Minimum Inhibitory Concentration Ratio Research Articles

Population pharmacokinetic analysis for dose regimen optimization of vancomycin in Southern Chinese children.

Changes in physiological factors may result in large pharmacokineticvariability of vancomycin in pediatric patients, thereby leading to either supratherapeutic or subtherapeutic exposure and potentially affecting clinical outcomes. This study set out to characterize the disposition of vancomycin, quantify the exposure target and establish an optimal dosage regimen among the Southern Chinese pediatric population. Routine therapeutic drug monitoring data of 453 patients were available. We performed a retrospective population pharmacokineticanalysis of hospitalized children prescribed intravenous vancomycin using NONMEM® software. A one-compartment PPK model of vancomycin with body weight and renal functions as covariates based on a cutoff of 2 years old children was proposed in this study. Both internal and external validation showing acceptable and robust predictive performance of the model to estimate PK parameters. The value of area under the curve over 24 h to minimum inhibitory concentration ratio (AUC0-24/MIC) ≥ 260 was a significant predictor for therapeutic efficacy. Monte Carlo simulations served as a model-informed precision dosing approach and suggested that different optimal dose regimens in various scenarios should be considered rather than flat dosing. The evaluation of vancomycin exposure-efficacy relationship indicated that lower target level of AUC0-24/MIC may be needed to achieve clinical effectiveness in children, which was used to derive the recommended dosing regimen. Further prospective studies will be needed to corroborate and elucidate these results.

Estimation of MBC: MIC Ratio of Herbal Extracts against Common Endodontic Pathogens

ABSTRACT Herbal extracts have evoked interest owing to the small number of terpenoids and phenolic compounds, which impart antimicrobial, antioxidant, and anti-inflammatory properties. The minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and minimum fungicidal concentration (MFC) of four herbal extracts (lemon grass oil, basil oil, peppermint oil, and Obicure tea extract) against endodontic pathogens along with the MIC: MBC/MFC ratio were evaluated. The antimicrobial activity by detecting the MIC of three essential oils and tea extract was evaluated against eight common endodontic pathogens by the broth dilution method, while MBC was detected by subculturing onto blood agar from the first –three to five tubes from the MIC dilution tubes (showing no turbidity), which were plated on blood agar. All herbal extracts proved to be effective antimicrobials against tested endodontic pathogens. Basil oil had a bacteriostatic effect on all the organisms (P < 0.05). Mint oil showed bacteriostatic activity on Enterococcus (E.) faecalis and Peptostreptococcus (P > 0.05). Tea extract had a bacteriostatic effect (P > 0.05) against all tested microbes except Actinomyces, Lactobacilli, Staphylococcus (S.) aureus, and Fusobacterium (F.) nucleatum. Lemon grass oil had a bactericidal effect against all the organisms and a bacteriostatic effect against Peptostreptococcus (P > 0.05). It can be concluded that basil oil showed a strong bactericidal effect on the test organisms. The MIC for the organisms ranged from 0.2 to 50 μg/ml.

Daptomycin Dose Optimization in Pediatric Staphylococcus aureus Bacteremia: A Pharmacokinetic/Pharmacodynamic Investigation.

Daptomycin is an antibiotic with Gram-positive activity, including methicillin-resistant Staphylococcus aureus, for which optimal pediatric dosing is unknown. This study aimed to evaluate daptomycin exposures achieved with package label dosing and to identify dosing regimens necessary to enhance efficacy and minimize toxicity in children with S. aureus bacteremia. Monte Carlo simulations were performed to determine probability of target attainment (PTA) for six pediatric age cohorts. Area under the curve to minimum inhibitory concentration ratio (AUC0-24 :MIC) ≥666 was used to determine the PTA for efficacy (PTAE ). Minimum concentration (Cmin ) ≥24.3mg/L determined the PTA for toxicity (PTAT ). Acceptable dosing regimens were those which achieved the combined target of ≥90% PTAE and ≤5% PTAT . Package label dosing of daptomycin yielded insufficient efficacy with only 26.3% PTAE in children 13-24 months, 39.5% PTAE in children 2-6 years, 30.1% PTAE in children 7-11 years, and 50.1% PTAE in adolescents ≥12 years. To achieve the combined efficacy and safety target, doses of 18-24mg/kg in children 3-12 months, 20-24mg/kg in children 13-24 months, 19-24mg/kg in children 2-6 years, 17-19mg/kg in children 7-11 years, and 10-14mg/kg in adolescents ≥12 years are necessary. Package label dosing resulted in suboptimal exposure for the majority of pediatric patients in all age groups evaluated. If targeting validated efficacy and safety endpoints, daily daptomycin doses of at least 20mg/kg in children ≤6 years, 17mg/kg in children 7-11 years, and 10mg/kg in adolescents ≥12 years are necessary. Clinical studies evaluating these higher doses are needed.

