Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis.

BACKGROUND: In February, 2017, the US Food and Drug Administration approved the blood infection marker procalcitonin for guiding antibiotic therapy in patients with acute respiratory infections. This meta-analysis of patient data from 26 randomised controlled trials was designed to assess safety of procalcitonin-guided treatment in patients with acute respiratory infections from different clinical settings. METHODS: Based on a prespecified Cochrane protocol, we did a systematic literature search on the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, and pooled individual patient data from trials in which patients with respiratory infections were randomly assigned to receive antibiotics based on procalcitonin concentrations (procalcitonin-guided group) or control. The coprimary endpoints were 30-day mortality and setting-specific treatment failure. Secondary endpoints were antibiotic use, length of stay, and antibiotic side-effects. FINDINGS: We identified 990 records from the literature search, of which 71 articles were assessed for eligibility after exclusion of 919 records. We collected data on 6708 patients from 26 eligible trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin-guided patients than in control patients (286 [9%] deaths in 3336 procalcitonin-guided patients vs 336 [10%] in 3372 controls; adjusted odds ratio [OR] 0·83 [95% CI 0·70 to 0·99], p=0·037). This mortality benefit was similar across subgroups by setting and type of infection (pinteractions>0·05), although mortality was very low in primary care and in patients with acute bronchitis. Procalcitonin guidance was also associated with a 2·4-day reduction in antibiotic exposure (5·7 vs 8·1 days [95% CI -2·71 to -2·15], p<0·0001) and a reduction in antibiotic-related side-effects (16% vs 22%, adjusted OR 0·68 [95% CI 0·57 to 0·82], p<0·0001). INTERPRETATION: Use of procalcitonin to guide antibiotic treatment in patients with acute respiratory infections reduces antibiotic exposure and side-effects, and improves survival. Widespread implementation of procalcitonin protocols in patients with acute respiratory infections thus has the potential to improve antibiotic management with positive effects on clinical outcomes and on the current threat of increasing antibiotic multiresistance. FUNDING: National Institute for Health Research.

Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections.

