S. Ruiz

Role of biomarkers in the management of antibiotic therapy: an expert panel review: I – currently available biomarkers for clinical use in acute infections

In the context of worldwide increasing antimicrobial resistance, good antimicrobial prescribing in more needed than ever; unfortunately, information available to clinicians often are insufficient to rely on. Biomarkers might provide help for decision-making and improve antibiotic management. The purpose of this expert panel review was to examine currently available literature on the potential role of biomarkers to improve antimicrobial prescribing, by answering three questions: 1) Which are the biomarkers available for this purpose?; 2) What is their potential role in the initiation of antibiotic therapy?; and 3) What is their role in the decision to stop antibiotic therapy? To answer these questions, studies reviewed were limited to recent clinical studies (<15 years), involving a substantial number of patients (>50) and restricted to controlled trials and meta-analyses for answering questions 2 and 3. With regard to the first question concerning routinely available biomarkers, which might be useful for antibiotic management of acute infections, these are currently limited to C-reactive protein (CRP) and procalcitonin (PCT). Other promising biomarkers that may prove useful in the near future but need to undergo more extensive clinical testing include sTREM-1, suPAR, ProADM, and Presepsin. New approaches to biomarkers of infections include point-of-care testing and genomics.

Role of biomarkers in the management of antibiotic therapy: an expert panel review II: clinical use of biomarkers for initiation or discontinuation of antibiotic therapy

Biomarker-guided initiation of antibiotic therapy has been studied in four conditions: acute pancreatitis, lower respiratory tract infection (LRTI), meningitis, and sepsis in the ICU. In pancreatitis with suspected infected necrosis, initiating antibiotics best relies on fine-needle aspiration and demonstration of infected material. We suggest that PCT be measured to help predict infection; however, available data are insufficient to decide on initiating antibiotics based on PCT levels. In adult patients suspected of community-acquired LRTI, we suggest withholding antibiotic therapy when the serum PCT level is low (<0.25 ng/mL); in patients having nosocomial LRTI, data are insufficient to recommend initiating therapy based on a single PCT level or even repeated measurements. For children with suspected bacterial meningitis, we recommend using a decision rule as an aid to therapeutic decisions, such as the Bacterial Meningitis Score or the Meningitest®; a single PCT level ≥0.5 ng/mL also may be used, but false-negatives may occur. In adults with suspected bacterial meningitis, we suggest integrating serum PCT measurements in a clinical decision rule to help distinguish between viral and bacterial meningitis, using a 0.5 ng/mL threshold. For ICU patients suspected of community-acquired infection, we do not recommend using a threshold serum PCT value to help the decision to initiate antibiotic therapy; data are insufficient to recommend using PCT serum kinetics for the decision to initiate antibiotic therapy in patients suspected of ICU-acquired infection. In children, CRP can probably be used to help discontinue therapy, although the evidence is limited. In adults, antibiotic discontinuation can be based on an algorithm using repeated PCT measurements. In non-immunocompromised out- or in- patients treated for RTI, antibiotics can be discontinued if the PCT level at day 3 is < 0.25 ng/mL or has decreased by >80-90%, whether or not microbiological documentation has been obtained. For ICU patients who have nonbacteremic sepsis from a known site of infection, antibiotics can be stopped if the PCT level at day 3 is < 0.5 ng/mL or has decreased by >80% relative to the highest level recorded, irrespective of the severity of the infectious episode; in bacteremic patients, a minimal duration of therapy of 5 days is recommended.

Increased creatinine clearance in polytrauma patients with normal serum creatinine: a retrospective observational study.