Organo-Ptii Complexes for Potent Photodynamic Inactivation of Multi-Drug Resistant Bacteria and the Influence of Configuration.

PtII based organometallic photosensitizers (PSs) have emerged as novel potent photodynamic inactivation (PDI) reagents through their enhanced intersystem crossing (ISC) processes. Currently, few PtII PSs have been investigated as antibacterial materials, with relatively poor performances reported and with structure-activity relationships not well described. Herein, a pair of configurational isomers are reported of Bis-BODIPY (4,4-difluoro-boradizaindacene) embedded PtII PSs. The cis-isomer (cis-BBP) displayed enhanced 1 O2 generation and better bacterial membrane anchoring capability as compared to the trans-isomer (trans-BBP). The effective PDI concentrations (efficiency > 99.9%) for cis-BBP in Acinetobacter baumannii (multi-drug resistant (MDR)) and Staphylococcus aureus are 400nM (12Jcm-2 ) and 100nM (18Jcm-2 ), respectively; corresponding concentrations and light doses for trans-BBP in the two bacteria are 2.50µM (30Jcm-2 ) and 1.50µM (18Jcm-2 ), respectively. The 50% and 90% minimum inhibitory concentration (MIC50 and MIC90 ) ratio of trans-BBP to cis-BBP is 22.22 and 24.02 in A. baumannii (MDR); 21.29 and 22.36 in methicillin resistant S. aureus (MRSA), respectively. Furthermore, cis-BBP displays superior in vivo antibacterial performance, with acceptable dark and photoinduced cytotoxicity. These results demonstrate cis-BBP is a robust light-assisted antibacterial reagent at sub-micromolecular concentrations. More importantly, configuration of PtII PSs should be an important issue to be considered in further PDI reagents design.

Antibacterial activity of Clove Syzygium aromaticum L. and synergism with antibiotics against multidrug-resistant uropathogenic E. coli

Relevance. Urinary tract infections pose a growing threat to humanity due to the rise of antibiotic resistance in uropathogens. Exploring natural sources for alternative treatments has become a prominent approach. The aim of the research was to investigate the antibacterial effects of clove (Syzygium aromaticum L.) against uropathogenic Escherichia coli (E. coli). Materials and Methods. The research was performed on three clinical multidrug-resistant uropathogenic E. coli isolates and E. coli ATCC 25922. Clove hydroalcoholic extract was obtained by cold maceration technique. To evaluate the antibacterial activity of the extract, agar well diffusion method was performed. Minimum inhibitory and minimum bactericidal concentrations of the extract were determined by microbroth dilution method. Light microscopy was used to investigate morphological changes in uropathogenic E. coli after exposure to clove extract. Checkerboard assay was used to assess synergism between clove extract and antibiotics. All obtained data were statistically processed. Results and Discussion. In well diffusion method, bacterial responses to clove extract were concentration-dependent with inhibition zone diameter of 7-10/10-15 mm for uropathogenic strains and E. coli ATCC 25922, respectively. Minimum inhibitory and minimum bactericidal concentrations of clove extract against uropathogenic strains were 25 mg/mL. The extract showed a lower minimum inhibitory concentration against E. coli ATCC 25922 (6.25 mg/ mL) with minimum bactericidal concentration being 25 mg/mL. Minimum inhibitory and minimum bactericidal concentrations ratio showed that clove extract tends to be bactericidal agent. Synergy test revealed that the combination of clove extract and nitrofurantoin or ciprofloxacin resulted in no interaction. However, minimum inhibitory concentrations of all tested agents in combinations exhibited varying degrees of decrease. Incubation of uropathogenic strains with the extract transformed them to unstable spherical L-form in percentage of 96-99 %. Conclusion. This study highlights clove as a potential natural antibacterial agent against multidrug-resistant uropathogenic E. coli, warranting further investigations into its antibacterial properties.

