Target Minimum Inhibitory Concentration Research Articles

Voriconazole as an alternative oral treatment in fluconazole-resistant urinary candidiasis

ObjectivesThis study aims to assess the urinary diffusion and clinical effectiveness of voriconazole in patients with fluconazole-resistant urinary candidiasis. Patients and methodsIn this prospective pilot study, we utilized a validated chromatography method to measure voriconazole in urine over a 12-hour period between two administrations of the drug and in plasma at trough. ResultsThirty-five patients, including five with fluconazole-resistant urinary candidiasis, were included. Urine and plasma voriconazole concentrations, mean 1.7 mg/L (range: 0.3–12.6) and mean 2.0 mg/L (range: 0.1–11.1) respectively, exhibited a strong correlation (R2 = 0.88). None of the five patients treated for candidiasis experienced clinical or microbiological failure following treatment, with urine concentrations ranging from 0.5 to 2.7 mg/L. ConclusionsThe urinary diffusion of voriconazole resulted in drug exposure above the target minimum inhibitory concentration (MIC) in the five patients treated for voriconazole-susceptible Candida strains in urine. Therapeutic drug monitoring may allow optimize in situ concentrations.

Relationship of imipenem therapeutic drug monitoring to clinical outcomes in critically ill patients: a retrospective cohort study.

The primary objective of this study was to evaluate the predictors associated with target concentration (non-)attainment of imipenem in critically ill patients. The secondary objective was to explore the correlation between achieving imipenem target concentrations and clinical outcomes of therapy. A retrospective cohort study was conducted in critically ill patients treated with imipenem. Clinical data were extracted from the patients' electronic medical records. The pharmacokinetic/pharmacodynamic target was defined as free imipenem concentrations above the minimum inhibitory concentration (MIC) of the pathogen at 100% (100%fT>MIC) of the dosing interval. Factors associated with the non-attainment of target concentrations were evaluated using binomial logistic regression. Kaplan-Meier analysis was used to investigate the correlation between (non-)attainment targets and 30-day mortality. A total of 406 patients were included, and 55.4% achieved the target of 100%fT>MIC. Regression analysis identified an initial daily dose of imipenem ≤ 2 g/day, augmented renal clearance, age ≤ 60 years, recent surgery, and absence of positive microbiology culture as risk factors for target non-attainment. Achieving the 100%fT>MIC target was significantly associated with clinical efficacy but not with 30-day mortality. Selective application of therapeutic drug monitoring in the early stages of imipenem treatment for critically ill patients can improve clinical outcomes. Further research should explore the potential benefits of TDM-guided dosing strategies for imipenem in critical care settings.

Recommendation of pharmacokinetics/pharmacodynamics target of ethambutol to suppress tuberculosis resistance: A population pharmacokinetics study on a large prospective cohort

The ability of ethambutol (EMB) to suppress bacterial resistance has been demonstrated in a time-dependent manner. Through the development of a population pharmacokinetics (PK) model, this study aimed to suggest the PK/pharmacodynamics (PD) target and identify the significant covariates that influence interindividual variability (IIV) in the PK of EMB. In total, 837 patients from 20 medical centres across Korea were enrolled in this study. The non-linear mixed-effect method was used to establish and validate the population PK model. A two-compartment model with transit compartment absorption was sufficient to describe the PK of EMB. Body weight and renal function were identified as significant covariates that affect IIV of the apparent clearance (CL/F) of EMB. Patients with moderate renal function showed 35% and 55% lower CL/F (CL/F 89.9 L/h) compared with those with mild and normal renal function, respectively. All the renal function groups with simulated doses ranging from 800 to 1200 mg achieved area under the curve over minimum inhibitory concentration (MIC) >119, and maintained T>MIC for >23 h for MIC of 0.5 µg/mL. Based on our simulation result, it is suggested that doses of 800, 1000, and 1200 mg should obtain the T>MIC target of 4, 6, and 8 h, respectively. This model was validated internally and externally. This study provides insight into the PK/PD indexes of EMB for three different renal function groups and T>MIC targets for different doses. The results could be used to provide optimal-dose suggestions for EMB.

Pharmacokinetic parameters over time during sepsis and the association of target attainment and outcomes in critically ill children and young adults receiving ceftriaxone.

