dgkh000271 10.3205/dgkh000271 urn:nbn:de:0183-dgkh0002711 Review Article Übersichtsarbeit Surveillance von Blutstrominfektionen in pädiatrischen onkologischen Zentren – was haben wir gelernt und wie soll die weitere Entwicklung aussehen? Simon Simon Arne A

Pädiatrische Onkologie und Hämatologie, Universitätsklinikum des Saarlandes, Kirrberger Str., Geb. 9, 66421 Homburg, GermanyPädiatrische Onkologie und Hämatologie, Universitätsklinikum des Saarlandes, Homburg, Germany

Pädiatrische Onkologie und Hämatologie, Universitätsklinikum des Saarlandes, Kirrberger Str., Geb. 9, 66421 Homburg, DeutschlandPädiatrische Onkologie und Hämatologie, Universitätsklinikum des Saarlandes, Homburg, Deutschland

Arne.Simon@uks.eu author Furtwängler Furtwängler Rhoikos R

Pädiatrische Onkologie und Hämatologie, Universitätsklinikum des Saarlandes, Kirrberger Str., Geb. 9, 66421 Homburg, GermanyPädiatrische Onkologie und Hämatologie, Universitätsklinikum des Saarlandes, Homburg, Germany

Pädiatrische Onkologie und Hämatologie, Universitätsklinikum des Saarlandes, Kirrberger Str., Geb. 9, 66421 Homburg, DeutschlandPädiatrische Onkologie und Hämatologie, Universitätsklinikum des Saarlandes, Homburg, Deutschland

rhoikos.furtwaengler@uks.eu author Graf Graf Norbert N

Pädiatrische Onkologie und Hämatologie, Universitätsklinikum des Saarlandes, Kirrberger Str., Geb. 9, 66421 Homburg, GermanyPädiatrische Onkologie und Hämatologie, Universitätsklinikum des Saarlandes, Homburg, Germany

Pädiatrische Onkologie und Hämatologie, Universitätsklinikum des Saarlandes, Kirrberger Str., Geb. 9, 66421 Homburg, DeutschlandPädiatrische Onkologie und Hämatologie, Universitätsklinikum des Saarlandes, Homburg, Deutschland

norbert.graf@uniklinikum-saarland.de author Laws Laws Hans Jürgen HJ

Klinik für Pädiatrische Onkologie, Hämatologie und Immunologie, Universitätskinderklinik, Heinrich-Heine-Universität, 40225 Düsseldorf, GermanyKlinik für Pädiatrische Onkologie, Hämatologie und Immunologie, Universitätskinderklinik, Heinrich-Heine-Universität, Düsseldorf, Germany

Klinik für Pädiatrische Onkologie, Hämatologie und Immunologie, Universitätskinderklinik, Heinrich-Heine-Universität, 40225 Düsseldorf, DeutschlandKlinik für Pädiatrische Onkologie, Hämatologie und Immunologie, Universitätskinderklinik, Heinrich-Heine-Universität, Düsseldorf, Deutschland

Laws@med.uni-duesseldorf.de author Voigt Voigt Sebastian S

Klinik für Pädiatrie m. S. Onkologie / Hämatologie / Stammzelltransplantation, Charité – Universitätsmedizin Berlin, Germany

Klinik für Pädiatrie m. S. Onkologie / Hämatologie / Stammzelltransplantation, Charité – Universitätsmedizin Berlin, Deutschland

sebastian.voigt@charite.de author Piening Piening Brar B

Institut für Hygiene und Umweltmedizin, Charité – Universitätsmedizin Berlin, Germany

Institut für Hygiene und Umweltmedizin, Charité – Universitätsmedizin Berlin, Deutschland

brar.piening@charite.de author Geffers Geffers Christine C

Institut für Hygiene und Umweltmedizin, Charité – Universitätsmedizin Berlin, Germany

Institut für Hygiene und Umweltmedizin, Charité – Universitätsmedizin Berlin, Deutschland

christine.geffers@charite.de author Agyeman Agyeman Philipp P

Pädiatrische Infektiologie und Pädiatrische Hämatologie-Onkologie, Universitätsklinik für Kinderheilkunde, Inselspital, 3010 Bern, SwitzerlandPädiatrische Infektiologie und Pädiatrische Hämatologie-Onkologie, Universitätsklinik für Kinderheilkunde, Inselspital, Bern, Switzerland

Pädiatrische Infektiologie und Pädiatrische Hämatologie-Onkologie, Universitätsklinik für Kinderheilkunde, Inselspital, 3010 Bern, SchweizPädiatrische Infektiologie und Pädiatrische Hämatologie-Onkologie, Universitätsklinik für Kinderheilkunde, Inselspital, Bern, Schweiz

philipp.agyeman@insel.ch author Ammann Ammann Roland A. RA

Pädiatrische Infektiologie und Pädiatrische Hämatologie-Onkologie, Universitätsklinik für Kinderheilkunde, Inselspital, 3010 Bern, SwitzerlandPädiatrische Infektiologie und Pädiatrische Hämatologie-Onkologie, Universitätsklinik für Kinderheilkunde, Inselspital, Bern, Switzerland

Pädiatrische Infektiologie und Pädiatrische Hämatologie-Onkologie, Universitätsklinik für Kinderheilkunde, Inselspital, 3010 Bern, SchweizPädiatrische Infektiologie und Pädiatrische Hämatologie-Onkologie, Universitätsklinik für Kinderheilkunde, Inselspital, Bern, Schweiz

