[Potential Nephrotoxicity of Combination of Vancomycin and Piperacillin-Tazobactam: Recommendations from the AG ABS of the DGPI supported by experts of the GPN]. / Potentielle Nephrotoxizität der Kombinationstherapie von Vancomycin und Piperacillin-Tazobactam: Empfehlungen der AG ABS der DGPI unter Beteiligung von Experten der GPN.

The combination of vancomycin and piperacillin/tazobactam (V+P/T) is used for empirical antibiotic treatment of severe infections, especially in immunocompromised patients and those colonized with multidrug-resistant bacteria. Nephrotoxicity is a frequently observed adverse effect of vancomycin. Its risk can be reduced by therapeutic drug monitoring and adjusted dosing. Piperacillin/tazobactam (P/T) rarely causes interstitial nephritis. The results of retrospective cohort studies in children predominantly show a low, clinically irrelevant, additive nephrotoxicity (defined as an increase in creatinine in the serum) of both substances. Due to the limitations of the existing publications, the ABS working group of the DGPI and experts of the GPN do not recommend against the use of P/T plus vancomycin. Preclinical studies and a prospective study with adult patients, which evaluated different renal function tests as well as clinical outcomes, do not support previous findings of additive nephrotoxicity. Time-restricted use of V+P/T can minimize exposure and the potential risk of nephrotoxicity. Local guidelines, developed in collaboration with the antibiotic stewardship team, should define the indications for empirical and targeted use of P/T and V+P/T. When using combination therapy with V+P/T, kidney function should be monitored through clinical parameters (volume status, balancing, blood pressure) as well as additional laboratory tests such as serum creatinine and cystatin C.

[Time to Antibiotics (TTA) - Reassessment from the German Working Group for Fever and Neutropenia in Children and Adolescents (DGPI/GPOH)]. / Time to Antibiotics (TTA) ­ Überlegungen der Arbeitsgruppe Fieber bei Granulozytopenie im Kindes- und Jugendalter (GPOH/DGPI) zu einer Neubewertung.

BACKGROUND: The current German guidance from 2016 recommends a Time to Antibiotics (TTA) of<60 min in children and adolescents with febrile neutropenia (FN). METHODS: Critical analysis of available studies and recent meta-analyses, and discussion of the practical consequences in the FN working group of the German Societies for Paediatric Oncology and Haematology and Paediatric Infectious Diseases. RESULTS: The available evidence does not support a clinically significant outcome benefit of a TTA<60 min in all paediatric patients with FN. Studies suggesting such a benefit are biased (mainly triage bias), use different TTA definitions and display further methodical limitations. In any case, a TTA<60 min remains an essential component of the 1st hour-bundle in paediatric cancer patients with septic shock or sepsis with organ dysfunction. CONCLUSION: Provided that all paediatric FN patients receive a structured medical history and physical examination (including vital signs) by experienced and trained medical personnel in a timely fashion, and provided that a sepsis triage and management bundle is established and implemented, a TTA lower than 3 hours is sufficient and reasonable in stable paediatric cancer patients with FN.

Antimicrobial use in pediatric oncology and hematology in Germany and Austria, 2020/2021: a cross-sectional, multi-center point-prevalence study with a multi-step qualitative adjudication process.

