Targeting of under-75 years for the optimization of medication reconciliation with an approach based on medication risks: An observational study.

PURPOSE: To date, how medication reconciliation (MR) could be prioritized in younger patients remains poorly evaluated. This study aimed at assessing whether a MR prioritization strategy based on the identification of high-risk medication at patients' admission treatment could be of interest in non-elderly patients. METHOD: This prospective study was conducted between July and September 2017 in an internal medicine unit at Bordeaux teaching hospital. All patients aged 16 to 74 years and receiving at least two long-term treatments at admission were considered eligible. High-risk medications were defined on the basis of a pharmacovigilance study, which identified the drugs most involved in serious adverse effects reported in the Nouvelle-Aquitaine region in non-elderly adults. They included antithrombotics, analgesics, antipsychotics and cardiac therapies. MR-induced treatment changes were compared according to the existence of high-risk medications at admission in study participants. RESULTS: Among the 92 study participants, 46 presented with high-risk medications at admission (median age 66 years, IQR 58-70) and 46 without such (median age 54 years, IQR 47-64). High risk-medications (HRM) existing at admission were antithrombotics (52.2%) and antipsychotics (22.4%). MR resulted in treatment changes in 37% of patients admitted with at-risk medications vs. 8.7% of those admitted without such (P=0.001). Overall, the mean number of treatment changes performed after MR was of 1 (95%CI 0.4-1.6) in patients with high-risk medication at admission and of 0.2 (95%CI 0-0.4) in patients without such. MR-induced treatment changes assessed as clinically major at least once by pharmacists or clinicians was greater in HRM group (43.5%) than in non-HRM group (31.6%). However, the consistency was low between clinicians and pharmacists, especially to distinguish the clinical importance of significant and minor interventions. CONCLUSION: Targeting high-risk medications at admission appeared efficient for the prioritization of MR in non-elderly patients hospitalised in internal medicine.

Subcutaneous Antibiotic Therapy: The Why, How, Which Drugs and When.

OBJECTIVES: To describe the rationale for subcutaneous (SC) administration of antibiotics from available published data and to make propositions to help clinicians in daily practice. DESIGN: Narrative review. SETTING AND PARTICIPANTS: Hospitalized patients, persons in long-term care facilities and ambulatory care. METHODS: We searched the MEDLINE/PubMed electronic database for evidence supporting SC administration of antibiotics up to September 2019; the results of this primary search were supplemented by searching the references of the identified articles, as well as by searching in Google Scholar. RESULTS: Regarding tolerability, efficacy, and pharmacokinetic/pharmacodynamic profiles, most studies suggest that the SC route could be an alternative to the intravenous route, particularly for time-dependent antibiotics and among certain patient populations, such as patients with poor venous access, swallowing disorders, or behavioral disturbance. However, clinical evidence of the benefits and risks of SC antibiotic administration is still scarce and of low level. CONCLUSIONS AND IMPLICATIONS: SC administration of antibiotics may be useful in various settings such as in hospitalized patients and among those in long-term care facilities or being cared for at home. However, further clinical studies are needed to assess the pharmacokinetic/pharmacodynamic properties, as well as the risks and benefits of SC administration of antibiotics. In this review, we highlight the potential benefits of SC administration of antibiotics and address practical recommendations for its use. This information will enable improvement of treatment strategies and present the SC route as a potential option in specific situations.

Population Pharmacokinetic Study of the Suitability of Standard Dosing Regimens of Amikacin in Critically Ill Patients with Open-Abdomen and Negative-Pressure Wound Therapy.

