Search

Contains fulltext : 291084.pdf (Publisher’s version ) (Open Access) Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.

Backgrounds Transcatheter-implanted aortic valve infective endocarditis (TAVI-IE) is difficult to diagnose when relying on the Duke Criteria. Our aim was to assess the additional diagnostic value of 18F-fluorodeoxyglucose (18F-FDG) positron emission/computed tomography (PET/CT) and cardiac computed tomography angiography (CTA) in suspected TAVI-IE. Methods A multicenter retrospective analysis was performed in all patients who underwent 18F-FDG-PET/CT and/or CTA with suspected TAVI-IE. Patients were first classified with Duke Criteria and after adding 18F-FDG-PET/CT and CTA, they were classified with European Society of Cardiology (ESC) criteria. The final diagnosis was determined by our Endocarditis Team based on ESC guideline recommendations. Results Thirty patients with suspected TAVI-IE were included. 18F-FDG-PET/CT was performed in all patients and Cardiac CTA in 14/30. Using the Modified Duke Criteria, patients were classified as 3% rejected (1/30), 73% possible (22/30), and 23% definite (7/30) TAVI-IE. Adding 18F-FDG-PET/CT and CTA supported the reclassification of 10 of the 22 possible cases as “definite TAVI-IE” (5/22) or “rejected TAVI-IE” (5/22). This changed the final diagnosis to 20% rejected (6/30), 40% possible (12/30), and 40% definite (12/30) TAVI-IE. Conclusions Addition of 18F-FDG-PET/CT and/or CTA changed the final diagnosis in 33% of patients and proved to be a valuable diagnostic tool in patients with suspected TAVI-IE.

Combination antiretroviral therapy (cART) can cause metabolic toxicities. How cART simplification to dual or monotherapies affects metabolic markers is unknown. We analyzed the metabolic effects of cART simplification to dolutegravir (DTG) monotherapy in the randomized clinical DOMONO (DOlutegravir MONOtherapy for HIV) trial including HIV-positive participants. Renal function, Framingham risk score (FRS), inflammation, and bone mineral density (BMD) with trabecular bone score (TBS) were measured during 48 weeks after simplification. The changes at 48 weeks by on-treatment analyses overall and for prior tenofovir disoproxil fumarate (TDF) exposure were analyzed separately, using Bonferroni corrected alpha (p = 0.00096). Ninety-five patients initiated DTG monotherapy, including 80 discontinuing TDF. At week 48, the switch to DTG monotherapy resulted in an expected −7.8 ml/min estimated glomerular filtration decline. In patients on prior TDF, proteinuria improved (p

Approximately 20% of the patients listed for liver transplantation die before transplantation can be accomplished. Understanding risk factors for waiting list mortality may help to improve survival and organ allocation. Infections are very common in patients with cirrhosis and are associated with significant morbidity and mortality. This study analysed the frequency and characteristics of infections in patients awaiting liver transplantation, identified risk factors for withdrawal from the waiting list and evaluated the impact of infections on the clinical outcome. A retrospective analysis of consecutive patients listed for liver transplantation in Rotterdam, the Netherlands from 2007 to 2014 was conducted. Infections occurred in 144 of 327 studied patients (44%). In this cohort, 23.4% of the patients on the liver transplantation waiting list were delisted or died before transplantation. Patients with an infection were 5.2 times more likely to become delisted than noninfected patients. In the 30 days after the first infection, patients were 33.8 times more likely to become delisted compared to noninfected patients. High age, high MELD score, refractory ascites and inappropriate antibiotic therapy were independent predictors for delisting due to infection. Infections occur frequently in patients on the liver transplantation waiting list. Emphasis on appropriate and timely antimicrobial therapy is required.

