Quantification of cefuroxime and flucloxacillin in synovial tissue and bone using ultra-performance convergence chromatography-tandem mass spectrometry.

After a revision surgery, approximately 1-2 % of patients will develop a periprosthetic joint infection (PJI). During the revision surgery, the infected prosthesis is removed, a debridement is performed and a new or temporary spacer is placed. Additionally, patients are treated with antibiotics during and after the surgery. Adequate exposure of the administered antibiotic to the pathogen is of crucial importance during the treatment of any infection. Inadequately low concentrations are associated with an increase in antibiotic resistance, antibiotic related side effects, treatment failures and prolonged infections. While high concentrations may lead to serious adverse events and potential lasting damage. Despite the importance of optimal dosing, there is a lack of knowledge with respect to the correlation between the plasma concentrations and target site concentrations of the antibiotics. Two of the commonly administered antimicrobial agents during the arthroplasty exchange are cefuroxime and flucloxacillin. Therefore, an accurate, specific, and sensitive quantification method is required in order to assess pharmacokinetics of cefuroxime and flucloxacillin in synovial tissue and bone. The aim of this study is to develop and validate a quantification method for the measurement of cefuroxime and flucloxacillin in human synovial tissue and bone using the UPC2-MS/MS conform Food and Drug Administration guidelines. The method was found linear for both compounds in both matrices (r2 > 0.990) from 1 µg/g to 20 µg/g, except for cefuroxime in bone, which was validated from 1 µg/g to 15 µg/g. We developed and validated a quantification method for cefuroxime and flucloxacillin in synovial tissue and bone using a simple sample preparation and a short analysis run time of 5.0 min, which has been already successfully applied in a clinical study. To our knowledge, no methods have been described earlier for the simultaneous quantification of cefuroxime and flucloxacillin in synovial tissue and bone.

An Overview of the Protein Binding of Cephalosporins in Human Body Fluids: A Systematic Review.

Introduction: Protein binding can diminish the pharmacological effect of beta-lactam antibiotics. Only the free fraction has an antibacterial effect. The aim of this systematic literature review was to give an overview of the current knowledge of protein binding of cephalosporins in human body fluids as well as to describe patient characteristics influencing the level of protein binding. Method: A systematic literature search was performed in Embase, Medline ALL, Web of Science Core Collection and the Cochrane Central Register of Controlled Trials with the following search terms: "protein binding," "beta-lactam antibiotic," and "body fluid." Only studies were included where protein binding was measured in humans in vivo. Results: The majority of studies reporting protein binding were performed in serum or plasma. Other fluids included pericardial fluid, blister fluid, bronchial secretion, pleural exudate, wound exudate, cerebrospinal fluid, dialysate, and peritoneal fluid. Protein binding differs between diverse cephalosporins and between different patient categories. For cefazolin, ceftriaxone, cefpiramide, and cefonicid a non-linear pattern in protein binding in serum or plasma was described. Several patient characteristics were associated with low serum albumin concentrations and were found to have lower protein binding compared to healthy volunteers. This was for critically ill patients, dialysis patients, and patients undergoing cardiopulmonary bypass during surgery. While mean/median percentages of protein binding are lower in these patient groups, individual values may vary considerably. Age is not likely to influence protein binding by itself, however limited data suggest that lower protein binding in newborns. Obesity was not correlated with altered protein binding. Discussion/Conclusion: Conclusions on protein binding in other body fluids than blood cannot be drawn due to the scarcity of data. In serum and plasma, there is a large variability in protein binding per cephalosporin and between different categories of patients. Several characteristics were identified which lead to a lower protein binding. The finding that some of the cephalosporins display a non-linear pattern of protein binding makes it even more difficult to predict the unbound concentrations in individual patients. Taken all these factors, it is recommended to measure unbound concentrations to optimize antibiotic exposure in individual patients. Systematic Review Registration: PROSPERO, identifier (CRD42021252776).

Using Residual Blood from the Arterial Blood Gas Test to Perform Therapeutic Drug Monitoring of Vancomycin: An Example of Good Clinical Practice Moving towards a Sustainable Intensive Care Unit.