The aim was to assess the appropriateness of recommended regimens for empirical MIC coverage in critically ill patients with open-abdomen and negative-pressure therapy (OA/NPT). Over a 5-year period, every critically ill patient who received amikacin and who underwent therapeutic drug monitoring (TDM) while being treated by OA/NPT was retrospectively included. A population pharmacokinetic (PK) modeling was performed considering the effect of 10 covariates (age, sex, total body weight [TBW], adapted body weight [ABW], body surface area [BSA], modified sepsis-related organ failure assessment [SOFA] score, vasopressor use, creatinine clearance [CLCR], fluid balance, and amount of fluids collected by the NPT over the sampling day) in patients who underwent continuous renal replacement therapy (CRRT) or did not receive CRRT. Monte Carlo simulations were employed to determine the fractional target attainment (FTA) for the PK/pharmacodynamic [PD] targets (maximum concentration of drug [Cmax]/MIC ratio of ≥8 and a ratio of the area under the concentration-time curve from 0 to 24 h [AUC0-24]/MIC of ≥75). Seventy critically ill patients treated by OA/NPT (contributing 179 concentration values) were included. Amikacin PK concentrations were best described by a two-compartment model with linear elimination and proportional residual error, with CLCR and ABW as significant covariates for volume of distribution (V) and CLCR for CL. The reported V) in non-CRRT and CRRT patients was 35.8 and 40.2 liters, respectively. In Monte Carlo simulations, ABW-adjusted doses between 25 and 35 mg/kg were needed to reach an FTA of >85% for various renal functions. Despite an increased V and a wide interindividual variability, desirable PK/PD targets may be achieved using an ABW-based loading dose of 25 to 30 mg/kg. When less susceptible pathogens are targeted, higher dosing regimens are probably needed in patients with augmented renal clearance (ARC). Further studies are needed to assess the effect of OA/NPT on the PK parameters of antimicrobial agents.

Implementation of infliximab standardized doses after pharmacokinetic modelization in a cohort of patients with Crohn's disease.

BACKGROUND: According to infliximab (IFX) license in Crohn's disease (CD), infusion doses are based on patient's body-weight. Dose banding providing standardized doses (SD) has been implemented in parenteral chemotherapy in order to optimize aseptic unit capacity and reduce drug expenditure, duration of hospital stay and costs without decreasing efficacy. MATERIAL AND METHOD: The first part was a single-center retrospective analysis of consecutive CD patients receiving IFX maintenance therapy to determine standardized doses covering more than 50% of infusions. The second part was a prospective cohort study assessing the impact of SD compared to body-weight doses (BWD) on admission duration and costs. RESULTS: Six IFX SD covering more than 90% of infusion doses were implemented for dose banding. According to the Monte-Carlo simulation, there was no significant difference between IFX SD and BWD maintenance regimens. When assessed prospectively in 116 patients (75 patients treated with SD and 41 with BWD) corresponding to 128 infusions, hospitalization duration was shortened by 70 min per patient (p < 0.001). CONCLUSION: According to a pharmacokinetic model, IFX SD has a pharmacokinetic profile close to BWD and is associated with reduced length of hospitalization in a cohort of patients with CD. IFX SD implementation could optimize infusion units functioning and, save time and costs without decreasing efficacy.

Is the subcutaneous route an alternative for administering ertapenem to older patients? PHACINERTA study.

BACKGROUND: Antibiotic administration by subcutaneous (SC) injection is common practice in French geriatric wards as an alternative to the intravenous (IV) route, but few pharmacokinetic/pharmacodynamic data are available. Ertapenem is useful for the treatment of infections with ESBL-producing enterobacteria. OBJECTIVES: To report and compare ertapenem pharmacokinetic data between IV and SC routes in older persons. METHODS: Patients >65 years of age receiving ertapenem (1 g once daily) for at least 48 h (IV or SC, steady-state) were prospectively enrolled. Total ertapenem concentrations [residual (C0), IV peak (C0.5) and SC peak (C2.5)] were determined by UV HPLC. Individual-predicted AUC0-24 values were calculated and population pharmacokinetic analyses were performed. Using the final model, a Monte Carlo simulation involving 10 000 patients evaluated the influence of SC or IV administration on the PTA. Tolerance to ertapenem and recovery were also monitored. ClinicalTrials.gov identifier: NCT02505386. RESULTS: Ten (mean ± SD age=87±7 years) and 16 (age=88±5 years) patients were included in the IV and SC groups, respectively. The mean C0 and C2.5 values were not significantly different between the IV and SC groups (C0=12±5.9 versus 12±7.4 mg/L, P=0.97; C2.5=97±42 versus 67±41 mg/L, P=0.99). The mean C0.5 was higher in the IV group compared with the SC group (C0.5=184±90 versus 51±66 mg/L, P=0.001). The mean individual AUCs (1126.92±334.99 mg·h/L for IV versus 1005.3±266.0 mg·h/L for SC, P=0.38) and PTAs were not significantly different between groups. No severe antibiotic-related adverse effects were noted. CONCLUSIONS: SC administration of ertapenem is an alternative to IV administration in older patients.

Are Standard Dosing Regimens of Ceftriaxone Adapted for Critically Ill Patients with Augmented Creatinine Clearance?

