Holger Knoth

Hospital use of systemic antifungal drugs

BackgroundSales data indicate a major increase in the prescription of antifungal drugs in the last two decades. Many new agents for systemic use that only recently have become available are likely to be prescribed intensively in acute care hospitals. Sales data do not adequately describe the developments of drug use density. Given the concerns about the potential emergence of antifungal drug resistance, data on drug use density, however, may be valuable and are needed for analyses of the relationship between drug use and antifungal resistance.MethodsHospital pharmacy records for the years 2001 to 2003 were evaluated, and the number of prescribed daily doses (PDD, defined according to locally used doses) per 100 patient days were calculated to compare systemic antifungal drug use density in different medical and surgical service areas between five state university hospitals.ResultsThe 3-year averages in recent antifungal drug use for the five hospitals ranged between 8.6 and 29.3 PDD/100 patient days in the medical services (including subspecialties and intensive care), and between 1.1 and 4.0 PDD/100 patient days in the surgical services, respectively. In all five hospitals, systemic antifungal drug use was higher in the hematology-oncology service areas (mean, 48.4, range, 24 to 101 PDD/100 patient days, data for the year 2003) than in the medical intensive care units (mean, 18.3, range, 10 to 33 PDD/100) or in the surgical intensive care units (mean, 10.7, range, 6 to 18 PDD/100). Fluconazole was the most prescribed antifungal drug in all areas. In 2003, amphotericin B consumption had declined to 3 PDD/100 in the hematology-oncology areas while voriconazole use had increased to 10 PDD/100 in 2003.ConclusionHematology-oncology services are intense antifungal drug prescribing areas. Fluconazole and other azol antifungal drugs are the most prescribed drugs in all patient care areas while amphotericin B use has considerably decreased. The data may be useful as a benchmark for focused interventions to improve prescribing quality.

Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial

In patients with relapsed or refractory (r/r) acute myeloid leukemia (AML), long-term disease control can only be achieved by allogeneic hematopoietic stem cell transplantation (HSCT). We studied the safety and efficacy of clofarabine-based salvage therapy. The study was designed as phase II, multicenter, intent-to-transplant (ITT) study. A total of 84 patients with r/r AML were enrolled. All patients received at least one cycle of CLARA (clofarabine 30 mg/m2 and cytarabine 1 g/m2, days 1–5). Chemo-responsive patients with a donor received HSCT in aplasia after first CLARA. Generally, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine (4 × 30 mg/m2) and melphalan (140 mg/m2). The median patient age was 61 years (range 40–75). On day 15 after start of CLARA, 26% of patients were in a morphologically leukemia-free state and 79% exposed a reduction in bone marrow blasts. Overall, 67% of the patients received HSCT within the trial. The primary end point, defined as complete remission after HSCT, was achieved by 60% of the patients. According to the ITT, overall survival at 2 years was 43% (95% confidence interval (CI), 32–54%). The 2-year disease-free survival for transplanted patients was 52% (95% CI, 40–69%). Clofarabine-based salvage therapy combined with allogeneic HSCT in aplasia shows promising results in patients with r/r AML.

Drug retention by inline filters – Effect of positively charged polyethersulfone filter membranes on drug solutions with low concentration

OBJECTIVE The use of infusion filters in pediatrics is controversially discussed. Their application is an excellent opportunity to prevent complications, but there are researchers, who do not see any advantage in using inline filters. This paper describes the interaction of five different drugs with a positively charged as opposed to an uncharged polyethersulfone (PES(+) versus PES(0)) membrane. METHODS To measure the extent and the mechanism of interaction, PES(+) versus PES(0) membranes and furosemide sodium, potassium canrenoate, digitoxin, digoxin and adenosine, each 30μmol/l, were investigated. Salt ions with different hydrodynamic radii and different concentrations have been used in the eluents. RESULTS During furosemide sodium and potassium canrenoate filtration with PES(+), the onset of UV absorption depends on the electrolyte concentration in the eluent: the lower the electrolyte concentration the later the onset of UV absorption. A correlation between the hydrodynamic volume of the different salt ions used and the onset of UV absorption could be proven for both substances: The larger the hydrodynamic volume of the extrinsic ion, the later the onset of the UV absorption if the same electrolyte concentration was used. Due to a higher structural density of PES(+) than PES(0) a delayed onset of UV absorption during filtration of digitoxin and digoxin with the PES(+) membrane could be observed. No correlation between the hydrodynamic volume of the different salt ions used and the onset of UV absorption could be seen. With adenosine neither the filter type nor the electrolyte concentration or the hydrodynamic volume of the salt ions had an influence on the onset time of absorption. CONCLUSION The results obtained with the anionic drugs investigated are particularly relevant if low drug concentrations in a saltless infusion solution are applied in combination with a charged filter membrane. Therefore, for each infusion formulation, a careful selection of the filter material is essential.