BACKGROUND: Acute respiratory infections (ARIs) comprise of a large and heterogeneous group of infections including bacterial, viral, and other aetiologies. In recent years, procalcitonin (PCT), a blood marker for bacterial infections, has emerged as a promising tool to improve decisions about antibiotic therapy (PCT-guided antibiotic therapy). Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in different patient populations with ARIs and different settings ranging from primary care settings to emergency departments, hospital wards, and intensive care units. However, the effect of using procalcitonin on clinical outcomes is unclear. This is an update of a Cochrane review and individual participant data meta-analysis first published in 2012 designed to look at the safety of PCT-guided antibiotic stewardship. OBJECTIVES: The aim of this systematic review based on individual participant data was to assess the safety and efficacy of using procalcitonin for starting or stopping antibiotics over a large range of patients with varying severity of ARIs and from different clinical settings. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE, and Embase, in February 2017, to identify suitable trials. We also searched ClinicalTrials.gov to identify ongoing trials in April 2017. SELECTION CRITERIA: We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm (PCT-guided antibiotic stewardship algorithm) or usual care. We excluded trials if they focused exclusively on children or used procalcitonin for a purpose other than to guide initiation and duration of antibiotic treatment. DATA COLLECTION AND ANALYSIS: Two teams of review authors independently evaluated the methodology and extracted data from primary studies. The primary endpoints were all-cause mortality and treatment failure at 30 days, for which definitions were harmonised among trials. Secondary endpoints were antibiotic use, antibiotic-related side effects, and length of hospital stay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression adjusted for age, gender, and clinical diagnosis using a fixed-effect model. The different trials were added as random-effects into the model. We conducted sensitivity analyses stratified by clinical setting and type of ARI. We also performed an aggregate data meta-analysis. MAIN RESULTS: From 32 eligible RCTs including 18 new trials for this 2017 update, we obtained individual participant data from 26 trials including 6708 participants, which we included in the main individual participant data meta-analysis. We did not obtain individual participant data for four trials, and two trials did not include people with confirmed ARIs. According to GRADE, the quality of the evidence was high for the outcomes mortality and antibiotic exposure, and quality was moderate for the outcomes treatment failure and antibiotic-related side effects.Primary endpoints: there were 286 deaths in 3336 procalcitonin-guided participants (8.6%) compared to 336 in 3372 controls (10.0%), resulting in a significantly lower mortality associated with procalcitonin-guided therapy (adjusted OR 0.83, 95% CI 0.70 to 0.99, P = 0.037). We could not estimate mortality in primary care trials because only one death was reported in a control group participant. Treatment failure was not significantly lower in procalcitonin-guided participants (23.0% versus 24.9% in the control group, adjusted OR 0.90, 95% CI 0.80 to 1.01, P = 0.068). Results were similar among subgroups by clinical setting and type of respiratory infection, with no evidence for effect modification (P for interaction > 0.05). Secondary endpoints: procalcitonin guidance was associated with a 2.4-day reduction in antibiotic exposure (5.7 versus 8.1 days, 95% CI -2.71 to -2.15, P < 0.001) and lower risk of antibiotic-related side effects (16.3% versus 22.1%, adjusted OR 0.68, 95% CI 0.57 to 0.82, P < 0.001). Length of hospital stay and intensive care unit stay were similar in both groups. A sensitivity aggregate-data analysis based on all 32 eligible trials showed similar results. AUTHORS' CONCLUSIONS: This updated meta-analysis of individual participant data from 12 countries shows that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic-related side effects. Results were similar for different clinical settings and types of ARIs, thus supporting the use of procalcitonin in the context of antibiotic stewardship in people with ARIs. Future high-quality research is needed to confirm the results in immunosuppressed patients and patients with non-respiratory infections.

Effects of procalcitonin testing on antibiotic use and clinical outcomes in patients with upper respiratory tract infections. An individual patient data meta-analysis.

BACKGROUND: Several trials found procalcitonin (PCT) helpful for guiding antibiotic treatment in patients with lower respiratory tract infections and sepsis. We aimed to perform an individual patient data meta-analysis on the effects of PCT guided antibiotic therapy in upper respiratory tract infections (URTI). METHODS: A comprehensive search of the literature was conducted using PubMed (MEDLINE) and Cochrane Library to identify relevant studies published until September 2016. We reanalysed individual data of adult URTI patients with a clinical diagnosis of URTI. Data of two trials were used based on PRISMA-IPD guidelines. Safety outcomes were (1) treatment failure defined as death, hospitalization, ARI-specific complications, recurrent or worsening infection at 28 days follow-up; and (2) restricted activity within a 14-day follow-up. Secondary endpoints were initiation of antibiotic therapy, and total days of antibiotic exposure. RESULTS: In total, 644 patients with a follow up of 28 days had a final diagnosis of URTI and were thus included in this analysis. There was no difference in treatment failure (33.1% vs. 34.0%, OR 1.0, 95% CI 0.7-1.4; p=0.896) and days with restricted activity between groups (8.0 vs. 8.0 days, regression coefficient 0.2 (95% CI -0.4 to 0.9), p=0.465). However, PCT guided antibiotic therapy resulted in lower antibiotic prescription (17.8% vs. 51.0%, OR 0.2, 95% CI 0.1-0.3; p<0.001) and in a 2.4 day (95% CI -2.9 to -1.9; p<0.001) shorter antibiotic exposure compared to control patients. CONCLUSIONS: PCT guided antibiotic therapy in the primary care setting was associated with reduced antibiotic exposure in URTI patients without compromising outcomes.

Prognostic value of procalcitonin in respiratory tract infections across clinical settings.

