Late dihydroartemisinin-piperaquine treatment failure of P. falciparum malaria attack related to insufficient dosing in an obese patient.

We report the case of an obese patient who experienced late failure on day28 of a well-conducted treatment with artesunate, followed by dihydroartemisinin-piperaquine (DHA-PPQ) for a severe P. falciparum malaria attack. The same P. falciparum strain was evidenced at day0 and day28. Genotypic and phenotypic resistance tests could not explain this treatment failure. The low plasma piperaquine concentration at failure may explain the poor elimination of residual parasites.

Tuberculosis treatment outcomes among precarious patients in France.

OBJECTIVES: Patients lost to follow-up and treatment failure in tuberculosis disease (TB) are major public health issues. In the absence of appropriate treatment, approximately 70 % of smear-positive patients will die within 10 years of disease progression. This study, conducted in the French region with the highest incidence, aimed to assess tuberculosis treatment outcomes and its determinants. PATIENTS AND METHODS: A prospective, multicenter cohort study (CO1TB) of adults and children treated for TB was conducted in four hospitals in the North of Paris. Treatment outcome at 1 year and associated socioeconomic and clinical factors were studied by multivariate logistic regression. RESULTS: Among 145 TB cases included from May 2018 to January 2020, patients were mainly born abroad and most lived in difficult socioeconomic conditions. During treatment, 25/145 (17 %) patients experienced adverse effects, which were not significantly associated with discontinuation of treatment (p = 0.99). At 1 year, 114 (78 %) had completed treatments, 26 (19 %) were lost to follow-up, three (2.1 %) were still being treated and two (1.4 %) had died. In the multivariate analysis, a history of TB was significantly associated with unfavorable treatment outcome (aOR = 5.3, 95 %CI (1.5;18.6) and a trend towards significance (p < 0.2) was observed among patients aged under 24 years (aOR = 2.9, 95 %-CI 0.95;8.5). CONCLUSION: In this precarious population, socioeconomic conditions were not found to be associated with unfavorable treatment outcome, whereas history of tuberculosis and young age played a role. Increased monitoring is thus required for these patients.

Treatment With a Three-Drug Regimen for Pulmonary Tuberculosis Based on Rapid Molecular Detection of Isoniazid Resistance: A Noninferiority Randomized Trial (FAST-TB).

Background: The rationale behind the use of ethambutol in the standard tuberculosis treatment is to prevent the emergence of resistance to rifampicin in case of primary resistance to isoniazid. We evaluated whether early detection of isoniazid resistance using molecular testing allows the use an ethambutol-free regimen. Methods: FAST-TB, a phase 4, French, multicenter, open-label, non-inferiority trial, compared 2 strategies: (1) polymerase chain reaction (PCR)-based detection of isoniazid and rifampicin resistance at baseline using Genotype MTBDRplus version 2.0 followed by ethambutol discontinuation if no resistance was detected (PCR arm) and (2) a standard 4-drug combination, pending phenotypic drug-susceptibility results (C arm). Adult patients with smear-positive pulmonary tuberculosis were enrolled. The primary endpoint was the proportion of patients with treatment success defined as bacteriological or clinical cure at the end of treatment. A non-inferiority margin of 10% was used. Results: Two hundred three patients were randomized, 104 in the PCR arm and 99 in the C arm: 26.6% were female, median age was 37 (interquartile range, 28-51) years, 72.4% were born in Africa, and 5.4% were infected with human immunodeficiency virus. Chest x-ray showed cavities in 64.5% of the cases. Overall, 169 patients met criteria of treatment success: 87 of 104 (83.7%) in the PCR arm and 82 of 99 (82.8%) in the C arm with a difference of +0.8% (90% confidence interval, -7.9 to 9.6), meeting the noninferiority criteria in the intention-to-treat population (P = .02). Conclusions: In a setting with low prevalence of primary isoniazid resistance, a 3-drug combination with isoniazid, rifampicin, and pyrazinamide, based on rapid detection of isoniazid resistance using molecular testing, was noninferior to starting the recommended 4-drug regimen.

