Therapeutic drug monitoring-guided treatment versus standard dosing of voriconazole for invasive aspergillosis in haematological patients: a multicentre, prospective, cluster randomised, crossover clinical trial.

OBJECTIVES: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treatment is superior to standard treatment for invasive aspergillosis. METHODS: A multicentre (n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged ≥18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treatment initiation of voriconazole and repeated during treatment in both groups. The TDM group had measured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. RESULTS: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups (P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) (P < 0.001). CONCLUSIONS: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov registration no. NCT00893555.

Exposure of anti-infective drugs and the dynamic changes of the gut microbiota during gastrointestinal mucositis in autologous stem cell transplant patients: a pilot study.

Gastrointestinal mucositis could potentially compromise drug absorption due to functional loss of mucosa and other pathophysiological changes in the gastrointestinal microenvironment. Little is known about this effect on commonly used anti-infectives. This study aimed to explore the association between different stages of gastrointestinal mucositis, drug exposure, and gut microbiota. A prospective, observational pilot study was performed in HSCT patients aged ≥ 18 years receiving anti-infectives orally. Left-over blood samples and fecal swabs were collected from routine clinical care until 14 days after HSCT to analyze drug and citrulline concentrations and to determine the composition of the gut microbiota. 21 patients with a median age of 58 (interquartile range 54-64) years were included with 252 citrulline, 155 ciprofloxacin, 139 fluconazole, and 76 acyclovir concentrations and 48 fecal swabs obtained. Severe gastrointestinal mucositis was observed in all patients. Due to limited data correlation analysis was not done for valacyclovir and fluconazole, however we did observe a weak correlation between ciprofloxacin and citrulline concentrations. This could suggest that underexposure of ciprofloxacin can occur during severe mucositis. A follow-up study using frequent sampling rather than the use of left-over would be required to investigate the relationship between gastrointestinal mucositis, drug exposure, and gut microbiome.

Sarcoidosis presenting with glazy mucoid sputum and dyspnea: a case report.

BACKGROUND: Patients with pulmonary sarcoidosis commonly present with a dry cough; a productive cough suggests a complicating airway infection or an alternative diagnosis such as tuberculosis or bronchiectasis. CASE PRESENTATION: A 36-year-old European (Frisian) woman recently diagnosed with pulmonary sarcoidosis presented with debilitating exertional dyspnea and cough productive of glazy mucoid sputum. Several different attempts including video-assisted thoracoscopic biopsies failed to reach a second or alternative diagnosis including an infectious, autoimmune or collagen-vascular condition. She responded to steroids but with poor tolerance to this treatment, which could not be tapered. After she was started on anti-tumor necrosis factor alpha (TNF-α) therapy with infliximab, 200 mg at three-monthly intervals, she has been fine for well over a decade. CONCLUSIONS: In this patient with sarcoidosis who had a productive cough accompanied by fever, an extensive workup and prolonged follow-up, an alternative or second diagnosis could be ruled out; we therefore conclude that this highly unusual presentation is part of the clinical spectrum of sarcoidosis.

Exploring failure of antimicrobial prophylaxis and pre-emptive therapy for transplant recipients: a systematic review.