roland.ammann@insel.ch author German Medical Science GMS Publishing House

Düsseldorf

610 pediatric oncology bloodstream infection Broviac Port surveillance Kinderonkologie Blutstrominfektion Broviac Port Surveillance 20160512 engl germ This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). 2196-5226 11 GMS Hygiene and Infection Control GMS Hyg Infect Control 11 Pädiatrisch-onkologische Patienten unter einer konventionellen Chemotherapie sind einem erhöhten Risiko für Blutstrominfektionen (BSI) ausgesetzt. Da diese mit einer erheblichen Gefährdung und Belastung der Patienten einhergehen, ist die Prävention von BSI ein wichtiger Bestandteil des Gesamtkonzepts zur Gewährleistung der Patientensicherheit während der intensiven Behandlung. Die Mehrzahl der Patienten (ca. 85%) hat einen langfristig implantierten zentralen Venenkatheter vom Typ Broviac oder Port (CVAD); nach den gängigen Definitionen der Infektionssurveillance sind daher ein erheblicher Anteil der BSI bei Patienten mit Fieber und Granuolozytopenie „Gefäßkatheter-assoziiert“ (CABSI). In dieser Übersicht zum Stand des Wissens werden die Epidemiologie und das besondere Erregerprofil von BSI bei pädiatrisch onkologischen Patienten aus der Perspektive der Infektionssurveillance beschrieben. Probleme bei der Anwendung der gängigen Definitionen werden aufgezeigt und es wird ein Vorschlag für ein neu aufgelegtes Erfassungsmodul für die Surveillance von BSI bei kinderonkologischen Patienten vorgestellt. Pediatric patients receiving conventional chemotherapy for malignant disease face an increased risk of bloodstream infection (BSI). Since BSI may represent an acute life-threatening event in patients with profound immunosuppression, and show further negative impact on quality of life and anticancer treatment, the prevention of BSI is of paramount importance to improve and guarantee patients’ safety during intensive treatment. The great majority of all pediatric cancer patients (about 85%) have a long-term central venous access catheter in use (type Broviac or Port; CVAD). Referring to the current surveillance definitions a significant proportion of all BSI in pediatric patients with febrile neutropenia is categorized as CVAD-associated BSI. This state of the art review summarizes the epidemiology and the distinct pathogen profile of BSI in pediatric cancer patients from the perspective of infection surveillance. Problems in executing the current surveillance definition in this patient population are discussed and a new concept for the surveillance of BSI in pediatric cancer patients is outlined. List of abbreviationsALL – acute lymphoblastic leukemiaAML – acute myeloblastic leukemiaARDS – acute respiratory distress syndromeBSI – bloodstream infectionCA-BSI – vascular catheter-associated bloodstream infectionCDC – Centers for Disease Control and PreventionCFU – colony forming unitsCoNS – coagulase-negative staphylococciCR-BSI – bloodstream infection with the vascular catheter as the most probable sourceCVAD – long-term tunneled or subcutaneously implanted central venous catheter, type Port, Broviac or HickmanFCH – fluoroquinolonesGPOH – German Society of Pediatric Oncology and HematologyGVHD – graft-versus-host diseaseMBI-LCBSI – mucosal barrier injury-associated laboratory-confirmed BSIMDS – myelodysplastic syndromeMNS – face mask (surgical grade)MRGN – multidrug-resistant Gram-negative pathogenMRSA – methicillin-resistant Staphylococcus aureusNFC – needleless (needle free) connecting deviceNI – nosocomial infectionNICU – neonatal intensive care unitPICU – pediatric intensive care unitPJP – Pneumocystis jrovecii pneumoniaPOC – pediatric oncology treatment centerSCT – stem cell transplantationVGS – viridans (alpha-hemolytic) streptococciVRE – vancomycin-resistant enterococci (in most cases: E. faecium)2 MRGN NeoPäd – Gram-negative pathogen, in vitro resistant to piperacillin and extended spectrum cephalosporins (cefotaxime, ceftriaxone, ceftazidime)3 MRGN – Gram-negative pathogen, in vitro resistant to 3 of 4 antibiotic classes utilized for empirical treatment of systemic infection in adult high risk patients (piperacillin, extended-spectrum cephalosporins, carbapenems and fluoroquinolones)4 MRGN – Gram-negative pathogen, in vitro resistant to 4 antibiotic classes utilized for empirical treatment of systemic infection in adult high risk patients (piperacillin, extended-spectrum cephalosporins, carbapenems and fluoroquinolones) Verzeichnis der AbkürzungenALL – Akute lymphoblastische LeukämieAML – Akute myeloische LeukämieARDS – Akutes Lungenversagen (Acute Respiratory Distress Syndrome)BSI – BlutstrominfektionCA-BSI – Gefäßkatheter-assoziierte BlutstrominfektionCDC – Centers for Disease Control and PreventionCoNS – Koagulase-negative StaphylokokkenCR-BSI – Vom Gefäßkatheter ausgehende BlutstrominfektionCVAD – Dauerhafter implantierter oder getunnelter zentraler Gefäßkatheter vom Typ Port oder Broviac / HickmanFCH – FluorchinoloneGPOH – Gesellschaft für Pädiatrische Onkologie und HämatologieGVHD – Graft-versus-Host-ErkrankungKBE – Kolonie-bildende EinheitenMBI-LCBSI – Mucosal Barrier Injury-Associated Laboratory-Confirmed BSIMDS – Myelodysplastisches SyndromMNS – Mund-Nasen-SchutzMRGN – Multiresistenter gramnegativer ErregerMRSA – Methicillin-resistenter Staphylococcus aureusNFC – Nadelfreies KonnektionsventilNI – nosokomiale InfektionNICU – Neonatologische IntensivstationPICU – Pädiatrische IntensivstationPJP – Pneumocystis jirovecii-PneumoniePOC – Pädiatrisch-onkologisches BehandlungszentrumSCT – StammzelltransplantationVGS – Vergrünende (alpha-hämolysierende) StreptokokkenVRE – Vancomycin-resistente Enterokokken (meist E. faecium)2 MRGN NeoPäd – Gramnegativer Erreger mit in vitro Resistenz gegen Piperacillin und Cephalosporine der Gruppe III (Cefotaxim, Ceftriaxon, Ceftazidim)3 MRGN – Gramnegativer Erreger mit in vitro Resistenz gegen 3 von 4 bei Erwachsenen zur empirischen Therapie schwerer Infektionen eingesetzten Antibiotikagruppen (Piperacillin, Cephalosporine, Carbapeneme und Fluorchinolone)4 MRGN – Gramnegativer Erreger mit in vitro Resistenz gegen 4 von 4 bei Erwachsenen zur empirischen Therapie schwerer Infektionen eingesetzten Antibiotikagruppen (Piperacillin, Cephalosporine, Carbapeneme und Fluorchinolone) BackgroundIn children with malignancy receiving conventional anticancer chemotherapy, bloodstream infections (BSI) caused by bacterial pathogens represent nearly half of all nosocomial infections (NI) in which a pathogen can be isolated , , , , , , , , , , , . In contrast to other high-risk pediatric patient populations , , , , , the great majority of all pediatric cancer patients (about 85%) have a long-term central venous access catheter in use (type Broviac, Hickman or Port; CVAD) , , which is surgically implanted early during induction treatment . Due to this high utilization rate of CVADs, a significant proportion of all BSI in this population is associated with a CVAD. Table 1 shows a number of prospective studies in which different protocols of prospective surveillance for BSI have been followed in pediatric cancer patients. In most malignancies deriving from or with extensive involvement of the bone marrow, the intensive chemotherapy and – in some patients – radiotherapy of the underlying disease result in a severely reduced number of granulocytes in peripheral blood cell counts (neutropenia; number of granulocytes in peripheral blood <0.5x109/L or <1.0x109/L and no differential count available). Neutropenia negatively affects the capacity of the child to defend against bacterial and fungal pathogens, and fosters the risk of BSI . On the other hand, BSI have been observed in pediatric cancer patients without neutropenia at the onset of symptoms (e.g. fever) , , , . This is the case in nearly half of all pediatric cancer patients with bacteremia (detection of a pathogen in blood cultures in a symptomatic child) who do not show clinical signs of sepsis . Beyond the acute phase after stem-cell transplantation , , the surveillance of BSI in pediatric cancer patients should not only be performed in those patients with neutropenia. It seems more reasonable to adjust the events (BSI) not to days of neutropenia, but to 1000 in-patient days or to 1000 utilization days for CVADs. Notwithstanding, the clinical severity of the BSI and the risk of severe and even life-threatening complications , are significantly influenced by the severity and duration of neutropenia after the onset of the infection.MucositisIntensive chemotherapy (in particular high-dose methotrexate, anthracyclines, high-dose cytarabine, high-dose etoposide) and radiotherapy may cause injury to mucosal surfaces in the mouth, oropharynx and deeper parts of the gastrointestinal system (mucosal barrier injury; mucositis) , . Both neutropenia and mucosal barrier injury increase the risk of translocation from the mucosal surface into the bloodstream . This concerns most prominently viridans group streptococci (VGS), Enterobacteriaceae (E. coli, Klebsiella spp., Enterobacter spp.), and enterococci (E. faecium and E. faecalis) . In the case of substantial failures in terms of prevention (hand hygiene, disinfection of IV connections or three-way stopcocks before any access) , infection with those pathogens may be exogenous in origin; the pathogens contact the inner surface of the CVAD via healthcare workers’ hands or through contaminated substances and infusions , . The latter may be even more probable in patients with severe mucositis, who are in need of many supportive-care manipulations of their CVAD (e.g. parenteral nutrition, continuous analgesic infusion).Antimicrobial prophylaxisMost pediatric oncology patients receive antimicrobial prophylaxis (cotrimoxazole at least once a week) to prevent Pneumocystis jirovecii pneumonia , , , , , . In contrast to adults with leukemia and a high risk of bacterial translocation from the gut , antimicrobial prophylaxis with fluoroquinolones (FCH) is only rarely used in children and adolescents with cancer , . In contrast, oral treatment with FCH (e.g., as sequential oral treatment after 48–72 hours of IV treatment, or after stem-cell transplantation) has recently been chosen more often as an alternative to other oral antibiotics even in pediatric cancer patients , ; however, we are not aware of any data describing the use of FCH in detail in this population in German pediatric oncology centers (POC). The historical selective oral decontamination concept with non-absorbable antibiotics, such as colistin, oral gentamicin or paromomycin , is no longer used by most German POCs due to a lack of scientific evidence for efficacy and compliance problems . In patients with acute myeloblastic leukemia, some POCs administer penicillin as prophylaxis against VGS infection between chemotherapy cycles . In addition, some POCs use teicoplanin infusions 3 times per week , . Since there is still no consensus, both preventive strategies have been outlined in the German AML BFM Protocol (Version 01.04.2012 Chapter 8.2.5 p.41).Felsenstein et al. performed a retrospective case series analysis to investigate the advantages and disadvantages of prophylactic FCH (ciprofloxacin) in pediatric patients with AML (n=45, 2008–2012; Children’s Hospital Los Angeles) . The analysis revealed a probable benefit in terms of less BSI caused by Gram-negative pathogens (13.4% vs. 4.7%); on the other hand, the incidence of BSI due to Gram-positive pathogens increased significantly (28% vs. 14%). The use of ciprofloxacin prophylaxis increased the risk of BSI due to VGS. Eventually, the incidence of BSI was equal in both retrospectively compared groups (35.9% vs. 31.5%). No influence on mortality was detected.Spectrum of bacterial pathogens of BSI in pediatric cancer patientsThe spectrum of pathogens derived from blood cultures in symptomatic pediatric oncology patients shows some differences compared to BSI in other pediatric populations. Coagulase-negative staphylococci (CoNS) account for 20% to 30% of all Gram-positive pathogens. It is probable that a significant proportion of these opportunistic pathogens obtain access to the bloodstream through the CVAD and its maintenance care.Since more than half of these CoNS display in-vitro resistance to methicillin, these BSI foster the extensive use of glycopeptides in POCs , . Depending on the subgroup of patients, between 15% and 26% of all BSI are caused by viridans group streptococci; (VGS) . In this regard, VGS are more prevalent than S. aureus (9%) as pathogens detected in BSIs . In contrast, VGS represent less than 2% of all pathogens detected in blood cultures of pediatric intensive-care patients . In a significant proportion of all cases (up to 15%; in particular S. mitis, often penicillin resistant) BSI caused by VGS is accompanied by clinical sepsis and pneumonia or acute respiratory failure (ARDS) , . BSI caused by VGS have significantly more often been reported in patients with AML, induction chemotherapy with cytarabine, neutropenia and mucositis , , . Pneumococci, which represent the most common pathogens in community acquired sepsis in pediatric patients without underlying malignancy , , are detected in only 2% of all BSI in POCs . Pediatric patients with ALL seem to face an increased risk S. pneumoniae BSI during maintenance treatment, since immunization against invasive isolates is regularly refreshed 4 months after the end of chemotherapy . The most common Gram-negative pathogen detected in blood cultures of symptomatic pediatric cancer patients is E. coli , , , followed by other Enterobacteriaceae (e.g. Enterobacter spp., Klebsiella spp.) and non-fermenters such as P. aeruginosa (6–7% in most studies) , .Pathogens with in vitro resistance against commonly used antibioticsIn recent studies of nosocomial BSI performed in POCS in Germany, Switzerland and the Netherlands, the proportion of bacterial pathogens which display in vitro multidrug-resistance to commonly used antibiotics in this setting (MRE) , (MRSA, VRE, MRGN) has been consistently low , , , . Simon et al. (2001–2005, 7 POCs in Germany and Switzerland) analyzed 138 BSI (145 isolates) and found no MRSA, 2 VRE (1.5% of all BSI) and only two cases with 2 MRGN NeoPäd [Please refer to list of abbreviations.] (1.5% of all BSI; K. pneumoniae and P. aeruginosa, resistant in vitro to piperacillin and extended spectrum cephalosporins) . In this study, the attributable mortality of nosocomial infections in POCs was 3%; 6 patients died due to invasive aspergillosis and 2 because of clinical sepsis and multi-organ failure without any pathogen detected in blood cultures.Miedema et al. (2004–2007; 2008–2011; Groningen, Amsterdam, Bern) did not find a single case of BSI due to MRSA or VRE among 248 Isolates (202 BSI) . Some of the Gram-negative pathogens displayed multidrug resistance in vitro due to the production of an extended-spectrum beta lactamase (ESBL; this is comparable to the 2 MRGN NeoPäd definition); in addition, 3 P. aeruginosa isolates with in vitro resistance to imipenem/cilastatin were found. In no case was the detection of MRE related to a fatal outcome (attributable mortality 0.5%, n=1). In this study, the proportion of Gram-negative pathogens resistant to FCH was higher in patients exposed to ciprofloxacin [3/7 (43%) vs. 25/28 (89%), p=0.044]. Interestingly, FCH resistant Gram-negative pathogens were detected in POCs using ciprofloxacin as prophylaxis even in patients without direct exposure to FCHs in their medical history. Besides sources in the outpatient setting (e.g., pets, pet food, contaminated meat from industrial breeding of animals) , , the possibility of nosocomial transmission in a POC must be taken into account .In a recently published surveillance study by Ammann et al. (Switzerland, Germany), no MRSA was found in 179 BSI (185 isolates); the study group described a single BSI due to VRE (0.6% ) and 2 BSI due to 2 MRGN NeoPäd (1.1%; one E. coli, and one E. cloacae). Overall attributable mortality was 1.8% (3/179 BSI). One of those children, in whom the cause of death was related to the BSI, was suffering from a sepsis syndrome caused by an E. cloacae isolate which expressed an extended-spectrum beta lactamase. This child had been empirically treated with piperacillin-tazobactam and gentamicin. Unfortunately, the isolate was resistant against both first line antibiotics. Haeusler et al. retrospectively investigated 280 Gram-negative BSI in 210 pediatric cancer patients (Royal Children’s Hospital, Melbourne, 2003–2010) . The most prevalent species detected in blood cultures were E. coli, Klebsiella spp., and Enterobacter spp. Out of 280 BSI, 42 (15%) were caused by MRGN. This study revealed independent risk factors for BSIs caused by MRGN: high-intensive chemotherapy (autologous SCT; OR 3.7, CI95 1.1–11.4), nosocomially acquired BSI (OR 4.3; CI95 2.0–9.6), and the presence of MRGN colonization or infection during the preceding 12 months (OR 9.9, CI95 3.8–25.5). Patients with BSI due to MRGN infection had a significantly prolonged length of stay in the hospital (plus 9.5 days) as well as in the PICU (plus 2.2 days), and were more often in need of mechanical ventilation (15% vs. 5.2%). Differences in mortality between the MRGN and the comparator group were not statistically significant.From an external perspective, it may be too easy to reach the conclusion that BSIs due to MRE , are not only extraordinarily rare but also have no significant negative impact on outcomes in POCs. This would be a grave misinterpretation, dangerous from the perspective of the individual patient. Some patients in POCs show a number of risk factors predisposing for colonization and infection with MRE , ; in our experience, patients transferred from high-prevalence countries should always be allocated to this group (e.g., from southern and eastern Europe, Syria, Arab countries, North Africa). In addition, a growing number of studies describe complicated and protracted clinical courses in pediatric cancer patients with fever and BSI, in whom the primary treatment was not adequate in terms of in vitro resistance of the responsible pathogen , , .Recent reports and case series from POCs in Italy are extremely alarming. These POC face an increasing prevalence of 4 MRGN P. aeruginosa , . Caselli et al. retrospectively evaluated data from a multicenter survey in Italian POCs (2000–2008). This survey detected 127 pediatric cancer patients (in 12 POCs) with a BSI caused by P. aeruginosa. Of these, 31% were caused by 4 MRGN P. aeruginosa. Overall mortality was 19.6% (25/127), with 36% (14/39) mortality in the 4 MRGN</PlainText></TextGroup> cases vs. 13&#37; (11&#47;88) in those BSI without a multidrug-resistance pattern. In multivariate analysis, the 4 MRGN status of the isolates was a significant independent risk factor for a fatal outcome <TextLink reference="72"></TextLink>. Cioffi Degli Atti et al. <TextLink reference="71"></TextLink> reported an outbreak of carbapenemase-positive, phenotypical 3 or 4 MRGN <Mark2>P. aeruginosa</Mark2>, which were eventually detected in 27 patients. Twelve of 27 children experienced a BSI&#47;sepsis, 6 experienced other focal infections, and 9 of 27 were only colonized with the outbreak strain (infection rate 67&#37;). BSI most often developed during periods of neutropenia. Eight of 12 children with BSI died related to the infection (attributable mortality 67&#37;). The local infection control strategy involved active surveillance cultures and additional isolation procedures. This resulted in a reduction of the incidence density (new detections) from 0.72 to 0.34&#47;1000 in-patient days. The authors suggest introducing the screening of all pediatric cancer patients in Italy for colonization with 3 or 4 MRGN to the routine prevention efforts to reduce nosocomial transmission and infection.</Pgraph><Pgraph>Unfortunately, there is currently no feasible and effective decolonization regime available for pediatric cancer patients with gastrointestinal colonization with MRGN isolates. In this regard, patients remain colonized for the whole duration of their intensive treatment. This observation is strongly related to individual consequences (e.g., determining the best empirical antimicrobial treatment in case of fever with or without neutropenia <TextLink reference="73"></TextLink>) and to precautions considering hospital hygiene and transmission control <TextLink reference="68"></TextLink>, <TextLink reference="74"></TextLink>. In this field, many questions regarding the most feasible prevention strategy are still a matter of ongoing discussion.</Pgraph><SubHeadline>Negative impact of BSIs</SubHeadline><Pgraph>Bacterial BSI may represent an acute life-threatening event in patients with profound immunosuppression <TextLink reference="75"></TextLink>. Patients are immediately hospitalized and treated with i.v. antibiotics and supportive care measures for at least 72 hours <TextLink reference="76"></TextLink>, <TextLink reference="77"></TextLink>, <TextLink reference="78"></TextLink>.</Pgraph><Pgraph>This concept primarily focuses on patient safety, but may result in additional reduction of quality of life in pediatric cancer patients and their families <TextLink reference="79"></TextLink>, <TextLink reference="80"></TextLink>. The direct cost of treatment is significantly increased in patients with BSI; a very conservative calculation from a German POC revealed that additional expenses of at least &#8364; 4,400 have to be allocated to each event <TextLink reference="81"></TextLink>, <TextLink reference="82"></TextLink>. Empirical broad-spectrum antimicrobial treatment of pediatric cancer patients with fever and neutropenia fosters the selective pressure for MRE in POCs <TextLink reference="83"></TextLink>, <TextLink reference="84"></TextLink>, <TextLink reference="85"></TextLink>. In individual patients, the risk of antibiotic-associated diarrhea and other <Mark2>C. difficile</Mark2>-associated diseases increases following antibiotic treatment of BSIs <TextLink reference="86"></TextLink>. Ultimately, each BSI may result in a delay of chemotherapy and reduced dose intensity, with negative consequences for long-term remission of the underlying malignancy.