ABX464 (obefazimod) for patients with COVID-19 at risk for severe disease: miR-AGE, a randomized, double-blind placebo-controlled trial.

Background: ABX464 (obefazimod) is a small molecule that upregulates a single microRNA (miR-124) in immune cells and reduces the production of various inflammatory cytokines and chemokines. Objective: We assessed the efficacy and safety of the standard of care (SoC) plus oral obefazimod (SoC plus ABX464), 50 mg once daily, versus the SoC plus placebo for prevention of severe acute respiratory syndrome in patients with coronavirus disease 2019 (COVID-19) who are at risk for severe disease. Methods: Eligible patients for this phase 2/3 double-blind, placebo-controlled miR-AGE study were randomized (2:1) into 2 groups: SoC-ABX464 (n = 339) and SoC-placebo (n = 170). The primary end point was the percentage of patients who did not require use of high-flow oxygen or invasive or noninvasive mechanical ventilation within 28 days. The safety analyses included patients who had been randomly assigned and had received at least 1 dose of the study treatment. Results: At the time of the interim analysis, obefazimod showed no benefit over placebo when added to the SoC; the study enrollment was stopped for futility. The evaluation of the safety of obefazimod in 505 patients showed significantly more treatment-emergent adverse events in the SoC-ABX464 group than in the SoC-placebo group (P = .007). Frequently reported AEs in the SoC-ABX464 group included headache (14.6%), abdominal pain (9.6%), diarrhea (9.0%), back pain (6.9%), and nausea (6.0%). No treatment-related changes in laboratory parameters were reported. Conclusion: For patients who have severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and are at risk for severe COVID-19, obefazimod, 50 mg, provided no benefit over placebo when added to the SoC, although it did have a good safety profile (comparable to that reported in many therapeutic areas).

Infectious disease hotlines to provide advice to general practitioners: a prospective study.

BACKGROUND: Telephone hotlines in infectious diseases (ID) are part of antimicrobial stewardship programs designed to provide support and expertise in ID and to control antibiotic resistance. The aim of the study was to characterize the activity of the ID hotlines and estimate their usefulness for general practitioners (GPs). METHODS: This was a multicenter prospective observational study in different French regions. ID teams involved in antimicrobial stewardship with a hotline for GPs were asked to record their advice from April 2019 to June 2022. In these regions, all GPs were informed of the ID hotline's operating procedures. The main outcome was usage rate of the hotlines by GPs. RESULTS: Ten volunteer ID teams collected 4138 requests for advice from 2171 GPs. The proportion of GPs using the hotline varied pronouncedly by region, from 54% in the Isere department, to less than 1% in departments with the lowest usage. These differences were associated with the number of physicians in ID teams and with the age of the hotline. These results highlighted the value of working time as a means of ensuring the permanence of expertise. The main reasons for calling were: a diagnostic question (44%); choice of antibiotic (31%). The ID specialist provided advice on antibiotic therapy (43%) or a proposal for specialized consultation or hospitalization (11%). CONCLUSIONS: ID hotlines could help to strengthen cooperation between primary care and hospital medicine. However, the deployment and perpetuation of this activity require reflection concerning its institutional and financial support.

Recurrent cystitis: patients' needs, expectations and contribution to developing an information leaflet - a qualitative study.

OBJECTIVES: Recurring cystitis (RC) is a common complaint among women. It has a significant impact on patients' quality of life. The physical discomfort and psychological distress related to RC are rarely addressed and women's needs in terms of information and advice have not been sufficiently explored, particularly in France in spite of their frequent episodes of RC. This study aimed to assess women's needs and expectations in view of developing a patient information leaflet to help them understand and better cope with their condition, thus offering them more autonomy and empowering them to self-manage whenever possible. METHOD: Qualitative study using recorded semistructured interviews with patients suffering from RC. SETTING: Interviews conducted with women suffering from RC in Corsica, France. PARTICIPANTS: 26 patients interviewed between January 2018 and April 2018. RESULTS: Knowledge of the condition was heterogeneous, but most women reported a major impact on daily life, a high level of anxiety, various management strategies and wished to avoid taking antibiotics, preferring alternative approaches. Patients reported a lack of understanding and sympathy on the part of physicians and society and wished for more autonomy with delayed/back-up prescriptions, a multidisciplinary follow-up and, most of all, appropriate information. CONCLUSION: The information leaflet should improve patients' knowledge and capacity for self-care, contribute to standardise practice and limit inappropriate antibiotic use.

