Anti-infective vaccination strategies in patients with hematologic malignancies or solid tumors-Guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO).

Infectious complications are a significant cause of morbidity and mortality in patients with malignancies specifically when receiving anticancer treatments. Prevention of infection through vaccines is an important aspect of clinical care of cancer patients. Immunocompromising effects of the underlying disease as well as of antineoplastic therapies need to be considered when devising vaccination strategies. This guideline provides clinical recommendations on vaccine use in cancer patients including autologous stem cell transplant recipients, while allogeneic stem cell transplantation is subject of a separate guideline. The document was prepared by the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) by reviewing currently available data and applying evidence-based medicine criteria.

Evaluation of the Use of Rectal Swabs for Laboratory Diagnosis of Clostridium difficile Infection.

For the diagnosis of Clostridium difficile infection (CDI), microbiological testing is almost always accomplished through the analysis of stool specimens. We evaluated the performances of rectal swabs with liquid transport medium (FS) and nylon flocked dry swabs for the detection of C. difficile Additionally, the impact on the diagnostic yield of storing swabs at -80°C for up to 3 months was evaluated. Sixty clinical stool samples positive for C. difficile by PCR were used for simulating rectal swabbing. FS and dry swabs were dipped into the stool and tested by PCR directly after swabbing at 1 and 3 months after storage at -80°C. Stool and the liquid medium of FS were additionally tested by a combination of glutamate dehydrogenase antigen (GDH) testing and toxin A/B enzyme immunoassay (EIA), as well as by toxigenic culture (TC). Using dry swabs, the PCR-based detection rate of C. difficile was equal to the rate using stool samples (30/30 [100%]), whereas the detection rate in FS was significantly lower (25/30 [83.2%]; P = 0.019). The sensitivities of FS for detecting C. difficile by PCR, TC, GDH testing, and toxin A/B EIA were 83.3%, 85.7%, 88%, and 68.9%, respectively. Storage of swabs at -80°C had no impact on the detection rate. FS cannot replace stool samples in the two-step laboratory diagnosis of CDI, as the sensitivities were too low, probably due to diluting effects of the fecal sample in the liquid medium. For simple PCR-based detection of C. difficile, dry swabs proved to be a suitable alternative to the use of stool samples.

Serial assessment of pulmonary lesion volume by computed tomography allows survival prediction in invasive pulmonary aspergillosis.

BACKGROUND: Serial chest CT is the standard of care to establish treatment success in invasive pulmonary aspergillosis (IPA). Data are lacking how response should be defined. METHODS: Digital CT images from a clinical trial on treatment of IPA were re-evaluated and compared with available biomarkers. Total volume of pneumonia was added up after manual measurement of each lesion, followed by statistical analysis. RESULTS: One-hundred and ninety CT scans and 309 follow-up datasets from 40 patients were available for analysis. Thirty-one were neutropenic. Baseline galactomannan (OR 4.06, 95%CI: 1.08-15.31) and lesion volume (OR 3.14, 95%CI: 0.73-13.52) were predictive of death. Lesion volume at d7 and trend between d7 and d14 were strong predictors of death (OR 20.01, 95%CI: 1.42-282.00 and OR 15.97, 95%CI: 1.62-157.32) and treatment being rated as unsuccessful (OR 4.75, 95%CI: 0.94-24.05 and OR 40.69, 95%CI: 2.55-649.03), which was confirmed by a Cox proportional hazards model using time-dependent covariates. CONCLUSION: Any increase in CT lesion volume between day 7 and day 14 was a sensitive marker of a lethal outcome (>50%), supporting a CT rescan each one and 2 weeks after initial detection of IPA. The predictive value exceeded all other biomarkers. Further CT follow-up after response at day 14 was of low additional value. KEY POINTS: • CT evaluation offers good prediction of outcome for invasive pulmonary aspergillosis. • Predictive capability exceeds galactomannan, blood counts, and lesion count. • Any progression between day 7 and day 14 constitutes a high-risk scenario.

