Maria J.G.T. Vehreschild

Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis

BACKGROUND Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis. METHODS In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response-ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)-according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353. FINDINGS Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19-179, range 2-882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595). INTERPRETATION Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated. FUNDING Astellas Pharma Global Development, Basilea Pharmaceutica International.

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.

Improvement in the outcome of invasive fusariosis in the last decade

Invasive fusariosis (IF) has been associated with a poor prognosis. Although recent series have reported improved outcomes, the definition of optimal treatments remains controversial. The objective of this study was to evaluate changes in the outcome of IF. We retrospectively analysed 233 cases of IF from 11 countries, comparing demographics, clinical findings, treatment and outcome in two periods: 1985-2000 (period 1) and 2001-2011 (period 2). Most patients (92%) had haematological disease. Primary treatment with deoxycholate amphotericin B was more frequent in period 1 (63% vs. 30%, p <0.001), whereas voriconazole (32% vs. 2%, p <0.001) and combination therapies (18% vs. 1%, p <0.001) were more frequent in period 2. The 90-day probabilities of survival in periods 1 and 2 were 22% and 43%, respectively (p <0.001). In period 2, the 90-day probabilities of survival were 60% with voriconazole, 53% with a lipid formulation of amphotericin B, and 28% with deoxycholate amphotericin B (p 0.04). Variables associated with poor prognosis (death 90 days after the diagnosis of fusariosis) by multivariable analysis were: receipt of corticosteroids (hazard ratio (HR) 2.11, 95% CI 1.18-3.76, p 0.01), neutropenia at end of treatment (HR 2.70, 95% CI 1.57-4.65, p <0.001), and receipt of deoxycholate amphotericin B (HR 1.83, 95% CI 1.06-3.16, p 0.03). Treatment practices have changed over the last decade, with an increased use of voriconazole and combination therapies. There has been a 21% increase in survival rate in the last decade.

Mucormycosis treated with posaconazole: review of 96 case reports.

Mucormycosis is an emerging invasive fungal infection, primarily affecting immunocompromised patients. The disease is difficult to diagnose and mortality reaches 40% even if treated adequately. Depending on site of infection and risk factors, surgical debridement in combination with systemically active antifungal drugs are the mainstay treatment strategies. Lipid-based amphotericin B is the treatment of choice for first-line therapy while posaconazole may be a promising alternative. We performed a PubMed search on reports of patients with mucormycosis treated with posaconazole. From 2003 to 2011, 96 cases have been published. Diagnosis was based on histology alone in 2 (2.1%) and microbiological evidence in 67 (69.8%), while no data on the diagnostic approach was reported in 27 (28.1%) patients. The most frequent pathogens were Rhizopus spp. (31.2%), followed by Mucor spp. (14.6%). The site of infection was predominantly rhino-orbital (38.5%, of which 43% also had central nervous system [CNS] involvement), followed by disseminated disease (22.1%). A complete response was achieved in 62 (64.6%), partial response in 7 (7.3%) patients, and stable disease in 1 (1%). Overall mortality was 24% (lacking data for three patients). In published case reports on posaconazole treatment for mucormycosis, the drug was frequently and successfully used in combination or as second line therapy.

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.

Colonization and infection with extended spectrum beta-lactamase producing Enterobacteriaceae in high-risk patients – Review of the literature from a clinical perspective

Abstract Background: The prevalence of extended-spectrum β-lactamase producing Enterobacteriaceae (ESBL-E) is increasing worldwide. ESBL-E are known to colonize different body sites and cause bloodstream infections (BSI), pneumonia, intra-abdominal infections and urinary tract infections. Even though ESBL-E-related morbidity and mortality in high-risk patients – patients receiving immunosuppressants or chemotherapy, as well as those treated in an ICU – is considerable, the management of ESBL-E in these populations has not been systematically reviewed. Methods: For the purpose of this review, ICU patients, patients in hematology and oncology wards and transplant recipients were considered high-risk. An English-language Medline search was conducted to identify literature on epidemiology, risk factors, clinical impact and measures of infection control regarding ESBL-E in high-risk patients published between June 2002 and May 2013. Results: Using the above described methodology, 43 relevant articles regarding high-risk patients and – for areas where literature on exclusively high-risk patients is scarce – 17 articles in standard risk settings were identified. The evidence on epidemiology, associated risk factors, treatment and hygiene measures were summarized. Discussion: This review gives a complete overview on the management of ESBL-E in the high-risk setting.

Combined antifungal approach for the treatment of invasive mucormycosis in patients with hematologic diseases: a report from the SEIFEM and FUNGISCOPE registries.

Invasive mucormycosis (IM) in patients with acute leukemia and allogeneic stem cell transplant (allo-SCT) recipients treated with antifungal monotherapy is associated with high mortality rates of 44–49%.[1][1]–[3][2] Among the available antifungals, amphotericin B (AmB) formulations and

Phase II Dose Escalation Study of Caspofungin for Invasive Aspergillosis

ABSTRACT 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.

Diagnosis and Management of Aspergillus Diseases: Executive Summary of the 2017 ESCMID-ECMM-ERS Guideline

The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

A multicentre cohort study on colonization and infection with ESBL-producing Enterobacteriaceae in high-risk patients with haematological malignancies

BACKGROUND Bloodstream infections (BSIs) caused by enterobacteria remain a leading cause of mortality in patients with chemotherapy-induced neutropenia. The rate and type of colonization and infection with ESBL-producing Enterobacteriaceae (ESBL-E) and their mode of transmission in German cancer centres is largely unknown. METHODS We performed a prospective, observational study at five German university-based haematology departments. Participating sites screened for intestinal ESBL-E colonization within 72 h of admission, every 10 ± 2 days thereafter and before discharge. Three of the five centres performed contact isolation for patients colonized or infected with ESBL-E. Molecular characterization of resistance mechanisms and epidemiological typing of isolates by repetitive extragenic palindromic PCR (rep-PCR) and PFGE was performed to assess strain transmission between patients. RESULTS Between October 2011 and December 2012, 719 hospitalizations of 497 haematological high-risk patients comprising 20,143 patient-days were analysed. Mean duration of in-hospital stay was 36.6 days (range: 2-159 days). ESBL-E were identified from screening samples (82.8% Escherichia coli and 14.6% Klebsiella pneumoniae) in 55/497 patients (11.1%; range by centre: 5.8%-23.1%). PFGE and rep-PCR revealed only a single case of potential cross-transmission among two patients colonized with K. pneumoniae. Six episodes of BSI with ESBL-E were observed. Multivariate analysis revealed previous colonization with ESBL-E as the most important risk factor for BSI with ESBL-E (OR 52.00; 95% CI 5.71-473.89). CONCLUSIONS Even though BSI with ESBL-E is still rare in this high-risk population, colonization rates are substantial and vary considerably between centres. In-hospital transmission of ESBL-E as assessed by molecular typing was the exception.