IntroductionThe aim of this study, performed in an intensive care unit (ICU) population with a normal serum creatinine, was to estimate urinary creatinine clearance (CLCR) in a population of polytrauma patients (PT) through a comparison with a population of non trauma patients (NPT).MethodsThis was a retrospective, observational study in a medical and surgical ICU in a university hospital. A total of 284 patients were consecutively included. Two different groups were studied: PT (n = 144) and NPT (n = 140). Within the second week after admission to the ICU, renal function was assessed using serum creatinine, 24 h urinary CLCR .ResultsAmong the 106 patients with a CLCR above 120 mL minute-1 1.73 m-2, 79 were PT and 27 NPT (P < 0.0001). Only 63 patients had a CLCR below 60 mL minute-1 1.73 m-2 with 15 PT and 48 NPT (P < 0.0001). Patients with CLCR greater than 120 mL minute-1. 1.73 m -2 were younger, had a lower SAPS II score and a higher male ratio as compared to those having CLCR lower than 120 mL minute-1. 1.73 m -2. Through a logistic regression analysis, age and trauma were the only factors independently correlated to CLCR.ConclusionsIn ICU patients with normal serum creatinine, CLCR, is higher in PT than in NPT. The measure of CLCR should be proposed as routine for PT patients in order to adjust dose regimen, especially for drugs with renal elimination.

Potential voriconazole and caspofungin sequestration during extracorporeal membrane oxygenation

Sir: A 31-year-old woman (weighing 50 kg) was admitted to our ICU for cardiogenic shock caused by fulminant myocarditis. Twelve hours later, extracorporeal oxygenation membrane (ECMO) support via percutaneous arterial and venous femoral cannulae was initiated; the system comprised a membrane oxygenator (Quadrox Bioline, Jostra-Maquet, Orleans, France) and a centrifugal pump (Rotaflow, Jostra-Maquet). Continuous venovenous hemodialfiltration (PRISMA machine; respective blood, dialysate and ultrafiltration flows: 120 ml/min, 500 ml/h and 1,000 ml/h) was started because of acute renal failure. Six days later, Aspergillus fumigatus was isolated from pulmonary secretions, obtained via bronchoalveolar lavage (BAL), and extensive tracheal pseudomembranous lesions. Although her serum was galactomannan-antigen-negative (enzyme immunoassay, Bio-Rad), the BAL galactomannan index was 4.8 (threshold, 0.5). Combined intravenous (IV) antifungal therapy was initiated with voriconazole [6 mg/kg bid day 1, then 4 mg/kg bid] and caspofungin (70 mg day 1, then 50 mg/day). Because of persistent A. fumigatus-positive tracheal lesion cultures on D11, respective antifungal doses were increased to 8 mg/kg bid and 70 mg/day. On D14, persistent extensive tracheal pseudomembranous lesions, positive BAL and tracheal aspirate cultures and a BAL galactomannan index of 8 indicated treatment failure. On D15, voriconazole was stopped, and based on in vitro results [1], caspofungin was combined with IV liposomal amphotericin B (3 mg/kg/ day) and flucytosine (1.5 g/day); nebulized liposomal amphotericin B (25 mg bid) was also administered. The patient was weaned from ECMO 21 days after ICU admission. BAL cultures became negative 16 days after starting the three-drug regimen, followed shortly thereafter by an undetectable galactomannan index. The patient was discharged from the ICU on D53. During ECMO, voriconazole, caspofungin and amphotericin B levels in blood collected from the indwelling arterial line were determined by high-performance liquid chromatography (respective quantification limits: 0.2, 0.5 and 0.1 mg/l; see Table 1). ECMO improves outcomes of patients with fulminant myocarditis [2]. During ECMO, drugs exhibit complex pharmacokinetics due to the larger volume of distribution, and their binding to various extracorporeal circuit components may markedly alter the pharmacokinetics of commonly used agents [3]. Molecular size, degree of ionization and physicochemical drug properties, e.g., the octanol–water partition coefficient, which is associated with a drug’s lipophilicity, may influence the degree of binding to plastics [3]. A recent ex vivo study [4] demonstrated a 71% ‘loss’ of voriconazole, a finding consistent with our very low or undetectable circulating levels, despite high doses, that is clinically relevant because of the significant association between trough blood voriconazole levels and outcome [5]. A renal replacement role was unlikely because nonhigh-volume hemodialfiltration contributes minimally to voriconazole elimination. ECMO also affected caspofungin pharmacokinetics, while blood amphotericin B levels remained within the therapeutic range. To the best of our knowledge, no data are available concerning blood caspofungin concentrations in patients on ECMO. In such patients, because adequate blood voriconazole and caspofungin concentrations may not be Table 1 Blood levels of antifungals during ECMO

