Malnutrition assessment methods in adult patients with tuberculosis: a systematic review.

OBJECTIVES: Malnutrition is associated with a twofold higher risk of dying in patients with tuberculosis (TB) and considered an important potentially reversible risk factor for failure of TB treatment. The construct of malnutrition has three domains: intake or uptake of nutrition; body composition and physical and cognitive function. The objectives of this systematic review are to identify malnutrition assessment methods, and to quantify how malnutrition assessment methods capture the international consensus definition for malnutrition, in patients with TB. DESIGN: Different assessment methods were identified. We determined the extent of capturing of the three domains of malnutrition, that is, intake or uptake of nutrition, body composition and physical and cognitive function. RESULTS: Seventeen malnutrition assessment methods were identified in 69 included studies. In 53/69 (77%) of studies, body mass index was used as the only malnutrition assessment method. Three out of 69 studies (4%) used a method that captured all three domains of malnutrition. CONCLUSIONS: Our study focused on published articles. Implementation of new criteria takes time, which may take longer than the period covered by this review. Most patients with TB are assessed for only one aspect of the conceptual definition of malnutrition. The use of international consensus criteria is recommended to establish uniform diagnostics and treatment of malnutrition. PROSPERO REGISTRATION NUMBER: CRD42019122832.

Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients.

The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of target attainment (PTA). A target 24-h area under the concentration-time curve (AUC) value of 98 mg·h/liter was used as an efficacy parameter. Secondarily, the AUC/MIC targets of 450, 865, and 1,185 were used to calculate PTAs for Candida glabrata, C. albicans, and C. parapsilosis, respectively. The final 2-compartment model included weight as a covariate on volume of distribution (V). The mean V of the central compartment was 7.71 (standard deviation [SD], 2.70) liters/kg of body weight, the mean elimination constant (Ke ) was 0.09 (SD, 0.04) h-1, the rate constant for the caspofungin distribution from the central to the peripheral compartment was 0.44 (SD, 0.39) h-1, and the rate constant for the caspofungin distribution from the peripheral to the central compartment was 0.46 (SD, 0.35) h-1 A loading dose of 2 mg/kg on the first day, followed by 1.25 mg/kg as a maintenance dose, was chosen. With this dose, 98% of the patients were expected to reach the AUC target on the first day and 100% of the patients on the third day. The registered caspofungin dose might not be suitable for critically ill patients who were all overweight (≥120 kg), over 80% of median weight (78 kg), and around 25% of lower weight (≤50 kg). A weight-based dose regimen might be appropriate for achieving adequate exposure of caspofungin in intensive care unit patients.

Health economic evaluation of current vaccination strategies and new vaccines against tuberculosis: a systematic review.

Introduction: Bacillus Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis, but its effectiveness is limited and varies by age. New candidate vaccines are currently being investigated. In response to the declining incidence of TB, practices relating to BCG vaccination have changed in various countries in recent years. A valid cost-effectiveness study is therefore needed in order to assist decision-makers in the implementation of cost-effective strategies for BCG vaccination. Areas covered: Studies involving economic evaluations of BCG vaccination were reviewed in order to present current findings concerning a range of BCG vaccination strategies in a variety of regions, target populations, and vaccine types. The Quality of Health Economic Studies (QHES) instrument was used to assess the quality of the studies included in the analysis. Expert opinion: Most of the studies showed a favorable economic profile of BCG vaccination. Selective strategies seem the most cost-effective option for low-incidence areas. Varying results on revaccination strategies did not lead to any conclusive finding on the cost-effectiveness of the strategies. A novel vaccine - either a BCG replacement or booster vaccine that provides better protection, especially in adults - has the potential to enhance the cost-effectiveness of vaccinating against tuberculosis.

Intermediate Susceptibility Dose-Dependent Breakpoints For High-Dose Rifampin, Isoniazid, and Pyrazinamide Treatment in Multidrug-Resistant Tuberculosis Programs.