Impact of admission to high-risk isolation room on patients' and healthcare workers' perceptions: A qualitative cross-assessment Approach.

INTRODUCTION: High-risk isolation units (HRIU) house patients at high risk of transmitting infectious agents, notably patients with suspected viral hemorrhagic fever or smear-positive tuberculosis. Admission to HRIU can alter the quality of care and impact patients' and healthcare workers' (HCWs) anxiety and dissatisfaction. METHODS: The Infectious Diseases Department of the Bichat Claude Bernard Hospital in Paris houses a 7-bed HRIU. We conducted a qualitative study based on individual semi-structured interviews to assess the perceptions of both patients and HCWs. RESULTS: We interviewed 14 patients and 16 HCWs routinely working in the HRIU. All 8 patients subject to isolation precautions and 1 of the 6 patients not subject to isolation precautions expressed a negative representation of the room with a feeling of confinement, stigma, and mistrust. They also reported a lack of information from healthcare staff and a need for entertainment, activities, and visits from relatives. HCWs did not like working in this unit because of the anteroom's technical constraints and a loss of frequent contact with patients. They also expressed a feeling of insecurity working in these units despite the use of interphones. CONCLUSION: Placing patients in an HRIU not only affects their emotions, but also impacts HCWs both emotionally and organizationally. Alert systems, intercoms, and videoconferencing systems can improve safety and security as well as exchanges with patients and their relatives. Psychological support is needed for patients who are subject to isolation precautions and for their attending HCWs.

Clinical trial protocols of repurposed prophylaxis for COVID-19: A review.

Efficient therapeutic strategies are needed to counter the COVID-19 pandemic, caused by the SARS-CoV-2 virus. In a context where specific vaccines are not yet available, the containment of the pandemic would be facilitated with efficient prophylaxis. We screened several clinical trials repositories and platforms in search of the prophylactic strategies being investigated against COVID-19 in July 2020. Up to July 5, 2020, only one clinical trial result was published, although we found 112 clinical trial protocols targeting medical workers (n=70, 63%), patients relatives (n=20, 18%) or individuals at risk of severe COVID-19 (n=14, 13%). (Hydroxy)chloroquine was the most frequently evaluated treatment (n=69, 62%), before BCG vaccine (n=12, 11%), this followed by numerous antivirals and immune enhancers. Ninety-eight (88%) clinical trials were randomized with a median of planned inclusions of 530 (IQR 258-1299). Both pre- and post-exposure prophylaxes are investigated.

Review of trials currently testing treatment and prevention of COVID-19.

BACKGROUND: As COVID-19 cases continue to rise globally, evidence from large randomized controlled trials is still lacking. Currently, numerous trials testing potential treatment and preventative options are being undertaken all over the world. OBJECTIVES: We summarized all registered clinical trials examining treatment and prevention options for COVID-19. Additionally, we evaluated the quality of the retrieved studies. DATA SOURCES: Clinicaltrials.gov, the Chinese Clinical Trial Registry and the European Union Clinical Trials Register were systematically searched. STUDY ELIGIBILITY CRITERIA: Registered clinical trials examining treatment and/or prevention options for COVID-19 were included. No language, country or study design restrictions were applied. We excluded withdrawn or cancelled studies and trials not reporting therapeutic or preventative strategies for COVID-19. PARTICIPANTS AND INTERVENTIONS: No restrictions in terms of participants' age and medical background or type of intervention were enforced. METHODS: The registries were searched using the term 'coronavirus' or 'COVID-19' from their inception until 26 March 2020. Additional manual search of the registries was also performed. Eligible studies were summarized and tabulated. Interventional trials were methodologically analysed, excluding expanded access studies and trials testing traditional Chinese medicine. RESULTS: In total, 309 trials evaluating therapeutic management options, 23 studies assessing preventive strategies and three studies examining both were retrieved. Finally, 214 studies were methodologically reviewed. Interventional treatment studies were mostly randomized (n = 150/198, 76%) and open label (n = 73/198, 37%) with a median number of planned inclusions of 90 (interquartile range 40-200). Major categories of interventions that are currently being investigated are discussed. CONCLUSIONS: Numerous clinical trials have been registered since the onset of the COVID-19 pandemic. Summarized data on these trials will assist physicians and researchers to promote patient care and guide future research efforts for COVID-19 pandemic containment.