The objective of the present study was to determine whether augmented renal clearance (ARC) impacts negatively on ceftriaxone pharmacokinetic (PK)/pharmacodynamic (PD) target attainment in critically ill patients. Over a 9-month period, all critically ill patients treated with ceftriaxone were eligible. During the first 3 days of antimicrobial therapy, every patient underwent 24-h creatinine clearance (CLCR) measurements and therapeutic drug monitoring of unbound ceftriaxone. ARC was defined by a CLCR of ≥150 ml/min. Empirical underdosing was defined by a trough unbound ceftriaxone concentration under 2 mg/liter (percentage of the time that the concentration of the free fraction of drug remained greater than the MIC [fT>MIC], 100%). Monte Carlo simulation (MCS) was performed to determine the probability of target attainment (PTA) of different dosing regimens for various MICs and three groups of CLCR (<150, 150 to 200, and >200 ml/min). Twenty-one patients were included. The rate of empirical ceftriaxone underdosing was 62% (39/63). A CLCR of ≥150 ml/min was associated with empirical target underdosing with an odds ratio (OR) of 8.8 (95% confidence interval [CI] = 2.5 to 30.7; P < 0.01). Ceftriaxone PK concentrations were best described by a two-compartment model. CLCR was associated with unbound ceftriaxone clearance (P = 0.02). In the MCS, the proportion of patients who would have failed to achieve a 100% fT>MIC was significantly higher in ARC patients for each dosage regimen (OR = 2.96; 95% CI = 2.74 to 3.19; P < 0.01). A dose of 2 g twice a day was best suited to achieve a 100% fT>MIC When targeting a 100% fT>MIC for the less susceptible pathogens, patients with a CLCR of ≥150 ml/min remained at risk of empirical ceftriaxone underdosing. These data emphasize the need for therapeutic drug monitoring in ARC patients.

Pharmacokinetics and Pharmacodynamics of Anti-infective Agents during Continuous Veno-venous Hemofiltration in Critically Ill Patients: Lessons Learned from an Ancillary Study of the IVOIRE Trial.

BACKGROUND: Hemofiltration rate, changes in blood and ultrafiltration flow, and discrepancies between the prescribed and administered doses strongly influence pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial agents during continuous veno-venous hemofiltration (CVVH) in critically ill patients. METHODS: Ancillary data were from the prospective multicenter IVOIRE (hIgh VOlume in Intensive caRE) study. High volume (HV, 70 mL/kg/h) was at random compared with standard volume (SV, 35 mL/kg/h) CVVH in septic shock patients with acute kidney injury (AKI). PK/PD parameters for all antimicrobial agents used in each patient were studied during five days. RESULTS: Antimicrobial treatment met efficacy targets for both percentage of time above the minimal inhibitory concentration and inhibitory quotient. A significant correlation was observed between the ultrafiltration flow and total systemic clearance (Spearman test: P < 0.005) and between CVVH clearance and drug elimination half-life (Spearman test: P < 0.005). All agents were easily filtered. Mean sieving coefficient ranged from 38.7% to 96.7%. Mean elimination half-life of all agents was significantly shorter during HV-CVVH (from 1.29 to 28.54 h) than during SV-CVVH (from 1.51 to 33.85 h) (P < 0.05). CONCLUSIONS: This study confirms that CVVH influences the PK/PD behavior of most antimicrobial agents. Antimicrobial elimination was directly correlated with convection rate. Current antimicrobial dose recommendations will expose patients to underdosing and increase the risk for treatment failure and development of resistance. Dose recommendations are proposed for some major antibiotic and antifungal treatments in patients receiving at least 25 mL/kg/h CVVH.

Higher than standard dosing regimen are needed to achieve optimal antibiotic exposure in critically ill patients with augmented renal clearance receiving piperacillin-tazobactam administered by continuous infusion.