Background: Bacterial susceptibility is categorized as susceptible, intermediate-susceptible dose-dependent (ISDD), and resistant. The strategy is to use higher doses of first-line agents in the ISDD category, thereby preserving the use of these drugs. This system has not been applied to antituberculosis drugs. Pharmacokinetic/pharmacodynamic (PK/PD) target exposures, in tandem with Monte Carlo experiments, recently identified susceptibility breakpoints of 0.0312 mg/L for isoniazid, 0.0625 mg/L for rifampin, and 50 mg/L for pyrazinamide. These have been confirmed in clinical studies. Methods: Target attainment studies were carried out using Monte Carlo experiments to investigate whether rifampin, isoniazid, and pyrazinamide dose increases would achieve the PK/PD target in >90% of 10000 patients with tuberculosis caused by bacteria, revealing minimum inhibitory concentrations (MICs) between the proposed and the traditional breakpoints. Results: We found that an isoniazid dose of 900 mg/day identified a new ISDD MIC range of 0.0312-0.25 mg/L and resistance at MIC ≥0.5 mg/L. Rifampin 1800 mg/day would result in an ISDD of 0.0625-0.25 mg/L and resistance at MIC ≥0.5 mg/L. At a dose of pyrazinamide 4 g/day, the ISDD MIC range was 37.5-50 mg/L and resistance at MIC ≥100 mg/L. Based on MIC distributions, 93% (isoniazid), 78% (rifampin), and 27% (pyrazinamide) of isolates would be within the ISDD range. Conclusions: Drug susceptibility testing at 2 concentrations delineating the ISDD range, and subsequently using higher doses, could prevent switching to a more toxic second-line treatment. Confirmatory clinical studies would provide evidence to change treatment guidelines.

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.

Correction: Variability and cost implications of three generations of the Roche LightCycler® 480.

[This corrects the article DOI: 10.1371/journal.pone.0190847.].

Variability and cost implications of three generations of the Roche LightCycler® 480.

Real time PCR has become a dominant method for the highly sensitive detection of pathogens in clinical material. Real time PCR can generate a fluorescence signal by using fluorescence labelled probes, allowing us to detect and semi quantify the amount of amplified DNA. Here we test the variability of the detection system and cost implications of three different versions of the LightCycler® 480 (LC480), focusing on the intensity of fluorescence and Cq in monoplex and multiplex rtPCRs. For gastro-intestinal pathogens there was no correlation between the intensity of fluorescence and the Cq value in the different LC480 types. For probes with the dyes FAMTM, HEXTM, Cy5 and Red610 a higher fluorescence intensity was seen in LC480 type II and III compared to LC480 type I. After lowering the probe concentration for the Cy5 dye three-fold (from 0.3µM to 0.1µM) the Cq value remains the same and the intensity of fluorescence decreases. For the LC480 type II and III the difference in fluorescence intensity was much more extreme. The concentration of the different labelled probes can be lowered at least six-fold in LC480 type II and III cyclers while maintaining a fluorescence intensity as high as achieved in the LC480 type I with undiluted probe. In conclusion, the strength of the fluorescence signal of the LightCycler® 480 type III is superior to that of LightCycler® 480 types I and II, allowing the use of lower probe concentrations for all dyes, particularly for the dyes Red610 and Cy5. This results in a two thirds reduction in PCR probe costs. Switching to these newer machines for real-time PCR can reduce dye labelled probe consumption and thus reduce costs significantly.

Assessment and Treatment of Pain during Treatment of Buruli Ulcer.