Background: Regarding sustainability in the intensive care unit (ICU), there is increasing interest in reducing material waste and avoiding unnecessary procedures. Therapeutic drug monitoring (TDM) of vancomycin, using a dedicated tube, is standard clinical care during treatment with vancomycin. Furthermore, in the ICU, on a daily basis, arterial blood gas (ABG) tests are frequently performed throughout the day. After analysis, a variable volume of blood is discarded. Lithium heparin (LiHep) syringes for ABG tests differ from normally used dipotassium ethylenediaminetetraacetic acid (K2EDTA) tubes. The primary objective was to compare both containers and validate the use of LiHep syringes. Secondary objectives were to evaluate the potential impact on saving materials, nursing time, and costs when implementing vancomycin TDM via LiHep syringes. Methods: Vancomycin analysis from sampling in lithium heparin (LiHep) syringes for ABG tests was validated and compared with the concentrations from conventional sampling in K2EDTA tubes. For method comparison, a Bland-Altman plot and Deming regression analysis were performed. The method was validated for inter- and intra-day precision and accuracy. Vancomycin was analyzed by means of the validated method using a particle-enhanced turbidimetric inhibition immunoassay (PETINIA) autoanalyzer. Furthermore, an analysis was conducted to evaluate the potential impact of implementing vancomycin sampling via ABG tests on savings in materials, nursing time, and costs. Results: From 18 patients, 24 plasma samples in both K2EDTA tubes and LiHep syringes were obtained and compared. The mean relative difference between the two containers was -2.0% (-3.0 to -0.93%). Both the Deming regression analysis and the Bland-Altman plot met the acceptance criteria. Potentially, over 1000 blood draws and accompanying materials and packaging can be saved when vancomycin samples are obtained by means of scavenged LiHep syringes. The vancomycin analysis for LiHep syringes showed a total interday precision of 1.95% and an accuracy of 99.7%. The total intraday precision was 2.22%, and the accuracy was 99.2%. Accuracy and precision values were within the acceptance criteria of recovery 85 to 115% and ≤15%, respectively. Conclusion: No significant differences were found in vancomycin concentration between the two analyses, and the LiHep analysis was validated for further implementation in clinical care. Residual blood from ABG test samples can be used for TDM of vancomycin, resulting in a potential reduction of materials used and the number of blood draws. These results will contribute to a more sustainable TDM process with benefits for the patient.

The effectiveness of nitrofurantoin, fosfomycin and trimethoprim for the treatment of cystitis in relation to renal function.

OBJECTIVES: We evaluated the effect of renal function on clinical failure rates of nitrofurantoin, fosfomycin and trimethoprim for the treatment of cystitis in primary care. METHODS: Data were retrospectively obtained from 78 Dutch general practitioner (GP) practices between 2013 and 2019. Eligible episodes in patients (>11 years) were those requiring 5 days of nitrofurantoin (NF5), single-dose fosfomycin-trometamol (FT1), 3 days of trimethoprim (TMP3) for uncomplicated cystitis, or 7 days of nitrofurantoin (NF7) or trimethoprim (TMP7) for complicated cystitis. Clinical failure was defined as second antibiotic prescription for cystitis or pyelonephritis within 28 days post-prescription. Mixed effects regression analysis was used, with patient and GP practice as random effects and demography, comorbidity, and cystitis history as fixed effects. RESULTS: Adjusted odds ratios (aORs) for clinical failure per 10mL/min decrease in estimated glomerular filtration rate (eGFR) were 1.05 (95% CI: 1.01-1.09) for NF5 (n = 24,591), 0.96 (95% CI: 0.92-1.01) for FT1 (n = 5359), 0.98 (95% CI: 0.89-1.08) for TMP3 (n = 1064), 1.05 (95% CI: 1.02-1.09) for NF7 (n = 10,628) and 1.02 (95% CI: 0.93-1.14) for TMP7 (n = 831). In uncomplicated cystitis and eGFR ≥60 mL/min, clinical failures occurred in 14.6% (1895/12 980) of NF5-treated, 20.7% (266/1283) of FT1-treated (aOR versus NF5 1.37, 95% CI 1.18-1.59) and 20.8% (66/318) of TMP3-treated patients (aOR 1.42, 95% CI 1.07-1.87 versus NF5). In uncomplicated cystitis and eGFR <60 mL/min, FT1 resulted in 16.0% (39/244) and NF5 in 23.3% clinical failures (110/472), aOR: 0.61, 95% CI: 0.39-0.95). CONCLUSIONS: In eGFR ≥60 mL/min treatment with fosfomycin or trimethoprim for uncomplicated cystitis was associated with more clinical failure than treatment with nitrofurantoin, while in eGFR <60 mL/min nitrofurantoin was associated with more clinical failure than fosfomycin-trometamol. Renal function, if known, should be considered in the clinical decision-making for cystitis treatment.