Population pharmacokinetics and target attainment analysis of vancomycin after intermittent dosing in adults with cystic fibrosis.

Vancomycin is the first-line agent to treat pulmonary infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis (PwCF). However, there is no consensus on vancomycin initial dosing in this population among health institutions, and there is a large variability in initial dosing across the United States. In this study, we characterized the pharmacokinetics (PK) of vancomycin in PwCF using a population PK approach. The clinical PK data to develop the population PK model were obtained from vancomycin therapeutic monitoring data from PwCF undergoing treatment for infections due to MRSA. The population PK model was then used to perform comprehensive Monte Carlo simulations to evaluate the probability of target attainment (PTA) of 12 different initial dosing scenarios. The area under the curve to minimum inhibitory concentration (MIC) ratio ≥400 mg*h/L and <650 mg*h/L were used as efficacy and toxicity targets for PTA analysis. A total of 181 vancomycin plasma concentrations were included in the analysis. A one-compartment model with first-order elimination best described the data. Weight significantly influenced the vancomycin PK (P < 0.05). In the final model, clearance was estimated as 5.52 L/h/70 kg, and the volume of distribution was 31.5 L/70 kg. The PTA analysis showed that at MIC = 1 µg/mL, doses 1,500 q8h and 2,000 q12h showed the highest %PTA in achieving both efficacy and toxicity targets. The PTA results from this study may potentially inform the initial dosing regimens of vancomycin to treat pulmonary infections due to MRSA in PwCF.

5-Flucytosine Longitudinal Antifungal Susceptibility Testing of Cryptococcus neoformans: A Substudy of the EnACT Trial Testing Oral Amphotericin.

The EnACT trial was a phase 2 randomized clinical trial conducted in Uganda, which evaluated a novel orally delivered lipid nanocrystal (LNC) amphotericin B in combination with flucytosine for the treatment of cryptococcal meningitis. When flucytosine (5FC) is used as monotherapy in cryptococcosis, 5FC can induce resistant Cryptococcus mutants. Oral amphotericin B uses a novel drug delivery mechanism, and we assessed whether resistance to 5FC develops during oral LNC-amphotericin B therapy. We enrolled Ugandans with HIV diagnosed with cryptococcal meningitis and who were randomized to receive 5FC and either standard intravenous (IV) amphotericin B or oral LNC-amphotericin B. We used broth microdilution to measure the minimum inhibitory concentration (MIC) of the first and last cryptococcal isolates in each participant. Breakpoints are inferred from 5FC in Candida albicans. We measured cerebral spinal fluid (CSF) 5FC concentrations by liquid chromatography and tandem mass spectrometry. Cryptococcus 5FC MIC50 was 4 µg/mL, and MIC90 was 8 µg/mL. After 2 weeks of therapy, there was no evidence of 5FC resistance developing, defined as a >4-fold change in susceptibility in any Cryptococcus isolate tested. The median CSF 5FC concentration to MIC ratio (interquartile range) was 3.0 (1.7-5.5) µg/mL. There was no association between 5FC/MIC ratio and early fungicidal activity of the quantitative rate of CSF yeast clearance (R2 = 0.004; P = .63). There is no evidence of baseline resistance to 5FC or incident resistance during combination therapy with oral or IV amphotericin B in Uganda. Oral amphotericin B can safely be used in combination with 5FC.

Cefepime pharmacokinetics in adult extracorporeal membrane oxygenation patients

BackgroundThe impact of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics/dynamics (PK/PD) of beta-lactam antibiotics have not been well studied in general, but cefepime specifically has the least amount of data. We aimed to investigate whether ECMO alters the PK of cefepime in adult intensive care unit (ICU) patients. MethodsThis single-center, retrospective case-control study evaluated cefepime therapeutic drug monitoring (TDM) results from ECMO patients that were matched 1:1 with TDM results in non-ECMO patients for drug regimen and renal function. The primary outcome was the difference in PK/PD of cefepime in ECMO compared with non-ECMO ICU patients. Secondary outcomes included hospital length of stay, treatment failure, superinfection, bacterial resistance, and survival to discharge. ResultsEighty-two patients were included with 44 matched cefepime concentrations in each group. ECMO patients had higher free maximum concentrations (fCmax) (p = 0.003), lower free minimum concentration (fCmin)/1x minimum inhibitory concentration (MIC) ratios (p = 0.040), and lower attainment of free Cmin/4x MIC (p = 0.010). There were no differences between the groups for free Cmin, time above 1xMIC or 4x MIC, and pharmacokinetic parameters (ke, half-life, and Vd). Of those who survived to discharge, hospital length of stay was longer in the ECMO group (p < 0.001). Patients on ECMO were more likely to experience treatment failure (p = 0.036). The incidence of bacterial resistance, superinfection, or survival were similar among the groups. ConclusionThese data suggest that more aggressive empiric dosing may be warranted in patients on ECMO. Therapeutic drug monitoring and future prospective studies would provide more evidence to guide decision making regarding dose adjustments.