A randomized trial on chlorhexidine dressings for the prevention of catheter-related bloodstream infections in neutropenic patients.

BACKGROUND: Central venous catheter (CVC)-related bloodstream infections (CRBSI) are a frequent cause of morbidity and mortality in patients with chemotherapy-induced neutropenia. Chlorhexidine containing catheter securement dressings may prevent CRBSI. PATIENTS AND METHODS: A multicenter randomized, controlled trial was conducted at 10 German hematology departments. We compared chlorhexidine-containing dressings with non-chlorhexidine control dressings in neutropenic patients. The primary end point was the incidence of definite CRBSI within the first 14 days (dCRBSI14) of CVC placement. Secondary end points included combined incidence of definite or probable CRBSI within 14 days (dpCRBSI14), overall (dpCRBSI), incidence of unscheduled dressing changes and adverse events. RESULTS: From February 2012 to September 2014, 613 assessable patients were included in the study. The incidence of dCRBSI14 was 2.6% (8/307) in the chlorhexidine and 3.9% (12/306) in the control group (P = 0.375). Both dpCRBSI14 and dpCRBSI were significantly less frequent in the study group with dpCRBSI14 in 6.5% (20/307) of the chlorhexidine group when compared with 11% (34/306) in the control group (P = 0.047), and dpCRBSI in 10.4% (32/307) versus 17% (52/306), respectively (P = 0.019). The frequency of dressing intolerance with cutaneous and soft tissue abnormalities at the contact area was similar in both groups (12.4% and 11.8%; P = 0.901). CONCLUSIONS: Although the trial failed its primary end point, the application of chlorhexidine containing catheter securement dressings reduces the incidence of definite or probable CRBSI in neutropenic patients. CLINICAL TRIALS NUMBER: NCT01544686 (Clinicaltrials.gov).

Emergence of azole-resistant invasive aspergillosis in HSCT recipients in Germany.

OBJECTIVES: Aspergillus fumigatus is the most common agent of invasive aspergillosis (IA). In recent years, resistance to triazoles, the mainstay of IA therapy, has emerged in different countries worldwide. IA caused by azole-resistant A. fumigatus (ARAF) shows an exceedingly high mortality. In this study, IA due to ARAF isolates in HSCT recipients in Germany was investigated. METHODS: The epidemiology of azole resistance in IA was analysed in two German haematology departments. Between 2012 and 2013, 762 patients received HSCT in Essen (n = 388) and Cologne (n = 374). Susceptibility testing of A. fumigatus isolates was performed by Etest, followed by EUCAST broth microdilution testing if elevated MICs were recorded. In all ARAF isolates the cyp51A gene was sequenced and the genotype was determined by microsatellite typing using nine short tandem repeats. RESULTS: In total, A. fumigatus was recovered from 27 HSCT recipients. Eight patients had azole-resistant IA after HSCT, and seven of the cases were fatal (88%). All except one patient received antifungal prophylaxis (in five cases triazoles). TR34/L98H was the most common mutation (n = 5), followed by TR46/Y121F/T289A (n = 2). In one resistant isolate no cyp51A mutation was detected. Genotyping revealed genetic diversity within the German ARAF isolates and no clustering with resistant isolates from the Netherlands, India and France. CONCLUSIONS: This report highlights the emergence of azole-resistant IA with TR34/L98H and TR46/Y121F/T289A mutations in HSCT patients in Germany and underscores the need for systematic antifungal susceptibility testing of A. fumigatus.

Candidemia in the intensive care unit: analysis of direct treatment costs and clinical outcome in patients treated with echinocandins or fluconazole.