OBJECTIVES: Infections remain a threat for solid organ and stem cell transplant recipients. Antimicrobial prophylaxis and pre-emptive therapy have improved survival of these patients; however, the failure rates of prophylaxis are not negligible. The aim of this systematic review is to explore the reasons behind failure of antimicrobial prophylaxis and pre-emptive therapy. SETTING: This systematic review included prospective randomised controlled trials and prospective single-arm studies. PARTICIPANTS: The studies included were on prophylaxis and pre-emptive therapy of opportunistic infections in transplant recipients. Studies were included from databases MEDLINE, CENTRAL and Embase published until October first 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measures were breakthrough infections, adverse events leading to stopping of treatment, switching medication or dose reduction. Secondary outcome measures were acquired resistance to antimicrobials, antifungals or antivirals and death. RESULTS: From 3317 identified records, 30 records from 24 studies with 2851 patients were included in the systematic review. Seventeen focused on prophylactic and pre-emptive treatment of cytomegalovirus and seven studies on invasive fungal infection. The main reasons for failure of prophylaxis and pre-emptive therapy were adverse events and breakthrough infections, which were described in 54% (13 studies) and 38% (9 studies) of the included studies, respectively. In 25%, six of the studies, a detailed description of patients who experienced failure of prophylaxis or pre-emptive therapy was unclear or lacking. CONCLUSIONS: Our results show that although failure is reported in the studies, the level of detail prohibits a detailed analysis of failure of prophylaxis and pre-emptive therapy. Clearly reporting on patients with a negative outcome should be improved. We have provided guidance on how to detect failure early in a clinical setting in accordance to the results from this systematic review. PROSPERO REGISTRATION NUMBER: CRD42017077606.

Buruli ulcer treatment: Rate of surgical intervention differs highly between treatment centers in West Africa.

BACKGROUND: Antibiotic treatment proved itself as the mainstay of treatment for Buruli ulcer disease. This neglected tropical disease is caused by Mycobacterium ulcerans. Surgery persists as an adjunct therapy intended to reduce the mycobacterial load. In an earlier clinical trial, patients benefited from delaying the decision to operate. Nevertheless, the rate of surgical interventions differs highly per clinic. METHODS: A retrospective study was conducted in six different Buruli ulcer (BU) treatment centers in Benin and Ghana. BU patients clinically diagnosed between January 2012 and December 2016 were included and surgical interventions during the follow-up period, at least one year after diagnosis, were recorded. Logistic regression analysis was carried out to estimate the effect of the treatment center on the decision to perform surgery, while controlling for interaction and confounders. RESULTS: A total of 1193 patients, 612 from Benin and 581 from Ghana, were included. In Benin, lesions were most frequently (42%) categorized as the most severe lesions (WHO criteria, category III), whereas in Ghana lesions were most frequently (44%) categorized as small lesions (WHO criteria, category I). In total 344 (29%) patients received surgical intervention. The percentage of patients receiving surgical intervention varied between hospitals from 1.5% to 72%. Patients treated in one of the centers in Benin were much more likely to have surgery compared to the clinic in Ghana with the lowest rate of surgical intervention (RR = 46.7 CI 95% [17.5-124.8]). Even after adjusting for confounders (severity of disease, age, sex, limitation of movement at joint at time of diagnosis, ulcer and critical sites), rates of surgical interventions varied highly. CONCLUSION: The decision to perform surgery to reduce the mycobacterial load in BU varies highly per clinic. Evidence based guidelines are needed to guide the role of surgery in the treatment of BU.

In Vivo Imaging of Bioluminescent Mycobacterium ulcerans: A Tool to Refine the Murine Buruli Ulcer Tail Model.

Buruli ulcer (BU) is a neglected tropical disease caused by infection with Mycobacterium ulcerans. Unclear transmission, no available vaccine, and suboptimal treatment regimens hamper the control of this disease. Carefully designed preclinical research is needed to address these shortcomings. In vivo imaging (IVIS®, Perkin Elmer, Waltham, MA) of infection is an emerging tool that permits monitoring of disease progression and reduces the need to using large numbers of mice at different time-points during the experiment, as individual mice can be imaged at multiple time-points. We aimed to further describe the use of in vivo imaging (IVIS) in BU. We studied the detection of M. ulcerans in experimentally infected BALB/c mouse tails and the subsequent histopathology and immune response in this pilot study. IVIS-monitoring was performed weekly in ten infected BALB/c mice to measure light emitted as a proxy for bacterial load. Nine of 10 (90%) BALB/c mice infected subcutaneously with 3.3 × 105 M. ulcerans JKD8049 (containing pMV306 hsp16+luxG13) exhibited light emission from the site of infection, indicating M. ulcerans growth in vivo, whereas only five of 10 (50%) animals developed clinical signs of the disease. Specific antibody titers were detected within 2 weeks of the infection. Interferon (IFN)-γ and interleukin (IL)-10 were elevated in animals with pathology. Histopathology revealed clusters of acid-fast bacilli in the subcutaneous tissue, with macrophage infiltration and granuloma formation resembling human BU. Our study successfully showed the utility of M. ulcerans IVIS monitoring and lays a foundation for further research.