Simultaneous determination of clofarabine and cytarabine in human plasma by LC–MS/MS

Combination of cytostatic agents is a basic principle in the treatment of cancer. For the treatment of acute myeloid leukemia (AML), purine analogs, like clofarabine and cytarabine act synergistically. Little is known, however, on their interaction in vivo. We developed a method for the simultaneous determination of clofarabine and cytarabine in human plasma. The substances were extracted from plasma samples by protein precipitation with acetonitrile. Cladribine was the internal standard (IS). The analytes were separated on Synergi HydroRP column (150mm×2.0mm, 4μm) and a triple-quadrupole mass spectrometry with an electrospray ionisation (ESI) source was applied for detection. The mobile phase consisted of acetonitrile, ammonium acetate 2mM and 0.5% formic acid in a gradient mode at a flow rate of 0.5ml/min. The injection volume was 10μl and the total run time was 6.0min. Retention times were 2.46min for clofarabine, 0.97min for cytarabine and 2.43min for the IS. Calibration ranges were 8-1000ng/ml for clofarabine and 20-2500ng/ml for cytarabine. The intra-day and inter-day precision was less than 15% and the relative standard deviation was all within ±15%. This new method allows a rapid and simple determination of both clofarabine and cytarabine in human plasma. It was applied to a pharmacokinetic investigation within a hematological trial in adult patients with AML.

Validation of adapted daily dose definitions for hospital antibacterial drug use evaluation: a multicentre study

Background The WHO/ATC (Anatomical Therapeutic Chemical) index DDD (WHO-DDD) is commonly used for drug consumption measurement. Discrepancies between WHO-DDD and actual prescribed daily doses (PDD) in hospitals have prompted alternative dose definitions adapted to doses recommended in hospital practice guidelines [recommended daily doses (RDD)]. Methods In order to validate RDD we performed modified point prevalence surveys in 24 acute care hospitals and recorded 20620 PDD of antibiotics given to 4226 adult patients on the day of the survey and the 6 preceding days. We calculated RDD and WHO-DDD and compared them with PDD. Results The rate of RDD corresponding to PDD was higher than the corresponding rate for WHO-DDD (pooled data, 55% versus 30%) and the differences were similar across the hospital sample, but varied according to drug/drug class, route of administration, indication and renal function. RDD underestimated actual consumption by 14% overall, while WHO-DDD overestimated total antibacterial consumption by 28% (pooled data; median values RDD -10% versus WHO-DDD +32%). The deviations of estimated from actual drug use volumes were largest for β-lactams (RDD -11% versus WHO-DDD +49%), in particular for penicillins (-11% versus +64%), if WHO-DDD were used. Conclusions Hospital antibiotic consumption surveillance systems using current WHO-DDD should address the uneven discrepancies between actual prescribing and consumption estimates according to drug class that may lead to misclassification in benchmark analyses. We recommend using validated RDD as a supplementary measure to the WHO-DDD for detailed analyses.

Positively Charged Polyethersulfone Membranes: The Influence of Furosemide on the Zeta Potential

The aim of the present work is to measure changes in the Zeta potential of uncharged (PES0) and positively charged (PES+) polyethersulfone membranes, and to investigate their chemical composition. Endotoxin-retentive filters with a 0.2 μm PES0 and PES+ membranes are used for filtration of a furosemide sodium solution, with an increasing concentration up to 60 μmol/l. To analyze the chemical composition of both membranes, X-Ray photoelectron spectroscopy (XPS) was used. The Zeta potential was determined by a streaming current electrokinetic analyzer. The positive charge of the PES+ membrane corresponding to a positive Zeta potential decreased with increasing furosemide sodium concentration. In contrast, the Zeta potential of PES0 membranes hardly changes with increasing drug concentration. XPS allows the determination of the chemical composition of the investigated membranes. Both membranes only contain oxygen, carbon, sulfur and nitrogen. On the surface of the PES+ membrane, the positive charge is caused by ammonium nitrogen. No ionic additives could be detected. The manufacturer’s intended period of PES+ filter use (96 h), should only be applied to nonionic infusion solutions. Hence, information should be given on the maximum period of filter use, if ionic infusion solutions are applied.

