Implementation of a clinical decision rule for selecting empiric treatment for invasive aspergillosis in a setting with high triazole resistance.

World-wide, emerging triazole resistance increasingly complicates treatment of invasive aspergillosis (IA). In settings with substantial (>10%) prevalence of triazole resistance, empiric combination therapy with both a triazole and liposomal amphotericin B (LAmB) can be considered because of the low yields of susceptibility testing. To avoid toxicity while optimizing outcome, a strategy with monotherapy would be preferable. A newly designed treatment algorithm based on literature and expert consensus provided guidance for empiric monotherapy with either voriconazole or LAmB. Over a four and a half year period, all adult patients in our hospital treated for IA were included and patient data were collected. An independent committee reviewed the attributability of death to IA for each patient. Primary outcomes were 30- and 100-day crude mortality and attributable mortality. In total, 110 patients were treated according to the treatment algorithm. Fifty-six patients (51%) were initially treated with voriconazole and 54 patients (49%) with LAmB. Combined attributable and contributable mortality was 13% within 30 days and 20% within 100 days. Treatment switch to LAmB was made in 24/56 (43%) of patients who were initially treated with voriconazole. Combined contributable and attributable 100-day mortality in this subgroup was 21% and was not increased when compared with patients initially treated with LAmB (P = 0.38). By applying a comprehensive clinical decision algorithm, an antifungal-sparing regime was successfully introduced. Further research is warranted to explore antifungal treatment strategies that account for triazole-resistance. LAY SUMMARY: Due to resistance of Aspergillus against triazoles, combination therapy with liposomal amphotericin B (LAmB) is applied more often as primary therapy against invasive aspergillosis. This study presents the results of a decision tool which differentiated between triazole or LAmB monotherapy.

Outpatient parenteral antifungal therapy (OPAT) for invasive fungal infections with intermittent dosing of liposomal amphotericin B.

Triazole resistant A. fumigatus has been documented in many parts of the world. In the Netherlands, incidence is now above 10% and results in the need for long-term parenteral therapy with liposomal amphotericin B (LAmB). The long terminal half-life of LAmB suggests that intermittent dosing could be effective, making the application of outpatient antifungal therapy (OPAT) possible. Here, we report our experience with the use of OPAT for Invasive Fungal Infections (IFI). All adult patients treated with LAmB with a 2 or 3 times weekly administration via the outpatient departments in four academic tertiary care centers in the Netherlands and Belgium since January 2010 were included in our analysis. Patient characteristics were collected, as well as information about diagnostics, therapy dose and duration, toxicity, treatment history and outcome of the IFI. In total, 18 patients were included. The most frequently used regimen (67%) was 5 mg/kg 3 times weekly. A partial response to the daily treatment prior to discharge was confirmed by CT-scan in 17 (94%) of patients. A favorable outcome was achieved in 13 (72%) patients. Decrease in renal function occurred in 10 (56%) cases but was reversible in all and was treatment limiting in one patient only. The 100-day mortality and 1-year mortality after initiation of OPAT were 0% and 6%, respectively. In a selected population, and after confirmation of initial response to treatment, our data support the use of OPAT with LAmB for treatment of IFI in an intermittent dosing regimen.

Clinical factors, C-reactive protein point of care test and chest X-ray in patients with pneumonia: A survey in primary care.

Background: In patients with an acute lower respiratory tract infection (LRTI), general practitioners (GPs) often find it challenging to decide to prescribe antibiotics or not. C-reactive protein (CRP) point of care test (POCT), and chest X-ray are diagnostic tests that can optimize the treatment decision. However, their usefulness in clinical practice is unknown.Objectives: To determine the proportion of Dutch GPs using CRP and chest X-ray in patients with an acute LRTI. To determine whether clinical factors and C-reactive protein point of care test affect the behaviour in requesting chest X-rays.Methods: In 2014, a questionnaire was sent to a random sample of 900 Dutch GPs. Outcome parameters are the use of CRP and chest X-ray, the percentage of GPs who guide their decision in requesting chest X-rays by CRP testing and the GP's expectation regarding presence or absence of pneumonia. In addition, considerations for requesting chest X-rays were assessed.Results: Two hundred and fifty-five completed questionnaires (29%) were returned. In 2014, 54% of the responding GPs used the CRP test. These GPs tend to use fewer chest X-rays (p = 0.07). GPs overestimate the chance that pneumonia will be present on the radiograph. Seventy percent consider the possibility of abnormalities other than pneumonia as the main reason for requesting a chest X-ray.Conclusion: In patients with an acute lower respiratory tract infection, GPs report that CRP results affect their behaviour regarding the request of a chest X-ray in patients with lower respiratory tract infection and therefore research is needed to substantiate the use of these diagnostic tools for this purpose.

Relapsed and secondary disease drive the risk profile for invasive aspergillosis prior to stem cell transplantation in patients with acute myeloid leukemia or myelodysplastic syndrome.

Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) are at risk for invasive aspergillosis (IA) even prior to the introduction of stem cell transplantation (SCT). In times of increasing triazole resistance and changing use of antifungal prophylaxis, insight into the risk factors for IA is needed to improve strategies for preventing IA in this population. Consecutive patients who received remission-induction therapy for AML or MDS at the Leiden Academic Medical Centre were included. Instead of standard antifungal prophylaxis, an assertive protocol for diagnosis of suspected fungal infection was in place. IA was classified according to the revised European Organization for Research and Treatment of Cancer criteria. Potential predisposing characteristics for IA were compared by uni- and multivariate analyses. In 45 (25%) of 184 included episodes (167 patients), IA was diagnosed prior to SCT. A multivariate Cox regression model demonstrated that relapsed AML (hazard ratio [HR] 2.4; 95% confidence interval [CI], 1.1-5.1; P = 0.02), secondary AML (HR, 5.2; 95% CI, 2.3-11.8; P < 0.001), and prolonged duration of neutropenia (HR, 2.2; 95% CI, 1.2-4.0; P = 0.01) were independently associated with IA. Use of granulocyte-colony-stimulating factor showed a trend toward a protective effect (HR, 0.37; 95% CI, 0.1-31.0; P = 0.06). Relapsed AML, secondary AML, and duration of neutropenia were independent factors for determining the risk for development of IA prior to SCT. The results provide further guidance for antifungal stewardship programs when integrating individual patient tailored decision making in antifungal prophylaxis strategies.