The Production of Antibiotics Must Be Reoriented: Repositioning Old Narrow-Spectrum Antibiotics, Developing New Microbiome-Sparing Antibiotics.

The development of broad-spectrum antibiotics to control multidrug-resistant bacteria is an outdated business model. This strategy has led to the introduction of highly effective antibiotics, but their widespread use has contributed to the emergence of even broader antibiotic resistance. In a strategy to combat antimicrobial resistance, we believe that the use of narrow-spectrum antibiotics should be promoted. This should involve both the repositioning of old antibiotics and the reorientation of research and development towards new narrow-spectrum antibiotics with a low ecological impact. These antibiotics could be prescribed for common conditions such as sore throats and cystitis, which account for the bulk of antibiotic use in humans. Narrow-spectrum, targeted, microbiome-sparing antibiotics could help control antibiotic resistance while being economically sustainable. Their development and production should be supported by governments, which would ultimately benefit from reduced health care costs.

Advocacy for Responsible Antibiotic Production and Use.

Antibiotic-resistant bacteria have become one of humankind's major challenges, as testified by the UN's Call to Action on Antimicrobial Resistance in 2021. Our knowledge of the underlying processes of antibiotic resistance is steadily improving. Beyond the inappropriate use of antimicrobials in human medicine, other causes have been identified, raising ethical issues and requiring an approach to the problem from a "One Health" perspective. Indeed, it is now clear that the two main issues regarding the subject of antibiotics are their misuse in the global food industry and their method of production, both leading to the emergence and spread of bacterial resistance.

Practical checklist for implementation of antifungal stewardship programmes.

Introduction. Antifungal stewardship programmes are needed in healthcare facilities to limit the overuse or misuse of antifungals, which are responsible for an increase in antifungal resistance.Hypothesis/Gap Statement. Core recommendations for antifungal stewardship were published by the Mycoses Study Group Education and Research Consortium, while the Centers for Disease Control and Prevention (CDC) provided a Core Elements of Hospital Antibiotic Stewardship Programs checklist. The recommendations offer global core elements for best practices in antifungal stewardship, but do not provide a framework for the implementation of antifungal stewardship programmes in healthcare facilities.Aim. In line with the recommendations, it is of the utmost importance to establish a practical checklist that may be used to implement antifungal stewardship programmes.Methodology. The practical checklist was established by a national consensus panel of experts involved in antifungal stewardship activities. A preliminary checklist was sent to all experts. The final document was approved by the panel after discussion and the resolution of any disagreements by consensus.Results. The final checklist includes the following items: leadership support; actions to support optimal antifungal use; actions to monitor antifungal prescribing, use and resistance; and an education programme.Conclusion. This antifungal stewardship checklist offers opportunities for antifungal resistance containment, given that antifungal stewardship activities promote the optimal use of antifungals.

Emergence of Lyme Disease on the French Riviera, a Retrospective Survey.

Background: The French Riviera has been declared free of Lyme Borreliosis (LB) for years. Many patients are referred for presumed LB, sometimes with atypical clinical signs and/or doubtful serology, calling the diagnosis into question. Methods: Patients were assessed for LB diagnosis, depending on clinical presentation, laboratory findings, and further examination by other medical professionals. Results: Among 255 patients, 45 (18%) were classified as confirmed LB cases [including 28 ongoing LB (10%) and 17 past LB (8%)], and for 210 (82%) a Lyme borreliosis diagnosis was ruled out. Among ongoing LB, 56% had been exposed to or bitten by ticks, exclusively in rural locations of the Alpes-Maritimes. As a result of the diagnostic procedure, 132 (52%) patients had been treated. An alternative diagnosis was established for 134 (52%) patients, covering a wide range of conditions, including mainly psychological (28%) and neurological conditions (25%) or inflammatory and systemic diseases (22%). Conclusions: Our results strongly suggest the endemicity of LB in the Alpes-Maritimes region. Confirmed LB accounted for 18% of patients while 52% were diagnosed with other conditions.