INTRODUCTION: Whether the inflammatory biomarker procalcitonin provides prognostic information across clinical settings and different acute respiratory tract infections (ARIs) is poorly understood. In the present study, we investigated the prognostic value of admission procalcitonin levels to predict adverse clinical outcome in a large ARI population. METHODS: We analysed data from 14 trials and 4,211 ARI patients to study associations of admission procalcitonin levels and setting specific treatment failure and mortality alone at 30 days. We used multivariable hierarchical logistic regression and conducted sensitivity analyses stratified by clinical settings and ARI diagnoses to assess the results' consistency. RESULTS: Overall, 864 patients (20.5%) experienced treatment failure and 252 (6.0%) died. The ability of procalcitonin to differentiate patients with from those without treatment failure was highest in the emergency department setting (treatment failure area under the curve (AUC): 0.64 (95% confidence interval (CI): 0.61, 0.67), adjusted odds ratio (OR): 1.85 (95% CI: 1.61, 2.12), P <0.001; and mortality AUC: 0.67 (95% CI: 0.63, 0.71), adjusted OR: 1.82 (95% CI: 1.45, 2.29), P <0.001). In lower respiratory tract infections, procalcitonin was a good predictor of identifying patients at risk for mortality (AUC: 0.71 (95% CI: 0.68, 0.74), adjusted OR: 2.13 (95% CI: 1.82, 2.49), P <0.001). In primary care and intensive care unit patients, no significant association of initial procalcitonin levels and outcome was found. CONCLUSIONS: Admission procalcitonin levels are associated with setting specific treatment failure and provide the most prognostic information regarding ARI in the emergency department setting.

Economic evaluation of procalcitonin-guided antibiotic therapy in acute respiratory infections: a US health system perspective.

BACKGROUND: Whether or not antibiotic stewardship protocols based on procalcitonin levels results in cost savings remains unclear. Herein, our objective was to assess the economic impact of adopting procalcitonin testing among patients with suspected acute respiratory tract infection (ARI) from the perspective of a typical US integrated delivery network (IDN) with a 1,000,000 member catchment area or enrollment. METHODS: To conduct an economic evaluation of procalcitonin testing versus usual care we built a cost-impact model based on patient-level meta-analysis data of randomized trials. The meta-analytic data was adapted to the US setting by applying the meta-analytic results to US lengths of stay, costs, and practice patterns. We estimated the annual ARI visit rate for the one million member cohort, by setting (inpatient, ICU, outpatient) and ARI diagnosis. RESULTS: In the inpatient setting, the costs of procalcitonin-guided compared to usual care for the one million member cohort was $2,083,545, compared to $2,780,322, resulting in net savings of nearly $700,000 to the IDN for 2014. In the ICU and outpatient settings, savings were $73,326 and $5,329,824, respectively, summing up to overall net savings of $6,099,927 for the cohort. RESULTS were robust for all ARI diagnoses. For the whole US insured population, procalcitonin-guided care would result in $1.6 billion in savings annually. CONCLUSIONS: Our results show substantial savings associated with procalcitonin protocols of ARI across common US treatment settings mainly by direct reduction in unnecessary antibiotic utilization. These results are robust to changes in key parameters, and the savings can be achieved without any negative impact on treatment outcomes.

Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections.

