A multicenter, real-world experience with recombinant FXIII for the treatment of patients with FXIII deficiency: from pharmacokinetics to clinical practice. The Italian FXIII Study.

BACKGROUND: Congenital factor XIII (FXIII) deficiency is a rare coagulation disorder characterized by muscular or mucocutaneous bleeding with life-threatening intracranial hemorrhages (ICHs), especially in cases with severe disease. The best treatment is the use of prophylactic plasma-derived or recombinant FXIII (rFXIII). Few data on the use of rFXIII in the real-world scenario are available. The main goal of this study was to assess the efficacy and safety of catridecacog (NovoThirteen®) in a population of patients with FXIII deficiency. Other objectives were to compare the different pharmacokinetic (PK) profiles of each patient and to use them to create a tailored prophylaxis regimen. MATERIALS AND METHODS: We collected and analyzed all pharmacokinetic and clinical data in our registry of the patients with congenital FXIII deficiency treated with rFXIII at eleven Italian hemophilia centers. Data were collected from January 2019 to December 2020. RESULTS: Overall, data on 20 patients with FXIII deficiency were collected, 16 of whom presented with severe disease. Pharmacokinetics was assessed in 18 cases before starting prophylaxis. Prophylaxis was subsequently started in these patients using a wide range of dosages (25.0-80.0 IU/kg; mean 33.8 IU/kg) and infusion intervals (3.0-8.0 weeks). During a mean follow up of 47 months, two minor bleeds and one ICH in a severe patient who had remained under on-demand treatment were reported. DISCUSSION: Efficacy and safety of rFXIII were proven in all patients. The dosage and infusion timing for the treated patients sometimes differed to those reported in the MENTOR pivotal studies, thus underlying the importance of tailored management in a real-world scenario.

Treatment of Candida infections with fluconazole in adult liver transplant recipients: Is TDM-guided dosing adaptation helpful?

BACKGROUND: Fluconazole represents a common antifungal option for the treatment of Candida infections in liver transplant recipients. Although adequate antifungal exposure is known to correlate with favorable outcomes in patients with invasive candidiasis, therapeutic drug monitoring (TDM) of fluconazole is currently not recommended. METHODS: We conducted a retrospective study including adult liver transplant recipients receiving fluconazole for invasive candidiasis and undergoing TDM. We assessed the correlation between clinical variables, fluconazole trough plasma levels (Cmin ), and outcome. RESULTS: Twenty-seven patients (74% males; median age 57 years) were included. Abdominal candidiasis was the most frequent infection (56%). Median duration of fluconazole therapy was 17 days (IQR 9-21). Fluconazole median Cmin was 11.0 mg/L (range 2.4-30.6 mg/L). Five (19%) patients required TDM-guided fluconazole dose increase. All-cause in hospital mortality was 33%. Fluconazole Cmin >11 mg/L significantly correlated with clinical success (OR 8.78, 95% CI 1.13-67.8, P = 0.04). CONCLUSIONS: Our study identified decreased fluconazole Cmin as a factor associated with negative outcomes in liver transplant recipients with Candida infection. TDM of fluconazole may be advisable in this patient population.

Is meropenem MIC increase against KPC-producing Klebsiella pneumoniae correlated with increased resistance rates against other antimicrobials with Gram-negative activity?

