Quantitative Risk Assessment of Susceptible and Ciprofloxacin-Resistant Salmonella from Retail Pork in Chiang Mai Province in Northern Thailand.

The adverse human health effects as a result of antimicrobial resistance have been recognized worldwide. Salmonella is a leading cause of foodborne illnesses while antimicrobial resistant (AMR) Salmonella has been isolated from foods of animal origin. The quantitative risk assessment (RA) as part of the guidelines for the risk analysis of foodborne antimicrobial resistance was issued by the Codex Alimentarius Commission more than a decade ago. However, only two risk assessments reported the human health effects of AMR Salmonella in dry-cured pork sausage and pork mince. Therefore, the objective of this study was to quantitatively evaluate the adverse health effects attributable to consuming retail pork contaminated with Salmonella using risk assessment models. The sampling frame covered pork at the fresh market (n = 100) and modern trade where pork is refrigerated (n = 50) in Chiang Mai province in northern Thailand. The predictive microbiology models were used in the steps where data were lacking. Susceptible and quinolone-resistant (QR) Salmonella were determined by antimicrobial susceptibility testing and the presence of AMR genes. The probability of mortality conditional to foodborne illness by susceptible Salmonella was modeled as the hazard characterization of susceptible and QR Salmonella. For QR Salmonella, the probabilistic prevalences from the fresh market and modern trade were 28.4 and 1.9%, respectively; the mean concentrations from the fresh market and modern trade were 346 and 0.02 colony forming units/g, respectively. The probability of illness (PI) and probability of mortality given illness (PMI) from QR Salmonella-contaminated pork at retails in Chiang Mai province were in the range of 2.2 × 10-8-3.1 × 10-4 and 3.9 × 10-10-5.4 × 10-6, respectively, while those from susceptible Salmonella contaminated-pork at retails were in the range 1.8 × 10-4-3.2 × 10-4 and 2.3 × 10-7-4.2 × 10-7, respectively. After 1000 iterations of Monte Carlo simulations of the risk assessment models, the annual mortality rates for QR salmonellosis simulated by the risk assessment models were in the range of 0-32, which is in line with the AMR adverse health effects previously reported. Therefore, the risk assessment models used in both exposure assessment and hazard characterization were applicable to evaluate the adverse health effects of AMR Salmonella spp. in Thailand.

[Ecological Risk Assessment of Quinolones Antibiotics and the Correlation Analysis Between QNs and Physical-Chemical Parameters in Groundwater, Shijiazhuang City].

Most studies on antibiotics in groundwater have focused on pollution characteristics, whereas less attention has been paid to the ecological risks of antibiotics and the correlation to environmental parameters. In this study, the groundwater in Shijiazhuang City was selected as the research area. Through high performance liquid chromatography-tandem mass spectrometry (HPLC-MS), the concentration of quinolones (QNs) in the groundwater was analyzed. Correlation analysis was conducted between QNs concentrations and physical-chemical parameters. The results showed that:① the detection frequency of flumequine (FLU) was the highest (100%), followed by enoxacin (ENO) (80.0%) and ciprofloxacin (CIP) (75.0%). ② The concentration of QNs ranged from 3.02 to 98.5 ng·L-1; in terms of spatial distribution, the highest concentration of QNs appeared at S4 (98.5 ng·L-1), whereas the lowest concentration was exhibited at S19 (3.02 ng·L-1). ③ Temperature (T), chemical oxygen demand (COD), total dissolved solids (TDS), total number of colonies (BCTC), and pH were significantly correlated with QNs (P<0.01 or P<0.05) based on correlation analysis. ④ For the spatial distribution of ecological risk, the results showed that the ecological risk at S4 was high, whereas the risks for other sites were low. For the type of QNs, ciprofloxacin (CIP) was at a medium-high risk level, whereas the other QNs were at a low-risk level. Thus, in order to guarantee the ecological safety of groundwater in Shijiazhuang City, more attention should be paid to the risk management and control of antibiotics in groundwater in the future.

Efficient with low-cost removal and adsorption mechanisms of norfloxacin, ciprofloxacin and ofloxacin on modified thermal kaolin: experimental and theoretical studies.

