Infection prevention for immunocompromised patients: A cross-translational multicentric survey of current organization in France.

OBJECTIVES: To evaluate current organization of infection prevention for immunocompromised patients (ICP) at a countrywide level. METHODS: Nationwide cross-sectional multicenter study based on an online survey disseminated in 2022 to physicians invested with preventive healthcare missions. RESULTS: A total of 341 physicians (96% graduates, 32% infectious disease specialists), participated in the survey, with a median age of 40 [35-51] years. On-site access to infection prevention consultations for ICP was reported by 30%, dedicated pre-travel consultations for ICPs by 29%, consultations for infection prevention in solid organ transplant candidates by 16% and return-to-work consultations for ICPs by 6%. Most participants (73%) were aware of nationwide vaccination guidelines for ICP, while 50% felt comfortable using them. Tools for infection prevention advice and ICP vaccination had been developed by 10%, while 89% would have appreciated access to tools developed by others. CONCLUSIONS: Infection prevention for ICPs remains neglected. Guidelines covering all fields of prevention for ICPs would be more than welcome.

Effect of achieving bone sterilisation on bone architecture and bone marrow, in an experimental rabbit model of osteomyelitis caused by carbapenemase-producing Enterobacterales.

OBJECTIVES: Natural history and treatment of bone infections caused by carbapenemase-producing Enterobacterales (CPE) are poorly defined. We evaluated the effect of treatment on the progression of subacute osteomyelitis in a rabbit model. METHODS: Two isolates were used: a KPC-producing Klebsiella pneumoniae and an Escherichia coli harbouring blaOXA-48 and blaCTX-M15 inserts, both susceptible to gentamicin, colistin, fosfomycin, and ceftazidime-avibactam. Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 colony-forming units/mL. Antibiotics were started 14 d later, for 7 d, in 6 groups of 12 rabbits. Three days after treatment completion (D24), rabbits were euthanised and bones were cultured. Bone marrow and bone architecture macroscopic changes were evaluated through analysis of pictures by investigators unaware of the rabbit treatment group and microbiological outcome, using scales ranging from 0 (normal) to 3 (severe lesions) depending on modifications. RESULTS: Bone marrow modifications induced by local infection were similar between prematurely deceased animals and non-sterilised animals (P = 0.14) but differed significantly from animals that achieved bone sterilisation after treatment (P = 0.04). Conversely, when comparing bone deformity, rabbits who died early (n = 13) had similar bone architecture as those achieving bone sterilisation (P = 0.12), as opposed to those not sterilised after treatment (P = 0.04). After a multivariate logistic regression, bone marrow scale ≤2 was associated with bone sterilisation (P < 0.001), and bone architecture scale ≤2 was associated with bone sterilisation (adjusted odds ratio = 2.7; 95% confidence interval 1.14-6.37) and KPC infection (adjusted odds ratio = 5.1; 95% confidence interval 2.17-12.13). CONCLUSION: Effective antibacterial treatment reduces bone architecture distortion and bone marrow changes. These variables may be used as proxy for bone sterilisation.

Prospective cohort of COVID-19 patients requiring hospital admission in Douala, Cameroon.

OBJECTIVES: To report characteristics and outcome of COVID-19 patients who required hospital admission in sub-Saharan Africa clinics with no access to invasive mechanical ventilation. METHODS: Between April and June 2021, documented COVID-19 patients with SaO2 < 95% who were admitted in two clinics in Douala (Cameroon) were invited to participate. Data were prospectively collected using a standardized questionnaire. RESULTS: We included 67 patients: 39 males (58%), median age 62 years [50-70]. Comorbidities included hypertension (n = 38, 57%), obesity (n = 26, 38%), and diabetes (n = 16, 24%). No patient reported COVID-19 vaccination. On admission, 35 patients (52%) required O2 > 6 L/min. CT scan demonstrated extended lesions (>50%) in 50/61 cases (82%). Most patients received dexamethasone (n = 64, 96%), heparin (n = 64, 96%), chloroquine/azithromycin (n = 59, 88%), and broad-spectrum antibiotics (n = 59, 88%). Sixteen patients died (24%), after a median of 11.5 days [7.5-15.5] post-admission. CONCLUSIONS: Despite the lack of invasive mechanical ventilation, 76% of COVID-19 patients survived.

A pilot project of expert nurses for the follow-up of complex intravenous antimicrobial treatment.