Comprehensive assessments and related interventions to enhance the long-term outcomes of child, adolescent and young adult cancer survivors - presentation of the CARE for CAYA-Program study protocol and associated literature review.

BACKGROUND: Improved, multimodal treatment strategies have been shown to increase cure rates in cancer patients. Those who survive cancer as a child, adolescent or young adult (CAYA), are at a higher risk for therapy-, or disease-related, late or long-term effects. The CARE for CAYA-Program has been developed to comprehensively assess any potential future problems, to offer need-based preventative interventions and thus to improve long-term outcomes in this particularly vulnerable population. METHODS: The trial is designed as an adaptive trial with an annual comprehensive assessment followed by needs stratified, modular interventions, currently including physical activity, nutrition and psycho-oncology, all aimed at improving the lifestyle and/or the psychosocial situation of the patients. Patients, aged 15-39 years old, with a prior cancer diagnosis, who have completed tumour therapy and are in follow-up care, and who are tumour free, will be included. At baseline (and subsequently on an annual basis) the current medical and psychosocial situation and lifestyle of the participants will be assessed using a survey compiled of various validated questionnaires (e.g. EORTC QLQ C30, NCCN distress thermometer, PHQ-4, BSA, nutrition protocol) and objective parameters (e.g. BMI, WHR, co-morbidities like hyperlipidaemia, hypertension, diabetes), followed by basic care (psychological and lifestyle consultation). Depending on their needs, CAYAs will be allocated to preventative interventions in the above-mentioned modules over a 12-month period. After 1 year, the assessment will be repeated, and further interventions may be applied as needed. During the initial trial phase, the efficacy of this approach will be compared to standard care (waiting list with intervention in the following year) in a randomized study. During this phase, 530 CAYAs will be included and 320 eligible CAYAs who are willing to participate in the interventions will be randomly allocated to an intervention. Overall, 1500 CAYAs will be included and assessed. The programme is financed by the innovation fund of the German Federal Joint Committee and will be conducted at 14 German sites. Recruitment began in January 2018. DISCUSSION: CAYAs are at high risk for long-term sequelae. Providing structured interventions to improve lifestyle and psychological situation may counteract against these risk factors. The programme serves to establish uniform regular comprehensive assessments and need-based interventions to improve long-term outcome in CAYA survivors. TRIAL REGISTRATION: Registered at the German Clinical Trial Register (ID: DRKS00012504, registration date: 19th January 2018).

Population Pharmacokinetic Modeling of Acetaminophen and Metabolites in Children After Cardiac Surgery With Cardiopulmonary Bypass.

Children undergoing cardiac surgery often receive acetaminophen (paracetamol) as part of their postoperative pain treatment. To date, there is no information on the pharmacokinetics (PK) of acetaminophen in this special population, even though differences, as a result of altered hemodynamics and/or use of cardiopulmonary bypass, may be anticipated. Therefore, the aim of this study was to investigate the PK of intravenous acetaminophen in children after cardiac surgery with cardiopulmonary bypass. In the study, both children with and without Down syndrome were included. A population PK analysis, using NONMEM 7.2, was performed based on 161 concentrations of acetaminophen, acetaminophen sulfate, acetaminophen glucuronide, and oxidative metabolites from 17 children with Down syndrome and 13 children without Down syndrome of a previously published study (median age, 177 days [range, 92-944], body weight, 6.1 kg [4.0-12.9]). All children received 3 intravenous acetaminophen doses of 7.5 mg/kg (<10 kg) or 15 mg/kg (≥10 kg) at 8-hour intervals after cardiac surgery. For acetaminophen and its metabolites, 1-compartment models were identified. Clearance of acetaminophen and metabolites increased linearly with body weight. Acetaminophen clearance in a typical child of 6.1 kg is 0.96 L/h and volume of distribution 7.96 L. Down syndrome did not statistically significantly impact any of the PK parameters for acetaminophen, nor did any other remaining covariate. When comparing the PK parameters of acetaminophen in children after cardiac surgery with cardiopulmonary bypass with those from children of the same age following noncardiac surgery reported in the literature, clearance of acetaminophen was lower and volume of distribution higher.