Quinolone antibiotics (QNs) can be potential hazard to environment and human. Combination of experimental and theoretical studies was used to analyze the adsorption properties of norfloxacin, ciprofloxacin and ofloxacin on modified thermally activated kaolin (KL). Main factors (calcination temperature, dose, pH, cations and regeneration) affecting the adsorption were discussed. Adsorption processes fit the pseudo-second order kinetic and Langmuir model well. The adsorption removal of norfloxacin, ciprofloxacin and ofloxacin can reach 88.53%, 89.43% and 91.46%, respectively. Cations inhibited adsorption, and AlS-KLB can maintain 80% efficiency in five cycles under optimal conditions. Simulations showed that the materials had good adsorption capacity for QNs, and the "①" of KL had the best capacity. Simulations explain the adsorption mechanism: F, H, O atoms of QNs are covalently bonded to O atoms from KL, Al2O3 and Al (OH)3, C atoms from amorphous carbon and H atoms from C-H and Al (OH)3. The Al atoms of Al2O3 and Al, Si atoms of KL are ionically bonded to F, H, O atoms of QNs. This study shed new light on the removal of QNs by providing low-cost and efficient modified KL and elucidating the adsorption mechanism in conjunction with DFT simulations.

Assessment of the Activity of Decoquinate and Its Quinoline-O-Carbamate Derivatives against Toxoplasma gondii In Vitro and in Pregnant Mice Infected with T. gondii Oocysts.

The quinolone decoquinate (DCQ) is widely used in veterinary practice for the treatment of bacterial and parasitic infections, most notably, coccidiosis in poultry and in ruminants. We have investigated the effects of treatment of Toxoplasma gondii in infected human foreskin fibroblasts (HFF) with DCQ. This induced distinct alterations in the parasite mitochondrion within 24 h, which persisted even after long-term (500 nM, 52 days) treatment, although there was no parasiticidal effect. Based on the low half-maximal effective concentration (IC50) of 1.1 nM and the high selectivity index of >5000, the efficacy of oral treatment of pregnant mice experimentally infected with T. gondii oocysts with DCQ at 10 mg/kg/day for 5 days was assessed. However, the treatment had detrimental effects, induced higher neonatal mortality than T. gondii infection alone, and did not prevent vertical transmission. Thus, three quinoline-O-carbamate derivatives of DCQ, anticipated to have better physicochemical properties than DCQ, were assessed in vitro. One such compound, RMB060, displayed an exceedingly low IC50 of 0.07 nM, when applied concomitantly with the infection of host cells and had no impact on HFF viability at 10 µM. As was the case for DCQ, RMB060 treatment resulted in the alteration of the mitochondrial matrix and loss of cristae, but the changes became apparent at just 6 h after the commencement of treatment. After 48 h, RMB060 induced the expression of the bradyzoite antigen BAG1, but TEM did not reveal any other features reminiscent of bradyzoites. The exposure of infected cultures to 300 nM RMB060 for 52 days did not result in the complete killing of all tachyzoites, although mitochondria remained ultrastructurally damaged and there was a slower proliferation rate. The treatment of mice infected with T. gondii oocysts with RMB060 did reduce parasite burden in non-pregnant mice and dams, but vertical transmission to pups could not be prevented.

Evaluation of the health and healthcare system burden due to antimicrobial-resistant Escherichia coli infections in humans: a systematic review and meta-analysis.

BACKGROUND: Assessment of the burden of disease due to antimicrobial-resistant Escherichia coli infections facilitates understanding the scale of the problem and potential impacts, and comparison to other diseases, which allows prioritization of research, surveillance, and funding. Using systematic review and meta-analysis methodology, the objectives were to evaluate whether humans with antimicrobial-resistant E. coli infections experience increases in measures of health or healthcare system burden when compared to susceptible E. coli infections. METHODS: Comprehensive literature searches were performed in four primary and seven grey literature databases. Analytic observational studies of human E. coli infections that assessed the impact of resistance to third/fourth/fifth-generation cephalosporins, resistance to quinolones, and/or multidrug resistance on mortality, treatment failure, length of hospital stay and/or healthcare costs were included. Two researchers independently performed screening, data extraction, and risk of bias assessment. When possible, random effect meta-analyses followed by assessment of the confidence in the cumulative evidence were performed for mortality and length of hospital stay outcomes, and narrative syntheses were performed for treatment failure and healthcare costs. RESULTS: Literature searches identified 14,759 de-duplicated records and 76 articles were included. Based on 30-day and all-cause mortality meta-analyses, regardless of the type of resistance, there was a significant increase in the odds of dying with resistant E. coli infections compared to susceptible infections. A summary mean difference was not presented for total length of hospital stay meta-analyses due to substantial to considerable heterogeneity. Since small numbers of studies contributed to meta-analyses for bacterium-attributable mortality and post-infection length of hospital stay, the summary results should be considered with caution. Studies contributing results for treatment failure and healthcare costs had considerable variability in definitions and reporting. CONCLUSIONS: Overall, resistant E. coli infections were associated with significant 30-day and all-cause mortality burden. More research and/or improved reporting are necessary to facilitate quantitative syntheses of bacterium-attributable mortality, length of hospital stay, and hospital costs. Protocol Registration PROSPERO CRD42018111197.