OBJECTIVE: To report a pilot project of expert nurses for outpatient parenteral antimicrobial treatment (OPAT) follow-up. METHODS: Three nurses with specific training on antibiotics started a state-funded programme including: i) consultations for OPAT follow-up; ii) hotline for satellite hospitals; iii) peer training. Patients' data were prospectively collected. A representative sample of patients and physicians was interviewed to learn about their opinion on the project. RESULTS: From December 2020 to December 2021, 118 patients (median age 66.5 years [52-75], male-to-female ratio 2.5) were enrolled, for a total of 621 consultations. Patients were mostly on OPAT for bone and joint infections (n = 76, 64 %) and cardiovascular infections (n = 16, 14 %), for a median duration of 29 days [22-57]. Eleven patients (9 %) required unplanned hospital admissions, and three experienced treatment failure. Most patients (21/22) and physicians in charge (10/10) reported a high level of satisfaction. CONCLUSIONS: Nurses may be important actors for OPAT follow-up.

SARS-CoV-2 seroprevalence and antibodies persistence among health care workers after the first COVID-19 wave in nine hospitals in Western France.

OBJECTIVES: To estimate the SARS-CoV-2 IgG seroprevalence rate in healthcare workers (HCWs) from Western France after the first 2020 wave, its determinants and the kinetics of total SARS-CoV-2 antibodies. PATIENTS AND METHODS: Overall, 9,453 HCWs responded to a self-questionnaire and underwent a lateral flow immunoassay to assess SARS-CoV-2 IgG presence. For 72 HCWs who tested positive, total anti-nucleocapsid antibodies were assessed at day 0, 30, and 90. RESULTS: SARS-CoV-2 IgG seroprevalence rate was 1.06 % [0.86 %-1.27 %]. Factors associated with IgG presence were gender, performing upper respiratory tract samples, contact with HCWs or household members diagnosed with COVID-19. Total antibodies decreased between day 0 and day 90, with anosmia or ageusia, and were higher in HCWs older than 50 years. CONCLUSION: We reported a low prevalence rate of IgG and identified several risk factors associated with its presence and persistence of total antibodies. Additional studies are needed to confirm these observations.

The intravenous vancomycin prescription practices of French infectious disease specialists: A cross-sectional observational study.

INTRODUCTION: Vancomycin prescription modalities remain non-consensual. We examined and evaluated the vancomycin prescription habits of infectious disease specialists in France. METHODS: Through an anonymized online questionnaire sent to members of the French Infectious Diseases Society, detailed information on vancomycin prescription modalities was collected. RESULTS: Out of the 712 physicians contacted, 179 (25%) completed the questionnaire; 174 (97%) of them routinely prescribed intravenous vancomycin: 95 (55%) by continuous infusion only, 12 (7%) by intermittent infusion, while 67 (38%) used the two modalities. Among continuous administration users, 157 (97%) applied a loading dose of 15 mg/kg or less (n = 80, 49%), 20-25 mg/kg (n = 33, 20%), or 30 mg/kg or more (n = 45, 28%); 143 (88%) used a maintenance dosage of 30 mg/kg/day and 157 (97%) carried out drug monitoring. CONCLUSION: In France, infectious disease specialists favor continuous administration of vancomycin using a loading dose, with systematic monitoring of vancomycin serum concentrations.

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.

Current clinical practice in antibiotic treatment of Staphylococcus aureus bacteraemia: results from a survey in five European countries.

OBJECTIVES: To determine clinical practice variation and identify knowledge gaps in antibiotic treatment of Staphylococcus aureus bacteraemia (SAB). METHODS: A web-based survey with questions addressing antibiotic treatment of SAB was distributed through the ESGAP network among infectious disease specialists, clinical microbiologists and internists in Croatia, France, Greece, the Netherlands and the UK between July 2021 and November 2021. RESULTS: A total number of 1687 respondents opened the survey link, of whom 677 (40%) answered at least one question. For MSSA and MRSA bacteraemia, 98% and 94% preferred initial monotherapy, respectively. In patients with SAB and non-removable infected prosthetic material, between 80% and 90% would use rifampicin as part of the treatment. For bone and joint infections, 65%-77% of respondents would consider oral step-down therapy, but for endovascular infections only 12%-32% would. Respondents recommended widely varying treatment durations for SAB with different foci of infection. Overall, 48% stated they used 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG-PET/CT) to guide antibiotic treatment duration. Persistent bacteraemia was the only risk factor for complicated SAB that would prompt a majority to extend treatment from 2 to 4-6 weeks. CONCLUSIONS: This survey in five European countries shows considerable clinical practice variation between and within countries in the antibiotic management of SAB, in particular regarding oral step-down therapy, choice of oral antibiotic agents, treatment duration and use of 18F-FDG-PET/CT. Physicians use varying criteria for treatment decisions, as evidence from clinical trials is often lacking. These areas of practice variation could be used to prioritize future studies for further improvement of SAB care.