Community-acquired pneumonia in the emergency department: an algorithm to facilitate diagnosis and guide chest CT scan indication.

OBJECTIVE: The aim was to create and validate a community-acquired pneumonia (CAP) diagnostic algorithm to facilitate diagnosis and guide chest computed tomography (CT) scan indication in patients with CAP suspicion in Emergency Departments (ED). METHODS: We performed an analysis of CAP suspected patients enrolled in the ESCAPED study who had undergone chest CT scan and detection of respiratory pathogens through nasopharyngeal PCRs. An adjudication committee assigned the final CAP probability (reference standard). Variables associated with confirmed CAP were used to create weighted CAP diagnostic scores. We estimated the score values for which CT scans helped correctly identify CAP, therefore creating a CAP diagnosis algorithm. Algorithms were externally validated in an independent cohort of 200 patients consecutively admitted in a Swiss hospital for CAP suspicion. RESULTS: Among the 319 patients included, 51% (163/319) were classified as confirmed CAP and 49% (156/319) as excluded CAP. Cough (weight = 1), chest pain (1), fever (1), positive PCR (except for rhinovirus) (1), C-reactive protein ≥50 mg/L (2) and chest X-ray parenchymal infiltrate (2) were associated with CAP. Patients with a score below 3 had a low probability of CAP (17%, 14/84), whereas those above 5 had a high probability (88%, 51/58). The algorithm (score calculation + CT scan in patients with score between 3 and 5) showed sensitivity 73% (95% CI 66-80), specificity 89% (95% CI 83-94), positive predictive value (PPV) 88% (95% CI 81-93), negative predictive value (NPV) 76% (95% CI 69-82) and area under the curve (AUC) 0.81 (95% CI 0.77-0.85). The algorithm displayed similar performance in the validation cohort (sensitivity 88% (95% CI 81-92), specificity 72% (95% CI 60-81), PPV 86% (95% CI 79-91), NPV 75% (95% CI 63-84) and AUC 0.80 (95% CI 0.73-0.87). CONCLUSION: Our CAP diagnostic algorithm may help reduce CAP misdiagnosis and optimize the use of chest CT scan.

Management of oral antiretroviral administration in patients with swallowing disorders or with an enteral feeding tube.

HIV infection has evolved into a chronic disease with comorbidities since the combination antiretroviral therapy era. Complications still occur and patients may need to be admitted to an intensive care unit. Acute respiratory failure is the first cause of these admissions, questioning the administration of solid oral dosage formulations. This issue is also observed in geriatric units where the prevalence of dysphagia is high and underestimated. The problem of antiretroviral administration is critical: altered solid oral dosage formulations and/or administration via enteral feeding tubes are sometimes the only option. The aim is to help manage antiretroviral treatment in unconscious or intubated patients and those with swallowing disorders who are hospitalized in intensive care units or geriatric units. This review provides information on the main antiretroviral regimens and on practical and legal aspects of manipulating solid oral dosage formulations and administration via enteral feeding tubes. Alternatives to the solid formulation are available for most of the 27 oral antiretrovirals available, or manufacturers provide recommendations for patients who are unable to swallow. Manipulation of solid oral dosage formulations such as crushing tablets or opening capsules and administration via feeding tubes are frequently reported but should be the last option for safety and liability issues. Before any off-label administration of a drug, physicians should consider alternatives to the solid oral dosage formulation and check whether the drug can be altered. Therapeutic monitoring is important in this particular setting as the pharmacokinetic profile of drugs is difficult to predict.