BACKGROUND: Acute respiratory infections (ARIs) comprise a large and heterogeneous group of infections including bacterial, viral and other aetiologies. In recent years, procalcitonin - the prohormone of calcitonin - has emerged as a promising marker for the diagnosis of bacterial infections and for improving decisions about antibiotic therapy. Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in different patient populations with acute respiratory infections and different settings ranging from primary care to emergency departments (EDs), hospital wards and intensive care units (ICUs). OBJECTIVES: The aim of this systematic review based on individual patient data was to assess the safety and efficacy of using procalcitonin for starting or stopping antibiotics over a large range of patients with varying severity of ARIs and from different clinical settings. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2011, Issue 2) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to May 2011) and EMBASE (1974 to May 2011) to identify suitable trials. SELECTION CRITERIA: We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm or usual care/guidelines. Trials were excluded if they exclusively focused on paediatric patients or if they used procalcitonin for another purpose than to guide initiation and duration of antibiotic treatment. DATA COLLECTION AND ANALYSIS: Two teams of review authors independently evaluated the methodology and extracted data from primary studies. The primary endpoints were all-cause mortality and treatment failure at 30 days. For the primary care setting, treatment failure was defined as death, hospitalisation, ARI-specific complications, recurrent or worsening infection, and patients reporting any symptoms of an ongoing respiratory infection at follow-up. For the ED setting, treatment failure was defined as death, ICU admission, re-hospitalisation after index hospital discharge, ARI-associated complications, and recurrent or worsening infection within 30 days of follow-up. For the ICU setting, treatment failure was defined as death within 30 days of follow-up. Secondary endpoints were antibiotic use (initiation of antibiotics, duration of antibiotics and total exposure to antibiotics (total amount of antibiotic days divided by total number of patients)), length of hospital stay for hospitalised patients, length of ICU stay for critically ill patients, and number of days with restricted activities within 14 days after randomisation for primary care patients. For the two co-primary endpoints of all-cause mortality and treatment failure, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression. The hierarchical regression model was adjusted for age and clinical diagnosis as fixed-effect. The different trials were added as random-effects into the model. We fitted corresponding linear regression models for antibiotic use. We conducted sensitivity analyses stratified by clinical setting and ARI diagnosis to assess the consistency of our results. MAIN RESULTS: We included 14 trials with 4221 participants. There were 118 deaths in 2085 patients (5.7%) assigned to procalcitonin groups compared to 134 deaths in 2126 control patients (6.3%) (adjusted OR 0.94, 95% CI 0.71 to 1.23). Treatment failure occurred in 398 procalcitonin group patients (19.1%) and in 466 control patients (21.9%). Procalcitonin guidance was not associated with increased mortality or treatment failure in any clinical setting, or ARI diagnosis. These results proved robust in various sensitivity analyses. Total antibiotic exposure was significantly reduced overall (median (interquartile range) from 8 (5 to 12) to 4 (0 to 8) days; adjusted difference in days, -3.47, 95% CI -3.78 to -3.17, and across all the different clinical settings and diagnoses. AUTHORS' CONCLUSIONS: Use of procalcitonin to guide initiation and duration of antibiotic treatment in patients with ARI was not associated with higher mortality rates or treatment failure. Antibiotic consumption was significantly reduced across different clinical settings and ARI diagnoses. Further high-quality research is needed to confirm the safety of this approach for non-European countries and patients in intensive care. Moreover, future studies should also establish cost-effectiveness by considering country-specific costs of procalcitonin measurement and potential savings in consumption of antibiotics and other healthcare resources, as well as secondary cost savings due to lower risk of side effects and reduced antimicrobial resistance.

Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections.