Feasibility of individualised patient modelling for continuous vancomycin infusions in outpatient antimicrobial therapy, a retrospective study.

The area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio is proposed as a therapeutic drug-monitoring parameter for dosing vancomycin continuous infusion in methicillin-resistant Staphylococcus aureus (MRSA) infection. Individualised pharmacokinetic-pharmacodynamic (PK/PD) calculation of AUC24 may better represent therapeutic dosing than current Therapeutic Drug Monitoring (TDM) practices, targeting a Steady State Concentration of 15-25mg/L. To compare real world TDM practice to theoretical, individualised, PK/PD target parameters utilising Bayesian predictions to steady state concentrations (Css) for outpatients on continuous vancomycin infusions. A retrospective single centre study was conducted at a tertiary hospital on adult patients, enrolled in an outpatient parenteral antimicrobial therapy (OPAT) program, receiving vancomycin infusions for MRSA infection. Retrospective Bayesian dosing was modelled to target PK/PD parameters and compared to real world data. Fifteen patients were evaluated with 53% (8/15) achieved target CSS during hospitalisation, and 83% (13/15) as outpatient. Median Bayesian AUC/MIC was 613mg.h/L with CSS 25mg/L. Patients suffering an Acute Kidney Injury (33%) had higher AUC0-24/MIC values. Retrospective Bayesian modelling demonstrated on median 250mg/24h lower doses than that administered was required (R2 = 0.81) which achieved AUC24/MIC median 444.8 (range 405-460) mg.h/L and CSS 18.8 (range 16.8-20.4) mg/L. Bayesian modelling could assist in obtaining more timely target parameters at lower doses for patients receiving continuous vancomycin infusion as part of an OPAT program, which may beget fewer adverse effects. Utilisation of personalised predictive modelling may optimise vancomycin prescribing, achieving earlier target concentrations as compared to empiric dosing regimens.

Antimicrobial activity and pathogen mutation prevention of originator and generics of cefepime, linezolid and piperacillin/tazobactam against clinical isolates of Staphylococcus aureus

Although generic medicinal products are required to have the same qualitative and quantitative composition of the active substance as their reference originator product, patients and health care professionals express concerns about their interchangeability and safety. Therefore, the present study investigated the antimicrobial activity and pathogen mutation prevention of original and generic cefepime, linezolid and piperacillin/tazobactam against Staphylococcus aureus. Two generic formulations of cefepime, linezolid and piperacillin/tazobactam were tested against their respective originator products. Susceptibility testing was performed with twenty-one clinical isolates of S. aureus and ATCC-29213 using broth microdilution. Time kill curves (TKC) were performed with ATCC-29213 at drug concentrations above and below the respective minimum inhibitory concentrations (MIC). Mutation prevention concentration was determined for each drug formulation against ATCC-29213. All experiments were performed in triplicate. Mutant colonies from mutation prevention concentration (MPC) experiments were genotypically tested by sequence analysis. MIC ratios between contiguous originator and generic drugs were similar for each isolate. No visual differences were observed in TKCs between originator and generic substances. The MPC did not differ between different formulations of the same substance. Although sequence analysis of mutant colonies revealed genomic differences compared with the original ATCC-29213, no differences in mutation frequencies were observed between clinical isolates and ATCC-29213 treated with originator or generic substances. Similar antimicrobial activity and pathogen mutation prevention was observed between contiguous substances. These results support the interchangeability of generic and originator drug formulations with the same active ingredient.

Recommendations of Gentamicin Dose Based on Different Pharmacokinetic/Pharmacodynamic Targets for Intensive Care Adult Patients: A Redefining Approach.