Early sepsis results in pharmacokinetic (PK) changes due to physiologic alterations. PK changes can lead to suboptimal drug target attainment, risking inadequate coverage from antibiotics like ceftriaxone. Little is known about how ceftriaxone PK and target attainment quantitatively change over time in patients with sepsis or the association between target attainment and outcomes in critically ill children and young adults. A retrospective analysis of a prospective study was conducted in a single-center pediatric intensive care unit. Septic patients given at least one ceftriaxone dose (commonly as 50 mg/kg every 12h) and who had blood obtained in both the first 48h of therapy (early) and afterwards (late) were included. Normalized clearance and central volume were estimated and compared in both sepsis phases. We evaluated target attainment, defined as concentrations above 1× or 4× the minimum inhibitory concentration (MIC) for 100% of dosing intervals, and investigated the association between target attainment and clinical outcomes. Fifty-five septic patients (median age: 7.5 years) were included. Normalized clearance and central volume were similar in both phases (6.18 ± 1.48 L/h/70 kg early vs. 6.10 ± 1.61 L/h/70 kg late, p=0.60; 26.6 [IQR 22.3, 31.3] L/70 kg early vs. 24.5 [IQR 22.0, 29.4] L/70 kg late, p=0.18). Individual percent differences in normalized clearance and central volume between sepsis phases ranged from -39% to 276% and -51% to 212% (reference, late sepsis), respectively. Fewer patients attained the 1× MIC target in late sepsis (82% late vs. 96% early, p=0.013), which was associated with transition to once daily dosing, typically done due to transfer from the pediatric intensive care unit (PICU) to a lower acuity unit. Failure to attain either target in late sepsis was associated with antibiotic broadening. Ceftriaxone PK parameters were similar between early and late sepsis, but there were large individual differences. Fewer patients attained MIC targets in late sepsis and all who did not attain the less stringent target received once daily dosing during this period. The failure to attain targets in late sepsis was associated with antibiotic broadening and could be an area for antibiotic stewardship intervention.

Effects of temperature on the pharmacokinetics, optimal dosage, tissue residue, and withdrawal time of florfenicol in asian seabass (lates calcarifer)

Drug behavior in the bodies of fish is largely influenced by the water temperature. Antimicrobial drugs are needed for the control of bacterial outbreaks in farmed fish including Asian seabass (Lates calcarifer). However, little is known about the temperature effect on appropriate drug uses in this species. The purpose of this study was to investigate the differences in pharmacokinetics (PK), optimal dosages, tissue depletion, and withdrawal time (WDT) of florfenicol (FF) in Asian seabass reared at 25 and 30 °C. In the PK study, the fish were administered with a single oral dose of 10 mg/kg FF. The optimal dosing regimen was determined by the pharmacokinetic-pharmacodynamic (PK-PD) approach. In the tissue depletion and WDT study, FF was administered at the optimal dosages once daily for 5 days and the WDT was determined by linear regression analysis based on the sum of FF and its metabolite florfenicol amine (FFA) in the muscle/skin. When the temperature was increased from 25 to 30 °C, the elimination half-life of FF was significantly decreased from 11.0 to 7.2 h. While the other PK parameters were not changed significantly, the calculated optimal dosages for the target minimum inhibitory concentration (MIC) of 2 µg/mL were 10.9 and 22.0 mg/kg/day, respectively for 25 and 30 °C. The sum of FF + FFA is a preferable marker residue for WDT determination because differential FF metabolism was observed at different temperatures. The depletion half-life of the muscle/skin was shortened from 41.1 to 32.4 h by the 5 °C temperature increase. Despite different absolute amounts of FF given between the two temperature levels, the WDTs were very similar at 6-7 days. Thus, it appears that a single temperature-independent WDT can potentially be assigned when the drug was applied at the optimal dosage.