Prescribers' experience and opinions on antimicrobial stewardship programmes in hospitals: a French nationwide survey.

OBJECTIVES: To assess prescribers' experiences and opinions regarding antimicrobial stewardship programme (ASP) activities. METHODS: A cross-sectional paper-based survey was conducted among prescribers in 27 out of 35 randomly selected large hospitals in France. RESULTS: All 27 investigated hospitals (20 non-university public, 4 university-affiliated and 3 private hospitals) had an ASP and an appointed antibiotic advisor (AA), with a median of 0.9 full-time equivalents per 1000 acute-care beds (IQR 0-1.4). Of the 1963 distributed questionnaires, 920 were completed (46.9%). Respondents were mainly attending physicians (658/918, 71.7%) and medical specialists (532/868, 61.3%). Prescribers identified two main ASP objectives: to limit the spread of resistance (710/913, 77.8%) and to improve patient care and prognosis (695/913, 76.1%). The presence of an AA constituted a core element of ASP (96.2% agreement between answers of ASP leader and respondents). Respondents acknowledged an AA's usefulness especially on therapeutic issues, i.e. choosing appropriate antibiotic (agreement 84.7%) or adapting treatment (89.6%), but less so on diagnostic issues (31.4%). Very few respondents reported unsolicited counselling and post-prescription controls. Three-quarters of prescribers identified local guidelines (692/918, 75.4%). Prescribers did not approve of measures counteracting their autonomy, i.e. automatic stop orders (agreement 23.4%) or pre-approval by AAs (28.8%). They agreed more with educational interventions (73.0%) and clinical staff meetings (70.0%). CONCLUSIONS: Prescribers perceived ASP mainly through its 'on-demand' counselling activities. They preferred measures that did not challenge their clinical autonomy. High levels of antibiotic consumption in French hospitals bring into question the effectiveness of such an approach. However, limited ASP staffing and resources may preclude extended activities.

Long-term plasma pharmacokinetics of bedaquiline for multidrug- and extensively drug-resistant tuberculosis.

SETTING: Bedaquiline (BDQ) has been approved for the treatment of multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB). For many patients treatment is prolonged beyond the recommended 6 months. The long-term pharmacokinetics of BDQ have yet to be elucidated. OBJECTIVE: To evaluate plasma concentrations of BDQ during treatment and its elimination after treatment discontinuation. DESIGN: This was a retrospective study conducted in two units in France that provide treatment for MDR/XDR-TB. Sociodemographic, clinical, biological and therapeutic parameters were collected from patients currently or formerly treated with BDQ. Plasma concentrations of BDQ and its active M2 (N-desmethyl) metabolite were determined using ultra-performance liquid chromatography with tandem mass spectrometry. RESULTS: Thirteen patients were recruited (35 samples): 10 (31 samples) during BDQ treatment and 3 (4 samples) after BDQ discontinuation. The median duration of treatment with BDQ was 11 months (interquartile range [IQR] 8-14). During treatment, the median plasma BDQ concentrations and M2 were respectively 1264 ng/ml (IQR 910-2244) and 252 ng/ml (IQR 134-290). In one patient, BDQ was detected in the plasma 200 days after treatment discontinuation (528 ng/ml). CONCLUSION: BDQ and M2 plasma concentrations were consistent with good drug efficacy/safety profiles, suggesting good treatment adherence with no relevant drug interactions. The long-term plasma detectability of BDQ after treatment discontinuation may raise the spectre of the emergence of resistance.

Contribution of brain imaging to the diagnosis of intracranial tuberculoma and other brain lesions in patients presenting with miliary tuberculosis.