Sensitivity and specificity of an electronic nose in diagnosing pulmonary tuberculosis among patients with suspected tuberculosis.

OBJECTIVE: To investigate the potency of a hand-held point-of-care electronic-nose to diagnose pulmonary tuberculosis (PTB) among those suspected of PTB. METHODS: Setting: Lung clinics and Dr. Sardjito Hospital, Yogyakarta, Indonesia. Participants: patients with suspected PTB and healthy controls. Sampling: 5 minutes exhaled breath. Sputum-smear-microscopy, culture, chest-radiography, and follow-up for 1.5-2.5 years, were used to classify patients with suspected PTB as active PTB, probably active PTB, probably no PTB, and no PTB. After building a breath model based on active PTB, no PTB, and healthy controls (Calibration phase), we validated the model in all patients with suspected PTB (Validation phase). In each variable (sex, age, Body Mass Index, co-morbidities, smoking status, consumption of alcohol, use of antibiotics, flu symptoms, stress, food and drink intake), one stratum's Receiver Operating Characteristic (ROC)-curve indicating sensitivity and specificity of the breath test was compared with another stratum's ROC-curve. Differences between Area-under-the-Curve between strata (p<0.05) indicated an association between the variable and sensitivity-specificity of the breath test. Statistical analysis was performed using STATA/SE 15. RESULTS: Of 400 enrolled participants, 73 were excluded due to extra-pulmonary TB, incomplete data, previous TB, and cancer. Calibration phase involved 182 subjects, and the result was validated in 287 subjects. Sensitivity was 85% (95%CI: 75-92%) and 78% (95%CI: 70-85%), specificity was 55% (95%CI: 44-65%) and 42% (95%CI: 34-50%), in calibration and validation phases, respectively. Test sensitivity and specificity were lower in men. CONCLUSION: The electronic-nose showed modest sensitivity and low specificity among patients with suspected PTB. To improve the sensitivity, a larger calibration group needs to be involved. With its portable form, it could be used for TB screening in remote rural areas and health care settings.

Posaconazole therapeutic drug monitoring in clinical practice and longitudinal analysis of the effect of routine laboratory measurements on posaconazole concentrations.

Posaconazole is indicated for prophylaxis and treatment of invasive aspergillosis. Therapeutic drug monitoring (TDM) of posaconazole is used to optimise drug exposure. The aim of this study was to analyse and describe the TDM practices and exposure of posaconazole tablets. Patients who received posaconazole for treatment or prophylaxis of fungal infections were included in the study. The following therapeutic window was defined: if concentration was low (<0.7 mg/L for prophylaxis or < 1.5 mg/L for treatment) or high (>3.75 mg/L), the hospital pharmacist provided the physician with dosage advice, which implementation to patient care was analysed. A longitudinal analysis was performed to analyse if different confounding variables had an effect on posaconazole concentrations. Forty-seven patients were enrolled resulting in 217 posaconazole trough concentrations. A median of 3 (IQR 1-7) samples was measured per patient. The median concentration was 1.7 mg/L (IQR 0.8-2.7) for prophylaxis and 1.76 mg/L (IQR 1.3-2.3) for treatment. Overall, 78 posaconazole concentrations were out of the therapeutic window. For 45 (54%) of these concentrations, a dosage change was recommended. In the longitudinal analysis, the laboratory markers and patient baseline variables did not have an effect on posaconazole concentrations. Adequate posaconazole exposure was shown in 64% (affected 28 patients) of the measured concentrations. TDM practice of posaconazole can be improved by increasing the implementation rate of dose recommendation by a multidisciplinary antifungal stewardship team.