Population pharmacokinetic modelling of intravenous paracetamol in fit older people displays extensive unexplained variability.

AIMS: Paracetamol is the analgesic most used by older people. The physiological changes occurring with ageing influence the pharmacokinetics (PK) of paracetamol and its variability. We performed a population PK-analysis to describe the PK of intravenous (IV) paracetamol in fit older people. Simulations were performed to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg every 6 h, every 8 h) using steady-state concentration (Css-mean ) of 10 mg l-1 as target for effective analgesia. METHODS: A population PK-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit older people (median age 77.3 years, range [61.8-88.5], body weight 79 kg [60-107]). All had received an IV paracetamol dose of 1000 mg (over 15 min) after elective knee surgery. RESULTS: A two-compartment PK-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a Css of 9.2 mg l-1 and 7.2 mg l-1 , for every 6 h and every 8 h respectively. Variability in paracetamol PK resulted in Css above 5.4 and 4.1 mg l-1 , respectively, in 90% of the population and above 15.5 and 11.7, respectively, in 10% at these dosing regimens. CONCLUSIONS: The target concentration was achieved in the average patient with 1000 mg every 6 h, while every 8 h resulted in underdosing for the majority of the population. Furthermore, due to a large (unexplained) interindividual variability in paracetamol PK a relevant proportion of the fit older people remained either under- or over exposed.

High interindividual variability in urinary fosfomycin concentrations in healthy female volunteers.

OBJECTIVES: Fosfomycin is increasingly being prescribed for treatment of uncomplicated urinary tract infections in an era of emerging drug resistance. Surprisingly, little is known of the urinary concentrations of fosfomycin and its interindividual variation after the standard single 3-g oral dose. We aimed to gain more insight into urinary fosfomycin pharmacokinetics to evaluate its effectiveness. METHODS: Three grams of fosfomycin trometamol was administered to 40 healthy female volunteers with an estimated mean glomerular filtration rate of >90 mL/min/1.73m2. Urine samples were collected from every urination during 48 hours, and then twice daily for up to 7 days. Time, volume, and pH were recorded. Concentrations were quantified with UPLC-MS/MS. Effectiveness was evaluated based on urinary concentrations and the target MIC of E. coli, the most common uropathogen. RESULTS: A high interindividual variability was found. Peak concentration was 1982.0 ± 1257.4 mg/L, urinary half-life 12.4 ± 5.7 hours, and excretion rate over 48 hours 29.9 ± 7.1 mg/h. Recovery was 44.5 ± 12.6% after 48 hours and 47.0 ± 10.4% after 7 days. Concentrations remained above the EUCAST breakpoint of 32 mg/L in 100% of the volunteers over the first 24 hours, 67.5% for 48 hours, and 30% for 72 hours. A high urinary output was associated with low urinary concentrations and consequently reduced time > MIC, AUC0-7days/MIC, and Cmax/MIC values. CONCLUSIONS: Considerable interindividual variability observed in the pharmacokinetics of fosfomycin signifies a risk for inadequate drug exposure in a significant proportion of the population. The current dosing regimen should therefore be reevaluated.

Population pharmacokinetics of haloperidol in terminally ill adult patients.