</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Hintergrund und Besonderheiten bei kinderonkologischen Patienten"> <MainHeadline>Hintergrund und Besonderheiten bei kinderonkologischen Patienten</MainHeadline><Pgraph>Bei Kindern mit Krebserkrankungen und einer konventionellen Chemotherapie machen Blutstrominfektionen (BSI), die durch bakterielle Infektionserreger ausgel&#246;st werden, in etwa die H&#228;lfte aller nosokomialen Infektionen mit Erregernachweis aus <TextLink reference="1"></TextLink>, <TextLink reference="2"></TextLink>, <TextLink reference="3"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="5"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="7"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="9"></TextLink>, <TextLink reference="10"></TextLink>, <TextLink reference="11"></TextLink>, <TextLink reference="12"></TextLink>. Im Unterschied zu anderen p&#228;diatrischen Patientenpopulationen mit hohem Risiko f&#252;r nosokomiale BSI <TextLink reference="13"></TextLink>, <TextLink reference="14"></TextLink>, <TextLink reference="15"></TextLink>, <TextLink reference="16"></TextLink>, <TextLink reference="17"></TextLink> erhalten die meisten (ca. 85&#37; aller) kinderonkologischen Patienten schon zu Beginn der Therapie <TextLink reference="20"></TextLink> einen dauerhaften getunnelten oder voll implantierten zentralen Gef&#228;&#223;katheter (CVAD) vom Typ Broviac&#47;Hickman oder Port <TextLink reference="18"></TextLink>, <TextLink reference="19"></TextLink>. Durch die hohe CVAD-Anwendungsrate ist ein erheblicher Anteil aller BSI bei diesen Patienten <Mark2>mit einem Gef&#228;&#223;katheter assoziiert</Mark2> (zur Definition siehe unten). Tabelle 1 <ImgLink imgNo="1" imgType="table"/> zeigt eine Zusammenstellung ausgew&#228;hlter Studien, in denen BSI in der Kinderonkologie prospektiv systematisch erfasst und ausgewertet wurden (Surveillance). Grunderkrankungen mit prim&#228;rem oder sekund&#228;rem (ausgedehntem) Befall des Knochenmarks, die intensive Chemotherapie und ggf. auch eine Strahlentherapie (mit ausgedehntem Feld, insbesondere mit Einschluss von Wirbelk&#246;rpern), f&#252;hren zu einer Leukozytopenie und Granulozytopenie (Engl.: neutropenia) und somit auch zu einer relevanten Schw&#228;chung der Erregerabwehr <TextLink reference="21"></TextLink>. Blutstrominfektionen treten aber auch bei kinderonkologischen Patienten auf, die zu Beginn des Fiebers keine Granulozytopenie aufweisen <TextLink reference="11"></TextLink>, <TextLink reference="22"></TextLink>, <TextLink reference="1"></TextLink>, <TextLink reference="6"></TextLink>. Dies gilt f&#252;r etwa die H&#228;lfte aller BSI mit dem klinischen Schweregrad &#8222;Bakteri&#228;mie ohne Zeichen einer Sepsis&#8220; <TextLink reference="1"></TextLink>. </Pgraph><Pgraph><Indentation>Au&#223;erhalb der akuten Phase nach Stammzelltransplantation <TextLink reference="23"></TextLink>, <TextLink reference="24"></TextLink> ist es nicht zielf&#252;hrend, die Erfassung von BSI ausschlie&#223;lich auf Patienten mit Granulozytopenie zu begrenzen oder die Zahl der Ereignisse &#8211; statt auf 1000 Patiententage (Inzidenzdichte) bzw. 1000 Anwendungstage f&#252;r Gef&#228;&#223;katheter (Inzidenzrate) &#8211; auf 1000 Granulozytopenietage zu beziehen. </Indentation></Pgraph><Pgraph>Der WHO-Grad (Grad IV entspricht &#60;0,5x10<Superscript>9</Superscript>&#47;L) und die Dauer der Granulozytopenie (z.B. weniger oder mehr als 10 Tage) sind assoziiert mit dem Krankheitsschweregrad der BSI von der Bakteri&#228;mie bis zum septischen Schock mit Multiorganversagen <TextLink reference="25"></TextLink> und somit auch mit dem Risiko schwerster Komplikationen <TextLink reference="1"></TextLink>, <TextLink reference="26"></TextLink>.</Pgraph><SubHeadline>Mukositis</SubHeadline><Pgraph>Die intensive Chemotherapie (v.a. hoch dosiertes Methotrexat, Anthrazykline, hoch dosiertes Cytarabin, hoch dosiertes Etoposid) und ggf. auch die Strahlentherapie verursachen eine Sch&#228;digung der mukosalen Barriere im Oropharynx und in den tieferen Abschnitten des Gastrointestinaltraktes (mucosal barrier injury; Mukositis) <TextLink reference="27"></TextLink>, <TextLink reference="28"></TextLink>. Sowohl die Granulozytopenie, als auch die Mukositis erh&#246;hen das Risiko einer Translokation von Bakterien von den Schleimh&#228;uten des Gastrointestinaltraktes ins Blut <TextLink reference="29"></TextLink>. Dies gilt zum Beispiel f&#252;r VGS, Enterobacteriaceae (<Mark2>E. coli</Mark2>, <Mark2>Klebsiella</Mark2> spp., <Mark2>Enterobacter</Mark2> spp.) und f&#252;r Enterokokken (<Mark2>E. faecium</Mark2> und <Mark2>E. faecalis</Mark2>) <TextLink reference="30"></TextLink>. Bei erheblichen L&#252;cken in der Pr&#228;ventionsstrategie zur Vermeidung von Infektionen, die vom Gef&#228;&#223;katheter ausgehen <TextLink reference="18"></TextLink>, k&#246;nnen Infektionen durch diese Erregerspezies auch vom Gef&#228;&#223;katheter oder aus kontaminierten Arzneimitteln und Infusionsl&#246;sungen stammen <TextLink reference="31"></TextLink>, <TextLink reference="32"></TextLink>. Gerade f&#252;r Letzteres besteht bei Patienten mit schwerer Mukositis ein erh&#246;htes Risiko, weil sie neben Schmerzmitteln h&#228;ufig auch komplexe Mischinfusionen zur parenteralen Ern&#228;hrung erhalten.</Pgraph><SubHeadline>Antibiotikaprophylaxen</SubHeadline><Pgraph>Die meisten kinderonkologischen Patienten erhalten parallel zur intensiven Chemotherapie eine Prophylaxe mit Cotrimoxazol zur Pr&#228;vention der <Mark2>Pneumocystis jirovecii-</Mark2>Pneumonie und zwar an mind. einem Tag pro Woche <TextLink reference="33"></TextLink>, <TextLink reference="34"></TextLink>, <TextLink reference="35"></TextLink>, <TextLink reference="36"></TextLink>, <TextLink reference="37"></TextLink>, <TextLink reference="38"></TextLink>. Im Unterschied zu erwachsenen onkologischen Hochrisikopatienten <TextLink reference="39"></TextLink> erhalten Kinder und Jugendliche mit hohem Risiko f&#252;r eine Translokationsbakteri&#228;mie durch Enterobacteriaceae in der Regel <Mark3>keine</Mark3> Fluorochinolon (FCH)-Prophylaxe <TextLink reference="40"></TextLink>, <TextLink reference="41"></TextLink>. Eine orale ambulante Behandlung mit FCH (z.B. als Sequenztherapie nach iv. Antibiotika, bei Patienten w&#228;hrend der ALL&#47;AML-Erhaltungstherapie oder nach Transplantation) wird in den letzten Jahren auch bei Kindern und Jugendlichen h&#228;ufiger verordnet <TextLink reference="42"></TextLink>, <TextLink reference="43"></TextLink>, genaue Daten hierzu liegen jedoch aus den GPOH-Zentren nicht vor. Eine selektive orale Dekontamination mit oralen nicht-resorbierbaren Antibiotika, wie z.B. Colistin, Gentamicin, Paromomycin <TextLink reference="44"></TextLink>, wird heute wegen fehlender Belege f&#252;r einen signifikanten klinischen Nutzen und schlechter Compliance <TextLink reference="45"></TextLink> nur noch selten durchgef&#252;hrt. Bei AML-Patienten w&#228;hrend der intensiven Chemotherapie wird von einigen Zentren zwischen den Chemotherapie-Zyklen eine orale VGS-Prophylaxe mit Penicillin V gegeben <TextLink reference="46"></TextLink>. Dar&#252;ber hinaus gibt es p&#228;diatrisch-onkologische Zentren (POCs), die mehrmals w&#246;chentlich Teicoplanin zur VGS-Prophylaxe verabreichen <TextLink reference="47"></TextLink>, <TextLink reference="48"></TextLink>. Zu beiden Strategien siehe Hinweise der AML-BFM-Studienzentrale (Empfehlung zur Diagnostik, Therapie und Nachsorge akuter myeloischer Leuk&#228;mien bei Kindern und Jugendlichen 01.04.2012 Kapitel 8.2.5 S.41). </Pgraph><Pgraph>Felsenstein et al. haben in einer retrospektiven Auswertung den Nutzen einer Prophylaxe mit Ciprofloxacin bei Kindern mit AML untersucht (n&#61;45, 2008&#8211;2012; Children&#8217;s Hospital Los Angeles) <TextLink reference="49"></TextLink>. Zwar kam es bei den Kindern mit Ciprofloxacin-Prophylaxe zu einer signifikanten Reduktion der BSI durch gramnegative Erreger (13,4&#37; vs. 4,7&#37;), parallel dazu stieg aber die Inzidenz der BSI durch grampositive Erreger signifikant an (28&#37; vs. 14&#37;). Der Einsatz von Ciprofloxacin erh&#246;hte signifikant das Risiko einer BSI durch VGS. Letztendlich war die Inzidenz von BSI daher in beiden Gruppen gleich (35,9&#37; vs. 31,5&#37;). Auf die Mortalit&#228;t hatte die Prophylaxe keinen Einfluss.</Pgraph><SubHeadline>Erregerspektrum von BSI in der Kinderonkologie</SubHeadline><Pgraph>Das Erregerspektrum von BSI bei kinderonkologischen Patienten zeigt einige Besonderheiten. Koagulase-negative Staphylokokken (CoNS) machen zwischen 20 und 30&#37; aller grampositiven Erreger aus. Als opportunistische Erreger gehen diese Infektionen wahrscheinlich oft von Gef&#228;&#223;kathetern aus. Da die hier nachgewiesenen nosokomial erworbenen CoNS zu einem erheblichen Anteil Methicillin-resistent sind, forciert diese Form der BSI in der Kinderonkologie den Einsatz von Glykopeptiden <TextLink reference="50"></TextLink>, <TextLink reference="51"></TextLink>. Je nachdem, welche Untergruppe kinderonkologischer Patienten betrachtet wird, werden in 15&#37; <TextLink reference="6"></TextLink> bis 26&#37; <TextLink reference="3"></TextLink> aller BSI &#8218;vergr&#252;nende&#8216; Streptokokken (viridans group streptococci; VGS) als Erreger in der Blutkultur nachgewiesen <TextLink reference="52"></TextLink>. VGS sind somit vor <Mark2>S. aureus</Mark2> (9&#37;) <TextLink reference="6"></TextLink> die zweith&#228;ufigste grampositive Erregerspezies. Im Gegensatz hierzu liegt bei p&#228;diatrischen Intensivpflegepatienten der Anteil von VGS an allen BSI unter 2&#37; <TextLink reference="14"></TextLink>. In einem relevanten Teil aller F&#228;lle (bis zu 15&#37;; v.a. bei BSI durch <Mark2>S. mitis</Mark2>, oft Penicillin-resistent) <TextLink reference="53"></TextLink> geht eine Blutstrominfektion durch VGS mit einer schweren Sepsis und einer Pneumonie bis zum ARDS einher <TextLink reference="54"></TextLink>, <TextLink reference="55"></TextLink>. Es gibt eine eindeutige Assoziation zwischen der Grunddiagnose AML, der Chemotherapie der AML mit dem schleimhauttoxischen Zytostatikum Cytarabin <TextLink reference="56"></TextLink>, <TextLink reference="57"></TextLink> und dem Auftreten von Blutstrominfektionen durch VGS bei Granulozytopenie und Chemotherapie-induzierter Entz&#252;ndung der Schleimh&#228;ute (Mukositis) <TextLink reference="58"></TextLink>. Pneumokokken, die zu den h&#228;ufigsten Erregern der ambulant erworbenen Sepsis bei ansonsten gesunden Kindern geh&#246;ren <TextLink reference="59"></TextLink>, <TextLink reference="60"></TextLink>, werden hingegen in der Kinderonkologie w&#228;hrend der intensiven Behandlung nur in 2&#37; aller BSI nachgewiesen <TextLink reference="6"></TextLink>. Sie k&#246;nnen jedoch auch bei ALL-Patienten in der Erhaltungstherapie auftreten, vor allem, weil diese Kinder und Jugendlichen noch keine Auffrischimpfung gegen Pneumokokken nach Chemotherapie erhalten haben <TextLink reference="61"></TextLink>.</Pgraph><Pgraph>Die H&#228;ufigkeitsliste der gramnegativen Erreger von BSI bei kinderonkologischen Patienten f&#252;hrt eindeutig <Mark2>E. coli</Mark2> an <TextLink reference="6"></TextLink>, <TextLink reference="1"></TextLink>, <TextLink reference="3"></TextLink>, gefolgt von anderen Enterobacteriaceae (z.B. <Mark2>Enterobacter</Mark2> spp., <Mark2>Klebsiella</Mark2> spp.) und dem Nonfermenter <Mark2>P. aeruginosa</Mark2> (in den meisten Studien bei 6&#8211;7&#37;) <TextLink reference="6"></TextLink>, <TextLink reference="44"></TextLink>.</Pgraph><SubHeadline>Erreger mit speziellen Resistenzen und Multiresistenzen</SubHeadline><Pgraph>In den aktuellsten Studien zu nosokomialen Blutstrominfektionen bei kinderonkologischen Patienten mit teilnehmenden Zentren aus Deutschland, der Schweiz und den Niederlanden ist der Anteil von Erregern mit speziellen Resistenzen und Multiresistenzen (MRE) <TextLink reference="62"></TextLink>, <TextLink reference="63"></TextLink> <TextGroup><PlainText>(MRSA</PlainText></TextGroup>, VRE, MRGN) &#8211; abgesehen von den bereits erw&#228;hnten Methicillin-resistenten CoNS &#8211; weiterhin sehr niedrig <TextLink reference="1"></TextLink>, <TextLink reference="3"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>. Bei Simon et al. (2001&#8211;2005, 7 POCs aus Deutschland und der Schweiz) wurden in 138 BSI (145 Isolate) kein MRSA, 2 VRE (1,5&#37; aller BSI) und zwei <TextGroup><PlainText>2 MRGN</PlainText></TextGroup> NeoP&#228;d nachgewiesen (1,5&#37; aller BSI; einmal <TextGroup><Mark2>K. pneumoniae</Mark2></TextGroup>, einmal <Mark2>P. aeruginosa</Mark2>, resistent gegen Piperacillin und Cephalosporine der 3.&#47;4. Generation) <TextLink reference="1"></TextLink>. Bei einer Gesamtletalit&#228;t von 3&#37; (n&#61;8; 6 Todesf&#228;lle bei invasiver Aspergillose) verstarben 2 Patienten an einer klinischen Sepsis mit Multiorganversagen <Mark2>ohne</Mark2> Erregernachweis.</Pgraph><Pgraph>Miedema et al. (2004&#8211;2007; 2008&#8211;2011; Groningen, Amsterdam, Bern) fanden unter 248 Isolaten bei 202 BSI keine MRSA und keine VRE <TextLink reference="3"></TextLink>. Unter den gramnegativen Erregern gab es vereinzelt Enterobacteriaceae mit Produktion von Betalaktamasen mit erweitertem Wirkspektrum (ESBL; entsprechen 2 MRGN Neo P&#228;d nach KRINKO) und au&#223;erdem drei Imipenem-resistente <Mark2>P. aeruginosa</Mark2>-Isolate. In keinem Fall f&#252;hrte der Nachweis resistenter gramnegativer Erreger zu einem fatalen Ausgang der Infektion (Gesamtletalit&#228;t 0,5&#37;, n&#61;1). Der Anteil Ciprofloxacin-resistenter gramnegativen Erreger war in der Gruppe der Kinder h&#246;her, die eine Ciprofloxacin-Prophylaxe erhalten hatten &#91;3&#47;7 (43&#37;) vs. 25&#47;28 (89&#37;), p&#61;0,044&#93;. Erreger mit einer solchen Resistenz wurden in den beiden niederl&#228;ndischen Zentren, die Ciprofloxacin in der Prophylaxe einsetzen, auch bei Patienten ohne eine solche Prophylaxe nachgewiesen. </Pgraph><Pgraph>Neben dem Eintrag resistenter Isolate aus dem ambulanten Umfeld (Haustiere, industrielle Tiermast) <TextLink reference="64"></TextLink>, <TextLink reference="65"></TextLink> kommt hier eine nosokomiale &#220;bertragung der St&#228;mme in Betracht <TextLink reference="41"></TextLink>. Auch in der k&#252;rzlich von Ammann et al. <TextLink reference="6"></TextLink> publizierten multizentrischen Studie (Schweiz, Deutschland) mit 179 BSI (185 Isolate) fanden sich kein MRSA, ein VRE (0,6&#37; aller BSI) und zwei Infektionen durch 2 MRGN NeoP&#228;d (1,1&#37; aller BSI; einmal <Mark2>E. coli</Mark2>, einmal <Mark2>Enterobacter cloacae</Mark2>). Bei einer Gesamtletalit&#228;t von 1,8&#37; (3&#47;179 BSI) fand sich unter den drei an einer foudroyanten Sepsis verstorbenen Kindern eines mit einem ESBL-bildenden <Mark2>E. cloacae</Mark2>-Isolat, bei dem die empirisch verabreichte Antibiotikatherapie (Piperacillin-Tazobactam plus Gentamicin) unwirksam war. </Pgraph><Pgraph>Haeusler et al. werteten retrospektiv 280 gramnegative BSI bei 210 p&#228;diatrisch-onkologischen Patienten aus (Royal Children&#8217;s Hospital, Melbourne, 2003&#8211;2010) <TextLink reference="66"></TextLink>. Die am h&#228;ufigsten nachgewiesenen Spezies waren <TextGroup><Mark2>E. coli</Mark2></TextGroup>, <Mark2>Klebsiella</Mark2> spp. und <Mark2>Enterobacter</Mark2> spp. Von 280 BSI wurden 42 (15&#37;) durch MRGN verursacht. Unabh&#228;ngige Risikofaktoren f&#252;r das Auftreten einer gramnegativen Bakteri&#228;mie durch Antibiotika-resistente Erreger (MRGN) waren hoch intensive Chemotherapie (autologe SCT; OR 3,7, CI95 1,1&#8211;11,4), nosokomial erworbene BSI (OR 4,3; CI95 2,0&#8211;9,6) und Nachweis einer Besiedlung oder einer Infektion mit einem MRGN in den letzten 12 Monaten (OR 9,9, CI95 3,8&#8211;25,5). Patienten mit einer BSI durch MRGN hatten einen signifikant verl&#228;ngerten Krankenhaus (plus 9,5 Tage) und ggf. auch Intensivaufenthalt (plus 2,2 Tage) und wurden h&#228;ufiger invasiv beatmet (15&#37; vs. 5,2&#37;). Die Mortalit&#228;t war in der Gruppe der Patienten mit BSI durch MRGN tendenziell, aber nicht signifikant erh&#246;ht.</Pgraph><Pgraph>Aus den zitierten Daten k&#246;nnte vorschnell abgeleitet werden, dass Erreger mit speziellen Resistenzen und Multiresistenzen (MRE) <TextLink reference="62"></TextLink>, <TextLink reference="63"></TextLink> in der Kinderonkologie von untergeordneter Bedeutung sind und keinen erkennbaren Einfluss auf den Verlauf und den Ausgang von Blutstrominfektionen haben. Dies w&#228;re allerdings eine f&#252;r die Patienten gef&#228;hrliche Fehleinsch&#228;tzung. Auch in der Kinderonkologie gibt es Patienten, die eine Vielzahl bekannter Risikofaktoren f&#252;r den Nachweis von MRE aufweisen <TextLink reference="67"></TextLink>, <TextLink reference="68"></TextLink>, unter denen der Verlegung aus Kliniken in Hochrisikol&#228;ndern ein besonderer Stellenwert zukommt. Insbesondere gilt dies bei Kindern aus Ost- und S&#252;deuropa (auch: Syrien u.a. arabische L&#228;nder, Nordafrika). </Pgraph><Pgraph>Des Weiteren gibt es Publikationen, die auf ein erh&#246;htes Risiko eines komplizierten Verlaufes bei kinderonkologischen Patienten hinweisen, deren BSI durch einen gegen die empirische Prim&#228;rtherapie resistenten Erreger verursacht wird <TextLink reference="69"></TextLink>, <TextLink reference="70"></TextLink>, <TextLink reference="66"></TextLink>.</Pgraph><Pgraph>Extrem beunruhigend sind aktuelle Berichte aus kinderonkologischen Zentren in Italien, in denen sich bestimmte 4 MRGN <TextLink reference="63"></TextLink> <Mark2>P. aeruginosa</Mark2>-Isolate auszubreiten scheinen <TextLink reference="71"></TextLink>, <TextLink reference="72"></TextLink>. Caselli et al. fanden in einem multizentrischen italienischen Survey (2000&#8211;2008) in 12 Zentren 127 kinderonkologische Patienten mit einer durch <Mark2>P. aeruginosa</Mark2> verursachten BSI. In 31&#37; handelte es sich um <TextGroup><PlainText>4 MRGN</PlainText></TextGroup>-Isolate. Die Letalit&#228;t betrug insgesamt 19,6&#37; (25&#47;127); an den 4 MRGN-Infektionen verstarben 36&#37; der Patienten (14&#47;39) versus 13&#37; (11&#47;88) bei den Infektionen ohne Multiresistenz. Das Vorhandensein einer <TextGroup><PlainText>4 MRGN</PlainText></TextGroup> war in der multivariaten Analyse der einzig identifizierbare signifikante Risikofaktor f&#252;r einen fatalen Ausgang <TextLink reference="72"></TextLink>.</Pgraph><Pgraph>Cioffi Degli Atti et al. <TextLink reference="71"></TextLink> beschreiben einen Ausbruch von Carbapenemase-positiven, ph&#228;notypisch 3 bzw. <TextGroup><PlainText>4 MRGN</PlainText></TextGroup> <Mark2>P. aeruginosa</Mark2>, die insgesamt bei 27 Patienten nachgewiesen wurden. Bei 12 dieser Kinder kam es zu einer Sepsis, bei 6 zu anderen Infektionen, 9 waren lediglich besiedelt (Infektionsrate 67&#37;). BSI traten v.a. bei den Patienten mit hochgradiger Granulozytopenie auf. Acht von 12 Kindern mit BSI verstarben infolge der Infektion (Letalit&#228;t 67&#37;). Aktive Surveillance und zus&#228;tzliche Barrierema&#223;nahmen konnten die Inzidenz der Erstnachweise von 0,72 auf 0,34 pro 1000 station&#228;re Patiententage senken. Die Autoren schlagen vor dem Hintergrund der hohen Nachweisrate von MRGN in Italien vor, alle Patienten bei Aufnahme auf eine intestinale Besiedlung mit MRGN zu untersuchen. </Pgraph><Pgraph>Einmal mit MRGN (meist im Darm) kolonisierte Kinder bleiben &#252;ber die gesamte Dauer der intensiven immunsuppressiven Therapie besiedelt; ein erwiesenerma&#223;en wirksames Regime zur Dekolonisierung gibt es bisher nicht. Insofern m&#252;ssen aus solchen Resultaten (neben individualmedizinischen Konsequenzen, v.a. zur bestm&#246;glichen empirischen Therapie bei Fieber) <TextLink reference="73"></TextLink> krankenhaushygienische und infektionspr&#228;ventive Ma&#223;nahmen abgeleitet werden <TextLink reference="68"></TextLink>, <TextLink reference="74"></TextLink>. In diesem Kontext gibt es f&#252;r die spezielle Behandlungssituation in der Kinderonkologie noch zahlreiche offene Fragen.</Pgraph><SubHeadline>Negative Konsequenzen von BSI</SubHeadline><Pgraph>Bakterielle BSI k&#246;nnen in Phasen der ausgepr&#228;gten Immunsuppression das Leben der Patienten akut gef&#228;hrden <TextLink reference="75"></TextLink>. Sie erfordern eine sofortige station&#228;re Aufnahme und intraven&#246;se Antibiotikatherapie <TextLink reference="76"></TextLink>, <TextLink reference="77"></TextLink>, <TextLink reference="78"></TextLink>, wodurch die Lebensqualit&#228;t der Patienten und ihrer Familien (im Vergleich zu Kindern ohne eine solche Infektion) beeintr&#228;chtigt wird <TextLink reference="79"></TextLink>, <TextLink reference="80"></TextLink>.</Pgraph><Pgraph>Des Weiteren erh&#246;hen sie die Behandlungskosten bei sehr konservativer Kalkulation um mindestens 4400 &#8364; pro Ereignis <TextLink reference="81"></TextLink>, <TextLink reference="82"></TextLink>. Die empirische (kalkulierte) und (bei positiver Blutkultur) die gezielte Therapie von BSI steigert den Selektionsdruck auf bakterielle Erreger mit speziellen Resistenzen und Multiresistenzen in kinderonkologischen Abteilungen <TextLink reference="83"></TextLink>, <TextLink reference="84"></TextLink>, <TextLink reference="85"></TextLink>. Sie erh&#246;ht beim individuellen Patienten das Risiko einer <Mark2>C. difficile</Mark2>-assoziierten Enterokolitis <TextLink reference="86"></TextLink>. Au&#223;erdem kann jede BSI zu einer relevanten Verz&#246;gerung der Chemotherapie f&#252;hren, was sich m&#246;glicherweise ung&#252;nstig auf die Gesamtprognose auswirkt.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Problems regarding the allocation of a BSI to the vascular catheter (CVAD)"> <MainHeadline>Problems regarding the allocation of a BSI to the vascular catheter (CVAD)</MainHeadline><SubHeadline>Two separate blood culture sets&#63;</SubHeadline><Pgraph>In most patients with a single lumen CVAD (Broviac or Port) who are suffering from fever and neutropenia, antibiotic treatment is started soon after one set &#91;<Mark2>One set refers to an aerobic and an anaerobic blood culture bottle.