BACKGROUND Dolutegravir is recommended as part of combination ART (cART) for HIV-1-infected patients. Toxicities, drug interactions and costs related to cART still warrant the search for improved treatment options. Dolutegravir's high resistance barrier might make it suitable as antiretroviral maintenance monotherapy. The feasibility of this strategy is currently unknown. METHODS This is a prospective case series on five consecutive HIV-1-infected patients on cART without previous virological failure who switched to dolutegravir monotherapy. All were HIV-RNA suppressed 50 copies/mL. RESULTS The five patients had been HIV-RNA suppressed

Glucocorticoid treatment increases the risk of opportunistic infection. Infections that can arise during glucocorticoid use, and for which preventative measures can be taken, include reactivation of latent tuberculosis and hepatitis B, pneumococcal and Pneumocystis jiroveci pneumonia, influenza, herpes zoster and Strongyloides stercoralis hyperinfection syndrome. The risk of such infections depends upon the duration of glucocorticoid use and dosage, as well as comorbidity and comedication. It is important to enquire about vaccinations, travel, exposure and previous infections when taking a case history. Possible infectious complications should be considered in patients who are receiving high-dose glucocorticoids treatment amounting to more than 420 mg PED per 4 weeks. Preventative measures are not usually required in patients who receive a short high-dosed treatment (30 mg PED in 7 days) or prednisolone at a dosage of15 mg/day.

Antimicrobial stewardship teams have been shown to increase appropriate empirical antibiotic therapy and reduce medical errors and costs in targeted populations, but the effect in non-targeted populations is still unclear. The aim of this study was to determine the prevalence of inappropriate antibiotic use in a large university hospital and identify areas in which antimicrobial stewardship will be the most effective. In a point prevalence survey we assessed the appropriateness of antibiotic therapy using an electronic surveillance system in combination with a standardized method for duration of therapy, dosage, dosage interval, route of administration, and choice of antibiotic drug. Patients using at least one antibiotic drug were included. Among 996 patients admitted in the surveyed wards, 337 patients (33.8 %) used one or more antibiotic drugs. Two hundred and twenty-one patients (22.2 %) used antibiotic medication therapeutically, with a total of 307 antibiotic prescriptions. Antibiotic therapy was deemed inappropriate in 90 (29.3 %) of these prescribed antibiotics, with an unjustified prescription as the most common reason for an inappropriate prescription. Use of fluoroquinolones and amoxicillin/clavulanic acid and a presumed diagnosis of fever of unknown origin, urinary tract infection, and respiratory tract infection were associated with inappropriate antibiotic therapy. Our study provides insight into the (in) appropriateness of antibiotic prescriptions in a tertiary care center in the Netherlands and identifies areas for improvement. The use of an electronic surveillance system for this point prevalence study is easy and may serve as a baseline measurement for the future effect of antibiotic stewardship.

Background: The high genetic barrier to resistance of dolutegravir might allow for its use as maintenance monotherapy in patients with HIV. We investigated whether dolutegravir monotherapy was non-inferior to combination antiretroviral therapy (ART) for maintaining virological suppression in patients with HIV-1 infection successfully treated with combination ART.Methods: We did this open-label, phase 2, randomised non-inferiority trial at two medical centres in the Netherlands. Eligible patients (aged ≥18 years) were on combination ART, had been virologically suppressed (HIV RNA vs 50 000–99 999 copies per mL). Investigators and patients were not masked to group allocation. The primary endpoint was the proportion of patients with plasma HIV RNA viral loads of less than 200 copies per mL at week 24, with a non-inferiority margin of 12%. We did analyses in the on-treatment and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, NCT02401828.Findings: Between March 10, 2015, and Feb 4, 2016, we randomly assigned 51 patients to the immediate switch group and 53 patients to the delayed switch group. One patient who received immediate monotherapy discontinued treatment at week 12 because of disturbed sleep. At week 24, dolutegravir monotherapy was non-inferior to combination ART, with plasma HIV RNA loads of 200 copies per mL or higher observed in 2% (1/50) of patients in the immediate switch group and in no patients in the delayed switch group (difference 2%, 95% CI-5 to 12). Of patients assigned to the delayed switch group, 47 (89%) switched to dolutegravir monotherapy at week 24, two (4%) of whom subsequently discontinued monotherapy because of headache (n=1) and disturbed sleep (n=1). Eight (8%) of the 95 patients who remained on dolutegravir monotherapy had virological failure; all had therapeutic plasma concentrations of dolutegravir. In three (38%) of the eight patients, mutations associated with resistance were detected in the integrase gene. According to a predefined stopping rule, detection of these mutations led to premature study discontinuation.Interpretation: Dolutegravir monotherapy was non-inferior to combination ART at 24 weeks. However, virological failure continued to occur thereafter and led to dolutegravir resistance. Dolutegravir should not be used as maintenance monotherapy.