In addition to the maximum plasma concentration (Cmax) to the minimum inhibitory concentration (MIC) ratio, the 24-hour area under the concentration-time curve (AUC24h) to MIC has recently been suggested as pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy and safety in once-daily dosing of gentamicin (ODDG) in critically ill patients. This study aimed to predict the optimal effective dose and risk of nephrotoxicity for gentamicin in critically ill patients for two different PK/PD targets within the first 3 days of infection. The gathered pharmacokinetic and demographic data in critically ill patients from 21 previously published studies were used to build a one-compartment pharmacokinetic model. The Monte Carlo Simulation (MCS) method was conducted with the use of gentamicin once-daily dosing ranging from 5-10 mg/kg. The percentage target attainment (PTA) for efficacy, Cmax/MIC ~8-10 and AUC24h/MIC ≥110 targets, were studied. The AUC24h >700 mg⋅h/L and Cmin >2 mg/L were used to predict the risk of nephrotoxicity. Gentamicin 7 mg/kg/day could achieve both efficacy targets for more than 90% when the MIC was <0.5 mg/L. When the MIC increased to 1 mg/L, gentamicin 8 mg/kg/day could reach the PK/PD and safety targets. However, for pathogens with MIC ≥2 mg/L, no studied gentamicin doses were sufficient to reach the efficacy target. The risk of nephrotoxicity using AUC24h >700 mg⋅h/L was small, but the risk was greater when applying a Cmin target >2 mg/L. Considering both targets of Cmax/MIC ~8-10 and AUC24h/MIC ≥110, an initial gentamicin dose of 8 mg/kg/day should be recommended in critically ill patients for pathogens with MIC of ≤1 mg/L. Clinical validation of our results is essential.

In silico Evaluation of a Vancomycin Dosing Guideline Among Adults with Serious Infections.

This study aimed to compare the achievement of pharmacokinetic-pharmacodynamic (PK-PD) exposure targets for vancomycin using a newly developed dosing guideline with product-information-based dosing in the treatment of adult patients with serious infections. In silico product-information- and guideline-based dosing simulations for vancomycin were performed across a range of doses and patient characteristics, including body weight, age, and renal function at 36-48 and 96 hours, using a pharmacokinetic model derived from a seriously ill patient population. The median simulated concentration and area under the 24-hour concentration-time curve (AUC 0-24 ) were used to measure predefined therapeutic, subtherapeutic, and toxicity PK-PD targets. Ninety-six dosing simulations were performed. The pooled median trough concentration target with guideline-based dosing at 36 and 96 hours was achieved in 27.1% (13/48) and 8.3% (7/48) of simulations, respectively. The pooled median AUC 0-24 /minimum inhibitory concentration ratio with guideline-based dosing at 48 and 96 hours was attained in 39.6% (19/48) and 27.1% (13/48) of simulations, respectively. Guideline-based dosing simulations yielded improved trough target attainment compared with product-information-based dosing at 36 hours and significantly less subtherapeutic drug exposure. The toxicity threshold was exceeded in 52.1% (25/48) and 0% (0/48) for guideline- and product-information-information-based dosing, respectively ( P < 0.001). A Critical care vancomycin dosing guideline appeared slightly more effective than standard dosing, as per product information, in achieving PK-PD exposure associated with an increased likelihood of effectiveness. In addition, this guideline significantly reduced the risk of subtherapeutic exposure. The risk of exceeding toxicity thresholds, however, was greater with the guideline, and further investigation is suggested to improve dosing accuracy and sensitivity.

Micafungin pharmacodynamics predict clinical outcomes in hospitalized patients with candidemia caused by certain Candida species.

Echinocandins are guideline-preferred therapies for invasive candidiasis (IC). Fixed dosing of echinocandins is commonly used despite variations in body mass index and echinocandin susceptibility. The purpose of this study was to evaluate clinical outcomes of micafungin based on population-predicted pharmacokinetic/pharmacodynamic (PK/PD) factors and susceptibility. Candida isolate results were screened from bloodstream or intraabdominal cultures of hospitalized patients admitted to a quaternary-care teaching hospital. Patients with a first episode of IC who received micafungin for at least 48 h were included. Patients with mixed cultures or Candida species with no minimum inhibitory concentration (MIC) differences were excluded. Breakpoints for micafungin MIC and area under the curve (AUC)/MIC ratio were calculated using classification and regression tree (CART) analysis and related to clinical outcomes. Primary efficacy outcome was candida-contributable mortality, defined as mortality within 28 days of positive culture with concomitant micafungin treatment failure; secondary outcome was micafungin treatment failure within 28 days, MAIN RESULTS: Seventy-two patients were included of whom 15 (21%) had Candida-contributable mortality and 34 (47%) experienced micafungin treatment failure. C. albicans and C. tropicalis did not have differing MICs and these patients were excluded from the study. Mortality using a CART-derived MIC breakpoint of ≥1.0 mg/L was 38% compared to 9% in patients infected with lower MIC strains (p = 0.003). Patients with a CART-derived AUC/MIC value >138.5 had a mortality rate of 9% compared to 41% for patients with AUC/MIC values below the breakpoint (p = 0.0013). Results were similar for treatment failure rates, and both were confirmed using multivariable models. CART-derived micafungin MIC and AUC/MIC breakpoints predicted patient mortality and treatment failure for certain Candida species. These results support the need for further PK/PD studies to optimize echinocandin dosing and improve patient outcomes.

