Minimum Inhibitory Concentration Activity Research Articles

Continuous Infusion of Piperacillin/Tazobactam and Meropenem in ICU Patients Without Renal Dysfunction: Are Patients at Risk of Underexposure?

Morbidity and mortality from serious infections are common in intensive care units(ICUs). The appropriateness of the antibiotic treatment is essential to combat sepsis. We aimed to evaluate pharmacokinetic/pharmacodynamic target attainment of meropenem and piperacillin/tazobactam administered at standard total daily dose as continuous infusion in critically ill patients without renal dysfunction and to identify risk factors of non-pharmacokinetic/pharmacodynamic target attainment. We included 118 patients (149 concentrations), 47% had microorganism isolation. Minimum inhibitory concentration (MIC)[median (interquartile range, IQR) values in isolated pathogens were: meropenem: 0.05 (0.02-0.12) mg/l; piperacillin: 3 (1-4) mg/l]. Pharmacokinetic/pharmacodynamic target attainments (100%fCss≥1xMIC, 100%fCss≥4xMIC and 100%fCss ≥ 8xMIC, respectively) were: 100%, 96.15%, 96.15% (meropenem) and 95.56%, 91.11%, 62.22% (piperacillin) for actual MIC; 98.11%, 71.70%, 47.17% (meropenem, MIC 2 mg/l), 95.83%, 44.79%, 6.25% (piperacillin, MIC 8 mg/l), 83.33%, 6.25%, 1.04% (piperacillin, MIC 16 mg/l) for EUCAST breakpoint of Enterobacteriaceae spp. and Pseudomonas spp. Multivariable linear analysis identified creatinine clearance (CrCL) as a predictive factor of free antibiotic concentrations (fCss) of both therapies (meropenem [β = - 0.01 (95% CI - 0.02 to - 0.0; p = 0.043)] and piperacillin [β = - 0.01 (95% CI - 0.02 to 0.01, p < 0.001)]). Neurocritical status was associated with lower piperacillin fCss [β = - 0.36 (95% CI - 0.61 to - 0.11; p = 0.005)]. Standard total daily dose of meropenem allowed achieving pharmacokinetic/pharmacodynamic target attainmentsin ICU patients without renal dysfunction. Higher doses of piperacillin/tazobactam would be needed to cover microorganisms with MIC > 8 mg/l. CrCL was the most powerful factor predictive of fCss in both therapies.

Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment.

Linezolid has been successfully used for treatment of multidrug-resistant tuberculosis (MDR-TB). However, dose- and duration-related toxicity limit its use. Here, our aim was to search relevant pharmacokinetics (PK)/pharmacodynamics (PD) literature to identify the effective PK/PD index and to define the optimal daily dose and dosing frequency of linezolid in MDR-TB regimens. The systematic search resulted in 8 studies that met inclusion criteria. A significant PK variability was observed. Efficacy of linezolid seems to be driven by area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC). Literature is inconclusive about the preferred administration of a daily dose of 600 mg. To prevent development of drug resistance, an AUC/MIC ratio of 100 in the presence of a companion drug at relevant exposure is required. A daily dose of 600 mg seems appropriate to balance between efficacy and toxicity. Being a drug with a very narrow therapeutic window, linezolid treatment may benefit from a more personalized approach, that is, measuring actual MIC values and therapeutic drug monitoring.