Recurring Cystitis: How Can We Do Our Best to Help Patients Help Themselves?

Recurrent cystitis (RC) has rarely been studied; its management varies and research on a holistic approach of these patients is scarce. We attempted to characterize patients suffering from RC and investigated their current care pathways, aiming to offer customized and autonomous management. In this paper, we present a descriptive, single-center, cross-sectional study of women presenting with RC at an infectious disease (ID) clinic. A questionnaire was developed and was completed by ID physicians during patient visits. From October 2016 to January 2019, 202 women were included (mean age 59 years). Sexual intercourse, stress and diarrhoea/digestive symptoms were reported as trigger factors by 35%, 34% and 19% of patients, respectively. A majority (54%) were at risk for complications and were those more exposed to inappropriate antibiotic prescriptions. In total, 56% of women suffered from more than 10 episodes/year and 48% suffered from relapses, mainly due to E. coli. Genitourinary syndrome of menopause (GSM) was a frequent complaint (74.5% of women). Fluoroquinolones and 3rd generation cephalosporins were prescribed in 38% and 30% of women, respectively. Most women wished for non-antimicrobial approaches and autonomy. Patients require comprehensive, tailored care in order to benefit from a broader range of treatment options in compliance with recommendations.

Clinical, Laboratory, and Interferon-Alpha Response Characteristics of Patients With Chilblain-like Lesions During the COVID-19 Pandemic.

Importance: Chilblain-like lesions have been reported during the coronavirus 2019 (COVID-19) pandemic. The pathophysiology of such manifestations remains largely unknown. Objective: To perform a systematic clinical, histologic, and biologic assessment in a cohort of patients with chilblain-like lesions occurring during the COVID-19 pandemic. Design, Setting, and Participants: In this prospective case series carried out with a COVID-19 multidisciplinary consultation group at the University Hospital of Nice, France, 40 consecutive patients presenting with chilblain-like lesions were included. Main Outcomes and Measures: Patients underwent a thorough general and dermatologic examination, including skin biopsies, vascular investigations, biologic analyses, interferon-alpha (IFN-α) stimulation and detection, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) and serologic analysis. Results: Overall, 40 consecutive patients with chilblain-like lesions were included. Most patients were young, with a median (range) age of 22 (12-67) years; 19 were male and 21 were female. The clinical presentation was highly reproducible with chilblain-like lesions mostly on the toes. Bullous and necrotic evolution was observed in 11 patients. Acrocyanosis or cold toes were reported in 19 (47.5%) cases. Criteria compatible with COVID-19 cases were noted in 11 (27.5%) within 6 weeks prior to the eruption. The real-time PCR (rt-PCR) testing results were negative in all cases. Overall, SARS-CoV-2 serology results were positive in 12 patients (30%). D-dimer concentration levels were elevated in 24 (60.0%) cases. Cryoglobulinemia and parvovirus B19 serologic results were negative for all tested patients. The major histologic findings were features of lymphocytic inflammation and vascular damage with thickening of venule walls and pericyte hyperplasia. A significant increase of IFN-α production after in vitro stimulation was observed in the chilblain population compared with patients with mild-severe acute COVID-19. Conclusions and Relevance: Taken together, our results suggest that chilblain-like lesions observed during the COVID-19 pandemic represent manifestations of a viral-induced type I interferonopathy. Trial Registration: ClinicalTrials.gov Identifier: NCT04344119.

High Prevalence of Acquired Thrombophilia Without Prognosis Value in Patients With Coronavirus Disease 2019.