A 35-year-old Moroccan man presented with pain in the upper left abdomen for one day. He had a 13-year history of high-dose albendazole treatment for inoperable cystic cardiac echinococcosis and dilated, but stable cardiomyopathy. Physical examination demonstrated a visible and palpable mass pulsating synchronous with every heartbeat in the left upper abdomen (Supplementary Video 1). Cardiac magnetic resonance imaging with contrast enhancement (Panel A: axial view, Panel B: coronal view of Fig. 1) demonstrated progression of pericardial Echinococcus granulosus cysts over a trajectory of 18 cm with breakthrough into the abdominal cavity. [...]

Dolutegravir is recommended as part of combination ART (cART) for HIV-1-infected patients. Toxicities, drug interactions and costs related to cART still warrant the search for improved treatment options. Dolutegravir's high resistance barrier might make it suitable as antiretroviral maintenance monotherapy. The feasibility of this strategy is currently unknown.This is a prospective case series on five consecutive HIV-1-infected patients on cART without previous virological failure who switched to dolutegravir monotherapy. All were HIV-RNA suppressed50 copies/mL and had contraindications to current and alternative combinations of antiretroviral drugs. HIV-RNA was measured at baseline, week 4, week 8, week 12 and every 6 weeks thereafter. Patients would be switched back to their original cART upon confirmed HIV-RNA50 copies/mL.The five patients had been HIV-RNA suppressed50 copies/mL for ≥1.5 years prior to the initiation of dolutegravir monotherapy. All were on NNRTI-containing regimens at the switch. HIV-RNA remained50 copies/mL at all timepoints in four patients. One patient, with end-stage renal disease and on calcium supplements, had a pre-cART HIV-RNA of 625 000 copies/mL with a CD4 nadir of 120 cells/mm(3) and had HIV-RNA of 8150 copies/mL at week 30. The dolutegravir Ctrough was 0.18 mg/L. This patient did not have acquired resistance or evidence of adherence problems and HIV-RNA was resuppressed after switching to his former cART.This case series indicates that dolutegravir monotherapy might be a valuable maintenance option in selected HIV-infected patients who are well suppressed on cART, if confirmed by future randomized clinical trials.

Clinical pulmonary infection score for ventilator-associated pneumonia: accuracy and inter-observer variability.Schurink CA, Van Nieuwenhoven CA, Jacobs JA, Rozenberg-Arska M, Joore HC, Buskens E, Hoepelman AI, Bonten MJ.Department of Medicine, Division of Acute Medicine and Infectious Diseases, Julius Centre for Health Sciences and Primary Health Care, University Hospital Maastricht, University Medical Centre Utrecht, The Netherlands. K.Schurink@azu.nlOBJECTIVE: Although quantitative microbiological cultures of samples obtained by bronchoscopy are considered the most specific tool for diagnosing ventilator-associated pneumonia, this labor-intensive invasive technique is not widely used. The Clinical Pulmonary Infection Score (CPIS), a diagnostic algorithm that relies on easily available clinical, radiographic, and microbiological criteria, could be an attractive alternative for diagnosing ventilator-associated pneumonia. Initially, the CPIS scoring system was validated upon 40 quantitative cultures of bronchoalveolar lavage fluid from 28 patients, and only few other studies have evaluated this scoring system since then. Therefore, little is known about the accuracy of this score. DESIGN: We compared the scores of a slightly adjusted CPIS with results from quantitative cultures of bronchoalveolar lavage fluid in 99 consecutive patients with suspicion of ventilator-associated pneumonia, using growth of > or =10(4) cfu/ml in bronchoalveolar lavage fluid as a cut-off for diagnosing ventilator-associated pneumonia. In addition, the CPIS were calculated for 52 patients by two different intensivists to determine the inter-observer variability. RESULTS: Ventilator-associated pneumonia was diagnosed in 69 (69.6%) patients. When using a CPIS >5 as diagnostic cutoff, the sensitivity of the score was 83% and its specificity was 17%. The area under the Receiver Operating Characteristic curve was 0.55. The level of agreement for prospectively measured Clinical Pulmonary Infection Score (< or =6 and >6) was poor (kappa =0.16). CONCLUSIONS: When compared to quantitative cultures of bronchoalveolar lavage fluid, the CPIS has a low sensitivity and specificity for diagnosing ventilator-associated pneumonia with considerable inter-observer variability.