PURPOSE: Over 80% of the terminally ill patients experience delirium in their final days. In the treatment of delirium, haloperidol is the drug of choice. Very little is known about the pharmacokinetics of haloperidol in this patient population. We therefore designed a population pharmacokinetic study to gain more insight into the pharmacokinetics of haloperidol in terminally ill patients and to find clinically relevant covariates that may be used in developing an individualised dosing regimen. METHODS: Using non-linear mixed effects modelling (NONMEM 7.2), a population pharmacokinetic analysis was conducted with 87 samples from 28 terminally ill patients who received haloperidol either orally or subcutaneously. The covariates analysed were patient and disease characteristics as well as co-medication. RESULTS: The data were accurately described by a one-compartment model. The population mean estimates for oral bioavailability, clearance and volume of distribution for an average patient were 0.86 (IIV 55%), 29.3 L/h (IIV 43%) and 1260 L (IIV 70%), respectively. This resulted in an average terminal half-life of haloperidol of around 30 h. CONCLUSION: Our study showed that the pharmacokinetics of haloperidol could be adequately described by a one-compartment model. The pharmacokinetics in terminally ill patients was comparable to other patients. We were not able to explain the wide variability using covariates.

Improved nutrition in adolescents and young adults after childhood cancer - INAYA study.

BACKGROUND: Multimodality treatment improves the chance of survival but increases the risk for long-term side effects in young cancer survivors, so-called" Adolescents and Young Adults"(AYAs). Compared to the general population AYAs have a 5 to 15-fold increased risk of cardiovascular morbidity. Thus, improving modifiable lifestyle risk factors is of particular importance. METHODS: The INAYA trial included AYAs between 18 and 39 years receiving an intensified individual nutrition counseling at four time points in a 3-month period based on a 3-day dietary record. At week 0 and 12 AYAs got a face-to-face counseling, at week 2 and 6 by telephone. Primary endpoint was change in nutritional behavior measured by Healthy Eating Index - European Prospective Investigation into Cancer and Nutrition (HEI-EPIC). RESULTS: Twenty-three AYAs (11 female, 12 male, median age 20 years (range 19-23 years), median BMI: 21.4 kg/m2 (range: 19.7-23.9 kg/m2) after completion of cancer treatment for sarcoma (n = 2), carcinoma (n = 2), blastoma (n = 1), hodgkin lymphoma (n = 12), or leukemia (n = 6) were included (median time between diagnosis and study inclusion was 44 month). The primary endpoint was met, with an improvement of 20 points in HEI-EPIC score in 52.2 % (n = 12) of AYAs. At baseline, median HEI-EPIC score was 47.0 points (range from 40.0 to 55.0 points) and a good, moderate and bad nutritional intake was seen in 4.3, 73.9 and 21.7 % of AYAs. At week 12, median HEI-EPIC improved significantly to 65.0 points (range from 55.0 to 76.0 points) (p ≤ 0.001) and a good, moderate and bad nutritional intake was seen in 47.8, 52.2 and 0 % of AYAs. No change was seen in quality of life, waist-hip ratio and blood pressure. CONCLUSION: Intensified nutrition counseling is feasible and seem to improve nutritional behavior of AYAs. Further studies will be required to demonstrate long-term sustainability and confirm the results in a randomized design in larger cohorts. TRIAL REGISTRATION: Clinical trial identifier DRKS00009883 on DRKS.

Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol.

INTRODUCTION: A variety of medications are used for symptom control in palliative care, such as morphine, midazolam and haloperidol. The pharmacokinetics of these drugs may be altered in these patients as a result of physiological changes that occur at the end stage of life. AREAS COVERED: This review gives an overview of how the pharmacokinetics in terminally ill patients may differ from the average population and discusses the effect of terminal illness on each of the four pharmacokinetic processes absorption, distribution, metabolism, and elimination. Specific considerations are also given for three commonly prescribed drugs in palliative care: morphine, midazolam and haloperidol). EXPERT OPINION: The pharmacokinetics of drugs in terminally ill patients can be complex and limited evidence exists on guided drug use in this population. To improve the quality of life of these patients, more knowledge and more pharmacokinetic/pharmacodynamics studies in terminally ill patients are needed to develop individualised dosing guidelines. Until then knowledge of pharmacokinetics and the physiological changes that occur in the final days of life can provide a base for dosing adjustments that will improve the quality of life of terminally ill patients. As the interaction of drugs with the physiology of dying is complex, pharmacological treatment is probably best assessed in a multi-disciplinary setting and the advice of a pharmacist, or clinical pharmacologist, is highly recommended.

The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison.

