Real-world experience of therapeutic drug monitoring and PK/PD achievement of ceftaroline administered by different infusion regimens in patients with confirmed infections caused by Gram-positive bacteria.

BACKGROUND: Ceftaroline is a novel cephalosporin active against MDR Gram-positive (GP) bacteria. For ß-lactam antibiotics, such as ceftaroline, prolonged infusions and therapeutic drug monitoring (TDM) are used for dosage optimization based on their pharmacokinetics/pharmacodynamics (PK/PD). OBJECTIVES: To describe our experience with TDM and PK/PD target attainment of ceftaroline administered by intermittent and prolonged infusion in a cohort of patients with MDR-GP bacterial infections. METHODS: Patients treated with ceftaroline administered by continuous (24 h), extended (3 h/6 h) and intermittent infusion (1 h) and undergoing TDM of plasma concentrations were included. A 100%fT>4×MIC was the pre-specified PK/PD target and 100%fT>10×MIC was considered overexposure. Dose recommendations were made based on TDM results and each patient's clinical condition. RESULTS: Twelve patients [83.3% male, median age of 73 (38-83) years] were included. Nine patients (75%) achieved 100%fT>4×MIC, all under prolonged infusions. In one patient, the 100%fT was >10×MIC but no toxicity was observed. Based on TDM results, initial doses were recommended to be maintained in eight patients, decreased in three and increased in one. CONCLUSIONS: The administration of ceftaroline by prolonged infusion together with TDM may be a useful strategy for achieving the desired PK/PD target in these patients. However, more studies evaluating the relationship between PK/PD attainment and clinical outcomes are needed.

A Loading Micafungin Dose in Critically Ill Patients Undergoing Continuous Venovenous Hemofiltration or Continuous Venovenous Hemodiafiltration: A Population Pharmacokinetic Analysis.

BACKGROUND: In this study, the authors aimed to compare the pharmacokinetics (PK) of micafungin in critically ill patients receiving continuous venovenous hemofiltration (CVVH, 30 mL·kg-1·h-1) with those of patients receiving equidoses of hemodiafiltration (CVVHDF, 15 mL·kg-1·h-1 + 15 mL·kg-1·h-1) and determine the optimal dosing regimen using the developed model. METHODS: Patients with septic shock undergoing continuous renal replacement therapy and receiving a conventional dose of 100 mg micafungin once daily were eligible for inclusion. Total micafungin plasma concentrations from 8 CVVH sessions and 8 CVVHDF sessions were subjected to a population PK analysis using Pmetrics. Validation of the model performance was reinforced by external validation. Monte Carlo simulations were performed considering the total ratio of free drug area under the curve (AUC) over 24 hours to the minimum inhibitory concentration (MIC) (AUC0-24/MIC) in plasma. RESULTS: The median total body weight (min-max) was 94.8 (66-138) kg. Micafungin concentrations were best described by a 2-compartmental PK model. No covariates, including continuous renal replacement therapy modality (CVVH or CVVHDF), were retained in the final model. The mean parameter estimates (SD) were 0.96 (0.32) L/h for clearance and 14.8 (5.3) L for the central compartment volume. External validation confirmed the performance of the developed PK model. Dosing simulations did not support the use of standard 100 mg daily dosing, except for Candida albicans on the second day of therapy. A loading dose of 150 mg followed by 100 mg daily reached the probability of target attainment for all C. albicans and C. glabrata, but not for C. krusei and C. parapsilosis. CONCLUSIONS: No difference was observed in micafungin PK between equidoses of CVVH and CVVHDF. A loading dose of 150 mg is required to achieve the PK/PD target for less susceptible Candida species from the first day of therapy.

Epidemiology and Treatment of Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa Infections.