Determination of temperature-dependent optimal oral doses of florfenicol and corresponding withdrawal times in Nile tilapia (Oreochromis niloticus) reared at 25 and 30°C

Antimicrobials are important tools for controlling bacterial outbreaks in aquaculture, but their misuse can bring more harms than benefits. For prudent use of antimicrobials, an optimal dosing regimen that is adjustable by rearing temperature and antimicrobial sensitivity are preferred over a universal dosage. The main objective of the present study was to investigate the advantage of using temperature-dependent optimal dosages of florfenicol (FF) on withdrawal time (WDT) reduction compared to a conventional recommended dosage in Nile tilapia. First, the pharmacokinetic (PK) parameters of FF at 25 and 30 °C were determined after a single oral administration of 10 mg/kg FF. Then, the optimal dosing regimens, calculated by the pharmacokinetic-pharmacodynamic (PK-PD) approach with a target minimum inhibitory concentration (MIC) of 3 μg/mL were used to evaluate tissue depletion and WDT. The optimal doses as determined by PK study were 4.46 and 12.60 mg/kg/day for 25 and 30 °C, respectively. Subsequently, the fish were orally administered with FF at the round-up optimal dosages (5 mg/kg/day at 25 °C and 13 mg/kg/day at 30 °C) or a general dosage (10 mg/kg/day at 25 °C) once daily for 5 days for tissue depletion and WDT study. The serum concentrations at 24 h after the last optimal dose were 3.26 (for the 5 mg/kg/day 25 °C) and 3.72 μg/mL (for the 13 mg/kg/day 30 °C), respectively, which were comparable to the target MIC of 3 μg/mL; whereas, the corresponding concentration of the general dosage at 25 °C was 8.06 μg/mL. Using the sum of FF and its major metabolite florfenicol amine (FFA) as the marker residue in the muscle/skin and the maximum residue limit (MRL) of 1 μg/g, the WDT for general dosage was 10 days, whereas those of the optimal dosages were 7–8 days. The current study revealed that overdosing may occur at lower while under-dosing could happen at higher rearing temperature if single general dosage was employed. With the established optimal dosing regimen, serum concentrations could be maintained above the target MIC and the WDT be shortened, a single WDT might be possible using the optimal dosages strategy regardless of water temperature.

Analysis of epidemiology and novel mutation of Helicobacter pylori antibiotic resistance in South Korea

BackgroundHelicobacter pylori is a Gram‐negative bacterium associated with upper gastrointestinal disease, peptic ulcer, mucosa‐associated lymphoid tissue lymphoma and eradication treatment is recommended because it is one of the causes of gastric cancer. However, resistance to some antibiotics used for treatment has developed, the eradication rate is declining worldwide. This study focused on antibiotic susceptibility test (AST) of H. pylori isolated from patient clinical specimens. The aim of this study is to identify the resistance epidemiology of H. pylori and to elucidate the resistance mechanism through gene analysis.methodsH. pylori isolated from patient clinical specimens is identified and AST for amoxicillin (AMX) and clarithromycin (CLR) are performed, and the results are analyzed through Whole Genome Sequencing (WGS) and MultiLocus Sequence Typing (MLST), respectively. The strain type of the MLST result is compared with the CLR resistance minimum inhibitory concentration (MIC) value to analyze the significant points.H. pylori is cultured on EYE Agar plate and incubated in Anaerobic Jar for 2~5 days with microaerophilic air condition (5% O2, 10% CO2, 85% N2). Cultured isolates are identified by MALDI‐TOF system and performed AST using Epsilometer test to determining MIC.Results366 H. pylori were isolated from 1952 clinical patients, and 36 AMX‐resistant H. pylori and 101 CLR‐resistant H. pylori were identified. Among the identified H. pylori, 9 AMX high MIC strains were selected and WGS was performed, and 12 CLR high MIC strains were selected and MLST was performed.As the WGS result of 9 clinical strains resistant to AMX, single nucleotide polymorphism (SNP) of the potential target gene was analyzed with reference to ATCC 26695. Six genes, Penicillin binding protein1A (PBP1), PBP2, NhaC, hofH, hofC, and hefC, were selected as potential target genes. As a result of the analysis, 8, 7, 4, 9, 16, and 2 SNPs were found, respectively, and it was specifically confirmed that there were many SNPs in the outer membrane component Gene. However, No correlation was found between AMX MIC value and target SNP.12 For the CLR resistance strain, MLST was performed using 7 housekeeping genes (atpA, efp, trpC, ppa, mutY, yphC, Ure1). In 12 strain, 10 CLR‐resistance H. pylori are not identified strain type(ST) to The National Center for Biotechnology Information(NCBI) database because they have a lots of mutation in 7 housekeeping gene. 2 CLR‐resistance H. pylori are identified the new type strains.ConclusionIn this study, we conclude that hofC, hofH related to outer membrane protein component may be associated to the AMX resistance. And additional research is continued to need about other resistance potential gene, especially hopC.