Background Recent literature reports a strong thrombotic tendency in patients hospitalized for a coronavirus disease 2019 (COVID-19) infection. This characteristic is unusual and seems specific to COVID-19 infections, especially in their severe form. Viral infections can trigger acquired thrombophilia, which can then lead to thrombotic complications. We investigate for the presence of acquired thrombophilia, which could participate in this phenomenon, and report its prevalence. We also wonder if these thrombophilias participate in the bad prognosis of severe COVID-19 infections. Methods and Results In 89 consecutive patients hospitalized for COVID-19 infection, we found a 20% prevalence of PS (protein S) deficiency and a high (ie, 72%) prevalence of antiphospholipid antibodies: mainly lupus anticoagulant. The presence of PS deficiency or antiphospholipid antibodies was not linked with a prolonged activated partial thromboplastin time nor with D-dimer, fibrinogen, or CRP (C-reactive protein) concentrations. These coagulation abnormalities are also not linked with thrombotic clinical events occurring during hospitalization nor with mortality. Conclusions We assess a high prevalence of positive tests detecting thrombophilia in COVID-19 infections. However, in our series, these acquired thrombophilias are not correlated with the severity of the disease nor with the occurrence of thrombotic events. Albeit the strong thrombotic tendency in COVID-19 infections, the presence of frequent acquired thrombophilia may be part of the inflammation storm of COVID-19 and should not systematically modify our strategy on prophylactic anticoagulant treatment, which is already revised upwards in this pathological condition. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT04335162.

Late clinical failure associated with cytochrome b codon 268 mutation during treatment of falciparum malaria with atovaquone-proguanil in traveller returning from Congo.

BACKGROUND: The drug combination atovaquone-proguanil, is recommended for treatment of uncomplicated falciparum malaria in France. Despite high efficacy, atovaquone-proguanil treatment failures have been reported. Resistance to cycloguanil, the active metabolite of proguanil, is conferred by multiple mutations in the Plasmodium falciparum dihydrofolate reductase (pfdhfr) and resistance to atovaquone by single mutation on codon 268 of the cytochrome b gene (pfcytb). CASE PRESENTATION: A 47-year-old female, native from Congo and resident in France, was admitted in hospital for uncomplicated falciparum malaria with parasitaemia of 0.5%, after travelling in Congo (Brazzaville and Pointe Noire). She was treated with atovaquone-proguanil (250 mg/100 mg) 4 tablets daily for 3 consecutive days. On day 5 after admission she was released home. However, many weeks after this episode, without having left France, she again experienced fever and intense weakness. On day 39 after the beginning of treatment, she consulted for fever, arthralgia, myalgia, photophobia, and blurred vision. She was hospitalized for uncomplicated falciparum malaria with a parasitaemia of 0.375% and treated effectively by piperaquine-artenimol (320 mg/40 mg) 3 tablets daily for 3 consecutive days. Resistance to atovaquone-proguanil was suspected. The Y268C mutation was detected in all of the isolates tested (D39, D42, D47). The genotyping of the pfdhfr gene showed a triple mutation (N51I, C59R, S108N) involved in cycloguanil resistance. CONCLUSION: This is the first observation of a late clinical failure of atovaquone-proguanil treatment of P. falciparum uncomplicated malaria associated with pfcytb 268 mutation in a traveller returning from Congo. These data confirm that the Y268C mutation is associated with delayed recrudescence 4 weeks or more after initial treatment. Although atovaquone-proguanil treatment failures remain rare, an increased surveillance is required. It is essential to declare and publish all well-documented cases of treatment failures because it is the only way to evaluate the level of resistance to atovaquone.

Improved quality of care for patients infected or colonised with ESBL-producing Enterobacteriaceae in a French teaching hospital: impact of an interventional prospective study and development of specific tools.