Background: Due to the high risk of severe infection among pediatric hematology and oncology patients, antimicrobial use is particularly high. With our study, we quantitatively and qualitatively evaluated, based on institutional standards and national guidelines, antimicrobial usage by employing a point-prevalence survey with a multi-step, expert panel approach. We analyzed reasons for inappropriate antimicrobial usage. Methods: This cross-sectional study was conducted at 30 pediatric hematology and oncology centers in 2020 and 2021. Centers affiliated to the German Society for Pediatric Oncology and Hematology were invited to join, and an existing institutional standard was a prerequisite to participate. We included hematologic/oncologic inpatients under 19 years old, who had a systemic antimicrobial treatment on the day of the point prevalence survey. In addition to a one-day, point-prevalence survey, external experts individually assessed the appropriateness of each therapy. This step was followed by an expert panel adjudication based upon the participating centers' institutional standards, as well as upon national guidelines. We analyzed antimicrobial prevalence rate, along with the rate of appropriate, inappropriate, and indeterminate antimicrobial therapies with regard to institutional and national guidelines. We compared the results of academic and non-academic centers, and performed a multinomial logistic regression using center- and patient-related data to identify variables that predict inappropriate therapy. Findings: At the time of the study, a total of 342 patients were hospitalized at 30 hospitals, of whom 320 were included for the calculation of the antimicrobial prevalence rate. The overall antimicrobial prevalence rate was 44.4% (142/320; range 11.1-78.6%) with a median antimicrobial prevalence rate per center of 44.5% (95% confidence interval [CI] 35.9-49.9). Antimicrobial prevalence rate was significantly higher (p < 0.001) at academic centers (median 50.0%; 95% CI 41.2-55.2) compared to non-academic centers (median 20.0%; 95% CI 11.0-32.4). After expert panel adjudication, 33.8% (48/142) of all therapies were labelled inappropriate based upon institutional standards, with a higher rate (47.9% [68/142]) when national guidelines were taken into consideration. The most frequent reasons for inappropriate therapy were incorrect dosage (26.2% [37/141]) and (de-)escalation/spectrum-related errors (20.6% [29/141]). Multinomial, logistic regression yielded the number of antimicrobial drugs (odds ratio, OR, 3.13, 95% CI 1.76-5.54, p < 0.001), the diagnosis febrile neutropenia (OR 0.18, 95% CI 0.06-0.51, p = 0.0015), and an existing pediatric antimicrobial stewardship program (OR 0.35, 95% CI 0.15-0.84, p = 0.019) as predictors of inappropriate therapy. Our analysis revealed no evidence of a difference between academic and non-academic centers regarding appropriate usage. Interpretation: Our study revealed there to be high levels of antimicrobial usage at German and Austrian pediatric oncology and hematology centers with a significant higher number at academic centers. Incorrect dosing was shown to be the most frequent reason for inappropriate usage. Diagnosis of febrile neutropenia and antimicrobial stewardship programs were associated with a lower likelihood of inappropriate therapy. These findings suggest the importance of febrile neutropenia guidelines and guidelines compliance, as well as the need for regular antibiotic stewardship counselling at pediatric oncology and hematology centers. Funding: European Society of Clinical Microbiology and Infectious Diseases, Deutsche Gesellschaft für Pädiatrische Infektiologie, Deutsche Gesellschaft für Krankenhaushygiene, Stiftung Kreissparkasse Saarbrücken.

Assessment of an umbilical venous catheter dwell-time of 8-14 days versus 1-7 days in very low birth weight infacts (UVC - You Will See): a pilot single-center, randomized controlled trial.