In recent years, the worldwide spread of the so-called high-risk clones of multidrug-resistant or extensively drug-resistant (MDR/XDR) Pseudomonas aeruginosa has become a public health threat. This article reviews their mechanisms of resistance, epidemiology, and clinical impact and current and upcoming therapeutic options. In vitro and in vivo treatment studies and pharmacokinetic and pharmacodynamic (PK/PD) models are discussed. Polymyxins are reviewed as an important therapeutic option, outlining dosage, pharmacokinetics and pharmacodynamics, and their clinical efficacy against MDR/XDR P. aeruginosa infections. Their narrow therapeutic window and potential for combination therapy are also discussed. Other "old" antimicrobials, such as certain ß-lactams, aminoglycosides, and fosfomycin, are reviewed here. New antipseudomonals, as well as those in the pipeline, are also reviewed. Ceftolozane-tazobactam has clinical activity against a significant percentage of MDR/XDR P. aeruginosa strains, and its microbiological and clinical data, as well as recommendations for improving its use against these bacteria, are described, as are those for ceftazidime-avibactam, which has better activity against MDR/XDR P. aeruginosa, especially strains with certain specific mechanisms of resistance. A section is devoted to reviewing upcoming active drugs such as imipenem-relebactam, cefepime-zidebactam, cefiderocol, and murepavadin. Finally, other therapeutic strategies, such as use of vaccines, antibodies, bacteriocins, anti-quorum sensing, and bacteriophages, are described as future options.

Efficacy of Ceftolozane-Tazobactam in Combination with Colistin against Extensively Drug-Resistant Pseudomonas aeruginosa, Including High-Risk Clones, in an In Vitro Pharmacodynamic Model.

Combination therapy is an attractive therapeutic option for extensively drug-resistant (XDR) Pseudomonas aeruginosa infections. Colistin has been the only treatment available for these infections for many years, but its results are suboptimal. Ceftolozane-tazobactam (C/T) is a newly available therapeutic option that has shown good antipseudomonal activity, even against a number of XDR P. aeruginosa strains. However, data about combinations containing C/T are scarce. The aim of this study was to analyze the activity of C/T and colistin alone and in combination against a collection of XDR P. aeruginosa strains containing 24 representative clinical isolates from a multicentre Spanish study. Twenty-four time-kill experiments performed over 24 h were conducted in duplicate to determine the effects of colistin and C/T alone and combined. An in vitro pharmacodynamic chemostat model then was used to validate this combination against three selected XDR P. aeruginosa ST175 isolates with different susceptibility levels to C/T. Static time-kill assays demonstrated superior synergistic or additive effect for C/T plus colistin against 21 of the 24 isolates studied. In the in vitro dynamic pharmacokinetic/pharmacodynamic (PK/PD) model, the C/T regimen of 2/1 g every 8 h with a steady-state concentration of 2 mg/liter colistin effectively suppressed the bacterial growth at 24 h. Additive or synergistic interactions were observed for C/T plus colistin against XDR P. aeruginosa strains and particularly against C/T-resistant strains. C/T plus colistin may be a useful treatment for XDR P. aeruginosa infections, including those caused by high risk-clones resistant to C/T.

Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial.

BACKGROUND: Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia. METHODS: Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. RESULTS: The median (IQR) of meropenem AUC0-24 h in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L. CONCLUSIONS: An increase in the dose of meropenem administered by CI achieved a higher exposure in the plasma and ELF. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC ≤ 2 mg/L) in patients with conserved renal function. An alternative therapy should be considered when the presence of microorganisms with a MIC greater than 2 mg/L is suspected. TRIAL REGISTRATION: The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT-no. 2016-002796-10). Registered on 27 December 2016.

Effects of the extracorporeal membrane oxygenation circuit on plasma levels of ceftolozane.

INTRODUCTION: New antibiotics with bactericidal activity against multi-drug-resistant bacteria are increasingly used in the intensive care units. Here, we aimed to evaluate the influence of the extracorporeal membrane oxygenation on plasma levels of ceftolozane. CASE REPORT: A 34-year-old female was admitted to the intensive care unit after bilateral lung transplantation, complicated by primary graft dysfunction and cardiogenic shock needing venoarterial extracorporeal membrane oxygenation. Ceftolozane/tazobactam was started. Plasma ceftolozane levels were monitored on the first and third days of antibiotic treatment. A non-compartment pharmacokinetic analysis was performed and the extraction rate through the oxygenator was calculated. DISCUSSION: The extracorporeal circuit of extracorporeal membrane oxygenation may alter the pharmacokinetics of antibiotics, to varying degrees due to drug sequestration and increased distribution volume. In this case, the extracorporeal membrane oxygenation circuit had little impact on the ceftolozane plasma concentration. CONCLUSION: Plasma levels of ceftolozane are stable in the extracorporeal membrane oxygenation circuit, suggesting that adjustment of standard doses of ceftolozane in patients with extracorporeal membrane oxygenation support may not be needed.

Systemic pharmacokinetics and safety of high doses of nebulized colistimethate sodium in critically ill patients with hospital-acquired and ventilator-associated pneumonia.

OBJECTIVES: To assess the pharmacokinetics of formed colistin in plasma and the safety of two different high doses of colistimethate sodium administered via nebulization in critically ill surgical patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). PATIENTS AND METHODS: Formed colistin plasma concentrations were measured in critically ill surgical patients with pneumonia treated with two different doses of nebulized colistimethate sodium (3 MIU/8 h versus 5 MIU/8 h). Adverse events possibly related to nebulized colistimethate sodium were recorded. RESULTS: Twenty-seven patients (15 in the 3 MIU/8 h group and 12 in the 5 MIU/8 h group) were included. Colistin plasma concentrations were unquantifiable (<0.1 mg/L) in eight (53.3%) patients in the 3 MIU/8 h group and in seven patients (58.3%) in the 5 MIU/8 h group. Median (IQR) quantifiable colistin plasma concentrations before nebulization and at 1, 4 and 8 h were 0.17 (0.12-0.33), 0.20 (0.11-0.24), 0.17 (0.12-0.23) and 0.17 (0.11-0.32) mg/L, respectively, in the 3 MIU/8 h group and 0.20 (0.11-0.35), 0.24 (0.12-0.44), 0.24 (0.10-0.49) and 0.23 (0.11-0.44) mg/L, respectively, in the 5 MIU/8 h group, with no differences between the two groups at any time. Renal impairment during nebulized treatment was observed in three patients in each group, but was unlikely to be related to colistimethate sodium treatment. Nebulized colistimethate sodium therapy was well tolerated and no bronchospasms or neurotoxicity events were observed. CONCLUSIONS: In this limited observational case series of critically ill patients with HAP or VAP treated with high doses of nebulized colistimethate sodium, systemic exposure was minimal and the treatment was well tolerated.

Serum albumin is a strong predictor of sepsis outcome in elderly patients.

The incidence of sepsis is disproportionately higher in elderly adults, and age is an independent predictor of mortality. Retrospective analysis was conducted among patients admitted to the emergency department in a tertiary teaching hospital from January 2016 to June 2017. To study the prognosis determinants of sepsis among elderly patients attended in the emergency room of a tertiary care hospital. As secondary objectives, we aimed to describe the causes of sepsis, the general outcome, and the general characteristics of these patients. Two hundred thirty-five episodes data of patients admitted throughout the 15-month study period who were diagnosed with sepsis, severe sepsis or septic shock, were included. Throughout the study cohort, 51 patients (21.7%) fulfilled the criteria of severe sepsis or septic shock. All-cause mortality was 11 patients (4.7%) on day 14 and 27 (11.5%) on day 30. Prognosis factors associated with 30-day mortality were the following: albumin level < 2.6 g/dl (first quartile of the overall population), odds ratio (OR 3.26, 95% CI 12-9.41; p = 0.029), Charlson comorbidity index (OR 1.23, 95% CI 1.04-1.45; p = 0.012), C-reactive protein on admission (OR 1.04, 95% CI 0.99-1.08; p = 0.062), and non-adequacy of the initial antimicrobial therapy (OR 3.3, 95% CI 1.06-10.4; p = 0.039). Among elderly patients with sepsis, strong predictors of mortality such as albumin could be considered as part of prognosis and future potential interventions. Adequacy of antimicrobial therapy at admission must be one of the objectives in the treatment of sepsis, also in the elderly, since it is an independent predictor of mortality.

Pharmacokinetics of Micafungin in Critically Ill Patients Receiving Continuous Venovenous Hemodialysis With High Cutoff Membranes.

BACKGROUND: An optimal antifungal therapy for invasive candidiasis in critically ill patients is essential to reduce the high mortality rates. Acute kidney injury is common, and continuous renal replacement therapies are frequently used. Previous studies have demonstrated a lack of effect from different continuous renal replacement techniques on micafungin clearance. However, the use of high cutoff pore size membranes could potentially allow for the loss of albumin and alter micafungin pharmacokinetics. The objective was to explore the pharmacokinetics of micafungin in critically ill patients undergoing continuous venovenous high cutoff membrane hemodialysis (CVVHD-HCO). METHODS: Prospective observational study performed in critically ill patients treated with 100 mg/d of micafungin and undergoing CVVHD-HCO. CVVHD-HCO sessions were performed using Prisma-Flex monitors and dialyzers with a membrane of polyarylethersulfone of 1.1-m surface area and 45-kDa pore size. Blood samples were collected from arterial prefilter, venous postfilter, and the drainage line ports at 0 (predose), 1, 4, 12, 24 hours after dose, and micafungin concentrations were determined using HPLC-UV. RESULTS: Nine patients (55.6% male; age: 28-80 years) were included. Median (range) of micafungin concentrations in the effluent were <0.2 (<0.2-0.4) mg/L at low (predose) and 0.4 (<0.2-0.7) mg/L at high (1 h) concentrations. The extraction ratio was <12% at each time point. A 2-compartment model best described the time course of plasma concentrations, and body weight was the only covariate that improved the model. CONCLUSIONS: This is the first study demonstrating that CVVHD-HCO does not alter the pharmacokinetics of micafungin, and that standard doses of this antifungal can be used.