Ganciclovir Therapeutic Drug Monitoring: A Case Series.

This article presents 3 cases of immunocompromised patients for whom therapeutic drug monitoring of ganciclovir in combination with cytomegalovirus viral load measurement was used to guide treatment. The first patient is diagnosed with thymoma A, the second is a heart transplant recipient, and the third is an HIV-positive patient. These patients were all diagnosed with cytomegalovirus and treated with ganciclovir. Our case studies illustrate how therapeutic drug monitoring-guided dosing can be helpful in the management of these complex cases.

Posaconazole trough concentrations are not influenced by inflammation: A prospective study.

During inflammation, several cytochrome P450 enzymes are downregulated. Recently it was shown that voriconazole metabolism is reduced during inflammation. Posaconazole, another triazole with broad-spectrum antifungal activity, is metabolised only to a limited extent by cytochrome P450 enzymes and to a wider extent by phase 2 enzyme systems. The aim of this study was to investigate posaconazole concentrations during inflammation. Patients aged ≥18 years receiving posaconazole prophylaxis or treatment for fungal infections were enrolled in a prospective observational study. Samples for posaconazole and C-reactive protein (CRP) concentrations were collected routinely for each patient. Longitudinal data analysis was performed to analyse the correlation between posaconazole serum trough concentrations and CRP values, corrected for potential factors that could influence the posaconazole concentration. Between August 2015 and June 2017, 64 patients were recruited to this study. Data for 55 patients (511 posaconazole samples) were included in the final analysis. The overall median posaconazole concentration was 1.8 mg/L [interquartile range (IQR) 1-2.9 mg/L, range 0.1-7.94 mg/L] and the overall median CRP concentration was 23.5 mg/L (IQR 5-75 mg/L, range 0-457 mg/L). Longitudinal data analysis showed that only the posaconazole daily dose (in mg/kg body weight) had a significant influence on posaconazole concentration after correction for other factors (P < 0.0001). Posaconazole concentrations were not influenced by CRP concentrations (P = 0.77). Posaconazole concentrations are not influenced by inflammation, reflected by CRP concentration. Therefore, more frequent therapeutic drug monitoring of posaconazole during inflammation or after an infection subsides is not necessary.

Delayed versus standard assessment for excision surgery in patients with Buruli ulcer in Benin: a randomised controlled trial.

BACKGROUND: Surgical intervention was once the mainstay of treatment for Buruli ulcer disease, a neglected tropical disease caused by Mycobacterium ulcerans. Since the introduction of streptomycin and rifampicin for 8 weeks as standard care, surgery has persisted as an adjunct therapy, but its role is uncertain. We investigated the effect of delaying the decision to operate to 14 weeks on rates of healing without surgery. METHODS: In this randomised controlled trial, we enrolled patients aged 3 years or older with confirmed disease at one hospital in Lalo, Benin. Patients were randomly assigned (1:1) to groups assessing the need for excision surgery 8 weeks (standard care) or 14 weeks after initiation of antimicrobial treatment. The primary endpoint was the number of patients healed without the need for surgery (not including skin grafting), assessed in all patients in follow-up at 50 weeks (or last observation for those healed for >10 weeks). A doctor masked to treatment assignment checked the indications for surgery according to predefined criteria. This study is registered with ClinicalTrials.gov, number NCT01432925. FINDINGS: Between July 1, 2011, and Jan 15, 2015, 119 patients were enrolled, with two patients per group lost to follow-up. 55 (96%) of 57 participants in the delayed-decision group and 52 (90%) of 58 participants in the standard-care group had healed lesions 1 year after start of antimicrobial treatment (relative risk [RR] 1·08, 95% CI 0·97-1·19). 37 (67%) of 55 patients in the delayed-decision group had their lesions healed without surgical intervention, as did 25 (48%) of 52 in the standard-care group (RR 1·40, 95% CI 1·00-1·96). The time to heal and residual functional limitations did not differ between the two groups (median time to heal 21 weeks [IQR 10-27] in the delayed-decision group and 21 weeks [10-39] in the standard-care group; functional limitations in six [11%] of 57 and three [5%] of 58 patients; p=0·32). Postponing the decision to operate resulted in reduced median duration of hospitalisation (5 days [IQR 0-187] vs 131 days [0-224]; p=0·024) and wound care (153 days [IQR 56-224] vs 182 days [94-307]; p=0·036). INTERPRETATION: In our study, patients treated for Buruli ulcer benefited from delaying the decision to operate. Even large ulcers can heal with antibiotics alone, without delaying healing rate and without an increase in residual functional limitations. FUNDING: NWO-VENI grant 241500, BUG Foundation, and UBS OPTIMUS.