Should anti-malarial chemoprophylaxis be reimbursed in France? A cost-effectiveness analysis of different reimbursement strategies.

OBJECTIVES: France is the Western country with the highest number of imported malaria cases. This study evaluates the cost and effectiveness of the potential reimbursement of drugs for malaria chemoprophylaxis (CP). It targets travelers with medical insurance in France who are heading to endemic regions in sub-Saharan Africa (SSA), the cost of which is currently fully borne by these travelers. PATIENTS AND METHODS: A decision-tree model was built to assess the cost-effectiveness of three CP reimbursement strategies compared to the current strategy of non-reimbursement from the French National Health Insurance (NHI) perspective. The three strategies targeted either (1) all travelers to SSA (2) travelers of African origin traveling to visit friends and relatives (VFR) and (3) all travelers to West and Central Africa (WCA). Base-case analysis is complemented with deterministic and probabilistic sensitivity analyses (PSA). RESULTS: Reimbursement of CP would lead to a decrease in malaria cases. The base-case incremental cost per additional malaria case prevented (ICER) for strategies 1, 2 and 3 is estimated at € 34,623, € 15,136 and € 23,640, respectively. PSA confirms our results, showing that reimbursement has a very high probability of being cost-effective, especially under strategies 2 and 3. CONCLUSION: Reimbursement of malaria CP by the French NHI could be cost-effective and have a positive effect on malaria prevention in France. Restricting reimbursement to VFRs allows lower ICERs but does not seem feasible in the current French context, while targeting travelers to WCA, who are at higher risk for malaria, could be a reasonably efficient policy.

Determinants of the willingness to get the third COVID-19 vaccine dose among health care workers.

OBJECTIVE: To characterize the willingness to get the third COVID-19 vaccine dose among health care workers (HCWs). METHODS: A cross-sectional study using a self-administered questionnaire proposed on a voluntary basis to all HCWs of a French teaching hospital in October and November 2021. RESULTS: Of 1,655 HCWs who completed the questionnaire, 64.2% were willing to receive the third dose, 20.1% were hesitant, and 15.7% were reluctant. On multivariate analysis, older age (P<0.0001), medical and executive staff, willingness to receive the flu vaccine (OR=5.72 [4.24-7.64]), previous vaccine scheme with ChAdOx1 nCoV-19 (AstraZeneca) (OR=2.13 [1.58-2.87]), and history of COVID-19 with a complete COVID-19 vaccine scheme (OR=2.77 [1.04-7.41]) were independent predictors of HCWs' willingness to get the third dose. CONCLUSIONS: One third of HCWs were hesitant or opposed to a third COVID-19 vaccine dose. Better knowledge of determinants of the willingness to get this third dose may improve communication and vaccine strategy.

Changing profile of encephalitis: Results of a 4-year study in France.

CONTEXT: In 2007, we performed a nationwide prospective study to assess the epidemiology of encephalitis in France. We aimed to evaluate epidemiological changes 10years later. METHODS: We performed a 4-year prospective cohort study in France (ENCEIF) from 2016 to 2019. Medical history, comorbidities, as well as clinical, biological, imaging, and demographic data were collected. For the comparison analysis, we selected similar data from adult patients enrolled in the 2007 study. We used Stata statistical software, version 15 (Stata Corp). Indicative variable distributions were compared using Pearson's Chi2 test, and means were compared using Student's t-test for continuous variables. RESULTS: We analyzed 494 cases from 62 hospitals. A causative agent was identified in 65.7% of cases. Viruses represented 81.8% of causative agents, Herpesviridae being the most frequent (63.6%). Arboviruses accounted for 10.8%. Bacteria and parasites were responsible for respectively 14.8% and 1.2% of documented cases. Zoonotic infections represented 21% of cases. When comparing ENCEIF with the 2007 cohort (222 adults patients from 59 hospitals), a higher proportion of etiologies were obtained in 2016-2019 (66% vs. 53%). Between 2007 and 2016-2019, the proportions of Herpes simplex virus and Listeria encephalitis cases remained similar, but the proportion of tuberculosis cases decreased (P=0.0001), while tick-borne encephalitis virus (P=0.01) and VZV cases (P=0.03) increased. In the 2016-2019 study, 32 causative agents were identified, whereas only 17 were identified in the 2007 study. CONCLUSION: Our results emphasize the need to regularly perform such studies to monitor the evolution of infectious encephalitis and to adapt guidelines.