Direct treatment costs caused by candidemia in German intensive care unit (ICU) patients are currently unknown. We analyzed treatment costs and the impact of antifungal drug choice. Comprehensive data of patients who had at least one episode of candidemia while staying in the ICU between 01/2005 and 12/2010 were documented in a database using the technology of the Cologne Cohort of Neutropenic Patients (CoCoNut). A detailed analysis of all disease-associated treatment costs was performed. Patients treated with echinocandins (i.e., anidulafungin, caspofungin, micafungin) or fluconazole were analyzed separately and compared. Forty-one and 64 patients received echinocandins and fluconazole, respectively. The mean Acute Physiology and Chronic Health Evaluation (APACHE) IV score was 114 (95 % confidence interval [CI]: 106-122) vs. 95 (95 % CI: 90-101, p = <0.001). Twenty-three (56 %) and 33 (52 %, p = 0.448) patients survived hospitalization, while 17 (41 %) and 22 (34 %, p = 0.574) survived one year after diagnosis. In the echinocandin and fluconazole groups, the mean costs per patient of ICU treatment were 20,338 (95 % CI: 12,893-27,883) vs. 11,932 (95 % CI: 8,016-15,849, p = 0.110), and the total direct treatment costs per patient were 37,995 (95 % CI: 26,614-49,376) vs. 22,305 (95 % CI: 16,817-27,793, p = 0.012), resulting in daily costs per patient of 1,158 (95 % CI: 1,036-1,280) vs. 927 (95 % CI: 828-1,026, p = 0.001). Our health economic analysis shows the high treatment costs of patients with candidemia in the ICU. Sicker patients had a prolonged hospitalization and were more likely to receive echinocandins, leading to higher treatment costs. Outcomes were comparable to those achieved in less sick patients with fluconazole.

Economic burden of Clostridium difficile associated diarrhoea: a cost-of-illness study from a German tertiary care hospital.

PURPOSE: Clostridium difficile associated diarrhoea (CDAD) is the most common cause of health-care-associated infectious diarrhoea. In the context of the German health-care system, direct and indirect costs of an initial episode of CDAD and of CDAD recurrence are currently unknown. METHODS: We defined CDAD as presence of diarrhoea (≥3 unformed stools/day) in association with detection of Clostridium difficile toxin in an unformed faecal sample. Patients treated with metronidazole (PO or IV) and/or vancomycin (PO) were included. Comprehensive data of patients were retrospectively documented into a database using the technology of the Cologne Cohort of Neutropenic Patients (CoCoNut). Patients with CDAD were matched to control patients in a 1:1 ratio. Analysis was split in three groups: incidence group (CDAD patients without recurrence), recurrence group (CDAD patients with ≥1 recurrence) and control group (matched non-CDAD patients). RESULTS: Between 02/2010 and 12/2011, 150 patients with CDAD (114 patients in the incidence and 36 (24 %) in the recurrence group) and 150 controls were analysed. Mean length of stay was: 32 (95 %CI: 30-37), 94 (95 %CI: 76-112) and 24 days (95 %CI: 22-27; P = <0.001), resulting in mean overall direct treatment costs per patient of €18,460 (95 %CI: €14,660-€22,270), €73,900 (95 %CI: €50,340-€97,460) and €14,530 (95 %CI: €11,730-€17,330; P = <0.001). In the incidence and recurrence group, the mean cumulative number of antibiotic CDAD treatment days was 11 (95 %CI: 10-12) and 36 (95 %CI: 27-45; P = <0.001). CONCLUSIONS: Especially CDAD recurrence was associated with excessive costs, which were mostly attributable to a significantly longer overall length of stay. Innovative treatment strategies are warranted to reduce treatment costs and prevent recurrence of CDAD.

Our 2015 approach to invasive pulmonary aspergillosis.