Higher versus standard amikacin single dose in emergency department patients with severe sepsis and septic shock: a randomised controlled trial

Recent studies suggest that intensive care unit patients treated with amikacin frequently do not attain the desired pharmacokinetic/pharmacodynamic (PK/PD) target, i.e. peak amikacin concentration (Cpeak) to minimum inhibitory concentration (MIC) ratio of ≥8, when a single dose of 15 mg/kg is used. No data are available for patients admitted to the emergency department (ED). The aim of this prospective randomised controlled study was to determine PK/PD target attainment in ED patients presenting with severe sepsis or septic shock treated with 15 mg/kg versus 25 mg/kg amikacin. Patients were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg. Amikacin Cpeak values were determined. The primary outcome was target attainment defined as Cpeak/MIC ≥ 8 both using EUCAST susceptibility breakpoints and actually documented MICs as denominator. A total of 104 patients were included. The EUCAST-based target was attained in 76% vs. 40% of patients assigned to the 25 mg/kg vs. 15 mg/kg dose groups (P < 0.0001). Target attainment using actual MICs (median of 2 mg/L, documented in 48 isolated Gram-negative pathogens) was achieved in 95% vs. 94% of patients in the 25 mg/kg vs. 15 mg/kg dose groups (P = 0.969). Risk factors associated with PK/PD target failure were identified in the multivariable analysis. At least 25 mg/kg amikacin as a single dose should be used in ED patients with severe sepsis and septic shock to attain the EUCAST-based PK/PD target. However, when using local epidemiology as denominator, 15 mg/kg appears to be sufficient. [ClinicalTrials.gov ID: NCT02365272.

Enhanced antifungal effects of amphotericin B-TPGS-b-(PCL-ran-PGA) nanoparticles in vitro and in vivo.

BackgroundAmphotericin B (AMB) is a polyene antibiotic with broad spectrum antifungal activity, but its clinical toxicities and poor solubility limit the wide application of AMB in clinical practice. Recently, new drug-loaded nanoparticles (NPs) – diblock copolymer D-α-tocopheryl polyethylene glycol 1000 succinate-b-poly(ε-caprolactone-ran-glycolide) (PLGA-TPGS) – have received special attention for their reduced toxicity, and increased effectiveness of drug has also been reported. This study aimed to develop AMB-loaded PLGA-TPGS nanoparticles (AMB-NPs) and evaluate their antifungal effects in vitro and in vivo.MethodsAMB-NPs were prepared with a modified nanoprecipitation method and then characterized in terms of physical characteristics, in vitro drug release, stability, drug-encapsulation efficiency, and toxicity. Finally, the antifungal activity of AMB-NPs was investigated in vitro and in vivo.ResultsAMB-NPs were stable and spherical, with an average size of around 110 nm; the entrapment efficacy was closed to 85%, and their release exhibited a typically biphasic pattern. The actual minimum inhibitory concentration of AMB-NPs against Candida albicans was significantly lower than that of free AMB, and AMB-NPs were less toxic on blood cells. In vivo experiments indicated that AMB-NPs achieved significantly better and prolonged antifungal effects when compared with free AMB.ConclusionThe AMB-PLGA-TPGS NP system significantly improves the AMB bioavailability by improving its antifungal activities and reducing its toxicity, and thus, these NPs may become a good drug carrier for antifungal treatment.

473Comparison of MicroScan System Prompt and Turbidity Methods for Measuring Vancomycin Minimum inhibitory concentration (MIC) against Methicillin-resistant Staphylococcus aureus (MRSA) with MIC of 2ug/ml, the Clinical Implications and economic impact of using alternative antimicrobial agents to vancomycin for MRSA with possible MIC of 2ug/ml

cost and potential for antibiotics resistance. A single-center, observational study included 21 MRSA cultures of sterile sites with vancomycin MIC of 2ug/ml by MicroScan Prompt method. MicroScan Turbidity and BMD method correlated with each other 100%. The effect of Vancomycin MIC 2ug/ml in tertiary care hospital on antibiotics change was observed. The average increase in cost was 16.2 times of the Vancomycin price.. The MicroScan Turbidity method which costs the same as Prompt method is a better test to estimate the actual Vancomycin MIC and its results are almost comparable to the standard BMD method.