BACKGROUND: Umbilical venous catheters (UVCs) are used for central vascular access in preterm infants, but controversy exits with regard to the optimum dwell-time. PATIENTS AND METHODS: Prospective, randomized controlled trial at a level III University neonatal intensive care unit (NICU), comparing a UVC dwell-time of 1-7 days (control group) to 8-14 days (intervention group) in very low birth weight (VLBW) infants. PRIMARY OUTCOME PARAMETER: Number of infants requiring additional peripherally inserted central catheters (PICC) after removal of UVC. SECONDARY OUTCOME PARAMETERS: Total number of central lines (CL = UVC and PICCs) until time point of full enteral feeds (130-160 mL/kg/d), total number of intravenous vascular catheters, number of CL-associated complications (infection, thrombosis/emboli, organ injury, secondary CL dislocation), number of X-rays for assessment of CL positioning, and days of therapy (DOT) (teicoplanin) for CL-associated blood stream infections (CLABSI). RESULTS: Of 116 patients screened for eligibility, 63 patients were enrolled - control group: 31 infants, mean gestational age (GA) 280 weeks (standard deviation (SD) 2.6 weeks), mean birth weight (BW) 988.9 g (SD 322.0 g); intervention group: 32 infants, mean GA 285 weeks (SD 3.0 weeks), mean BW 1078.9 g (SD 324.6 g). In the control group, 28 infants required additional PICCs versus 16 in the intervention group (p < 0.001); total number of CLs: control group n = 58 versus intervention group n = 28; p < 0.001, and the total number of venous vascular devices was also significantly higher in the control group (109 versus 61; p = 0.04). No significant differences were seen with regard to CL-associated complications (p = 0.09). The number of X-rays for assessment of correct CL-position significantly lower in the intervention group (144 versus 96; p = 0.03). In the intervention group, length of hospital stay was significantly shorter (88.1 (SD: 35.3 days) versus 68.1 (SD: 32.6 days); p = 0.03) and GA significantly lower at discharge from the hospital (404: SD: 33 weeks) versus 385: SD: 25 weeks; p = 0.02. No differences existed with regard to neonatal morbidities and mortality at 36 weeks gestational age. CONCLUSIONS: A longer UVC dwell-time of up to 14 days significantly decreased the number of painful invasive vascular procedures and radiation exposure, and shortened the length of the hospital stay. The findings of our pilot study should be confirmed in a larger, multi-center RCT with the primary focus on catheter-associated complications.

Association of viral load with TRAIL, IP-10, CRP biomarker signature and disease severity in children with respiratory tract infection or fever without source: A prospective, multicentre cohort study.

BACKGROUND: To investigate the association of viral load (VL) with (i) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein-10, C-reactive protein, and a combinatorial score (BV score), and (ii) clinical severity. STUDY DESIGN: In this prospective, multicentre cohort substudy, children with respiratory tract infection or fever without source were enrolled. VL for influenza virus, rhinovirus, respiratory syncytial virus, and adenovirus was measured from nasopharyngeal swabs. The reference standard diagnosis was established based on expert panel adjudication. RESULTS: Of 1140 recruited patients, 333 had a virus monodetection. VL for the aggregated data set correlated with TRAIL and IP-10 levels, with the length of oxygen therapy, and inversely with the BV score. At a single viral level, only the influenza VL yielded a correlation with TRAIL, IP-10 levels, and the BV score. Children with a viral reference standard diagnosis had significantly higher VL than those with bacterial infection (p = 0.0005). Low TRAIL (incidence rate ratio [IRR] 0.6, 95% confidence interval [CI] 0.39-0.91) and young age (IRR 0.62, 95% CI 0.49-0.79) were associated with a longer hospital stay, while young age (IRR 0.33, 95% CI 0.18-0.61), low TRAIL (IRR 0.25, 95% CI 0.08-0.76), and high VL (IRR 1.16, 95% CI 1.00-1.33) were predictive of longer oxygen therapy. CONCLUSION: These findings indicate that VL correlates with biomarkers and may serve as a complementary tool pertaining to disease severity.

Antimicrobial Use in Pediatric Oncology and Hematology: Protocol for a Multicenter Point-Prevalence Study With Qualitative Expert Panel Assessment.

BACKGROUND: Because infections are a major driver of morbidity and mortality in children with hematologic or oncologic diseases, antimicrobials are frequently prescribed in pediatric oncology practice. However, excess or inappropriate use of antimicrobials is directly linked to the emergence of antimicrobial resistance. Although point-prevalence studies have examined the extent of antimicrobial use, a comprehensive qualitative evaluation of individual antimicrobial prescriptions remains lacking. OBJECTIVE: The aim of this study is to identify appropriate versus inappropriate antimicrobial use among pediatric cancer patients in a point-prevalence study, followed by an expert panel adjudication process and a subsequent report of these findings to participating centers. This study also aims to improve the quality of patient care by informing centers about discrepancies between internal standards of care and national guidelines. METHODS: Our point-prevalence study is performed at pediatric cancer centers in Germany and Austria. All patients under 18 years old who are hospitalized at the time of the study are included. As a supplement to the point-prevalence study, an expert panel is qualitatively assessing each of the antimicrobial prescriptions at the participating centers to review local guidelines and compare them with national guidelines. RESULTS: As of December 2021, the point-prevalence survey has been conducted at 30 sites and expert panel adjudication for qualitative assessment of each antimicrobial use is ongoing. Results of the study are expected in 2022. CONCLUSIONS: This is the first point-prevalence study conducted among pediatric cancer centers with an integrated, multistep, qualitative approach that assesses each antimicrobial prescription. The results of this study will inform possible interventions for internal guidelines and antimicrobial stewardship programs implemented at pediatric cancer centers. In addition, local guidelines will be compared with national guidelines. Furthermore, this study will contribute to the overall integration of antimicrobial stewardship principles and initiatives in pediatric oncology and hematology, thereby improving safety and quality of care for children and adolescents with cancer and blood disorders. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35774.