BACKGROUND: Circadian variation in renal toxicity of aminoglycosides has been demonstrated in animal and human studies. People with CF are frequently prescribed aminoglycosides. Altered pharmacokinetics of aminoglycosides are predictive of toxicity. AIM: To investigate whether the time of day of aminoglycoside administration modulates renal excretion of tobramycin and toxicity in children with CF. To determine whether circadian rhythms are disrupted in children with CF during hospital admission. METHODS: Children (age 5-18years) with CF scheduled for tobramycin therapy were randomly allocated to receive tobramycin at 0800 or 2000h. Serum tobramycin levels were drawn at 1h and between 3.5 and 5h post-infusion between days 5 and 9 of therapy. Melatonin levels were measured serially at intervals from 1800h in the evening until 1200h on the next day. Circadian rhythm was categorised as normal when dim light melatonin onset was demonstrated between 1800 and 2200h and/or peak melatonin levels were observed during the night. Weight and spirometry were measured at the start and end of the therapy. Urinary biomarkers of kidney toxicity (KIM1, NAG, NGAL, IL-18 and CysC) were assayed at the start and end of the course of tobramycin. RESULTS: Eighteen children were recruited to the study. There were no differences in renal clearance between the morning and evening groups. The increase in urinary KIM-1 was greater in the evening dosage group compared to the morning group (mean difference, 0.73ng/mg; 95% CI, 0.14 to 1.32; p=0.018). There were no differences in the other urinary biomarkers. There was normal circadian rhythm in 7/11 participants (64%). CONCLUSIONS: Renal elimination of tobramycin was not affected by the time of day of administration. Urinary KIM-1 raises the possibility of greater nephrotoxicity with evening administration. Four children showed disturbed circadian rhythm and high melatonin levels (ClinicalTrials.gov NCT01207245).

[Reference values for arterial oxygen content]. / Referenzwerte für den arteriellen Sauerstoffgehalt.

BACKGROUND: In clinical practice, oxygen saturation as measured by photoplethysmography and arterial oxygen tension as determined by blood gas analysis are the parameters used frequently to estimate the oxygen status of a patient. Additionally, the cardiac output CO and the arterial oxygen content CaO2 are critical for the delivery of oxygen DO2 to organs and tissues. So far, CaO2 reference values published by Mertzlufft and Zander (1984) and Siggaard-Andersen (1990) are widely used. The aim of the present study was to reevaluate previously published results using the results of a population-based study. Furthermore, the impact of smoking on CaO2 will be assessed. PATIENTS AND METHODS: Data of 1018 volunteers from the Study of Health in Pomerania (SHIP) were analyzed. CaO2 was calculated from blood gas analysis of capillary blood obtained from a hyperemised ear lobe. Reference value equations controlled for sex, age and smoking were derived with quantile regression analysis and fractional polynomials. RESULTS: Lower limits of normal (LLN) decline with age. Current smoking has no significant influence on LLN for CaO2. CONCLUSION: Sex, age and smoking-specific normal values can be calculated using the current equations.

Airflow limitation, lung volumes and systemic inflammation in a general population.

Although several levels of evidence have suggested an association between systemic inflammation and spirometric lung volumes, data addressing the potential interrelationship between airflow limitation and inflammatory markers are sparse and remain controversial. Potential associations between high-sensitivity C-reactive protein (hsCRP), fibrinogen and lung function were investigated in 1,466 individuals aged 25-85 yrs, representing a general population. Within this cross-sectional population, data on body plethysmography, spirometry, helium dilution and diffusing capacity of the lung for carbon monoxide (D(L,CO)) were analysed. After adjustment for potential confounding factors, such as smoking, obesity and cardiorespiratory fitness, there was an inverse association of hsCRP with forced expiratory and static lung volumes. In neither apparently healthy nor the entire population was inflammation associated with airflow limitation in central airways. In smokers only, higher hsCRP and fibrinogen were associated with an impaired D(L,CO). This study shows that higher levels of hsCRP are associated with decreased lung volumes in a general population over a wide age range. A consistent interrelationship of central airflow limitation and inflammation was not verifiable. Smoking is related to an impaired D(L,CO) in association with an increase in systemic inflammation.

Anti-inflammatory properties of montelukast, a leukotriene receptor antagonist in patients with asthma and nasal polyposis.

