Minimum Inhibitory Concentration Data Research Articles

Prediction of antimicrobial minimal inhibitory concentrations for Neisseria gonorrhoeae using machine learning models

The lowest concentration of an antimicrobial agent that can inhibit the visible growth of a microorganism after overnight incubation is called as minimum inhibitory concentration (MIC) and the drug prescriptions are made on the basis of MIC data to ensure successful treatment outcomes. Therefore, reliable antimicrobial susceptibility data is crucial, and it will help clinicians about which drug to prescribe. Although few prediction studies based on strategies have been conducted, however, no single machine learning (ML) modelling has been carried out to predict MICs in N. gonorrhoeae. In this study, we propose a ML based approach that can predict MICs of a specific antibiotic using unitigs sequences data. We retrieved N. gonorrhoeae genomes from European Nucleotide Archive and NCBI and analysed them combined with their respective MIC data for cefixime, ciprofloxacin, and azithromycin and then we constructed unitigs by using de Brujin graphs. We built and compared 35 different ML regression models to predict MICs. Our results demonstrate that RandomForest and CATBoost models showed best performance in predicting MICs of the three antibiotics. The coefficient of determination, R2, (a statistical measure of how well the regression predictions approximate the real data points) for cefixime, ciprofloxacin, and azithromycin was 0.75787, 0.77241, and 0.79009 respectively using RandomForest. For CATBoost model, the R2 value was 0.74570, 0.77393, and 0.79317 for cefixime, ciprofloxacin, and azithromycin respectively. Lastly, using feature importance, we explore the important genomic regions identified by the models for predicting MICs. The major mutations which are responsible for resistance against these three antibiotics were chosen by ML models as a top feature in case of each antibiotics. CATBoost, DecisionTree, GradientBoosting, and RandomForest regression models chose the same unitigs which are responsible for resistance. This unitigs-based strategy for developing models for MIC prediction, clinical diagnostics, and surveillance can be applicable for other critical bacterial pathogens.

The Evaluation of Meropenem Dosing Regimens Against ESBL-Producing Escherichia coli in ICU Patients Using Monte Carlo Simulation.

PurposeTo evaluate the optimal dosing regimens of meropenem against extended-spectrum beta-lactamase-producing Escherichia coli (ESBL E. coli) in critically ill patients with varying degrees of renal function using Monte Carlo simulation (MCS).MethodsThe MCS was performed using the minimum inhibitory concentration (MIC) data from Right Laboratory and Health Screen in Naypyitaw, Myanmar, as well as reported meropenem pharmacokinetic parameters in the target population and the pharmacokinetic-pharmacodynamic index. For each dosing regimen, 10,000 virtual patients were generated to assess the probability of target attainment (PTA) and the cumulative fraction of response (CFR). The most effective dosage regimens were determined using PTA and a CFR of 90%.ResultsESBL E. coli made up 93 of the 396 clinical E. coli isolates, and they are all multidrug-resistant, with resistance to at least five antibiotic classes. The MIC50 and MIC90 were determined to be 0.25 μg/mL. The PTA was affected by five factors: creatinine clearance (CLcr), vasopressor usage, MIC, infusion time, and dosage fractionation. In patients who did not receive vasopressors, the current regimens (US-FDA and EMA) were ineffective in all renal function for MIC >0.25μg/mL. In the subset group of CLcr >80 mL/min for MIC 2μg/mL, the maximum total daily dose of 6g/day (2g q 8hr; 3hr infusion) was still ineffective, but 4g/day (1g q 6hr; 3hr infusion) achieved 98.96% PTA. Almost majority of the simulated regimens produced >90% PTA in vasopressor-dependent patients with all levels of renal function, resulting in a decreased total daily dose requirement.ConclusionFor high MIC (>1μg/mL) patients who do not use vasopressors and have a CLcr >80 mL/min, a combination of dosage fractionation and the extended infusion was considered as an effective technique to maximize target attainment. Neither prolonged infusion nor dosage fractionation should be explored in patients using vasopressors.

