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The mortality of patients with sepsis and septic shock is still unacceptably high. An effective antibiotic treatment within 1 h of recognition of sepsis is an important target of sepsis treatment. Delays lead to an increase in mortality;therefore, structured treatment concepts form a rational foundation, taking relevant diagnostic and treatment steps into consideration. In addition to the assumed focus and individual risks of each patient, local resistance patterns and specific problem pathogens must be taken into account for selection of anti-infection treatment. Many pathophysiological alterations influence the pharmacokinetics of antibiotics during sepsis. The principle of standard dosing should be abandoned and replaced by an individual treatment approach with stronger weighting of the pharmacokinetics/pharmacodynamics (PK/PD) index of the substance groups. Although this is not yet the clinical standard, prolonged (or continuous) infusion of beta-lactam antibiotics and therapeutic drug monitoring (TDM) can help to achieve defined PK targets. Prolonged infusion is sufficient without TDM but for continuous infusion TDM is basically necessary. A further argument for individual PK/PD-oriented antibiotic approaches is the increasing number of infections due to multidrug resistant pathogens (MDR) in the intensive care unit. For effective treatment antibiotic stewardship teams (ABS team) are becoming more established. Interdisciplinary cooperation of the ABS team with infectiologists, microbiologists and clinical pharmacists leads not only to a rational administration of antibiotics but also has a positive influence on the outcome. The gold standards for pathogen detection are still culture-based detection and microbiological resistance testing for the various antibiotic groups. Despite the rapid investigation time, novel polymerase chain reaction (PCR)-based procedures for pathogen identification and resistance determination, are currently only an adjunct to routine sepsis diagnostics due to the limited number of studies, high costs and limited availability. In complicated septic courses with multiple anti-infective treatment or recurrent sepsis, PCR-based procedures can be used in addition to therapy monitoring and diagnostics. Novel antibiotics represent potent alternatives in the treatment of MDR infections. Due to the often defined spectrum of pathogens and the practically absent resistance, they are suitable for targeted treatment of severe MDR infections (therapy escalation).

Epidemiologische Studien der letzten Jahre belegen sowohl eine steigende Inzidenz invasiver Pilzinfektionen als auch ein zunehmendes Problem mit Therapieversagen auf Intensivstationen. In bis zu 70 % der Falle zeigt sich ein Nichtansprechen der primaren antimykotischen Therapie abhangig von der auslosenden Spezies bzw. von vorliegenden Grunderkrankungen. Der vorliegende Review-Beitrag soll fur das Thema des Therapieversagens sensibilisieren, die klinischen Umstande des Therapieversagens beschreiben sowie ein systematisches Vorgehen bei Verdacht auf ein Scheitern der primaren antimykotischen Therapie vorschlagen.

Objective of the study The purpose of this prospective intervention study was to assess the number of patients with Y-site incompatibilities before and after implementation of quality improvement measures to prevent incompatibilities consisting of a focused instruction for pantoprazole as a drug frequently involved in incompatible drug pairs and of a recommendation to use 4-lumen instead of 3-lumen catheters to increase the number of available central infusion lines. Setting Cardiovascular intensive care unit where several standard operating procedures (SOPs) dealing with compatibility were already in place. Method In a prospective intervention study, patients’ IV medication was assessed for potential incompatibilities using a database containing compatibility information on approximately 60,000 drug pairs. In a first period, routine administration was monitored in 53 consecutive patients (control group). Then, quality improvement measures were implemented recommending a purging procedure before and after bolus administration of pantoprazole as a drug frequently causing incompatibilities in this setting. Additionally, the use of 4-lumen instead of 3-lumen catheters was suggested whenever considered useful by the responsible physicians. The monitoring was repeated during a second period in another 58 patients consecutively admitted to the same unit (intervention group). Main outcome measure Overall number of patients with at least one incompatible drug pair and number of patients receiving incompatible pantoprazole combinations. Results The number of patients receiving incompatible pantoprazole combinations decreased from 15 of the 15 patients receiving pantoprazole (100.0%) in controls to 9/16 (56.2%) in the intervention group (P < 0.01). The overall number of patients with incompatibilities was not influenced by the intervention with 36/58 (62.1%) compared to controls with 38/53 (71.7%, P = 0.28). The fraction of central lines contributed by four lumen central catheters was larger due to the intervention (80/168 lines, 47.6%) compared to controls (16/184, 8.7%, P < 0.001). Only sporadically there were incompatible combinations of drugs governed by the already existing SOPs. Conclusion In an intensive care setting with good SOP adherence, purging before and after administration decreased the respective incompatibility rate whereas the use of 4-lumen instead of 3- lumen catheters had not the expected benefit on separating drug pairs.