PURPOSE: To determine whether augmented renal clearance (ARC) impacts negatively on piperacillin-tazobactam unbound concentrations in critically ill patients receiving 16 g/2 g/day administered continuously. MATERIAL AND METHODS: Fifty nine critically ill patients without renal impairment underwent 24-h creatinine clearance (CrCL) measurement and therapeutic drug monitoring during the first three days of antimicrobial therapy by piperacillin-tazobactam. The main outcome was the rate of piperacillin underexposure, defined by at least one of three samples under 16 mg/L. Monte Carlo simulation was performed to predict the distribution of piperacillin concentrations for various CrCL and minimal inhibitory concentration (MIC) values. RESULTS: The rate of piperacillin underexposure was 19%, significantly higher in ARC patients (0 vs. 31%, p = .003). A threshold of CrCL ≥ 170 mL/min had a sensitivity and specificity of 1 (95%CI: 0.79-1) and 0.69 (95%CI: 0.61-0.76) to predict piperacillin underexposure. In ARC patients, a 20 g/2.5 g/24 h PTZ dosing regimen was associated with the highest probability to reach the 16 mg/L empirical target, without risk of excessive dosing. CONCLUSIONS: When targeting a theoretical MIC at the upper limit of the susceptibility range, the desirable target (100%fT>16) may not be achieved in patients with CrCL ≥ 170 mL/min receiving PTZ 16 g/2 g/day administered continuously.

Breakthrough invasive aspergillosis and diagnostic accuracy of serum galactomannan enzyme immune assay during acute myeloid leukemia induction chemotherapy with posaconazole prophylaxis.

Posaconazole prophylaxis has demonstrated efficacy in the prevention of invasive aspergillosis during prolonged neutropenia following acute myeloid leukemia induction chemotherapy. Antifungal treatment decreases serum galactomannan enzyme immunoassay diagnostic accuracy that could delay the diagnosis and treatment. We retrospectively studied patients with acute myeloid leukemia who underwent intensive chemotherapy and antifungal prophylaxis by posaconazole oral suspension. Clinical, radiological, microbiological features and treatment response of patients with invasive aspergillosis that occurred despite posaconazole prophylaxis were analyzed. Diagnostic accuracy of serum galactomannan assay according to posaconazole plasma concentrations has been performed. A total of 288 patients with acute myeloid leukemia, treated by induction chemotherapy, who received posaconazole prophylaxis for more than five days were included in the present study. The incidence of invasive aspergillosis was 8% with 12 (4.2%), 8 (2.8%) and 3 (1%), possible, probable and proven invasive aspergillosis, respectively. Posaconazole plasma concentration was available for 258 patients. Median duration of posaconazole treatment was 17 days, and median posaconazole plasma concentration was 0.5 mg/L. None of patients with invasive aspergillosis and posaconazole concentration ≥ 0.5 mg/L had a serum galactomannan positive test. Sensitivity of serum galactomannan assay to detect probable and proven invasive aspergillosis was 81.8%. Decreasing the cut-off value for serum galactomannan optical density index from 0.5 to 0.3 increased sensitivity to 90.9%. In a homogenous cohort of acute myeloid leukemia patients during induction chemotherapy, increasing the posaconazole concentration decreases the sensitivity of serum galactomannan assay.

Association between augmented renal clearance, antibiotic exposure and clinical outcome in critically ill septic patients receiving high doses of ß-lactams administered by continuous infusion: a prospective observational study.

This study assessed whether augmented renal clearance (ARC) impacts negatively on antibiotic concentrations and clinical outcomes in patients treated by high-dose ß-lactams administered continuously. Over a 9-month period, all critically ill patients without renal impairment treated by one of the monitored ß-lactams for a documented infection were eligible. During the first 3 days of antibiotic therapy, every patient underwent 24-h CLCr measurements and therapeutic drug monitoring. The main outcome was the rate of ß-lactam underdosing, defined as a free drug concentration <4 × MIC of the known pathogen. Secondary outcomes were rates of subexposure for ß-lactams and therapeutic failure. The performance of CLCr in predicting underdosing was assessed by a ROC curve, and multivariable logistic regression was performed to determine risk factors for subexposure and therapeutic failure. A total of 79 patients were included and 235 samples were analysed. The rate of underdosing<4×MIC was 12%, with a significant association with CLCr (P <0.0001). A threshold of CLCr ≥ 170 mL/min had a sensitivity and specificity of 0.93 (95% CI 0.77-0.99) and 0.65 (95% CI 0.58-0.71) for predicting ß-lactam underdosing<4×MIC. Mean CLCr values ≥170 mL/min were significantly associated with subexposure<4xMIC [OR = 10.1 (2.4-41.6); P = 0.001]. Patients with subexposure<4×MIC presented higher rates of therapeutic failure [OR = 6.3 (1.2-33.2); P = 0.03]. Mean CLCr values ≥170 mL/min remain a risk factor for subexposure to ß-lactams despite high doses of ß-lactams administered continuously. ß-Lactam subexposure was associated with higher rates of therapeutic failure in septic critically ill patients.