In vitro and ex vivo antibacterial activity of levofloxacin against Pasteurella multocida and Escherichia coli isolated from rabbits (Oryctolagus cuniculus) - A preliminary study.

Levofloxacin veterinary formulations are available in Argentina, China and India for the use in dogs, cattle, pig and sheep, but not currently in the rabbit. Only the extra-label use in rabbits is possible. Levofloxacin is not labelled for veterinary use in the EU or the USA. The activity of levofloxacin against rabbit pathogens Pasteurella multocida (P. multocida) and Escherichia coli (E. coli) was evaluated. Minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were determined in broth and serum for 10 P. multocida isolates and 5 E. coli isolates from rabbits. One isolate of each bacterial species was used for the time-killing curve study in vitro and ex vivo. In vitro AUC24 /MIC ratios were used for building the inhibitory pharmacodynamic Imax model. The P. multocida MIC were 0.008-0.5 μg/mL, MBC - 0.015-0.5 μg/mL. Escherichia coli MIC was 0.008-0.03 μg/mL and MBC - 0.03-0.25 μg/mL. Bacterial counts were reduced to the limit of detection after 24 h with levofloxacin concentrations of 2 MIC and higher. All serum samples from rabbits treated with levofloxacin eliminated the bacteria within 24 h. AUC24 /MIC ratios for bacteriostatic, bactericidal and bacterial elimination effects for P. multocida and E. coli isolates were 21, 29 and 75 h and 27, 32 and 60 h, respectively. Proposed daily doses against P. multocida (MIC = 0.015 μg/mL) and E. coli (MIC = 0.03 μg/mL) isolates were calculated as ≤0.91 and ≤1.43 mg/kg, respectively. Fluoroquinolones are categorized by WHO as 'highest priority critically important antimicrobials'. Considering the increasing importance of antimicrobial stewardship, antimicrobials from a lower importance category that are active against the isolate of interest should be used in preference to fluoroquinolones. Fluoroquinolone use in veterinary medicine should be based on antimicrobial susceptibility testing in order to mitigate the risk to public health and prevent the spread of bacterial resistance.

Integrating in Silico and In Vitro Studies to Screen Anti-Staphylococcus aureus Activity From Vietnamese Ganoderma multiplicatum and Ganoderma sinense

Background: Staphylococcus aureus is a nosocomial pathogen responsible for many serious infectious diseases in humans. Finding the anti- S. aureus agents is a time-consuming and costly process. Recently, computational methods have provided a better understanding of the interactions between herbal medicine drug targets to help clinical practitioners rationally design herbal formulae. Methods: In this study, molecular docking simulation was applied to screen a list of natural secondary metabolites from Ganoderma sp. on the protein target S. aureus sortase A. Molecular dynamics models were used to assess the stability of protein–ligand complexes during the first 100 ns. To validate the computational results, 2 Ganoderma species, G. multiplicatum VNKKK1901 and G. sinense VNKKK1902, were tested for antibacterial activity against S. aureus using the disk diffusion method. Results: The results showed that, among the selected compounds, ganosinensin B and ganosinoside A generated the highest binding energy on S. aureus sortase A, and demonstrated strong and stable binding capacity to proteins. In addition, the extracts of G. sinense VNKKK1902 and G. multiplicatum VNKKK1901 were bactericidal, with minimum bactericidal concentration (MBC)/minimum inhibitory concentration (MIC) ratios of 2. Conclusion: Our findings provide the first scientific report on the antibacterial activity of Ganoderma sp., which contain 2 promising compounds, ganosinensin B and ganosinoside A, as potential hits for developing novel drugs capable of supporting treatment of S. aureus infection.