The increasing incidence of ESBL-producing Enterobacteriaceae (ESBL-E) in France prompted the publication of national recommendations in 2010. Based on these, we developed a toolkit and a warning system to optimise management of ESBL-E infected or colonised patients in both community and hospital settings. The impact of this initiative on quality of care was assessed in a teaching hospital. The ESBL toolkit was developed in 2011 during multidisciplinary meetings involving a regional network of hospital, private clinic and laboratory staff in Southeastern France. It includes antibiotic treatment protocols, a check list, mail templates and a patient information sheet focusing on infection control. Upon identification of ESBL-E, the warning system involves alerting the attending physician and the infectious disease (ID) advisor, with immediate, advice-based implementation of the toolkit. The procedure and toolkit were tested in our teaching hospital. Patient management was compared before and after implementation of the toolkit over two 3-month periods (July-October 2010 and 2012). Implementation of the ESBL-E warning system and ESBL-E toolkit was tested for 87 patients in 2010 and 92 patients in 2012, resulting in improved patient management: expert advice sought and followed (16 vs 97%), information provided to the patient's general practitioner (18 vs 63%) and coding of the condition in the patient's medical file (17 vs 59%), respectively. Our multidisciplinary strategy improved quality of care for in-patients infected or colonised with ESBL-E, increasing compliance with national recommendations.

Managing ESBL-producing Enterobacteriaceae-related urinary tract infection in primary care: a tool kit for general practitioners.

In Southern France, approximately 4% of E. coli isolates from community-acquired urinary tract infections are extended spectrum beta-lactamase producers, while carriage rates for enterobacteriaceae (ESBL-E) range from 3 to 6%. General practitioners (GP) are unfamiliar with the management of patients harboring ESBL-E. Providing them with a specific tool kit should assist in their therapeutic approach and optimize antimicrobial prescription an ESBL-E tool kit was developed by a multidisciplinary team: infectious diseases (ID) specialists, microbiologists, pharmacologists, and nursing home staff. This tool kit includes treatment protocols, GP and patient information leaflets, a list of infection control measures, and contact details of ID physicians for specialized advice. A community-based (including nursing homes) prospective study was conducted in 2012 in Southeastern France to test the tool kit in the context of ESBL-E-related urinary tract infections (UTI). ESBL-E-related UTI were identified in 88 patients, 66 GPs were contacted by the microbiology laboratory, 56 stated they were offered the tool kit, 48 said they had received it, and 41 stated they had read its contents. Use of the tool kit was significantly correlated with appropriate antibiotic prescription, which concerned 36/39 tool kit users versus 13/20 non-users (p = 0.0125) and 40 GPs expressed an average satisfaction rate of 4.2 on a scale of 0 to 5. Availability of a specific tool for managing patients harboring ESBL-E, now completed with a website, can assist community-based GPs and improve antimicrobial prescription.

Fast track consultation in the infectious diseases department of a French university hospital: evaluation of the service delivered to the general practitioner.

PURPOSE: Since 2010, the Infectious Diseases (ID) department of the Nice university hospital (France) has implemented a fast track consultation (FTC): it allows General Practitioners (GP) to directly reach an ID specialist through a dedicated phone number for initial advice. Depending on the first observation, a formal consultation can be planned within 48 h. Our aim was to evaluate in a pilot study, the contribution of the FTC regarding the management of patients 28 days after the first phone contact. METHODS: This prospective current care study was conducted between November 2014 and January 2015 in our ID department. The GP indicates the most likely diagnosis, the therapeutic strategy and the patient's management he would have applied. After the formal consultation, ID specialist provides his diagnosis, therapeutic strategy and patient's management. An adjudicative committee has evaluated the benefit of the FTC after 28 days of follow-up. RESULTS: Fifty-one patients referred by 49 GP were included. ID specialists modified the diagnosis in 22 (43%) patients, antibiotic treatment in 35 (68%) and treatment plan in 30 patients (59%). FTC provided at least one service for 41/51 patients (94%): antibiotic treatment was reassessed for 11 (22%) patients, averted for 9 (18%) patients, unnecessary hospitalization was avoided for 8 (16%) of them and emergency room visit averted for 5 (10%) patients. CONCLUSIONS: FTC can provide significant improvement in the management of the patients in terms of decrease in unnecessary hospitalization, emergency room visit averted and appropriate use of antibiotics.

Direct-acting antiviral treatment in adults infected with hepatitis C virus: Reactivation of hepatitis B virus coinfection as a further challenge.