OBJECTIVES: The aim of this study was to assess the minimum inhibitory concentration (MIC) distribution for meropenem and other antimicrobials with Gram-negative activity against Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) clinical isolates collected at a tertiary hospital in Italy between 2013-2016. METHODS: The antimicrobial susceptibility of KPC-Kp strains was tested by the broth microdilution method using customised 96-well plates and the results were interpreted according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations. RESULTS: Among 169 consecutive KPC-Kp clinical isolates, 45 (26.6%) were susceptible to meropenem (MIC≤2mg/L). Among the 124 meropenem-resistant isolates, 73 (58.9%) had a meropenem MIC between 16-64mg/L. The overall resistance rate for the other antimicrobials tested was very high both for ciprofloxacin and levofloxacin (99.0%), was moderate for amikacin (37.4%) and was low for gentamicin (11.2%), colistin (8.2%) and tigecycline (7.7%). Aminoglycosides had a dichotomous behaviour in relation to meropenem MIC increase. The resistance rate for gentamicin remained <20% across all meropenem MICs; conversely, that for amikacin increased from <20% in the presence of meropenem MIC≤8mg/L up to ca. 80% in the presence of meropenem MIC≥64mg/L. Resistance rates for tigecycline and colistin remained <20% in the presence of meropenem MICs up to 64mg/L. CONCLUSION: The overall susceptibility rates of antimicrobials with Gram-negative activity may vary greatly among KPC-Kp clinical isolates. A tight relationship between meropenem MIC increase and the resistance rate for amikacin was documented.

Population Pharmacokinetics and Dosing Considerations for the Use of Linezolid in Overweight and Obese Adult Patients.

BACKGROUND: Linezolid is an anti-Gram-positive antimicrobial agent used at a fixed dose of 600 mg every 12 h. OBJECTIVES: The objective of this study was to assess the population pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of overweight and obese hospitalized patients. PATIENTS AND METHODS: Population pharmacokinetic and Monte Carlo simulations were conducted to assess the probability of target attainment (PTA) of an area under the concentration-time curve from time zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) ratio > 100, defined as the pharmacodynamic target of efficacy, with incremental candidate dosages. Maximum permissible doses were defined as those causing a ≤ 25% of probability of a linezolid trough of > 8.06 mg/L, associated with thrombocytopenia. The cumulative fraction of response was calculated for the permissible linezolid doses by testing the PTA against the MIC distributions of a large collection of Staphylococci and Enterococci. RESULTS: A total of 352 trough (minimum) and 293 peak (maximum) linezolid concentrations from 112 patients were included. The final mixed-saturative model accounted for 88% of drug concentrations variability over time, and estimated creatinine clearance [by means of the Chronic Kidney Diseases Epidemiology formula (CrCLCKD-EPI)] was the only covariate that improved the model fit. Dose reduction to 450 mg every 12 h may be optimal for patients with coagulase-negative staphylococcal infections and a CrCLCKD-EPI < 130 mL/min/1.73 m2. Dose escalation to 450 mg every 8 h may be optimal for patients with a CrCLCKD-EPI ≥ 60 mL/min/1.73 m2. Escalation to 600 mg every 8 h should not be recommended due to an unacceptable high risk of thrombocytopenia. Patients with CrCLCKD-EPI ≥ 130 mL/min/1.73 m2 and/or co-medication with P-glycoprotein modulators require therapeutic drug monitoring to optimize linezolid doses. CONCLUSIONS: Dosage adjustments of linezolid in this population should be based on CrCLCKD-EPI estimates, rather than on body size descriptors.

Clinical and pharmacokinetic drug evaluation of delafloxacin for the treatment of acute bacterial skin and skin structure infections.

INTRODUCTION: In the era of multi-drug resistant pathogens, the adequate treatment of skin and skin structure infections remains a challenge for clinicians. Delafloxacin, with its broad spectrum against Gram-positive, Gram-negative and anaerobic organisms, represents a new therapeutic option in this setting, especially when coverage of methicillin-resistant Staphylococcus aureus is required in the empirical or targeted approach. Areas covered: In this drug evaluation, the Authors have reviewed the pharmacokinetic and pharmacodynamic characteristics of delafloxacin. In addition, recent data on clinical efficacy and safety from clinical trials have been included. Expert opinion: Delafloxacin represents an attractive therapeutic option due to a broad antimicrobial and favorable pharmacokinetic and pharmacodynamic profile. Several in vitro studies have demonstrated the low potential for resistance selection if used in empirical regimens. Delafloxacin is a promising candidate for the treatment of Gram-positive infections, especially if co-infection with other pathogens is suspected. This is because of the very low MIC of the agent for Gram-positive (including MRSA) and anaerobic bacteria and because of the wide spectrum of activity against Gram-negative organisms. For these interesting microbiological and PK/PD characteristics we expect future uses of this drug in other indications such as diabetic foot infection, osteomyelitis, prosthetic joint infections, abdominal infections and central nervous system infections.