Surveillance of Fluoroquinolone Resistance in Wisconsin: Geographic Variation and Impact of Revised CLSI Breakpoints

Objective: Many clinical microbiology laboratories procure antimicrobial susceptibility testing data using guidelines established by Clinical and Laboratory Standards Institute (CLSI). When necessary, CLSI revises interpretive breakpoints in efforts to improve clinical correlation, with two revisions relative to fluoroquinolone agents occurring in 2019. The purpose of this investigation was to determine the impact of fluoroquinolone breakpoint revisions on Wisconsin clinical isolates of Escherichia coli, Proteus mirabilis, and Pseudomonas aeruginosa. Design: Multi-center laboratory surveillance, with testing at a single location utilizing standardized media and susceptibility testing protocols.Methods: From the Surveillance of Wisconsin Organisms for Trends in Antimicrobial Resistance and Epidemiology (SWOTARE) program, levofloxacin and ciprofloxacin minimum inhibitory concentration (MIC) values for 1911, 1521, and 1463 Wisconsin isolates of E. coli, P. mirabilis, and P. aeruginosa, respectively, were determined by broth microdilution testing. In separate data analyses, all MIC data were interpreted using CLSI breakpoints published prior to 2019, then secondarily by using CLSI breakpoints published since 2019 (which reflect lower breakpoints for both levofloxacin and ciprofloxacin resistance). Findings were further stratified by Wisconsin Department of Health Services region.Results: Up to 3.2% decreased statewide fluoroquinolone susceptibility was observed for E. coli isolates, while 5.1% and 6.3% decreases in levofloxacin susceptibility were noted for P. aeruginosa and P. mirabilis isolates, respectively, when revised breakpoints were applied. E. coli isolates from the Western region and P. mirabilis isolates from the Southeastern region demonstrated significant shifts toward decreased fluoroquinolone susceptibility upon application of revised breakpoints. Northern region P. mirabilis isolates exhibited consistently decreased fluoroquinolone susceptibility.Conclusions: Fluoroquinolone resistance has been underreported in Wisconsin as a whole, yet geographic variability continues to exist. Targeted annual surveillance is important to identify and monitor resistance trending. Compilations of SWOTARE surveillance data can be utilized to predict the impact of future CLSI interpretive breakpoint revisions in Wisconsin.

Exploring the Chemical Composition and Bioactivity of Ethanol Extract from Russula pseudocyanoxantha (Agaricomycetes), a Novel Mushroom of Tribal Preference in India.

At present, wild edible mushrooms have attracted considerable interest for their applications in the treatment of degenerative diseases, even though the majority of members have yet to be fully described. In this regard, our team has recently discovered a new macrofungus, Russula pseudocyanoxantha Paloi, K. Acharya & S. Khatua, from tribal cuisine that has long been valued for its health-promoting effects. However, the traditional wisdom remains confined to inhabiting forest dwellers, as the species is not being purchased in the outskirts due to a lack of awareness. This background inspired us to carry out a thorough investigation; thus, the goal of the present study was to explore R. pseudocyanoxantha chemically and pharmacologically using ethanol as the extractant solvent. Metabolite profiling demonstrated enrichment of the fraction with a range of phenolics (5.58 μg of gallic acid equivalents/mg of extract) such as chlorogenic acid, p-coumaric acid, salicylic acid, quercetin, cinnamic acid, and pyrogallol. The presence of flavonoid (4.07 μg of quercetin extracts/mg of extract), β-carotene (0.04 μg/mg of extract), lycopene (0.02 μg/mg of extract), and ascorbic acid (2.34 μg/mg of extract) was also evident. Conversely, notable antioxidant activity was perceived in terms of DPPH· scavenging, ABTS·+ quenching, and Fe2+ chelating ability where half maximal effective concentration EC50 values ranged from 776 to 1357 μg/mL. In addition, the extract possessed good antibacterial properties, particularly against Gram-positive microorganisms (Listeria monocytogenes, Bacillus subtilis, and Staphylococcus aureus), as evident by low minimum inhibitory concentration data (72-280.5 μg/mL). In addition, a noteworthy antiproliferative effect was also observed as the preparation inhibited Hep3B cell proliferation (IG50 of 481.59 μg/mL), suppressed cell migration, caused nuclear condensation, altered mitochondrial membrane potential, and triggered reactive oxygen species production, indicating involvement of mitochondria-mediated pathway. Thus, the present study showcases R. pseudocyanoxantha as a value-added mushroom that can be used in the food, pharmaceutical, and cosmeceutical fields.