</Mark2>&#93; of blood cultures has been taken from the CVAD <TextLink reference="75"></TextLink>; a second set of blood cultures is drawn 12 to 24 h later, in particular in patients with ongoing fever. Thus, the interpretation of common skin flora, such as CoNS, <Mark2>Corynebacteria</Mark2> spp. or <Mark2>Propionibacteria</Mark2> spp., growing in blood cultures drawn from a symptomatic pediatric cancer patient may be challenging. The CDC criterion of &#8220;growth of potential contaminants (e.g., CoNS) in at least two independently drawn blood cultures&#8221; <TextLink reference="87"></TextLink> is often not fulfilled in pediatric cancer patients with BSI. If the CDC criteria for BSI are strictly followed, a significant proportion of all BSI in pediatric cancer patients will be lost to surveillance issues due to this definition alone.</Pgraph><Pgraph>It has been proven that the proportion of positive blood cultures increases as a result of taking initial blood samples not only from the CVAD but additionally from a peripheral vein; the magnitude of this higher yield was 12&#37; <TextLink reference="88"></TextLink> to 18&#37; <TextLink reference="89"></TextLink> in recent studies. </Pgraph><Pgraph>In spite of these observations, the sampling of peripheral venous blood cultures is not recommended in the current guidelines of the German Society of Pediatric Oncology and Hematology <TextLink reference="18"></TextLink>, <TextLink reference="90"></TextLink>, due to inconvenience and anxiety on the patients&#8217; part related to an additional peripheral venous puncture. As a consequence of the missing second independently drawn blood culture, in accordance with standard CDC definitions <TextLink reference="87"></TextLink>, Kelly et al. <TextLink reference="10"></TextLink> did not include a significant proportion of all detected BSI in pediatric cancer patients in their analysis. Subsequently, CoNS were no longer the most prevalent pathogens, but ranked fourth place (7&#37;) behind enterococci, <Mark2>S. aureus</Mark2> and VGS. In the study by Choi et al., the corresponding change in definition &#8220;reduced&#8221; the incidence of BSI by 18.6&#37; <TextLink reference="91"></TextLink>. </Pgraph><Pgraph><Indentation>Surveillance protocols for BSI in pediatric cancer patients should evaluate all positive blood culture sets together with the clinical assessment of the attending pediatric oncologists. In the multicenter Oncoped studies (Germany and Switzerland), BSIs due to CoNS were counted as real BSI if CoNS grew in both bottles of the initial blood culture set and the attending pediatric oncologists adjusted antimicrobial treatment to this result (clinical assessment) <TextLink reference="6"></TextLink>, <TextLink reference="1"></TextLink>. The treatment team may eventually lose confidence in surveillance protocols which do not take the clinical assessment of the attending physicians into account.</Indentation></Pgraph><SubHeadline>Is the CVAD the source of the BSI&#63;</SubHeadline><Pgraph>In all pediatric cancer patients with fever but without a clinical focus of the infection, the question remains as to whether the BSI originated from the CVAD. Since in most cases, initial blood cultures are only drawn from the CVAD, it is not possible to determine a <Mark2>differential time to </Mark2><TextGroup><Mark2>positivity</Mark2></TextGroup> (DTP) <TextLink reference="89"></TextLink>. Most BSI are treated successfully in situ with antibiotics administered via the CVAD <TextLink reference="92"></TextLink>, <TextLink reference="76"></TextLink>. Therefore, the CVAD is removed only in a minority of all cases during the course of the infection, making the tip of the CVAD unavailable for microbiological examination (e.g., with the Maki method) <TextLink reference="51"></TextLink>, <TextLink reference="93"></TextLink>. </Pgraph><Pgraph><Indentation>Any recommendation to draw additional peripheral venous blood cultures (in addition to at least one blood culture set taken from the CVAD) will probably not be followed by the majority of POCs in Germany, since currently 90&#37; of all POCs only take blood cultures from the CVAD <TextLink reference="19"></TextLink>, <TextLink reference="34"></TextLink>. This practice has been implemented for many years to reduce pain, inconvenience and anxiety in pediatric cancer patients with fever and neutropenia <TextLink reference="94"></TextLink>.</Indentation></Pgraph><Pgraph>Before any sampling of blood from the CVAD, a thorough disinfection of the catheter hub is recommended, usually with an alcoholic disinfectant (short dwell time of 15&#8211;30 seconds) <TextLink reference="95"></TextLink>, <TextLink reference="18"></TextLink>, <TextLink reference="96"></TextLink>. Given a double-lumen Broviac&#47;Hickman, this procedure is performed for both lumina (one blood culture set from each lumen) <TextLink reference="97"></TextLink>, <TextLink reference="98"></TextLink>. Referring to a survey from 2013 <TextLink reference="19"></TextLink>, only 7&#37; of 29 GPOH-POCs were able to perform a quantitative analysis of blood cultures or a <Mark2>differential time to positivity</Mark2> in their in-house or external microbiology department.</Pgraph><Pgraph>The DTP measures the time from blood culture sampling to the first positive signal indicating growth in a blood culture bottle. If a difference in time to detection of more than 2 hours is automatically documented (blood culture from the CVAD positive at least 2 hours earlier than from the peripheral venous cultures), the origin of the BSI may be the CVAD <TextLink reference="99"></TextLink>. Chen et al. investigated the DTP method in children and adults with cancer <TextLink reference="100"></TextLink>, finding that the sensitivity of the DTP was 83&#37; concerning those infections in which the origin of the BSI was the CVAD (catheter-related BSI; CR-BSI).</Pgraph><Pgraph>Handrup et al. from Aarhus (Denmark) examined 654 paired blood cultures between April 2008 and December 2012 in pediatric cancer patients with fever. The authors ultimately detected 112 BSI (17&#37; of all febrile events). Of these, 64 (57&#37;) were allocated to the category of CR-BSI, indicating that in 43&#37; of all BSI, the CVAD was probably not the source of the BSI <TextLink reference="89"></TextLink>.</Pgraph><Pgraph>The validity of the DTP method depends on many critical control points. For instance, the CVAD must allow the necessary amount of blood to be drawn, and it is essential that this be the same volume per bottle as the peripheral venous blood culture. Furthermore, the time of sampling must be documented correctly; the storage and transport of the samples must be identical. Not all results of the DTP are discriminative (more than 2 h difference). In contrast to a quantitative examination of the blood cultures&#8217; yield, the DTP is quite easily conducted in the microbiology laboratory. All things considered, the DTP appears to be the most feasible method to identify or exclude the CVAD as the source of the BSI without removal of the device. </Pgraph><Pgraph><Indentation>Certain clinical information may indicate that the CVAD is the most probable source of the BSI: </Indentation></Pgraph><Pgraph><UnorderedList><UnorderedList><ListItem level="2">Fever appears soon after flushing the CVAD;</ListItem></UnorderedList><UnorderedList><ListItem level="2">Subsequent blood cultures drawn from the CVAD remain positive for the same pathogen despite antibiotic treatment:</ListItem></UnorderedList><UnorderedList><ListItem level="2">Fever disappears after an ethanol-lock <TextLink reference="51"></TextLink>, <TextLink reference="101"></TextLink> or immediately after removal of the CVAD.</ListItem></UnorderedList></UnorderedList></Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Probleme bei der Zuordnung zum Gef&#228;&#223;katheter"> <MainHeadline>Probleme bei der Zuordnung zum Gef&#228;&#223;katheter</MainHeadline><SubHeadline>Zwei unabh&#228;ngige Blutkulturen bei V.a. eine Blutstrominfektion&#63;</SubHeadline><Pgraph>Bei einem einlumigen System (einlumiger Broviac oder Port) wird in der Regel sofort nach Abnahme des ersten Blutkultursets &#91;<Mark2>Ein Blutkulturset entspricht einer aeroben und einer anaeroben Blutkulturflasche.</Mark2>&#93; mit der empirischen antibiotischen Therapie begonnen <TextLink reference="75"></TextLink>, ein zweites Blutkulturset wird oft erst im Verlauf nach 12&#8211;24 Stunden abgenommen. Die Interpretation von Blutkulturen mit Nachweis von Hautflora (z.B. CoNS, Corynebakterien, Propionibakterien) ist daher aus der Perspektive der Infektionssurveillance bei einem erheblichen Teil aller kinderonkologischen Patienten mit BSI eine Herausforderung. Das von der CDC 2008 eingef&#252;hrte Paradigma der zweiten positiven und &#8222;zeitlich unabh&#228;ngig entnommenen&#8220; Blutkultur <TextLink reference="87"></TextLink> wird bei Fieber in Neutropenie oft nicht vor Einleitung der empirischen Therapie erf&#252;llt. Kann einer der oben genannten Erreger nur in einem initial abgenommenem Blutkulturset nachgewiesen werden, wird diese Bakteri&#228;mie nach den CDC-Kriterien trotz des Vorhandenseins von Risikofaktoren (CVAD) als nicht relevant eingestuft.</Pgraph><Pgraph>Es ist erwiesen, dass sich der Anteil positiver Blutkulturen bei kinderonkologischen Patienten durch die parallele Abnahme zentral- und peripherven&#246;ser Blutkulturen um 12&#37; <TextLink reference="88"></TextLink> bis 18&#37; <TextLink reference="89"></TextLink> erh&#246;hen l&#228;sst. </Pgraph><Pgraph>Trotzdem ist die Abnahme von parallelen Blutkulturen nach den aktuellen GPOH-Empfehlungen nicht obligat <TextLink reference="18"></TextLink>, <TextLink reference="90"></TextLink>. </Pgraph><Pgraph>Durch die &#8218;fehlende&#8216; zweite positive Blutkultur f&#252;r BSI mit Nachweis von Hautflora wurden bei Kelly et al. <TextLink reference="10"></TextLink> nach der US-amerikanischen Definition <TextLink reference="87"></TextLink> ein erheblicher Anteil aller CA-BSI nicht mehr gez&#228;hlt; demnach fanden sich in der Erregerliste CoNS nicht mehr an erster, sondern nur noch an 4. Stelle (hinter Enterokokken, <Mark2>S. aureus</Mark2> und VGS) mit einem Gesamtanteil von 7&#37;. Bei Choi et al. reduzierte sich die Zahl der erfassten BSI nur durch die &#196;nderung dieser Definition um 18,6&#37; <TextLink reference="91"></TextLink>. </Pgraph><Pgraph><Indentation>Die Praxis des Ausschlusses aller BSI mit nur einem verf&#252;gbaren, aber positiven Blutkulturset, ohne Einbeziehung des klinischen Urteils der behandelnden &#196;rzte, f&#252;hrt in der Kinderonkologie zu Problemen bei der Surveillance von BSI. Um den Gegebenheiten in der klinischen Praxis besser gerecht zu werden, wurden in den multizentrischen Oncoped-Surveillancestudien CoNS-Infektionen auch zugelassen, wenn beide Blutkulturflaschen einer einzigen Abnahme positiv waren (aerob und anaerob), eine gezielte Antibiotikatherapie der CoNS-Infektion erfolgte und die behandelnden Kinderonkologen die positive Kultur nicht als Kontamination eingeordnet haben (<Mark2>clinical judgment</Mark2>) <TextLink reference="6"></TextLink>, <TextLink reference="1"></TextLink>. Die Surveillance sollte die klinische Einsch&#228;tzung der behandelnden &#196;rzte ber&#252;cksichtigen, um nicht an Akzeptanz zu verlieren.</Indentation></Pgraph><SubHeadline>Geht die BSI vom Gef&#228;&#223;katheter aus&#63;</SubHeadline><Pgraph>Immer dann, wenn bei Fieber in der Blutkultur eines kinderonkologischen Patienten bakterielle Infektionserreger nachgewiesen werden, stellt sich die Frage, ob der CVAD die Quelle der Blutstrominfektion ist. Da meistens nur ein aus dem CVAD abgenommenes Blutkulturset vorliegt, kann eine <Mark2>differential time to positivity</Mark2> (DTP, siehe unten) nicht ermittelt werden <TextLink reference="89"></TextLink>. Die meisten BSI werden in situ (&#252;ber den liegenden CVAD) behandelt <TextLink reference="92"></TextLink>, <TextLink reference="76"></TextLink>, so dass die Spitze des CVAD nicht (oder erst nach einer bereits begonnenen in situ Therapie) <TextLink reference="51"></TextLink> f&#252;r eine semiquantitative mikrobiologische Untersuchung zur Verf&#252;gung steht <TextLink reference="93"></TextLink>. </Pgraph><Pgraph><Indentation>Eine Empfehlung zur obligaten parallelen Abnahme von zentral- und peripherven&#246;sen Blutkulturen bei jedem kinderonkologischen Patienten mit Fieber und CVAD h&#228;tte in der Praxis wahrscheinlich nur sehr geringe Chancen auf Implementierung, weil in 90&#37; aller kinderonkologischen Abteilungen <TextLink reference="19"></TextLink>, <TextLink reference="34"></TextLink> bei Fieber und einem r&#252;ckl&#228;ufigen CVAD ausschlie&#223;lich Blutkulturen aus dem CVAD entnommen werden, um den Kindern Angst, Schmerzen und Stress zu ersparen, die mit der peripherven&#246;sen Punktion einhergehen <TextLink reference="94"></TextLink>. </Indentation></Pgraph><Pgraph>Vor der aseptischen Abnahme aus dem CVAD wird &#8211; wie bei jeder anderen Blutentnahme auch &#8211; eine sorgf&#228;ltige alkoholische Desinfektion des Katheterhubs durchgef&#252;hrt <TextLink reference="95"></TextLink>, <TextLink reference="18"></TextLink>, <TextLink reference="96"></TextLink>. Wenn es sich um ein mehrlumigen Broviac handelt, werden aus beiden Schenkeln eine aerobe und eine anaerobe Blutkultur entnommen <TextLink reference="97"></TextLink>, <TextLink reference="98"></TextLink>. Nur in 7&#37; aller 29 GPOH-Zentren, die 2013 an einem multizentrischen Survey teilgenommen haben <TextLink reference="19"></TextLink>, werden spezielle mikrobiologische Verfahren wie eine quantitative Auswertung von Blutkulturen oder eine Bestimmung der DTP eingesetzt. Bei dieser Methode werden zeitnah vor Beginn der Antibiotikatherapie sowohl aus dem CVAD als auch peripherven&#246;s Blutkulturen entnommen (gleiche Menge pro Flasche; exakte Dokumentation der Abnahmezeit) und in Bezug auf den Transport und die Bebr&#252;tung gleich behandelt. Der Blutkulturautomat dokumentiert Datum und Uhrzeit des ersten Signals, das ein Wachstum in der Flasche anzeigt. Ist bei diesem Verfahren die Blutkultur aus dem CVAD mindestens zwei Stunden vor der peripherven&#246;s entnommenen Blutkultur positiv (Latenz zwischen Abnahmezeitpunkt und erstem Signal), weist dies auf den CVAD als Quelle der BSI hin <TextLink reference="99"></TextLink>. Chen et al. fanden bei onkologisch behandelten Kindern und Erwachsenen <TextLink reference="100"></TextLink> eine Sensitivit&#228;t der DTP von 83&#37; f&#252;r Infektionen, die vom Gef&#228;&#223;katheter ausgehen (CR-BSI).</Pgraph><Pgraph>In einer prospektiven Studie aus Aarhus (D&#228;nemark) wurden zwischen April 2008 und Dezember 2012 bei kinderonkologischen Patienten mit Fieber insgesamt 654 gepaarte Blutkulturen (aus dem VCAD und peripherven&#246;s) abgenommen. Auf diese Weise wurden insgesamt 112 Blutstrominfektionen diagnostiziert (17&#37; aller Fieberepisoden), von denen mittels der DTP-Methode 64 (57&#37;) als CR-BSI ausgewiesen wurden. Umgekehrt bedeutet dies jedoch, dass der CVAD in 43&#37; wahrscheinlich nicht die Quelle der BSI war <TextLink reference="89"></TextLink>. </Pgraph><Pgraph>Die DTP setzt einen r&#252;ckl&#228;ufigen CVAD und ein strikt standardisiertes Vorgehen in Bezug auf die Blutmenge pro Flasche, die Dokumentation der Abnahmezeit sowie die Lagerung und den Transport der Blutkulturen voraus. Nicht alle Ergebnisse der DTP sind eindeutig (mehr als <TextGroup><PlainText>2 h</PlainText></TextGroup> Differenz). </Pgraph><Pgraph>Im Unterschied zu einer vergleichenden quantitativen Auswertung von Blutkulturen ist diese Methode jedoch nicht mit einem erheblichen Mehraufwand an Zeit und mikrobiologischem Fachpersonal verbunden. Zusammengefasst ist die DTP die praktikabelste Methode, den CVAD bei einer in situ Therapie (ohne Explantation) als Quelle einer Bakteri&#228;mie zu identifizieren oder auszuschlie&#223;en. Sie ist jedoch in der Kinderonkologie aufgrund mangelnder Akzeptanz bei Patienten und Behandlungsteam nicht durchsetzbar. </Pgraph><Pgraph><Indentation>Auch bestimmte klinische Verlaufsdaten k&#246;nnen auf den CVAD als Infektionsquelle hinweisen: </Indentation></Pgraph><Pgraph><UnorderedList><UnorderedList><ListItem level="2">Auffiebern des Patienten unmittelbar nach dem Sp&#252;len des Katheters;</ListItem></UnorderedList><UnorderedList><ListItem level="2">anhaltend oder rezidivierend positive Blutkultur aus dem CVAD (gleicher Erreger) trotz in situ Antibiotikatherapie;</ListItem></UnorderedList><UnorderedList><ListItem level="2">prompte Entfieberung des Patienten nach einem Ethanol-Block <TextLink reference="51"></TextLink>, <TextLink reference="101"></TextLink> oder nach Explantation des CVAD.</ListItem></UnorderedList></UnorderedList></Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Different types of BSI in pediatric cancer patients"> <MainHeadline>Different types of BSI in pediatric cancer patients</MainHeadline><SubHeadline>CVAD-associated versus CVAD-related BSI (CA- vs. CR-BSI)</SubHeadline><Pgraph>If the CVAD has been confirmed as the source of the BSI, the BSI is categorized as CR-BSI (<Mark1>c</Mark1>atheter <Mark1>r</Mark1>elated-BSI). Since this is difficult to prove in clinical practice (see above), many BSI in pediatric cancer patients without an identified alternative focus of bacteremia match the definition criteria for CVAD-associated BSIs (<Mark1>c</Mark1>atheter <Mark1>a</Mark1>ssociated-BSI; any positive blood culture in a symptomatic patient with a CVAD in use without another identifiable focus). Anglo-American surveillance systems use the term &#8220;central line-associated bloodstream infection (CLABSI)&#8221; to describe this category. In pediatric cancer patients with fever and neutropenia (with or without mucositis), it remains a challenge to detect the definite source of the BSI clinically. Even in well-trained surveillance personnel, this leads to uncertainties in how to correctly categorize a BSI, in particular when the attending physicians&#8217; assessment classifies the BSI as secondary (related to a clinically undefined focus or to translocation from the mucous membranes of the patient) <TextLink reference="102"></TextLink>. The <Mark1>CA-BSI</Mark1> definition aims for the almost complete detection and documentation of all BSIs (high sensitivity). </Pgraph><Pgraph>On the other hand, a substantial proportion of all CA-BSI are not <Mark2>related</Mark2> to the CVAD (low specificity) <TextLink reference="87"></TextLink> in this particular patient population <TextLink reference="103"></TextLink>, <TextLink reference="104"></TextLink>. Based on these it is legitimate to question why it still makes sense to use the CA-BSI category in pediatric cancer patients.</Pgraph><Pgraph>In the recently published surveillance study by Ammann et al. <TextLink reference="6"></TextLink>, the proportion of CVAD removal in CA-BSIs was identical to the corresponding proportion in secondary BSIs (5&#37; and 4&#37;, respectively). In contrast, 26&#37; of all CR-BSIs eventually resulted in the decision of the attending pediatric oncologist to remove the device.</Pgraph><Pgraph>If the infection control personnel only relies on the current definition of CA-BSI, this will interfere with the clinical practice and assessment of the attending pediatric oncologists <TextLink reference="105"></TextLink>, <TextLink reference="104"></TextLink>. In addition, these BSI categorization problems have led to a plethora of different definitions <TextLink reference="106"></TextLink> and to the suggestion to develop more specific, uniform definitions for this particular clinical setting <TextLink reference="107"></TextLink>. </Pgraph><Pgraph><Indentation>The validity of the surveillance results becomes questionable when a significant proportion of all BSI is denominated <Mark2>CVAD-associated</Mark2>, although these BSIs are <Mark2>not related</Mark2> to the CVAD. Many CVAD-<Mark2>associated</Mark2> BSI cannot be prevented by increasing the clinical implementation of and compliance with preventive CVAD maintenance-care bundles <TextLink reference="108"></TextLink>. This uncertainty may be one reason why only 42&#37; of all German POCs included in a 2013 survey performed a prospective surveillance of BSI <TextLink reference="19"></TextLink>.</Indentation></Pgraph><SubHeadline>Community- vs. nosocomially acquired BSI </SubHeadline><Pgraph><Indentation>One dubious strategy to &#8220;decrease&#8221; BSI rates (adjusted to utilization days of the CVAD) in pediatric cancer patients is to differentiate community- and nosocomially acquired BSI and to exclude all &#8220;community-acquired BSI&#8221; from the final analysis of the surveillance data. </Indentation></Pgraph><Pgraph>Neither the CDC definitions nor the definitions of the German National Reference Center for the Surveillance of Nosocomial Infection (NRZ, Charit&#233; Berlin) offer a definite time frame within which to assign the BSI to one of the above categories. US-American authors <TextLink reference="109"></TextLink>, <TextLink reference="110"></TextLink>, <TextLink reference="111"></TextLink> defined a latency of 48 hours (before or after admission to the hospital). The specificity of such an agreement is questionable in pediatric cancer patients, who often alternate between inpatient and outpatient treatment even during intensive chemotherapy periods <TextLink reference="10"></TextLink>, <TextLink reference="11"></TextLink>, <TextLink reference="109"></TextLink>, <TextLink reference="111"></TextLink>. It is impossible to definitely determine when the contamination&#47;colonization of the CVAD, which eventually leads to a CR-BSI in some but not all patients, has taken place.