Population Pharmacokinetics of High-Dose Continuous-Infusion Meropenem and Considerations for Use in the Treatment of Infections Due to KPC-Producing Klebsiella pneumoniae.

We assessed the population pharmacokinetics of high-dose continuous-infusion (HDCI) meropenem in a cohort of patients with Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) infections. Monte Carlo simulations were used to define the permissible HDCI meropenem regimens that could be safely considered for the treatment of KPC-Kp infections due to meropenem-resistant strains. Permissible doses were arbitrarily defined as those associated with a ≤10% to 15% likelihood of meropenem steady-state concentrations (Css) of >100 mg/liter. Probabilities of target attainment (PTA) of four incremental pharmacodynamic determinants for meropenem efficacy (100% T>1×MIC, 100% T>2×MIC, 100% T>3×MIC, and 100% T>4×MIC, where "T>MIC" represents the time during which the plasma concentration of this time-dependent antibacterial agent is maintained above the MIC for the pathogen) in relation to different classes of renal function were calculated. The cumulative fractions of response (CFR) for the permissible HDCI meropenem regimens were calculated against the MIC distribution of the KPC-Kp clinical isolates that were collected routinely at our University Hospital between 2013 and 2016 (n = 169). Ninety-seven meropenem Css were included in the analysis. The final model included creatinine clearance (CrCL) as a covariate and explained 94% of the population variability. Monte Carlo simulations based on licensed dosages of up to 6 g/day predicted an acceptable PTA (>80%) of 100% T>1×MIC against KPC-Kp with a meropenem MIC of ≤32 mg/liter in patients with a CrCL level of <130 ml/min. Dosages of 8 g/day were needed for achieving the same target in patients with CrCL at levels of 130 to 200 ml/min. In dealing with pathogens with a meropenem MIC of 64 mg/liter, HDCI regimens using meropenem at higher than licensed levels should be considered. In these cases, real-time therapeutic drug monitoring could be a useful adjunct for optimized care. The predicted CFR were >75% in all of the classes of renal function.

Limited sampling strategies for determining the area under the plasma concentration-time curve for isoniazid might be a valuable approach for optimizing treatment in adult patients with tuberculosis.

This study aimed to develop clinically feasible models of limited sampling strategy (LSS) for estimation of the area under the concentration-time curve (AUC24h) for isoniazid, that could be applied easily in daily clinical practice for dosage adjustment in adult patients with tuberculosis. Isoniazid plasma concentrations (n = 1665) from 185 adult tuberculous patients were used for the development and validation of LSS models to estimate AUC24h following administration of the standard 5 mg/kg dose of isoniazid. Population pharmacokinetic analysis for appropriate estimation of isoniazid pharmacokinetic parameters was performed in a modelling group (n = 100). The Bayesian estimates of AUC24h (AUCref) obtained for each individual were used as the dependent variable in the regression analysis for the development of various LSS models. The LSS models were validated in a separate cohort (n = 85). Several three and four time point LSS models were built and tested. Model H (AUC24h = -1.88 + 1.05 × C1 + 0.78 × C2 + 9.44 × C5) and Model I (AUC24h = -0.65 + 1.00 × C1 + 1.94 × C2 + 15.45 × C9) had the best performances [adj-R2 = 0.93, median prediction error (MPE) = -0.20, root median squared prediction error (RMSE) = 4.65 for Model H; adj-R2 = 0.96, MPE = -0.05 RMSE = 3.56 for Model I]. The very high R2 values (≥0.94) of these regression equations in the validation cohort confirmed their high reliability. These LSS models could be applied in the context of therapeutic drug monitoring programmes aiming to personalize isoniazid dosing regimens for adult patients with tuberculosis.

