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Purpose: According to the Surviving Sepsis Campaign, aminoglycosides (AG) can be administered together with a β-lactam in patients with septic shock. Some authors propose administering a single dose of an AG combined with a β-lactam antibiotic in septic patients to extend the spectrum of antibiotic therapy. The aim of this study has been to investigate whether a single shot of AG when septic patients present at the Emergency Department (ED) is associated with acute kidney injury (AKI). Methods: We retrospectively enrolled patients based on a 3-year internal registry of septic patients visited in the Emergency Department (ED) of Pordenone Hospital. We compared the patients treated with a single dose of gentamicin (in addition to the β-lactam) and those who had not been treated to verify AKI incidence. Results: 355 patients were enrolled. The median age was 71 years (IQR 60-78). Less than 1% of the patients had a chronic renal disease. The most frequent infection source was the urinary tract (31%), followed by intra-abdominal and lower respiratory tract infections (15% for both). 131 patients received gentamicin. Unmatched data showed a significant difference between the two groups in AKI (79/131, 60.3% versus 102/224, 45.5%; p=0.010) and in infectious disease specialist's consultation (77/131, 59% versus 93/224, 41.5%; p=0.002). However, after propensity score matching, no significant difference was found. Conclusion: Our experience shows that a single-shot administration of gentamicin upon admission to the ED does not determine an increased incidence of AKI in septic patients., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Objectives: The study aims to assess the population pharmacokinetics of fluconazole and the adequacy of current dosages and breakpoints against Candida albicans and non-albicans spp. in liver transplant (LT) patients., Patients and Methods: Patients initiated i.v. fluconazole within 1 month from liver transplantation (LTx) for prevention or treatment of Candida spp. infections. Multiple assessments of trough and peak plasma concentrations of fluconazole were undertaken in each patient by means of therapeutic drug monitoring. Monte Carlo simulations were performed to define the probability of target attainment (PTA) with a loading dose (LD) of 400, 600, and 800 mg at day 1, 7, 14, and 28 from LTx, followed by a maintenance dose (MD) of 100, 200, and 300 mg daily of the pharmacokinetic/pharmacodynamic target of AUC 24h /MIC ratio ≥ 55.2., Results: Nineteen patients were recruited. A two-compartment model with first-order intravenous input and first-order elimination was developed. Patient's age and time elapsed from LTx were the covariates included in the final model. At an MIC of 2 mg/L, a LD of 600 mg was required for optimal PTAs between days 1 and 20 from LTx, while 400 mg was sufficient from days 21 on. A MD of 200 mg was required for patients aged 40-49 years old, while a dose of 100 mg was sufficient for patients aged ≥ 50 years., Conclusions: Fluconazole dosages of 100-200 mg daily may ensure optimal PTA against C. albicans, C. parapsilosis, and C. tropicalis. Higher dosages are required against C. glabrata. Estimated creatinine clearance is not a reliable predictor of fluconazole clearance in LT patients.

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., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Background: Invasive fungal infection (IFI) following liver transplant is associated with significant morbidity and mortality. Antifungal prophylaxis is rational for liver transplant patients at high IFI risk., Methods: In this open-label, noninferiority study, patients were randomized 1:1 to receive intravenous micafungin 100 mg or center-specific standard care (fluconazole, liposomal amphotericin B, or caspofungin) posttransplant. The primary endpoint was clinical success (absence of a proven/probable IFI and no need for additional antifungals) at end of prophylaxis (EOP). Noninferiority (10% margin) of micafungin vs standard care was assessed in the per protocol and full analysis sets. Safety assessments included adverse events and liver and kidney function tests., Results: The full analysis set comprised 344 patients (172 micafungin; 172 standard care). Mean age was 51.2 years; 48.0% had a Model for End-Stage Liver Disease score ≥20. At EOP (mean treatment duration, 17 days), clinical success was 98.6% for micafungin and 99.3% for standard care (Δ standard care - micafungin [95% confidence interval], 0.7% [-2.7% to 4.4%]) in the per protocol set and 96.5% and 93.6%, respectively (-2.9% [-8.0% to 1.9%]), in the full analysis set. Incidences of drug-related adverse events for micafungin and standard care were 11.6% and 16.3%, leading to discontinuation in 6.4% and 11.6% of cases, respectively. At EOP, liver function tests were similar but creatinine clearance was higher in micafungin- vs standard care-treated patients., Conclusions: Micafungin was noninferior to standard care as antifungal prophylaxis in liver transplant patients at high risk for IFI. Adverse event profiles and liver function at EOP were similar, although kidney function was better with micafungin., Clinical Trials Registration: NCT01058174., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Sequential portal and arterial revascularization (SPAr) is the most common method of graft reperfusion at liver transplantation (LT), contemporaneous portal and arterial revascularization (CPAr) was used to reduce arterial ischemia to the bile ducts. Aim of this pilot study is to prospectively compare SPAr (group 1 #38) versus CPAr (group 2 #42) in 80 consecutive LTs. Biliary anastomosis was always duct to duct [T-tube in 21 % of cases (p = 0.83) in both groups]. CPAr had longer warm ischemia 61 ± 10 versus 39 ± 13 min, p < 0.0001, while SPAr had longer arterial ischemia 96 ± 39 min (p = 0.0001). No PNF while DGF was encountered in 10 versus 5 % (p = 0.32). One-year graft and patient's survival were respectively 87 versus 93 % and 83 versus 88 % in groups 1 and 2 (p = 0.31 and p = 0.39). At a median follow-up of 19 ± 8 versus 17 ± 8 months (p = 0.24), biliary complications were 28 %, being 39 % in group 1 and 19 % in group 2 (p = 0.04). Anastomotic stenoses were present in 11 versus 12 % (p = 0.84), biliary leakage in 5 versus 5 % (p = 0.72) and intrahepatic non-anastomotic biliary strictures in 23 versus 0 % (p = 0.0008) in groups 1 and 2. CPAr is safe and feasible and reduces the incidence of intrahepatic biliary strictures by decreasing the duration of arterial ischemia to the intrahepatic bile ducts.