A new reliable, transposable and cost-effective assay for absolute quantification of total plasmatic bevacizumab by LC-MS/MS in human plasma comparing two internal standard calibration approaches.

The quantification of monoclonal antibodies (mAbs) such as bevacizumab, a recombinant humanized immunoglobulin G1 (hIgG1), in biological fluids, is an essential prerequisite to any pharmacokinetic preclinical and clinical study. To date, reference techniques used to quantify mAbs rely on enzyme-linked immunosorbent assay (ELISA) lacking specificity. Furthermore, the commercially available ELISA kit to quantify bevacizumab in human plasma only assesses the free fraction of the drug. However, the conditions of storage and analysis of plasma samples could alter the physiological equilibrium between the free, bound and partially bound forms of bevacizumab and this could result in over- or underestimation of drug concentration. We developed a new assay for absolute quantification of total fraction of bevacizumab by liquid chromatography tandem mass spectrometry (LC-MS/MS) basing identification and quantification of bevacizumab on two specific peptides. In this report we compare our assay with two internal standard (IS) calibration approaches: one using a different human mAb (Trastuzumab) and the other using a stable isotope labeled specific peptide. After enrichment by affinity chromatography on protein A and concentration by ultrafiltration, human plasma samples were proteolyzed by trypsin. Linearity was established from 12.5 to 500µg/mL with an interday accuracy ranging from 101.7 to 110.6% and precision from 7.0% to 9.9%. This study demonstrates the importance of the choice of the IS in quantifying bevacizumab in human plasma and highlights the difficulty of reaching a reliable proteolysis with a sufficient recovery. We developed a reliable and cost-effective LC-MS/MS method to quantify total plasmatic fraction of bevacizumab in human plasma. Through our development we proposed a generic methodology easily transposable to quantify all IgG1 subclass very useful for clinical pharmacokinetics studies.

Repeated Piperacillin-Tazobactam Plasma Concentration Measurements in Severely Obese Versus Nonobese Critically Ill Septic Patients and the Risk of Under- and Overdosing.

OBJECTIVE: Obesity and critical illness modify pharmacokinetics of antibiotics, but piperacillin-tazobactam continuous IV infusion pharmacokinetics has been poorly studied in obese critically ill patients. We aimed to compare pharmacokinetics of piperacillin in severely obese and nonobese patients with severe sepsis or septic shock. We hypothesized that plasma concentration variability would expose the critically ill to both piperacillin under and overdosing. METHODS: Prospective comparative study. Consecutive critically ill severely obese (body mass index, > 35 kg/m) and nonobese patients (body mass index, < 30 kg/m) were treated with 16 g/2 g/24 hr continuous piperacillin-tazobactam infusion. Piperacillin plasma concentration was measured every 12 hours over a 7-day period by high-pressure liquid chromatography. Unbound piperacillin plasma concentration and fractional time of plasma concentration spent over 64 mg/L (4-fold the minimal inhibitory concentration for Pseudomonas aeruginosa) were compared between the two groups. We performed 5,000 Monte Carlo simulations for various dosing regimens and minimal inhibitory concentration and calculated the probability to spend 100% of the time over 64 mg/L. RESULTS: We enrolled 11 severely obese and 12 nonobese patients and obtained 294 blood samples. We did not observe a statistically significant difference in piperacillin plasma concentrations over time between groups. The fractional time over 64 mg/L was 64% (43-82%) and 93% (85-100%) in obese and nonobese patients, respectively, p = 0.027 with intra- and intergroup variability. Five nonobese and two obese patients experienced potentially toxic piperacillin plasma concentrations. When 64 mg/L was targeted, Monte Carlo simulations showed that 12 g/1.5 g/24 hr was inadequate in both groups and 16 g/2 g/24 hr was adequate only in nonobese patients. CONCLUSION: Using a conventional dosing of 16 g/2 g/24 hr continuous infusion, obese patients were more likely than nonobese patients to experience piperacillin underdosing when facing high minimal inhibitory concentration pathogens. The present study suggests that piperacillin drug monitoring might be necessary in the sickest patients who are at the highest risk of unpredictable plasma concentration exposing them to overdose, toxicity, underdosing, and treatment failure.