Impact of extracorporeal membrane oxygenation (ECMO) support on piperacillin exposure in septic patients: a case-control study.

OBJECTIVES: To describe the impact of extracorporeal membrane oxygenation (ECMO) devices on piperacillin exposure in ICU patients. METHODS: This observational, prospective, multicentre, case-control study was performed in the ICUs of two tertiary care hospitals in France. ECMO patients with sepsis treated with piperacillin/tazobactam were enrolled. Control patients were matched according to SOFA score and creatinine clearance. The pharmacokinetics of piperacillin were described based on a population pharmacokinetic model, calculating the proportion of time the piperacillin plasma concentration was above 64 mg/L (i.e. 4× MIC breakpoint for Pseudomonas aeruginosa). RESULTS: Forty-two patients were included. Median (IQR) age was 60 years (49-66), SOFA score was 11 (9-14) and creatinine clearance was 47 mL/min (5-95). There was no significant difference in the proportion of time piperacillin concentrations were ≥64 mg/L in patients treated with ECMO and controls during the first administration (P = 0.184) or at steady state (P = 0.309). Following the first administration, 36/42 (86%) patients had trough piperacillin concentrations <64 mg/L. Trough concentrations at steady state were similar in patients with ECMO and controls (P = 0.535). Creatinine clearance ≥40 mL/min was independently associated with piperacillin trough concentration <64 mg/L at steady state [OR = 4.3 (95% CI 1.1-17.7), P = 0.043], while ECMO support was not [OR = 0.5 (95% CI 0.1-2.1), P = 0.378]. CONCLUSIONS: ECMO support has no impact on piperacillin exposure. ICU patients with sepsis are frequently underexposed to piperacillin, which suggests that therapeutic drug monitoring should be strongly recommended for severe infections.

Impact of time to antibiotic therapy on clinical outcome in patients with bacterial infections in the emergency department: implications for antimicrobial stewardship.

BACKGROUND: Rapid initiation of antibiotic treatment is considered crucial in patients with severe infections such as septic shock and bacterial meningitis, but may not be as important for other infectious syndromes. A better understanding of which patients can tolerate a delay in start of therapy is important for antibiotic stewardship purposes. OBJECTIVES: To explore the existing evidence on the impact of time to antibiotics on clinical outcomes in patients presenting to the emergency department (ED) with bacterial infections of different severity of illness and source of infection. SOURCES: A literature search was performed in the PubMed/MEDLINE database using combined search terms for various infectious syndromes (sepsis/septic shock, bacterial meningitis, lower respiratory tract infections, urinary tract infections, intra-abdominal infections and skin and soft tissue infections), time to antibiotic treatment, and clinical outcome. CONTENT: The literature search generated 8828 hits. After screening titles and abstracts and assessing potentially relevant full-text papers, 60 original articles (four randomized controlled trials, 43 observational studies) were included. Most articles addressed sepsis/septic shock, while few studies evaluated early initiation of therapy in mild to moderate disease. The lack of randomized trials and the risk of confounding factors and biases in observational studies warrant caution in the interpretation of results. We conclude that the literature supports prompt administration of effective antibiotics for septic shock and bacterial meningitis, but there is no clear evidence showing that a delayed start of therapy is associated with worse outcome for less severe infectious syndromes. IMPLICATIONS: For patients presenting with suspected bacterial infections, withholding antibiotic therapy until diagnostic results are available and a diagnosis has been established (e.g. by 4-8 h) seems acceptable in most cases unless septic shock or bacterial meningitis are suspected. This approach promotes the use of ecologically favourable antibiotics in the ED, reducing the risks of side effects and selection of resistance.

Genesis and dissemination of a controversial disease: Chronic Lyme.

OBJECTIVES: To describe the role of the internet and cognitive biases in the controversy surrounding chronic Lyme disease. The attribution of chronic but aspecific symptoms to Lyme borreliosis is a source of worldwide controversy. PATIENTS AND METHODS: Some patients attribute their aspecific symptoms to Lyme borreliosis even though, in fact, they have a functional somatic syndrome. RESULTS: These patients' diagnostic and therapeutic wandering contributes to the above attribution and to their suffering. The Internet has deregulated the information market. Cognitive confirmation bias contributes to confinement in belief. Negativity bias explains the tendency of the human brain to select the most alarming information available. The narrative force of alarmist videos or personal testimonies acts like a nocebo effect. The social exclusion generated by adherence to this belief is a factor of reinforcement and aggravation. CONCLUSIONS: Deconstructing chronic Lyme disease with empathy and conviction is in patients' best interests.

