Risicofactoren, diagnose en behandeling van (azole-resistente) invasieve aspergillose

This thesis describes the risk factors, diagnosis and treatment of (azole-resistant) invasive aspergillosis

A bird’s-eye view of chronic unilateral conjunctivitis : remember about Chlamydia psittaci

Chlamydia psittaci causes psittacosis in humans, mainly in people in contact with birds in either the setting of occupational or companion bird exposure. Infection is associated with a range of clinical manifestations from asymptomatic infection to severe atypical pneumonia and systemic disease. C. psittaci has also been associated with ocular adnexal lymphoma in human patients. The current paper describes successful doxycycline treatment of a male patient suffering from C. psittaci chronic unilateral conjunctivitis, most probably linked to the visit of a South African wildlife reserve. Increased awareness among general and occupational physicians, ophthalmologists, clinicians, and the public on the potential of C. psittaci to cause ocular infection is needed

Epidemiology of Pneumocystis jirovecii pneumonia and (non-)use of prophylaxis

Objectives: Pneumocystis jirovecii pneumonia (PCP) is an AIDS-defining illness. In patients with HIV, the benefit of PCP prophylaxis is well-defined when the CD4 T-cell count decreases below 200 cells/μL. In other immunocompromised patients, the value of PCP prophylaxis is not always as well-established. This study aimed to describe the epidemiology of PCP in recent years and assess how many patients with PCP did or did not receive prophylaxis in the month preceding the infection. Material and Methods: A multicenter retrospective study was performed in 3 tertiary care hospital. A list of patients that underwent broncho-alveolar lavage sampling and Pneumocystis jirovecii (PJ) PCR testing was retrieved from the microbiology laboratories. An in-house PJ quantitative PCR (qPCR) was used in each center. A cycle threshold (Ct) value of ≤ 28.5–30 was considered a probable PCP. For patients with a positive PJ qPCR but above this threshold, a predefined case definition of possible PCP was defined as a qPCR Ct value ≤ 34–35 and both of the following criteria: 1. Clinical and radiological features compatible with PCP and 2. The patient died or received PCP therapy and survived. Patient files from those with a qPCR Ct value ≤ 35 were reviewed to determine whether the patient fulfilled the case definition and if PCP prophylaxis had been used in the weeks preceding the PCP. Disease-specific guidelines, as well as hospital-wide guidelines, were used to evaluate if prophylaxis could be considered indicated. Results: From 2012 to 2018, 482 BAL samples were tested. Two hundred and four had a qPCR Ct value ≤ 35 and were further evaluated: 90 fulfilled the definition of probable and 63 of possible PCP while the remaining 51 were considered colonized. Seventy-four percentages of the patients with PCP were HIV-negative. Only 11 (7%) of the 153 patients had received prophylaxis, despite that in 133 (87%) cases prophylaxis was indicated according to guidelines. Conclusion: In regions where HIV testing and treatment is available without restrictions, PCP is mainly diagnosed in non-HIV immunocompromised patients. More than four out of five patients with PCP had not received prophylaxis. Strategies to improve awareness of antimicrobial prophylaxis guidelines in immunocompromised patients are urgently needed

Epidemiology of Pneumocystis jirovecii Pneumonia and (Non-)use of Prophylaxis

Objectives: Pneumocystis jirovecii pneumonia (PCP) is an AIDS-defining illness. In patients with HIV, the benefit of PCP prophylaxis is well-defined when the CD4 T-cell count decreases below 200 cells/μL. In other immunocompromised patients, the value of PCP prophylaxis is not always as well-established. This study aimed to describe the epidemiology of PCP in recent years and assess how many patients with PCP did or did not receive prophylaxis in the month preceding the infection. Material and Methods: A multicenter retrospective study was performed in 3 tertiary care hospital. A list of patients that underwent broncho-alveolar lavage sampling and Pneumocystis jirovecii (PJ) PCR testing was retrieved from the microbiology laboratories. An in-house PJ quantitative PCR (qPCR) was used in each center. A cycle threshold (Ct) value of ≤ 28.5–30 was considered a probable PCP. For patients with a positive PJ qPCR but above this threshold, a predefined case definition of possible PCP was defined as a qPCR Ct value ≤ 34–35 and both of the following criteria: 1. Clinical and radiological features compatible with PCP and 2. The patient died or received PCP therapy and survived. Patient files from those with a qPCR Ct value ≤ 35 were reviewed to determine whether the patient fulfilled the case definition and if PCP prophylaxis had been used in the weeks preceding the PCP. Disease-specific guidelines, as well as hospital-wide guidelines, were used to evaluate if prophylaxis could be considered indicated. Results: From 2012 to 2018, 482 BAL samples were tested. Two hundred and four had a qPCR Ct value ≤ 35 and were further evaluated: 90 fulfilled the definition of probable and 63 of possible PCP while the remaining 51 were considered colonized. Seventy-four percentages

