal ward was assessed by screening neonates' rectums, maternal and healthcare workers' hands, and neonatal cots. Isolates were cultured, identified, and tested for antimicrobial resistance, while generalized linear models identified risk factors for carriage.

Results: A total of 437 neonates were screened for ESBL-producing E. coli and K. pneumoniae, with 235 (54%) being male. In addition, 77 maternal hand swabs, 118 neonatal cots, and 45 healthcare workers' hand swabs were collected. ESBL-producing K. pneumoniae was isolated from 198 neonates (45%), and E. coli from 96 (23%). Additionally, 5% of maternal hands and 22% of neonatal cots were contaminated with these resistant bacteria. Overall ampicillin resistance was frequent in ESBL-producing E. coli and ESBL K. pneumoniae neonatal colonization (n=261,100%), as was resistance to trimethoprim-sulfamethoxazole (n = 233,89%), gentamicin (n = 169, 66%), and tetracycline (n = 140,54%). Only three (1%) of the ESBL-producing E. coli and ESBL K. pneumoniae isolates were resistant to meropenem. Risk factors significantly associated with carriage of either ESBL-producing E. coli or K. pneumoniae were being born in an admission room [odds ratio (OR)=1.95, confidence interval (CI)=1.31-3.13, p=0.006] and delivery mode, with vaginal delivery associated with a reduced risk of carriage (OR=0.57, CI=0.35-0.92, p=0.023).

Conclusion: The study reveals a high burden of ESBL-producing K. pneumoniae and E. coli in neonates and their environment, with frequent resistance to ampicillin and gentamicin. Hospital admission and cesarean delivery increase the risk of carriage, while vaginal delivery lowers it. Active screening upon admission and advanced diagnostic methods can help reduce transmission and guide effective antimicrobial treatment.

Background: Tuberculosis (TB) remains a global health challenge. Culture-free, rapid, and quantitative biomarkers to monitor treatment response are critical to accelerate development of better TB treatments. The PATHFAST TB LAM Ag assay (PATHFAST-LAM), a desktop chemiluminescent enzyme immunoassay that measures mycobacterial lipoarabinomannan (LAM) in sputum within 1 hour, is a promising candidate for this purpose. This study aimed to assess whether the PATHFAST-LAM can serve as a rapid, reliable biomarker for monitoring early treatment response in pulmonary TB.

Methods: We conducted a retrospective longitudinal repository study using stored sputum samples from 14-day early bactericidal activity trials involving 75 pulmonary TB patients who received one of five different regimens. The results were compared with those from the TB LAM ELISA "Otsuka" (LAM-ELISA), which was previously shown to measure early bactericidal activity but takes more than 5 hours to obtain results, and conventional culture-based methods.

Results: The LAM concentrations in both raw and decontaminated sputum showed strong correlations between the PATHFAST-LAM and the LAM-ELISA, with Spearman's correlation coefficients of 0.975 (95% CI: 0.971 - 0.979) and 0.987 (95% CI: 0.984 - 0.989), respectively. LAM concentrations in raw and decontaminated sputum by the PATHFAST-LAM were also highly correlated with a Spearman coefficient of 0.957 (95% CI: 0.950 - 0.964). Importantly, the LAM concentrations by the PATHFAST-LAM correlated with bacterial loads determined by culture-based methods in all five treatment arms (Spearman's coefficients: 0.723 - 0.947). Furthermore, the change in LAM levels over the treatment period mirrored the changes in bacterial load. Additionally, culture-based methods often result in missing data due to contamination: in our study, we observed a missing data rate of 9.6% (62/649) on quantifying CFU counts and 4.2% (27/649) on obtaining a valid MGIT TTD, while we obtained a valid LAM value with the PATHFAST-LAM (0/634 in raw samples and 0/637 in decontaminated samples).

Conclusion: Our findings suggest that the PATHFAST-LAM can quantify bactericidal activity in the first 14 days of treatment with a quick turnaround time. The test's utility to monitor conversion from positive to negative and to predict relapse-free cure compared to culture-based methods should be determined in longer trials.

Introduction: Optimizing vancomycin dosing in neonates is a critical yet complex goal. Traditional trough concentration-based dosing strategies correlate poorly with therapeutic efficacy and often fail to account for the significant renal function variability and drug clearance in neonates. The 24-hour area under the concentration-time curve to minimum inhibitory concentration (AUC₂₄/MIC) ≥ 400 mg h/L has emerged as a superior pharmacodynamic target. Population pharmacokinetics (PopPK) models allow optimized dosing by incorporating neonatal-specific factors such as postmenstrual age (PMA), gestational age (GA), serum creatinine (SCr), and weight.

Objective: To develop optimized vancomycin dosing regimens for neonates that achieve an 80% probability of target attainment (PTA) for an AUC₂₄/MIC ≥ 400 mg h/L across diverse clinical cohorts and simulated neonatal populations.

Methods: Real-world data from three international centers (Belgium, New Zealand, USA), including 610 individuals and 2399 vancomycin concentrations, were used to externally evaluate a previously published PopPK model (NONMEM^®). Missing data, including body weight, were imputed using Amelia II version 1.7.3 for R, while Zelig for R integrated multiple imputed datasets. A virtual population of 10,000 neonates was independently generated using MATLAB to simulate clinical scenarios considering covariates such as PMA, GA, SCr, body weight, and imputed body length.

Results: Simulations showed that PMA and SCr were key covariates that significantly improved PTA, particularly in preterm neonates. Preterm neonates achieved PTAs of 80% with daily doses of 30 or 40 mg/kg/day, while term neonates required 15 mg/kg every 8 hours or 20 mg/kg every 12 hours. The simulations demonstrated that these optimized dosing strategies achieved an 80% PTA for AUC₂₄/MIC ≥ 400 mg h/L in the virtual neonatal population. For neonates with PMA < 29 weeks and SCr > 0.6 mg/dL, including SCr as a covariate increased the likelihood of achieving the target from 65% to 87%.

Conclusion: Incorporating developmental factors like PMA and SCr into vancomycin dosing strategies achieved robust and clinically relevant outcomes. The optimized regimens achieved an 80% PTA for the AUC₂₄/MIC target for preterm and term neonates. These findings offer a scalable framework for improving neonatal vancomycin pharmacotherapy across diverse populations and clinical settings.