Pharmacokinetic/pharmacodynamic analysis of vancomycin in patients with Enterococcus faecium bacteraemia: a retrospective cohort study

ObjectivesThe trough concentration of vancomycin and the area under the concentration–time curve (AUC)/minimum inhibitory concentration (MIC) ratio are crucial in determining vancomycin efficacy against methicillin-resistant Staphylococcus aureus. However, the use...

Determining the Antibacterial Effect of Mentha Longifolia Essential Oil on Cariogenic Bacteria and Its Compounds: an in vitro Study.

Continuous use of chemical agents to reduce the number of cariogenic bacteria leads to adverse effects; therefore, in recent years, many studies have focused on plant-based substances. This study explores the antibacterial effects of Mentha Longifolia (M. longifolia) essential oil on Streptococcus mutans (S. mutans), Streptococcus sobrinus (S. sobrinus), and Lactobacillus as cariogenic microorganisms and determines the compounds in it. In this experimental study, S. mutans, S. sobrinus, and Lactobacillus isolates were collected from the saliva samples of five children with severe early childhood caries (S-ECC). The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of M. longifolia essential oil were determined by Broth microdilution method. Chlorhexidine 0.2% and phosphate-buffered normal saline (pH= 7.0) were used as positive and negative controls, respectively. The chemical composition of M. longifolia essential oil was evaluated by gas chromatography-mass spectrometry. The data were analyzed with a paired t-test and the p below 0.05 was considered significant. The MIC and MBC ratios for S. mutans were 3.12% and 6.25%, for S. sobrinus were 6.25% and 12.5%, ​​and Lactobacillus were 3.12% and 6.25%, respectively. Chemical analysis of M. longifolia essential oil showed that 34 various compounds. Piperitone oxide (27.59%), Transcariophylline (14.55%), and 2-cyclohexane-1-one (12.24%) were the major constituents. M. longifolia essential oil has both growth inhibitory and bactericidal effects on all the three species of bacteria. This antibacterial effect was similar against S. mutans and Lactobacillus, which was greater than S. sobrinus, thus, it can be used as a supplementary for caries prevention compounds.

What is the right gentamicin dose for multiple trauma patients? A Monte Carlo simulation exploration study.

The appropriate dose of gentamicin is important to prevent and treat infections. The study aimed to determine the optimal dose of gentamicin to achieve the probability of pharmacokinetic/pharmacodynamic (PK) targets for efficacy and safety in multiple trauma patients. PK parameters of gentamicin in multiple trauma patients were gathered to develop a one-compartment PK model for prediction. The Monte Carlo simulation method was performed. The 24-h area under the concentration time curve to the minimum inhibitory concentration ratio (AUC24h/MIC) ≥50 was defined for the infection prevention target. AUC24h/MIC ≥110 or the maximum serum concentration to MIC ratio ≥8-10 was for the treatment of serious Gram-negative infection target. The risk of nephrotoxicity was the minimum serum concentration ≥2 mg/L. The optimal dose of gentamicin was determined when the efficacy target was >90% and the risk of nephrotoxicity was lowest. The optimal gentamicin dose to prevent infection when the MIC was <1 mg/L was 6-7 mg/kg/day. A higher dose of gentamicin up to 10 mg/kg/day could not reach the target for treating serious Gram-negative infection when the expected MIC was ≥1 mg/L. The probability of nephrotoxicity was minimal at 0.2-4% with gentamicin doses of 5-10 mg/kg/day for 3 days. Once daily gentamicin doses of 6-7 mg/kg are recommended to prevent infections in patients with multiple trauma. Gentamicin monotherapy could not be recommended for serious infections. Further clinical studies are required to confirm our results.

Pharmacokinetic/Pharmacodynamic Analysis of Continuous-Infusion Fosfomycin in Combination with Extended-Infusion Cefiderocol or Continuous-Infusion Ceftazidime-Avibactam in a Case Series of Difficult-to-Treat Resistant Pseudomonas aeruginosa Bloodstream Infections and/or Hospital-Acquired Pneumonia.