BACKGROUND: Acute respiratory infections (ARIs) comprise a large and heterogeneous group of infections including bacterial, viral and other aetiologies. In recent years, procalcitonin - the prohormone of calcitonin - has emerged as a promising marker for the diagnosis of bacterial infections and for improving decisions about antibiotic therapy. Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in different patient populations with acute respiratory infections and different settings ranging from primary care to emergency departments (EDs), hospital wards and intensive care units (ICUs). OBJECTIVES: The aim of this systematic review based on individual patient data was to assess the safety and efficacy of using procalcitonin for starting or stopping antibiotics over a large range of patients with varying severity of ARIs and from different clinical settings. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2011, Issue 2) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to May 2011) and EMBASE (1974 to May 2011) to identify suitable trials. SELECTION CRITERIA: We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm or usual care/guidelines. Trials were excluded if they exclusively focused on paediatric patients or if they used procalcitonin for another purpose than to guide initiation and duration of antibiotic treatment. DATA COLLECTION AND ANALYSIS: Two teams of review authors independently evaluated the methodology and extracted data from primary studies. The primary endpoints were all-cause mortality and treatment failure at 30 days. For the primary care setting, treatment failure was defined as death, hospitalisation, ARI-specific complications, recurrent or worsening infection, and patients reporting any symptoms of an ongoing respiratory infection at follow-up. For the ED setting, treatment failure was defined as death, ICU admission, re-hospitalisation after index hospital discharge, ARI-associated complications, and recurrent or worsening infection within 30 days of follow-up. For the ICU setting, treatment failure was defined as death within 30 days of follow-up. Secondary endpoints were antibiotic use (initiation of antibiotics, duration of antibiotics and total exposure to antibiotics (total amount of antibiotic days divided by total number of patients)), length of hospital stay for hospitalised patients, length of ICU stay for critically ill patients, and number of days with restricted activities within 14 days after randomisation for primary care patients.For the two co-primary endpoints of all-cause mortality and treatment failure, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression. The hierarchical regression model was adjusted for age and clinical diagnosis as fixed-effect. The different trials were added as random-effects into the model. We fitted corresponding linear regression models for antibiotic use. We conducted sensitivity analyses stratified by clinical setting and ARI diagnosis to assess the consistency of our results. MAIN RESULTS: We included 14 trials with 4221 participants. There were 118 deaths in 2085 patients (5.7%) assigned to procalcitonin groups compared to 134 deaths in 2126 control patients (6.3%) (adjusted OR 0.94, 95% CI 0.71 to 1.23). Treatment failure occurred in 398 procalcitonin group patients (19.1%) and in 466 control patients (21.9%). Procalcitonin guidance was not associated with increased mortality or treatment failure in any clinical setting, or ARI diagnosis. These results proved robust in various sensitivity analyses. Total antibiotic exposure was significantly reduced overall (median (interquartile range) from 8 (5 to 12) to 4 (0 to 8) days; adjusted difference in days, -3.47, 95% CI -3.78 to -3.17, and across all the different clinical settings and diagnoses. AUTHORS' CONCLUSIONS: Use of procalcitonin to guide initiation and duration of antibiotic treatment in patients with ARI was not associated with higher mortality rates or treatment failure. Antibiotic consumption was significantly reduced across different clinical settings and ARI diagnoses. Further high-quality research is needed to confirm the safety of this approach for non-European countries and patients in intensive care. Moreover, future studies should also establish cost-effectiveness by considering country-specific costs of procalcitonin measurement and potential savings in consumption of antibiotics and other healthcare resources, as well as secondary cost savings due to lower risk of side effects and reduced antimicrobial resistance.

Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis.

BACKGROUND: Procalcitonin algorithms may reduce antibiotic use for acute respiratory tract infections (ARIs). We undertook an individual patient data meta-analysis to assess safety of this approach in different ARI diagnoses and different clinical settings. METHODS: We identified clinical trials in which patients with ARI were assigned to receive antibiotics based on a procalcitonin algorithm or usual care by searching the Cochrane Register, MEDLINE, and EMBASE. Individual patient data from 4221 adults with ARIs in 14 trials were verified and reanalyzed to assess risk of mortality and treatment failure-overall and within different clinical settings and types of ARIs. RESULTS: Overall, there were 118 deaths in 2085 patients (5.7%) assigned to procalcitonin groups compared with 134 deaths in 2126 control patients (6.3%; adjusted odds ratio, 0.94; 95% confidence interval CI, .71-1.23)]. Treatment failure occurred in 398 procalcitonin group patients (19.1%) and in 466 control patients (21.9%; adjusted odds ratio, 0.82; 95% CI, .71-.97). Procalcitonin guidance was not associated with increased mortality or treatment failure in any clinical setting or ARI diagnosis. Total antibiotic exposure per patient was significantly reduced overall (median [interquartile range], from 8 [5-12] to 4 [0-8] days; adjusted difference in days, -3.47 [95% CI, -3.78 to -3.17]) and across all clinical settings and ARI diagnoses. CONCLUSIONS: Use of procalcitonin to guide initiation and duration of antibiotic treatment in patients with ARIs was effective in reducing antibiotic exposure across settings without an increase in the risk of mortality or treatment failure. Further high-quality trials are needed in critical-care patients.