Given the high incidence (1.5%–10%) of invasive aspergillosis (IA) after liver transplantation and the associated mortality, prophylaxis according to the patients’ circumstances is a reasonable approach. The purpose of this investigation was to determine the effect and significance of risk factors for IA in a specialized transplantation center. We collected data from patients who underwent liver transplantation at the Transplantation Center of the University Hospital Heidelberg (Germany) between December 2001 and December 2004 in a specifically designed database for retrospective analysis. Invasive aspergillosiswas defined according to the European Organization for Research and Treatment of Cancer classifications. Univariate analysis and logistic regression were performed to assess the influence of each assumed risk factor. A total of 195 liver transplantationswere performed in 170 patients, with two patients (1.2%) developing a proven IA, seven (4.1%) developing a probable IA, and five developing a possible IA (2.9%). All patients received oral itraconazole prophylaxis. Of these 14 patients with proven, probable or possible IA, 13 died within 4 weeks after the initial diagnosis; this represents 33.3% of all patients with a fatal outcome. Univariate significant factors were retransplantation (p = 0.004), cytomegalovirus (CMV) infection (p = 0.024), dialysis (p < 0.001), renal insufficiency (p = 0.05), thrombocytopenia (p = 0.001), and leukocytopenia (p = 0.002). Multivariate analysis showed an independent influence of CMV infection (OR 6.032, 95% CI 1.446–25.163) and dialysis (OR 14.985, 95%CI 2.936–76.486). The rate of IA found in this investigation is within the range reported in published studies. Based on our data, extended antifungal prophylaxis should be given to liver transplant patients with specific risk factors, such as renal insufficiency, requirement for dialysis, CMV infection, or thrombocytopenia. Additional focus should be on the prevention of CMV infections.

Objective Medication errors are frequent in a hospital setting and often caused by inappropriate drug handling. Systematic strategies for their prevention however are still lacking. We developed and applied a classification model to categorise medication handling errors and defined the urgency of correction on the basis of these findings. Setting Nurses on medical wards (including intensive and intermediate care units) of a 1,680-bed teaching hospital. Method In a prospective observational study we evaluated the prevalence of 20 predefined medication handling errors on the ward. In a concurrent questionnaire survey, we assessed the knowledge of the nurses on medication handling. The severity of errors observed in individual areas was scored considering prevalence, potential risk of an error, and the involved drug. These scores and the prevalence of corresponding knowledge deficits were used to define the urgency of preventive strategies according to a four-field decision matrix. Main outcome measure Prevalence and potential risk of medication handling errors, corresponding knowledge deficits in nurses committing the errors, and priority of quality improvement. Results In 1,376 observed processes 833 medication handling errors were detected. Errors concerning preparation (mean 0.88 errors per observed process [95% CI: 0.81–0.96], N = 645) were more frequent than administration errors (0.36 [0.32–0.41], N = 701, P

Changes in drug treatment are frequently mandatory with hospital admission and discharge because hospital drug formularies are generally restricted to about 3000 drugs as compared to the many times this number – 62,000 in Germany – that are commercially available. Without computerised support, the process involved with switching drugs to a corresponding generic or a therapeutic equivalent is time-consuming and error-prone. We have developed and tested a standardised interchange algorithm for subsequent implementation into a computerised decision support system that switches drugs to the corresponding generic or a therapeutic equivalent if they are not listed on the hospital drug formulary. The algorithm was retrospectively applied to the medication regimens of 120 patients (774 prescribed drugs containing 886 active ingredients) at their time of admission to surgical wards. Of the prescribed drugs, 52.8% (409/774) were part of the hospital drug formulary, thereby rendering a switch unnecessary. The 365 drugs not listed consisted of 392 active ingredients that were successfully switched to a corresponding generic (84.7%) or a therapeutic equivalent (10.2%). No specific switching procedures were defined for only 2.3% (20/886) of the active ingredients. In these cases, the drugs were either discontinued (4/20) or special drug classes, current diseases or co-medication required manual switching (8/20), or the drugs were continued unchanged and ordered from a wholesaler (8/20). Using a standardised interchange algorithm, pre-admission drug regimens can successfully be switched to drugs on a hospital drug formulary. These findings suggest that a computerised decision support system will likely be useful to support this important practice.