An integrated approach to evaluate different tetracycline derivatives for formulary decisions

Stenotrophomonas maltophilia has emerged as a critical opportunistic pathogen associated with significant morbidity and mortality. Tetracycline derivatives have been recognized as alternative treatment options, but they have varied pharmacokinetic properties. An integrated approach to different tetracycline derivatives for formulary decisions is reported. The minimum inhibitory concentration (MIC) data from clonally diverse bloodstream S. maltophilia isolates were examined, along with the pharmacokinetic profiles of 4 tetracycline derivatives, to predict achievable pharmacodynamic exposures with standard intravenous dosing regimens. Antimicrobial therapy was assessed using the ratio of daily drug acquisition cost relative to the ratio of the free-drug area under the time-concentration curve (fAUC) to minimum inhibitory concentration (MIC) for 90% of isolates (fAUC/MIC90). In our analysis, minocycline had the greatest fAUC/MIC90. Doxycycline was the most financially preferred agent, as calculated using 2020 average wholesale price for base-case estimates of drug acquisition cost. An integrated evaluation for antimicrobial formulary decision-making addressed local susceptibility data, pharmacokinetics, pharmacodynamics, dosing regimens, and drug acquisition costs. This comprehensive method is more objective than the conventional approach and warrants validation.

Optimized protocols for assessing libraries of poorly soluble sortase A inhibitors for antibacterial activity against medically-relevant bacteria, toxicity and enzyme inhibition

Increasing antimicrobial resistance is a major global health concern. Conventional antibiotics apply selection pressures, which promote the accumulation of resistant microbes. Anti-virulence strategies, in contrast, are less potent antimicrobials, but are less likely to select for resistance, can be combined with existing antibiotics to improve their activity, and in some cases can overcome antimicrobial resistance towards other antimicrobials. Sortase A inhibitors (SrtAIs) represent an exciting example of this class; however, many reported examples demonstrate poor water solubility, which complicates their biological assessment and activity. This includes reports that use antimicrobial concentrations of organic solvents or conditions that fail to solubilise these compounds for minimal inhibitory concentration (MIC) assessments. Herein, we report the first study to optimise screening processes for a library of prospective SrtAIs (trans-chalcone (TC), berberine (BR), curcumin (CUR), and quercetin (QC)), including comparative assessment of the effects of various co-solvent concentrations, along with comparative assessment of their antimicrobial activities against multiple disease relevant bacterial strains (methicillin-sensitive and resistant S. aureus, E. coli, and P. aeruginosa), inhibition of the sortase A enzyme, and toxicity towards mammalian cells (HEK-293), using these optimised conditions. Optimal solubility with minimal effect on bacterial viability was observed in the presence of 5% (v/v) dimethyl sulfoxide (DMSO)-Mueller-Hinton Broth. Three antimicrobial susceptibility tests (broth microdilution, agar dilution, and disk diffusion) were assessed for their ability to accurately determine minimal inhibitory concentration (MIC) data for each SrtAI. Broth microdilution and agar dilution were both effective; however, the broth microdilution assay required the addition of a colorimetric metabolic indicator (resazurin) to enable simple and reliable MIC determination due to the development of precipitants over time. In contrast, disk diffusion did not provide reliable zone of inhibition data. Identical MIC data was observed with methicillin-sensitive and -resistant S. aureus (MRSA; ATCC43300), with lower potency activity against E. coli and P. aeruginosa. Under these conditions, TC and CUR demonstrated significant toxicity towards human embryonic kidney (HEK-293) cells, with QC showing less toxicity and BR limited-to-no toxicity at its MIC. Overall, the findings of this work provide optimised processes, which will prove useful for the study of other poorly soluble antimicrobial agents and SrtAIs. The obtained data suggests that BR should be considered in preference to the other SrtAIs for the development of new antimicrobial formulations, based on its superior antimicrobial and SrtA inhibition potency, and greatly reduced toxicity.

Prevalence, Risk Factors, and Antimicrobial Resistance Profile of Respiratory Pathogens Isolated From Suckling Beef Calves to Reprocessing at the Feedlot: A Longitudinal Study.