Assessment of antibacterial activity of levonadifloxacin against contemporary gram-positive clinical isolates collected from various Indian hospitals using disk-diffusion assay.

Objectives: Levonadifloxacin is a novel benzoquinolizine subclass of quinolone with broad-spectrum activities against problematic pathogens such as methicillin-resistant Staphylococcus aureus, quinolone-resistant S. aureus, vancomycin intermediate S. aureus, and vancomycin-resistant S. aureus. Levonadifloxacin and its oral prodrug, alalevonadifloxacin, have been recently approved in India for the treatment of acute bacterial skin and skin structure infections, including concurrent bacteraemia and diabetic foot infections. The aim of the study is to assess the activity of levonadifloxacin against Gram-positive clinical isolates collected from various Indian hospitals using the disc-diffusion method. Materials and Methods: Nonduplicate isolates of S. aureus and other Gram-positive isolates collected from June 2019 to March 2020 were subjected to levonadifloxacin susceptibility testing (disk diffusion method) as per the Clinical and Laboratory Standards Institute guidelines (Year 2019). Levonadifloxacin 10 µg impregnated disks were used during the testing. Results: A total of 664 diverse Gram-positive clinical isolates collected from six different hospitals in India were analyzed. Majority (65.5%) of the isolates were S. aureus. All the S. aureus and other Gram-positive isolates were found to be susceptible to levonadifloxacin as per the prespecified interpretive criteria identified based on population pharmacokinetic model and Monte Carlo simulation enabled probability of pharmacodynamic target attainment analysis. Conclusions: The present study showed that levonadifloxacin was highly active against contemporary Gram-positive pathogens and furthermore demonstrated that levonadifloxacin susceptibilities can be reliably determined using the disc-diffusion method.

Appropriateness of Otic Quinolone Use among Privately Insured US Patients.

OBJECTIVE: Considering emerging safety concerns involving otic quinolones, we assessed the extent of otic quinolone use for questionable indications. STUDY DESIGN: Descriptive cross-sectional study of a national sample of privately insured patients. SETTING: Outpatient encounters in the United States. SUBJECTS AND METHODS: Children and adults with outpatient pharmacy-dispensing claims for new prescriptions of otic or ophthalmic quinolones in 2017 were identified within the IBM MarketScan Commercial Claims & Encounters and the Medicare Supplemental Database. Each dispensing ≥30 days apart constituted a unique episode. Only claims with supporting ear-related diagnoses on outpatient encounters ±3 days of dispensing were considered. Ophthalmic drops were excluded if eye-related diagnoses were found ±30 days. Prescribing was classified as appropriate, questionable, or undetermined. RESULTS: We found 214,897 episodes in 200,270 patients. Adults were twice as likely as children to have otic treatment with questionable indications (6.2% vs 3.0%). Sensitivity analyses with broader time windows to ascertain diagnoses showed similar proportions of questionable use. Otalgia and cerumen impaction constituted 90% of questionable indications. Family physicians (6.8%) and internists (8.0%) had higher percentages of questionable use than other specialties. CONCLUSION: Based on the demonstrated risks of quinolone ear drops, opportunities exist to decrease otic quinolone use, especially in adults.

Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals.

In Japan, hospitals' pharmaceutical affairs committees freely select the drugs to be purchased depending on the regulations of each hospital. This system poses a risk of the absence of essential drugs or an excess of similar drugs, and may promote inappropriate use of third-generation cephalosporins (3GCs) and quinolones. Against this backdrop, we researched availability of antibacterial agents in Japanese hospitals. We conducted a questionnaire-based study in eastern Shizuoka Prefecture, Japan. Questionnaires were sent to 33 hospitals that had established an interactive regional partnership on infection control. We analyzed the number of available oral cephalosporins, macrolides, and quinolones in each hospital, and the correlation between the number of total available antibacterial agents and the hospital scale and cephalexin availability. Thirty-one hospitals participated in this study. First-generation cephalosporin (1 GC) was available in only 22.5% of them. In all participating hospitals, 3GCs were available, with more than one 3 GC available in 74.2%. Quinolones were available in all hospitals, and more than one quinolone in 67.7%. The numbers of hospital beds and total available antibacterial agents were positively correlated and hospitals that owned cephalexin available also significantly more often owned other available antibacterial agents. 1 GC were available in only a few hospitals, while multiple 3GCs and quinolones were available in most. This situation may lead to excess use of 3GCs or quinolones in Japan. A low number of available drugs was associated with cephalexin unavailability. Outpatient antimicrobial stewardship may focus not only on the quality of medicine, but also on the prescribing environment.