Pharmacokinetics of ampicillin/sulbactam in critically ill patients with acute kidney injury undergoing extended dialysis.

BACKGROUND AND OBJECTIVES: The fixed antibacterial combination of ampicillin and sulbactam is frequently used for various infections. Intact kidneys eliminate approximately 71% of ampicillin and 78% of sulbactam. Patients on thrice-weekly low-flux hemodialysis exhibit an ampicillin t(1/2) of 2.3 hours on and 17.4 hours off dialysis. Despite its frequent use in intensive care units, there are no available dosing recommendations for patients with AKI undergoing renal replacement therapy. The aims of this study were to evaluate the pharmacokinetics of ampicillin/sulbactam in critically ill patients with AKI undergoing extended dialysis (ED) and to establish a dosing recommendation for this treatment method. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twelve critically ill patients with anuric AKI being treated with ED were enrolled in a prospective, open-label, observational pharmacokinetic study. Pharmacokinetics after a single dose of ampicillin/sulbactam (2 g/1 g) was obtained in 12 patients. Multiple-dose pharmacokinetics after 4 days of twice-daily ampicillin/sulbactam (2 g/1 g) was obtained in three patients. RESULTS: The mean dialyzer clearance for ampicillin/sulbactam was 80.1 ± 7.7/83.3 ± 12.1 ml/min. The t(1/2) of ampicillin and sulbactam in patients with AKI undergoing ED were 2.8 ± 0.8 hours and 3.5 ± 1.5 hours, respectively. There was no significant accumulation using a twice-daily dosage of 2 g/1 g ampicillin/sulbactam. CONCLUSIONS: Our data suggest that in patients treated with ED using a high-flux dialyzer (polysulphone, 1.3 m(2); blood and dialysate flow, 160 ml/min; treatment time, 480 minutes), a twice-daily dosing schedule of at least 2 g/1 g ampicillin/sulbactam, with one dose given after ED, should be used to avoid underdosing.

Rapid HPLC-MS/MS method for simultaneous quantitation of four routinely administered triazole antifungals in human plasma.

BACKGROUND: Fluconazole, itraconazole, posaconazole and voriconazole are four triazole antifungal drugs administered for the prevention and in the treatment of invasive fungal infections. Therapeutic drug monitoring of these antifungals in human plasma is advised. METHODS: After protein precipitation by adding methanol/ZnSO(4) containing ketoconazole as internal standard (IS) the analytes were isolated from matrix and enriched by solid-phase extraction (SPE) and were separated on an Allure PFP HPLC column, maintained at 60°C. The retention times were 1.12, 1.09, 1.09, 1.15 and 1.94 min for fluconazole, voriconazole, posaconazole, itraconazole and ketoconazole, respectively. Cycle time was 3 min, injection to injection. The analytes were monitored by means of a tandem mass spectrometer. Selected reaction monitoring (SRM) in positive ion mode was used for quantitation. RESULTS: The presented method has limits of detection of 2-10 ng/mL, a lower limit of quantitation of 14 ng/mL and linearities ≥0.999 for the different analytes. The intra- and interday correlation coefficients of variation were <8.1 and <9.8%, respectively. The accuracy ranged from 85 to 106%. CONCLUSIONS: A rapid, sensitive, and robust HPLC-MS/MS method for quantifying fluconazole, itraconazole, posaconazole and voriconazole levels in human plasma was validated and successfully applied to samples from antifungal treated patients.

Quantitative analysis of the antifungal drug anidulafungin by LC-online SPE-MS/MS in human plasma.