Pharmacokinetics of a Single Intramuscular Injection of Ceftiofur Crystalline Free Acid in Bald Eagles (Haliaeetus leucocephalus).

The objective of this study was to evaluate the pharmacokinetic properties of ceftiofur crystalline free acid (CCFA) administered intramuscularly at dosages of 10 and 20 mg/kg in bald eagles (BAEAs) (Haliaeetus leucocephalus). Ceftiofur crystalline free acid is a long-acting, injectable, third-generation cephalosporin antibiotic drug. A prospective, randomized, complete crossover design was used for this pharmacokinetic investigation. CCFA (10 or 20 mg/kg) was administered intramuscularly, and blood samples were obtained from 6 adult, nonreleasable, healthy BAEAs at predetermined sampling times. After a 4-week washout period, the protocol was repeated with each bird receiving the dose not given during the initial sample collection according to the randomized crossover design. Plasma ceftiofur free acid equivalents were quantified and data were analyzed by a noncompartmental pharmacokinetic approach. The mean observed peak plasma concentrations were 9.23 µg/mL and 15.08 µg/mL for 10 and 20 mg/kg CCFA IM administration, respectively. The mean observed time to maximum plasma concentration was 18 and 17.6 hours, and the mean terminal elimination half-life was 32.38 and 38.08 hours for intramuscular administration of 10 and 20 mg/kg CCFA, respectively, in the BAEAs. Reported minimum inhibitory concentrations of raptor bacterial isolates from a prior study was used to determine the target minimum inhibitory concentration of 1 µg/mL selected for this investigation. From the previously published information, a target plasma concentration of 4 µg/mL was determined for the CCFA in the BAEAs. From the results of this study, CCFA may be dosed every 60 and 110 hours at 10 mg/kg IM, and every 80 and 160 hours at 20 mg/kg IM in BAEAs.

Monte Carlo simulation evaluation of tigecycline dosing for bacteria with raised minimum inhibitory concentrations in non-critically ill adults.

Tigecycline is one of few antibiotics active against multidrug-resistant bacteria; however, the assessment of dosing strategies to optimize its activity is needed. The purpose was to use Monte Carlo Simulation (MCS) to determine if safe tigecycline dosing options attaining breakpoints for pharmacokinetic/pharmacodynamic (PK-PD) targets in non-critically ill adults could be identified. Publications that evaluated tigecycline dosing regimens and provided mean PK variables of interest (minimum 2 of: elimination rate constant or half-life and volume of distribution or clearance), with SDs, were included. Weighted mean (±SDs) for each PK parameter were determined. Food and Drug Administration minimum inhibitory concentration (MIC) tigecycline breakpoints for susceptible (MIC ≤ 2μg/mL), intermediate (MIC 4μg/mL), and resistant (MIC ≥ 8μg/mL) Enterobacteriaceae were used. MCS probability distributions for PK-PD target attainment of AUC for total tigecycline plasma concentration from 0 to 24h following an intravenous dose (AUCtotal, 0-24h) to MIC ratios of ≥ 18, 7, and 4.5 were generated, with success defined as ≥ 80% probability of target attainment at a given MIC. Ten studies (n = 442) were eligible. Tigecycline 150mg IV q12h for ward patients with resistant bacteria up to a MIC of 0.48, 1, and 2μg/mL for an AUCtotal, 0-24h/MIC target attainment of 18, 7, and 4.5, respectively, may be appropriate. Bacterial infections with tigecycline MICs ≥ 0.48-2μg/mL, depending on AUCtotal, 0-24h/MIC target, may require treatment with alternate antibiotics due to target attainment failure.

Therapeutic drug monitoring of commonly used anti-infective agents: A nationwide cross-sectional survey of Australian hospital practices

