A high-dose aminoglycoside regimen combined with renal replacement therapy for the treatment of MDR pathogens: a proof-of-concept study.

BACKGROUND: Infections caused by MDR Gram-negative (GN) organisms in critically ill patients are a therapeutic challenge. The administration of high-dose aminoglycoside (HDA) therapy coupled with high-flow continuous veno-venous haemodiafiltration (CVVHDF) could allow required high drug peaks to be achieved with acceptable drug elimination. METHODS: All adult patients present on the ICU between October 2009 and July 2014 who had MDR GN sepsis were considered for HDA and high-flow (>45 mL/kg/h) CVVHDF when an isolated pathogen was susceptible or had intermediate susceptibility to aminoglycosides and the patient's condition was not improving with conventional therapy. Optimal antibacterial activity was defined as a peak concentration of at least eight times the MIC. RESULTS: Fifteen patients infected with MDR GN pathogens (11 with Pseudomonas aeruginosa; 10 with abdominal infections and 5 with respiratory infections) were treated with amikacin (n = 11), gentamicin (n = 3) or tobramycin (n = 1) and high-flow CVVHDF. A favourable clinical response was observed in eight (53%) patients, including three in whom microbial eradication was obtained. Six patients were discharged alive from the ICU, and five from the hospital. No renal toxicity was observed among survivors. CONCLUSION: In this cohort of septic patients with MDR GN infections, HDA combined with high-flow CVVHDF represented a valuable therapeutic option. The effectiveness of this approach should be further evaluated in larger studies.

Population pharmacokinetics and dosing simulations of cefepime in septic shock patients receiving continuous renal replacement therapy.

The aim of this study was to describe the population pharmacokinetics of cefepime in septic shock patients requiring continuous renal replacement therapy and to determine whether current or alternative dosing regimens can achieve PK/PD targets. In this observational PK study, 62 samples from 13 patients were analysed using non-linear mixed-effects modelling. Different dosing regimens were evaluated using Monte Carlo simulations with ultrafiltration flow rates (UFRs) of 1000, 1500 and 2000 mL/h. The probability of target attainment was calculated against a conservative (60% T(>MIC)) and a higher PK/PD target (100% T(>MIC)) against an MIC of 8 mg/L, the clinical susceptibility breakpoint for Pseudomonas aeruginosa. A one-compartment model with between-subject variability (BSV) on clearance and volume of distribution (V(d)) described the data adequately. UFR was supported as a covariate on both parameters. Typical values for clearance and V(d) were 4.4L/h (BSV 37%) and 40.9L (BSV 20%), respectively. Dosing simulations showed failure to achieve both a conservative and a higher PK/PD target using a dose of 1g q12h for patients treated with a high UFR (≥1500 mL/h). The dose of 2g q8h or 1g q6h leads to optimal target attainment for high UFR. One gram q8h is optimal for low UFR (≤1000 mL/h). We found important variability in PK parameters. Dosing simulations show that a dose of 2g q8h or 1g q6h is needed to ensure rapid achievement of adequate levels if the UFR is ≥1500 mL/h and 1g q8h for low UFR (≤1000 mL/h).

ß-lactam antibiotic concentrations during continuous renal replacement therapy.