Use of direct-acting antiviral drugs (DAAs) greatly improves management of adults infected with hepatitis C virus (HCV) whether patients are treatment-naive or unsuccessfully pre-treated. Several inhibitors of viral nonstructural proteins (NS3/4A protease, NS5A and NS5B polymerase) allow a rapid HCV clearance and increase rates of sustained virological response. Both the EASL and AASLD guidelines have recently published up-to-date recommendations for their use, addressing each HCV genotype and particular situations. However, management of patients coinfected with hepatitis B virus (HBV) has been developed by these guidelines with reference to cases of HBV reactivation reported during previous anti-HCV regimens containing interferon known active against both HBV and HCV. In the setting of the interferon-free HCV therapies with DAAs only, the possibility of HBV reactivation during treatment of hepatitis C is raised due to viral interferences in HCV/HBV coinfected persons. Herein, we report a case of early HBV reactivation during DAAs-based anti-HCV treatment (ledipasvir/sofosbuvir) in a patient having a resolved HBV infection and chronically infected with HCV genotype 4 and HIV. Moreover, we review similar recent cases of HBV reactivation in patients infected with HBV and HCV genotype 1 during treatment of hepatitis C by regimen incorporating other combination of DAAs (sofosbuvir/simeprevir or daclatasvir/asunaprevir). Due to the potential risk of early HBV reactivation in HCV/HBV-coinfected patients during interferon-free DAAs-based HCV therapies, altogether these cases highlight the necessity to closely monitor HBV coinfection, regardless its stage (chronic, occult, resolved), whatever HCV genotype or class of DAAs used.

Concomitant Staphylococcus aureus bacteriuria is associated with complicated S. aureus bacteremia.

OBJECTIVES: To identify factors associated with complicated Staphylococcus aureus bacteremia (SAB) in adults. METHODS: Prospective observational multicenter study during 2 years in Nice University Hospital and during 6 months in the Hôpital Européen Georges Pompidou, Paris, including all adult inpatients with SAB assessed by an Infectious Diseases (ID) specialist. RESULTS: We included 104 SAB (79 in Nice and 25 in Paris), of which 45 were complicated, including 18 endocarditis and 23 bone and joint infections. A concomitant urine sample was performed in 65% of the cases, showing S. aureus bacteriuria 23/68 (34%) times. Blood cultures were drawn 48-96h after an appropriate antibiotic therapy had been started in 70 of the 104 cases (67%) and were positive in 28 cases (40%). CONCLUSIONS: The 3 following factors were found to be associated with complicated SAB in univariate analysis: community acquisition (56% vs 26%, P=0.002), concomitant bacteriuria (47% vs 19%, P=0.016) and persistent bacteremia (55% vs 26%, P=0.016). This last factor was associated with endocarditis, but not with other complications such as bone and joint infections.

Two cases of cellulitis in the course of African tick bite fever: a fortuitous association?

In African tick bite fever (ATBF), inoculation eschar - resulting from disruption of the cutaneous barrier - may be a risk factor for cellulitis. We report 2 cases of ATBF associated with cellulitis. A 77-year-old woman was referred for severe leg cellulitis upon returning from sub-Saharan Africa. She developed erythematous macules. Rickettsia africae was detected by PCR assay from a skin biopsy specimen, and ATBF diagnosis was confirmed. A 75-year-old man was hospitalized after his return from Zimbabwe for a maculopapular exanthema and erysipelas-like rash of the leg. The diagnosis of cellulitis associated with ATBF was confirmed by PCR and serological methods. Both patients were treated for ATBF and cellulitis by a combination of doxycycline and beta-lactam antibiotics, and both had a good recovery. Inoculation eschar may be a risk factor for cellulitis; thus, we hypothesize a non-fortuitous association between ATBF and cellulitis.

Fluoroquinolone prescriptions in a teaching hospital: a prospective audit.

The aim of this study was to identify prospectively the prevalence of unnecessary or inappropriate fluoroquinolone prescriptions in our teaching hospital and to identify the contributing factors. 55% of the 110 prescriptions evaluated were unnecessary or inappropriate. Ward and combination therapies were significantly associated with misuse.