Comparing the effectiveness of bevacizumab to ranibizumab in patients with exudative age-related macular degeneration. The BRAMD study

Purpose: To compare the effectiveness of bevacizumab and ranibizumab in the treatment of exudative age-related macular degeneration (AMD). Design: Multicentre, randomized, controlled, double-masked clinical trial in 327 patients. The noninferiority margin was 4 letters. Patients: Patients ≥ 60 years of age with primary or recurrent sub- or juxtafoveal choroidal neovascularization (CNV) secondary to AMD with a total area of CNV < 12 disc areas and a best corrected visual acuity (BCVA) score between 20 and 78 letters on an EDTRS like chart in the study eye. Methods: Monthly intravitreal injections with 1.25 mg bevacizumab or 0.5 mg ranibizumab were given during one year. Intention to treat with last observation carried forward analysis was performed. Main Outcome Measures: Primary outcome was the change in BCVA in the study eye from baseline to 12 months. Results: The mean gain in BCVA was 5.1 (±14.1) letters in the bevacizumab group (n = 161) and 6.4 (±12.2) letters in the ranibizumab group (n = 166) (p = 0.37). The lower limit of the 95% confidence interval of the difference in BCVA gain was 3.72. The response to bevacizumab was more varied; 24% of patients showed a gain of ≥15 letters, 11% a loss of ≥15 letters and 65% a gain or loss < 15 letters compared to 19%, 5% and 76% respectively for ranibizumab (p = 0.038). No significant differences in absolute CRT and CRT change (p = 0.13) or in the presence of subretinal or intraretinal fluid (p = 0.14 and 0.10, respectively) were observed. However, the presence of any fluid on SD-OCT (subretinal and/or intraretinal) differed significantly (p = 0.020), with definite fluid on SD-OCT in 45% of the patients for bevacizumab versus 31% for ranibizumab. The occurrence of serious adverse events and adverse events was similar, with 34 SAEs and 256 AEs in the bevacizumab group and 37 SAEs and 299 AEs in the ranibizumab group (p = 0.87 and p = 0.48, respectively). Conclusions: Bevacizumab was not inferior to ranibizumab. The response to bevacizumab was more varied with higher percentages of both gainers and losers and more frequently observed retinal fluid on SD-OCT at 12 months when compared to the ranibizumab group. Trial Registration: Trialregister.nl NTR1704

Comparing the effectiveness and costs of Bevacizumab to Ranibizumab in patients with Diabetic Macular Edema: A randomized clinical trial (the BRDME study)

Background: The effectiveness of ranibizumab in the treatment of diabetic macular edema has been proven with large clinical trials. For bevacizumab only two clinical trials have been published and a head-to-head comparison is lacking to date. However, if proved non-inferior to ranibizumab, use of the off-label bevacizumab could reduce costs enormously without a loss in visual acuity. A cost-effectiveness study has been designed to substantiate this hypothesis. Aim: To compare the effectiveness and costs of 1.25 mg of bevacizumab to 0.5 mg ranibizumab given as monthly intravitreal injections during 6 months in patients with diabetic macular edema. It is hypothesized that bevacizumab is non-inferior to ranibizumab regarding its effectiveness. Design: This is a randomized, controlled, double masked, clinical trial in 246 patients in seven academic trial centres in The Netherlands. Outcomes: The primary outcome measure is the change in best-corrected visual acuity (BCVA) in the study eye from baseline to month 6. Secondary outcomes are the proportions of patients with a gain or loss of 15 letters or more or a BCVA of 20/40 or more at 6 months, the change in leakage on fluorescein angiography and the change in foveal thickness by optical coherence tomography at 6 months, the number of adverse events in 6 months, and the costs per quality adjusted life-year of the two treatments