Linezolid Dosing in Patients With Liver Cirrhosis: Standard Dosing Risk Toxicity.

BACKGROUND: Limited data regarding altered linezolid pharmacokinetics in patients with liver cirrhosis are available. The objective of this study was to evaluate the pharmacokinetics, efficacy and safety of linezolid in cirrhotic patients. METHODS: A case-control 1:1 study of patients undergoing linezolid therapeutic drug monitoring was conducted between January 2015 and June 2017. Cases with liver cirrhosis were matched with controls by age, body weight, comorbidities, renal function, and intensive care unit (ICU) admission. RESULTS: Fifty-two patients were included, 26 in each group. Patients with Child-Pugh Scores A, B, and C were 1 (3.8%), 13 (50.0%), and 12 (46.2%), respectively. Cases had higher median linezolid trough plasma concentrations than controls [20.6 (17.4) versus 2.7 (11.3); P < 0.001)] and more frequently achieved an optimal pharmacodynamic index [26 (100%) versus 16 (61.5%); P = 0.002]. In addition, potentially toxic concentrations and treatment discontinuation due to overexposure and hematological toxicity were also more frequently seen in cirrhotic patients. Overall clinical cure rate was high (67.4%), and in-hospital mortality was 28.8%. No differences in clinical outcomes were observed between both groups. CONCLUSIONS: Linezolid showed a high clinical cure rate. Nevertheless, plasma concentrations and treatment discontinuation due to hematological toxicity were higher in cirrhotic patients. Liver cirrhosis may influence linezolid pharmacokinetics and question the use of standard doses. Therapeutic drug monitoring of linezolid would be valuable in these patients.

Colistin Use in Patients with Chronic Kidney Disease: Are We Underdosing Patients?

Colistin is administered as its inactive prodrug colistimethate (CMS). Selection of an individualized CMS dose for each patient is difficult due to its narrow therapeutic window, especially in patients with chronic kidney disease (CKD). Our aim was to analyze CMS use in patients with CKD. Secondary objectives were to assess the safety and efficacy of CMS in this special population. In this prospective observational cohort study of CMS-treated CKD patients, CKD was defined as the presence of a glomerular filtration rate (GFR) < 60 mL/min/m² for more than 3 months. The administered doses of CMS were compared with those recently published in the literature. Worsened CKD at the end of treatment (EOT) was evaluated with the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria. Colistin plasma concentrations (Css) were measured using high-performance liquid chromatography. Fifty-nine patients were included. Thirty-six (61.2%) were male. The median age was 76 (45⁻95) years and baseline GFR was 36.6 ± 13.6. The daily mean CMS dosage used was compared with recently recommended doses (3.36 vs. 6.07; p < 0.001). Mean Css was 0.9 (0.2⁻2.9) mg/L, and Css was <2 mg/L in 50 patients (83.3%). Clinical cure was achieved in 43 (72.9%) patients. Worsened renal function at EOT was present in 20 (33.9%) patients and was reversible in 10 (52.6%). The CMS dosages used in this cohort were almost half those currently recommended. The mean achieved Css were under the recommended target of 2 mg/dL. Despite this, clinical cure rate was high. In this patient cohort, the incidence of nephrotoxicity was similar to those found in other recent studies performed in the general population and was reversible in 52.6%. These results suggest that CMS is safe and effective in patients with CKD and may encourage physicians to adjust dosage regimens to recent recommendations in order to optimize CMS treatments.

Population pharmacokinetics/pharmacodynamics of micafungin against Candida species in obese, critically ill, and morbidly obese critically ill patients.