Here, we investigated the prevalence and risk factors for the presence of Histophilus somni, Mannheimia haemolytica, Mycoplasma bovis, and Pasteurella multocida in the respiratory tract of calves from the spring processing to the reprocessing at feedlots. Additionally, we characterized, phenotypically and genotypically, the antimicrobial resistance (AMR) profile of the four species. Calves from 22 cow–calf operations were enrolled in the study (n = 30 calves per operation) and sampled by deep nasopharyngeal swabs at three time points: spring processing, weaning, or induction into feedlots, and at reprocessing at the feedlot. Isolates were tested for susceptibility using the minimum inhibitory concentration (MIC) test against commonly administered antimicrobials. Additionally, a subset of isolates underwent whole-genome sequencing to infer presence of AMR genes and resistance determinants. Among studied pathogens, P. multocida was the most prevalent species, regardless of time point, followed by M. haemolytica, M. bovis, and H. somni. For M. bovis, a sharp increase in prevalence was detected at the reprocessing sampling, whereas for P. multocida, an increase in prevalence was observed at the weaning/induction sampling. Comingling and co-location of feedlots were not associated with prevalence of any respiratory pathogen. In terms of AMR, resistance against macrolides was prevalent in M. bovis, with most isolates resistant against tildipirosin, tilmicosin, and tylosin. In general, there was limited evidence to support an increase in resistance rates of respiratory bacteria from the spring processing to reprocessing at feedlots, with the exception of florfenicol resistance in M. bovis, which increased at reprocessing. Metaphylactic administration of tetracyclines at feedlot induction was not associated with the MIC of tetracyclines in any respiratory bacteria. Conversely, there were clear associations between the parenteral use of macrolides as metaphylaxis at the feedlot induction, and increased MIC against macrolides in P. multocida, M. haemolytica, and H. somni. Overall, the AMR phenotypes were corroborated by presence of AMR genes. We hypothesize that the administration of macrolides such as tulathromycin at feedlot induction contributes to historical changes in macrolides MIC data of respiratory bacteria of beef cattle.

PepVAE: Variational Autoencoder Framework for Antimicrobial Peptide Generation and Activity Prediction.

New methods for antimicrobial design are critical for combating pathogenic bacteria in the post-antibiotic era. Fortunately, competition within complex communities has led to the natural evolution of antimicrobial peptide (AMP) sequences that have promising bactericidal properties. Unfortunately, the identification, characterization, and production of AMPs can prove complex and time consuming. Here, we report a peptide generation framework, PepVAE, based around variational autoencoder (VAE) and antimicrobial activity prediction models for designing novel AMPs using only sequences and experimental minimum inhibitory concentration (MIC) data as input. Sampling from distinct regions of the learned latent space allows for controllable generation of new AMP sequences with minimal input parameters. Extensive analysis of the PepVAE-generated sequences paired with antimicrobial activity prediction models supports this modular design framework as a promising system for development of novel AMPs, demonstrating controlled production of AMPs with experimental validation of predicted antimicrobial activity.

Silver nanoparticles: an ecological method of synthesis, properties and use against antibiotic resistant microflora

A quantitative assessment of the antibacterial effect of silver nanoparticles on polyantibiotic-resistant grampositive and gram-negative microorganisms was carried out. Silver nanoparticles were synthesized by the environmentally friendly metal-steam synthesis method. The size and electronic state of nanoparticles were investigated by transmission electron and X-ray photoelectron spectroscopy. The antibacterial properties of nanomaterials were assessed on two clinical pathogenic strains of gram-positive and four strains of gram-negative microorganisms. The typing and assessment of bacterial resistance to antibiotics were carried out on a microbiological analyzer. The antibacterial effect of nanoparticles was quantitatively assessed using the dilution method and the determination of the minimum inhibitory and minimum bactericidal concentrations.It was found that the studied silver nanoparticles have sizes in the range from 5 to 24 nm with an average diameter of 10.8 nm. It was shown that all clinical strains of microorganisms used in the study are characterized by multiple antibacterial resistance; the percentage of their antibiotic resistance ranges from 12.5 to 93.3 %. It was found that for the studied microorganism, the values of the minimum inhibitory concentration (MIC) are in the range from 7.81 to 31.25 μg/ml, and the minimum bactericidal concentration (MBC) is in the range from 31.25 to 62.50 μg/ml. The obtained MIC and MBC data can be used to create promising antimicrobial drugs and medical next generation devices.

Identification and Characterization of a Novel Aminoglycoside 3''-Nucleotidyltransferase, ANT(3'')-IId, From Acinetobacter lwoffii.