Die effektive Antibiotikabehandlung stellt neben der chirurgischen Sanierung einen der Eckpfeiler des therapeutischen Managements von Patienten mit postoperativer Sepsis dar. Die initiale Wahl und der fruhe Zeitpunkt der antimikrobiellen Therapie sind fur den Ausgang einer komplizierten intraabdominellen Infektion hochst entscheidend, da eine nichtadaquate Antibiotikatherapie zu verzogerter Heilung, langerem Krankenhausaufenthalt und hoherer Letalitat fuhrt. Tigecyclin ist eine wichtige therapeutische Option in der Behandlung von Infektionen, die durch multiresistente grampositive und gramnegative Erreger, einschlieslich Vancomycin-resistenter Enterokokken (VRE), verursacht werden. Eine grose randomisierte Studie (Patienten mit APACHE-II-Score >30 ausgeschlossen, durchschnittlicher APACHE-II-Score 6) konnte zeigen, dass Tigecyclin dem Imipenem/Cilastatin in der Behandlung von komplizierten intraabdominellen Infektionen nicht unterlegen ist. Jedoch ist bisher kein Fall mit septischem Schock, verursacht durch VRE, und klinischer Heilung berichtet. Im Folgenden wird der Fall eines Patienten mit postoperativer Peritonitis und schwerem septischen Schock (APACHE-II-Score 34) berichtet. Die chirurgische Sanierung beinhaltete das Einlegen von Spuldrainagen. Aufgrund des mikrobiologischen Befundes wurde antibiogrammgerecht eine Monotherapie mit Tigecyclin durchgefuhrt, die zu einem klinischen Erfolg fuhrte. Tigecyclin stellt eine neue Therapiealternative bei intraabdominellen Infektionen dar und ist als Monotherapie aus medizinokonomischer Sicht interessant.

The combination of chloroquine and methylene blue is potentially effective for the treatment of chloroquine-resistant malaria caused by Plasmodium falciparum. The aim of this study was to investigate whether methylene blue influences the pharmacokinetics of chloroquine.In a randomized, placebo-controlled, parallel group design, a 3-day course of therapeutic oral doses of chloroquine (total 2.5 g in male, 1.875 g in female participants) with oral co-administration of placebo or 130 mg methylene blue twice daily for 3 days was administered to 24 healthy individuals. Chloroquine, desethylchloroquine, and methylene blue concentrations were determined by means of HPLC/UV or LC/MS/MS assays in whole blood, plasma, and urine for 28 days after the last dose.During methylene blue exposure, the area under the chloroquine whole blood concentration-time curve normalized to body weight (AUC(0-24 h)/BW) yielded a trend of reduction (249+/-98.2 h mug l(-1) kg(-1) versus 315+/-65.0 h mug l(-1) kg(-1), P=0.06). The AUC(0-24 h)/BW of desethylchloroquine was reduced by 35% (104+/-40.3 h mug l(-1) kg(-1) versus 159+/-66.6 h mug l(-1) kg(-1), P=0.03), whereas the metabolic ratio between chloroquine and desethylchloroquine remained unchanged (2.25+/-0.49 versus 1.95+/-0.42, P=0.17). The renal clearance of chloroquine and the ratio between chloroquine in whole blood and plasma remained unchanged (P0.1).Oral co-administration of methylene blue appears to result in a small reduction of chloroquine exposure which is not expected to be clinically relevant and thus represents no concern for further development as an anti-malarial combination.

Background There is concern about an increasing infiltration of markets by substandard and fake medications against life-threatening diseases in developing countries. This is particularly worrying with regard to the increasing resistance development of Plasmodium falciparum against affordable anti-malarial medications, which has led to a change to more expensive drugs in most endemic countries. Methods A representative sample of modern anti-malarial medications from licensed (public and private pharmacies, community health workers) and illicit (market and street vendors, shops) sources has been collected in the Nouna Health District in north-western Burkina Faso in 2006. All drugs were tested for their quality with the standard procedures of the German Pharma Health Fund-Minilab. Detected low standard drugs were re-tested with European Pharmacopoeia 2.9.1 standards for disintegration and ultraviolet-visible spectroscopy at the laboratory of the Heidelberg University for confirmation. Results Overall, 86 anti-malarial drug samples were collected, of which 77 samples have been included in the final analysis. The sample consisted of 39/77 (50%) chloroquine, 10/77 (13%) pyrimethamine-sulphadoxine, 9/77 (12%) quinine, 6/77 (8%) amodiaquine, 9/77 (12%) artesunate, and 4/77 (5%) artemether-lumefantrine. 32/77 (42%) drug samples were found to be of poor quality, of which 28 samples failed the visual inspection, nine samples had substandard concentrations of the active ingredient, four samples showed poor disintegration, and one sample contained non of the stated active ingredient. The licensed and the illicit market contributed 5/47 (10.6%) and 27/30 (90.0%) samples of substandard drugs respectively. Conclusion These findings provide further evidence for the wide-spread existence of substandard anti-malarial medications in Africa and call for strengthening of the regulatory and quality control capacity of affected countries, particularly in view of the now wider available and substantially more costly artemisinin-based combination therapies.