Search

(1) Background: Antibiotic resistance is a worldwide health threat. The WHO published a global strategic plan in 2001 to contain antimicrobial resistance. In the following year, a workshop identified crucial barriers to the implementation of the strategy, e.g., underdeveloped health infrastructures and the scarcity of valid data as well as a lack of implementation of antibiotic stewardship (ABS) programs in medical curricula. Here, we show that interprofessional learning and education can contribute to the optimization of antibiotic use and preserving antibiotic effectiveness. We have initiated interprofessional rounds on a medical intensive care unit (MICU) with a focus on gastroenterology, hepatology, infectious diseases, endocrinology, and liver transplantation. We integrated ICU physicians, hospital pharmacists, nursing staff, and medical students as well as students of pharmacy to broaden the rather technical concept of ABS with an interprofessional approach to conceptualize awareness and behavioral change in antibiotic prescription and use. Methods: Clinical performance data and consumption figures for antibiotics were analyzed over a 10-year period from 2012 to 2021. The control period covered the years 2012–2014. The intervention period comprised the years 2015–2021, following the implementation of an interprofessional approach to ABS at a MICU of a German university hospital. Data from the hospital pharmacy, hospital administration, and hospital information system were included in the analyses. A specific electronic platform was developed for the optimization of documentation, interprofessional learning, education, and sustainability. The years 2020 and 2021 were analyzed independently due to the SARS-CoV-2 pandemic and the care of numerous COVID-19 patients at the MICU. Results: Implementation of an interprofessional ABS program resulted in the optimization of antibiotic management at the MICU. The suggestions of the hospital pharmacist for optimization can be divided into the following categories (i) indication for and selection of therapy (43.6%), (ii) optimization of dosing (27.6%), (iii) drug interactions (9.4%), (iv) side effects (4.1%), and (v) other pharmacokinetic, pharmacodynamic, and pharmacoeconomic topics (15.3%). These suggestions were discussed among the interprofessional team at the MICU; 86.1% were consequently implemented and the prescription of antibiotics was changed. In addition, further analysis of the intensive care German Diagnosis Related Groups (G-DRGs) showed that the case mix points increased significantly by 31.6% during the period under review. Accordingly, the severity of illness of the patients treated at the ICU as measured by the Simplified Acute Physiology Score (SAPS) II increased by 21.4% and the proportion of mechanically ventilated patients exceeded 50%. Antibiotic spending per case mix point was calculated. While spending was EUR 60.22 per case mix point in 2015, this was reduced by 42.9% to EUR 34.37 per case mix point by 2019, following the implementation of the interprofessional ABS program on the MICU. Through close interprofessional collaboration between physicians, hospital pharmacists, and staff nurses, the consumption of broad-spectrum antibiotics, e.g., carbapenems, was significantly reduced, thus improving patient care. In parallel, the case mix and case mix index increased. Thus, the responsible use of resources and high-performance medicine are not contradictory. In our view, close interprofessional and interdisciplinary collaboration between physicians, pharmacists, and nursing staff will be of outstanding importance in the future to prepare health care professionals for global health care to ensure that the effectiveness of our antibiotics is preserved.

In klinischen Studien konnte gezeigt werden, dass eine zu niedrig dosierte antibiotische Therapie das Behandlungsergebnis insbesondere bei Intensivpatienten verschlechtert sowie der Entwicklung von resistenten Erregern Vorschub leistet. Die nach wie vor hohe Mortalität bei schwerer Sepsis von bis zu 80 % verdeutlicht eindringlich die klinische Relevanz dieser Tatsache. Zu hoch dosierte Therapien gefährden hingegen durch Toxizität den Patienten, ohne zusätzlichen antiinfektiven Nutzen zu erzielen. Kritisch kranke Patienten weisen in Folge ihrer schweren Erkrankung eine stark veränderte und variable Pharmakokinetik auf. Da die Standarddosierungen für Antibiotika aus pharmakokinetischen Studien an gesunden Probanden abgeleitet wurden, ist zu hinterfragen, ob mit diesen Dosierungen auch bei Intensivpatienten optimale Wirkspiegel erreicht werden. Die Betalaktam-Antibiotika stellen die in der klinischen Routine am Universitätsklinikum Regensburg am häufigsten eingesetzten Antibiotika dar. Linezolid und Tigecyclin sind wichtige Reserveantibiotika zur Behandlung von Infektionen durch multiresistente grampositive Erreger. Trotz der großen Relevanz dieser Antibiotika für die klinische Praxis ist es bisher am Universitätsklinikum Regensburg nicht möglich, in der klinischen Routine die Plasmakonzentrationen dieser Substanzen im Rahmen eines Therapeutischen-Drug-Monitoring (TDM) zu bestimmen. Zur Bestimmung der o.g. Antibiotika in Plasma wurden isokratische HPLC-Methoden mit UV-photometrischer Detektion entwickelt und validiert. Das chromatographische System bestand aus C18-Kieselgel-Säulen und Mischungen aus Phosphatpuffer und Acetonitril als mobile Phase. Da für die pharmakologische Wirkung eines Arzneistoffs aber nur die freie, nicht an Plasmaproteine gebundene Fraktion zu Verfügung steht, erfolgte auch die Messung freier Konzentrationen. Hierzu wurde eine schnelle und einfache Ultrafiltrationsmethode entwickelt und validiert. Da dass das Ausmaß der Proteinbindung von den experimentellen Bedingungen wie Temperatur, pH-Wert und Zentrifugalkraft beeinflusst werden kann, wurde die Bedeutung dieser Parameter für die gemessene freie Konzentration der untersuchten Substanzen evaluiert. Es konnte gezeigt werden, dass die freie Konzentration substanzspezifisch stark von den experimentellen Bedingungen abhängt. Daher wurde für die Routinemethode zur Bestimmung der freien Konzentration durch Ultrafiltration die Aufrechterhaltung physiologischer Temperatur- und pH-Werte etabliert, d.h. ein pH von 7,4 und 37°C. Das Verfahren war zur zuverlässigen Messung der freien Wirkstoffkonzentrationen gut geeignet. So konnte gezeigt werden, dass die Ultrafiltration eine schnelle, einfache und elegante Methode zur Vorbereitung von Plasma für die HPLC-Analyse darstellt. Die entwickelten Methoden erwiesen sich als hinreichend präzise, sensitiv und selektiv zur Bestimmung der Konzentrationen der Arzneistoffe im Plasma von Intensivpatienten. Die Ergebnisse der klinischen Untersuchung für Meropenem und Piperacillin konnten zeigen, dass bei ca. 50 % der Patienten der PK/PD-Zielparameter einer Plasmakonzentration oberhalb der MHK des Leitkeims Pseudomonas aeruginosa über das gesamte Dosisintervall nicht erreicht wurde. Die gemessenen Spiegel zeigten eine breite Streuung. Beide Faktoren sprechen für die Anwendung modifizierter Dosierungsstrategien, sowie eines TDM zur Optimierung der Dosierung von Antibiotika in der klinischen Routine., Insufficient antibiotic therapy worsens the outcome in patients and promotes the development of resistant organisms, most importantly in ICU patients. The persistently high mortality in severe sepsis of up to 80% vividly illustrates the clinical relevance of an appropriate antibiotic therapy. On the other hand, overdosage jeopardizes the patient by toxicity without additional anti-infective benefits. Due to physiological changes in critical illness, the pharmacokinetics of antibiotics is heavily altered and variable in ICU patients. Since the standard doses for antibiotics are derived from pharmacokinetic studies in healthy volunteers, it is doubtful, whether optimal drug levels can be achieved in intensive care patients with dosing schedules derived from normal patients or even healthy volunteers. The beta-lactam antibiotics represent the most commonly used antibiotics in ICU units. Linezolid and tigecycline are important reserve antibiotics to treat infections caused by multidrug-resistant Gram-positive pathogens. Despite the great importance of these antibiotics for clinical practice, it is so far not possible at the Regensburg University Hospital to determine the plasma concentrations of these substances routinely in the context of a TDM program. In the present work, isocratic HPLC methods with UV spectrophotometric detection were developed and validated to determine the concentration in plasma of the above mentioned antibiotics. The chromatographic system included C18 silicagel columns and phosphate buffer/acetonitrile as mobile phase. As only the free, non-protein bound drug is responsible for the pharmacological effect of a drug, the measurement of free concentrations was carried out. For this purpose, a fast and simple ultrafiltration method has been developed and validated. The extent of protein binding may be influenced by the experimental conditions such as temperature, pH or centrifugal force. Therefore, the importance of these parameters for the measured free concentration was evaluated. It was shown that the measured free concentration was substance specific highly dependent on the experimental conditions. Consequently, an ultrafiltration method was established which maintains physiological conditions i.e. pH 7.4 and 37°C. The method is suitable to reliably measure the free drug concentrations. Moreover, ultrafiltration has been proved to be a fast, simple and elegant method for preparation of plasma prior to HPLC analysis. The developed methods were sufficiently precise, sensitive and selective to determine the concentrations of the drugs in plasma of intensive care patients. The analysis of plasma samples from ICU patients treated with standard doses of meropenem and piperacillin showed that up to 50% of patients did not reach the target concentrations (MIC of Pseudomonas aeruginosa) over the entire dosing interval. Moreover, the measured concentrations showed a wide dispersion. Both factors favor the use of modified dosing strategies as well as TDM in ICU patients to optimize dosage of antibiotics in clinical routine.