A novel plasmid-encoded aminoglycoside 3''-nucleotidyltransferase ANT(3")-IId, was discovered in Acinetobacter lwoffi strain H7 isolated from a chick on an animal farm in Wenzhou, China. The whole-genome of A. lwoffii H7 consisted of one chromosome and five plasmids (pH7-250, pH7-108, pH7-68, pH7-48, and pH7-11). ant(3")-IId was identified as being encoded on pH7-250, sharing the highest amino acid identity of 50.64% with a function-known resistance gene, ant(3")-IIb (KB849358.1). Susceptibility testing and enzyme kinetic parameter analysis were conducted to determine the function of the aminoglycoside 3"-nucleotidyltransferase. The ant(3")-IId gene conferred resistance to spectinomycin and streptomycin [the minimum inhibitory concentration (MIC) levels of both increased 16-fold compared with the control strain]. Consistent with the MIC data, kinetic analysis revealed a narrow substrate profile including spectinomycin and streptomycin, with Kcat/Km ratios of 4.99 and 4.45×103M−1 S−1, respectively. Sequencing analysis revealed that the ant(3")-IId gene was associated with insertion sequences (IS) element [ΔISAba14-ΔISAba14-hp-orf-orf-orf1-ant(3")-IId], and ant(3")-IId were identified in plasmids from various Acinetobacter species. This study of the novel aminoglycoside 3"-nucleotidyltranferase ANT(3")-IId helps us further understand the functional and sequence characteristics of aminoglycoside 3"-nucleotidyltranferases, highlights the risk of resistance gene transfer among Acinetobacter species and suggests that attention should be given to the emergence of new aminoglycoside 3"-nucleotidyltranferase genes.

Correlation of minimum inhibitory concentrations between human and animal antimicrobials against Escherichia coli isolated from livestock.

We analyzed the correlation between minimum inhibitory concentrations (MICs) of antimicrobials used in humans and those used in animals to enable comparison of antimicrobial susceptibility between Escherichia coli isolated from humans and those from animals. We compared the following pairs of MIC data: piperacillin (PIPC) to ampicillin (ABPC), amikacin (AMK) to kanamycin (KM), minocycline (MINO) to oxytetracycline (OTC), and levofloxacin (LVFX) to enrofloxacin (ERFX) using 103 isolates of E. coli from healthy livestock (cattle, pigs, broiler chickens, and layer chickens). Kappa analysis of the agreement for resistance and susceptibility between PIPC and ABPC, AMK and KM, MINO and OTC, and LVFX and ERFX showed almost perfect (κ = 0.81), slight (κ = 0.12), fair (κ = 0.37), and moderate (κ = 0.46) agreement, respectively. Within the antimicrobial pairs, all isolates resistant to the human antimicrobial were also resistant to the veterinary antimicrobial. However, there was less agreement within the pairs for those isolates that were sensitive to the human antimicrobial. The percentage agreement for susceptibility, defined as the percentage of isolates sensitive to both antimicrobials compared with isolates sensitive to both antimicrobials, as well as those sensitive only to the human antimicrobial, was 89.9%, 87.3%, 64.0%, and 89.9% for PIPC and ABPC, AMK and KM, MINO and OTC, and LVFX and ERFX, respectively. Our results suggest that the possibility of missing the resistance for antimicrobials used in human medicine by examining MICs for the equivalent antimicrobials used in veterinary medicine is low.

Repurposing Avermectins and Milbemycins against Mycobacteroides abscessus and Other Nontuberculous Mycobacteria.

Infections caused by nontuberculous mycobacteria (NTM) are increasing worldwide, resulting in a new global health concern. NTM treatment is complex and requires combinations of several drugs for lengthy periods. In spite of this, NTM disease is often associated with poor treatment outcomes. The anti-parasitic family of macrocyclic lactones (ML) (divided in two subfamilies: avermectins and milbemycins) was previously described as having activity against mycobacteria, including Mycobacterium tuberculosis, Mycobacterium ulcerans, and Mycobacterium marinum, among others. Here, we aimed to characterize the in vitro anti-mycobacterial activity of ML against a wide range of NTM species, including Mycobacteroides abscessus. For this, Minimum Inhibitory Concentration (MIC) values of eight ML were determined against 80 strains belonging to nine different NTM species. Macrocyclic lactones showed variable ranges of anti-mycobacterial activity that were compound and species-dependent. Milbemycin oxime was the most active compound, displaying broad-spectrum activity with MIC lower than 8 mg/L. Time kill assays confirmed MIC data and showed bactericidal and sterilizing activity of some compounds. Macrocyclic lactones are available in many formulations and have been extensively used in veterinary and human medicine with suitable pharmacokinetics and safety properties. This information could be exploited to explore repurposing of anti-helminthics for NTM therapy.

In Vitro Antifungal Drug Resistance Profiles of Clinically Relevant Members of the Mucorales (Mucoromycota) Especially with the Newer Triazoles.