Epidemiology of Staphylococcus aureus in a burn unit of a tertiary care center in Ghana.

BACKGROUND: In developing countries, hospitalized burn victims are at high risk of nosocomial infections caused by Staphylococcus aureus. Risk factors include poor infection control practices, prolonged hospitalisation and limited capacity for laboratory microbiological analyses. These problems are compounded by widespread use of antibiotics that drives the spread of multi-drug resistant bacteria. METHODS: During the study period (November 2014-June 2015), nasal and invasive S. aureus isolates were collected consecutively from patients and healthcare workers (HCWs) within the burn unit of the Reconstructive Plastic Surgery and Burn Center of Korle Bu Teaching Hospital in Ghana. Antibiotic prescription, antibiotic susceptibility and bacterial typing were used to assess antibiotic pressure, antibiotic resistance, and possible transmission events among patients and HCWs. RESULTS: Eighty S. aureus isolates were obtained from 37 of the 62 included burn patients and 13 of the 29 HCWs. At admission, 50% of patients carried or were infected with S. aureus including methicillin resistant S. aureus (MRSA). Antibiotic use per 100 days of hospitalization was high (91.2 days), indicating high selective pressure for resistant pathogens. MRSA isolates obtained from 11 patients and one HCW belonged to the same spa-type t928 and multi-locus sequence type 250, implying possible transmission events. A mortality rate of 24% was recorded over the time of admission in the burn unit. CONCLUSION: This study revealed a high potential for MRSA outbreaks and emergence of resistant pathogens amongst burn patients due to lack of patient screening and extended empirical use of antibiotics. Our observations underscore the need to implement a system of antibiotic stewardship and infection prevention where microbiological diagnostics results are made available to physicians for timely and appropriate patient treatment.

Skin advanced glycation end products in HIV infection are increased and predictive of development of cardiovascular events.