At the University Hospital of Cologne, in general two patient groups at high risk for invasive aspergillosis receive posaconazole prophylaxis: Acute myelogenous leukaemia patients during remission induction chemotherapy and allogeneic haematopoietic stem cell transplant recipients. Other patients at risk undergo serum galactomannan testing three times weekly. At 72-96 h of persisting fever despite broad-spectrum antibiotics, or at onset of lower respiratory tract symptoms a thoracic computed tomography (CT) scan is performed. Without lung infiltrates on CT, IPA is ruled out. In lung infiltrates not suggestive for IPA mycological confirmation is pursued. In patients without posaconazole prophylaxis empiric caspofungin will be considered. CT findings typical for IPA prompt targeted treatment, and mycological confirmation. Bronchoalveolar lavage (BAL) is most important for cultural identification and susceptibility testing, and facilitates diagnosing other pathogens. BAL performance is virtually independent of platelet counts. If despite suggestive infiltrates BAL does not yield the diagnosis, CT-guided biopsy follows as soon as platelet counts allow. Surgery can also be beneficial in diagnosis and treatment of IPA. If the diagnosis of IPA is not established, mucormycosis is a valid concern. In patients with breakthrough IPA during posaconazole prophylaxis liposomal amphotericin B is the drug of choice. If no posaconazole prophylaxis was given, voriconazole is the treatment of choice for IPA.

[Resistant fungi]. / Resistenz bei Pilzen.

Particularly in the area of hematology/oncology and intensive care medicine, infections due to resistant fungi are to be expected. Emergence of resistance in fungi is a less dynamic process than in bacteria; it can, however, have an equally important impact on treatment strategies. In the following article, the most important resistance patterns of yeasts and molds (Candida albicans , Aspergillus fumigatus, the order Mucorales and the genus Fusarium) will be presented and discussed. Their diagnosis mostly being based on blood cultures, resistance testing for yeasts is usually readily available. Culture-based therapeutic adjustments in mold infections are, however, only rarely possible, as most antifungal therapies for these infections are initiated on an empirical basis after identification of typical infiltrates on a CT scan. Response to therapy is then evaluated on the basis of clinical signs and symptoms in combination with follow-up CT scans. In case of therapeutic failure or appearance of suspicious infiltrates under antifungal prophylaxis, an open or CT-guided biopsy is recommended to allow efficient adaptation of antifungal treatment. In individual cases, particularly in patients diagnosed with mucormycosis, resection of the focus of infection may be necessary to achieve a satisfactory treatment response.

Prophylaxis of infectious complications with colony-stimulating factors in adult cancer patients undergoing chemotherapy-evidence-based guidelines from the Infectious Diseases Working Party AGIHO of the German Society for Haematology and Medical Oncology (DGHO).

BACKGROUND: Current evidence on myelopoietic growth factors is difficult to overview for the practicing haematologist/oncologist. International guidelines are sometimes conflicting, exclude certain patient groups, or cannot directly be applied to the German health system. This guideline by the Infectious Diseases Working Party (AGIHO) of the German Society of Haematology and Medical Oncology (DGHO) gives evidence-based recommendations for the use of G-CSF, pegylated G-CSF, and biosimilars to prevent infectious complications in cancer patients undergoing chemotherapy, including those with haematological malignancies. METHODS: We systematically searched and evaluated current evidence. An expert panel discussed the results and recommendations. We then compared our recommendations to current international guidelines. RESULTS: We summarised the data from eligible studies in evidence tables, developed recommendations for different entities and risk groups. CONCLUSION: Comprehensive literature search and expert panel consensus confirmed many key recommendations given by international guidelines. Evidence for growth factors during acute myeloid leukaemia induction chemotherapy and pegfilgrastim use in haematological malignancies was rated lower compared with other guidelines.

Prevalence and molecular characterization of azole resistance in Aspergillus spp. isolates from German cystic fibrosis patients.