To perform a pharmacokinetic/pharmacodynamic (PK/PD) analysis of continuous-infusion (CI) fosfomycin combined with extended-infusion (EI) cefiderocol or CI ceftazidime-avibactam in a case series of severe difficult-to-treat Pseudomonas aeruginosa (DTR-PA) infections. A single-center retrospective study of patients who were treated with CI fosfomycin plus EI cefiderocol or CI ceftazidime-avibactam for severe DTR-PA infections and who underwent therapeutic drug monitoring (TDM), from 1 September 2021 to 30 June 2022 was performed. Concentrations were measured at steady-state (Css) for CI fosfomycin and ceftazidime-avibactam and at trough (Cmin) for EI cefiderocol. Joint PK/PD targets of combination therapy were analyzed (thresholds: area-under-the curve to minimum inhibitory concentration (AUC/MIC) ratio &gt; 40.8 for fosfomycin; ceftazidime Css/MIC ratio ≥ 4 coupled with avibactam Css &gt; 4 mg/L for ceftazidime-avibactam; Cmin/MIC ratio ≥ 4 for cefiderocol). Joint PK/PD targets of the combination therapy were analyzed and defined as optimal when both were achieved, quasi-optimal if only one of the two was achieved, and suboptimal if none of the two was achieved). The relationship between joint PK/PD target attainment and microbiological response was assessed. Six patients (three pneumonia, two BSI + pneumonia, and one BSI) were included. The joint PK/PD targets were optimal in four cases and quasi-optimal in the other two. Microbiological eradication (ME) occurred in 4/4 of patients with optimal joint PK/PD targets and in one of the two patients with quasi-optimal joint PK/PD targets. Attaining optimal joint PK/PD targets with a combo-therapy of CI fosfomycin plus EI cefiderocol or CI ceftazidime-avibactam could represent an effective strategy for granting favorable microbiological outcomes in patients with DTR-PA pneumonia and/or BSI.

618. Pharmacokinetic/pharmacodynamic analysis of combination therapy with continuous infusion (CI) fosfomycin plus extended-infusion (EI) or CI beta-lactams for treating documented carbapenem-resistant Gram-negative bloodstream infections and/or hospital-acquired pneumonia: a case series

Abstract Background To describe the pharmacokinetic/pharmacodynamic (PK/PD) behaviour and the microbiological outcome of combination therapy with continuous infusion (CI) fosfomycin plus extended-infusion (EI) or CI beta-lactams for treating severe carbapenem-resistant Gram-negative (CR-GN) infections. Methods Single-center retrospective study of patients who were treated with CI fosfomycin plus EI or CI beta-lactams for severe CR-GN infections and who underwent therapeutic drug monitoring (TDM), from 01 April 2021 to 31 January 2022. Concentrations of CI fosfomycin, meropenem and ceftazidime-avibactam were determined at steady-state (Css), while those of EI cefiderocol were measured at trough (Cmin). The desired joint PK/PD targets of combination therapy were considered as optimal when simultaneously the area-under-the curve to minimum inhibitory concentration (AUC/MIC) ratio for fosfomycin was &amp;gt; 83 and the Css/MIC for meropenem or for ceftazidime-avibactam or the Cmin/MIC ratio for cefiderocol was &amp;gt; 4 (quasi-optimal if only one of the two was achieved, and suboptimal if none of the two was achieved). Relationship between the joint PK/PD targets and microbiological failure (MF) defined as isolation of the same pathogens from follow-up blood cultures or BAL and assessed within 30 days of treatment onset, was investigated. Results Among the 16 retrieved patients with documented CR-GN infections, 12 underwent TDM of both fosfomycin and beta-lactams, and seven out of these (3 HAP, 3 BSI+HAP, and one BSI) had determination of fosfomycin MIC determined by agar-dilution (see Table). The joint PK/PD targets were optimal in 4 cases and quasi-optimal in the other 3y. MF occurred in two patients (29%) who were affected by HAP, received combination therapy with ceftazidime-avibactam, and achieved only quasi-optimal joint PK/PD targets (with fosfomycin AUC/MIC &amp;lt; 83). No MF occurred in patients with optimal joint PK/PD targets. Summary of the relationship between PK/PD targets and microbiological failure in patients receiving combination therapy with CI fosfomycin plus EI/CI beta-lactams Conclusion CI fosfomycin in combination with EI/CI beta-lactams may allow for the achievement of optimal joint PK/PD targets in most patients with CR-GN infections, and may represent a potential strategy for minimizing the risk of MF. Disclosures All Authors: No reported disclosures.