OBJECTIVE: HIV-1 infection is associated with an increased cardiovascular disease (CVD) risk. Advanced glycation end products are formed as stable markers of glycaemic and oxidative stress. Skin autofluorescence (SAF) as marker of accumulated advanced glycation end products is increased and predictive of CVD events in diabetes mellitus, chronic kidney disease (CKD), and preexisting CVD. We determined SAF levels in HIV-1 infected patients, testing the hypothesis that SAF predicts CVD events in HIV infection. DESIGN: Single-centre prospective cohort study. METHODS: In 2010-2011, SAF was measured in 91 patients. Development of CVD events was monitored during a median follow-up of 4.8 years. SAF values of the patients were expressed as a ratio (rSAF) to expected SAF levels in age-matched healthy volunteers. RESULTS: Seventy-nine men and 12 women were included, mean age 47 years; 81 patients were on combination antiretroviral therapy. With a mean rSAF of 1.155, SAF levels in patients were 15.5% higher than predicted for their age (95% confidence interval, 10.0-20.0; P < 0.001). In multivariate regression analysis, rSAF was associated with nadir CD4 cell count less than 200 cells/µl (ß -0.274; P = 0.01), smoking (ß 0.240; P = 0.03), and men who have sex with men (MSM) (ß 0.202; P = 0.07). CVD events occurred in six patients (7%). In Cox regression analysis including age, SAF, smoking, diabetes, hypertension and CKD, SAF (P = 0.01), and (Wet Medisch-wetenschappelijk Onderzoek met mensen; WMO) CKD (P = 0.03) remained as independent predictors of CVD events. CONCLUSION: SAF is increased in HIV-infected patients, and related with smoking, low nadir CD4 cell count, and MSM. Larger studies are needed to confirm whether SAF is an independent predictor of CVD events.

Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Tobramycin Free Base in Non-Cystic Fibrosis Bronchiectasis Patients.

RATIONALE: Bronchiectasis is a condition characterised by dilated and thick-walled bronchi. The presence of Pseudomonas aeruginosa in bronchiectasis is associated with a higher hospitalisation frequency and a reduced quality of life, requiring frequent and adequate treatment with antibiotics. OBJECTIVES: To assess local tolerability and the pharmacokinetic parameters of inhaled excipient free dry powder tobramycin as free base administered with the Cyclops dry powder inhaler to participants with non-cystic fibrosis bronchiectasis. The free base and absence of excipients reduces the inhaled powder dose. METHODS: Eight participants in the study were trained in handling the device and inhaling correctly. During drug administration the inspiratory flow curve was recorded. Local tolerability was assessed by spirometry and recording adverse events. Serum samples were collected before, and 15, 30, 45, 60, 75, 90, 105, 120 min; 4, 8 and 12 h after inhalation. RESULTS AND DISCUSSION: Dry powder tobramycin base was well tolerated and mild tobramycin-related cough was reported only once. A good drug dose-serum concentration correlation was obtained. Relatively small inhaled volumes were computed from the recorded flow curves, resulting in presumably substantial deposition in the central airways-i.e., at the site of infection. CONCLUSIONS: In this first study of inhaled dry powder tobramycin free base in non-cystic fibrosis bronchiectasis patients, the free base of tobramycin and the administration with the Cyclops dry powder device were well tolerated. Our data support further clinical studies to evaluate safety and efficacy of this compound in this population.

Validation of a visual analogue score (LRTI-VAS) in non-CF bronchiectasis.

BACKGROUND AND AIM: Quality of life in patients with non-cystic fibrosis (non-CF) bronchiectasis is largely defined by respiratory symptoms. To date, no disease-specific tool for symptom measurement in this patient group was available. We developed the lower respiratory tract infections - visual analogue scale (LRTI-VAS) in order to quickly and conveniently quantify symptoms in non-CF bronchiectasis. This study aimed to validate LRTI-VAS for use in non-CF bronchiectasis. METHODS: This study included outpatients with radiologically proven bronchiectasis and no evidence of CF. Results of LRTI-VAS were compared with other markers of disease activity {lung function parameters, oxygen saturation and three health-related quality of life questionnaires [Medical Outcomes Study Short-Form 36 Health Survey (SF-36), St Georges Respiratory Questionnaire (SGRQ) and Leicester Cough Questionnaire (LCQ)]} and validity, reliability and responsiveness were assessed. RESULTS: Thirty stable and 30 exacerbating participants completed the LRTI-VAS questionnaire. When testing for repeatability on two separate occasions, no statistically significant difference between total scores was found {1.4 [standard deviation (SD)] 5.3}, P = 0.16). Internal consistency was high across items (Cronbach's alpha 0.86). Correlation with SGRQ, SF-36 and LCQ total scores was high. Following antibiotic treatment, mean (SD) LRTI-VAS total score improved from 18.1 (SD 9.9) to 26.1 (SD 6.6) (P < 0.001). CONCLUSIONS: LRTI-VAS showed excellent validity, reliability and responsiveness to change and therefore appears a reliable tool for symptom measurement in non-CF bronchiectasis.