Objectives: Percutaneous endoscopic gastrostomy (PEG) tubes have become an excellent alternative for the long-term management of patients with proximal obstructions of the gastrointestinal tract. However, their use has limitations and can be associated with serious complications. We therefore studied the frequency and severity of complications related to the use of PEG tubes in our clinic. Design: All adults (aged 18 years and above) in whom a PEG tube was placed between January 1 1994 and January 1 1999 at the Free University Hospital in Amsterdam were included in this study. In initial cases, the indication and procedure were individually judged according to a liberal protocol. However, after several major complications, a strict procedure protocol was implemented in September 1996. Results: During the study period, 263 PEG tubes were placed in 254 patients with head and neck cancer (n = 183; 70%), neurological disorders (n = 52; 20%) or severe upper gastrointestinal motility disorders (n = 28; 11%). In period I, 167 PEG tubes were placed and in period II, 96 PEG tubes were inserted. Patients were followed for a median 111 days. Minor complications occurred in 13% of the patients. Major complications occurred in 8% of the patients. In period I, the percentage of major complications was higher than in period II (9.5% versus 6%). Conclusion: PEG tube placement is a safe procedure when performed according to strict guidelines. By doing so, PEG tubes allow optimal feeding for prolonged periods with the occasional need for replacement of the tube. PEG tubes should not be introduced in acutely ill patients, patients with a short life expectancy and preferably not to patients with severe coughing.

We report the first case of homograft endocarditis caused by Campylobacter jejuni , which was treated successfully with antibiotic therapy and valve replacement. To our knowledge, only two other cases of C. jejuni endocarditis, involving native valves, have been reported in the medical literature.

Objective: Appropriate antimicrobial treatment of infections in critically ill patients should be started as soon as possible, as delay in treatment may reduce a patient's prognostic outlook considerably. Ventilator-associated pneumonia (VAP) occurs in patients in intensive care units who are mechanically ventilated and is almost always preceded by colonisation of the respiratory tract by the causative microorganisms. It is very difficult to clinically diagnose VAP and, therefore, some form of computer-based decision support might be helpful for the clinician. Materials and methods: As diagnosing and treating VAP involves reasoning with uncertainty, we have used a Bayesian network as the primary tool. for building a decision-support system. The effects of usage of antibiotics on the colonisation of the respiratory tract by various pathogens and the subsequent antibiotic choices in case of VAP were modelled using the notion of causal independence. In particular, the conditional probability distribution of the random variable that represents the overall coverage of pathogens by antibiotics was modelled in terms of the conjunctive effect of the seven different pathogens, usually referred to as the noisy-AND model. In this paper, we investigate different coverage models, as well as generalisations of the noisy-AND, called noisy-threshold models, and test them on clinical data of intensive care unit (ICU) patients who are mechanically ventilated. Results: Some of the constructed noisy-threshold models offered further improvement of the performance of the Bayesian network in covering present causative pathogens by advising appropriate antimicrobial treatment. Conclusions: By reconsidering the modelling of interactions between the random variables in a Bayesian network using the theory of causal independence, it is possible to refine its performance. This was clearly shown for our Bayesian network concerning VAP, indicating that only specific noisy-threshold models might be appropriate for the modelling of the interaction between pathogens and antimicrobial treatment with respect to susceptibility. The results obtained also provide evidence that the noisy-OR and noisy-AND might not always be the best functions to model interactions among random variables. (C) 2008 Elsevier B.V. All rights reserved.

Background: We previously validated a Bayesian network (BN) model for diagnosing ventilatorassociated pneumonia (VAP). Here, we report on the performance of the model to predict microbial causes of VAP and to select antibiotics. Methods: Pathogens were grouped into seven categories based upon the antibiotic susceptibility and epidemiological characteristics. Colonization of the upper respiratory tract was modelled in the BN and depended—in additional steps—on (i) duration of admission and ventilation, (ii) previous culture results and (iii) previous antibiotic use. A database with 153 VAP episodes and their microbial causes was used as reference standard. Appropriateness of antibiotic prescription, with fixed choices for pathogens predicted, was determined. Results: One hundred and seven VAP episodes were monobacterial and 46 were caused by two pathogens. Using duration of admission and ventilation only, areas under the receiver operating curve (AUC) ranged from 0.511 to 0.772 for different pathogen groups, and model predictions significantly improved when adding information on culture results, but not when adding information on antibiotic use. The best performing model (with all information) had AUC values ranging from 0.859 for Acinetobacter spp. to 0.929 for Streptococcus pneumoniae. With this model, 91 (85%) and 29 (63%) of all pathogen groups were correctly predicted for monobacterial and polymicrobial VAP, respectively. With fixed antibiotic choices linked to pathogen groups, 92% of all episodes would have been treated appropriately. Conclusions: The BN models’ performance to predict pathogens causing VAP improved markedly with information on colonization, resulting in excellent pathogen prediction and antibiotic selection. Prospective external validation is needed.