Mucoromycoses (infections caused by members of the order Mucorales, phylum Mucoromycota [ex-Zygomycota]) are highly destructive, rapidly progressive infections, with dire prognoses especially when they occur in immunocompromised hosts. Current treatment guidelines recommend liposomal formulations of amphotericin B with adjunctive surgery as first line therapy, with the newer triazoles posaconazole or isavuconazole as alternative treatments, or as salvage therapy. Among the many organisms belonging to this order, a limited number of species in the genera Rhizopus, Mucor, Lichtheimia and Rhizomucor are responsible for most cases of human infection. Here, we present the minimum inhibitory concentration data (MICs) for amphotericin B, posaconazole, isavuconazole, itraconazole and voriconazole with a panel of over 300 isolates of the five most common agents of human infection (Lichtheimia corymbifera, Rhizopus arrhizus, R. microsporus, Rhizomucor pusillus and Mucor spp.) determined using the CLSI broth microdilution method. In agreement with previous studies, the most active antifungal drug for all Mucorales was amphotericin B, with MICs within the range that would predict susceptibility with Aspergillus fumigatus. Conversely, MICs for voriconazole against all species tested were high, and above the range associated with clinical efficacy with A. fumigatus. Interestingly, whilst isavuconazole and posaconazole MIC distributions indicated in vitro activity against some members of the Mucorales, activity was species-dependent for both agents. These data underscore the importance of accurate identification of the causative agents of mucoromycosis, coupled with antifungal susceptibility testing of individual isolates, in determining the optimal treatment of infections caused by these aggressive opportunistic human fungal pathogens.

Meloxicam and Study of Their Antimicrobial Effects against Phyto- and Human Pathogens.

Recently, the design of new biological metal-ligand complexes has gained a special interest all over the world. In this research, new series of mixed ligand complexes from meloxicam (H2mel) and glycine (Gly) were synthesized. Structures of the compounds were investigated employing elemental analyses, infrared, electronic absorption, 1H NMR, thermal analyses, effective magnetic moment and conductivity. The estimated molar conductivity of the compounds in 1 × 10−3 M DMF solution indicates the non-electrolyte existence of the examined complexes. Additionally, the effective magnetic moment values refer to the complexes found as octahedral molecular geometry. The data of the infrared spectra showed the chelation of H2mel and Gly with metal ions from amide oxygen and nitrogen of the thyizol groups of H2mel and through nitrogen of the amide group and oxygen of the carboxylic group for Gly. Thermal analyses indicated that the new complexes have good thermal stability and initially lose hydration water molecules followed by coordinated water molecules, Gly and H2mel. The kinetic parameters were calculated graphically using Coats–Redfern and Horowitz–Metzeger methods at n = 1 and n ≠ 1. The density functional theory (DFT) calculations were performed at B3LYP levels. The optimized geometry of the ligand and its complexes were obtained based on the optimized structures. The data indicated that the complexes are soft with η value in the range 0.114 to 0.086, while η = 0.140 for free H2mel. The new prepared complexes were investigated as antibacterial and antifungal agents against some phyto- and human pathogens and the minimum inhibitory concentration (MIC) data showed that complex (A) has the lowest MIC for Listeria and E. coli (10.8 µg/mL).

Super Bioavailable Itraconazole and Its Place and Relevance in Recalcitrant Dermatophytosis: Revisiting Skin Levels of Itraconazole and Minimum Inhibitory Concentration Data.

Itraconazole, is the most commonly prescribed oral antifungal agent in India, and has a low minimum inhibitory concentration as compared to other oral antifungals, and in conjunction with the markedly high skin levels, the drug should have a predictably good clinical response which is not the consistent experience of clinicians. Probably the variation in pelletization parameters might affect the bioavailability of the drug and consequently affect the serum levels. The maximum bioavailability of conventional itraconazole is 55 percent, which is neither consistent nor predictable. However, the novel itraconazole (Super bioavailable Itraconazole) with targeted drug release in the small intestine has predictable serum levels with minimum interindividual variability, which could make it a potentially useful drug in recalcitrant dermatophytosis.

Genome Research for Asian Tuberculosis (GReAT)

Aims and objectives: To establish a Mycobacterium tuberculosis genome database in collaboration with Asian countries, and to utilise the data for genotypic drug susceptibility and testing molecular epidemiology Methods: M. tuberculosis isolates collected in each participating country based on drug resistance and/or prevalence survey was collected as bacteria or genomic DNA, and whole genome sequencing was performed using Illumina sequencers. As a meta-data, the minimum inhibitory concentration (MIC) and conventional drug susceptibility testing (DST) data were collected for each isolate. Results: Approximately 5,000 genome data has been collected from Japan, China, Korea, Taiwan, Philippines, Vietnam, and Mongolia. Approximately 75% of isolates belonged to lineage 2.2.1. Base on the MIC and mutations/indels data, some confident mutations/indels were identified. With the data, the sensitivity of genetic DST for pyrazinamide was increased from 60.1% to 97.2% without losing specificity. Conclusions: Genome database will be a basis of genotypic DST and molecular epidemiology. However, the confidence of meta-data including MIC and other clinical information will be the key factor of genome database. In addition, genome data solution programme/software will be of great importance.