BACKGROUND: Buruli ulcer (BU) is described as a relatively painless condition; however clinical observations reveal that patients do experience pain during their treatment. Knowledge on current pain assessment and treatment in BU is necessary to develop and implement a future guideline on pain management in BU. METHODOLOGY: A mixed methods approach was used, consisting of information retrieved from medical records on prescribed pain medication from Ghana and Benin, and semi-structured interviews with health care personnel (HCP) from Ghana on pain perceptions, assessment and treatment. Medical records (n = 149) of patients treated between 2008 and 2012 were collected between November 2012 and August 2013. Interviews (n = 11) were audio-taped, transcribed verbatim and qualitatively analyzed. PRINCIPAL FINDINGS: In 113 (84%) of the 135 included records, pain medication, mostly simple analgesics, was prescribed. In 48% of the prescriptions, an indication was not documented. HCP reported that advanced BU could be painful, especially after wound care and after a skin graft. They reported not be trained in the assessment of mild pain. Pain recognition was perceived as difficult, as patients were said to suppress or to exaggerate pain, and to have different expectations regarding acceptable pain levels. HCP reported a fear of side effects of pain medication, shortage and irregularities in the supply of pain medication, and time constraints among medical doctors for pain management. CONCLUSIONS: Professionals perceived BU disease as potentially painful, and predominantly focused on severe pain. Our study suggests that pain in BU deserves attention and should be integrated in current treatment.

Incidence, direct costs and duration of hospitalization of patients hospitalized with community acquired pneumonia: A nationwide retrospective claims database analysis.

BACKGROUND: Community-acquired pneumonia (CAP) is one of the most common acute infections associated with a substantial clinical and economic burden. There have been few studies assessing incidence rate, duration of hospitalization, and costs of hospitalized CAP by age and care-setting. METHODS: A retrospective study was conducted using a nationwide Dutch database containing healthcare claims data of 16.7 million inhabitants. Patients with at least one claim with a discharge diagnosis of CAP between January 2008 and December 2011 were selected. The main outcome measures considered were the incidence rate, duration of hospitalization, and the direct costs of hospitalized CAP stratified by age and care-setting. RESULTS: In total, 195,372 CAP cases were included in the analysis resulting in an average incidence of 295 per 100,000 population per year. Sixty-three percent (123,357) of the included patients were hospitalized for 1 or more nights, of which 5.9% (n=7241) spent at least one night in the Intensive Care Unit (ICU). Overall, these 123,357 patients spent 824,985 days in the hospital of which 48,324 were spent on the ICU. The mean duration of hospitalization of ICU patients and general ward patients was 15.2 days and 6.2 days, respectively. The total costs related to all 195,372 CAP episodes during these 4 years were €711 million, with the majority (76%) occurring among those aged 50 years and older. Median (and mean) costs were dependent on age and type of care with costs ranging from €344 (€482) per episode for 0-9 year olds treated in the outpatient hospital setting up to €10,284 (€16,374) per episode for 50-64 year olds admitted to the ICU. CONCLUSION: There is a large variation in terms of incidence, disease burden and costs across different age groups and the treatment setting. Effective interventions, targeted at older adults, to prevent pneumonia could reduce the (financial) burden due to pneumonia.

Results of a cohort model analysis of the cost-effectiveness of routine immunization with 13-valent pneumococcal conjugate vaccine of those aged > or =65 years in the Netherlands.