Objective: Bacterial respi- ratory tract colonization predisposes critically ill patients to intensive care unit (ICU)-acquired infections. It is unclear to what extent systemic antibiotics affect colonization per- sistence. Persistence of respiratory tract colonization, and the effects of systemic antibiotics hereon, were de- termined in a cohort of ICU patients. Design: Clinical and microbiological data were collected from 715 admitted mechanically ventilated ICU patients with bacterial growth documented in respiratory tract samples. First day of colonization, persistence of coloniza- tion and antibiotic effects hereon were analyzed for six groups of pathogens: Pseudomonas aeruginosa, Acineto- bacter species, Enterobacteriaceae, Staphylococcus aureus, Streptococ- cus pneumoniae and Haemophilus influenzae. Systemic antibiotics were grouped into 'effective' and 'ineffective' antibiotics, based on in-vitro susceptibility data for the relevant bacteria. The effects of an- tibiotics were quantified as relative risk (RR) of bacterial persistence in the absence of effective antibiotics. Measurements and results: Persis- tence of colonization differed signif- icantly between pathogens, ranging from 4 days (median) for H. influen- zae and Strep. pneumoniae to 8d ays for P. aeruginosa. Systemic antibi- otics were administered on 7,102 (61%) of patient days. Antibiotic use was associated with non-persistence for all pathogens, except Acinetobac- ter species and P. aeruginosa .R R for non-persistence (as compared to ineffective or no antibiotics) ranged from 3.1 (95% CI 1.4-6.6) for H. influenzae to 0.5 (0.3-1.0) for Acinetobacter species. Conclusions: In mechanically ventilated patients, persistence dynamics of bacterial respiratory tract colonization, and the effects of (in-vitro) effective antibiotics hereon, are pathogen- specific.

We report the first case of homograft endocarditis caused by Campylobacter jejuni, which was treated successfully with antibiotic therapy and valve replacement. To our knowledge, only two other cases of C. jejuni endocarditis, involving native valves, have been reported in the medical literature.

OBJECTIVE: To determine the diagnostic performance of a Bayesian Decision-Support System (BDSS) for ventilator-associated pneumonia (VAP). DESIGN: A previously developed BDSS, automatically obtaining patient data from patient information systems, provides likelihood predictions of VAP. In a prospectively studied cohort of 872 ICU patients, VAP was diagnosed by two infectious-disease specialists using a decision tree (reference diagnosis). After internal validation daily BDSS predictions were compared with the reference diagnosis. For data analysis two approaches were pursued: using BDSS predictions (a) for all 9422 patient days, and (b) only for the 238 days with presumed respiratory tract infections (RTI) according to the responsible physicians. MEASUREMENTS AND RESULTS: 157 (66%) of 238 days with presumed RTI fulfilled criteria for VAP. In approach (a), median daily BDSS likelihood predictions for days with and without VAP were 77% [Interquartile range (IQR) = 56-91%] and 14% [IQR 5-42%, p < 0.001, Mann-Whitney U-test (MWU)], respectively. In receiver operating characteristics (ROC) analysis, optimal BDSS cut-off point for VAP was 46%, and with this cut-off point positive predictive value (PPV) and negative predictive value (NPV) were 6.1 and 99.6%, respectively [AUC = 0.857 (95% CI 0.827-0.888)]. In approach (b), optimal cut-off for VAP was 78%, and with this cut-off point PPV and NPV were 86 and 66%, respectively [AUC = 0.846 (95% CI 0.794-0.899)]. CONCLUSIONS: As compared with the reference diagnosis, the BDSS had good test characteristics for diagnosing VAP, and might become a useful tool for assisting ICU physicians, both for routinely daily assessment and in patients clinically suspected of having VAP. Empirical validation of its performance is now warranted