Might real-time pharmacokinetic/pharmacodynamic optimisation of high-dose continuous-infusion meropenem improve clinical cure in infections caused by KPC-producing Klebsiella pneumoniae?

The effect of real-time pharmacokinetic/pharmacodynamic (PK/PD) optimisation of high-dose continuous-infusion meropenem on the clinical outcome of patients receiving combination antimicrobial therapy for treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp) infections was retrospectively assessed. Data for all patients with KPC-Kp-related infections who received antimicrobial combination therapy containing high-dose continuous-infusion meropenem optimised by means of therapeutic drug monitoring (TDM) were retrieved. Optimal PK/PD exposure was considered a steady-state concentration to minimum inhibitory concentration ratio (Css/MIC) of 1-4. Univariate binary logistic regression analysis was performed to identify independent predictors of clinical outcome. Among the 30 eligible patients, 53.3% had infections caused by meropenem-resistant KPC-Kp (MIC ≥ 16 mg/L). Tigecycline and colistin were the two antimicrobials most frequently combined with meropenem. Mean doses of continuous-infusion meropenem ranged from 1.7 to 13.2 g/daily. The Css/MIC ratio was ≥1 in 73.3% of cases and ≥4 in 50.0%. Clinical outcome was successful in 73.3% of cases after a median treatment length of 14.0 days. In univariate analysis, a significant correlation with successful clinical outcome was found for a Css/MIC ratio ≥1 (OR = 10.556, 95% CI 1.612-69.122; P = 0.014), a Css/MIC ratio ≥4 (OR = 12.250, 95% CI 1.268-118.361; P = 0.030) and a Charlson co-morbidity index of ≥4 (OR = 0.158, 95% CI 0.025-0.999; P = 0.05). High-dose continuous-infusion meropenem optimised by means of real-time TDM may represent a valuable tool in improving clinical outcome when dealing with the treatment of infections caused by KPC-Kp with a meropenem MIC ≤ 64 mg/L.

Polytherapy and the risk of potentially inappropriate prescriptions (PIPs) among elderly and very elderly patients in three different settings (hospital, community, long-term care facilities) of the Friuli Venezia Giulia region, Italy: are the very elderly at higher risk of PIPs?

PURPOSE: The aim of this point-prevalence study was to assess the occurrence of polypharmacy and hyperpolypharmacy and the risk of potentially inappropriate prescriptions (PIPs) among elderly and very elderly patients in different health-care settings of the Friuli-Venezia Giulia region in the North-East of Italy. METHODS: Prescription pattern of elderly (65-79 years) and very elderly (>79 years) patients in three different health-care settings [hospitals, general practitioners, and long-term care facilities (LTCFs)] was assessed in March 2014, and PIPs were assessed according to the Beers criteria. Other situations at potentially high risk were checked. RESULTS: A total of 1582 patients (hospital, n = 528; outpatients, n = 527; nursing homes, n = 527) were included. Very elderly were more represented in hospitals (60.4%) and LTCFs (77.1%) than among general practitioners (37.6%). Polypharmacy and hyperpolypharmacy rates ranged 57.7-73.7% and 9.7-15.6%, respectively. The most frequently prescribed drugs were the proton pump inhibitors, whereas the most common PIPs resulted the benzodiazepines. Multinomial regression analysis showed that female sex, age > 79 years, hyperpolypharmacy, and chronic kidney disease were associated with the risk of having ≥2 PIPs. Two situations at high risk of PIPs not contemplated by the Beers criteria were recurrent in the study population and concerned the statins and metformin. CONCLUSIONS: Polypharmacy and hyperpolypharmacy among elderly and very elderly are strictly associated with the risk of multiple PIPs. The findings offer the opportunity to remark that improvement of the knowledge of safe drug use is generally needed in aging societies and may become of utmost relevance among health-care workers operating in LTCFs. Copyright © 2016 John Wiley & Sons, Ltd.