</Pgraph><Pgraph>Even in the outpatient setting, many manipulations of the CVAD hub are necessarily related to medical interventions, such as drawing blood for laboratory tests, outpatient chemotherapy, or transfusion of erythrocyte or thrombocyte concentrates. </Pgraph><Pgraph>In the German Infection Protection Act, all infections related to a medical intervention are considered nosocomial <TextLink reference="62"></TextLink>, <TextLink reference="112"></TextLink>.</Pgraph><Pgraph>On the other hand, the relative risk of a CR-BSI is much higher in the inpatient setting. Two studies in pediatric cancer patients identified a risk ratio of about 8 compared to the outpatient setting <TextLink reference="2"></TextLink>, <TextLink reference="9"></TextLink>; this seems plausible since inpatients require many more manipulations of the CVAD and the infusion system, and the proportion of patients with severe neutropenia and mucositis requiring morphine infusion and parenteral nutrition is much higher in inpatients. Referring to the above-mentioned definition, Rinke et al. compared all BSI in 319 pediatric oncology patients during a 22-month surveillance <TextLink reference="111"></TextLink>. The authors detected 55 community-acquired CA-BSI (infection rate, IR, 0.65&#47;1000 utilization days; CI95 0.49&#8211;0.85) and 19 inpatient CA-BSIs (infection rate 2.2, CI95 1.3&#8211;3.4). Of the patients with community-acquired CA-BSI, 13&#37; had to be admitted to the PICU, and in 44&#37;, the CVAD was removed during the course of the infection. As in many previous studies, the relative risk of a BSI event was significantly greater with Broviac&#47;Hickman CVADS vs. Ports (odds ratio 20.6; CI95 7.6&#8211;69; p&#60;0.001). Further independent risk factors were bone marrow transplantation in the preceding 10 days (odds ratio OR 16, CI95 1.1&#8211;264), medical history of a previous CA-BSI (OR 10, CI95 2.5&#8211;43), and CVAD implantation less than 4 weeks before the event (OR 4.2; CI95 1.0&#8211;17). Although the outpatient infection rate was lower (due to the greater number of &#8220;utilization days&#8221; in the denominator; RR 3.4; 0.65 vs. 2.2 CA-BSI per 1000 utilization days), the absolute number of events was 2.9-times higher in the outpatient setting (n&#61;55 vs. n&#61;19). Allen et al. previously came to the same conclusion (n&#61;41 in outpatients vs. n&#61;17 in inpatients) <TextLink reference="9"></TextLink>. The recent Oncoped Surveillance study used 72 hours as an arbitrary time latency to assign the CA-BSI to the category &#8220;community-acquired&#8221;; this was the case in 43&#37; of all documented BSIs <TextLink reference="6"></TextLink>. </Pgraph><Pgraph><Indentation>The results of several recent studies demonstrate <TextLink reference="109"></TextLink>, <TextLink reference="111"></TextLink>, <TextLink reference="9"></TextLink>, <TextLink reference="6"></TextLink> that the surveillance of BSI in pediatric cancer patients should not focus only on the inpatient setting, since this excludes important parts of the problem (epidemiology, risk profiles, pathogen distribution, in vitro resistance, clinical course of and resource allocation to &#8220;community-acquired BSIs&#8221;). The maintenance care of CVADs in POC outpatient clinics may increase the risk of CR-BSIs <TextLink reference="113"></TextLink>. This may be particularly relevant if relatives&#47;caregivers of the pediatric cancer patients are actively involved in maintenance care of the CVAD or manage these issues during home parenteral nutrition <TextLink reference="114"></TextLink>, <TextLink reference="115"></TextLink>.</Indentation></Pgraph><SubHeadline>Mucosal barrier injury-associated bloodstream infection</SubHeadline><Pgraph>To manage the uncertainties and challenges described above, in particular in patients with high risk of translocation &#91;severe and protracted neutropenia, mucositis and&#47;or graft-versus-host disease (GVHD)&#93; <TextLink reference="29"></TextLink>, a consensus working group in the USA has recently developed a new category&#47;definition: &#8220;Mucosal Barrier Injury Laboratory-Confirmed Bloodstream Infection&#8221; (MBI-LCBI). Referring to the unique epidemiology of BSI in patients with severe and protracted neutropenia, mucositis and&#47;or GVHD <TextLink reference="30"></TextLink>, oncologists, infectious disease physicians, and infection control specialists (surveillance) piloted criteria for such a definition <TextLink reference="116"></TextLink> and evaluated their feasibility and applicability in a study including 38 oncology centers <TextLink reference="117"></TextLink>. The new MBI-LCBI category was implemented after minor modification <TextLink reference="118"></TextLink>. The pilot study elucidated certain limitations of the new definition <TextLink reference="117"></TextLink>. First, in many oncology centers, a differential leucocyte count was not available when the total number of leukocytes fell below a certain cut-off (e.g., 0.3x10<Superscript>9</Superscript>&#47;L) <TextLink reference="119"></TextLink>. In this regard, the criterion of neutropenia was adjusted to &#60;0.5x10<Superscript>9</Superscript>&#47;L (with a duration of at least 2 days temporally related to the BSI) <TextLink reference="117"></TextLink>. Interestingly, in a recent Delphi study performed with a consortium of 45 international experts, no consensus was reached how to define <Mark2>neutropenia</Mark2> in the clinical context of fever in pediatric cancer patients <TextLink reference="120"></TextLink>. </Pgraph><Pgraph>The second obstacle in the above-mentioned pilot trial was the documentation of symptoms in the patient file, which may allow the grading of any GVHD of the gastrointestinal tract (in particular, number of bowel movements and quantification of volume losses related to diarrhea). These items were incompletely documented in 55&#37; of the patients&#8217; files. In 47&#37;, grading of the GVHD was available in writing as case note derived from the attending oncologists <TextLink reference="121"></TextLink>. In addition, the question remains as to which grading system this documentation of GVHD should finally refer to. </Pgraph><Pgraph>Clinical studies often use the Common Terminology Criteria for Adverse Events (CTCAE; <Hyperlink href="http:&#47;&#47;evs.nci.nih.gov&#47;ftp1&#47;CTCAE&#47;About.html">http:&#47;&#47;evs.nci.nih.gov&#47;ftp1&#47;CTCAE&#47;About.html</Hyperlink>). The optimal&#47;most feasible grading system for GVHD is still a matter of debate among oncologists performing allogeneic bone marrow or stem cell transplants <TextLink reference="122"></TextLink>. Severe GVHD, with fluid loss of more than 1 liter per day or more than 20ml&#47;kg bodyweight in children, leads to medical intervention intended to reduce fluid- and electrolyte losses in patients with GVHD-related diarrhea. Different medical intervention strategies certainly have a variable influence on the GVHD severity (risk of confounding).</Pgraph><Pgraph>Finally, the new MBI-CLBSI definition has worked as a self-fulfilling prophecy, leading to a significant reduction of CA-BSI in oncology patients as a result of a change in categorization. In the study performed by See et al. <TextLink reference="117"></TextLink>, this was the case in 37&#37; of all BSI (45&#37; in 10 participating specialized oncology treatment centers, including <TextGroup><PlainText>2 POCS</PlainText></TextGroup>). In 91&#37;, neutropenia was the leading criterion (GVHD only in 9&#37;). The study by Metzger et al. <TextLink reference="118"></TextLink> describes a more pronounced consequence of the new definition: of 66 BSIs without a clinically or microbiologically defined secondary focus of infection, 47 (71&#37;) were allocated to the new MBI-LCBI category; only 19 (29&#37;) remained in the traditional CA-BSI category. As in the See study, neutropenia was the leading criterion; only 9&#37; of all cases in the MBI-LCBI group displayed GVHD (&#8220;any grade&#8221;), and only 40&#37; mucositis (&#8220;any grade&#8221;). The most prevalent pathogens in MBI-LCBIs were <Mark2>E. coli</Mark2> (32&#37;), <Mark2>Enterococcus faecium</Mark2> (30&#37;) and VGS (21&#37;), in contrast to <Mark2>S. aureus</Mark2> (26&#37;), CoNS (21&#37;), and <Mark2>P. aeruginosa</Mark2> (16&#37;) in the remaining cases. How did this new categorization influence infection rates&#63; Without the new definition of MBI-LCBI, the IR was 3.21 BSI&#47;1000 utilization days, but after implementation of the MBI-LCBI definition, the IR was much lower (0.6). In this regard, the new definition led to a relative reduction of the IR by a factor of 5.4 (only 6 of 32 events were defined as CA-BSI). Surprisingly, 47&#37; of the non-MBI-LCBI patients had mucositis (&#8220;any grade&#8221;), and in both groups, the majority of the central venous catheters were removed related to the infection (MBI-LCBI group, 64&#37;; non-MBI-LCBI group, 74&#37;).</Pgraph><Pgraph>No patient in the non-MBI-LCBI group died related to the BSI, but 15&#37; of all patients in the MBI-LCBI group did, temporally related to the BSI (p&#61;0.18). In 74&#37; of the non-MBI-LCBI patients with granulocytopenia (74&#37;), the isolated pathogen did not allow allocation to the MBI-LCBI group (only certain species are allowed).</Pgraph><Pgraph>At best, the introduction and practical implementation of this new BSI category in the CDC definition can be described as a &#8220;work in progress&#8221; <TextLink reference="119"></TextLink>; unfortunately, it appears that one unspecific definition (CA-BSI) has been replaced by another (MBI-LCBI), which still leaves a great deal of room for individual interpretation <TextLink reference="102"></TextLink>, <TextLink reference="123"></TextLink>. In addition, it is not known how or whether the incidence of MBI-LCBI is influenced by CVAD maintenance care bundles <TextLink reference="118"></TextLink>, although it remains probable that some of these BSI stem from the CVAD.</Pgraph><Pgraph>This assumption was proven very impressively in a recent study by Shelburne et al. <TextLink reference="31"></TextLink>. Those authors retrospectively analyzed BSI caused by VGS (n&#61;82). In these febrile adult oncology patients, central venous and peripheral venous cultures were drawn and quantitatively analyzed. The BSI was attributed to the CVAD when the quantitative analysis revealed a &#8805;3x higher CFU count in the central venous culture or when a semiquantiative culture of the catheter tip after removal showed growth of more than 15 CFU <TextLink reference="93"></TextLink>. Following this diagnostic stratification, 27 of 82 VGS BSI (33&#37;) were categorized as CR-BSI. Patients with such an event were significantly more often neutropenic and had significantly more often received FCH prophylaxis (in this group, the prevalence of FCH-resistant VGS reached 81&#37;, as opposed to 54&#37; in those patients without FCH prophylaxis). In the CR-BSI group, the central venous catheter was significantly more often removed during the infection (22&#37; vs. 2&#37;). If the new MBI-LCBI criteria had been applied, 71 (87&#37;) would have been assigned to this category, in most cases due to the concomitant items neutropenia and BSI due to VGS <TextLink reference="31"></TextLink>.</Pgraph><SubHeadline>Pay for Performance as an important reason for changing the surveillance definitions in the U.S.A</SubHeadline><Pgraph>In the U.S.A., the surveillance definitions for healthcare-associated infections are determined by the Centers for Disease Control and Prevention (CDC) and the National Health and Safety Network (NHSN) <TextLink reference="87"></TextLink>. Since 2011, some health care authorities&#47;regulation agencies have regional recommendations to publish infections rates on public websites (public reporting) <TextLink reference="124"></TextLink>. This decision was prompted by the assumption that most of these BSI are preventable events <TextLink reference="125"></TextLink>, <TextLink reference="126"></TextLink>. Hospitals with continuously high IRs should realize that public reporting may result in a negative medical reputation and are requested to increase their efforts in terms of prevention <TextLink reference="127"></TextLink>. In addition, some of the most important reimbursement institutions, such as the Centers for Medicare and Medicaid Services (<Hyperlink href="http:&#47;&#47;medicaid.gov&#47;">http:&#47;&#47;medicaid.gov&#47;</Hyperlink>), refuse to pay for this &#8220;bad performance&#8221; (preventable complications). This pay-for-performance concept coupled with zero tolerance towards preventable BSIs compels the hospital administration to invest in prevention <TextLink reference="128"></TextLink>. </Pgraph><Pgraph>Such a legal and financial framework places substantial pressure on those institutions which define the corresponding events; the question &#8220;<Mark2>Is this BSI really a CR-BSI&#63;</Mark2>&#8221; gains paramount importance <TextLink reference="105"></TextLink>. Physicians who care for high-risk oncology patients may experience a conflict of interest, and the official allocation of a BSI event to the CA-BSI or CR-BSI category will become less probable. Public benchmarking between hospitals exacerbates this conflict <TextLink reference="129"></TextLink>, <TextLink reference="130"></TextLink>. Fortunately, there is hitherto no recommendation for public reporting and benchmarking of BSI infection rates in Germany, Austria, or Switzerland (in Germany, there is only a notification requirement for BSI caused by methicillin-resistant <Mark2>S. aureus</Mark2>).</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Verschiedene Formen von Blutstrominfektionen"> <MainHeadline>Verschiedene Formen von Blutstrominfektionen</MainHeadline><SubHeadline>Gef&#228;&#223;katheter-assoziierte vs. vom Gef&#228;&#223;katheter ausgehende Infektion (CA- vs. CR-BSI)</SubHeadline><Pgraph>Kann der CVAD als Quelle der BSI gesichert werden, spricht man von einer vom Gef&#228;&#223;katheter ausgehenden Infektion (<Mark1>c</Mark1>atheter-<Mark1>r</Mark1>elated BSI). Wenn keine besonderen mikrobiologischen Testverfahren zur Sicherung des CAVD als Infektionsquelle eingesetzt wurden (DTP, siehe oben) und es sich <Mark3>nicht</Mark3> um eine BSI handelt, die von einem klinisch oder mikrobiologisch gesicherten Infektionsfokus an anderer Stelle ausgeht, entsprechen die meisten BSI bei kinderonkologischen Patienten den Kriterien einer prim&#228;ren Gef&#228;&#223;katheter-assoziierten Infektion (<Mark1>c</Mark1>atheter-<Mark1>a</Mark1>ssociated-BSI). In der angloamerikanischen Terminologie werden diese Infektionen als &#8218;central line-associated bloodstream infection (CLABSI)&#8216; ausgewiesen. Prinzipiell handelt es sich um laborbest&#228;tigte Ereignisse mit positiver Blutkultur. Bei kinderonkologischen Patienten mit Fieber, Granulozytopenie und Mukositis kann sehr h&#228;ufig kein &#8218;sonstiger Fokus&#8216; als Quelle der Bakteri&#228;mie gesichert werden. </Pgraph><Pgraph>Auch bei gut trainiertem Surveillance-Personal besteht dann eine erhebliche Unsicherheit in der Zuordnung (CA-BSI vs. sekund&#228;re BSI), v.a. bei den Erregern, die aus klinisch-onkologischer&#47;infektiologischer Sicht von den entz&#252;ndeten Schleimh&#228;uten des granulozytopenischen Patienten ausgehen <TextLink reference="102"></TextLink>. Die Definition der <Mark1>CA-BSI</Mark1> f&#252;hrt im Interesse der Erfassung m&#246;glichst aller BSI bei kinderonkologischen Patienten zu einer hohen Sensitivit&#228;t, ein erheblicher Anteil dieser mit dem Gef&#228;&#223;katheter <Mark2>assoziierten</Mark2> Infektionen geht jedoch nicht vom CVAD aus. Der Definition mangelt es an Spezifit&#228;t <TextLink reference="87"></TextLink> in der hier betrachteten besonderen Patientenpopulation <TextLink reference="103"></TextLink>, <TextLink reference="104"></TextLink>. Insofern stellt sich die Frage, welchen Nutzen die Kategorie CA-BSI f&#252;r die Surveillance von Blutstrominfektionen bei kinderonkologischen Patienten hat.</Pgraph><Pgraph>In einer k&#252;rzlich publizierten multizentrischen Surveillancestudie von Ammann et al. <TextLink reference="6"></TextLink> zeigte sich, dass bei CA-BSI die Rate der im Verlauf der BSI explantierten CVADs mit 5&#37; nahezu genauso hoch war, wie bei den sekund&#228;ren Bakteri&#228;mien (4&#37;). Im Unterschied dazu wurden bei CR-BSI 26&#37; der CVADs im Verlauf der Infektion nicht-elektiv entfernt. Wendet das mit der Surveillance beauftragte Hygienefachpersonal die Standarddefinitionen (CA-BSI) konsequent an, f&#252;hrt dies unweigerlich zu einem Konflikt mit dem klinischen Urteil des kinderonkologischen Behandlungsteams <TextLink reference="105"></TextLink>, <TextLink reference="104"></TextLink>. Dies und die Vielzahl der in klinischen Studien verwendeten Definitionen <TextLink reference="106"></TextLink> hat zu der Forderung gef&#252;hrt, die Definitionen f&#252;r BSI bei onkologischen Patienten zu verbessern und zu vereinheitlichen <TextLink reference="107"></TextLink>. </Pgraph><Pgraph><Indentation>Die Glaubw&#252;rdigkeit und der Nutzen der prospektiven Surveillance wird in Frage gestellt, wenn ein erheblicher Anteil aller BSI, die nicht vom CVAD ausgehen und somit auch nicht durch eine Verbesserung der Erhaltungspflege am CVAD zu vermeiden sind, dem CVAD zugeordnet werden (CA-BSI) <TextLink reference="108"></TextLink>. <LineBreak></LineBreak>M&#246;glicherweise ist auch diese Unsch&#228;rfe in den Definitionen ein Grund daf&#252;r, dass nur 42&#37; der im Survey von 2013 befragten 29 GPOH-Zentren im Jahr 2011 eine prospektive Surveillance von Blutstrominfektionen durchgef&#252;hrt haben <TextLink reference="19"></TextLink>.</Indentation></Pgraph><SubHeadline>Ambulant vs. nosokomial erworbene BSI </SubHeadline><Pgraph><Indentation>Eine M&#246;glichkeit, die Zahl und die Rate der dokumentierten Blutstrominfektionen (CA-BSI) eines kinderonkologischen Behandlungszentrums vermeintlich zu &#8218;senken&#8216;, ist die Unterscheidung zwischen ambulant und nosokomial erworbenen CA-BSI und der Ausschluss aller &#8218;ambulant erworbenen&#8216; BSI von der Auswertung. </Indentation></Pgraph><Pgraph>In diesem Kontext ist weder in den CDC-Definitionen noch in den KISS Definitionen eine feste Zeitgrenze festgelegt worden. US-amerikanische Autoren <TextLink reference="109"></TextLink>, <TextLink reference="110"></TextLink>, <TextLink reference="111"></TextLink> haben eine solche Zeitgrenze definiert (ambulant erworben: Symptombeginn oder Abnahme der ersten Blutkultur weniger als 48 Stunden nach der station&#228;ren Aufnahme und l&#228;nger als 48 Stunden nach Entlassung). Die Spezifit&#228;t einer solchen Definition ist fraglich in einer Patientenpopulation, die w&#228;hrend der intensiven Therapie st&#228;ndig zwischen ambulanter und station&#228;rer Versorgung wechselt <TextLink reference="10"></TextLink>, <TextLink reference="11"></TextLink>, <TextLink reference="109"></TextLink>, <TextLink reference="111"></TextLink>. Wir k&#246;nnen nicht mit Sicherheit sagen, wann die bakterielle Kontamination des Katheterhubs oder -lumens erfolgt ist. Selbst wenn es in der onkologischen Ambulanz beim Sp&#252;len des Gef&#228;&#223;katheters nach einer Bluttransfusion geschehen ist, erf&#252;llt die nachfolgende Infektion bei einem ambulanten Patienten die Kriterien einer nosokomialen Infektion nach dem (deutschen) Infektionsschutzgesetz <TextLink reference="62"></TextLink>, <TextLink reference="112"></TextLink>.</Pgraph><Pgraph>Das Risiko einer CA-BSI ist &#8211; bemessen an der Infektionsrate pro 1000 Anwendungstage &#8211; w&#228;hrend des station&#228;ren Aufenthaltes um den Faktor 8 erh&#246;ht <TextLink reference="2"></TextLink>, <TextLink reference="9"></TextLink>, wahrscheinlich auch weil bei den station&#228;r behandelten Patienten deutlich mehr Manipulationen am Katheter bzw. am Infusionssystem erfolgen und ein h&#246;herer Anteil dieser Patienten eine Granulozytopenie und eine schwere Mukositis mit parenteraler Ern&#228;hrung und Morphin-Dauerinfusion aufweist. Rinke et al. haben eine vergleichende Studie publiziert <TextLink reference="111"></TextLink>, die in 22 Monaten bei insgesamt 319 kinderonkologischen Patienten alle BSI erfasste. Insgesamt kam es im Beobachtungszeitraum zu 55 ambulant erworbenen CA-BSI (Infektionsrate 0,65&#47;1000 Anwendungstage; 95&#37;-Konfidenzintervall CI95 0,49&#8211;0,85) sowie zu 19 CA-BSIs bei station&#228;ren Patienten (Infektionsrate 2,2 pro 1000 Anwendungstage; CI95 1,3&#8211;3,4). Unter den Patienten mit ambulant erworbener CA-BSI mussten 13&#37; intensivmedizinisch behandelt werden und bei 44&#37; wurde der CVAD im Verlauf der Infektion explantiert. </Pgraph><Pgraph>Wie in zahlreichen anderen Studien war das Risiko einer BSI beim externalisierten getunnelten Hickman&#47;Broviac CVAD im Vergleich mit dem voll implantierten Port deutlich erh&#246;ht (relative Infektionsrate 20,6; CI95 7,6&#8211;69; P&#60;0.001). Weitere unabh&#228;ngige Risikofaktoren waren eine Knochenmarktransplantation in den letzten 100 Tagen (Odds ratio OR 16, CI95 1,1&#8211;264), eine vorausgegangene CA-BSI (OR 10, CI95 2,5&#8211;43) und ein Abstand zur Katheterinsertion von weniger als 4 Wochen (OR 4,2; CI95 1,0&#8211;17). Obwohl aufgrund der kumulativ deutlich h&#246;heren Zahl an ambulanten &#8218;Anwendungstagen&#8216; die ambulante Infektionsrate um den Faktor 3,4 niedriger ist (0,65 vs. 2,2&#47;1000 Anwendungstage) war die absolute Zahl der ambulant erworbenen BSI 2,9-mal h&#246;her als die der station&#228;ren Ereignisse (55 vs. 19). Auch bei Allen et al. war im Beobachtungszeitraum die absolute Zahl der ambulant erworbenen BSI h&#246;her (41 vs. 17) <TextLink reference="9"></TextLink>. In der aktuellsten multizentrischen Oncoped Surveillancestudie waren 43&#37; der Patienten (mit einer Zeitgrenze von 72 Stunden) vor dem Ereignis in ambulanter Behandlung <TextLink reference="6"></TextLink>. </Pgraph><Pgraph><Indentation>Die Ergebnisse dieser Studien <TextLink reference="109"></TextLink>, <TextLink reference="111"></TextLink>, <TextLink reference="9"></TextLink>, <TextLink reference="6"></TextLink> unterstreichen, dass eine Surveillance, die sich nur auf die &#8222;station&#228;r erworbenen F&#228;lle&#8220; beschr&#228;nkt, in der Kinderonkologie lediglich von eingeschr&#228;nktem Nutzen ist, da sie wichtige Aspekte des Problems ausblendet (Vorkommen, Risikoprofil, Erregerspektrum, Resistenzprofil, Verlauf und erforderliche Allokation von Ressourcen f&#252;r die ambulant erworbenen BSI). Auch die Erhaltungspflege des CVAD in kinderonkologischen Ambulanzen und Tageskliniken (ambulante Chemotherapie, Transfusionen&#33;) birgt ein Risiko f&#252;r die Entstehung von BSI <TextLink reference="113"></TextLink>. Erst recht gilt dies, wenn die Kinder heimparenteral ern&#228;hrt werden und geschulte Angeh&#246;rige die Pflege des CVAD mit &#252;bernehmen m&#252;ssen <TextLink reference="114"></TextLink>, <TextLink reference="115"></TextLink>.