BACKGROUND: Miliary tuberculosis (miliary TB) is characterized by a hematogenous spread of Mycobacterium tuberculosis. Cerebral lesions associated with miliary TB have been reported with diverse frequencies. METHODS: We retrospectively analyzed brain imaging in 34 patients presenting with proven miliary TB hospitalized in our teaching hospital between 2008 and 2014. RESULTS: Neurological symptoms were present at admission in 15 patients, emerged during treatment in six, and were never reported in 13. Twenty-one of 34 patients had cerebral involvement, of which five patients did not present with any neurological symptoms. The most common brain lesions on MRI were tuberculomas. Cerebrospinal fluid (CSF) analysis showed elevated cell count in eight patients who all had abnormal MRI results. Nine patients with normal CSF had abnormal MRI results. CSF cultures were positive in only eight patients. Paradoxical clinical worsening during TB and corticosteroid treatment was observed in six patients. CONCLUSION: Among patients presenting with miliary TB who underwent brain imaging, more than 60% demonstrated cerebral involvement. Abnormal imaging could occur without any clinical nor CSF impairment. Systematically performing brain imaging in miliary TB patients could therefore be informative.

Plague: Bridging gaps towards better disease control.

After centuries of epidemics and more than a hundred years since the identification of the causative bacterium, very little is known about the plague dynamics in animal reservoirs, vectors and the changing vulnerabilities for humans. The recent plague epidemic in Madagascar in 2017 highlights these gaps existing within the knowledge of the disease dynamics, the factors influencing it, the performance of diagnostic tests and the best recommended treatment. As the eradication of plague will not be possible due to the widespread existence of the bacterium in wildlife, a One Health approach, drawing on animal, human and environmental health disciplines is needed to better control this poverty-related disease. This article focused on the various aspects of the disease for which more tools and better understanding are required to better control the disease in endemic countries.

[The plague: An overview and hot topics]. / La peste : mise au point et actualités.

Plague is a bacterial zoonosis caused by Yersinia pestis, usually found in fleas and small rodents that constitute the reservoir of the disease. It is transmitted to humans by flea bite, contact with rodents or inhalation of infected droplets. There are three clinical forms: bubonic plague, pulmonary plague and septicemic plague. The usual presentation is a flu-like syndrome possibly accompanied by an inflammatory lymphadenopathy which appears after 1 to 7days of incubation. Bubonic plague has a case fatality rate of about 50% while other forms of plague are almost always fatal without treatment. Diagnosis can be confirmed by usual bacteriological techniques (Gram examination, culture) but also by serological examination, use of rapid diagnostic tests or PCR. Although aminoglycosides are traditionally regarded as the most effective treatment, fluoroquinolones or cyclins are currently recommended in France. Plague is one of the re-emerging diseases according to the WHO and Madagascar suffered in 2017 the most important plague epidemic of the 21st century with more than 2000 cases and 200 deaths. Peru and the Democratic Republic of Congo are also considered endemic areas. Public health measures and a relentless fight against poverty are the cornerstone of the control of the disease. Vaccine improvement in endemic areas may also play an important role.

Effectiveness and cost-effectiveness of interventions targeting harm reduction and chronic hepatitis C cascade of care in people who inject drugs: The case of France.

Direct-acting antivirals (DAAs) represent an opportunity to improve hepatitis C virus (HCV) care cascade. This combined with improved harm reduction interventions may lead to HCV elimination especially in people who inject drugs (PWID). We assessed the effectiveness/cost-effectiveness of improvements in harm reduction and chronic hepatitis C (CHC) care cascade in PWID in France. We used a dynamic model of HCV transmission and CHC natural history and evaluated the following: improved needle/syringe programmes-opioid substitution therapies, faster diagnosis/linkage to care, earlier treatment initiation, alone and in combination among active PWID (mean age = 36). Outcomes were as follows: life expectancy in discounted quality-adjusted life years (QALYs); direct lifetime discounted costs; incremental cost-effectiveness ratio (ICER); number of infections/reinfections. Under the current practice, life expectancy was 15.846 QALYs, for a mean lifetime cost of €20 762. Treatment initiation at F0 fibrosis stage alone was less effective and more costly than faster diagnosis/linkage to care combined with treatment initiation at F0, which increased life expectancy to 16.694 QALYs, decreased new infections by 37%, with a ICER = €5300/QALY. Combining these interventions with harm reduction improvements was the most effective scenario (life expectancy = 16.701 QALYs, 41% decrease in new infections) but was not cost-effective (ICER = €105 600/QALY); it became cost-effective with higher initial HCV incidence rates and lower harm reduction coverage than in our base-case scenario. This study illustrated the high effectiveness, and cost-effectiveness, of a faster diagnosis/linkage to care together with treatment from F0 with DAAs. This "Test and treat" strategy should play a central role both in improving the life expectancies of HCV-infected patients, and in reducing HCV transmission.