Might isoniazid plasma exposure be a valuable predictor of drug-related hepatotoxicity risk among adult patients with TB?

OBJECTIVES: To investigate the relationship between isoniazid plasma exposure and the likelihood of elevation of ALT (≥51 IU/L) among adult patients with TB. METHODS: A retrospective observational study was conducted in patients who underwent periodic monitoring of hepatic function and in whom pharmacokinetic data were collected. Monte Carlo simulation was performed with the intent of identifying the probability of achieving an AUC24 greater than the identified threshold of hepatotoxicity with different dosing regimens (2.5, 5.0 and 7.5 mg/kg/day). RESULTS: Forty-one out of 185 evaluable patients (22.2%) had an ALT elevation. A mild correlation between isoniazid AUC0-24 and ALT increase was observed (Spearman's ρ = 0.34, P < 0.001). Patients with ALT ≥51 IU/L showed significantly higher isoniazid exposure than those with ALT <51 IU/L (mean AUC24 of 58.33 versus 31.28 mg·h/L, P < 0.001). The probabilities of ALT elevation were 0.82 and 0.12 for isoniazid AUC24 ≥55.0 and <55.0 mg·h/L, respectively. Use of a logistic regression model estimated a likelihood of developing hepatotoxicity of 0.5 and 0.9 when in the presence of an isoniazid AUC24 of 53.7 and 70.0 mg·h/L, respectively. Simulation showed that the standard isoniazid 5 mg/kg daily dose gave a probability of ALT increase of 0.46 for slow acetylators and 0.03 for rapid acetylators. CONCLUSIONS: Plasma isoniazid exposure might be a valuable predictor of drug-related hepatotoxicity. Early assessment of isoniazid exposure at the beginning of treatment might allow prompt dosage reduction among those patients who are experiencing drug overexposure, thus containing the risk of hepatotoxicity occurrence.

Variability of Voriconazole Trough Levels in Haematological Patients: Influence of Comedications with cytochrome P450(CYP) Inhibitors and/or with CYP Inhibitors plus CYP Inducers.

Voriconazole plasma exposure greatly varies among haematological patients. The purpose of this study was to identify the magnitude of influence of comedications with CYP inhibitors and/or with CYP inhibitors plus CYP inducers on voriconazole trough level (Cmin ). Voriconazole Cmin was retrospectively assessed among haematological patients who underwent therapeutic drug monitoring (TDM). Univariate and multivariate linear mixed-effect regression analyses were performed to identify the independent predictors of normalized Cmin . Of the 83 included patients, 35 had comedications with CYP inhibitors (omeprazole or pantoprazole) and 21 with CYP inhibitors (omeprazole or pantoprazole) plus CYP inducers (methylprednisolone, dexamethasone, phenobarbital, rifampin or carbamazepine). Median Cmin value (n = 199) was 2.4 mg/L with a wide range of distribution (<0.2-13.5 mg/L). Median (IQR) normalized voriconazole Cmin value was significantly higher in the presence of CYP inhibitors (4.20 mg/L, 3.23-5.51 mg/L) than either in the absence of interacting cotreatments (2.55 mg/L, 1.54-3.47 mg/L) or in the presence of CYP inhibitors plus CYP inducers (2.16 mg/L, 1.19-3.09 mg/L). The presence of CYP inhibitors was highly significantly associated with Cmin >5.5 mg/L (OR: 23.22, 95% CI: 3.01-179.09, p = 0.003). No significant association emerged when CYP inhibitors were coadministered with CYP inducers (OR: 3.53, 95% CI: 0.36-34.95, p = 0.280). The amount of expected Cmin increase was significantly influenced by both the type and the dose of the administered proton pump inhibitor. The study highlights that the benefit from TDM of voriconazole may be maximal in those patients who are cotreated with CYP inhibitors and/or with CYP inhibitors plus CYP inducers, especially when receiving proton pump inhibitors (PPIs) at very high dosages intravenously.