Multidrug-resistant organisms in paediatric palliative care patients - Prevalence, risk factors and the impact of a liberal hygiene concept.

AIM: Multidrug-resistant organisms (MDRO) deserve special attention in health-care facilities for children with life-limiting conditions because these children have an increased risk for colonisation. To avoid nosocomial transmissions to other inpatients, single-room isolation is usually recommended. In the context of paediatric palliative care (PPC), such isolation counters the aim of participation in social activities for the patients. This study aimed to determine the prevalence of MDRO, the predictive value of risk factors and the incidence of nosocomial infections and nosocomial colonisations on a PPC inpatient unit applying a special hygiene concept that enables participation in social activities through risk-adaption and barrier nursing. METHODS: Two-year surveillance with MDRO screening of all intakes (N = 386) of a PPC unit on the day of admission and discharge. To determine the predictive value of pre-defined risk factors, logistic regression analyses were calculated. Receiver operating characteristic analyses were performed to determine the predictive power of the number of risk factors on the presence of MDRO. RESULTS: The rate of MDRO colonisation at admission was 12.7%; previous positive MDRO screening was the only significant individual risk factor. Over the 2-year period, no MDRO-related nosocomial infections occurred; nosocomial colonisation incidence density was 0.6. CONCLUSION: Results demonstrate that patients with at least one risk factor have to be cared for by barrier nursing until MDRO screening results are negative. Following these guidelines prevents nosocomial MDRO transmission.

SARS-CoV-2 in pediatric cancer: a systematic review.

The outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 in Wuhan challenges pediatric oncologists in an unexpected way. We provide a comprehensive overview, which systematically summarizes and grades evidence (QoE) on SARS-CoV-2 infections in pediatric cancer patients at 1.5 years of pandemic. A systematic literature search in PubMed combined with an additional exploratory literature review in other international databases was conducted to identify studies on children (aged < 18 years) with a malignant disease and COVID-19 infections. In total, 45 reports on 1003 pediatric cancer patients with SARS-CoV-2 infections were identified out of 1397 reports analyzed. The clinical course of COVID-19 was reported mild or moderate in 358 patients (41.7%), whereas 11.1% of patients showed severe COVID-19. In 12.7% of patients, chemotherapy was postponed, whereas 19% of patients with different underlying malignancies received chemotherapy during SARS-CoV-2 infection. Twenty-five patients with SARS-CoV-2 infections died, potentially related to COVID-19. CONCLUSION: Despite a favorable COVID-19 outcome in most pediatric cancer patients, the morbidity is reported higher than in children without comorbidities. However, no severe COVID-19 complications were associated to the continuation of chemotherapy in some cohort studies and reports on two patients. Therefore, the risk of cancer progress or relapse due to interruption of chemotherapy has carefully to be weighed against the risk of severe COVID-19 disease with potentially fatal outcome. WHAT IS KNOWN: • Most of pediatric patients with malignant diseases show an asymptomatic, mild or moderate clinical course of SARS-CoV-2 infection. • Current need for a basis for decision-making, whether to stop or interrupt cancer treatment in a patient infected with SARS-CoV-2, and when to continue chemotherapy. WHAT IS NEW: • Review results comprising over 1000 pediatric COVID-19 cancer patients confirm mild courses of SARS-CoV-2 infection in most patients but also show the attributable mortality is at least 10 times higher compared to reports on hospitalized children without comorbidities. • Review identifies that chemotherapy was continued despite SARS-CoV-2 positivity in 18% of patients with individual chemotherapy modification according to the clinical course of SARS-CoV-2 infection and existing comorbidities. On this basis, no severe COVID-19 complications were associated to the continuation of chemotherapy in several cohort studies and two case reports.