OBJECTIVES: Aspergillus spp. are the most frequently isolated filamentous fungi in the sputum of patients with cystic fibrosis (CF). Resistance to the azoles, the mainstay of current antifungal therapy, has been increasingly observed worldwide, but few data are available on the resistance of Aspergillus spp. in German CF patients. This study investigated the epidemiology of Aspergillus spp. and the molecular origin of azole resistance in a large German CF centre. METHODS: In total, 2677 respiratory samples from 221 CF patients collected between April 2010 and April 2013 were analysed; of these, 573 yielded Aspergillus spp., which were screened for azole resistance. Isolates with reduced susceptibility to itraconazole and/or voriconazole were tested according to the EUCAST reference procedure. Sequencing of cyp51A, the target of azole antifungals, was performed in all resistant isolates. RESULTS: Six isolates obtained from four patients were highly resistant to itraconazole (all identified as Aspergillus fumigatus sensu stricto); five of them were pan-azole resistant. The TR34/L98H mutation was the most frequent mutation identified in azole-resistant isolates (n = 4), followed by M220L and TR46/Y121F/T289A, a mutation previously reported from Belgium and the Netherlands only. Three of four patients harbouring azole-resistant A. fumigatus had not received any prior azole treatment. CONCLUSIONS: Resistance to azoles in Aspergillus spp. is still infrequent in German CF patients and is mainly caused by the TR34/L98H mutation. Worryingly, pan-azole-resistant TR46/Y121F/T289A has spread to Germany. Azole resistance has to be considered also in azole-naive CF patients and susceptibility testing of Aspergillus spp. isolates should be performed in all patients requiring treatment.

Different doses of micafungin for prophylaxis of invasive fungal diseases in hemato-oncological high-risk patients: a web-based non-interventional trial in four large university hospitals in Germany.

INTRODUCTION: Treatment indications of new antifungals in clinical practice often deviate from the strict criteria used in controlled clinical trials. Under routine clinical conditions, beneficial and adverse effects, not previously described in clinical trials may be observed. The aim of this study was to describe customary prescription and treatment strategies of micafungin (MCFG). METHODS: A registry was set up on www.ClinicalSurveys.net and physicians were invited to provide retrospective information on cases they had treated with MCFG. Documentation comprised demographic information, underlying disease, effectiveness, safety, and tolerability of MCFG. RESULTS: A total of 125 episodes of patients hospitalized between September 2009 and February 2012 were documented, of which 7 had to be excluded because of incomplete documentation. The most common risk factors of patients were hematological malignancy (n = 116, 98.3%) and antibiotic treatment >3 days (n = 115, 97.5%). MCFG was administered as prophylaxis in 106 (89.9%) patients. Median duration of MCFG application as prophylaxis was 21 days (range: 3-78); 53 of the patients (50%) received a dose of 50 mg, while the other 53 (50%) received 100 mg/day. For the different doses, prophylactic outcome was rated as success in 42 (79.2%) vs. 52 (98.1%; P = 0.004) patients. Fifty-five patients (51.9%) were treated with posaconazole before initiation of MCFG. Four patients (7.5%) developed a proven invasive fungal disease (IFD) while being treated with 50 mg MCFG, compared to no patient treated with 100 mg (P = 0.118). At the end of MCFG prophylaxis, 24 (22.6%) patients were switched to fluconazole and 64 (60.3%) patients to posaconazole. CONCLUSION: Our study shows clinical effectiveness of MCFG prophylaxis with low rates of breakthrough fungal infections. In most cases, MCFG was part of a multi-modal antifungal prophylactic strategy. Investigators reported fewer proven IFDs in patients receiving therapeutic doses of MCFG as prophylaxis.

Diagnosis and management of gastrointestinal complications in adult cancer patients: evidence-based guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO).

BACKGROUND: Cancer patients frequently suffer from gastrointestinal complications. However, a comprehensive, practical and evidence-based guideline on this issue is not yet available. PATIENTS AND METHODS: An expert group was put together by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) to develop a guideline on gastrointestinal complications in cancer patients. For each subtopic, a literature search was carried out in PubMed, Medline and Cochrane databases and the strength of recommendation and the quality of the published evidence for major therapeutic strategies were categorized using a modification of the 'Infectious Diseases Society of America' criteria. Consensus discussions were held on each of the topics. RESULTS: Recommendations were made with respect to non-infectious and infectious gastrointestinal complications. For all recommendations, the strength of the recommendation and the level of evidence are presented. CONCLUSION: This guideline is an evidence-based approach to the diagnosis and management of gastrointestinal complications in cancer patients.