</Indentation></Pgraph><SubHeadline>Mucosal Barrier Injury-Associated Bloodstream Infection</SubHeadline><Pgraph>Um dem Problem der mangelnden Spezifit&#228;t der Definition von CA-BSI bei onkologischen Patienten zu begegnen und neben der Granulozytopenie auch die Risikofaktoren GVHD und Chemotherapie-induzierte Mukositis (Translokationen) <TextLink reference="29"></TextLink> einzubeziehen, wurde in den USA in den letzten Jahren eine neue Definition f&#252;r eine sogenannte &#8222;Mucosal Barrier Injury Laboratory-Confirmed Bloodstream Infection&#8220; (MBI-LCBI) entwickelt. Ausgehend von Erregerprofilen bei Patienten mit schwerer Mukositis oder mit GVHD des Gastrointestinaltraktes nach allogener Stammzelltransplantation (SCT) <TextLink reference="30"></TextLink> wurden von Onkologen, Infektiologen und Surveillance-Fachpersonal Kriterien f&#252;r eine solche Infektion projektiert <TextLink reference="116"></TextLink>, in einem Feldversuch mit 38 Kliniken evaluiert <TextLink reference="117"></TextLink> und schlie&#223;lich in modifizierter Form eingef&#252;hrt und angewendet <TextLink reference="118"></TextLink>. In der Erprobungsphase wurden einige wesentliche Limitationen der neuen Definition deutlich <TextLink reference="117"></TextLink>. Zum einen gab es in vielen Zentren keine detaillierte quantitative Z&#228;hlung der Granulozyten, wenn ein bestimmter Mindestwert (z.B. 300&#47;&#181;l&#61;0,3x10<Superscript>9</Superscript>&#47;L) unterschritten wird <TextLink reference="119"></TextLink>. Daraus resultierte letztendlich das Kriterium f&#252;r die Granulozytopenie von &#60;500&#47;&#181;l (&#60;0,5x10<Superscript>9</Superscript>&#47;L) &#252;ber mindestens 2 Tage im zeitlichen Kontext mit der BSI <TextLink reference="117"></TextLink>. Interessanterweise konnte k&#252;rzlich ein Konsortium aus 45 internationalen Experten zu Infektionen in der Kinderonkologie keinen Konsensus (Delphi-Verfahren, mehr als 80&#37; &#220;bereinstimmung) in Bezug auf die Frage erzielen, welche absoluten Werte hier als Grenze f&#252;r eine &#8222;Granulozytopenie&#8220; eingesetzt werden sollen <TextLink reference="120"></TextLink>. Zum anderen war die Dokumentation von Symptomen, die dem Eintrittskriterium einer schweren GVHD des Darmes (Grad III&#8211;IV) zugeordnet werden k&#246;nnen (v.a. Ausma&#223; der Diarrhoe in Liter&#47;Tag), in 55&#37; der Patientenkurven unvollst&#228;ndig. In 47&#37; erfolgte keine schriftliche Dokumentation des GVHD-Schweregrades durch die behandelnden Onkologen <TextLink reference="121"></TextLink>. Hier stellt sich auch die Frage, unter Bezug auf welchen Standard dies erfolgen soll. In klinischen Studien kommen meist die &#8222;Common Terminology Criteria for Adverse Events&#8220; (CTCAE) zur Anwendung (<Hyperlink href="http:&#47;&#47;evs.nci.nih.gov&#47;ftp1&#47;CTCAE&#47;About.html">http:&#47;&#47;evs.nci.nih.gov&#47;ftp1&#47;CTCAE&#47;About.html</Hyperlink>). Die am besten geeignete Einteilung des Schweregrads einer GVHD ist immer noch Gegenstand intensiver internationaler Diskussionen unter den Transplanteuren <TextLink reference="122"></TextLink>. Patienten mit schwerer GVHD erhalten nicht nur Immunsuppressiva zur Therapie der GVHD, sondern auch motilit&#228;tshemmende Medikamente (z.B. Morphin, Loperamid und weitere), was therapeutischen Einfluss auf das Ausma&#223; der Diarrhoe nimmt (&#8222;mehr als 1 L pro Tag oder mehr als 20 ml&#47;kg&#47;Tag bei Kindern und Jugendlichen&#8220;).</Pgraph><Pgraph>Letztendlich hat dieser Versuch einer Neudefinition im Sinne einer &#8222;selbsterf&#252;llenden Prophezeiung&#8220; dazu gef&#252;hrt, dass ein erheblicher Anteil aller prim&#228;ren bei onkologischen Patienten dokumentierten BSI nicht mehr den CA-BSI, sondern der Gruppe der MBI-LCBI zugeordnet wurden. Dies waren bei See et al. <TextLink reference="117"></TextLink> zum Beispiel 37&#37; aller prim&#228;ren BSI und 45&#37; aller in 10 onkologischen Spezialkliniken dokumentierten BSI (unter diesen auch 2 p&#228;diatrische Zentren). Dabei war das Kriterium der Granulozytopenie in 91&#37; der F&#228;lle zielf&#252;hrend, nur in 9&#37; handelte es sich um Patienten mit GVHD nach allogener SCT.</Pgraph><Pgraph>Bei Metzger et al. <TextLink reference="118"></TextLink> verschiebt sich diese Korrelation noch ausgepr&#228;gter: von 66 prim&#228;ren BSI ohne sonstigen Infektionsfokus wurden letztlich vollkommen protokollgerecht 47 (71&#37;) der MBI-LCBI-Kategorie zugewiesen; nur 19 (29&#37;) verblieben in der Kategorie der CA-BSI. Auch hier war die Granulozytopenie als Kriterium zielf&#252;hrend, in der MBI-LCBI-Gruppe hatten nur 9&#37; eine GVHD (&#8218;any grade&#8216;) und nur 40&#37; eine Mukositis (&#8218;any grade&#8216;). Spitzenreiter im Erregerspektrum bei den MBI-LCBI waren <TextGroup><Mark2>E. coli</Mark2></TextGroup> (32&#37;), <Mark2>Enterococcus faecium</Mark2> (30&#37;) und VGS (21&#37;) w&#228;hrend in der Non-MBI-LCBI-Gruppe <Mark2>S. aureus</Mark2> (26&#37;), CoNS (21&#37;) und <Mark2>P. aeruginosa</Mark2> (16&#37;) dominierten. Auch hier wurde die gro&#223;e Mehrzahl der Ereignisse der Kategorie MBI-LCBI aufgrund der Granulozytopenie zugeordnet (94&#37;), nur bei 6&#37; f&#252;hrte eine im Vorfeld durchgef&#252;hrte SCT mit akuter GVHD zur Einordnung in die MBI-LCBI-Kategorie. Wie wirkte sich dies auf die Infektionsraten aus&#63; Ohne die Kategorie MBI-LCBI lag die Infektionsrate bei 3,21 BSI&#47;1000 Anwendungstage, mit MBI-LCBI nur noch bei 0,6&#47;1000 Anwendungstage. Somit wurde die CA-BSI Rate allein durch eine &#196;nderung der Definitionen um den Faktor 5,4 gesenkt (nur noch 6 von 32 Ereignissen wurden als CA-BSI ausgewiesen). Erstaunlicherweise bestand bei 47&#37; der Non-MBI-LCBI-Patienten ein Mukositis (&#8218;any grade&#8216;) und in beiden Gruppen wurde die Mehrzahl aller zentraler Gef&#228;&#223;katheter im zeitlichen Zusammenhang mit der Infektion entfernt (MBI-LCBI-Gruppe 64&#37;, Non-MBI-LCBI-Gruppe 74&#37;). W&#228;hrend in der signifikant seltener granulozytopenischen Non-MBI-LCBI-Gruppe alle Patienten die Infektion &#252;berlebten, verstarben 15&#37; der Patienten in der MBI-LCBI-Gruppe im zeitlichen Kontext der Infektion (P&#61;0,18). Bei den Non MBI-LCBI-Patienten mit Granulozytopenie (74&#37;) war in der Regel die in der Blutkultur nachgewiesene Erregerspezies ausschlaggebend f&#252;r die Zuordnung (nur bestimmte Erreger lassen eine Einordnung in die Kategorie MBI-LCBI zu).</Pgraph><Pgraph>Wohlwollend kann man die Einf&#252;hrung und die praktische Implementierung der CDC-Definition f&#252;r MBI-LCBI als &#8222;Work in Progress&#8220; bezeichnen <TextLink reference="119"></TextLink>; leider wird hier eine wenig spezifische Definition (CA-BSI) durch eine andere, ebenfalls sehr unspezifische Definition (MBI-LCBI) ersetzt, die zudem einen erheblichen Interpretationsspielraum zul&#228;sst <TextLink reference="102"></TextLink>, <TextLink reference="123"></TextLink>. Au&#223;erdem bleibt unklar, wie sich Pr&#228;ventionsb&#252;ndel zur Vermeidung von CR-BSI auf die Rate von MBI-LCBI auswirken <TextLink reference="118"></TextLink>, weil wahrscheinlich auch ein Teil der MBI-LCBI tats&#228;chlich vom Gef&#228;&#223;katheter ausgeht.</Pgraph><Pgraph>Besonders eindr&#252;cklich wurde dies in einer aktuellen Studie aus der Arbeitsgruppe von Isam Raad aufgezeigt <TextLink reference="31"></TextLink>. Diese retrospektive Analyse befasste sich explizit mit BSI, die durch vergr&#252;nende Streptokokken (VGS) hervorgerufen wurden (n&#61;82). Bei Fieber wurden peripher und zentralven&#246;s Blutkulturen abgenommen und quantitativ ausgewertet. Wenn die Zahl der Kolonie-bildenden Einheiten (KBE) in der aus dem Gef&#228;&#223;katheter entnommenen Blutkultur &#8805;3-mal h&#246;her war als in der parallel abgenommenen peripherven&#246;sen Kultur, oder wenn die semiquantitative mikrobiologische Analyse der Katheterspitze nach Explantation VGS in einer Keimzahl von mehr als 15 KBE ergab <TextLink reference="93"></TextLink>, wurde die Infektion zur CR-BSI erkl&#228;rt. Insgesamt konnten so 27 von 82 VGS Bakteri&#228;mien (33&#37;) dem CVAD zugeordnet werden (CR-BSI). Patienten mit einem solchen Ereignis waren signifikant h&#228;ufiger granulozytopenisch und hatten signifikant h&#228;ufiger eine Fluorochinolon-Prophylaxe erhalten (in dieser Gruppe fanden sich signifikant h&#228;ufiger FCH-resistente VGS; 81&#37; vs. 54&#37;). In der CR-BSI Gruppe wurde der CVAD signifikant h&#228;ufiger im zeitlichen Kontext der Infektion entfernt (22&#37; vs. 2&#37;). Bei Anwendung der neuen MBI-LCBI Kriterien w&#228;ren 71 (87&#37;) der Patienten der Kategorie MBI-LCBI zugewiesen worden und zwar vorwiegend wegen des Zusammentreffens eines bestimmten Erregers (VGS) mit einer Granulozytopenie <TextLink reference="31"></TextLink>.</Pgraph><SubHeadline>Pay for Performance als treibende Kraft f&#252;r die &#196;nderung von Surveillance Definitionen in den USA</SubHeadline><Pgraph>In den USA werden die Definitionen f&#252;r CA-BSI von den Centers for Disease Control and Prevention (CDC) &#252;ber das National Health and Safety Network (NHSN) vorgegeben <TextLink reference="87"></TextLink>. Es besteht zudem in einigen Bundesstaaten seit 2011 die Pflicht zur Publikation von bestimmten Infektionsraten, u.a. auch von CA-BSI bei Intensivpatienten (auch PICU und NICU) auf &#246;ffentlich zug&#228;nglichen Webseiten <TextLink reference="124"></TextLink>. Dahinter steht, dass es sich bei diesen Infektionen in den meisten F&#228;llen um vermeidbare medizinische Komplikationen handelt <TextLink reference="125"></TextLink>, <TextLink reference="126"></TextLink>. Kliniken mit anhaltend hohen &#8222;&#246;ffentlich einsehbaren&#8220; Infektionsraten gef&#228;hrden ihre Reputation und sollen dazu gezwungen werden, mehr in die Pr&#228;vention zu investieren <TextLink reference="127"></TextLink>. Gleichzeitig verweigert einer der wichtigsten Refinanzierer (Centers for Medicare and Medicaid Services; CMS; <Hyperlink href="http:&#47;&#47;medicaid.gov&#47;">http:&#47;&#47;medicaid.gov&#47;</Hyperlink>) die Erstattung aller Behandlungskosten, die mit der Therapie von CA-BSI auf Intensivstationen einhergehen (pay for perfomance, zero tolerance). Auch dies soll ein sehr konkreter Anreiz daf&#252;r sein, mehr f&#252;r die Pr&#228;vention solcher Ereignisse zu tun <TextLink reference="128"></TextLink>. Aufgrund dieser Rahmenbedingungen geraten diejenigen, die solche Ereignisse definieren, unter erheblichen Druck der Anwender, wenn die Definitionen eine mangelnde Spezifit&#228;t aufweisen (&#8222;Ist der CVAD die Infektionsquelle oder nicht&#63;&#8220;) <TextLink reference="105"></TextLink>. Auf Seiten der Anwender entsteht zudem ein massiver Interessenskonflikt zwischen dem Schutz des Patienten, dem Benchmarking zwischen den Kliniken <TextLink reference="129"></TextLink>, <TextLink reference="130"></TextLink>, der Pflicht zur Ver&#246;ffentlichung und dem drohenden Ausfall der Kosten&#252;bernahme.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Preventive bundle studies to prevent CR-BSI"> <MainHeadline>Preventive bundle studies to prevent CR-BSI</MainHeadline><Pgraph>Prospective surveillance of BSIs and regular feedback of infection rates are not ends in themselves; following the primary assumptions of the infection protection act, data derived from prospective surveillance is necessary to support the preventive efforts of the treatment team. The prevention of BSI is one of the most important means of infection prevention in pediatric cancer patients, and optimizes patient safety, quality of medical treatment, and reasonable allocation of limited resources <TextLink reference="18"></TextLink>, <TextLink reference="109"></TextLink>, <TextLink reference="110"></TextLink>, <TextLink reference="131"></TextLink>, <TextLink reference="132"></TextLink>. One step in the right direction is to implement preventive maintenance-care bundles for CVADs.</Pgraph><Pgraph>Table 2 <ImgLink imgNo="2" imgType="table"/> summarizes maintenance-care bundle studies performed in POCs and published by the end of 2015. In contrast to corresponding efforts in neonatal or pediatric intensive care units <TextLink reference="133"></TextLink>, <TextLink reference="15"></TextLink>, the most important components of prevention do not concern the insertion&#47;implantation <TextLink reference="134"></TextLink> but maintenance care of the CVAD <TextLink reference="46"></TextLink>, <TextLink reference="132"></TextLink>, since the implantation of the CVAD is performed in a pediatric surgical theater accompanied by perioperative antibiotic prophylaxis (in some POCs).</Pgraph><Pgraph>Examples for critical control points of CVAD maintenance care to increase patient safety <TextLink reference="18"></TextLink> are:</Pgraph><Pgraph><UnorderedList><ListItem level="1">Hand disinfection before any manipulation of the CVAD hub or the infusion system <TextLink reference="135"></TextLink>;</ListItem><ListItem level="1">The use of antiseptics containing octenidine or chlorhexidine for local care of the catheter exit site, as local antiseptic before transcutaneous access to a fully implanted port, and on the catheter hub&#47;on needle-free connecting devices or three-way stopcocks before and after each manipulation;</ListItem><ListItem level="1">Strict aseptic approach when changing the dressing at the Broviac exit site;</ListItem><ListItem level="1">Flushing of the Broviac catheter only once or twice per week if not in use; no flushing of ports which are not in use (but locked with heparin 100 U&#47;ml or a lock solution containing taurolidin);</ListItem><ListItem level="1">The use of ready-to-use flushing syringes with 10 ml sterile 0.9&#37; sodium chloride solution;</ListItem><ListItem level="1">The reduction of the frequency of routine IV system changes to at least 96 hours &#91;exceptions: lipid-containing parenteral nutrition (24 hours) or after blood transfusion (8 hours)&#93;</ListItem><ListItem level="1">Education and training in, as well as supervision of any aseptic reconstitution of IV medication following a written, internal standard operating procedure;</ListItem><ListItem level="1">In case of sustained high infection rates: use of chlorhexidine-releasing dressings at the entry site of the Broviac&#47;Hickman <TextLink reference="136"></TextLink>, <TextLink reference="137"></TextLink> or use of lock solutions which possess antimicrobial activity <TextLink reference="138"></TextLink>, <TextLink reference="101"></TextLink>.</ListItem></UnorderedList></Pgraph><Pgraph>It remains an unresolved issue whether the routine use of chlorhexidine-containing washcloths <TextLink reference="91"></TextLink>, <TextLink reference="132"></TextLink>, <TextLink reference="139"></TextLink>, <TextLink reference="140"></TextLink>, <TextLink reference="141"></TextLink> or octenidine-containing shower gels (formerly used for MRSA decolonization <TextLink reference="142"></TextLink>, <TextLink reference="143"></TextLink>) provides an additional benefit in terms of BSI prevention in pediatric cancer patients outside the acute post-bone-marrow or -stem-cell transplantation setting <TextLink reference="91"></TextLink>, <TextLink reference="132"></TextLink>.</Pgraph><Pgraph>The implementation of prevention bundles may depend on some changes in clinical practice and culture:</Pgraph><Pgraph><UnorderedList><ListItem level="1">Some healthcare workers and physicians may have to change their individual perspective on BSI (BSIs are not a matter of fate, but in many cases a preventable complication within the scope of our clinical responsibilities);</ListItem><ListItem level="1">Strategies for maintenance care have to be defined following an interdisciplinary approach involving all frontline personnel and perhaps some of the parents&#47;caregivers;</ListItem><ListItem level="1">Correct handling should be practiced on a dummy before being performed without supervision by medical personnel;</ListItem><ListItem level="1">Implementation must be accompanied and followed by quality assurance efforts (audits, plan-do-check-act cycles) <TextLink reference="144"></TextLink>, <TextLink reference="145"></TextLink>,</ListItem><ListItem level="1">Local leaders have to accept and exercise their outstanding responsibility <TextLink reference="146"></TextLink>.</ListItem></UnorderedList></Pgraph><Pgraph>It is very important to guarantee timely feedback on obstacles and circumstances which hinder the practical implementation of the prevention bundle. In addition, frontline personnel should receive regular feedback on the effects of this intervention.</Pgraph><SubHeadline>Problems regarding the statistical significance of prevention studies</SubHeadline><Pgraph>In most German POCS, the number of admitted patients is too low to reach statistical significance in terms of reduced infection rates in a monocentric epidemiological study, even when adjusted statistical methods, such as interrupted time series analysis, are used and the observation period in each group is longer than 24 months <TextLink reference="147"></TextLink>, <TextLink reference="110"></TextLink>. Referring to monocentric results from Homburg&#47;Germany <TextLink reference="148"></TextLink>, more than 400 consecutive pediatric cancer patients would have to be included to demonstrate a significant benefit (power of 80&#37;, two-sided testing, p&#60;0.05).</Pgraph><Pgraph>Although such a large number of included patients may be generated in multicenter studies (e.g., involving all interested GPOH pediatric oncology centers), an identical prevention bundle must be defined for all participating POCs <TextLink reference="19"></TextLink>, <TextLink reference="149"></TextLink>.</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Studien mit Pr&#228;ventionsb&#252;ndeln zur Vermeidung von CR-BSI"> <MainHeadline>Studien mit Pr&#228;ventionsb&#252;ndeln zur Vermeidung von CR-BSI</MainHeadline><Pgraph>Die prospektive Surveillance von BSI ist kein Selbstzweck. Sie soll nach dem Grundgedanken des Infektionsschutzgesetzes die Behandler langfristig und nachhaltig dabei unterst&#252;tzen, BSI zu verhindern, die vom Gef&#228;&#223;katheter ausgehen. Dies ist eines der wichtigsten Pr&#228;ventionsziele kinderonkologischer Behandlungszentren im Interesse der Patientensicherheit, der Behandlungsqualit&#228;t und zur besseren Ausnutzung nur begrenzt vorhandener Ressourcen <TextLink reference="18"></TextLink>, <TextLink reference="109"></TextLink>, <TextLink reference="110"></TextLink>, <TextLink reference="131"></TextLink>, <TextLink reference="132"></TextLink>.</Pgraph><Pgraph>Dieses Pr&#228;ventionsziel kann u.a. durch die Implementierung von Pr&#228;ventionsb&#252;ndeln f&#252;r die Erhaltungspflege von CVAD praktisch angegangen werden. In Tabelle 2 <ImgLink imgNo="2" imgType="table"/> sind die bis Ende 2015 publizierten Studien zusammengestellt, in denen Pr&#228;ventionsb&#252;ndel in der Kinderonkologie zum Einsatz kamen. </Pgraph><Pgraph>Im Unterschied zu p&#228;diatrischen Intensivpflegepatienten mit nicht getunnelten zentralen Venenkathetern <TextLink reference="133"></TextLink>, <TextLink reference="15"></TextLink> liegt bei kinderonkologischen Patenten das Hauptaugenmerk der Pr&#228;ventionsb&#252;ndel nicht auf der Katheterinsertion <TextLink reference="134"></TextLink>, sondern auf der Erhaltungspflege <TextLink reference="46"></TextLink>, denn implantiert wird der CVAD in der Regel im Operationsaal von einem Kinderchirurgen, oft mit einer perioperativen Antibiotikaprophylaxe.</Pgraph><Pgraph>Aspekte der Erhaltungspflege (siehe GPOH-Empfehlung von 2013) <TextLink reference="18"></TextLink>, die im positiven Sinne standardisiert und schrittweise implementiert werden k&#246;nnen sind (Auswahl):</Pgraph><Pgraph><UnorderedList><ListItem level="1">Ganz zuvorderst: eine Verbesserung der Compliance mit der hygienischen H&#228;ndedesinfektion vor jeder Manipulation am CVAD <TextLink reference="135"></TextLink>.</ListItem><ListItem level="1">Der Einsatz von Octenidin- oder Chlorhexidin-haltigen Antiseptika an der Eintrittsstelle eines Broviac (z.B. Octenidin plus Phenoxyethanol), bei der Hautantisepsis vor Punktion eines Ports (z.B. Octenidin oder Chlorhexidin plus Isopropanol) und am Katheter-Hub &#47; an Dreiwegeh&#228;hnen oder an einem nadelfreien Konnektionsventil vor und nach jeder Manipulation (z.B. Octenidin oder Chlorhexidin plus Isopropanol).</ListItem><ListItem level="1">Aseptisches Vorgehen beim Verbandswechsel an der Broviac-Eintrittstelle.</ListItem><ListItem level="1">Das Sp&#252;len eines nicht in Gebrauch befindlichen Broviac-Katheters nur einmal pro Woche und der Verzicht auf das regelm&#228;&#223;ige Sp&#252;len eines ruhenden Ports.</ListItem><ListItem level="1">Die Verwendung von vorkonfektionierten NaCl 0,9&#37; Sp&#252;lspritzen mit sterilem Inhalt.</ListItem><ListItem level="1">Eine Reduktion des Routine-Systemwechselintervalls (komplettes Infusionssystem inklusive aller Verl&#228;ngerungen, Zuleitungen, Filter und Konnektionsventile) auf 96 Stunden (Ausnahmen: fetthaltige parenterale Ern&#228;hrung und Blutprodukte).</ListItem><ListItem level="1">Schulung, Training und Kontrolle in Bezug auf die aseptische Rekonstitution &#47; Zubereitung von Infusaten auf der Station &#47; in der onkologischen Ambulanz; wenn m&#246;glich: Herstellung komplexer Infusionsl&#246;sungen in der Klinikapotheke.