Meropenem Use in Pediatric Oncology - Audit on Indication, Appropriateness and Consumption Comparing Patient Derived and Pharmacy Dispensing Data.

BACKGROUND: Meropenem is an important second- or third-line antibiotic in pediatric cancer patients with febrile neutropenia (FN). Concise utilization data of meropenem in this setting is limited. It remains unclear how drug dispensing data from the hospital pharmacy correlate with data derived from patients' files. METHODS: Retrospective audit of meropenem-consumption in a University-affiliated pediatric oncology center in days of therapy (DOT)/100 inpatient days. The individual indication for meropenem was critically reviewed. The real consumption (in g/100 inpatient days) was compared with the drug amounts dispensed by the hospital pharmacy (in gram and in defined daily doses (DDD)/100 inpatient days). All patients receiving at least one dose of meropenem from 1st of April 2016 until the 30th of June 2018 were included. RESULT: Of 235 consecutive patients, 45 (19%) received meropenem, comprising 57 FN events. The probability of receiving at least one dose of meropenem was significantly higher in patients with ALL, AML, NHL and certain CNS tumors. Preceding the use of meropenem, only 5% of patients were known to be colonized with multidrug-resistant Gram-negative pathogens. Meropenem was administered as first-line treatment in 26% of all meropenem cycles, in 74% of all FN events with meropenem, Piperacillin-Tazobactam was used for initial treatment. In 5 of 57 FN events (8.8%), initial blood cultures yielded a Gram-negative pathogen. Concerning definite treatment, appropriate alternatives to meropenem with a smaller spectrum of activity would have been available in 4 cases, but a de-escalation was not performed. The median length of therapy in the meropenem group was 6 days, the corresponding median for days of therapy (DOT) was 12 days. This corresponds with combination therapy in 56% of all meropenem treatments, mostly with teicoplanin. On average, drug dispensing data from the hospital pharmacy were 1.53 times higher than real use (relying on patients' data) without a significant correlation. A higher Case-mix Index positively correlated with meropenem-consumption. CONCLUSION: The use of meropenem should become a target of antibiotic stewardship programs in order to restrict its use to certain indications and preserve its outstanding role as second- or third-line antibiotic in this vulnerable population. Irrespective of the metrics used (g or DDD/100 inpatient days), pharmacy dispensing data do not accurately depict real patient-derived data concerning meropenem use in pediatric cancer patients.

Preclinical evaluation of passive disinfection caps with a long-term catheter for the prevention of catheter-related bloodstream infection in pediatric cancer patients.

The use of passive disinfection devices (disinfection caps) may be a beneficial part of a maintenance care bundle, aiming at the prevention of catheter-related bloodstream infections in pediatric cancer patients. This preclinical in vitro investigation tested the visual and mechanical integrity of a Broviac™ catheter hub after simulation testing with 122 3M™ CurosTM Stopper Disinfection Caps for Open Female Luers repeatedly attached and removed over 6 months. We found that these catheter hubs were compatible, fully operational, and airtight with use of 3M Curos stopper caps after 6 months of use with 122 caps per catheter hub.

[Antibacterial Prophylaxis in Children and Adolescents Undergoing Therapy for Cancer - Statement of the Society of Pediatric Oncology and Hematology (GPOH) and of the German Society for Pediatric Infectious Diseases (DGPI) on Two Current International Guidelines]. / Antibakterielle Prophylaxe in der Pädiatrischen Hämatologie und Onkologie.