Hepatitis C: The beginning of the end-key elements for successful European and national strategies to eliminate HCV in Europe.

Hepatitis C virus (HCV) infection is a major public health problem in the European Union (EU). An estimated 5.6 million Europeans are chronically infected with a wide range of variation in prevalence across European Union countries. Although HCV continues to spread as a largely "silent pandemic," its elimination is made possible through the availability of the new antiviral drugs and the implementation of prevention practices. On 17 February 2016, the Hepatitis B & C Public Policy Association held the first EU HCV Policy Summit in Brussels. This summit was an historic event as it was the first high-level conference focusing on the elimination of HCV at the European Union level. The meeting brought together the main stakeholders in the field of HCV: clinicians, patient advocacy groups, representatives of key institutions and regional bodies from across European Union; it served as a platform for one of the most significant disease elimination campaigns in Europe and culminated in the presentation of the HCV Elimination Manifesto, calling for the elimination of HCV in Europe by 2030. The launch of the Elimination Manifesto provides a starting point for action in order to make HCV and its elimination in Europe an explicit public health priority, to ensure that patients, civil society groups and other relevant stakeholders will be directly involved in developing and implementing HCV elimination strategies, to pay particular attention to the links between hepatitis C and social marginalization and to introduce a European Hepatitis Awareness Week.

Cost-effectiveness of vaccination against cytomegalovirus (CMV) in adolescent girls to prevent infections in pregnant women living in France.

BACKGROUND: CMV infections are the most frequent congenital infections worldwide. AIM: Assess the cost-effectiveness of vaccination strategies of adolescent girls vs. current practice (hygiene counseling) to prevent CMV seroconversions during pregnancy in France. METHOD: A Markov decision-tree model simulated overtime the trajectory of a single fictive cohort of 390,000 adolescent women aged 14 years old, living in France. Impact of vaccination was explored until the end of their reproductive live 40 years later. STRATEGIES COMPARED: "S1: No vaccination" (current practice); "S2: Routine vaccination"; "S3: Screening and vaccination of the seronegative". MODEL PARAMETERS: Seroconversion rate without vaccination (0.035%/pregnant woman-week); fetal transmission risk (41%). Vaccine vs. no vaccination: a 50% decrease in maternal seroconversions. OUTCOMES: Quality-Adjusted Life-Years (QALYs) of the cohort-born babies; discounted costs; Incremental Cost-Effectiveness Ratio (ICER). RESULTS: S2 was the most effective strategy (with 35,000 QALYs gained) and the most expensive (€211,533,000); S1 was the least effective and least costly (€75,423,000). ICERs of strategy S3 vs. S1, and S2 vs. S3 were 6,000€/QALY gained (95% uncertainty range [2700-13,300]) and 16,000€/QALY [negative ICER (S3 dominated by S2) - 94,000] gained, respectively; highly cost-effective because ICER < 1∗France's GPD/capita = €30,000. SENSITIVITY ANALYSIS: If the seroprevalence was >62% (vs. 20% in the base case), S3 would become the most efficient strategy. CONCLUSION: In France, systematic vaccination of adolescent girls was the most efficient strategy to prevent maternal seroconversions. If the population was less than 62% immune, systematic screening and vaccination of susceptibles would become the most cost-effective approach.