BACKGROUND: Leukotrienes, especially LTC4, are important inflammatory mediators in allergic and nonallergic inflammation of the entire airways. Of particular interest are numerous theories regarding the pathogenesis of aspirin intolerance with subsequent hyperproduction of leukotrienes and inhibition of cyclooxygenase. OBJECTIVE: To examine the influence of the cysteinyl-leukotriene receptor antagonist montelukast on clinical symptoms and inflammatory markers in nasal lavage fluid in patients with bronchial asthma and nasal polyps, and determine its dependency on aspirin sensitization. METHODS: Twenty-four patients (7 women, 17 men; median age, 55.5 years) with nasal polyps and controlled asthma (n=12 with aspirin intolerance) were treated with 10 mg montelukast once daily for 6 weeks in a blinded, placebo-controlled fashion. The placebo phase was randomly assigned 4 weeks before (n=12) or after treatment (n=12). Symptom score, rhinoendoscopy, rhinomanometry, smears for eosinophils, and nasal lavages for the determination of different mediators were performed. RESULTS: Compared to placebo, there were significant improvements in the nasal symptom score and airflow limitation as well as a reduction in the inflammatory mediators in nasal lavage fluid after treatment. Furthermore, reduced eosinophils in nasal smears and peripheral blood were observed 2 and 6 weeks after treatment. CONCLUSION: Leukotriene 1 receptor blockade led to a significant decrease in eosinophil inflammation accompanied by a reduction in other mediators such as neurokinin A and substance P in the nasal lavage fluid of patients with nasal polyps and asthma, with or without aspirin intolerance.

Catheter-associated aspergillosis of the chest wall following allogeneic hematopoietic stem cell transplantation.

Invasive aspergillosis (IA) at the insertion site of central venous catheters is a rare event. Here we report the occurrence of chest wall aspergillosis at the insertion site of a Broviac catheter in a 5-year-old child undergoing allogeneic hematopoietic stem cell transplantation. The infection arose during profound granulocytopenia under conditions of reverse isolation with laminar air flow and high efficiency particulate air filtration and was successfully managed with repeat surgical debridement, voriconazole/caspofungin combination therapy guided by therapeutic drug monitoring, and adjunctive use of granulocyte colony-stimulating factor. The case reflects the occurrence of IA despite reverse isolation and air decontamination, the principles of treatment of Aspergillus soft tissue infections in granulocytopenic patients, and the need for therapeutic drug monitoring of voriconazole particularly in young children.

Comorbidity as a prognostic variable in multiple myeloma: comparative evaluation of common comorbidity scores and use of a novel MM-comorbidity score.

Comorbidities have been demonstrated to affect progression-free survival (PFS) and overall survival (OS), although their impact in multiple myeloma (MM) patients is as yet unsettled. We (1) assessed various comorbidities, (2) compared established comorbidity indices (CIs; Charlson comorbidity index (CCI), hematopoietic cell transplantation-specific comorbidity index (HCT-CI)), Kaplan Feinstein (KF) and Satariano index (SI) and (3) developed a MM-CI (Freiburger comorbidity index, FCI) in 127 MM patients. Univariate analysis determined moderate or severe pulmonary disease (hazard ratio (HR): 3.5, P<0.0001), renal impairment (via estimated glomerular filtration rate (eGFR); HR: 3.4, P=0.0018), decreased Karnofsky Performance Status (KPS, HR: 2.7, P=0.0004) and age (HR: 2, P=0.0114) as most important variables for diminished OS. Through multivariate analysis, the eGFR ⩽30 ml/min/1.73m(2), impaired lung function and KPS ⩽70% were significant for decreased OS, with HRs of 2.9, 2.8 and 2.2, respectively. Combination of these risk factors within the FCI identified significantly different median OS rates of 118, 53 and 25 months with 0, 1 and 2 or 3 risk factors, respectively, (P<0.005). In light of our study, comorbidities are critical prognostic determinants for diminished PFS and OS. Moreover, comorbidity scores are important treatment decision tools and will be valuable to implement into future analyses and clinical trials in MM.

Resting alveolar gas tensions as a mortality prognosticator in chronic heart failure.