Immunocompromised children and adolescents receiving treatment for cancer have an increased risk for potentially life-threatening infectious complications such as blood stream infections with Gram-positive and Gram-negative pathogens. Therefore, several centers for Pediatric Hematology and Oncology administer antibacterial prophylaxis to these patients to lower morbidity and mortality. Two pediatric specific guidelines on antibacterial prophylaxis were recently published. One of these guidelines was drawn up by an international group of pediatric experts of Europe, North and South America and Australia. The other guideline was prepared by an European group convened at the Eighth European Conference on Infections in Leukaemia (ECIL-8). In this review article, the working groups "Infections" of the Society of Pediatric Oncology and Hematology (GPOH) and "Fever in the neutropenic host" of the German Society for Pediatric Infectious Diseases" (DGPI) summarize the available data from randomized studies, systematic reviews and meta-analyses on antibacterial prophylaxis as well of current data on the emergence of resistance and discuss methodological aspects and the recommendations of the two guidelines.

Antibiotic Resistant Bloodstream Infections in Pediatric Patients Receiving Chemotherapy or Hematopoietic Stem Cell Transplant: Factors Associated with Development of Resistance, Intensive Care Admission and Mortality.

Bloodstream infections (BSI) are a severe complication of antineoplastic chemotherapy or hematopoietic stem cell transplantation (HSCT), especially in the presence of antibiotic resistance (AR). A multinational, multicenter retrospective study in patients aged ≤ 18 years, treated with chemotherapy or HSCT from 2015 to 2017 was implemented to analyze AR among non-common skin commensals BSI. Risk factors associated with AR, intensive care unit (ICU) admission and mortality were analyzed by multilevel mixed effects or standard logistic regressions. A total of 1291 BSIs with 1379 strains were reported in 1031 patients. Among Gram-negatives more than 20% were resistant to ceftazidime, cefepime, piperacillin-tazobactam and ciprofloxacin while 9% was resistant to meropenem. Methicillin-resistance was observed in 17% of S. aureus and vancomycin resistance in 40% of E. faecium. Previous exposure to antibiotics, especially to carbapenems, was significantly associated with resistant Gram-negative BSI while previous colonization with methicillin-resistant S. aureus was associated with BSI due to this pathogen. Hematological malignancies, neutropenia and Gram-negatives resistant to >3 antibiotics were significantly associated with higher risk of ICU admission. Underlying disease in relapse/progression, previous exposure to antibiotics, and need of ICU admission were significantly associated with mortality. Center-level variation showed a greater impact on AR, while patient-level variation had more effect on ICU admission and mortality. Previous exposure to antibiotics or colonization by resistant pathogens can be the cause of AR BSI. Resistant Gram-negatives are significantly associated with ICU admission and mortality, with a significant role for the treating center too. The significant evidence of center-level variations on AR, ICU admission and mortality, stress the need for careful local antibiotic stewardship and infection control programs.

School and kindergarten attendance and home schooling of pediatric cancer patients before and during the SARS-CoV-2 pandemic: results of a survey of the German Society for Pediatric Oncology and Hematology.

In this multicenter survey (July 07 to August 08, 2020) in pediatric oncology centers (POCs) belonging to the German Society for Pediatric Oncology and Hematology (GPOH), 36 POCs participated (response rate 70.6%). Home schooling practice was judged as satisfying by 79% prior to and by 38% during the pandemic (P=0.0007). The individual risk of a SARS-CoV-2 infection and the risk of transmission to other patients/caregivers were arguments against attendance. Most POCs recommended regular social participation/school attendance after the end of intensive therapy. 81% stated that persisting restrictions result in serious negative psychosocial consequences for the patients and their families. In-hospital school education, home schooling and re-attendance of school and kindergarten among pediatric cancer patients have suffered a severe setback during the SARS-CoV-2 pandemic. Continuous communication and education concerning protective measures as well as an individual risk assessment are required to avoid the detrimental exclusion of pediatric oncology patients from kindergarten and school.