When performed according to best-practice principles, therapeutic drug monitoring (TDM) can optimise anti-infective treatment and directly benefit clinical outcomes. We evaluated TDM performance and clinical decision-making for established anti-infective agents amongst Australian hospitals. A nationwide cross-sectional survey was conducted between August and September 2019. The survey consisted of multiple-choice questions regarding TDM of anti-infective agents in general as well as clinical vignettes specific to vancomycin, gentamicin and voriconazole. We sought to survey all Australian hospitals operating both in the public and private health sectors. Responses were captured from 85 unique institutions, from all Australian states and territories. Regarding guidelines, 26% of hospitals did not have endorsed guidelines to advise on the ordering, sampling and interpretation of TDM for any anti-infective agent. Admitting teams were predominantly responsible for ordering TDM (85%) and interpreting results (76%). Only 51% of hospitals had access to dose prediction software, with access generally better amongst principal referral (69%) (P = 0.01) and children's hospitals (100%) (P = 0.04). Whenever a laboratory-derived minimum inhibitory concentration (MIC) was not available to guide dosing decisions, a surrogate target MIC was assumed in 77% of hospitals. This was based on a ‘worst-case’ scenario infection in 11% of hospitals. The rates of clinical practice consistent with current guideline recommendations across all aspects of TDM were demonstrated to be 0% for vancomycin, 4% for gentamicin and 35% for voriconazole. At present, there is significant institutional variability in the clinical practice of TDM for anti-infective agents in Australia for established TDM drugs.

Evaluation of Intravenous Fosfomycin Disodium Dosing Regimens in Critically Ill Patients for Treatment of Carbapenem-Resistant Enterobacterales Infections Using Monte Carlo Simulation.

There are limited intravenous fosfomycin disodium (IVFOS) dosing regimens to treat carbapenem-resistant Enterobacterales (CRE) infections. This study aimed to use Monte Carlo simulation (MCS) for evaluation of IVFOS dosing regimens in critically ill patients with CRE infections. The dosing regimens in critically ill patients with various creatinine clearance were evaluated with MCS using minimum inhibitory concentration (MIC) distributions of fosfomycin against CRE clinical isolates in Thailand and the 24 h area under the plasma drug concentration–time curve over the minimum inhibitory concentration (AUC0-24/MIC) of ≥21.5 to be a target for IVFOS. The achieved goal of the probability of target attainment (PTA) and a cumulative fraction of response (CFR) were ≥90%. A total of 129 non-duplicated CRE clinical isolates had MIC distributions from 0.38 to >1024 mg/L. IVFOS 8 g every 8 h, 1 h, or 4 h infusion, could achieve approximately 90% PTA of AUC0-24/MIC target to treat CRE infections with MICs ≤ 128 mg/L. According to PTA target, an IVFOS daily dose to treat carbapenem-resistant Escherichia coli based on Clinical Laboratory Standards Institute (CLSI) breakpoints for urinary tract infections and one to treatment for CRE infections based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints were 16 g/day and 8 g/day, respectively. All dosing regimens of IVFOS against CRE achieved CFR ≤ 70%. This study proposes the IVFOS dosing regimens based on CLSI and EUCAST breakpoints for the treatment of CRE infections. However, further clinical studies are needed to confirm the results of these findings.

Sustained-release voriconazole-thermogel for subconjunctival injection in horses: ocular toxicity and in-vivo studies

BackgroundKeratomycosis is a relatively common, sight threatening condition in horses, where treatment is often prolonged and costly. Subconjunctival (SCo) injections offer less resistance to drug diffusion than the topical route, resulting in better penetration to the ocular anterior segment. Voriconazole, a second generation triazole antifungal, is effective against common fungal organisms causing keratomycosis. If combined with a thermogel biomaterial, voriconazole can be easily injected in the SCo space to provide sustained drug release. The purpose of this study was to evaluate the drug concentrations in the anterior segment and clinical effects after SCo injections of voriconazole-containing thermogel: poly (DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) in healthy equine eyes.ResultsVoriconazole aqueous humor (AH) and tear concentrations were compared between 6 horses, receiving 1% voriconazole applied topically (0.2 mL, q4h) (Vori-Top) or 1.7% voriconazole-thermogel (0.3 mL) injected SCo (Vori-Gel). For the Vori-Gel group, voriconazole concentrations were measured in AH and tears at day 2 and then weekly for 23 days, and at day 2 only for the Vori-Top group. Ocular inflammation was assessed weekly (Vori-Gel) using the modified Hackett-McDonald scoring system. Ocular tissue concentrations of voriconazole following SCo 1.7% voriconazole-thermogel (0.3 mL) injections were evaluated post euthanasia in 6 additional horses at 3 different time points. Three horses received bilateral injections at 2 h (n = 3, right eye (OD)) and 48 h (n = 3, left eye (OS)) prior to euthanasia, and 3 horses were injected unilaterally (OS), 7 days prior to euthanasia. Voriconazole-thermogel was easily injected and well tolerated in all cases, with no major adverse effects. On day 2, drug concentrations in tears were higher in the Vori-Top, but not statistically different from Vori-Gel groups. For the Vori-Gel group, voriconazole was non-quantifiable in the AH at any time point. Total voriconazole concentrations in the cornea were above 0.5 μg/g (the target minimum inhibitory concentration (MIC) for Aspergillus sp.) for up to 48 h; however, concentrations were below this MIC at 7 days post treatment.ConclusionsVoriconazole-thermogel was easily and safely administered to horses, and provided 48 h of sustained release of voriconazole into the cornea. This drug delivery system warrants further clinical evaluation.