</ListItem><ListItem level="1">Bei anhaltend hohen CR-BSI Raten ggf. zus&#228;tzlich: Einsatz von Chlorhexidin-freisetzenden Pflastern an der Eintrittsstelle des Broviac <TextLink reference="136"></TextLink>, <TextLink reference="137"></TextLink> oder Einsatz von antimikrobiellen Blockl&#246;sungen <TextLink reference="138"></TextLink>, <TextLink reference="101"></TextLink>.</ListItem><ListItem level="1">Unklar: Ganzk&#246;rperwaschung mit Chlorhexidin- oder Octenidin-haltigen Waschl&#246;sungen bei Stammzelltransplantierten oder Patienten mit sehr lang anhaltender Granulozytopenie (z.B. in der AML-Induktionstherapie).</ListItem></UnorderedList></Pgraph><Pgraph>Hierzu bedarf es: </Pgraph><Pgraph><UnorderedList><ListItem level="1">M&#246;glicherweise bei einem Teil der Mitarbeiter einer &#196;nderung ihrer subjektiven Perspektive (&#8222;BSI sind <Mark3>keine</Mark3> schicksalhaften Ereignisse, sondern zum Teil vermeidbare Komplikationen und ich bin daf&#252;r pers&#246;nlich mit verantwortlich&#8220;),</ListItem><ListItem level="1">gemeinsamer Festlegungen (Pflegepersonal, &#196;rzte, Hygienefachpersonal) in Standard-Arbeitsanweisungen, die f&#252;r alle g&#252;ltig sind,</ListItem><ListItem level="1">Vermittlung von Wissen, praktisches Training zum Erwerb von hygienisch korrekter Handlungsabl&#228;ufe (ggf. erst an einem Dummy),</ListItem><ListItem level="1">einer regelm&#228;&#223;ige Qualit&#228;tskontrolle im klinischen Alltag <TextLink reference="144"></TextLink>, <TextLink reference="145"></TextLink>,</ListItem><ListItem level="1">eines besonderen Engagements der vor Ort verantwortlichen F&#252;hrungskr&#228;fte <TextLink reference="146"></TextLink>.</ListItem></UnorderedList></Pgraph><Pgraph>Ganz ohne Zweifel werden Pr&#228;ventionsb&#252;ndel langfristig nur dann vollst&#228;ndig umgesetzt, wenn durch hierf&#252;r autorisiertes Personal (Mitarbeiter aus dem Pflegteam) eine regelm&#228;&#223;ige &#220;berpr&#252;fung der Compliance erfolgt (Monitoring, ggf. auch h&#228;ufige Begleitung auf Station durch das Hygienefachpersonal) und dieses Monitoring von Anfang an fester Bestandteil des Gesamtkonzeptes ist. Wichtig ist die schnelle R&#252;ckmeldung von mangelnder Compliance, aber auch die Hervorhebung guter Compliance bei den Mitarbeitern (siehe Tabelle 2 <ImgLink imgNo="2" imgType="table"/>).</Pgraph><Pgraph>In einigen Studien wird inzwischen auch eine Ganzk&#246;rperwaschung von kinderonkologischen Hochrisikopatienten (meist nach Stammzelltransplantation) mit Chlorhexidin-haltigen Wascht&#252;chern empfohlen <TextLink reference="91"></TextLink>, <TextLink reference="132"></TextLink>. Dieses aus der Intensivmedizin &#252;bernommene Vorgehen <TextLink reference="139"></TextLink>, <TextLink reference="140"></TextLink>, <TextLink reference="141"></TextLink> wird in Deutschland bisher vorwiegend zur Reduktion der Erregerdichte bzw. zur Dekolonisation bei Patienten eingesetzt, die mit bestimmten MRE kolonisiert sind <TextLink reference="142"></TextLink>, <TextLink reference="143"></TextLink>. Es ist bisher nicht klar, wie sich diese Strategie langfristig im Gesamtkonzept der Infektionspr&#228;vention bei hochgradig immunsupprimierten Kindern und Jugendlichen einordnen wird <TextLink reference="21"></TextLink>. In den Studien von Choi et al. und Duffy et al. handelte es sich um Patientenkollektive mit einem hohen Anteil an allogen transplantierten Kindern und Jugendlichen, bei denen m&#246;glicherweise der Chlorhexidin-Waschung (in Deutschland auch mit Octenidin-haltiger Waschl&#246;sung m&#246;glich) eine andere Rolle zukommt als unter einer konventionellen Chemotherapie <TextLink reference="91"></TextLink>, <TextLink reference="132"></TextLink>.</Pgraph><SubHeadline>Probleme der statistischen Signifikanz bei Pr&#228;ventionsstudien</SubHeadline><Pgraph>Tats&#228;chlich ist es in der Kinderonkologie aufgrund der in solche Untersuchungen konsekutiv eingebrachten Patientenzahl in einer monozentrischen infektionsepidemiologischen Studie auch mit ausgefeilten Methoden der medizinischen Statistik (z.B. Analyse unterbrochener Zeitserien) <TextLink reference="147"></TextLink> kaum m&#246;glich, in einem &#252;berschaubaren Zeitraum (&#60;36 Monate) eine statistisch signifikante Senkung von Infektionsraten nachzuweisen <TextLink reference="110"></TextLink>. Auf der Grundlage eigener monozentrischer Resultate aus Homburg <TextLink reference="148"></TextLink> m&#252;ssten f&#252;r ein signifikantes Resultat mit einer statistischen Power von 80&#37; (zweiseitiger Chi-Quadrat-Test, p&#60;0,05) prospektiv mehr als 400 Patienten eingeschlossen werden. Dies er&#246;ffnet zwar Perspektiven f&#252;r multizentrische Studien unter dem Dach der GPOH; allerdings m&#252;sste zuvor eine weitgehende Vereinheitlichung der Pr&#228;ventionsb&#252;ndel in den teilnehmenden Zentren erreicht werden <TextLink reference="19"></TextLink>, <TextLink reference="149"></TextLink>.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="How to move on"> <MainHeadline>How to move on</MainHeadline><Pgraph>Considering the previously discussed framework of information regarding the surveillance of BSI in POCs, the pediatric oncologists among the current authors suggest some hallmarks for the conception of a standard surveillance module (registry) for BSI in POCs. It is important to emphasize that the discussion of the related issues with our colleagues from the NRZ for the Surveillance of Nosocomial Infection (Charit&#233;, Berlin) is an ongoing process. </Pgraph><Pgraph>The following suggestions were made by pediatric oncologists, some of whom have been principal investigators or local coordinators of previous surveillance studies in this field. The issue at stake is to determine which data are needed from the perspective of the attending physicians</Pgraph><Pgraph><UnorderedList><ListItem level="1">to investigate the effectiveness and safety of the local preventive strategy (maintenance care bundle) in the long term;</ListItem><ListItem level="1">to fulfil the documentation requirements of the German Infection Prevention Act (&#167; 23; no public reporting but obligatory internal documentation) <TextLink reference="112"></TextLink> considering <LineBreak></LineBreak>a) infection rates related to the use of CVADS and <LineBreak></LineBreak>b) local epidemiology (pathogens and resistance profiles derived from blood culture analysis) <TextLink reference="62"></TextLink>.</ListItem></UnorderedList></Pgraph><Pgraph>The resources (personnel and time) for these efforts are limited; a realistic exploration of the current situation leads to the conclusion that the items included in such a surveillance module must be much more restricted than those necessary for a scientific study.</Pgraph><SubHeadline>Requirements for organizational structure</SubHeadline><Pgraph>Participation of POCS in the new surveillance module should remain voluntary, although the managing board of the GPOH will definitely endorse participation. In the near future, participation in the new surveillance module will become an item of quality assurance in POCs. </Pgraph><Pgraph>The medical director and the hospital administration of the POC have to approve and declare participation in the new module in advance. The local coordinators should perform an upfront analysis concerning the personnel and time resources necessary for its active implementation. </Pgraph><Pgraph><Indentation>The results of local surveillance are primarily used for long-term quality assurance and infection prevention in the participating POC. In any benchmarking presentation of results comparing data of different POCs (national reference data), the location from which the results have been retrieved will be anonymized. Infection rates of individual POCS will be handled confidentially within the cooperative multicenter surveillance group. </Indentation></Pgraph><Pgraph>All participating centers provide the central coordinators with basic epidemiological information considering their POC, such as the absolute number of newly admitted pediatric cancer patients per year, number of patients with relapsed malignancy per year, number of autologous stem cell transplantations, and details of the local strategy of BSI prevention.</Pgraph><SubHeadline>Inclusion criteria</SubHeadline><Pgraph>All pediatric cancer patients up to 21 years of age will be included anonymously if they have a CVAD in use and are being treated with conventional chemotherapy, radiation therapy, or high dose chemotherapy with autologous stem cell transplantation.</Pgraph><SubHeadline>Diagnostic blood culture sampling</SubHeadline><Pgraph>The local coordinators of the surveillance initiative will receive a Word file, which may be used as a template to adjust the local guideline concerning blood culture sampling in pediatric cancer patients with fever (with or without concomitant neutropenia). The purpose of this document is to guarantee a minimum of standardization, e.g., considering the minimal volume of blood sampling for blood cultures depending on body weight of the patient. The participating POCS should have an internal, written consensus protocol for the sampling and processing of blood cultures. Details of this protocol are left at the discretion of the local coordinators and the respective microbiology laboratory.</Pgraph><SubHeadline>Which BSI should be documented&#63;</SubHeadline><Pgraph>The surveillance documents all blood-culture-positive (laboratory confirmed) BSI in symptomatic patients. The basic list of all events should be matched with the monthly microbiological laboratory results <TextLink reference="150"></TextLink>. All BSI are included, in which the attending physicians do not attribute the positive yield to contamination. In case of a primary focus at any other site considered as the probable focus of the BSI by the attending pediatric oncologists, the BSI is marked as secondary. The primary focus should be documented in the case report form of the module.</Pgraph><Pgraph>Even if only one positive blood culture set was taken before antibiotic treatment was implemented, the clinical assessment of the attending physicians may allow the inclusion of the event. In this regard, it must be borne in mind that opportunistic pathogens such as CoNS, VGS and enterococci represent real pathogens in pediatric cancer patients. The probability of a true-positive result is higher when the pathogen grows in both bottles (aerobic and anaerobic) with a positive yield in the first <TextGroup><PlainText>48 hours</PlainText></TextGroup> after sampling.</Pgraph><Pgraph>All BSI are included independent of the setting in which the patients developed initial symptoms (as an out- or in-patient). Although this time latency remains arbitrary, BSIs may be allocated to the category &#8220;acquired during inpatient treatment&#8221; if the first symptoms occur 72 hours after admission or less than 72 hours after the patient has left the hospital <TextLink reference="6"></TextLink>. This allows for the normalization of inpatient BSIs to 1000 inpatient treatment days (incidence density &#61; events &#47; inpatient treatment days x 1000). Monthly inpatient treatment days can easily be obtained from hospital administration.</Pgraph><SubHeadline>Reporting microbiology results</SubHeadline><Pgraph>The results of blood culture diagnostics should be reported by the microbiology laboratory as follows:</Pgraph><Pgraph><UnorderedList><ListItem level="1">Detected pathogens on a species level (max. 3 per blood culture) &#91;<Mark2>The definite documentation of polymicrobial BSI requires a consensus in the coordination group.</Mark2>&#93;;</ListItem><ListItem level="1">Specific in vitro resistance and multidrug resistance <TextLink reference="62"></TextLink>, <TextLink reference="63"></TextLink> including penicillin G resistance in VGS, MRSA, VRE, 2 MRGN NeoP&#228;d <TextLink reference="151"></TextLink>, 3 and 4 MRGN <TextLink reference="63"></TextLink>, <TextLink reference="74"></TextLink>.</ListItem></UnorderedList></Pgraph><Pgraph>In POCs, in which FCH are routinely used for prophylaxis or treatment, FCH resistance (cipro- and levofloxacin) in Gram-negative pathogens should be additionally reported.</Pgraph><SubHeadline>Additional clinical items reported in the CRF</SubHeadline><Pgraph>Additional items which may be reported in the CRF (related to a particular BSI event) are a local identification code for the patient (second or third BSI&#63;), age of the patient in years&#47;months, gender, underlying malignancy, first illness or relapse, treatment protocol (GPOH), treatment with antibiotics (therapeutically or prophylactically, except cotrimoxazol prophylaxis), type of CVAD (Broviac or Port), home parenteral nutrition, local infection at the CVAD entry site (or port pocket), probable source of the BSI in secondary cases, presence of neutropenia (&#60;0.5x10<Superscript>9</Superscript>&#47;L or leukocytes &#60;1x10<Superscript>9</Superscript>&#47;L and no differential cell count available &#177;3 days from the event), mucositis which results in morphine infusion or parenteral nutrition, any clinically significant GVHD of the mucous membranes, anorectal infiltration, and <Mark2>Ecthyma gangraenosum</Mark2> <TextLink reference="152"></TextLink>, <TextLink reference="153"></TextLink>.</Pgraph><Pgraph>Further items describing the clinical course of the event may be documented:</Pgraph><Pgraph><UnorderedList><ListItem level="1">Clinical severity (bacteremia, sepsis, septic shock, septic shock with multiorgan failure) <TextLink reference="25"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="1"></TextLink>;</ListItem><ListItem level="1">Adjuvant use of ethanol-lock therapy <TextLink reference="101"></TextLink> (or any other antimicrobial lock therapy) <TextLink reference="154"></TextLink>;</ListItem><ListItem level="1">Removal of the CVAD related to the BSI;</ListItem><ListItem level="1">Outcome: recovery, palliative care or death of the patient (related to the BSI);</ListItem><ListItem level="1">Inpatient treatment days and intensive care treatment days related to the BSI;</ListItem><ListItem level="1">Duration of antibiotic treatment (days of antibiotics related to the BSI);</ListItem><ListItem level="1">Duration of neutropenia after the onset of treatment (if documented in the patient&#8217;s file).</ListItem></UnorderedList></Pgraph><Pgraph>Items to be documented optionally</Pgraph><Pgraph><UnorderedList><ListItem level="1">Empirical first-line treatment of the BSI (e.g. piperacillin-tazobactam &#177; aminoglycoside, ceftazidime, meropenem, etc.);</ListItem><ListItem level="1">Targeted therapy (after the pathogen and its in vitro sensitivity is available);</ListItem><ListItem level="1">Concomitant antifungal treatment (amphotericin B, caspofungin, voriconazole, etc.).</ListItem></UnorderedList></Pgraph><SubHeadline>Responsibility, accountability, leadership and necessary resources</SubHeadline><Pgraph>In Germany, the medical directors of the POC are responsible for the implementation of prospective surveillance and preventive strategies according to the Infection Prevention Act (IfSG). In general, the medical directors have a profound interest in guaranteeing patient safety in their unit, and in the avoidance of preventable medical complications. The same should valid for hospital administration, accountable for personnel allocation, purchasing all necessary materials and medical products, and quality management.</Pgraph><Pgraph>Without the personal investment of the POC leaders <TextLink reference="155"></TextLink>, <TextLink reference="146"></TextLink>, such a surveillance initiative cannot be implemented sustainably (leadership and clinical culture promoting patient safety are mandatory) <TextLink reference="156"></TextLink>, <TextLink reference="157"></TextLink>. The prospective surveillance of BSI is paramount to the quality management in POCS, and sampling the primary data is the responsibility of the local infection control personnel <TextLink reference="158"></TextLink>. The infection control personnel should be supported by members of the pediatric oncology treatment team. The necessary personnel and time resources must be prospectively provided by hospital administration. The time required to educate new team members in the details of the surveillance module must also be taken into account.</Pgraph><Pgraph>It is of utmost importance to inform the whole treatment team (frontline physicians and healthcare workers) about the aims, methods, and scope of the surveillance initiative. The sampling of primary data is much more efficient if these items are clearly documented in the patient&#8217;s file. The completion of any electronic case report form needs confirmation by the infection control personnel and a pediatric oncologist.</Pgraph><SubHeadline>Analysis and feedback</SubHeadline><Pgraph>If such a surveillance module is available on a protected internet platform and all basic data (such as inpatient treatment days) have been provided by the local coordinators, it allows timely, automatic reporting of cumulative results. A standard format for these reports should be developed, which contains information on the bacterial species spectrum and on specific resistance profiles in the most prevalent pathogens (see above) (&#167; 23 IfSG) <TextLink reference="62"></TextLink>, <TextLink reference="159"></TextLink>. In most centers, such feedback should be generated every 6 months. The report should detail the results month by month in a clearly arranged format. These results are not generated for confidential storage but should be regularly discussed with the treatment team <TextLink reference="112"></TextLink>, the microbiologists, and the infection control personnel. In addition, the establishment of a multicenter surveillance consortium will facilitate the discussion of the results between the local coordinators of the participating POCs. All issues related to this important topic should be discussed at least once a year in a central meeting of the local study coordinators.</Pgraph><SubHeadline>BSI rates and patient-to-nurse ratios</SubHeadline><Pgraph>Since there may be a relationship between the number of available, well-qualified healthcare workers (HCWs) and BSI rates, the general assembly of the GPOH in Berlin (Charit&#233;, May 30, 2015) suggested documenting the number of available pediatric oncology HCWs in the module. One feasible method is the daily documentation of the number of inpatients and the number of available HCWs as a patient-to-nurse ratio (inpatients : HCWs) <TextLink reference="160"></TextLink>. One obstacle is that many centers provide care for patients during the day (e.g., diagnostic procedures with analgosedation, blood transfusion, chemotherapy), but these patients &#8211; although on the ward during daylight hours &#8211; do not appear in the midnight census. This issue should be discussed and decided in the surveillance coordination group.</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Ausblick auf ein neues Konzept der Surveillance von BSI"> <MainHeadline>Ausblick auf ein neues Konzept der Surveillance von BSI</MainHeadline><Pgraph>Ausgehend von den hier vorgelegten Daten und Interpretationen der bis heute verf&#252;gbaren Studien schlagen die kinderonkologischen&#47;kinderinfektiologischen Autorinnen und Autoren dieser &#220;bersicht einige Grundmerkmale f&#252;r die Neukonzeption eines Erfassungsmoduls (Registers) zur Surveillance von Blutstrominfektionen in der p&#228;diatrischen Onkologie vor. Allerdings ist die diesbez&#252;gliche Diskussion in der Arbeitsgruppe des Nationalen Referenzzentrums (inklusive der beratenden Kliniker und Wissenschaftler aus der Kinderonkologie) f&#252;r die Surveillance von nosokomialen Infektionen noch nicht abgeschlossen. </Pgraph><Pgraph><Indentation>Insofern sind die folgenden Abschnitte nur als unverbindliche Vorschl&#228;ge der kinderonkologischen&#47;kinderinfektiologischen Expertengruppe zu verstehen. Selbstverst&#228;ndlich m&#252;ssen diese mit den internen Vorarbeiten und Konzepten des NRZ zu einem neuen onkologischen Erfassungsmodul (das auch das alte Onko-KISS-Modul ersetzen wird) harmonisiert werden. </Indentation></Pgraph><Pgraph>Zielf&#252;hrend f&#252;r die Konzeption muss vor allem die Frage sein, welche Daten die Anwender (kinderonkologische Behandlungszentren) ben&#246;tigen um ihren Dokumentationspflichten nach &#167; 23 IfSG in sinnvoller und konstruktiver Weise nachzukommen (z.B. Device-assoziierte Infektionen, Erreger mit besonderen Resistenzen) <TextLink reference="62"></TextLink> und um die Wirksamkeit eines vor Ort implementierten Pr&#228;ventionsb&#252;ndels in der Vermeidung von CR-BSI langfristig zu &#252;berpr&#252;fen. Dabei spielen naturgem&#228;&#223; im klinischen Alltag und im Sinne einer nachhaltigen Konzeption Kosten-Nutzen-Abw&#228;gungen f&#252;r die Zuordnung des vorhandenen Personals eine wichtige Rolle. Es kann hier &#8211; was die Anzahl der zu erfassenden Items angeht &#8211; nicht um eine prim&#228;r wissenschaftlich orientierte Studie gehen, sondern es muss ein Kompromiss gefunden werden zwischen dem, was unbedingt wissenswert, und dem, was arbeitst&#228;glich machbar ist.</Pgraph><SubHeadline>Strukturell-organisatorische Grundvoraussetzungen</SubHeadline><Pgraph>Die Teilnahme der Zentren soll freiwillig bleiben, wobei sie vom Vorstand der Deutschen Gesellschaft f&#252;r P&#228;diatrische Onkologie und H&#228;matologie (GPOH) ausdr&#252;cklich bef&#252;rwortet wird und in Zukunft ein <Mark1>Qualit&#228;tsmerkmal f&#252;r GPOH-Zentren</Mark1> darstellt. Eine Klinik oder Abteilung kann nur teilnehmen, wenn die &#228;rztliche, administrative und pflegerische Leitung dieser Teilnahme ausdr&#252;cklich und schriftlich zugestimmt hat.