Evaluation of an infectious disease consultation programme in a German tertiary care hospital.

PURPOSE: To evaluate a newly implemented infectious disease (ID) consultation service in terms of patient care, outcome and antibiotic prescription and to describe factors influencing adherence to recommendations. METHODS: Data from consultations during the first 6 months of the ID consultation program were collected and evaluated. Consultation requests, diagnostic results, treatment outcomes and antibiotic recommendations were categorised. Diagnostic and therapeutic recommendations were assessed and rated for adherence and outcome. Statistical analysis was performed to identify factors influencing adherence and treatment outcome. RESULTS: A total of 251 consultations were assessed. In most cases, ID specialists were asked for further advice regarding a previously initiated anti-infective treatment (N = 131, 52 %). In 54 of 195 (28 %) first consultations, the ID specialist proposed a differential diagnosis that differed from that of the working diagnoses submitted with the consultation request, and which was subsequently confirmed in 80 % of these cases. Diagnostic and therapeutic recommendations were made in 190 (76 %) and 240 (96 %) of the consultations, respectively. A change in the current treatment was recommended in 66 % of consultations; 37 % of recommendations were cost-saving and 26 % were cost-neutral. Compliance with diagnostic and therapeutic recommendations was rated as good by pre-specified criteria in 65 and 86 % of consultations, respectively. Treatment outcome was correlated with adherence to diagnostic recommendations (P = 0.012). Twenty-nine patients (16 %) died during the same hospital stay. CONCLUSION: Infectious disease consultations may help to establish the correct diagnosis, resulting in the appropriate treatment being provided to a severely sick patient population. Treatment outcome was improved in cases of good diagnostic adherence to the recommendations of the ID specialist.

Intestinal colonisation and blood stream infections due to vancomycin-resistant enterococci (VRE) and extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBLE) in patients with haematological and oncological malignancies.

BACKGROUND: In patients with haematological or oncological malignancies, we aimed to assess the rate of intestinal colonisation and blood stream infections (BSI) with extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBLE) and vancomycin-resistant enterococci (VRE), mortality and risk factors associated with ESBLE/VRE BSI, as well as the impact of faecal screening for ESBLE and VRE in combination with adapted empiric treatment of febrile neutropenia. METHODS: Within 72 h of admission to our department, an ESBLE and VRE screening stool sample was collected. In the case of neutropenic fever, blood cultures were drawn. Data of all admitted patients were prospectively documented. Explorative forward-stepwise logistic regression analyses were used to identify risk factors for progression from intestinal colonisation to BSI. RESULTS: During the study period, 1,805 stool samples were obtained from 513 patients during 1,012 inpatient stays, and 2,766 blood cultures were obtained from 578 patients during 1,091 inpatient stays. Ninety (17.5 %) of these patients were colonised with ESBLE and 51 (9.9 %) with VRE. Proportions of 40 % (36/90) of ESBLE and 61 % (31/51) of VRE colonisations were healthcare-associated. Six of 90 (6.6 %) ESBLE-colonised patients and 1/51 (2 %) VRE-colonised patients developed BSI with the respective organism. None of these patients died after receiving early appropriate empiric antibiotics based on colonisation status. Colonisation with ESBLE or VRE was associated with increased risk ratios (RR) towards developing ESBLE BSI [RR 4.5, 95 % confidence interval (CI): 2.89-7.04] and VRE BSI (RR 10.2, 95 % CI: 7.87-13.32), respectively. Acute myelogenous leukaemia and prior treatment with platinum analogues or quinolones were identified as independent risk factors for ESBLE BSI in colonised patients. CONCLUSIONS: Intestinal ESBLE/VRE colonisation predicts BSI. Faecal screening in haematology/oncology patients in combination with directed empiric treatment may reduce ESBLE BSI-related mortality.