The objective of this study was to develop a fast and robust method for the quantitation of the antifungal drug anidulafungin in human plasma samples by generic two-dimensional liquid chromatography (online-SPE/reversed phase LC) coupled to a tandem-quadrupole mass spectrometer (LC-online SPE-MS/MS). Online SPE was performed using an Oasis HLB cartridge column and for reversed-phase chromatography a Nucleodur Gravity C(18) column was used. A 100 µL aliquot of human plasma was extracted with 200 µL of 80:20 MeOH-0.2 M ZnSO(4) (v/v) as precipitation reagent containing ascomycin as internal standard (IS). The supernatant was directly injected for analysis. The total run time was 4.5 min. Anidulafungin and ascomycin were detected in the positive ionization mode. The method performance data for anidulafungin, such as limit of detection (0.013 µg/mL), lower limit of quantitation (0.04 µg/mL), linearity (R(2) = 0.9999) and concentration range (0.04-10 µg/mL) were ascertained. Intra- and inter-day precisions were ≤6.6% and intra- and inter-day accuracies were 98.5-101.0 and 100.0-102.5%, respectively. The assay was successfully applied for quantitation of anidulafungin in patient plasma samples.

Daptomycin for a complicated urinary tract infection with vancomycin-resistant Enterococcus faecium in a renal transplant recipient.

There is an increasing prevalence of urinary tract infection (UTI) caused by multiresistant gram-negative enteric bacilli such as extended-spectrum beta-lactamase as well as Gram-positive enterococci whose vancomycin-resistance can be as high as 25%. We report on a 68-year-old Caucasian female with a UTI caused by a vancomycin-resistant Enterococcus faecium, only tested to be susceptible to gentamycin, linezolid and daptomycin. Within a day after administration of the bactericidal daptomycin clinical and laboratory signs of infection regressed and graft function recovered. Our case suggests that daptomycin might be an effective alternative for UTI caused by vancomycin-resistant enterococci.

Dosing of antibiotics in critically ill patients undergoing renal replacement therapy.

On September 11, 1945 Maria Schafstaat was the first patient who successfully underwent a dialysis treatment for acute kidney injury (AKI), formerly known as acute renal failure. Since then, the number of patients with AKI is increasing worldwide. Today AKI is generally one feature of a multiple organ dysfunction syndrome (MODS), which develops in response to major surgery, cardiogenic shock or sepsis. Several clinical studies have shown that early and appropriate antibiotic therapy in those patients is of utter importance, yet it remains one of the most difficult challenges to meet. Even in critically ill patients with conserved renal function a myriad of pathophysiological changes, resulting in increased volume of distribution, decreased protein binding and altered hepatic drug clearance, makes appropriate antibiotic dosin difficult. Adequate pharmacotherapy, i.e. dose of anti-infective agens is becoming even more complicated if it has to be tailored to counteract their removal by different modes and intensities of renal replacement therapy. This review summarizes our sparse knowledge about pharmacokinetic studies and dosing recommendations of drugs in patients with AKI undergoing continuous renal replacement therapies (CRRTs) such as continuous venovenous hemofiltration (CVVH) as well as extended dialysis (ED), an increasingly used method to treat patients with AKI in the intensive care setting. We reflect on failure of several large prospective controlled studies to show a survival benefit of higher doses of renal replacement therapy, a finding that might be caused by the fact that we still adhere to dosing guidelines for antibiotics which are at best ineffectual but might also lead to potentially dangerous underdosing of these life saving drugs. Lastly we address possible strategies to overcome the lack of knowledge, the lack of data and the lack of interest in this important area of critical care medicine. Improvement of clinical outcomes and reduction of antibiotic resistance in this patient population will require nephrologist, intensivists and pharmacists to work together.

Pharmacokinetics of moxifloxacin in patients with severe sepsis or septic shock.

PURPOSE: To investigate the steady-state pharmacokinetics of moxifloxacin in critically ill patients after intravenous administration of the 400 mg fixed dose. METHODS: Fifteen adult patients with severe sepsis (n = 3) or septic shock (n = 12) were enrolled in this dual-centre, prospective, open-label study. Moxifloxacin was administered with the recommended dose of 400 mg once daily i.v. for at least 5 days. Blood samples were obtained before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18 and 24 h after the third administration. Moxifloxacin concentrations in plasma were measured by HPLC with fluorescence detection. RESULTS: Data for 400 mg moxifloxacin i.v. were as follows (geometric mean): C (max): 3.5 mg/l, t(1/2): 7.8 h and AUC (48-72 h): 25 mg h/l. In five individual patients AUC (48-72 h) was <20 mg h/l. CONCLUSION: The main pharmacokinetics/pharmacodynamics parameter predicting clinical efficacy of moxifloxacin is AUC/MIC. The mean AUC of patients with severe sepsis or septic shock was lower compared to healthy volunteers (39 mg h/l). In 5 of 12 patients the AUC was halved compared to healthy volunteers.

A simplified three-times weekly daptomycin dosing regimen for chronic hemodialysis patients.

Approximately 2.3 million patients worldwide are undergoing chronic renal replacement therapy. In that population, acute infections substantially contribute to the excessive morbidity and mortality. The risk for invasive methicillin-resistant Staphylococcus aureus infections in this population is approximately 100-fold higher than in the general population, therefore dialysis patients currently account for up to approximately 15% of all invasive methicillin-resistant Staphylococcus aureus infections. A simplified three-times weekly dosing regimen for hemodialysis patients now allows for practical, hassle-free and effective treatment with daptomycin, which is licensed for the treatment of complicated skin and soft tissue infections, including resistant strains of Staphylococcus aureus and life-threatening Gram-positive infections, vancomycin-resistant enterococcal infections and right-sided endocarditis.

Dosing of daptomycin in intensive care unit patients with acute kidney injury undergoing extended dialysis--a pharmacokinetic study.

BACKGROUND: Daptomycin is a new intravenous cyclic lipopeptide antibiotic, licensed for the treatment of complicated skin and soft tissue infections caused by Gram-positive organisms including both susceptible and resistant strains of Staphylococcus aureus and for the treatment of various infections due to susceptible organisms, including serious and life-threatening Gram-positive infections, vancomycin-resistant enterococcal infections and right-sided endocarditis with associated bacteremia. Currently, no dosing recommendations exist for this drug for patients with acute kidney injury (AKI) undergoing renal replacement therapy. The aim of this study was to evaluate pharmacokinetics of daptomycin in critically ill patients with AKI undergoing extended dialysis (ED), a frequently used mean of renal replacement therapies in intensive care units (ICUs) around the world. Patients and methods. A prospective, single-dose pharmacokinetic study was performed in the medical and surgical ICUs of a tertiary care center. The aim was to investigate critically ill patients with anuric AKI being treated with ED and receiving daptomycin (n = 10). Daptomycin (6 mg/kg) was administered 8 h before ED was started. RESULTS: Key pharmacokinetic parameters like half-life in critically ill patients treated with ED were comparable to healthy controls. The dialyser clearance for daptomycin was 63 +/- 9 ml/min. Based on the amount of the drug recovered from the collected spent dialysate, the mean fraction of the drug removed by one dialysis treatment was 23.3%. CONCLUSION: Our data suggest that patients treated with ED using a high-flux dialyzer (polysulphone, 1.3 m(2); blood and dialysate flow, 160 ml/min; ED time, 480 min) and employing current dosing regimen, 6 mg/kg daptomycin every 48 h, run the risk of becoming significantly under dosed if one adheres to a twice daily dosing schedule that is recommended for patients on maintenance haemodialysis. Our data suggest that a daily dose of 6 mg/kg daptomycin is necessary in this special patient population to avoid under dosing, which may have detrimental effects in critically ill patients suffering from life-threatening infections.