Pre-dose plasma concentration monitoring of mycophenolate mofetil in patients with autoimmune diseases.

AIM: To date, neither the benefit of mycophenolic acid (MPA) therapeutic drug monitoring (TDM), the prodrug of mycophenolate mofetil (MMF), nor the optimal monitoring technique have been established in autoimmune diseases. This study was undertaken to confirm, in a cohort of new patients, the plasma MPA thresholds previously published in patients with systemic lupus erythematosus (SLE) or vasculitis. METHODS: MPA areas under the concentration-time curves between 0 and 12 h, 12 h trough concentrations and pre-dose concentrations (C0 ) were determined for 23 patients with SLE and 21 with systemic vasculitis. The relationship between patients' pharmacokinetic (PK) variables and their clinical outcomes during follow-up were analyzed. RESULTS: In both autoimmune diseases, at PK assessment, median MPA C0 for patients with uncontrolled disease was significantly lower than that of patients with stable disease or in remission, 1.6 mg l(-1) (IQR 0.9-2.1 mg l(-1)) vs. 2.95 mg l(-1) (IQR 1.38-3.73 mg l(-1)) for SLE (P = 0.048) and 1.55 mg l(-1) (IQR 0.98-2.18 mg l(-1)) vs. 3 mg l(-1) (IQR 2.2-4.4 mg l(-1)) for vasculitis (P = 0.016). According to our receiver operating characteristics curve analysis, a C0 threshold of 2.5-3 mg l(-1) was best able to discriminate a flare (SLE: 88% sensitivity, 80% specificity; vasculitis: 100% sensitivity, 90% specificity). Patients with C0 ≥ 2.5-3 mg l(-1) at inclusion had better clinical outcomes during the 12 months following PK assessment. CONCLUSION: Provided that the benefit of TDM in patients with autoimmune diseases could be confirmed by randomized, controlled trials, it might be based on the C0 measured approximately 12 h post-dose.

In vivo interactions of continuous flucloxacillin infusion and high-dose oral rifampicin in the serum of 15 patients with bone and soft tissue infections due to Staphylococcus aureus - a methodological and pilot study.

BACKGROUND: Increased antibiotic resistance against Staphylococcus aureus and low penetration into bone requires regimen optimization of available drugs. METHODS: We evaluate pharmoacokinetic and pharmacodynamic parameters (PK/PD) as well as in vivo interactions of continuous flucloxacillin 12 g/d administration combined with high dose oral rifampicin 600 mg bid in the serum of 15 adult patients with bone and soft tissue infections. We use the patient's own serum directed against his own isolated S. aureus strain to reproduce in vivo conditions as closely as possible. RESULTS: The continuous flucloxacillin infusion constantly generated plasma free drug levels largely exceeding the serum minimal inhibitory concentrations (mean 74-fold). Combination with rifampicin significantly increased flucloxacillin levels by 44.5%. Such an increase following rifampicin introduction was documented in 10/15 patients, whereas a decrease was observed in 1/15 patients. Finally, all infections were cured and the combination was well tolerated. CONCLUSIONS: In this in vivo methodological pilot study among adult patients with orthopaedic infections due to S. aureus, we describe a new method and reveal substantial but inconsistent interactions between flucloxacillin and rifampicin, of which the clinical significance remains unclear.

Chemical stability of azacitidine suspensions for injection after cold-chain reconstitution of powder and storage.

PURPOSE: The 72-hour chemical stability of refrigerated syringes of azacitidine suspension prepared via a cold-chain method is investigated. METHODS: Three 25-mg/mL azacitidine suspensions were prepared from different lots of powdered drug. The suspensions were stored in 2-mL polypropylene syringes at 2-8 °C and protected from light. The concentrations of azacitidine and the mean area under the concentration-time curve (AUC) values for its degradation products were determined after 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours using high-performance liquid chromatography with ultraviolet detection. RESULTS: The degradation process was slow during the first 48 hours and then accelerated. During the first 48 hours of storage, 4.23% of the azacitidine was lost relative to the mean concentration measured at time zero, which complied with International Conference on Harmonisation (ICH) guidance specifying a maximum change of 5% from the initial measured value. Two degradation products were present immediately after syringe preparation; N-formylribosylguanylurea formed rapidly (as indicated by a 35.62% increase from the baseline AUC in the first 12 hours), whereas ribosylguanylurea formation occurred more slowly (a 7.69% mean increase from the baseline AUC at 12 hours) but then rapidly accelerated. The study results indicate that properly prepared azacitidine syringes for injection can be administered up to two days later while maintaining conformance with ICH stability standards. CONCLUSION: Azacitidine 25-mg/mL suspensions reconstituted with refrigerated water (2-8 °C) and stored in propylene syringes were chemically stable during the first 48 hours when stored protected from light at 2-8 °C.