Long-Term Follow-Up and Impact of Comorbidity before Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed or Refractory Acute Myeloid Leukemia—Lessons Learned from the Prospective BRIDGE Trial

In patients with relapsed or refractory (r/r) acute myeloid leukemia (AML), allogeneic hematopoietic stem cell transplantation (HSCT) is considered to be the only treatment providing long-term disease control. The BRIDGE trial studied the safety and efficacy of a clofarabine-based salvage therapy before HSCT in patients with r/r AML. Here, we report the long-term follow-up of this phase II multicenter trial and exploratory analyses on the impact of comorbidity on outcome. Eighty-four patients with a median age of 61 years (range, 40 to 75) were enrolled. Patients were scheduled for at least 1 cycle of salvage therapy with CLARA (clofarabine 30 mg/m2; cytarabine 1 g/m2, days 1 to 5). Chemo-responsive patients with a donor received HSCT after first CLARA. The conditioning regimen consisted of clofarabine 30 mg/m2, day -6 to -3, and melphalan 140 mg/m2 day -2. The Eastern Cooperative Oncology Group (ECOG) score, the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), and the Cumulative Illness Rating Scale were obtained at study enrollment as well as before HSCT. Sixty-seven percent of the patients received HSCT within the trial. After a median follow up of 40 months, the estimated 3-year overall survival (OS) for all enrolled patients and those with HSCT within the trial was 40% and 55%, respectively. Relapse-free survival for patients who underwent transplantation with a complete remission afterwards (n = 50) was 48%, calculated from the day of transplantation. In multivariate analysis, both the HCT-CI and ECOG score had a statistically significant impact on OS with a hazard ratio of 1.22 (P = .025)and 1.72 (P = .001), respectively. Using a clofarabine-based salvage therapy combined with early allogeneic HSCT, we were able to achieve good long-term results for patients with r/r AML. In this cohort, both the HCT-CI and the ECOG scores gave prognostic information on OS, showing the feasibility and clinical relevance of comorbidity evaluation at the time of diagnosis of r/r AML patients.