[Prospektives Audit des Gentamicin Drug Monitorings in einem Kinderkrebszentrum]. / Prospective Audit of Gentamicin Drug Monitoring Practice in a Pediatric Cancer Center.

BACKGROUND: Many pediatric cancer centers still use Gentamicin as first line combination treatment in patients with fever and neutropenia. Since 2011, our center has implemented a dosing regimen with 250 mg/m2 BSA (max. 10 mg/kg, max. 400 mg) as a single daily infusion according to the German guideline. PATIENTS AND METHODS: In this prospective audit (February 2011 to December 2019), 105 Gentamicin treatment cycles were analyzed in 66 pediatric cancer patients, focusing on adherence to the dosing regimen and the drug monitoring results. RESULTS: Adherence to the dosing regimen was high (89%). In 64% of all cycles, the Cmax (drawn 1 h after the 2nd dose) reached the target of 10-20 µg/ml. Cmax significantly correlated with dosing in mg/m2 BSA (p=0,007), but not with dosing in mg/kg (p=0,366). Age below 6 years did not influence these results. The Gentamicin Ctrough (drawn 8-10 h after the second dose) was < 2 µg/ml in 93% of all cycles without any dose correlation. None of the patients experienced Gentamicin-associated nephrotoxicity. DISCUSSION AND CONCLUSION: This prospective audit of single daily infusion Gentamicin in pediatric cancer patients without impaired renal function elicits the feasibility and safety of the dosing regimen in mg/m2 BSA according to the German guideline. Since indications for first-line gentamicin are limited, a multicenter prospective study would be advantageous to confirm these observations.

Persistent aseptic meningitis in a child-think patch.

BACKGROUND: In patients with neurosurgical interventions requiring dura reconstruction, the use of bovine graft material may be required. PATIENTS AND METHODS: Case report. RESULTS: We present a 12-year-old girl with a profound graft reaction with severe neurologic symptoms mimicking post-neurosurgical bacterial meningitis after resection of an infra-tentorial brain tumour. CONCLUSION: It is important to take into consideration this rare clinical entity in children and adults after dura reconstruction using allogenic graft (bovine) material in order to avoid the unnecessary use of antibiotics and antiviral drugs.

Management of children with fever and neutropenia: results of a survey in 51 pediatric cancer centers in Germany, Austria, and Switzerland.

PURPOSE: Investigation of the current practice of diagnostics and treatment in pediatric cancer patients with febrile neutropenia. METHODS: On behalf of the German Society for Pediatric Oncology and Hematology and the German Society for Pediatric Infectious Diseases, an Internet-based survey was conducted in 2016 concerning the management of febrile neutropenia in pediatric oncology centers (POC). This survey accompanied the release of the corresponding German guideline to document current practice before its implementation in clinical practice. RESULTS: In total, 51 POCs participated (response rate 73%; 43 from Germany, and 4 each from Austria and Switzerland). Identified targets for antimicrobial stewardship concerned blood culture diagnostics, documentation of the time to antibiotics, the use of empirical combination therapy, drug monitoring of aminoglycosides, the time to escalation in patients with persisting fever, minimal duration of IV treatment, sequential oral treatment in patients with persisting neutropenia, indication for and choice of empirical antifungal treatment, and the local availability of a pediatric infectious diseases consultation service. CONCLUSION: This survey provides useful information for local antibiotic stewardship teams to improve the current practice referring to the corresponding national and international guidelines.

39·0°C versus 38·5°C ear temperature as fever limit in children with neutropenia undergoing chemotherapy for cancer: a multicentre, cluster-randomised, multiple-crossover, non-inferiority trial.