1594. Evaluating Clinical Outcomes of an Alternative Cefepime Dosing Regimen as Empiric Antibiotic Therapy in Hospitalized Adults with Febrile Neutropenia

BackgroundA cefepime dosing regimen of 1 g every 6 hours (1 g Q6h) has shown to provide similar exposure above the target minimum inhibitory concentration than the higher FDA-approved regimen of 2 g Q8h for febrile neutropenia. We hypothesize clinical outcomes among patients receiving either dosing strategy will be similar.MethodsA retrospective chart review of hospitalized patients who received cefepime for documented febrile neutropenia over a two-year period was performed. Patients were grouped based on cefepime dosing strategy: 1 g Q6h vs. 2 g Q8h. The primary objective was to compare time to defervescence after cefepime initiation. Secondary objectives looked at all-cause and infection-related 30-day mortality, duration of therapy, and length of stay (LOS).ResultsSeventy-five patients in each arm were included. There were no differences in baseline age or severity of illness between groups. There was no difference in the primary objective as average time to defervescence was similar between the 1 g Q6h and 2 g Q8h groups (85.9 hours vs. 89.7 hours: P = 0.206), respectively. Additionally, no differences were found in the secondary objectives including all-cause 30-day mortality (6.7% vs. 9.3%: P = 0.547), duration of therapy (95.7 hours vs. 99.1 h: P = 0.174), or LOS (9 vs. 7 days: P = 0.251).ConclusionThe regimen of cefepime 1 g Q6h provides similar clinical outcomes as the traditional FDA-approved 2 g Q8h regimen in the treatment of febrile neutropenia. The lower total daily dose will result in less drug exposure and a potential decreased risk of cefepime-related adverse drug events. Disclosures All authors: No reported disclosures.

Pharmacokinetics of a Single Intramuscular Injection of Long-Acting Ceftiofur Crystalline-Free Acid in Cattle Egrets (Bubulcus ibis)

We determined the pharmacokinetic properties of ceftiofur crystalline-free acid (CCFA), a long-acting antibiotic, after a single intramuscular injection in cattle egrets ( Bubulcus ibis). A dose of 20 mg/kg was administered intramuscularly to 18 birds and blood samples were collected via jugular venipuncture at 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours after CCFA administration. Plasma concentrations of ceftiofur free acid equivalents (CFAEs) were measured via high-performance liquid chromatography. The minimum inhibitory concentration (MIC) of 1 μg/mL was reached by 1 hour after administration and remained higher than the MIC for at least 72 hours in all birds. This target concentration is effective for many bacterial infections in avian species. The area under the plasma concentration versus time curve was 451.3 h*μg/mL, maximum plasma concentration was 16.22 μg/mL, time to maximum plasma concentration was 3.2 hours, mean harmonic half-life was 37.92 hours, and time that the concentrations of CFAEs were higher than the target MIC was a minimum of 72 hours.

Clinical pharmacokinetics and pharmacodynamic target attainment of pazufloxacin in prostate tissue: Dosing considerations for prostatitis.