</Pgraph><Pgraph>Vorab sollen in der Klinik die erforderlichen personellen&#47;zeitlichen Ressourcen ermittelt und von der Krankenhausadministration bereitgestellt werden. </Pgraph><Pgraph><Indentation>Die Ergebnisse dienen vorrangig den teilnehmenden Zentren f&#252;r ihre interne Qualit&#228;tskontrolle. Werden die Ergebnisse verschiedener Zentren untereinander verglichen (Treffen der Projektgruppe, Pr&#228;sentation, Publikation), so geschieht dies ausschlie&#223;lich anonymisiert (Infektionsraten einzelner Zentren sind selbstverst&#228;ndlich vertraulich). </Indentation></Pgraph><Pgraph>Alle an der prospektiven Erfassung teilnehmenden Zentren stellen Informationen zur Zahl der station&#228;ren Behandlungspl&#228;tze und ggf. auch zu weiteren Strukturmerkmalen zur Verf&#252;gung (z.B. Anzahl der Neudiagnosen und der autologen Transplantationen; lokaler Einsatz von Pr&#228;ventionsb&#252;ndeln).</Pgraph><SubHeadline>Einschluss</SubHeadline><Pgraph>Eingeschlossen werden (anonymisiert) alle kinderonkologischen Patienten bis zum 21. Lebensjahr, die einen CVAD haben, der regelm&#228;&#223;ig genutzt wird (konventionelle Chemotherapie oder Hochdosischemotherapie mit autologer Stammzelltransplantation, Strahlentherapie).</Pgraph><SubHeadline>Blutkultur-Diagnostik</SubHeadline><Pgraph>Den Koordinatoren des neuen Erfassungsmoduls in den Kliniken sollte eine Word-Vorlage als Template f&#252;r einen internen Standard zur Blutkulturdiagnostik zur Verf&#252;gung gestellt werden, nach dem weiterhin die Abnahmen beim fiebernden Kind aus dem CVAD erfolgt (sorgf&#228;ltige Desinfektion des Hubs, Entfernung von nadelfreien Konnektionsventilen vor Abnahme, Mindestblutmengen, Blutkultursets aerob und anaerob, aus allen Lumina usw). Vor Ort soll es zu diesem essentiellen kritischen Kontrollpunkt eine schriftliche Vereinbarung geben, &#252;ber deren Inhalt die &#228;rztliche Direktion des teilnehmenden Zentrums entscheidet.</Pgraph><SubHeadline>Welche BSI sollen erfasst werden&#63;</SubHeadline><Pgraph>Erfasst werden sollten alle Blutkultur-positiven (Labor-best&#228;tigten) Blutstrominfektionen. Die ungefilterte Basisliste aller positiven Blutkulturen, an der sich das f&#252;r die Datenerfassung zust&#228;ndige Personal orientiert, liefert monatlich die Mikrobiologie <TextLink reference="150"></TextLink>. Erfasst werden alle BSI, bei denen die behandelnden &#196;rzte die positive Blutkultur nicht als Kontamination einstufen. Wenn es nach Einsch&#228;tzung der behandelnden Kinderonkologen Hinweise auf einen sonstigen Infektionsfokus gibt, sollten hierzu zus&#228;tzliche Angaben gemacht werden k&#246;nnen.</Pgraph><Pgraph>Auch wenn vor Beginn der empirischen Therapie nur ein Blutkulturset (eine aerobe und eine anaerobe Blutkulturflasche) aus dem CVAD (oder bei nicht r&#252;ckl&#228;ufigem CVAD peripherven&#246;s) entnommen wurde, kann eine BSI erfasst werden, insofern ein obligat oder fakultativ pathogener Erreger isoliert wird (hierzu z&#228;hlen bei kinderonkologischen Patienten auch vergr&#252;nende Streptokokken &#8211; VGS &#8211; und Enterokokken) oder wenn</Pgraph><Pgraph><UnorderedList><ListItem level="1">beide Flaschen eines Blutkultursets innerhalb von 48 Stunden nach Abnahme positiv f&#252;r einen Erreger der Hautflora sind (z.B. CoNS) und&#47;oder</ListItem><ListItem level="1">die behandelnden &#196;rzte die nachgewiesenen Erreger nicht als Kontamination bewerten (die gezielte antibiotische Behandlung nach Mitteilung des Befundes muss auch gegen diese Erreger gerichtet &#47; in vitro wirksam sein).</ListItem></UnorderedList></Pgraph><Pgraph>Alle BSI werden unabh&#228;ngig davon erfasst, ob sie ambulant oder station&#228;r erworben wurden; die Ereignisse k&#246;nnen jedoch als &#8218;ambulant erworben&#8216; oder als &#8218;nosokomial erworben&#8216; ausgewiesen werden. Auch wenn dies letztendlich eine arbitr&#228;re Festlegung bleibt, erscheint zur Unterscheidung dieser Kategorien bei der Auswertung in der Kinderonkologie ein Zeitfenster von 72 Stunden geeignet. Patienten werden mitunter auch w&#228;hrend der intensiven Therapie &#252;ber das Wochenende entlassen bzw. mind. zweimal pro Woche in der Ambulanz gesehen <TextLink reference="6"></TextLink>. Durch eine solche Unterscheidung ist es m&#246;glich einen einheitlichen Bezug der &#8222;station&#228;r erworbenen&#8220; Ereignisse auf 1000 station&#228;re Patiententage herzustellen (Inzidenzdichte &#61; Anzahl der station&#228;ren BSI&#47;station&#228;re Patiententage x 1000). Die station&#228;ren Patiententage m&#252;ssen monatlich von der Verwaltung zur&#252;ckgemeldet und in das Modul eingegeben werden.</Pgraph><SubHeadline>Ergebnisse der Mikrobiologie</SubHeadline><Pgraph>Die Ergebnisse der Mikrobiologie (nur Blutkultur) sollten wie folgt ausgewiesen werden: Erregerspezies (maximal 3) &#91;<Mark2>Wie mit polymikrobiellen Bakteri&#228;mien umgegangen werden soll, erfordert noch genaue Festlegungen.</Mark2>&#93;, spezielle Resistenzen und Multiresistenzen <TextLink reference="62"></TextLink>, <TextLink reference="63"></TextLink> (inklusive einer Penicillin-Resistenz bei den VGS), MRSA, VRE, 2 MRGN NeoP&#228;d <TextLink reference="151"></TextLink>, 3 und 4 MRGN <TextLink reference="63"></TextLink>, <TextLink reference="74"></TextLink>, Fluorchinolon-Resistenz (Cipro- und Levofloxacin) bei gramnegativen Erregern.</Pgraph><SubHeadline>Zus&#228;tzliche ereignisbezogene Parameter</SubHeadline><Pgraph>Zus&#228;tzliche Parameter, die zum Zeitpunkt der Infektion erfasst werden sollen, sind lokal generierter Code zur eineindeutigen Zuordnung eines Patienten (wiederholte BSI&#63;) Lebensalter, Geschlecht, Grunderkrankung, Erkrankungsstatus (Ersterkrankung oder Rezidiv), Therapieprotokoll, vorbestehende Antibiotikatherapie oder Antibiotikaprophylaxe (au&#223;er Cotrimoxazol), CVAD-Typ (Broviac oder Port), heimparenterale Ern&#228;hrung, BSI in der Vorgeschichte, Lokalinfektion am CVAD, wahrscheinliche Quelle der BSI (bei sekund&#228;ren BSI); Granulozytopenie (Granulozyten &#60;0,5x10<Superscript>9</Superscript>&#47;L oder Leukozyten &#60;1x10<Superscript>9</Superscript>&#47;L und kein Differentialblutbild verf&#252;gbar &#177;3 Tage zum Ereignis), Mukositis (Mukositis mit der Notwendigkeit einer parenteralen Ern&#228;hrung und&#47;oder einer Opiat-Dauerinfusion), GVHD von Haut- und&#47;oder Schleimh&#228;uten, perianale Schleimhautl&#228;sionen, <Mark2>Ecthyma gangraenosum</Mark2> <TextLink reference="152"></TextLink>, <TextLink reference="153"></TextLink>. Klinische Parameter, die <Mark3>im Kontext der Blutstrominfektion</Mark3> erfasst werden sollen, sind</Pgraph><Pgraph><UnorderedList><ListItem level="1">Schweregrad der BSI (Bakteri&#228;mie, Sepsis, septischer Schock, septischer Schock mit Multiorganversagen) &#91;25,6,1&#93;,</ListItem><ListItem level="1">Adjuvante Ethanol-Blocktherapie &#91;101&#93; (oder andere antimikrobiell wirksame Blocktherapie) &#91;154&#93;,</ListItem><ListItem level="1">Explantation des CVAD, </ListItem><ListItem level="1">Ausgang Heilung, Ausgang palliative Behandlung, Ausgang Tod,</ListItem><ListItem level="1">Behandlungstage auf der Intensivstation,</ListItem><ListItem level="1">Dauer der intraven&#246;sen Antibiotikatherapie,</ListItem><ListItem level="1">station&#228;re Behandlungstage ausgehend vom Tag der ersten positiven Blutkultur (falls keine station&#228;re Entlassung vor der n&#228;chsten Therapie k&#246;nnen hier die Tage der Antibiotikatherapie der BSI eingetragen werden).</ListItem></UnorderedList></Pgraph><Pgraph>Ebenfalls von erheblichem Interesse ist die Dauer der Granulozytopenie (soweit aus dem Verlauf der Blutbilder ersichtlich). </Pgraph><Pgraph>Fakultativ zu dokumentierende Items: </Pgraph><Pgraph><OrderedList><ListItem level="1" levelPosition="1" numString="1.">Empirische Therapie (z.B. Piperacillin-Tazobactam, Meropenem usw.);</ListItem><ListItem level="1" levelPosition="2" numString="2.">Gezielte Therapie (Antibiotikum und Behandlungstage);</ListItem><ListItem level="1" levelPosition="3" numString="3.">Begleitende antimykotische Therapie (nicht Prophylaxe).</ListItem></OrderedList></Pgraph><SubHeadline>Verantwortlichkeiten und notwendige Ressourcen </SubHeadline><Pgraph>In Deutschland sind die Leiter einer kinderonkologischen Abteilung verantwortlich f&#252;r die Umsetzung des Infektionsschutzgesetzes (IfSG) und die Vermeidung von nosokomialen Infektionen in ihrem Zust&#228;ndigkeitsbereich. Neben dieser justitiablen pers&#246;nlichen Verantwortung sind die &#228;rztlichen Leiter einer kinderonkologischen Abteilung auch aus Gr&#252;nden der Patientensicherheit und der vern&#252;nftigen Allokation von begrenzten Ressourcen unmittelbar daran interessiert, vermeidbare Komplikationen bei den ihnen anvertrauten Patienten zu verhindern. </Pgraph><Pgraph>Das Gleiche sollte auch f&#252;r die Krankenhausadministration z.B. im Bereich der Personalverwaltung, der Materialbeschaffung und des Qualit&#228;tsmanagements gelten. Ohne F&#252;hrungsqualit&#228;t (Leadership) <TextLink reference="155"></TextLink>, <TextLink reference="146"></TextLink> im Sinne einer offensiven und nachhaltigen Unterst&#252;tzung durch die medizinische und pflegerische Leitung kann kein Programm der Infektionssurveillance und Infektionspr&#228;vention auf Dauer zum Nutzen der Patienten und der Klinik implementiert werden <TextLink reference="156"></TextLink>, <TextLink reference="157"></TextLink>. Die Erfassung nosokomialer Infektionen nach dem IfSG ist eine zentrale Aufgabe im Qualit&#228;tsmanagement jedes kinderonkologischen Zentrums und zudem eine genuine Aufgabe des f&#252;r die Kinderonkologie vor Ort zust&#228;ndigen Hygienefachpersonals <TextLink reference="158"></TextLink>. Das Hygienefachpersonal soll hierbei von geschulten Mitarbeitern der Abteilung unterst&#252;tzt werden. </Pgraph><Pgraph>Zeitkontingente f&#252;r hiermit beauftragte Mitarbeiter im Bereich der Stationen zur Durchf&#252;hrung der gesetzlich geforderten Infektionssurveillance und zur Schulung neuer Mitarbeiter in der Methodik und praktischen Anwendung des Surveillance-Moduls m&#252;ssen im Krankenhausbudget eindeutig ausgewiesen sein und entsprechend umgesetzt werden.</Pgraph><Pgraph>Sehr wichtig ist eine nachhaltige Information der patientennahen Behandler (Pflegepersonal und &#196;rzte) &#252;ber die Methode der Surveillance. Sie k&#246;nnen die Arbeit des Erfassungspersonals durch eine vollst&#228;ndige und &#252;bersichtliche Dokumentation der erforderlichen Items in der Patientenkurve erleichtern (z.B. Sepsiszeichen, Schweregrad der Infektion, Mukositis, GVHD, Antibiotikatage). F&#252;r den Abschluss einer Falldokumentation ist eine elektronisch signierte Pr&#252;fung sowohl durch das mit der Datenerhebung beauftragte Personal als auch durch einen hiermit beauftragten Kinderonkologen erforderlich.</Pgraph><SubHeadline>Auswertung und R&#252;ckmeldung</SubHeadline><Pgraph>Wenn ein solches Erfassungsmodul im Internet auf einer gesch&#252;tzten Plattform verf&#252;gbar ist und mit einer entsprechenden Auswertungssoftware zur automatisierten Erstellung von Ergebnisberichten verkn&#252;pft wird, kann es dem Behandlungsteam f&#252;r die bis zum Zeitpunkt der Auswertung abgeschlossen dokumentierten BSI-F&#228;lle alle relevanten Informationen per Knopfdruck zur Verf&#252;gung stellen. Hierzu geh&#246;rt auch die Erreger- und Resistenzstatistik als Bericht f&#252;r das zust&#228;ndige Gesundheitsamt (<TextGroup><PlainText>&#167; 23</PlainText></TextGroup> IfSG) <TextLink reference="62"></TextLink>, <TextLink reference="159"></TextLink>.</Pgraph><Pgraph>Eine solche Auswertung sollte zur R&#252;ckmeldung an das Behandlungsteam alle 6 Monate erfolgen. Dabei ist es sehr wichtig, den zeitlichen Verlauf der monatlich errechneten Inzidenzdichte in &#252;bersichtlicher Form zu pr&#228;sentieren. Diese Daten sind nicht f&#252;r die Schublade gedacht sondern sollen (unbedingt auch im Sinne des 2011 novellierten &#167; 23 des IfSG) <TextLink reference="112"></TextLink> im Behandlungsteam gemeinsam mit dem Krankenhaushygieniker und den Mikrobiologen diskutiert werden. Hinzu kommt der Austausch der an der Infektionssurveillance beteiligten kinderonkologischen Zentren untereinander. Hierf&#252;r soll von der Studienleitung ein geeignetes Forum im Internet und auch ein j&#228;hrliches Pr&#228;senztreffen mit gezielter Diskussion besonders relevanter Themen der Infektionssurveilla<TextGroup><PlainText>nc</PlainText></TextGroup>e und Infektionspr&#228;vention angesto&#223;en werden.</Pgraph><SubHeadline>BSI-Raten und Personalisierung in der Pflege</SubHeadline><Pgraph>Bei der Diskussion &#252;ber die Neukonzeption des OnkoKISS-Moduls im Rahmen der GPOH Jahrestagung in Berlin (Charit&#233;, 30.05.2015) wurde aus dem Auditorium nachdr&#252;cklich vorgeschlagen, parallel mit diesem Modul auch die tats&#228;chliche Personalisierung der kinderonkologischen Zentren zu dokumentieren (Anzahl der examinierten Krankenpfleger&#47;-schwestern pro Arbeitstag) <TextLink reference="160"></TextLink>. Damit sollen Zusammenh&#228;nge zwischen einer personellen Unterbesetzung (understaffing&#47;overcrowding) und der Inzidenz von BSI dargestellt werden, die in anderen Patientenkollektiven wissenschaftlich gesichert sind.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Conception and ethical framework of quality management initiatives"> <MainHeadline>Conception and ethical framework of quality management initiatives</MainHeadline><Pgraph>Quality management (QM) and quality improvement initiatives in healthcare facilities comprise a specific approach of experimental learning, with sustained development and implementation of new standards of care and defined workflows as central elements of clinical practice <TextLink reference="145"></TextLink>, <TextLink reference="161"></TextLink>. The particular instruments and strategies involved in QM initiatives are chosen by the treatment team after a thorough examination of the available evidence and experience, assuming that these strategies will result in a significant benefit for the patients and the hospital. These initiatives depend on the sampling of structured data documented in the patients&#8217; files during routine clinical workflows.</Pgraph><Pgraph>Patients and their families&#47;caregivers are vitally interested in receiving the best available treatment; this implies consent with clinical initiatives implemented systematically to improve patient safety <TextLink reference="162"></TextLink>. In contrast to controlled scientific studies comparing different interventions, for which written informed consent of the patients and&#47;or their parents&#47;caregivers is obligatory, QM initiatives feature other points:</Pgraph><Pgraph><UnorderedList><ListItem level="1">QM initiatives refer to a clinical standard of care which is executed in all patients;</ListItem><ListItem level="1">QM initiatives only rely on clinical routine data available in the patients&#8217; files.</ListItem><ListItem level="1">QM initiatives do not contain a specific intervention associated with or suspected to display an increased risk of any medical complication.</ListItem><ListItem level="1">The protection of personal data privacy is guaranteed, since the central data analysis uses anonymized patient data, although the sampling of the primary data necessitates confidential access of qualified medical personnel to the patients&#8217; files.</ListItem><ListItem level="1">The primary goal of QM is improvement of the quality of medical care and safety in the participating institution.</ListItem></UnorderedList></Pgraph><Pgraph>The prospective surveillance of BSIs in pediatric cancer patients to investigate the effects of a preventive maintenance care bundle is a concrete example for such a QM initiative. </Pgraph><Pgraph>The suggestions presented here, derived from a comprehensive review of the available evidence and experience in this field, set the stage for a new surveillance module adjusted to &#167; 23 of the German Infection Prevention Act <TextLink reference="112"></TextLink>. The IfSG and its translation and integration into the hospital hygiene regulations of the different federal states in Germany constitute a legal framework for local <TextLink reference="163"></TextLink>, <TextLink reference="164"></TextLink> and multicenter QM projects aiming at the reduction of BSI in pediatric cancer patients <TextLink reference="165"></TextLink>. It appears reasonable to inform the patients and their caregivers upon their first hospital admission that the POC takes part in such a QM initiative in order to continually improve clinical practice.</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Konzeptioneller und ethischer Rahmen f&#252;r Projekte des klinischen Qualit&#228;tsmanagements"> <MainHeadline>Konzeptioneller und ethischer Rahmen f&#252;r Projekte des klinischen Qualit&#228;tsmanagements</MainHeadline><Pgraph>Qualit&#228;tsmanagement (QM) im Gesundheitswesen (Engl. quality improvement in health care) umfasst eine Form des experimentellen Lernens in der klinischen Praxis, die kontinuierliche Entwicklung und Verbesserung von Standards und Arbeitsabl&#228;ufen als zentralen Bestandteil jeglicher medizinischen T&#228;tigkeit begreift <TextLink reference="145"></TextLink>, <TextLink reference="161"></TextLink>. QM-Aktivit&#228;ten setzen hierzu gezielt Ma&#223;nahmen ein, von denen nach sorgf&#228;ltiger Pr&#252;fung und Bewertung des verf&#252;gbaren Wissens eine relevante Verbesserung der Versorgungsqualit&#228;t erwartet werden kann.</Pgraph><Pgraph>Zur Objektivierung ihrer Ergebnisse und zur schrittweisen Implementierung ihres Gegenstandes sind sie auf die Erhebung, Auswertung und R&#252;ckmeldung patientenbezogener Daten angewiesen, die im Rahmen der klinischen Routineversorgung dokumentiert werden.</Pgraph><Pgraph>Das grundlegende Interesse der Patienten, die bestm&#246;gliche Behandlung zu erhalten, impliziert das Einverst&#228;ndnis mit Initiativen, die im Interesse der Patienten auf eine systematische Verbesserung der Versorgungsqualit&#228;t und -sicherheit abzielen <TextLink reference="162"></TextLink>.</Pgraph><Pgraph>Wesentliche Merkmale von QM-Aktivit&#228;ten (in Abgrenzung von klinischer Forschung, die ausnahmslos einer individuellen Aufkl&#228;rung und Zustimmung der eingeschlossenen Patienten bzw. ihrer Sorgeberechtigten bedarf) sind folgenderma&#223;en charakterisiert:</Pgraph><Pgraph><UnorderedList><ListItem level="1">Sie beziehen sich auf vorhandene Standards der medizinischen Versorgung und nutzen lediglich Daten, die in der klinischen Routine dokumentiert werden.</ListItem><ListItem level="1">Sie beinhalten keine spezifische Intervention, von der bekannterma&#223;en ein relevantes zus&#228;tzliches Risiko f&#252;r die Sicherheit der Patienten ausgeht.</ListItem><ListItem level="1">Der Schutz pers&#246;nlicher Daten und der Privatsph&#228;re der Patienten ist gew&#228;hrleistet. Die Datenakquise beinhaltet notwendigerweise die detaillierte Analyse von Einzelf&#228;llen durch Mitarbeiter mit einem medizinischen Behandlungsauftrag bzw. Dokumentationspersonal, das an die medizinische Schweigepflicht gebunden ist. </ListItem><ListItem level="1">Die finale Datenauswertung erfolgt anonymisiert.</ListItem><ListItem level="1">Das prim&#228;re Ziel der Aktivit&#228;t ist die Verbesserung der medizinischen Versorgungsqualit&#228;t und -sicherheit in der teilnehmenden Institution.</ListItem></UnorderedList></Pgraph><Pgraph>Ein konkretes Beispiel f&#252;r eine solche QM-Aktivit&#228;t im Bereich der Krankenhaushygiene und Infektionspr&#228;vention ist die praktische Implementierung von Pr&#228;ventionsb&#252;ndeln zur Senkung der Rate von CA-BSI und CR-BSI mit begleitender systematischer Surveillance. </Pgraph><Pgraph>Der hier vorgelegte Expertenentwurf &#91;<Mark2>Wie oben bereits dargestellt muss das finale Protokoll f&#252;r die Surveillance erst noch im Detail mit dem Nationalen Referenzzentrum abgestimmt werden.</Mark2>&#93; f&#252;r den Aufbau eines Surveillancemoduls f&#252;r Blutstrominfektionen in der Kinderonkologie stellt gem&#228;&#223; &#167; 23 IfSG <TextLink reference="112"></TextLink> den aktuellen Stand des Wissens zur Verf&#252;gung. Sowohl das IfSG als auch die Krankenhaushygieneverordnungen der Bundesl&#228;nder schaffen einen gesetzlichen Rahmen zur Umsetzung von Pr&#228;ventionsstrategien (Pr&#228;ventionsb&#252;ndeln) im Rahmen lokaler <TextLink reference="163"></TextLink>, <TextLink reference="164"></TextLink> oder auch multizentrischer QM-Projekte <TextLink reference="165"></TextLink>. Sinnvollerweise k&#246;nnen die Patienten und ihre Familien bereits im ersten Aufnahmevertrag dar&#252;ber informiert werden, dass die im Verlauf der regul&#228;ren Behandlung erhobenen Routinedaten f&#252;r QM-Projekte zur &#220;berpr&#252;fung und ggf. Verbesserung der Behandlungsqualit&#228;t genutzt werden.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Notes"> <MainHeadline>Notes</MainHeadline><SubHeadline>Competing interests</SubHeadline><Pgraph>The authors declare that they have no competing interests.</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Anmerkungen"> <MainHeadline>Anmerkungen</MainHeadline><SubHeadline>Interessenkonflikte</SubHeadline><Pgraph>Die Autoren erkl&#228;ren, dass sie keine Interessenkonflikte in Zusammenhang mit diesem Artikel haben.</Pgraph></TextBlock> <References linked="yes"> <Reference refNo="1"> <RefAuthor>Simon A</RefAuthor> <RefAuthor>Ammann RA</RefAuthor> <RefAuthor>Bode U</RefAuthor> <RefAuthor>Fleischhack G</RefAuthor> <RefAuthor>Wenchel HM</RefAuthor> <RefAuthor>Schwamborn D</RefAuthor> <RefAuthor>Gravou C</RefAuthor> <RefAuthor>Schlegel PG</RefAuthor> <RefAuthor>Rutkowski S</RefAuthor> <RefAuthor>Dannenberg C</RefAuthor> <RefAuthor>K&#246;rholz D</RefAuthor> <RefAuthor>Laws HJ</RefAuthor> <RefAuthor>Kramer MH</RefAuthor> <RefTitle>Healthcare-associated infections in pediatric cancer patients: results of a prospective surveillance study from university hospitals in Germany and Switzerland</RefTitle> <RefYear>2008</RefYear> <RefJournal>BMC Infect Dis</RefJournal> <RefPage>70</RefPage> <RefTotal>Simon A, Ammann RA, Bode U, Fleischhack G, Wenchel HM, Schwamborn D, Gravou C, Schlegel PG, Rutkowski S, Dannenberg C, K&#246;rholz D, Laws HJ, Kramer MH. 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