An Efficient and Scalable Synthesis of Quinolone 006.

Quinolone 006 is under development as an anti-methicillin-resistant Staphylococcus aureus quinolone antibiotic. A linear synthetic route was utilized to prepare the compound on a multi-kilogram scale with an overall yield of 71%. The process was optimized by controlling the temperature and the vacuum pressure. Examples of parameters examined in an effort to control the polymorphism of the 006 active pharmaceutical ingredient are described.

Utilization, Spending, and Price Trends for Quinolones in the US Medicaid Programs: 25 Years' Experience 1991-2015.

BACKGROUND: Given that the quinolones is one of the antibacterial classes most frequently used to treat patients with bacterial infections in the United States, any change in prescribing patterns of quinolones will impact Medicaid medical expenditures. OBJECTIVES: This study was undertaken to examine trends in utilization, reimbursement, and prices of quinolone antibacterials for the US Medicaid population. METHODS: The publicly available Medicaid State Drug Utilization outpatient pharmacy files were used for this study. Quarterly and annual prescription counts and reimbursement amounts were calculated for each of the quinolones reimbursed by Medicaid from quarter 1, 1991 through quarter 2, 2015. Average per-prescription reimbursement, as a proxy for drug price, was calculated as the drug reimbursement divided by the number of prescriptions. RESULTS: The total annual number of quinolone prescriptions increased 402%, from 247,395 in the first quarter of 1991 to 1.2 million in the second quarter of 2015, peaking at 1.3 million in the first quarter of 2005. Similarly, the total reimbursement for quinolone agents increased by 245.5% over the same period. More than 80% of quinolone prescriptions reimbursed by Medicaid were for the second-generation agent, ciprofloxacin, and the third-generation agent, levofloxacin. The average payment per prescription for quinolones increased from US$43.8 in the first quarter of 1991 to US$87.6 in the second quarter of 2015. CONCLUSIONS: A substantial rise in Medicaid expenditures on quinolones was observed during the 25-year study period, which was mainly because of rising utilization. Therefore, there is a need for additional research that has access to clinically relevant data with which to measure the rate of inappropriate quinolone use among the Medicaid population and associated clinical outcomes and healthcare costs.

Distribution and risk assessment of quinolone antibiotics in the soils from organic vegetable farms of a subtropical city, Southern China.

Organic fertilizer or manure containing antibiotics has been widely used in organic farms, but the distribution and potential impacts of antibiotics to the local environment are not well understood. In this study, four quinolone antibiotics in soil samples (n=69) from five organic vegetable farms in a subtropical city, Southern China, were analyzed using high performance liquid chromatography-tandem mass spectrometry. Our results indicated that quinolone compounds were ubiquitous in soil samples (detection frequency>97% for all compounds), and their concentrations ranged from not detectable to 42.0 µg/kg. Among the targets, enrofloxacin (ENR) was the dominant compound, followed by ciprofloxacin (CIP) and norfloxacin (NOR). The average total concentrations of four compounds in the soils were affected by vegetable types and species cultivated, decreasing in the order of fruit>rhizome>leaf vegetables. Moreover, the average concentrations of quinolone compounds (except ENR) in open-field soils were higher than those in greenhouse soils. The concentrations of quinolone antibiotics in this study were lower than the ecotoxic effect trigger value (100 µg/kg) proposed by the Veterinary Medicine International Coordination commission. Risk assessment based on the calculated risk quotients indicated that NOR, CIP, and ENR posed mainly medium to low risks to bacteria.

A simplified and cost-effective method combining real-time PCR and pyrosequencing for detection of aac(6')-Ib-cr gene.

We previously described a pyrosequencing-based method able to guarantee detection of aac(6')-Ib-cr by characterizing precisely the single nucleotide polymorphisms leading to Trp102Arg and Asp179Tyr. By gaining in simplicity and cost-effectiveness, through the use of real-time PCR, we propose here a cutting-edge evolution of our existing pyrosequencing method.