BACKGROUND: Community-acquired pneumonia and invasive pneumococcal disease are common among older people (ie, those aged > or =65 years). A new 13-valent pneumococcal conjugate vaccine (PCV-13) is under study in the Netherlands. OBJECTIVE: The aim of this work was to model the cost-effectiveness of PCV-13 vaccination among those aged > or =65 years in the Netherlands, both in the total population and in those at increased risk for pneumonia, for various levels of efficacy (30%-90%) assumed. METHODS: Our previously published cost-effectiveness model was updated to include age-specific epidemiologic data and health-care utilization and costs for a hypothetical cohort of adults aged > or =65 years in the Netherlands. This cohort was followed twice-once as unvaccinated and once as vaccinated-over a time period of 5 years, with differences between both analyses reported. Outcome measures included costs, life-years gained (LYGs), quality-adjusted life-years, and incremental cost-effectiveness ratios (ICERs). All analyses were performed from a societal perspective. RESULTS: In the model, the ICER for vaccination remained below euro80,000/LYG, except when the vaccine was assumed to protect only against bacteremic pneumonia, with a relatively low effectiveness (40%) in combination with a high vaccine price (euro65), and indirect effects of serotype replacement would largely offset the direct effect of vaccination. For various assumptions, introduction of widespread PCV-13 vaccination (assuming a 60% efficacy against invasive and noninvasive disease because of vaccine serotypes, and a cost of euro50 per vaccinated person) was associated with the ICERs varying from cost-saving to euro50,676/LYG. CONCLUSIONS: In this model analysis of a hypothetical cohort in the Netherlands, vaccination with PCV-13 might be considered cost-effective, both for the total population and for the high-risk population aged > or =65 years, from a societal perspective, over a 5-year time horizon. The main limitation of this study was uncertainty regarding how great a proportion of pneumonia could be attributed to pneumococcal disease.

Healthcare seeking behaviour for Buruli ulcer in Benin: a model to capture therapy choice of patients and healthy community members.

Buruli ulcer is a devastating condition emerging in West Africa. We investigated why patients often report late to the hospital. Health seeking behaviour determinants and stigma were studied by in-depth interviews in patients treated in hospital (n=107), patients treated traditionally (n=46) of whom 22 had active disease, and healthy community control subjects (n=107). We developed a model capturing internal and external factors affecting decision making. With increasing severity, extent and duration of Buruli ulcer, a shift of influencing factors on health seeking behaviour appears to occur. Factors causing delay in presenting to hospital were the use of traditional medicine before presenting at the treatment centre; costs and duration of admission; disease considered not serious enough; witchcraft perceived as the cause of disease; and fear of treatment, which patients expected to be amputation. This study confirms the importance of self-treatment and traditional healing in this area. Our study was performed before antimicrobial treatment was introduced in Benin; we suggest that this model and the results from this analysis should be used as a baseline from which to measure the influence of the introduction of antimicrobial treatment on health seeking behaviour for Buruli ulcer in Benin.

Pandemic influenza and hospital resources.

Using estimates from the Centers for Disease Control and Prevention, the World Health Organization, and published models of the expected evolution of pandemic influenza, we modeled the surge capacity of healthcare facility and intensive care unit (ICU) requirements over time in northern Netherlands (approximately 1.7 million population). We compared the demands of various scenarios with estimates of maximum ICU capacity, factoring in healthcare worker absenteeism as well as reported and realistic estimates derived from semistructured telephone interviews with key management in ICUs in the study area. We show that even during the peak of the pandemic, most patients requiring ICU admission may be served, even those who have non-influenza-related conditions, provided that strong indications and decision-making rules are maintained for admission as well as for continuation (or discontinuation) of life support. Such a model should be integral to a preparedness plan for a pandemic with a new human-transmissible agent.

Assessment of functional limitations caused by Mycobacterium ulcerans infection: towards a Buruli ulcer functional limitation score.

The purpose of this study of treated Buruli ulcer patients in Ghana was to identify and assess late sequelae of treated Buruli ulcer using a goniometer, and to develop a scoring system for functional limitations. Of 78 patients, 58% (n = 45) had a reduction in the range of motion of one or more joints: 30% (n = 23) had one or more functional limitations of the leg and 21% (n = 16) of the arm; 49% (n = 38) had a functional limitation. Of all patients with affected knees, the predicted average extent of limitation was 63%. In patients with affected ankles, limitation was 78% on average; in those with elbow involvement, this was 76% on average, and in wrists involved, 65%. All of the hands involved were markedly restricted. We propose a simplified and functional scoring system that should be tested for validation in a second patient sample, and, if properly validated and adjusted, can be used in future intervention trials.