Synthesis and antitubercular activity of novel pyrazole–quinazolinone hybrid analogs

A series of 2-(substituted-phenyl)-3-(((3-(pyridin-4-yl)-1-(p-tolyl)-1H-pyrazol-4-yl)methylene)amino)-quinazolin-4(3H)-ones have been synthesized. The structures of the synthesized compounds were assigned on the basis of IR, 1H NMR, 13C NMR, and mass spectral data, while their abilities to inhibit growth of Mycobacterium tuberculosis in vitro have been determined. The results show that compounds 5a, 5c, 5d, 5g, and 5k exhibited excellent antitubercular activity with percentage inhibition of 96, 90, 94, 93, and 92, respectively at a minimum inhibitory concentration (MIC) of 6.25 μg/mL. From the secondary screening, the actual MIC of compounds 5a, 5c, 5d, 5g, and 5k are <3.125.

Effect of MIC interpretative breakpoint revision on cephalosporin and carbapenem susceptibility among ESBL-producing Enterobacteriaceae

Background: Minimum inhibitory concentration (MIC) breakpoints of selected cephalosporins and carbapenems against Enterobacteriaceae have been revised by major guidelines including CLSI and EUCAST mainly according to available pharmacokinetic/pharmacodynamic data. A decrease of breakpoint may obviate the need to detect specific resistance mechanisms such as extended-spectrum �-lactamase (ESBL) and carbapenemase, which may be less correlated to treatment outcome than does the actual MIC of each agent. Objective: To analyze cephalosporin and carbapenem MIC distributions among ESBL-producing Enterobacteriaceae at a university hospital against revised interpretative breakpoints. Methods: MIC distributions of selected cephalosporins and carbapenems among 505 isolates of genotypically confirmed ESBL-producing Enterobacteriaceae were determined by E-test TM method and analyzed according to interpretative breakpoints comparing between CLSI and EUCAST guidelines. Results: ESBL-producing Enterobacteriaceae demonstrated a wide range of cephalosporin MIC ( 64). Up to 9.7% of isolates displayed MIC lower than a revised cephalosporin breakpoint. Most isolates remained susceptible to imipenem and meropenem while as high as 24.6% were not susceptible to ertapenem. Lowered breakpoints may result in a change in categorical interpretations. Conclusion: ESBL-producing isolates could be reported as susceptible to a cephalosporin with revised breakpoints although clinical use is uncertain. A higher proportion of isolates would be reported as nonsusceptible to cephalosporins or carbapenems with lowered breakpoints and thus increasing use of broadspectrum antimicrobial agents should be monitored.

Comparative MIC evaluation of a generic ceftriaxone by both microdilution on clinically relevant isolates from an academic hospital complex in South Africa

We evaluated the in vitro microbiological efficacy of a generic ceftriaxone product against several clinically significant organisms collected from sterile sites. The minimum inhibitory concentration (MIC) of each was determined simultaneously with the reference and the generic ceftriaxone product. Comparative analysis of MICs between the two products for each isolate was performed using both categorical (interpretive) agreement and essential (actual MIC value) agreement. A total of 260 isolates were tested. Overall, there was categorical agreement of 98.9% and essential agreement of 95.8%. The categorical agreement for all isolates (96.7 - 100%) accorded with international standards, as no very major errors were seen and the major error rate was less than 3%. Of the 90 isolates of E. coli (40), Klebsiella spp. (40) and Salmonella spp. (10), 87.6% had an MIC less than or equal to 0.12mg/l. The generic ceftriaxone product showed equivalent efficacy by MIC determination to the reference formulation. Ceftriaxone remains a viable and useful antimicrobial agent against a variety of clinically relevant organisms in our setting.

4-(3-coumarinyl)-4-thiazolin-2-one benzylidenehydrazones with antituberculosis activity.