Monitoring Polypharmacy in Healthcare Systems Through a Multi-Setting Survey: Should We Put More Attention on Long Term Care Facilities?

BACKGROUND: Polypharmacy is a main issue of patient safety in all healthcare settings (i.e. increase adverse drug reactions and incidence of drug-drug interactions, etc.). The main object of the study was to evaluate the prevalence of polypharmacy and the appropriateness of drugs prescriptions in the regional health system (RHS) of Friuli Venezia-Giulia Region, Italy. DESIGN AND METHODS: We carried out a point prevalence study in May 2014; 1582 patients ≥65 years were included from: 14 acute hospitals, 46 Long Term Care Facilities (LTCFs) and 42 general practitioners' (GPs) clinics. Data analysis included the evaluation of potentially inappropriate prescriptions (PIPs) taking Beers criteria as a reference. RESULTS: Patients in therapy with 10 drugs or more were 13.5%: 15.2% in hospitals, 9.7% in GPs' clinics and 15.6% in LTCFs. According to Beers criteria we identified 1152 PIPs that involved globally almost half of patients (46.0%): 41.9% in hospitals, 59.6% in LTCFs and 37.0% in GP's clinics. The 53.9% of patients received at least one mainly kidney excreted drug; for these patients the evaluation of serum creatinine was overall present in the 87.7% (747/852): 96.4% in hospital ones, 87.5% in GPs' clinics and 77.8% in LTCFs. LTCFs residents were significantly (P<0.05) more exposed to PIPs and less monitored for the renal function. CONCLUSIONS: A reliable estimation of the phenomenon in all the main healthcare settings is a necessary prerequisite to set tailored policies for facing polypharmacy within a RHS; the results showed the necessity to put a special attention on LTCFs.

A 1 year retrospective audit of quality indicators of clinical pharmacological advice for personalized linezolid dosing: one stone for two birds?

AIM: This study explored the clinical and economic impact of clinical pharmacological advice (CPA) (based on therapeutic drug monitoring [TDM] results, and on patients' characteristics and co-medications) on personalized linezolid therapy in a tertiary care hospital. METHODS: A 1 year retrospective analysis of quality indicators of CPA (clinicians' adherence rate to CPA, pre-post rate of linezolid trough concentrations within the desired range and cost balance analysis) was conducted. RESULTS: Five hundred and forty-four CPAs were provided to clinicians during 2014 for personalizing linezolid therapy in 168 patients. Clinicians' adherence to CPAs was very high (94.7%). The pre-post rate of linezolid Cmin distribution showed a favourable impact of CPA on patient care (pre-post ratio of Cmin within the desired range + 23.4%, pre, 51.2% vs. post, 74.6%). Overall, linezolid dosage was mainly reduced (56.9% of cases), whereas dose augmentation was needed only in a minority of cases (7.7%). Cost balance analysis showed that overall 1258 standard doses of linezolid (unitary dose 600 mg) were spared for treating 168 patients with a personalized dosage for a median duration of 11 days (range 3-128 days) with a cost saving of 60038.05 €. CONCLUSION: Active computerized advice elaborated by the clinical pharmacologist on the basis of TDM results and of patient's pathophysiological data and co-medications may be cost-effective for personalizing linezolid treatment.

Does Critical Illness Change Levofloxacin Pharmacokinetics?

Levofloxacin is commonly used in critically ill patients for which existing data suggest nonstandard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and in non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analyzed and population pharmacokinetic analysis was undertaken using Pmetrics. Thirty-five patients (18 critically ill) were included. The mean (standard deviation [SD]) age, weight, and Cockcroft-Gault creatinine clearance for the critically ill and for the non-critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg, and 71.9 (65.8) and 68.2 (30.1) ml/min, respectively. A two-compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were as follows: clearance, 8.66 (3.85) liters/h; volume of the central compartment (Vc), 41.5 (24.5) liters; intercompartmental clearance constants from central to peripheral, 2.58 (3.51) liters/h; and peripheral to central compartments, 0.90 (0.58) liters/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen, and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function.