242. Seasonality in antibiotic use and resistance across multiple bacterial pathogens and antibiotic classes

BackgroundAntibiotic use is an important driver of antibiotic resistance. Previous studies have shown that this relationship is detectable on a seasonal timescale, where seasonally cycling antibiotic prescribing corresponds with cycling levels of resistance. Here, we evaluated the seasonal relationship between antibiotic use and resistance across multiple species and antibiotic classes in Boston, Massachusetts.MethodsTo conduct our study, we analyzed antibiotic claims data from the Massachusetts All Payers Claims Database for five antibiotic classes, beta-lactams, macrolides, quinolones, tetracyclines, and nitrofurans, which together account for 74% of the total outpatient antibiotic claims in this dataset. In addition, we analyzed antibiotic susceptibility data for clinical isolates collected from two tertiary care hospitals, focusing on three clinically important bacterial pathogens. Our analysis included a total of 131,815 Escherichia coli, 47,208 Staphylococcus aureus, and 27,237 Klebsiella pneumoniae isolates collected over the years 2007–2019, with susceptibility testing data for 5–6 antibiotics per species. To determine the extent of seasonality in use and resistance, we fit the antibiotic claims data for each antibiotic class and the minimum inhibitory concentration (MIC) data for each species-antibiotic combination to a sinusoidal model with either a 6 or 12-month period.ResultsWe found that use of all 5 antibiotic classes and resistance in 9 out of 15 species-antibiotic combinations showed a significant amplitude of seasonality (p-value < 0.05). Despite different seasonal peaks in antibiotic use across classes, resistance peaked in the winter for almost all species-antibiotic combinations and was most highly correlated with use of winter-peaking antibiotic classes, beta-lactams and macrolides.ConclusionOverall, these results suggest that co-resistance and “bystander” selection – selection for resistance in asymptomatically colonizing and potentially pathogenic bacteria that are not the direct target of treatment – mediate the effects of antibiotic prescribing on the landscape of resistance.Disclosures All Authors: No reported disclosures

915. Global 2018 Surveillance of Eravacycline Against Gram-positive Pathogens, Including Resistant Isolates

BackgroundEravacycline (ERV) is a fully-synthetic, fluorocycline antibacterial approved by the FDA and EMA for the treatment of complicated intra-abdominal infections (cIAI) in patients ≥18 years of age. The purpose of this study was to further monitor the in vitro activity of ERV against Gram-positive pathogens, such as Staphylococcus aureus (including methicillin-resistant S. aureus, MRSA), Enterococcus spp. (including vancomycin-resistant Enterococcus, VRE) and Streptococcus spp.MethodsIsolates were collected globally during 2018 from various body sites. Minimum inhibitory concentrations (MICs) were determined by CLSI broth microdilution. Antibiotic susceptibility was determined using the most recent CLSI breakpoints (30th ed CLSI M100 document), except for ERV and tigecycline (TGC) where FDA breakpoints from 2018 and 2005, respectively, were applied.ResultsSummary MIC data for ERV and select comparators are shown in the Table. ERV MIC50/90 for Enterococcus spp were 0.06/0.12 μg/mL and were not affected by the presence of vancomycin resistant mechanisms. The MIC90 of ERV against VRE was 2-fold lower than TGC, at a value of 0.12 μg/mL. ERV MIC90 values for methicillin-susceptible S. aureus (MSSA) was 0.12 μg/mL and for MRSA was 0.25 μg/mL. Generally, for all pathogens, ERV MIC90 values were 2- to 4-fold lower than TGC.Table ConclusionERV in vitro activity was demonstrated for clinically important Gram-positive pathogens, including resistant isolates. Overall, ERV demonstrated lower MIC90 values than comparators for all organisms. This 2018 global surveillance highlights ERV’s utility against Gram-positive organisms and further underscores its role in cIAI, where these pathogens play a causative role.DisclosuresSteven Morgan, PharMD, Tetraphase Pharmaceuticals (Employee) Sara Hwang, PharMD, Tetraphase Pharmaceuticals (Employee) Ekaterina Efimova, PharMD, Tetraphase Pharmaceuticals (Employee) Stephen Hawser, PhD, Tetraphase Pharmaceuticals (Scientific Research Study Investigator) Virgil Lijfrock, PharMD, Tetraphase (Employee)