BACKGROUND: Dosing in obese critically ill patients is challenging due to pathophysiological changes derived from obesity and/or critical illness, and it remains fully unexplored. This study estimated the micafungin probability of reaching adequate 24-h area under the curve (AUC0-24h)/minimum inhibitory concentration (MIC) values against Candida spp. for an obese/nonobese, critically ill/noncritically ill, large population. METHODS: Blood samples for pharmacokinetic analyses were collected from 10 critically ill nonobese patients, 10 noncritically ill obese patients, and 11 critically ill morbidly obese patients under empirical/directed micafungin treatment. Patients received once daily 100-150 mg micafungin at the discretion of the treating physician following the prescribing information and hospital guidelines. Total micafungin concentrations were determined by high-performance liquid chromatography (HPLC). Monte-Carlo simulations were performed and the probability of target attainment (PTA) was calculated using the AUC0-24/MIC cut-offs 285 (C. parapsilosis), 3000 (all Candida spp.), and 5000 (nonparapsilosis Candida spp.). Intravenous once-daily 100-mg, 150-mg, and 200-mg doses were simulated at different body weights (45, 80, 115, 150, and 185 kg) and age (30, 50, 70 and 90 years old). PTAs ≥ 90% were considered optimal. Fractional target attainment (FTA) was calculated using published MIC distributions. A dosing regimen was considered successful if the FTA was ≥ 90%. RESULTS: Overall, 100 mg of micafungin was once-daily administered for nonobese and obese patients with body mass index (BMI) ≤ 45 kg/m2 and 150 mg for morbidly obese patients with BMI > 45 kg/m2 (except two noncritically ill obese patients with BMI ~ 35 kg/m2 receiving 150 mg, and one critically ill patient with BMI > 45 kg/m2 receiving 100 mg). Micafungin concentrations in plasma were best described using a two-compartment model. Weight and age (but not severity score) were significant covariates and improved the model. FTAs > 90% were obtained against C. albicans with the 200 mg/24 h dose for all body weights (up to 185 kg), and with the 150 mg/24 h for body weights < 115 kg, and against C. glabrata with the 200 mg/24 h dose for body weights < 115 kg. CONCLUSION: The lack of adequacy for the 100 mg/24 h dose suggested the need to increase the dose to 150 mg/24 h for C. albicans infections. Further pharmacokinetic/pharmacodynamic studies should address optimization of micafungin dosing for nonalbicans Candida infections.

Urinary Concentrations of Colistimethate and Formed Colistin after Intravenous Administration in Patients with Multidrug-Resistant Gram-Negative Bacterial Infections.

Limited information is available on the urinary excretion of colistin in infected patients. This study aimed to investigate the pharmacokinetics of colistimethate sodium (CMS) and formed colistin in urine in patients with multidrug-resistant (MDR) Gram-negative bacterial infections. A pharmacokinetic study was conducted on 12 patients diagnosed with an infection caused by an extremely drug-resistant (XDR) P. aeruginosa strain and treated with intravenous CMS. Fresh urine samples were collected at 2-h intervals, and blood samples were collected predose (Cmin ss) and at the end of the CMS infusion (Cmax ss) for measurement of concentrations of CMS and formed colistin using high-performance liquid chromatography (HPLC). CMS urinary recovery was determined as the summed amount of CMS and formed colistin recovered in urine for each 2-h interval divided by the CMS dose. There were 12 enrolled patients, 9 of whom were male (75%). Data [median (range)] were as follows: age, 65.5 (37 to 86) years; colistimethate urinary recovery 0 to 6 h, 42.6% (2.9% to 72.8%); range of concentrations of colistin in urine, <0.1 to 95.4 mg/liter; Cmin ss and Cmax ss of colistin in plasma, 0.9 (<0.2 to 1.4) and 0.9 (<0.2 to 1.4) mg/liter, respectively. In 6/12 (50%) patients, more than 40% of the CMS dose was recovered in the urine within the first 6 h after CMS administration. This study demonstrated rapid urinary excretion of CMS in patients within the first 6 h after intravenous administration. In all but one patient, the concentrations of formed colistin in urine were above the MIC for the most predominant isolate of P. aeruginosa in our hospital. Future studies are warranted for optimizing CMS dosage regimens in urinary tract infection (UTI) patients.

Impact of colistin plasma levels on the clinical outcome of patients with infections caused by extremely drug-resistant Pseudomonas aeruginosa.