Evaluation of a web-based self-reporting method for monitoring international passengers returning from an area of emerging infection.

OBJECTIVES: Emerging infectious diseases are a public health issue of international concern. Identifying methods to limit their expansion is essential. We assessed the feasibility of a screening strategy in which each traveler would actively participate in the screening process after an intercontinental flight by reporting their own health status via a web-based self-administered questionnaire. PATIENTS AND METHODS: In 2015 and 2017, we invited passengers arriving at or departing from Pointe-à-Pitre international airport to answer an online health questionnaire during the four days following their arrival from or at Paris-Orly international airport. SPIRE 1 was intended for passengers arriving at Pointe-à-Pitre and was conceived as a pilot study. SPIRE 2 was an improved version of SPIRE 1 and consisted in three parts, which permitted to further assess the benefits of pre-flight request and email follow-up. Endpoints were the connection rates and response rates to online health questionnaire. RESULTS: For SPIRE 1, 4/1038 travelers (0.4%) completed the two steps of the online health questionnaire. In SPIRE 2, response rates ranged from 3/1059 (0.3%) to 19/819 (2.3%). Response rates were significantly better when passengers were approached before their flight. CONCLUSIONS: The yield of an online health questionnaire was unexpectedly low.

Efficacy of generic meropenem products in combination with colistin in carbapenemase-producing Klebsiella pneumoniae experimental osteomyelitis.

Guidelines for the management of carbapenemase-producing Enterobacterales (CPE) infections recommend a combination of two active agents, including meropenem if the minimum inhibitory concentration (MIC) is ≤8 mg/L. The therapeutic equivalence of meropenem generics has been challenged. We compared the bactericidal activity of meropenem innovator (AstraZeneca) and four generic products (Actavis, Kabi, Mylan and Panpharma), both in vitro and in vivo, in association with colistin. In vitro time-kill studies were performed at 4 × MIC. An experimental model of KPC-producing Klebsiella pneumoniae osteomyelitis was induced in rabbits by tibial injection of a sclerosing agent followed by 2 × 108 CFU of K. pneumoniae KPC-99YC (meropenem MIC = 4 mg/L; colistin MIC = 1 mg/L). At 14 days after inoculation, treatment for 7 days started in seven groups of ≥10 rabbits, including a control group, a colistin group, and one group for each meropenem product (i.e. the innovator and four generics), in combination with colistin. In vitro, meropenem + colistin was bactericidal with no viable bacteria after 6 h, and this effect was similar with all meropenem products. In the osteomyelitis model, there was no significant difference between meropenem generics and the innovator when combined with colistin. Colistin-resistant strains were detected after treatment with colistin + meropenem innovator (n = 3) and generics (n = 3). The efficacy of four meropenem generics did not differ from the innovator in vitro and in an experimental rabbit model of KPC-producing K. pneumoniae osteomyelitis in terms of bactericidal activity and the emergence of resistance.

Incidence and characteristics of nosocomial influenza in a country with low vaccine coverage.

BACKGROUND: Influenza vaccination coverage is low in France, in at-risk patients and in healthcare workers. AIM: We aimed to estimate the incidence of nosocomial influenza, its characteristics and outcome. METHODS: During one influenza season, we retrospectively evaluated all cases of documented influenza. Inpatients with symptoms onset ≥48 h after admission were enrolled. Data were collected on a standardized questionnaire. RESULTS: From November 2017 to April 2018, 860 patients tested positive for influenza by polymerase chain reaction analysis on a respiratory sample. Among them, 204 (23.7%) were diagnosed ≥48 h after admission, of whom 57 (6.6% of all influenza cases) fulfilled inclusion criteria for nosocomial influenza: 26 women and 31 men, median age 82 years (interquartile range, 72.2-86.9). Twenty patients (38.6%) had recently (<6 months) received the seasonal influenza vaccine. Median time between admission and symptoms onset, and between symptoms onset and diagnosis were, respectively, 11 days (7-19.5) and 29 h (15.5-48). Influenza was mostly acquired in a double-bedded room (N = 39, 68.4%), with documented exposure in 14 cases. Influenza B virus was more common in nosocomial (46/57, 80.7%), than in community-acquired cases (359/803, 44.6%), P<0.001. Mortality rate at three months was 15.8% (N = 9). Incidence of nosocomial influenza was estimated at 0.22 per 1000 hospital-days during the study period. CONCLUSION: Nosocomial influenza is not rare in elderly inpatients, and may have severe consequences. Influenza B virus was over-represented, which suggests higher transmissibility and/or transmission clusters.