Objectives: The aim of the study was to assess the biliary penetration of linezolid and the probabilities of attaining optimal pharmacodynamic exposure against vancomycin-resistant enterococci (VRE) in the bile of liver transplant (LTx) patients who received linezolid for the treatment of multidrug-resistant Gram-positive hospital infections., Methods: After at least 2 days of standard 600 mg twice-daily therapy, simultaneous bile and blood samples for linezolid assay were collected from six LTx patients just prior to drug administration to determine trough concentrations (Cmin) at steady-state in both sites. Linezolid concentrations in plasma and in bile were analysed by means of HPLC. Biliary penetration of linezolid was calculated as the ratio between Cmin in bile and in plasma. Optimal theoretical pharmacodynamic exposure of linezolid against VRE in bile was defined as biliary Cmin>MIC90., Results: C(min) of linezolid in bile achieved very high values at steady-state, which were significantly higher than in plasma (median of 21.77 versus 8.08 mg/L, P=0.021). The very high biliary penetration of linezolid (median value of 1.93; range 1.31-4.83) enabled achievement of optimal theoretical pharmacodynamic exposure against VRE in bile (Cmin>2 mg/L) on all of the occasions., Conclusions: These preliminary data suggest a potential role for linezolid in the treatment of cholangitis due to VRE in LTx patients. Obviously, further confirmatory data assessing also the AUC/MIC ratio of linezolid in bile are needed.

Objective: This study aimed to compare continuous cardiac output (CCO) obtained using the arterial pulse wave (APCO) measurement with a simultaneous measurement of the intermittent cardiac output (ICO) and CCO obtained with a pulmonary artery catheter (PAC) in liver transplant patients., Design: A prospective, single-center evaluation., Setting: A university hospital intensive care unit., Patients: Eighteen patients after liver transplantation., Interventions: Pulmonary artery catheters were placed in all patients, and ICO and CCO were determined using thermodilution. APCO measurements were made with the Vigileo System (Edwards Lifesciences, Irvine, CA)., Measurements and Main Results: The authors obtained 126 data pairs of ICO and APCO and 864 pairs of CCO and APCO. ICO data were collected after intensive care unit admission and every 8 hours until the 48th postoperative hour. CCO and APCO data were collected every hour from admission until the 48th postoperative hour. Bias and precision were 0.95 +/- 1.41 L/min for ICO versus APCO and 1.29 +/- 1.28 L/min for CCO and APCO. Bias and precision for cardiac output (CO) data pairs less than 8 L/min were 0.32 +/- 1.14 L/min between ICO and APCO and 0.71 +/- 0.98 L/min between CCO and APCO. For CO data pairs higher than 8 L/min, bias and precision were 1.79 +/- 1.54 L/min between ICO and APCO and 2.25 +/- 1.14 L/min between CCO and APCO., Conclusions: APCO enables the assessment of CO with clinically acceptable bias and precision. At higher CO levels, APCO underestimates PAC measurements and it is not as reliable as thermodilution in hyperdynamic liver transplant patients.

Linezolid is a new oxazolidinone antibiotic active against most Gram-positive microorganisms the renal elimination of which accounts for about 30% to 35% of all the clearance. Its pharmacokinetic ability was assessed during continuous venovenous hemofiltration (CVVH) in 2 anuric patients with severe postsurgical intraabdominal infections who were receiving standard dosages (600 mg intravenously twice a day). Blood samples for quantification of linezolid in plasma and in filtrate were collected after more than 4 days of therapy before dosing and at 0, 0.5, 1, 2, 3, 5, 7, 9, and 11 hours after the morning 1-hour intravenous infusion, and concentrations were determined by means of high-performance liquid chromatography. Linezolid was partially cleared by CVVH in both the patients (hemofiltration clearance [CL CVVH ] = 0.38 and 0.35 mL/min/kg), with high sieving coefficient values (0.76 to 0.92). Efficacious plasma exposure for time-dependent antibacterial activity of linezolid, either in terms of trough levels above minimum inhibitory concentration (MIC) at which 90% of the isolates are inhibited (Cmin >MIC90 ) or of area under the plasma concentration time curve to MIC90 ratio (AUC/MIC90 ) >100 hours, was ensured during CVVH in both patients. However, despite similar CL CVVH , significant interindividual pharmacokinetic variability was found in the 2 patients (AUC during the observational period [AUC 0-tau ] 334.71 versus 109.34 mg/L x h), mainly owing to substantial differences in non-CVVH-related clearance of linezolid (total CL, 0.55 versus 1.21 mL/min/kg). Our findings indicate that linezolid, although partially removed, does not warrant dosage modification during the first 48 hours when CVVH (with polysulfide hemofilter) at standard 2,000 mL/h substitution flow rate in predilution is applied to anuric patients. Thereafter, this choice is a reasonable one with the exception of those patients who have other features of linezolid toxicity and in which non-CVVH-related clearance might be impaired, although further evaluations are warranted.