BACKGROUND: Colistin has a narrow therapeutic window with nephrotoxicity being the major dose-limiting adverse effect. Currently, the optimal doses and therapeutic plasma levels are unknown. METHODS: Prospective observational cohort study, including patients infected by colistin-susceptible P. aeruginosa treated with intravenous colistimethate sodium (CMS). Clinical data and colistin plasma levels at steady-state (Css) were recorded. The primary and secondary end points were clinical cure and 30-day all-cause mortality. RESULTS: Ninety-one patients were included. Clinical cure was observed in 72 (79%) patients. The mean (SD) Css was 1.49 (1.4) mg/L and 2.42 (1.5) mg/L (p = 0.01) in patients who achieved clinical cure and those who not, respectively. Independent risk factors for clinical failure were male sex (OR 5.88; 95% CI 1.09-31.63), APACHE II score (OR 1.15; 95% CI 1.03-1.27) and nephrotoxicity at the EOT (OR 9.13; 95% CI 95% 2.06-40.5). The 30-day mortality rate was 30.8%. Risk factors for 30-day mortality included the APACHE II score (OR 1.98; 95% CI 1-1.20), the McCabe score (OR 2.49; 95% CI 1.14-5.43) and the presence of nephrotoxicity at the end of treatment (EOT) (OR 3.8; 95% CI 1.26-11.47). CONCLUSION: In this series of patients with infections caused by XDR P. aeruginosa infections, Css is not observed to be related to clinical outcome.

What is the effect of obesity on piperacillin and meropenem trough concentrations in critically ill patients?

OBJECTIVES: The objectives of this study were to determine the effects of obesity on unbound trough concentrations and on the achievement of pharmacokinetic (PK)/pharmacodynamic (PD) targets of piperacillin and meropenem in critically ill patients. METHODS: This study retrospectively analysed therapeutic-drug-monitoring data from ICU databases in Australia, Germany and Spain, as well as from a large PK study. The presence of obesity was defined as a BMI ≥30 kg/m(2), and patients were also categorized based on level of renal function. The presence of obesity was compared with unbound piperacillin and meropenem trough concentrations. We also used logistic regression to describe factors associated with the achievement of the PK/PD targets, an unbound concentration maintained above the MIC breakpoint (100% fT>MIC and 100% fT>4×MIC) of Pseudomonas aeruginosa. RESULTS: In all, 1400 patients were eligible for inclusion in the study. The median age and weight were 67 years (IQR 52-76 years) and 79 kg (69-90 kg), respectively, and 65% of participants were male. Significantly lower median piperacillin trough concentrations [29.4 mg/L (IQR 17.0-58.0 mg/L)] were found in obese patients compared with non-obese patients [42.0 mg/L (21.5-73.5 mg/L)] (P = 0.001). There was no difference for meropenem trough concentrations [obese 10.3 mg/L (IQR 4.8-16.0 mg/L) versus non-obese 11.0 mg/L (4.3-18.5 mg/L); P = 0.296]. Using logistic regression, we found that the presence of obesity was not associated with achievement of 100% fT>MIC, but the use of prolonged infusion, a creatinine clearance ≤100 mL/min, increasing age and female gender were for various PK/PD targets for both piperacillin and meropenem (P < 0.05). CONCLUSIONS: This large dataset has shown that the presence of obesity in critically ill patients may affect piperacillin, but not meropenem, unbound trough concentrations.

Low Non-structured Antiretroviral Therapy Interruptions in HIV-Infected Persons Who Inject Drugs Receiving Multidisciplinary Comprehensive HIV Care at an Outpatient Drug Abuse Treatment Center.

Continuous HIV treatment is necessary to ensure successful combined antiretroviral therapy (cART). The aim of this study was to evaluate the incidence of patient-initiated non-structured treatment interruptions in HIV-infected persons who inject drugs and who received a multidisciplinary comprehensive program, including medical HIV care, drug-dependence treatment and psychosocial support, at a drug outpatient addiction center. Non-structured treatment interruptions were defined as ≥30 consecutive days off cART without medical indication. During a median follow-up of 53.8 months, 37/132 (28 %) patients experienced the first non-structured treatment interruptions. The cumulative probability of cART interruption at 5 years was 31.2 % (95 % CI 22.4-40.0). Current drug use injection ≥1/day (HR 14.77; 95 % CI 5.90-36.96) and cART naive patients (HR 0.35, 95 % CI 0.14-0.93) were predictive factors for non-structured treatment interruptions. HIV care provided at a drug addiction center is a useful strategy to sustain continuous cART, however, drug abstinence is essential for the long-term maintenance of cART.

Pharmacokinetics of micafungin in patients with pre-existing liver dysfunction: A safe option for treating invasive fungal infections.

In this prospective observational study performed in 12 hospitalized patients with proven or suspected invasive fungal infection treated for a mean of 14 days with micafungin (MCF), 8 of whom with pre-existing liver function impairment, plasma levels of MCF at steady state were not correlated with liver function tests at the beginning of treatment. Liver function remained stable or even improved in all patients, except in one in which MCF was discontinued due to liver toxicity.

Micafungin pharmacokinetic/pharmacodynamic adequacy for the treatment of invasive candidiasis in critically ill patients on continuous venovenous haemofiltration.

OBJECTIVES: To explore the pharmacokinetics (PK) and pharmacodynamics (PD) of micafungin in patients undergoing continuous venovenous haemofiltration (CVVH). PATIENTS AND METHODS: Ten patients receiving CVVH treated with 100 mg/day micafungin were included (April-December 2012). CVVH was performed using polyethersulphone or polysulphone haemofilters. Dialysis membranes were not changed on sampling days. On Days 1 and 2, blood samples from arterial pre-filter and venous post-filter ports and ultrafiltrate samples were collected at the start and end of the infusion and at 3, 5, 8, 18 and 24 h. Concentrations were determined using HPLC. Values for the area under the concentration-time curve (AUC0-24) were calculated. Monte Carlo simulations were performed using pre-filter and post-filter AUC0-24/MIC ratios on Days 1 and 2. The probability of target attainment (PTA) was calculated using AUC0-24/MIC cut-offs: 285 (C. parapsilosis), 3000 (all Candida spp.) and 5000 (non-parapsilosis Candida spp.). Cumulative fraction responses (CFRs) were calculated using EUCAST MIC distributions. RESULTS: Mean post-filter AUC0-24 (mg·h/L) values were higher than pre-filter values on Day 1 (83.31 ±â€Š15.87 versus 71.31 ±â€Š14.24; P = 0.008) and Day 2 (119.01 ±â€Š27.20 versus 104.54 ±â€Š21.23; P = 0.005). PTAs were ≥90% for MICs of 0.125 mg/L (cut-off = 285), 0.016 mg/L (cut-off = 3000) and 0.008 mg/L (cut-off = 5000) on Day 1, and for MICs of 0.25 mg/L (cut-off = 285) and 0.016 mg/L (cut-off = 3000 and 5000) on Day 2, without differences between pre- and post-filter values. On Day 2, CFRs >90% were obtained for C. albicans (cut-off = 3000 and 5000) and C. glabrata (cut-off = 3000), but not for C. parapsilosis. CONCLUSIONS: There was no removal of micafungin by CVVH or need for dose adjustment, and there was optimal PK/PD coverage for non-parapsilosis Candida and equivalence of pre- and post-filter PD.

Design of a score to identify hospitalized patients at risk of drug-related problems.

PURPOSE: The potential impact of drug-related problems (DRP) on morbidity and mortality is a serious concern in hospitalized patients. This study aimed to design a risk score to identify patients most at risk of a DRP. METHODS: Data from patients admitted to a tertiary university hospital between January and August 2009 were used to design the risk score (training set). DRP were detected through a pharmacy warning system integrated in the computerized medical history. The variables associated with developing a DRP were identified through a binary multivariate logistic regression analysis and were used to compute the DRP risk score, which was subsequently validated in patients admitted between September and December 2009 (validation set). RESULTS: Of the 8713 patients included in the training set, at least one DRP was detected in 2425 (27.8%). Prescription of a higher number of drugs, higher comorbidity, advanced age, certain groups of the Anatomical Therapeutic Chemical classification system, and some major diagnostic categories were associated with risk of DRP. These variables were used to compute the DRP risk score. The area under the receiver operator characteristic curve was 0.778 (95%CI [0.768, 0.789]). Of the 4058 admissions included in the validation set, at least one DRP was detected in 876 (21.6%). The area under the receiver operator characteristic curve was 0.776 (95%CI [0.759, 0.792]). CONCLUSIONS: Knowledge of the variables associated with DRP could aid their early detection in at-risk patients. The use of an application that can be continually updated in daily clinical practice helps to optimize resources.