High-dose posaconazole for azole-resistant aspergillosis and other difficult-to-treat mould infections

Background: Oral follow-up therapy is problematic in moulds with reduced azole-susceptibility, such as azole-resistant Aspergillus fumigatus infection. Currently, only intravenous liposomal amphotericin B (L-AmB) is advocated by guidelines for the treatment of azole-resistant aspergillosis infections. Preclinical research indicates that high-dose posaconazole (HD-POS) might be a feasible option provided that high drug exposure (ie POS serum through levels >3 mg/L) can be achieved and is safe. Objectives: To describe our experience with the use of oral HD-POS as treatment strategies for patients infected with pathogens with a POS MIC close to the clinical breakpoint. Patients/Methods: We review evidence supporting the use of HD-POS and describe our experience on safety and efficacy in 16 patients. In addition, we describe the adverse events (AE) observed in 25 patients with POS concentrations at the higher end of the population distribution during treatment with the licensed dose. Results: Sixteen patients were treated intentionally with HD-POS for voriconazole-resistant invasive aspergillosis (7/16), mucormycosis (4/16), salvage therapy for IA (4/16) and IA at a sanctuary site (spondylodiscitis) in 1. Grade 3-4 AEs were observed in 6, and all of them were considered at least possibly related. Grade 3-4 AEs were observed in 5 of the 25 patients with spontaneous high POS serum through levels considered at least possibly related using Naranjo scale. Conclusions: High-dose posaconazole is a treatment option if strict monitoring for both exposure and for AE is possible

High-dose posaconazole for azole-resistant aspergillosis and other difficult-to-treat mould infections

Background: Oral follow-up therapy is problematic in moulds with reduced azole-susceptibility, such as azole-resistant Aspergillus fumigatus infection. Currently, only intravenous liposomal amphotericin B (L-AmB) is advocated by guidelines for the treatment of azole-resistant aspergillosis infections. Preclinical research indicates that high-dose posaconazole (HD-POS) might be a feasible option provided that high drug exposure (ie POS serum through levels >3 mg/L) can be achieved and is safe. Objectives: To describe our experience with the use of oral HD-POS as treatment strategies for patients infected with pathogens with a POS MIC close to the clinical breakpoint. Patients/Methods: We review evidence supporting the use of HD-POS and describe our experience on safety and efficacy in 16 patients. In addition, we describe the adverse events (AE) observed in 25 patients with POS concentrations at the higher end of the population distribution during treatment with the licensed dose. Results: Sixteen patients were treated intentionally with HD-POS for voriconazoleresistant invasive aspergillosis (7/16), mucormycosis (4/16), salvage therapy for IA (4/16) and IA at a sanctuary site (spondylodiscitis) in 1. Grade 3- 4 AEs were observed in 6, and all of them were considered at least possibly related. Grade 3- 4 AEs were observed in 5 of the 25 patients with spontaneous high POS serum through levels considered at least possibly related using Naranjo scale. Conclusions: High-dose posaconazole is a treatment option if strict monitoring for both exposure and for AE is possible

Management of cerebral azole-resistant Aspergillus fumigatus infection : a role for intraventricular liposomal-amphotericin B

Objectives: In the pre-azole era, central nervous system (CNS) infections with Aspergillus had a dismal outcome. Survival improved with voriconazole but CNS infections caused by azole-resistant Aspergillus fumigatus preclude its use. Intravenous liposomal-amphotericin B (L-AmB) is the preferred treatment option for azole-resistant CNS infections but has suboptimal brain concentrations. Methods: We describe three patients with biopsy-proven CNS aspergillosis where intraventricular L-AmB was added to systemic therapy. Two patients with azole-resistant aspergillosis and one patient with azole-susceptible CNS aspergillosis were treated with intraventricular L-AmB at a dose of 1 mg weekly. Results: We describe three patients successfully treated with a combination of intravenous and intraventricular L-AmB. All three patients survived but one patient developed serious headaches, most likely not related to this treatment. Conclusions: Intraventricular L-AmB may have a role in the treatment of therapy-refractory CNS aspergillosis when added to systemic therapy. (C) 2020 The Author(s). Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy