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.

[Chronic diarrhoea in daily practice; article for education and training purposes]. / Chronische diarree in de dagelijkse praktijk.

Chronic diarrhoea occurs in patients of all ages and is a very common reason for patient visits to a general practitioner or medical specialist. The differential diagnosis of chronic diarrhoea is extensive and identification of the underlying cause can be challenging. In this article we answer 12 topical questions concerning the management of chronic diarrhoea in practice.

Vasculitis in Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia: A Report of Two Cases.

There is a clear association between myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (CMML) and autoimmune manifestations such as vasculitis. It is not clear if autoimmune manifestations in myelodysplastic syndrome are a cause or consequence. We describe two patients with polyarteritis nodosa and large vessel vasculitis, as presenting symptom of a myelodysplastic syndrome with excess blasts type 2 and chronic myelomonocytic leukemia respectively. Immunosuppressive treatment resulted in amelioration of the vasculitis with improvement of the myelodysplastic features in the first patient and rapid evolution to acute myeloid leukemia in the other patient. The association between MDS/CMML and autoimmune manifestations, such as vasculitis, emphasizes the role of autoimmunity in the clinical features and even pathogenesis of MDS/CMML.

Hospitalization for community-acquired febrile urinary tract infection: validation and impact assessment of a clinical prediction rule.

BACKGROUND: There is a lack of severity assessment tools to identify adults presenting with febrile urinary tract infection (FUTI) at risk for complicated outcome and guide admission policy. We aimed to validate the Prediction Rule for Admission policy in Complicated urinary Tract InfeCtion LEiden (PRACTICE), a modified form of the pneumonia severity index, and to subsequentially assess its use in clinical practice. METHODS: A prospective observational multicenter study for model validation (2004-2009), followed by a multicenter controlled clinical trial with stepped wedge cluster-randomization for impact assessment (2010-2014), with a follow up of 3 months. Paricipants were 1157 consecutive patients with a presumptive diagnosis of acute febrile UTI (787 in validation cohort and 370 in the randomized trial), enrolled at emergency departments of 7 hospitals and 35 primary care centers in the Netherlands. The clinical prediction rule contained 12 predictors of complicated course. In the randomized trial the PRACTICE included guidance on hospitalization for high risk (>100 points) and home discharge for low risk patients (<75 points), in the control period the standard policy regarding hospital admission was applied. Main outcomes were effectiveness of the clinical prediction rule, as measured by primary hospital admission rate, and its safety, as measured by the rate of low-risk patients who needed to be hospitalized for FUTI after initial home-based treatment, and 30-day mortality. RESULTS: A total of 370 patients were included in the randomized trial, 237 in the control period and 133 in the intervention period. Use of PRACTICE significantly reduced the primary hospitalization rate (from 219/237, 92%, in the control group to 96/133, 72%, in the intervention group, p < 0.01). The secondary hospital admission rate after initial outpatient treatment was 6% in control patients and 27% in intervention patients (1/17 and 10/37; p < 0.001). CONCLUSIONS: Although the proposed PRACTICE prediction rule is associated with a lower number of hospital admissions of patients presenting to the ED with presumptive febrile urinary tract infection, futher improvement is necessary to reduce the occurrence of secondary hospital admissions. TRIAL REGISTRATION: NTR4480 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4480 , registered retrospectively 25 mrt 2014 (during enrollment of subjects).

Treatment duration of febrile urinary tract infection: a pragmatic randomized, double-blind, placebo-controlled non-inferiority trial in men and women.

BACKGROUND: In adults with febrile urinary tract infection (fUTI), data on optimal treatment duration in patients other than non-pregnant women without comorbidities are lacking. METHODS: A randomized placebo-controlled, double-blind, non-inferiority trial among 35 primary care centers and 7 emergency departments of regional hospitals in the Netherlands. Women and men aged ≥ 18 years with a diagnosis of fUTI were randomly assigned to receive antibiotic treatment for 7 or 14 days (the second week being ciprofloxacin 500 mg or placebo orally twice daily). Patients indicated to receive antimicrobial treatment for at least 14 days were excluded from randomization. The primary endpoint was the clinical cure rate through the 10- to 18-day post-treatment visit with preset subgroup analysis including sex. Secondary endpoints were bacteriologic cure rate at 10-18 days post-treatment and clinical cure at 70-84 days post-treatment. RESULTS: Of 357 patients included, 200 were eligible for randomization; 97 patients were randomly assigned to 7 days and 103 patients to 14 days of treatment. Overall, short-term clinical cure occurred in 85 (90%) patients treated for 7 days and in 94 (95%) of those treated for 14 days (difference -4.5%; 90% CI, -10.7 to 1.7; P non-inferiority = 0.072, non-inferiority not confirmed). In women, clinical cure was 94% and 93% in those treated for 7 and 14 days, respectively (difference 0.9; 90% CI, -6.9 to 8.7, P non-inferiority = 0.011, non-inferiority confirmed) and, in men, this was 86% versus 98% (difference -11.2; 90% CI -20.6 to -1.8, P superiority = 0.025, inferiority confirmed). The bacteriologic cure rate was 93% versus 97% (difference -4.3%; 90% CI, -9.7 to 1.2, P non-inferiority = 0.041) and the long-term clinical cure rate was 92% versus 91% (difference 1.6%; 90% CI, -5.3 to 8.4; P non-inferiority = 0.005) for 7 days versus 14 days of treatment, respectively. In the subgroups of men and women, long-term clinical cure rates met the criteria for non-inferiority, indicating there was no difference in the need for antibiotic retreatment for UTI during 70-84 days follow-up post-treatment. CONCLUSIONS: Women with fUTI can be treated successfully with antibiotics for 7 days. In men, 7 days of antibiotic treatment for fUTI is inferior to 14 days during short-term follow-up but it is non-inferior when looking at longer follow-up. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov [ NCT00809913 ; December 16, 2008] and trialregister.nl [ NTR1583 ; December 19, 2008].

A case of rickettsialpox in Northern Europe.

We report the first case of rickettsialpox caused by Rickettsia akari in the Netherlands. The diagnosis was suspected based on clinical grounds and was confirmed by Western blot analysis with cross-adsorption. Because the arthropod vector (Liponyssoides sanguineus) is ubiquitous, we suspect that the disease is under-diagnosed in non-endemic areas.

Risk factors for fluoroquinolone-resistant Escherichia coli in adults with community-onset febrile urinary tract infection.

OBJECTIVES: To assess risk factors for fluoroquinolone resistance in community-onset febrile Escherichia coli urinary tract infection (UTI). METHODS: A nested case-control study within a cohort of consecutive adults with febrile UTI presenting at primary healthcare centres or emergency departments during January 2004 through December 2009. Resistance was defined using EUCAST criteria (ciprofloxacin MIC >1.0 mg/L). Cases were subjects with fluoroquinolone-resistant E. coli, and controls those with fluoroquinolone-susceptible isolates. Multivariable logistic regression analysis was used to identify potential risk factors for fluoroquinolone resistance. RESULTS: Of 787 consecutive patients, 420 had E. coli-positive urine cultures. Of these, 51 (12%) were fluoroquinolone resistant. Independent risk factors for fluoroquinolone resistance were urinary catheter [odds ratio (OR) 3.1; 95% confidence interval (CI) 0.9-11.6], recent hospitalization (OR 2.0; 95% CI 1.0-4.3) and fluoroquinolone use in the past 6 months (OR 17.5; 95% CI 6.0-50.7). Environmental factors (e.g. contact with animals or hospitalized household members) were not associated with fluoroquinolone resistance. Of fluoroquinolone-resistant strains, 33% were resistant to amoxicillin/clavulanate and 65% to trimethoprim/sulfamethoxazole; 14% were extended-spectrum ß-lactamase (ESBL) positive compared with <1% of fluoroquinolone-susceptible isolates. CONCLUSIONS: Recent hospitalization, urinary catheter and fluoroquinolone use in the past 6 months were independent risk factors for fluoroquinolone resistance in community-onset febrile E. coli UTI. Contact with animals or hospitalized household members was not associated with fluoroquinolone resistance. Fluoroquinolone resistance may be a marker of broader resistance, including ESBL positivity.

Procalcitonin reflects bacteremia and bacterial load in urosepsis syndrome: a prospective observational study.

INTRODUCTION: Guidelines recommend that two blood cultures be performed in patients with febrile urinary tract infection (UTI), to detect bacteremia and help diagnose urosepsis. The usefulness and cost-effectiveness of this practice have been criticized. This study aimed to evaluate clinical characteristics and the biomarker procalcitonin (PCT) as an aid in predicting bacteremia. METHODS: A prospective observational multicenter cohort study included consecutive adults with febrile UTI in 35 primary care units and 8 emergency departments of 7 regional hospitals. Clinical and microbiological data were collected and PCT and time to positivity (TTP) of blood culture were measured. RESULTS: Of 581 evaluable patients, 136 (23%) had bacteremia. The median age was 66 years (interquartile range 46 to 78 years) and 219 (38%) were male. We evaluated three different models: a clinical model including seven bed-side characteristics, the clinical model plus PCT, and a PCT only model. The diagnostic abilities of these models as reflected by area under the curve of the receiver operating characteristic were 0.71 (95% confidence interval (CI): 0.66 to 0.76), 0.79 (95% CI: 0.75 to 0.83) and 0.73 (95% CI: 0.68 to 0.77) respectively. Calculating corresponding sensitivity and specificity for the presence of bacteremia after each step of adding a significant predictor in the model yielded that the PCT > 0.25 µg/l only model had the best diagnostic performance (sensitivity 0.95; 95% CI: 0.89 to 0.98, specificity 0.50; 95% CI: 0.46 to 0.55). Using PCT as a single decision tool, this would result in 40% fewer blood cultures being taken, while still identifying 94 to 99% of patients with bacteremia.The TTP of E. coli positive blood cultures was linearly correlated with the PCT log value; the higher the PCT the shorter the TTP (R(2) = 0.278, P = 0.007). CONCLUSIONS: PCT accurately predicts the presence of bacteremia and bacterial load in patients with febrile UTI. This may be a helpful biomarker to limit use of blood culture resources.

Treatment duration of febrile urinary tract infection (FUTIRST trial): a randomized placebo-controlled multicenter trial comparing short (7 days) antibiotic treatment with conventional treatment (14 days).

BACKGROUND: Current guidelines on the management of urinary tract infection recommend treating febrile urinary tract infection or acute pyelonephritis with antimicrobials for at least 14 days. Few randomized trials showed the effectiveness of treatment durations of 5 to 7 days but this has only been studied in young previously healthy women. METHODS/DESIGN: A randomized placebo-controlled double-blind multicenter non-inferiority trial in which 400 patients with community acquired febrile urinary tract infection will be randomly allocated to a short treatment arm (7 days of ciprofloxacin or 7 days of empirical beta-lactams +/- gentamicin intravenously with early switch to oral ciprofloxacin followed by 7 days of blinded placebo) or standard treatment arm (7 days of ciprofloxacin or 7 days of empirical beta-lactams +/- gentamicin intravenously with early switch to oral ciprofloxacin followed by 7 days of blinded ciprofloxacin). The study is performed in the Leiden region in which one university hospital, 6 general hospitals and 32 primary health care centers are clustered. Patients eligible for randomization are competent patients aged 18 years or above with a presumptive diagnosis of acute pyelonephritis as defined by the combination of fever, one or more symptoms of urinary tract infection and a positive urine nitrate test and/or the presence of leucocyturia. Exclusion criteria are known allergy to fluoroquinolones, female patients who are pregnant or lactating, polycystic kidney disease, permanent renal replacement therapy, kidney transplantation, isolation of ciprofloxacin-resistant causal uropathogen, renal abscess, underlying chronic bacterial prostatitis, metastatic infectious foci and inability to obtain follow-up. The primary endpoint is the clinical cure rate through the 10- to 18-day post-treatment visit. Secondary endpoints are the microbiological cure rate 10- to 18-day post-treatment, the 30- and 90-day overall mortality rate, the clinical cure rate 70- to 84-day post-treatment, relapse rate of UTI and adverse events or complications during 90 days of follow-up. DISCUSSION: This study aims to demonstrate that 7 days of antimicrobial treatment is non-inferior as compared with 14 days of treatment in patients with febrile urinary tract infection. In addition, it will generate insights into the side-effects of antimicrobial treatment in relation to its duration. The study population will also include men, the elderly and patients with significant co-morbidity. Reflecting daily practice of primary health care and emergency departments, the results of this study can be generalized to other locations.

Cladribine therapy for systemic mastocytosis.

Patients with systemic mastocytosis (SM) can suffer from disabling symptoms related to mast cell mediator release or mast cell infiltration, requiring mast cell eradication. In the present absence of any curative therapy, a recent case report describing the efficacy of cladribine showed promising results. In a pilot study, the efficacy of cladribine (0.10-0.13 mg/kg in a 2-hour infusion, days 1-5; repeated at 4-8 weeks until 6 cycles) was studied. Ten patients with SM with severe symptoms were treated. Four patients were classified as having indolent or smoldering mastocytosis, 3 as having aggressive systemic mastocytosis, and 3 as having SM with an accompanying hematologic malignancy. Nine patients received 6 courses, 1 patient stopped because of toxicodermia. All responded concerning signs, symptoms, and mast cell parameters (serum tryptase and urinary histamine metabolite excretion), although none achieved a complete remission. Prolonged follow-up is required, as response is ongoing in most cases. One patient relapsed within 11 months and showed a second response. Side effects were mainly related to bone marrow suppression. Single-agent cladribine is an effective and relatively safe treatment for severe systemic mastocytosis. The optimal dose and schedule need to be explored.

Antimicrobial peptides: therapeutic potential for the treatment of Candida infections.

The increasing frequency of fungal infections in immunocompromised patients together with the emergence of strains resistant to currently used antifungal drugs point to an increased need for a new class of antimycotics. Antimicrobial peptides are promising candidates for the treatment of fungal infections since they have both mechanisms of action distinct from available antifungal agents and the ability to regulate the host immune defence systems as well. This review focuses on Candida albicans as a large amount of work on the mechanisms of action of classical antifungals as well as antimicrobial peptides, such as defensins, protegrins, histatins and lactoferrin (LF)-derived peptides, has been performed in this yeast. Analogues of these antimicrobial peptides and combinations of antimicrobial peptides with classical antimycotics are under investigation for treatment of candidiasis.