The present study examined the clinical pharmacokinetics of pazufloxacin in prostate tissue and estimated the probability of target attainment for tissue-specific pharmacodynamic goals related to treating prostatitis using various intravenous dosing regimens. Patients with prostatic hypertrophy received prophylactic infusions of pazufloxacin (500mg, n=23; 1000mg, n=25) for 0.5h prior to transurethral prostate resection. Drug concentrations in plasma (0.5-5h) and prostate tissue (0.5-1.5h) were measured by high-performance liquid chromatography and used for subsequent noncompartmental and three-compartmental analysis. Monte Carlo simulation was performed to evaluate the probability of target attainment of a specific minimum inhibitory concentration (MIC) in prostate tissue: the proportion that achieved both area under the drug concentration over time curve (AUC)/MIC=100 and maximum concentration (Cmax)/MIC=8. Prostatic penetration of pazufloxacin was good with mean Cmax ratios (prostate tissue/plasma) of 0.82-0.99 and for AUC, 0.80-0.98. The probability of reaching target MIC concentrations in prostate tissue was more than 90% for dosing schedules of 0.25mg/L for 500mg every 24h (500mg daily), 0.5mg/L for 500mg every 12h (1000mg daily), 1mg/L for 1000mg every 24h (1000mg daily), and 2mg/L for 1000mg every 12h (2000mg daily). Importantly, the 2000mg daily regimen of pazufloxacin produced a profile sufficient to have an antibacterial effect in prostate tissue against clinical isolates of Escherichia coli and Klebsiella pneumonia with MIC values less than 2mg/L.

Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps.

Background. Infants and toddlers often present with disseminated and lymph node tuberculosis, in which Mycobacterium tuberculosis (Mtb) is predominantly intracellular. Linezolid, used to treat tuberculosis in adults, has not been formally studied in infants. Infants clear linezolid 5 times faster than adults and achieve lower 0- to 24-hour area under the concentration-time curves (AUC0–24).Methods. To mimic intracellular disease, we infected human-derived THP-1 macrophages with Mtb and inoculated hollow fiber systems. We performed dose-effect and dose-scheduling studies in which we recapitulated the linezolid half-life of 3 hours encountered in infants. Repetitive sampling for linezolid pharmacokinetics, Mtb intracellular burden, viable monocyte count, and RNA sequencing reads were performed up to 28 days.Results. The linezolid extracellular half-life was 2.64 ± 0.38 hours, whereas intracellular half-life was 8.93 ± 1.30 hours (r2 = 0.89). Linezolid efficacy was linked to the AUC0–24 to minimum inhibitory concentration (MIC) ratio (r2 = 0.98). The exposure associated with maximal Mtb kill was an AUC0–24/MIC of 23.37 ± 1.16. We identified a 414-gene transcript on exposure to toxic linezolid doses. The largest number of genes mapped to ribosomal proteins, a signature hitherto not associated with linezolid toxicity. The second-largest number of differentially expressed genes mapped to mitochondrial enzyme inhibition. Linezolid AUC0–24 best explained the mitochondrial gene inhibition, with 50% inhibition at 94 mg × hour/L (highest r2 = 0.98).Conclusions. We identified the linezolid AUC0–24/MIC target for optimal efficacy against pediatric intracellular tuberculosis, and an AUC0–24 threshold associated with mitochondrial inhibition. These constitute a therapeutic window to be targeted for optimal linezolid doses in children with tuberculosis.

We need to optimize piperacillin-tazobactam dosing in critically ill patients-but how?

We need to optimize piperacillin-tazobactam dosing in critically ill patients-but how?

Pharmacokinetics of an extended 4-hour infusion of piperacillin-tazobactam in critically ill patients undergoing continuous renal replacement therapy.

To evaluate the pharmacokinetic and pharmacodynamic profiles of piperacillin-tazobactam administered as a 4-hour infusion in critically ill patients undergoing continuous renal replacement therapy (CRRT). Prospective, observational, pharmacokinetic study. Intensive care unit of a tertiary care hospital in Montréal, Canada. Twenty critically ill adults who were undergoing continuous venovenous hemodiafiltration and receiving a 4-hour infusion of piperacillin 4g-tazobactam 0.5g every 8hours for a documented or suspected infection. Blood samples were collected every hour over an 8-hour dosing interval. Prefilter and postfilter blood samples, and effluent and urine samples were also collected. The primary outcome was the proportion of patients who achievedan unbound piperacillin plasma concentration above a target minimum inhibitory concentration (MIC) of 64mg/L (MIC that inhibits 90% of isolates for Pseudomonas aeruginosa) for at least 50% of the dosing interval; 18 (90%) of the 20 patients achieved this outcome. In all patients, the free piperacillin concentrations were above the Pseudomonas aeruginosa breakpoint of 16mg/L for the entire time interval. Regarding piperacillin pharmacokinetic parameters, the median (interquartile range) minimum unbound plasma concentration was 65.15mg/L (51.30-89.30), maximum unbound plasma concentration was 141.3mg/L (116.75-173.90), sieving coefficient was 0.809 (0.738-0.938), total clearance was 65.82ml/minute (53.79-102.87), and renal clearance was 0.16ml/minute (0.05-3.04). The median CRRT dose was 32.0ml/kg/h (25.0-39.8). Administration of a 4-hour infusion of piperacillin-tazobactam was associated with a favorable pharmacodynamic profile in patients undergoing CRRT. Concentrations associated with maximal activity were attained in our patients.