Antibiotikaeintrag in das urbane Abwasser

Antibiotics are essential for the successful treatment of bacterial infections. Recently, the increasing number of resistant bacteria and the occurrence of residues of antibiotics in the environment has become the focus of scientific interest. The aim of the cooperative project ANTI-Resist was to investigate the release of antibiotics and the occurrence and distribution of antibiotic resistance in the urban waste water system of the city of Dresden.This article presents the main results of the secondary data analysis for the determination of outpatient and inpatient antibiotic consumption and provides an insight into the complexity of the topic antibiotics in waste water.Based on the data of outpatient prescriptions provided by the AOK PLUS for the period 2005 to 2013, thirteen focus substances were identified to estimate antibiotic consumption. Furthermore, delivery data from the pharmacies of three hospitals in Dresden were available.Depending on the substances investigated, seasonality and age dependency were determined. The results at a regional level were mostly in good accordance with general trends throughout Germany. It should be noted that the total amount of antibiotics used remained nearly constant over the whole period investigated, but the prescription of fluoroquinolones increased. This must be questioned when taking into account the increasingly critical situation in the treatment of Gram-negative bacteria in particular. Examinations of waste water conducted indicated that sewage treatment plants are not able to remove antibiotics or their metabolites completely from waste water. The residues are released into surface waters via the treatment plants. The impact cannot be assessed at the moment and further investigations are necessary.ZusammenfassungAntibiotika sind zur erfolgreichen Behandlung bakterieller Infektionen unerlässlich. Zuletzt sind jedoch die zunehmende Resistenzproblematik und die Auswirkungen von Antibiotikarückständen in der Umwelt in den wissenschaftlichen Fokus gerückt. Ziel des hier vorgestellten ANTI-Resist-Verbundprojekts war die Untersuchung von Antibiotikaeinträgen und die Analyse der Bildung und Verbreitung von Antibiotikaresistenzen im urbanen Abwassersystem der Stadt Dresden. Der vorliegende Beitrag stellt zentrale Ergebnisse der Sekundärdatenanalyse zur Ermittlung des ambulanten und stationären Antibiotikaverbrauchs vor und gibt einen Einblick in die Komplexität der Thematik Antibiotika im Abwasser. Auf Basis der ambulanten Verschreibungsdaten der AOK PLUS für den Zeitraum 2005 bis 2013 wurden 13 Fokussubstanzen identifiziert, um den Antibiotikaverbrauch abzuschätzen. Außerdem standen Lieferdaten von Krankenhausapotheken dreier Krankenhäuser in Dresden zur Verfügung. Je nach den betrachteten Substanzen konnten Saisonalitäten und Altersabhängigkeiten festgestellt werden. Die Ergebnisse auf regionaler Ebene decken sich überwiegend mit bundesweiten Trends. Dabei ist festzustellen, dass der Antibiotikaeinsatz insgesamt über den betrachten Zeitraum hinweg konstant bleibt, die Verschreibung von Fluorchinolonen jedoch zunimmt. Vor dem Hintergrund der vor allem im gram-negativen Bereich zunehmenden Resistenzsituation sind diese Befunde besonders kritisch zu hinterfragen. Durchgeführte Abwasseranalysen konnten zeigen, dass Kläranlagen nicht dazu geeignet sind, Antibiotika und deren Metabolite vollständig aus dem Abwasser zu entfernen. Über die Kläranlage gelangen die Rückstände in Oberflächengewässer. Die genauen Auswirkungen sind derzeit noch nicht absehbar und müssen weiter untersucht werden.AbstractAntibiotics are essential for the successful treatment of bacterial infections. Recently, the increasing number of resistant bacteria and the occurrence of residues of antibiotics in the environment has become the focus of scientific interest. The aim of the cooperative project ANTI-Resist was to investigate the release of antibiotics and the occurrence and distribution of antibiotic resistance in the urban waste water system of the city of Dresden.This article presents the main results of the secondary data analysis for the determination of outpatient and inpatient antibiotic consumption and provides an insight into the complexity of the topic antibiotics in waste water.Based on the data of outpatient prescriptions provided by the AOK PLUS for the period 2005 to 2013, thirteen focus substances were identified to estimate antibiotic consumption. Furthermore, delivery data from the pharmacies of three hospitals in Dresden were available.Depending on the substances investigated, seasonality and age dependency were determined. The results at a regional level were mostly in good accordance with general trends throughout Germany. It should be noted that the total amount of antibiotics used remained nearly constant over the whole period investigated, but the prescription of fluoroquinolones increased. This must be questioned when taking into account the increasingly critical situation in the treatment of Gram-negative bacteria in particular. Examinations of waste water conducted indicated that sewage treatment plants are not able to remove antibiotics or their metabolites completely from waste water. The residues are released into surface waters via the treatment plants. The impact cannot be assessed at the moment and further investigations are necessary.

Contamination of 0.2-micrometer infusion filters by N,N-dimethylacrylamide

PURPOSE Infusion filters, 0.2 mum, are commonly used in intensive care units as in-line filters to minimize particle and microbiological burden on patients. These filters usually contain either a positively charged or an uncharged membrane. The aim of the present study was to identify and to quantify an additive causing an unexpected maximum at 234.5 nm in the ultraviolet spectrum of a filtered drug solution using a filter. MATERIALS AND METHODS For identification and quantification of the substance, water for injection was used as eluent. Measurements were done by mass spectrometry and ultraviolet spectroscopy. RESULTS The unexpected additive in the filter was found to be N,N-dimethylacrylamide. The eluate of 2 filter batches had a mean N,N-dimethylacrylamide concentration of 3.9 and 2.5 microg/mL, respectively. Further investigations showed that after infusion breaks of different duration, the N,N-dimethylacrylamide concentration at the beginning of the next infusion cycle reaches a higher level than that at the end of the preceding infusion cycle. CONCLUSIONS The type of filter examined in this study is primarily used in premature infants, newborns, and infants. These patients are vulnerable to neurotoxic substances having a long-term effect. Therefore, N,N-dimethylacrylamide should be completely removed from the final filter product.

In vitro detection of Candida and Aspergillus antigen in parenteral nutrition and fixed combinations of piperacillin-tazobactam

Screening for Aspergillus (Asp‐AG) and Candida antigen (Ca‐AG) with immunoassays is established for stem cell recipients at high risk for invasive fungal infections (IFI). While parenteral nutrition (PN) will be applied in case of complications leading to insufficient alimentation, piperacillin‐tazobactam (TZP) is started at the onset of febrile neutropenia.