Subtherapeutic Posaconazole Exposure and Treatment Outcome in Patients With Invasive Fungal Disease.

BACKGROUND: Posaconazole exposure seems to be subtherapeutic in some patients with invasive fungal disease. Due to the pharmacokinetic variability of posaconazole, therapeutic drug monitoring may help to optimize the efficacy of this antifungal drug. METHODS: A retrospective study of patients treated with posaconazole from January 2008 to April 2014 and for whom posaconazole serum concentrations were available was conducted. Risk factors for underexposure of posaconazole were detected, and the relationship between posaconazole exposure and treatment outcome according to the European Organization for Research and Treatment of Cancer (EORTC) criteria was assessed. RESULTS: Seventy patients met the inclusion criteria, 45 patients received posaconazole as treatment, and 25 patients received posaconazole as a prophylactic. Posaconazole serum trough concentrations were <1.25 mg/L in 44.4% of patients receiving treatment and <0.7 mg/L in 40.0% of patients receiving prophylactic posaconazole. Multiple linear regression analysis showed a significant, independent, and negative association of the posaconazole serum trough concentration with a lack of enteral nutrition (P < 0.001), vomiting (P = 0.035), the use of a proton pump inhibitor or H2-receptor antagonist (P < 0.001), a liquid diet (P = 0.002), concomitant chemotherapy (P = 0.004), and a posaconazole dose frequency of 2 times daily (P = 0.015). A higher posaconazole concentration was associated with a better treatment outcome [odds ratio = 22.22 (95% confidence interval, 3.40-145.33); P = 0.001]. CONCLUSIONS: Posaconazole exposure is insufficient in more than 40% of patients at risk of or with invasive fungal disease, and posaconazole exposure is positively correlated with a successful treatment outcome. Therapeutic drug monitoring of posaconazole can detect underexposure and can be helpful in treatment optimization.

[A sore throat: tumour, tuberculosis or both?]. / Keelklachten: tumor, tuberculose of beide?

The incidence of tuberculosis in the Netherlands has dropped dramatically over the past 50 years. With declining experience of tuberculosis, misdiagnosis can easily happen. Laryngeal tuberculosis often presents as a tumorous mass that may initially be mistaken for cancer. As laryngeal tuberculosis is usually highly infectious, this poses a risk to the patient as well as his/her contacts including healthcare providers. We describe three patients with (suspected) laryngeal tuberculosis and discuss potential pitfalls. Pivotal for a correct diagnosis are thorough history-taking, physical examination and relatively simple radiological and laboratory tests. Risk groups have been identified for tuberculosis and this can provide a clue. Differentiation between tuberculosis and cancer can be difficult, and the two diseases may concur. Even in low-incidence settings for tuberculosis, knowledge of the disease remains necessary as it is curable and further spread can be prevented with simple measures.

Buruli ulcer control in a highly endemic district in Ghana: role of community-based surveillance volunteers.

Buruli ulcer (BU) is an infectious skin disease that occurs mainly in West and Central Africa. It can lead to severe disability and stigma because of scarring and contractures. Effective treatment with antibiotics is available, but patients often report to the hospital too late to prevent surgery and the disabling consequences of the disease. In a highly endemic district in Ghana, intensified public health efforts, mainly revolving around training and motivating community-based surveillance volunteers (CBSVs), were implemented. As a result, 70% of cases were reported in the earliest-World Health Organization category I-stage of the disease, potentially minimizing the need for surgery. CBSVs referred more cases in total and more cases in the early stages of the disease than any other source. CBSVs are an important resource in the early detection of BU.