INTRODUCTION: The use of standard doses of ß-lactam antibiotics during continuous renal replacement therapy (CRRT) may result in inadequate serum concentrations. The aim of this study was to evaluate the adequacy of unadjusted drug regimens (i.e., similar to those used in patients with normal renal function) in patients treated with CRRT and the influence of CRRT intensity on drug clearance. METHODS: We reviewed data from 50 consecutive adult patients admitted to our Department of Intensive Care in whom routine therapeutic drug monitoring (TDM) of broad-spectrum ß-lactam antibiotics (ceftazidime or cefepime, CEF; piperacillin/tazobactam; TZP; meropenem, MEM) was performed using unadjusted ß-lactam antibiotics regimens (CEF = 2 g q8h; TZP = 4 g q6h; MEM = 1 g q8h). Serum drug concentrations were measured twice during the elimination phase by high-performance liquid chromatography (HPLC-UV). We considered therapy was adequate when serum drug concentrations were between 4 and 8 times the minimal inhibitory concentration (MIC) of Pseudomonas aeruginosa during optimal periods of time for each drug (≥70% for CEF; ≥ 50% for TZP; ≥ 40% for MEM). Therapy was considered as early (ET) or late (LT) phase if TDM was performed within 48 hours of antibiotic initiation or later on, respectively. RESULTS: We collected 73 serum samples from 50 patients (age 58 ± 13 years; Acute Physiology and Chronic Health Evaluation II (APACHE II) score on admission 21 (17-25)), 35 during ET and 38 during LT. Drug concentrations were above 4 times the MIC in 63 (90%), but above 8 times the MIC in 39 (53%) samples. The proportions of patients with adequate drug concentrations during ET and LT were quite similar. We found a weak but significant correlation between ß-lactam antibiotics clearance and CRRT intensity. CONCLUSIONS: In septic patients undergoing CRRT, doses of ß-lactam antibiotics similar to those given to patients with normal renal function achieved drug levels above the target threshold in 90% of samples. Nevertheless, 53% of samples were associated with very high drug levels and daily drug regimens may need to be adapted accordingly.

Antibiotic strategies in severe nosocomial sepsis: why do we not de-escalate more often?

OBJECTIVES: To assess the use of antibiotic de-escalation in patients with hospital-acquired severe sepsis in an academic setting. DESIGN: We reviewed all episodes of severe sepsis treated over a 1-yr period in the department of intensive care. Antimicrobial therapy was considered as appropriate when the antimicrobial had in vitro activity against the causative microorganisms. According to the therapeutic strategy in the 5 days after the start of antimicrobial therapy, we classified patients into four groups: de-escalation (interruption of an antimicrobial agent or change of antibiotic to one with a narrower spectrum); no change in antibiotherapy; escalation (addition of a new antimicrobial agent or change in antibiotic to one with a broader spectrum); and mixed changes. SETTING: A 35-bed medico-surgical intensive care department in which antibiotic strategies are reviewed by infectious disease specialists three times per week. PATIENTS: One hundred sixty-nine patients with 216 episodes of severe sepsis attributable to a hospital-acquired infection who required broad-spectrum ß-lactam antibiotics alone or in association with other anti-infectious agents. MEASUREMENTS AND MAIN RESULTS: The major sources of infection were the lungs (44%) and abdomen (38%). Microbiological data were available in 167 of the 216 episodes (77%). Initial antimicrobial therapy was inappropriate in 27 episodes (16% of culture-positive episodes). De-escalation was applied in 93 episodes (43%), escalation was applied in 22 episodes (10%), mixed changes were applied in 24 (11%) episodes, and there was no change in empirical antibiotic therapy in 77 (36%) episodes. In these 77 episodes, the reasons given for maintaining the initial antimicrobial therapy included the sensitivity pattern of the causative organisms and previous antibiotic therapy. The number of episodes when the chance to de-escalate may have been missed was small (4 episodes [5%]). CONCLUSION: Even in a highly focused environment with close collaboration among intensivists and infectious disease specialists, de-escalation may actually be possible in <50% of cases.

Optimal meropenem concentrations to treat multidrug-resistant Pseudomonas aeruginosa septic shock.

A patient with septic shock due to extensively drug resistant (XDR) Pseudomonas aeruginosa was cured by optimizing the meropenem (MEM) regimen to obtain at least 40% of the time between two administrations in which drug levels were four times higher than the MIC of the pathogen. As the standard drug dose did not achieve these optimal concentrations, the MEM regimen was progressively increased up to 12 g/day (3 g every 6 h in a 3-h extended infusion), which eventually resulted in sepsis resolution. High MEM dosage may represent a valuable therapeutic option for infection due to multidrug-resistant (MDR) strains, and drug monitoring would allow rapid regimen adjustment in clinical practice.

Recommended ß-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy.

INTRODUCTION: Sepsis is responsible for important alterations in the pharmacokinetics of antibiotics. Continuous renal replacement therapy (CRRT), which is commonly used in septic patients, may further contribute to pharmacokinetic changes. Current recommendations for antibiotic doses during CRRT combine data obtained from heterogeneous patient populations in which different CRRT devices and techniques have been used. We studied whether these recommendations met optimal pharmacokinetic criteria for broad-spectrum antibiotic levels in septic shock patients undergoing CRRT. METHODS: This open, prospective study enrolled consecutive patients treated with CRRT and receiving either meropenem (MEM), piperacillin-tazobactam (TZP), cefepime (FEP) or ceftazidime (CAZ). Serum concentrations of these antibiotics were determined by high-performance liquid chromatography from samples taken before (t = 0) and 1, 2, 5, and 6 or 12 hours (depending on the ß-lactam regimen) after the administration of each antibiotic. Series of measurements were separated into those taken during the early phase (< 48 hours from the first dose) of therapy and those taken later (> 48 hours). RESULTS: A total of 69 series of serum samples were obtained in 53 patients (MEM, n = 17; TZP, n = 16; FEP, n = 8; CAZ, n = 12). Serum concentrations remained above four times the minimal inhibitory concentration for Pseudomonas spp. for the recommended time in 81% of patients treated with MEM, in 71% with TZP, in 53% with CAZ and in 0% with FEP. Accumulation after 48 hours of treatment was significant only for MEM. CONCLUSIONS: In septic patients receiving CRRT, recommended doses of ß-lactams for Pseudomonas aeruginosa are adequate for MEM but not for TZP, FEP and CAZ; for these latter drugs, higher doses and/or extended infusions should be used to optimise serum concentrations.

Pharmacokinetics of a loading dose of amikacin in septic patients undergoing continuous renal replacement therapy.

Data on the optimal amikacin regimen during continuous renal replacement therapy (CRRT) are scarce and the proposed loading dose of 10mg/kg may result in inadequate drug levels. The aim of this study was to describe the pharmacokinetics of a 25 mg/kg first dose of amikacin in septic shock patients treated with CRRT. Serum samples were collected before (t=0 h) and at 1 (peak), 1.5, 4.5, 8 and 24 h after a 30-min amikacin infusion in 13 consecutive patients treated with a combination of amikacin and ß-lactam. Blood amikacin levels were measured using a validated fluorescence polarisation immunoassay method. In 9 patients (69%) the peak concentration was >64 mg/L, which corresponds to eight times the minimal inhibitory concentration breakpoints defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for Enterobacteriaceae and Pseudomonas aeruginosa (susceptible <8 mg/L, resistant >16 mg/L). The median (range) total volume of distribution was 0.50 L/kg (0.22-4.05 L/kg), the elimination half-life was 6.5h (4.5-279.6h) and total drug clearance (CL) was 1.26 mL/min/kg (0.1-3.30 mL/min/kg). Only three patients had drug concentrations at 24h (C(min)) of <5mg/L and the median predicted time needed to reach this value was 34 h (14-76 h). There was no correlation between CRRT parameters and C(min), CL or the time to C(min)<5mg/L. In septic shock patients treated with CRRT, a first dose of ≥ 25 mg/kg amikacin is therefore required to reach therapeutic peak concentrations. However, as drug clearance is reduced, amikacin concentrations remained above the threshold of renal toxicity at 24h. The therapeutic benefit of high-dose aminoglycoside therapy should be balanced with its potential renal effects in septic patients receiving CRRT.

In vivo development of antimicrobial resistance in Pseudomonas aeruginosa strains isolated from the lower respiratory tract of Intensive Care Unit patients with nosocomial pneumonia and receiving antipseudomonal therapy.

Pseudomonas aeruginosa causes severe nosocomial pneumonia in Intensive Care Unit (ICU) patients, with an increased prevalence of multiresistant strains. We examined the impact of the use of antipseudomonal antibiotic(s) on the susceptibility of P. aeruginosa isolated from ICU patients with clinically suspected hospital-acquired pneumonia collected in five teaching hospitals (110 non-duplicate initial isolates; 62 clonal pairs of initial and last isolates during treatment). Minimum inhibitory concentrations (MICs) were determined for amikacin, ciprofloxacin, meropenem, piperacillin/tazobactam (TZP), cefepime and ceftazidime (used in therapy) as well as five reporter antibiotics (aztreonam, colistin, gentamicin, piperacillin and ticarcillin) using Clinical and Laboratory Standards Institute (CLSI) methodology. Susceptibility was assessed according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) and CLSI breakpoints. Resistance rates prior to treatment exceeded 25% for cefepime, ceftazidime, piperacillin, ticarcillin and aztreonam (EUCAST and CLSI) and for gentamicin, TZP and colistin (EUCAST only). The highest rates of cross-resistance were noted for ceftazidime and cefepime and the lowest rate for amikacin. Mean MIC values were systematically higher in isolates from patients previously exposed (1 month) to the corresponding antibiotic. For clonal pairs, a systematic increase in MIC between initial and last isolates (significant for amikacin, cefepime, meropenem and TZP) was noted. There was a significant correlation between the use of antibiotics (adjusted for respective proportional use of each drug) and loss of susceptibility at the population level when using EUCAST breakpoints. The high level of resistance of P. aeruginosa in ICU patients with nosocomial pneumonia as well as its further increase during treatment severely narrows the already limited therapeutic options. Further observational studies and the development of early diagnosis for resistant isolates are warranted.