BACKGROUND: Fever in neutropenia is the most frequent complication of chemotherapy for cancer. The temperature limit defining fever used clinically varies. A higher limit can avoid unnecessary diagnoses in patients spontaneously recovering from fever. This trial primarily aimed to determine if a limit of 39·0°C ear temperature is non-inferior to 38·5°C regarding safety. METHODS: This cluster-randomised, multiple crossover, non-blinded, non-inferiority trial was done in six Swiss Paediatric Oncology Group centres (clusters) in Switzerland. Patients (aged 1 to <18 years) with any malignancy and treated with myelosuppressive chemotherapy expected to last 2 months or more were repeatedly randomly assigned (1:1), at the cluster level, to either monthly 39·0°C or 38·5°C ear temperature limits for diagnosis of fever in neutropenia. Diagnosis below the randomised limit was allowed for clinical reasons. Such a diagnosis implied emergency hospitalisation, examinations (including blood culture), as-needed antipyretics, and empirical intravenous broad-spectrum antibiotics. The primary outcome was the rate of fever in neutropenia with safety relevant events (SRE) per chemotherapy year; we also assessed efficacy in terms of rate of fever in neutropenia. The non-inferiority margin was 1·33 for safety, and for effiacy, the superiority margin was 1·00. This trial is registered at ClinicalTrials.gov, number NCT02324231. FINDINGS: 269 patients were recruited between April 28, 2016, to Aug 27, 2018, until the trial was stopped for success after the second interim analysis. Patients were repeatedly randomly assigned, with 1210 (48%) of 2547 randomisation periods and 92 (47%) of 195 chemotherapy years randomised to 39·0°C. SREs were diagnosed in 72 (20%) of 360 fever in neutropenia episodes (zero deaths, 16 intensive care unit admissions, 22 cases of severe sepsis, and 56 cases of bacteraemia). In 92 chemotherapy years randomised to the 39·0°C fever limit, 151 episodes of fever with neutropenia were diagnosed (1·64 per year), including 22 (15%) with SRE (0·24 per year). In 103 chemotherapy years randomised to 38·5°C, 209 episodes were diagnosed (2·03 per year), including 50 (24%) with SRE (0·49 per year). The mixed Poisson regression rate ratio (RR) of fever in neutropenia with SRE in 39·0°C versus 38·5°C was 0·56 (95% upper confidence bound 0·72). The corresponding RR of fever in neutropenia was 0·83 (95% upper confidence bound 0·98). INTERPRETATION: In children with neutropenia and chemotherapy for cancer, 39·0°C ear temperature was safe and seemed efficacious. For Switzerland and comparable settings, 39·0°C can be recommended as new evidence-based standard fever limit except for patients with acute myeloid leukaemia or haematopoietic stem cell transplantation. FUNDING: Swiss Cancer League (KLS-3645-02-2015).

Vancomycin-induced ototoxicity in very-low-birthweight infants.

BACKGROUND: Vancomycin is an extensively used anti-infective drug in neonatal ICUs. However, exposure-toxicity relationships have not been clearly defined. OBJECTIVES: To evaluate the risk profile for hearing deficits in vancomycin-exposed very-low-birthweight infants (VLBWI). METHODS: In a large cohort study of the German Neonatal Network (GNN; n = 16 967 VLBWI) we assessed the association of vancomycin treatment and pathological hearing tests at discharge and at 5 year follow-up. We performed audits on vancomycin exposure, drug levels, dose adjustments and exposure to other ototoxic drugs in a subgroup of 1042 vancomycin-treated VLBWI. RESULTS: In the GNN cohort, 28% (n = 4739) were exposed to IV vancomycin therapy. In multivariable logistic regression analysis, vancomycin exposure proved to be independently associated with pathological hearing test at discharge (OR 1.18, 95% CI 1.03-1.34, P = 0.016). Among vancomycin-treated infants, a cumulative vancomycin dose above the upper quartile (>314 mg/kg bodyweight) was associated with pathological hearing test at discharge (OR 2.1, 95% CI 1.21-3.64, P = 0.009), whereas a vancomycin cumulative dose below the upper quartile was associated with a reduced risk of pathological tone audiometry results at 5 years of age (OR 0.29, 95% CI 0.1-0.8, P = 0.02, n = 147). CONCLUSIONS: Vancomycin exposure in VLBWI is associated with an increased, dose-dependent risk of pathological hearing test results at discharge and at 5 years of age. Prospective studies on long-term hearing impairment are needed.