Anesthetic regimen for cardiac function evaluation by echocardiography in mice: comparison between ketamine, etomidate and isoflurane versus conscious state

Mice with genetic alterations are used in heart research for the extrapolation of human diseases. Echocardiography is an essential tool for evaluating cardiac and hemodynamic functions in small animals. The purpose of this study was to compare the effect of different anesthetic regimens and the conscious state on the evaluation of cardiac function by echocardiography. Mice were examined in the conscious state after three days of training, and then for a 7 min period after a single intraperitoneal injection of ketamine at 100 mg/kg, etomidate at 10, 20 or 30 mg/kg, or after inhalation of isoflurane at 1.5% with or without a short period of induction with isoflurane 3%. Intra- and inter-observer variabilities were assessed. The operator’s comfort was also assessed. Heart rate, left ventricular end diastolic diameter, fraction shortening and cardiac output were measured using echocardiography. Ketamine at 5 and 7 min after induction and isoflurane at 3, 5 and 7 min after induction provided good anesthetic conditions and a quick awakening time, and did not influence cardiac performance, whereas the conscious state was associated with a non-physiological sympathetic activation and other anesthetic drugs induced a significant decrease in heart rate. Etomidate 10 mg/kg and 20 mg/kg were not enough to provide adequate anesthesia. Etomidate 30 mg/kg induced a good anesthetic condition but influenced cardiac performance and had a long awakening time. Our results indicate that ketamine and isoflurane with a short induction period are better anesthetic drugs than isoflurane without induction or etomidate for evaluating cardiac function in healthy mice.

Ceftazidime dosage regimen in intensive care unit patients: from a population pharmacokinetic approach to clinical practice via Monte Carlo simulations

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT The large variability in drug pharmacokinetic disposition has already been described in ICU patients leading to important variations in drugs concentrations. The usual recommended dosage of ceftazidime is not adapted for all ICU situations and ceftazidime should be monitored closely. New recommendations have to be given for some specific cases. WHAT THIS STUDY ADDS Our results propose individual therapeutic drug monitoring taking into account: For the patient: the reason of admission in the ICU, the mechanical ventilation status and the creatinine clearance calculated by the modified diet in renal disease (MDRD). • For the antibiotics: the lung distribution, the minimal inhibitory concentration (MIC) of the strain to eradicate and the potential toxicity. AIM To predict the ceftazidime dosage regimen as a function of the glomerular filtration rate expressed by the modification of the diet in renal disease (MDRD), reason for admission and mechanical ventilation in intensive care unit (ICU) patients to treat Pseudomonas aeruginosa pneumonia. METHOD A published and qualified population pharmacokinetic model was used to perform Monte Carlo simulations of ceftazidime concentrations. The serum target of 40-100 mg l(-1) was defined based on the minimal inhibitory concentration (MIC), the European break point (EBP), the pulmonary drug diffusion and toxicity. The recommended dosage regimens were based on the maximum percentile of the patients with simulated steady state concentrations reaching the target. RESULTS Steady-state was reached at 72 h whatever the MDRD. The simulations of serum concentrations generated higher percentiles of the population reaching the target after continuous administration. We recommend a 4 g continuous dose after the usual 2 g loading dose for patients with MDRD from 10 to 30 ml min(-1) , 6 g for MDRD between 40 and 80 ml min(-1) , 8 g for MDRD from 90 to 110 ml min(-1) , 10 g for MDRD from 120 to 190 ml min(-1) and 12 g day(-1) for patients with MDRD higher than 200 ml min(-1) . CONCLUSION Our study demonstrated that in ICU patients for a given MDRD, steady-state takes longer to reach in polytrauma patients than in patients with medical or post surgery reasons for admission. Continuous infusion ensures that a higher percentage of patients reaches the target than the same dose given by discontinuous administration and this only depends on MDRD.