Pharmacokinetics and pharmacodynamics of continuous-infusion meropenem in pediatric hematopoietic stem cell transplant patients.

This study explored the pharmacokinetics and the pharmacodynamics of continuous-infusion meropenem in a population of pediatric hematopoietic stem cell transplant (HSCT) patients who underwent therapeutic drug monitoring. The relationship between meropenem clearance (CLM) and estimated creatinine clearance (CLCR) was assessed by nonlinear regression. A Monte Carlo simulation was performed to investigate the predictive performance of five dosing regimens (15 to 90 mg/kg of body weight/day) for the empirical treatment of severe Gram-negative-related infections in relation to four different categories of renal function. The optimal target was defined as a probability of target attainment (PTA) of ≥90% at steady-state concentration-to-MIC ratios (C SS/MIC) of ≥1 and ≥4 for MICs of up to 8 mg/liter. A total of 21 patients with 44 meropenem C SS were included. A good relationship between CLM and estimated CLCR was observed (r (2) = 0.733). Simulations showed that at an MIC of 2 mg/liter, the administration of continuous-infusion meropenem at doses of 15, 30, 45, and 60 mg/kg/day may achieve a PTA of ≥90% at a C SS/MIC ratio of ≥4 in the CLCR categories of 40 to <80, 80 to <120, 120 to <200, and 200 to <300 ml/min/1.73 m(2), respectively. At an MIC of 8 mg/liter, doses of up to 90 mg/kg/day by continuous infusion may achieve optimal PTA only in the CLCR categories of 40 to <80 and 80 to <120 ml/min/1.73 m(2). Continuous-infusion meropenem at dosages up to 90 mg/kg/day might be effective for optimal treatment of severe Gram-negative-related infections in pediatric HSCT patients, even when caused by carbapenem-resistant pathogens with an MIC of up to 8 mg/liter.

Pharmacokinetics and pharmacodynamics of continuous infusion meropenem in overweight, obese, and morbidly obese patients with stable and unstable kidney function: a step toward dose optimization for the treatment of severe gram-negative bacterial infections.

BACKGROUND: Meropenem is an anti-Gram-negative antimicrobial, the time-dependent activity of which may be maximized through administration by continuous infusion. OBJECTIVES: The objectives of this study were to characterize the pharmacokinetics of continuous infusion meropenem in relation to body size and Cockcroft-Gault estimated creatinine clearance (CLCR) in overweight and obese patients with stable and unstable kidney function with the intent of creating a nomogram for optimal dosing. PATIENTS AND METHODS: Patients from a single institution with a body mass index ≥25 kg/m(2) receiving meropenem by continuous infusion with measurement of meropenem steady-state concentrations (C ss) were identified. Individual Bayesian estimates of meropenem volume of distribution of the central compartment (V c) and clearance (CL) were calculated and relationships to body size descriptors and CLCR estimated using these body size descriptors were defined by regression. Kidney function stability was defined based on median absolute deviation, stratification by the ratio of maximum to minimum serum creatinine (SCr) and individual patient-level regression of SCr over time. The influence of kidney function stability on meropenem CL estimation by CLCR was tested. RESULTS: A total of 375 patients (77.9 % male) with 846 C ss values (62.4 % of patients with ≥2 measurements) were identified. The median daily dose of meropenem and frequency of infusion bag changes were 2000 mg/day and four times per day, respectively. The meropenem C ss values were ≥16, ≥8, ≥4, and ≥2 mg/L for 41.1, 76.1, 97.4, and 99.9 % of observations, respectively. The median (range) age, weight, and BMI were 66 (24-90) years, 90 (70-250) kg, and 30.8 (25.1-81.6) kg/m(2), respectively. The mean [standard deviation (SD)] serum creatinine at baseline was 1.57 (1.37) mg/dL. The mean (SD) V c was 28.1 (1.36) L and not related to body size, while CL was 8.85 (6.40) L/h and best related to CLCR estimated using adjusted body weight (ABW). The meropenem CL to CLCR relationship was not significantly impacted by the presence or absence of kidney function stability. The user-friendly dosing nomogram based on CLCR estimated using ABW showed that optimal drug exposure [Css ≥ minimum inhibitory concentration (MIC)] may be obtained even against multi-drug resistant (MDR) pathogens when considering dosages up to 1250 mg every 6 h by continuous infusion. CONCLUSIONS: Meropenem CL is best estimated using CLCR with ABW in patients with a BMI ≥25 kg/m(2) and this relationship is not altered by unstable kidney function. Application of our dosing nomogram may improve the care of overweight and obese patients with severe MDR Gram-negative infections treated with meropenem by continuous infusion.