In this study a new series of 4-(3-coumarinyl)-4-thiazoline-2-one benzylidenehydrazones (3a-v) were synthesized by condensation of 3-(omega-bromoacetyl)coumarins (1a and 1b) with 1-substituted benzylidene-4-substituted thiosemicarbazides (2a-1). Structures of the title compounds were elucidated by elemental analyses and spectrometric data (UV, IR, 1H-NMR and EIMS). These new compounds and some previously reported compounds (1a-d) were evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv. The compounds exhibited varying degrees of inhibition in the in vitro primary screening that was conducted at 12 micrograms/ml against M. tuberculosis H37Rv in BACTEC 12B medium using the BACTEC 460 radiometric system. 1b, 3b, 3e, 3h, 3o and 3p demonstrating activity in the primary screen were re-tested at lower concentrations against M. tuberculosis H37Rv to determine the actual minimum inhibitory concentration (MIC) in CABTEC 460 and Alamar Blue assay (MABA). The most active compound was found to be 1b. The structure-activity relationships of the derivatives were investigated.

Synthesis and antituberculosis activity of cycloalkylidenehydrazide and 4-aza-1-thiaspiro[4.5]decan-3-one derivatives of imidazo[2,1-b]thiazole.

New N2-cycloalkylidene-(6-phenyl/4-chlorophenylimidazo[2,1-b]thiazol-3-yl) acetic acid hydrazides (2a-h and 3a-b) were synthesized by reacting (6-phenyl/4-chlorophenylimidazo[2,1-b]thiazol-3-yl)acetic acid hydrazides with cyclohexanones or cyclopentanone. Furthermore, 2a-h were refluxed with thioglycolic or thiolactic acid to give 4-[[(6-phenyl/4-chlorophenylimidazo[2,1-b]thiazol-3-yl) acetyl]amino]-4-aza-1-thiaspiro[4.5]decan-3-ones (4a-h and 5a-h). The structures of the title compounds were established by spectral data (IR, 1H-NMR, 13C-NMR and EIMS (Electron Impact Mass Spectrometry)) and elemental analysis. The synthesized compounds were evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv (ATCC 27294). The compounds exhibited varying degrees of inhibition in the in vitro primary screening that was conducted at a concentration of 6.25 micrograms/ml against M. tuberculosis H37Rv (ATCC 27294) in Bactec 12B medium using the Bactec 460 radiometric system or a broth microdilution assay, the Microplate Alamar Blue Assay (MABA). Compounds 2f, 2h, 3b, 4a, 4c, 4d, 5a-e and 5h demonstrating at 1-east 90% inhibition in the primary screen were re-tested at lower concentrations against M. tuberculosis H37Rv (ATCC 27294) to determine the actual minimum inhibitory concentration (MIC) using MABA. The most active compounds were found to be 4d and 5c. The structure-activity relationships of the derivatives were investigated.

Some toxicological impacts and invitro antibacterial activity of Datura innoxia extract in rats

The study was carried out to investigate some toxicological effects and in-vitro antibacterial activity of Datura innoxia dried leaves.The yield percentage of Datura innoxia 95% ethyl alcohol leaves extract was 19%. Phytochemicals analysis of both Datura innoxia leaves powder and alcoholic extract, indicated the presence of alkaloids, phenols, glycosides, tannins, resins, saponins, flavonoids and steroids which are responsible for toxic and therapeutic effects. The acute toxicological effect of Datura innoxia ethanolic extract in male rats was determined by estimation the oral median lethal dose (LD50) by up and down method was 1214 mg/kg. BW. The in-vitro antibacterial activity of Datura innoxia ethanolic extract and its minimum inhibitory concentration activity (MIC) showed that E. coli was more sensitive to D.I ethanolic extract than Staph. aureus, the MIC for D.I extract against E. coli was less than MIC against Staph. aureus which was 5 and 10 mg/ml respectively, also E. coli was more sensitive to ciprofloxacin .

Synthesis and Antituberculosis Activity of Cycloalkylidenehydrazide and 4‐Aza‐1‐thiaspiro[4.5]decan‐3‐one Derivatives of Imidazo[2,1‐b]thiazole.

AbstractFor Abstract see ChemInform Abstract in Full Text.