1613. Global 2018 Surveillance of Eravacycline Against Gram-negative Pathogens, Including Multi-drug Resistant Isolates

BackgroundEravacycline (ERV) is a fully-synthetic, fluorocycline antibacterial approved by the FDA and EMA for treatment of complicated intra-abdominal infections (cIAI) in patients ≥18 years of age. The purpose of this study was to describe the in vitro activity of ERV against Gram-negative pathogens, including multi-drug resistant (MDR) isolates, collected in 2018.MethodsIsolates were collected during 2018 from various body sites. Minimum inhibitory concentrations (MICs) were determined by CLSI broth microdilution. Antibiotic susceptibility was determined using the most updated CLSI breakpoints, except for ERV and tigecycline (TGC) where FDA breakpoints established in 2018 and 2005 respectively, were used. MDR was defined as resistance to ≥3 antibiotics from aztreonam, a carbapenem (meropenem or ertapenem [ETP]), cefepime/cefotaxime/ceftazidime/ceftriaxone (any one), gentamicin, levofloxacin, piperacillin-tazobactam TZP, tetracycline or TGC.ResultsSummary MIC data for ERV and select comparators are shown in the Table. ERV MIC90 for all-Enterobacteriaceae was 0.5 μg/ml and for MDR-Enterobacteriaceae was 1μg/ml. The susceptibilities for all-Enterobacteriaceae were 93%, 95%, 93% and 82% for ERV, TGC, ETP and TZP, respectively. ERV further demonstrated higher rates of susceptibility than ETP and TZP against MDR-Enterobateriaceae, 81% vs 71% vs 38%. ERV MIC50/90 for carbapenem-resistant Acinetobacter baumannii (CRAB) were 4-fold lower than TGC.Table ConclusionERV in vitro activity was demonstrated and comparable susceptibility rates were observed for clinically important Gram-negative pathogens, including resistant isolates. Overall, ERV MIC90 values were 2- to 8- fold lower than TGC. this study further highlights the in vitro activity of ERV against Gram-negative pathogens identified in patients with cIAI.DisclosuresVirgil Lijfrock, PharMD, Tetraphase (Employee) Steven Morgan, PharMD, Tetraphase Pharmaceuticals (Employee) Sara Hwang, PharMD, Tetraphase Pharmaceuticals (Employee) Ekaterina Efimova, PharMD, Tetraphase Pharmaceuticals (Employee) Kenneth Lawrence, PharmD, Tetraphase Pharmaceuticals (Employee) Stephen Hawser, PhD, Tetraphase Pharmaceuticals (Scientific Research Study Investigator) Ian Morrissey, PhD, Tetraphase Pharmaceuticals (Scientific Research Study Investigator)

Revisiting the Revised CLSI Breakpoint for Detecting Fluoroquinolones Resistance in Salmonella

Resistance towards fluoroquinolones and treatment failure is a matter of concern in enteric fever. The present study was undertaken to analyze the susceptibility pattern of Salmonella towards fluoroquinolones using 2006 and 2013 Clinical Laboratory Standards Institute (CLSI) breakpoint for interpretation and revisit the efficacy of Nalidixic acid resistance (NAR) as a phenotypic marker. A retrospective analysis of the zone of inhibition (ZOI) diameter data and minimum inhibitory concentration (MIC) data of 105 Salmonella was conducted. The ZOI diameter analysis showed that all isolates were susceptible to Ofloxacin and Ciprofloxacin using the previous 2006 ZOI breakpoint. However, with the revised 2013 breakpoint of Ciprofloxacin, the susceptibility percent dropped significantly and for Ofloxacin the breakpoint was not revised, so the percentage remained unchanged. The MIC analysis showed that all isolates were susceptible towards Ofloxacin and 97.14 % of isolates were susceptible to Ciprofloxacin using the previous 2006 MIC breakpoint, while the susceptibility decreased for both antibiotics with the revised 2013 MIC breakpoint. Statistically, the ZOI diameter of Nalidixic acid and MIC values of Ciprofloxacin and Ofloxacin was negatively correlated. To conclude, the revision of breakpoints addresses the problem of screening fluoroquinolones resistance but the emerging fluoroquinolones resistance situation is still a matter of concern in healthcare facilities of Nepal. Thus a reliable screening method is need of the hour as NAR cannot be considered a reliable marker to screen fluoroquinolones resistance