BACKGROUND: Increased end-tidal oxygen (ET-O(2)) and decreased end-tidal carbon dioxide (ET-CO(2)) gas tensions are noninvasively measurable correlates of ventilatory inefficiency, leading to increased ventilatory requirements relative to gas exchange among patients with chronic heart failure (CHF). We investigated the prognostic value of ET-O(2) and ET-CO(2) as predictors of CHF mortality. METHODS: We measured resting ET-O(2) and ET-CO(2) electrochemically in 134 patients with symptomatic CHF in the supine position. We used Kaplan-Meier analysis, Cox proportional hazard models, and receiver operating characteristic curves to test our hypothesis. RESULTS: At a median follow-up of 16.5 months, 32 patients had died. ET-O(2) levels were increased (P = .001) and ET-CO(2) levels decreased (P = .002) with increased New York Heart Association class (I-IV). Survivors showed lower ET-O(2) (121 vs 118 mm Hg; P = .021) and higher ET-CO(2) (33.2 vs 32.1 mm Hg; P = .032) levels than nonsurvivors. Patients with ET-O(2) values ≥121 mm Hg and/or ET-CO(2) values <31 mm Hg had an increased risk of death with hazard ratios of 2.93 (95% confidence interval [CI], 1.43-6.01) and 2.47 (95% CI, 1.23-4.97), respectively. Kaplan-Meier estimates for follow-up mortality with ET-O(2) ≥121 mm Hg and/or ET-CO(2) <31 mm Hg were 83.8% (vs 60.1%; P = .0014) and 80.3% (vs 60.2%; P = .0061), respectively. Areas under the receiver operating characteristic curves for prediction of death with ET-O(2) and ET-CO(2) were both significant and similar to that of echocardiographic left ventricular function. CONCLUSIONS: In CHF, high levels of ET-O(2) and low levels of ET-CO(2) are associated with increased mortality. We suggest that the measurements may be useful prognostic markers for risk stratification.

Effect of fluticasone on neuropeptides in nasal lavage in persistent allergic rhinitis.

OBJECTIVE: Recent guidelines reveal that allergic rhinitis impairs quality of life. Neuropeptides play a central role in allergy-related nasal inflammation. The objective of this study was to analyze the release of neuropeptides (substance P, neurokinin A, and vasoactive intestinal peptide) in nasal lavage and their modification by intranasal fluticasone propionate as an established therapy in patients with allergic rhinitis. METHODS: Eleven patients with proven allergic rhinitis induced by house dust mite were challenged before and after administration of fluticasone propionate nasal spray. Nasal lavage samples were collected after allergen challenge, and neuropeptides were measured using enzyme-linked immunosorbent assay. Values for histamine, protein, and human serum albumin were also recorded. Eight healthy individuals were included as nonatopic controls. RESULTS: The neuropeptides investigated were detectable in nasal lavage fluid in both patients and controls. Treatment with fluticasone propionate significantly decreased clinical response to allergen challenge (P < .01) compared with the controls and led to a decrease in values for substance P, neurokinin A, vasoactive intestinal peptide, histamine release, human serum albumin, and total protein after allergen challenge (P < .01). CONCLUSIONS: The demonstration of proinflammatory neuropeptides in NAL and suppression of their release after allergen challenge caused by a topical corticosteroid suggest a role for neuropeptides in allergic inflammation. Diminished release of neuropeptides induced b fluticasone propionate was accompanied by an improvement in the clinical symptoms of patients with persistent allergic rhinitis.

[Gastric metastasis from small cell lung cancer]. / Magenmetastasierung eines kleinzelligen Bronchialkarzinoms.

Small cell carcinomas are most frequently localised within the lung, however, they also may be detected at extrapulmonary sites such as the gastrointestinal tract and the genitourinary tract. The confirmation of a small cell carcinoma outside of the lung may not necessarily indicate the presence of a metastasis, however, it also may represent the primary tumor itself. We present the case of a patient with a small cell carcinoma of the lung with metastases to the stomach. A regression of the primary lung tumor and the disappearance of the gastric metastases could be achieved by chemotherapeutic treatment with carboplatin, etoposide, and vincristine. However, death due to pneumonia occurred 3 months after initial diagnosis. This case illustrates that in rare cases a metastasis from small cell lung cancer may occur in the intestinal tract even without leading to distinctive symptoms.