Insufficient ß-lactam concentrations in the early phase of severe sepsis and septic shock.

INTRODUCTION: Altered pharmacokinetics (PK) in critically ill patients can result in insufficient serum ß-lactam concentrations when standard dosages are administered. Previous studies on ß-lactam PK have generally excluded the most severely ill patients, or were conducted during the steady-state period of treatment. The aim of our study was to determine whether the first dose of piperacillin-tazobactam, ceftazidime, cefepime, and meropenem would result in adequate serum drug concentrations in patients with severe sepsis and septic shock. METHODS: Open, prospective, multicenter study in four Belgian intensive care units. All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom treatment with the study drugs was indicated, were included. Serum concentrations of the antibiotics were determined by high-pressure liquid chromatography (HPLC) before and 1, 1.5, 4.5 and 6 or 8 hours after administration. RESULTS: 80 patients were treated with piperacillin-tazobactam (n = 27), ceftazidime (n = 18), cefepime (n = 19) or meropenem (n = 16). Serum concentrations remained above 4 times the minimal inhibitory concentration (T > 4 × MIC), corresponding to the clinical breakpoint for Pseudomonas aeruginosa defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), for 57% of the dosage interval for meropenem (target MIC = 8 µg/mL), 45% for ceftazidime (MIC = 32 µg/mL), 34% for cefepime (MIC = 32 µg/mL), and 33% for piperacillin-tazobactam (MIC = 64 µg/mL). The number of patients who attained the target PK profile was 12/16 for meropenem (75%), 5/18 for ceftazidime (28%), 3/19 (16%) for cefepime, and 12/27 (44%) for piperacillin-tazobactam. CONCLUSIONS: Serum concentrations of the antibiotic after the first dose were acceptable only for meropenem. Standard dosage regimens for piperacillin-tazobactam, ceftazidime and cefepime may, therefore, be insufficient to empirically cover less susceptible pathogens in the early phase of severe sepsis and septic shock.

Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial.

BACKGROUND: Invasive candidosis is increasingly prevalent in seriously ill patients. Our aim was to compare micafungin with liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidosis. METHODS: We did a double-blind, randomised, multinational non-inferiority study to compare micafungin (100 mg/day) with liposomal amphotericin B (3 mg/kg per day) as first-line treatment of candidaemia and invasive candidosis. The primary endpoint was treatment success, defined as both a clinical and a mycological response at the end of treatment. Primary analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, number NCT00106288. FINDINGS: 264 individuals were randomly assigned to treatment with micafungin; 267 were randomly assigned to receive liposomal amphotericin B. 202 individuals in the micafungin group and 190 in the liposomal amphotericin B group were included in the per-protocol analyses. Treatment success was observed for 181 (89.6%) patients treated with micafungin and 170 (89.5%) patients treated with liposomal amphotericin B. The difference in proportions, after stratification by neutropenic status at baseline, was 0.7% (95% CI -5.3 to 6.7). Efficacy was independent of the Candida spp and primary site of infection, as well as neutropenic status, APACHE II score, and whether a catheter was removed or replaced during the study. There were fewer treatment-related adverse events--including those that were serious or led to treatment discontinuation--with micafungin than there were with liposomal amphotericin B. INTERPRETATION: Micafungin was as effective as--and caused fewer adverse events than--liposomal amphotericin B as first-line treatment of candidaemia and invasive candidosis.