A 5-year survey of antimicrobial susceptibility profiles of methicillin-resistant Staphylococcus aureus (MRSA) isolated from patients with bloodstream infections in Northeast Italy.

A 5-year survey (2009-2013) of antimicrobial susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) isolated from patients with bloodstream infections was carried out in Northeast Italy. No upward creep of glycopeptides MICs was documented among 582 nonduplicate MRSA blood isolates, which were tested in accordance with broth microdilution and interpreted in accordance with EUCAST recommendations. Teicoplanin showed stably a lower MIC50 in comparison with vancomycin (0.25-0.5 versus 1 mg/L). The activities of newer anti-MRSA antibacterials stratified by glycopeptides MICs showed similar trends in MICs of either vancomycin or teicoplanin with those of daptomycin, linezolid, and tigecycline. We hypothesize that in centers with different distribution of glycopeptides MICs, downward for teicoplanin and upward for vancomycin, teicoplanin could be a more effective alternative to vancomycin for empirical treatment of MRSA-related bacteremia.

Pharmacokinetic/pharmacodynamic evaluation of linezolid in hospitalized paediatric patients: a step toward dose optimization by means of therapeutic drug monitoring and Monte Carlo simulation.

OBJECTIVES: To report on linezolid exposure in a paediatric population who routinely underwent therapeutic drug monitoring (TDM) for dosage optimization and to assess the factors affecting interpatient variability. METHODS: We performed a retrospective study of patients whose plasma C(min) and Cmax levels were measured during linezolid treatment. Adequate exposure was defined as a C(min) of 2-7 mg/L and/or an estimated AUC24 of 160-300 mg · h/L. Patients were divided into two subgroups (Group 1, 2-11 years; Group 2, 12-18 years). Monte Carlo simulation was performed to investigate whether or not the currently recommended dosages might enable a high probability of target attainment (PTA) of two thresholds for linezolid efficacy (AUC24/MIC ≥ 80 or ≥ 100). Data on demographic characteristics, disease, microbiology and haematochemical parameters and outcomes were collected. RESULTS: A total of 23 patients were included. Standard dosages were suboptimal in 50.0% and 44.4% of patients in Group 1 and Group 2, respectively. Among those who underwent multiple instances of TDM, the dosages were increased in 33.3% of cases in both groups, and decreased in 6.6% and 9.5% of cases in Group 1 and Group 2, respectively. Co-treatment with phenobarbital, proton pump inhibitors and amiodarone accounted for most of the variability in C(min) (adjusted R(2) of 0.692). Simulations showed a PTA of ≥ 90% with the current dosing regimens in both groups only for pathogens with an MIC ≤ 1 mg/L. CONCLUSIONS: Higher dosages of linezolid may be needed, especially in Group 1 when in the presence of pathogens with an MIC >1 mg/L. The role of TDM should be encouraged for optimization of linezolid exposure in the paediatric setting in the presence of infections caused by pathogens with borderline susceptibility and/or for patients co-treated with drugs that may alter linezolid exposure.