Carbapenems.

OBJECTIVE: To assess the relative strengths and weaknesses of carbapenems by considering their microbiological, clinical, pharmacokinetics and pharmacokinetic/pharmacodynamic (PK/PD) properties and defining optimal conditions of uses of the new generation of carbapenems. METHODS: Literature review. RESULTS: Except for ertapenem, the spectrum of activity is similar for all carbapenems, with little differences in activities of individual agents. The absence or reduced expression of two major porins in combination with various beta-lactamases and alteration of some penicillin binding proteins have been implicated in carbapenem resistance. All carbapenems are not alike, although they have very similar pharmacokinetic properties. The most important PK/PD parameter predicting bacteriological and clinical efficacy is T(>MIC). There is some circumstantial evidence, such as clinical data in severe critically ill septic patients, impaired renal function patients and neutropenic patients that imipenem has to exceed 66% of T(>MIC) to result in good clinical outcome. Continuous or extend infusion of carbapenems should result in at least equal efficacy to that of intermittent infusion in the treatment of infections with susceptible bacteria and appear highly appropriate for use in critically ill patients. CONCLUSIONS: Maximizing clinical outcomes and minimizing antibiotic resistance using individualized doses may be best achieved with therapeutic drug monitoring of carbapenems.

Chemotherapy and targeted agents for colorectal cancer in a real-life setting anticipate guidelines: the COLCHIC cohort study.

Introduction of new agents for the treatment for colorectal cancer (CRC) has been accompanied by the publication of guidelines. The COLCHIC cohort was set up to evaluate CRC treatment practices and the use of these innovative and expensive agents. Patients initiating CRC treatment at the Bordeaux teaching hospital between 1 March 2005 and 1 March 2006 were identified, and treatment courses from 1 March 2005 to 31 December 2006 were studied; 192 patients were included, 188 with analysable data: 43 patients initiated 51 courses for non-metastatic cancer, 153 initiated 366 courses for metastatic cancer, eight patients initiated courses for both non-metastatic and metastatic cancer. Most treatments were used for indications found in guidelines published during the study (83.9%). Of the others, nearly half were approved in guidelines published subsequently. In this teaching hospital, prescribing practice was generally in line with recommendations, with an anticipation of future guidelines. This mostly concerned monoclonal antibodies, which were new at the time of the study.

Alveolar diffusion and pharmacokinetics of linezolid administered in continuous infusion to critically ill patients with ventilator-associated pneumonia.

OBJECTIVES: This study aimed to determine the steady-state serum and alveolar concentrations of linezolid administered by continuous infusion to critically ill patients with ventilator-associated pneumonia (VAP). PATIENTS AND METHODS: This was a prospective, open-label study performed in an intensive care unit and research ward in a university hospital. Twelve critically ill adult patients with VAP received 600 mg of linezolid as a loading dose followed by 1200 mg/day by continuous infusion. After 2 days of therapy, the steady-state serum and alveolar (collected by a mini-bronchoalveolar procedure) concentrations of linezolid were determined by HPLC. RESULTS: The median (IQR) serum and epithelial lining fluid (ELF) linezolid concentrations at steady state (C(ss)) were 7.1 (6.1-9.8) and 6.9 (5.8-8.6) mg/L, respectively, and the median (IQR) AUC (AUC(0-24)) values were 169 (146-235) and 164 (139-202) mg · h/L, respectively, corresponding to a median (IQR) linezolid alveolar diffusion of 97% (80%-108%). CONCLUSIONS: Our study shows that the continuous infusion of 1200 mg of linezolid daily in critically ill patients with VAP provides satisfactory pharmacokinetic results, with a linezolid alveolar diffusion of 100% and concentrations exceeding almost twice the susceptibility breakpoint for Staphylococcus aureus (4 mg/L) in both serum and ELF for 100% of the time. However, the clinical benefit of continuous infusion in comparison with standard intermittent infusion is still to be determined.