Development and Assessment of a Nomogram to Propose the Initial Dosage Regimen of a Meropenem Infusion Based on Serum Creatinine and Age Using a Monte Carlo Simulation.

A conventional nomogram, based on serum creatinine (sCr) and age, was developed in order to determine the correct initial dosage regimen for meropenem (MEPM) infusions in elderly patients with severe community-acquired pneumonia (CAP), using a target minimum inhibitory concentration (MIC) of 2 mg/L. A correlation between age and actual bodyweight (BW) in a development cohort of 44 males and 45 females was performed by linear regression using the least-squares method (male: y=-0.4676x+80.281, R(2)=0.4888; female: y=-0.4373x+77.502, R(2)=0.3194). There were no significant differences between actual BW and the BW (e-BW) estimated using this equation in this cohort (male: e-BW 41.6±3.1 kg, BW 41.7±3.5 kg, p=0.93; female: e-BW 39.5±2.1 kg, BW 39.5±3.7 kg, p=0.20). By integrating these equations using the Monte Carlo simulation method, a dosage regime was calculated which would have an 80% probability of maintaining plasma drug levels above the MIC for more than 40% of the time (>40%TAM), using only the age and sCr of individual patients. This relationship was summarized as a nomogram. The nomogram was validated using an independent validation cohort (n=28) of patients. An optimized dosage regimen could be predicted in 84 patients (94.4%) in the development cohort and 25 patients (89.3%) in the validation cohort. This nomogram may be a useful tool for clinicians and pharmacists in determining an initial MEPM regimen in elderly patients with severe CAP, based only on age and sCr.

Risk factors for target non-attainment during empirical treatment with β-lactam antibiotics in critically ill patients.

Risk factors for β-lactam antibiotic underdosing in critically ill patients have not been described in large-scale studies. The objective of this study was to describe pharmacokinetic/pharmacodynamic (PK/PD) target non-attainment envisioning empirical dosing in critically ill patients and considering a worst-case scenario as well as to identify patient characteristics that are associated with target non-attainment. This analysis uses data from the DALI study, a prospective, multi-centre pharmacokinetic point-prevalence study. For this analysis, we assumed that these were the concentrations that would be reached during empirical dosing, and calculated target attainment using a hypothetical target minimum inhibitory concentration (MIC), namely the susceptibility breakpoint of the least susceptible organism for which that antibiotic is commonly used. PK/PD targets were free drug concentration maintained above the MIC of the suspected pathogen for at least 50 % and 100 % of the dosing interval respectively (50 % and 100 % f T (>MIC)). Multivariable analysis was performed to identify factors associated with inadequate antibiotic exposure. A total of 343 critically ill patients receiving eight different β-lactam antibiotics were included. The median (interquartile range) age was 60 (47-73) years, APACHE II score was 18 (13-24). In the hypothetical situation of empirical dosing, antibiotic concentrations remained below the MIC during 50 % and 100 % of the dosing interval in 66 (19.2 %) and 142 (41.4 %) patients respectively. The use of intermittent infusion was significantly associated with increased risk of non-attainment for both targets; creatinine clearance was independently associated with not reaching the 100 % f T( >MIC) target. This study found that-in empirical dosing and considering a worst--case scenario--19 % and 41 % of the patients would not achieve antibiotic concentrations above the MIC during 50 % and 100 % of the dosing interval. The use of intermittent infusion (compared to extended and continuous infusion) was the main determinant of non-attainment for both targets; increasing creatinine clearance was also associated with not attaining concentrations above the MIC for the whole dosing interval. In the light of this study from 68 ICUs across ten countries, we believe current empiric dosing recommendations for ICU patients are inadequate to effectively cover a broad range of susceptible organisms and need to be reconsidered.