Pandemic 2009 influenza A(H1N1) virus infection coinciding with invasive pulmonary aspergillosis in neutropenic patients.

SIn patients receiving anti-neoplastic chemotherapy, the impact of influenza on the incidence of invasive pulmonary aspergillosis (IPA) remains unknown. We matched data of the Cologne Cohort of Neutropenic Patients (CoCoNut) with records from the Institute for Virology and compared the findings to historical data. During the pandemic, we diagnosed influenza A(H1N1) in five patients with malignancies and febrile neutropenia refractory to antibiotic therapy. Probable IPA was diagnosed in three of these patients on the grounds of typical computed tomography morphology and microbiological results. Three of five patients receiving remission-induction chemotherapy for acute myeloid leukaemia developed aspergillosis although receiving posaconazole prophylaxis. In the 3 years before the influenza pandemic, only 2/77 patients of this group developed infection. Infection with influenza A(H1N1) may increase the risk for invasive aspergillosis in neutropenic patients. Pulmonary aspergillosis is an important additional differential diagnosis in neutropenic influenza patients with pneumonia.

Factors influencing the pharmacokinetics of prophylactic posaconazole oral suspension in patients with acute myeloid leukemia or myelodysplastic syndrome.

OBJECTIVES: To estimate the pharmacokinetic (PK) properties of posaconazole in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing chemotherapy in a clinical setting. METHODS: Posaconazole concentrations in patients with AML/MDS receiving prophylactic posaconazole were determined by high-performance liquid chromatography. A population PK model with nonlinear mixed effect modeling was developed. The list of tested covariates included age, weight, height, gender, posaconazole dose, ethnicity, co-administration of antineoplastic chemotherapy, ranitidine or pantoprazole, coincident fever, diarrhea, leukocyte counts, and γ-glutamyltransterase plasma activity. RESULTS: A total of 643 serum concentrations of posaconazole from 84 patients were obtained. A one-compartment model with first order absorption and elimination as the basic structural model appropriately described the data, with an apparent clearance of 56.8 L/h [95% confidence interval (CI) 52.8­60.8 L/h] and an apparent volume of distribution of 2,130 L (95% CI 1,646­2,614 L). Significant effects on apparent clearance (CL/F) were found for presence of diarrhea and for co-medication with proton-pump inhibitors (1.5- and 1.6-fold increase in CL/F, respectively), weight (33.4 L larger apparent volume of distribution per kilogram), and co-administration of chemotherapy (0.6-fold lower apparent volume of distribution). CONCLUSION: We developed a prediction basis for mean posaconazole concentrations in AML/MDS patients. Patient weight, presence of diarrhea, and concomitant medication (chemotherapy and pantoprazole) showed significant effects on posaconazole exposure. Corresponding adjustments of the starting dose according to the presence of diarrhea and during the co-administration of chemotherapy or proton-pump inhibitors appear justified before therapeutic drug monitoring results are available. Further investigation of the interaction between different chemotherapeutic regimens and posaconazole is warranted.

[Urinary bladder microbiome analysis and probiotic treatment options for women with recurrent urinary tract infections]. / Mikrobiomanalyse der Harnblase und probiotische Therapieoptionen bei Frauen mit rezidivierenden Harnwegsinfektionen.

Novel preventive measures and therapeutic approaches are needed to reduce the frequency of recurrent urinary tract infections (rUTI) and the associated emergence of multidrug-resistant uropathogens. The aim of this review is to systematically present the available evidence on the urinary bladder microbiome of healthy women and those with rUTIs. In addition, relevant studies on the efficacy of probiotics in rUTIs are presented in a structured manner. This will provide an overview on the current state of research and an outlook on treatment strategies beyond the usual antimicrobial options.

Phase II dose escalation study of caspofungin for invasive Aspergillosis.

Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥ 4 in 2 of 8 patients or ≥ 3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin.