Neutralizing Antibody Levels as a Correlate of Protection Against SARS-CoV-2 Infection: A Modeling Analysis.

Although anti-severe acute respiratory syndrome-coronavirus 2 antibody kinetics have been described in large populations of vaccinated individuals, we still poorly understand how they evolve during a natural infection and how this impacts viral clearance. For that purpose, we analyzed the kinetics of both viral load and neutralizing antibody levels in a prospective cohort of individuals during acute infection with alpha variant. Using a mathematical model, we show that the progressive increase in neutralizing antibodies leads to a shortening of the half-life of both infected cells and infectious viral particles. We estimated that the neutralizing activity reached 90% of its maximal level within 11 days after symptom onset and could reduce the half-life of both infected cells and circulating virus by a 6-fold factor, thus playing a key role to achieve rapid viral clearance. Using this model, we conducted a simulation study to predict in a more general context the protection conferred by pre-existing neutralization titers, due to either vaccination or prior infection. We predicted that a neutralizing activity, as measured by 50% effective dose > 103 , could reduce by 46% the risk of having viral load detectable by standard polymerase chain reaction assays and by 98% the risk of having viral load above the threshold of infectiousness. Our model shows that neutralizing activity could be used to define correlates of protection against infection and transmission.

Erratum: Considerations for de-escalating universal masking in healthcare centers - CORRIGENDUM.

[This corrects the article DOI: 10.1017/ash.2023.200.].

Considerations for de-escalating universal masking in healthcare centers.

Three years after the beginning of the COVID-19 pandemic, better knowledge on the transmission of respiratory viral infections (RVI) including the contribution of asymptomatic infections encouraged most healthcare centers to implement universal masking. The evolution of the SARS-CoV-2 epidemiology and improved immunization of the population call for the infection and prevention control community to revisit the masking strategy in healthcare. In this narrative review, we consider factors for de-escalating universal masking in healthcare centers, addressing compliance with the mask policy, local epidemiology, the level of protection provided by medical face masks, the consequences of absenteeism and presenteeism, as well as logistics, costs, and ecological impact. Most current national and international guidelines for mask use are based on the level of community transmission of SARS-CoV-2. Actions are now required to refine future recommendations, such as establishing a list of the most relevant RVI to consider, implement reliable local RVI surveillance, and define thresholds for activating masking strategies. Considering the epidemiological context (measured via sentinel networks or wastewater analysis), and, if not available, considering a time period (winter season) may guide to three gradual levels of masking: (i) standard and transmission-based precautions and respiratory etiquette, (ii) systematic face mask wearing when in direct contact with patients, and (iii) universal masking. Cost-effectiveness analysis of the different strategies is warranted in the coming years. Masking is just one element to be considered along with other preventive measures such as staff and patient immunization, and efficient ventilation.

Rationale and evidence for the use of new beta-lactam/beta-lactamase inhibitor combinations and cefiderocol in critically ill patients.

BACKGROUND: Healthcare-associated infections involving Gram-negative bacteria (GNB) with difficult-to-treat resistance (DTR) phenotype are associated with impaired patient-centered outcomes and poses daily therapeutic challenges in most of intensive care units worldwide. Over the recent years, four innovative ß-lactam/ß-lactamase inhibitor (BL/BLI) combinations (ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam and meropenem-vaborbactam) and a new siderophore cephalosporin (cefiderocol) have been approved for the treatment of certain DTR-GNB infections. The literature addressing their microbiological spectrum, pharmacokinetics, clinical efficacy and safety was exhaustively audited by our group to support the recent guidelines of the French Intensive Care Society on their utilization in critically ill patients. This narrative review summarizes the available evidence and unanswered questions on these issues. METHODS: A systematic search for English-language publications in PUBMED and the Cochrane Library database from inception to November 15, 2022. RESULTS: These drugs have demonstrated relevant clinical success rates and a reduced renal risk in most of severe infections for whom polymyxin- and/or aminoglycoside-based regimen were historically used as last-resort strategies-namely, ceftazidime-avibactam for infections due to Klebsiella pneumoniae carbapenemase (KPC)- or OXA-48-like-producing Enterobacterales, meropenem-vaborbactam for KPC-producing Enterobacterales, ceftazidime-avibactam/aztreonam combination or cefiderocol for metallo-ß-lactamase (MBL)-producing Enterobacterales, and ceftolozane-tazobactam, ceftazidime-avibactam and imipenem-relebactam for non-MBL-producing DTR Pseudomonas aeruginosa. However, limited clinical evidence exists in critically ill patients. Extended-infusion scheme (except for imipenem-relebactam) may be indicated for DTR-GNB with high minimal inhibitory concentrations and/or in case of augmented renal clearance. The potential benefit of combining these agents with other antimicrobials remains under-investigated, notably for the most severe presentations. Other important knowledge gaps include pharmacokinetic information in particular situations (e.g., pneumonia, other deep-seated infections, and renal replacement therapy), the hazard of treatment-emergent resistance and possible preventive measures, the safety of high-dose regimen, the potential usefulness of rapid molecular diagnostic tools to rationalize their empirical utilization, and optimal treatment durations. Comparative clinical, ecological, and medico-economic data are needed for infections in whom two or more of these agents exhibit in vitro activity against the causative pathogen. CONCLUSIONS: New BL/BLI combinations and cefiderocol represent long-awaited options for improving the management of DTR-GNB infections. Several research axes must be explored to better define the positioning and appropriate administration scheme of these drugs in critically ill patients.

Advances in antibacterial treatment of adults with high-risk febrile neutropenia.

BACKGROUND: High-risk febrile neutropenia (HR-FN) is a life-threatening complication in patients with haematological malignancies or receiving myelosuppressive chemotherapy. Since the last international guidelines were published over 10 years ago, there have been major advances in the understanding and management of HR-FN, including on antibiotic pharmacokinetics and discontinuation/de-escalation strategies. OBJECTIVES: Summarizing major advances in the field of antibacterial therapy in patients with HR-FN: empirical therapy, pharmacokinetics of antibiotics and antibiotic stewardship. SOURCES: Narrative review based on literature review from PubMed. We focused on studies published between 2010 and 2023 about the pharmacokinetics of antimicrobials, management of antimicrobial administration, and discontinuation/de-escalation strategies. We did not address antimicrobial prophylaxis, viral or fungal infections. CONTENT: Several high-quality publications have highlighted important modifications of antibiotic pharmacokinetics in HR-FN, with standard dosages exposing patients to underdosing. These recent clinical and population pharmacokinetics studies help improve management protocols with optimized initial dosing and infusion rules for ß-lactams, vancomycin, daptomycin and amikacin; they highlight the potential benefits of therapeutic drug monitoring. A growing body of evidence also shows that antibiotic discontinuation/de-escalation strategies are beneficial for bacterial ecology and patients' outcome. We further discuss methods and limitations for implementation of such protocols in haematology. IMPLICATIONS: We highlight recent information about the management of antibacterial therapy in HR-FN that might be considered in updated guidelines for HR-FN management.

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.

Surgical site infection after pelvic bone and soft tissue sarcoma resection: Risk factors, microbiology, and impact of extended postoperative antibiotic prophylaxis.

BACKGROUND: Pelvic bone and/or soft tissue sarcoma removal surgeries are associated with a high rate of surgical site infection (SSI). The recommended antibiotic prophylaxis (ABP) duration is 24-48 h. We aimed to assess the impact of extended ABP (5 days) on the SSI rate and describe the microbiology of SSI in bone and/or soft tissue pelvic sarcomas. METHODS: We retrospectively included all consecutive patients who underwent pelvic bone and/or soft tissue sarcoma removal surgery between January 2010 and June 2020. RESULTS: We analyzed 146 patients with pelvic bone (45, 31%) or soft tissue (101, 69%). Sixty patients (41%) developed SSI. SSI occurred in 13/28 (46.4%) in the extended ABP group versus 47/118 (39.8%) in the standard group (p = 0.53). In multivariable analysis, risk factors for SSI were surgery duration (OR: 1.94 [1.41-2.92] per h), stay in postoperative ICU for more than 2 days (12.0 [2.8-61.3]), and shred or autologous skin flap (39.3 [5.8-409.5]). Extended ABP was not associated with SSI. SSI were mainly polymicrobial with Enterobacterales (57.4%) and Enterococcus (45%). CONCLUSIONS AND DISCUSSION: Pelvic bone and/or soft tissue sarcoma removal surgery is highly prone to postoperative infection. Extending the ABP to 5 days does not reduce the level of SSI.

Efficacy of vancomycin lock therapy for totally implantable venous access port-related infection due to coagulase-negative staphylococci in 100 patients with cancer.

OBJECTIVES: Data on the efficacy of vancomycin catheter lock therapy (VLT) for conservative treatment of totally implantable venous access port-related infections (TIVAP-RI) due to CoNS are scarce. The aim of this study was to evaluate the effectiveness of VLT in the treatment of TIVAP-RI due to CoNS in cancer patients. METHODS: This prospective, observational, multicentre study included adults with cancer treated with VLT for a TIVAP-RI due to CoNS. The primary endpoint was the success of VLT, defined as no TIVAP removal nor TIVAP-RI recurrence within 3 months after initiation of VLT. The secondary endpoint was 3 month mortality. Risk factors for VLT failure were also analysed. RESULTS: One hundred patients were included [men 53%, median age 63 years (IQR 53-72)]. Median duration of VLT was 12 days (IQR 9-14). Systemic antibiotic therapy was administered in 87 patients. VLT was successful in 44 patients. TIVAP could be reused after VLT in 51 patients. Recurrence of infection after completion of VLT occurred in 33 patients, among which TIVAP was removed in 27. Intermittent VLT (antibiotic solution left in place in the TIVAP lumen part of the time) was identified as a risk factor for TIVAP-RI recurrence. At 3 months, 26 deaths were reported; 1 (4%) was related to TIVAP-RI. CONCLUSIONS: At 3 months, success of VLT for TIVAP-RI due to CoNS was low. However, removing TIVAP was avoided in nearly half the patients. Continuous locks should be preferred to intermittent locks. Identifying factors of success is essential to select patients who may benefit from VLT.

Hospital Clonal Outbreak of Fluconazole-Resistant Candida parapsilosis Harboring the Y132F ERG11p Substitution in a French Intensive Care Unit.

We report the first identification of a fluconazole-resistant Candida parapsilosis (FR-Cp) strain in our hospital, which subsequently caused an outbreak involving 17 patients (12 deaths) within a 26-bed French intensive care unit. Microsatellite genotyping confirmed that all FR-Cp isolates belonged to the same clone. Given recent reports of rapid dissemination of these emerging clones, routine testing of azole susceptibility for all Candida parapsilosis isolates should be encouraged, at least in ICU patients.

Impact of Antibiotic Prophylaxis on Surgical Site Infections in Cardiac Surgery.

(1) Background: Cephalosporins (CA) are the first-line antibiotic prophylaxis recommended to prevent surgical site infection (SSI) after cardiac surgery. The combination of vancomycin/gentamicin (VGA) might represent a good alternative, but few studies have evaluated its efficacy in SSI prevention. (2) Methods: A single-centre retrospective study was conducted over a 13-year period in all consecutive adult patients undergoing elective cardiac surgery. Patients were stratified according to the type of antibiotic prophylaxis. CA served as the first-line prophylaxis, and VGA was used as the second-line prophylaxis. The primary endpoint was SSI occurrence at 90 days, which was defined as the need for reoperation due to SSI. (3) Results: In total, 14,960 adult patients treated consecutively from 2006 to 2019 were included in this study, of whom 1774 (12%) received VGA and 540 (3.7%) developed SSI. VGA patients had higher severity with increased 90-day mortality. Nevertheless, the frequency of SSI was similar between CA and VGA patients. However, the microbiological aetiologies were different, with more Gram-negative bacteria noted in the VGA group. (4) Conclusions: VGA seems to be as effective as CA in preventing SSI.

Dual Monoclonal Antibodies on Sars-Cov-2 Alpha and Delta Variants: Clinical and Virological Efficacy.

Monoclonal antibodies (MAbs) targeting the Spike glycoprotein of SARS-CoV-2 is a key strategy to prevent severe COVID-19. Here, the efficacy of two monoclonal antibody bitherapies against SARS-CoV-2 was assessed on 92 patients at high risk of severe COVID-19 between March and October 2021 (Bichat-Claude Bernard Hospital, Paris, France). Nine patients died despite appropriate management. From 14 days following treatment initiation, we observed a slower viral load decay for patients treated with the bitherapy Bamlanivimab/Etsevimab compared to the Casirivimab/Imdevimab association therapy (P = 0.045). The emergence of several mutations on the Spike protein known to diminish antiviral efficacy was observed from 1 to 3 weeks after infusion. The Q493R mutation was frequently selected, located in a region of joint structural overlap by Bamlanivimab/Etsevimab antibodies. Despite that this study was done on former SARS-CoV-2 variants (Alpha and Delta), the results provide new insights into resistance mechanisms in SARS-CoV-2 antibodies neutralization escape and should be considered for current and novel variants. IMPORTANCE Monoclonal antibody bitherapies (MAbs) are commonly prescribed to treat severe SARS-CoV-2-positive patients, and the rapid growth of resistance mutation emergence is alarming globally. To explore this issue, we conducted both clinical and genomic analyses of SARS-CoV-2 in a series of patients treated in 2021. We first noticed that the two dual therapies prescribed during the study had different kinetics of viral load decay. Rapidly after initiation of the treatments, resistance mutations emerged in the interface between the MAbs and the target Spike glycoprotein, demonstrating the importance to continuously screen the viral genome during treatment course. Taken together, the results highlight that viral mutations may emerge under selective pressure, conferring a putative competitive advantage, and could rapidly spread, as observed for the Omicron variant.

Cost-effectiveness of strategies to control the spread of carbapenemase-producing Enterobacterales in hospitals: a modelling study.

BACKGROUND: Spread of resistant bacteria causes severe morbidity and mortality. Stringent control measures can be expensive and disrupt hospital organization. In the present study, we assessed the effectiveness and cost-effectiveness of control strategies to prevent the spread of Carbapenemase-producing Enterobacterales (CPE) in a general hospital ward (GW). METHODS: A dynamic, stochastic model simulated the transmission of CPE by the hands of healthcare workers (HCWs) and the environment in a hypothetical 25-bed GW. Input parameters were based on published data; we assumed the prevalence at admission of 0.1%. 12 strategies were compared to the baseline (no control) and combined different prevention and control interventions: targeted or universal screening at admission (TS or US), contact precautions (CP), isolation in a single room, dedicated nursing staff (DNS) for carriers and weekly screening of contact patients (WSC). Time horizon was one year. Outcomes were the number of CPE acquisitions, costs, and incremental cost-effectiveness ratios (ICER). A hospital perspective was adopted to estimate costs, which included laboratory costs, single room, contact precautions, staff time, i.e. infection control nurse and/or dedicated nursing staff, and lost bed-days due to prolonged hospital stay of identified carriers. The model was calibrated on actual datasets. Sensitivity analyses were performed. RESULTS: The baseline scenario resulted in 0.93 CPE acquisitions/1000 admissions and costs 32,050 €/1000 admissions. All control strategies increased costs and improved the outcome. The efficiency frontier was represented by: (1) TS with DNS at a 17,407 €/avoided CPE case, (2) TS + DNS + WSC at a 30,700 €/avoided CPE case and (3) US + DNS + WSC at 181,472 €/avoided CPE case. Other strategies were dominated. Sensitivity analyses showed that TS + CP might be cost-effective if CPE carriers are identified upon admission or if the cases have a short hospital stay. However, CP were effective only when high level of compliance with hand hygiene was obtained. CONCLUSIONS: Targeted screening at admission combined with DNS for identified CPE carriers with or without weekly screening were the most cost-effective options to limit the spread of CPE. These results support current recommendations from several high-income countries.

SARS-CoV-2 exposures of healthcare workers from primary care, long-term care facilities and hospitals: a nationwide matched case-control study.

OBJECTIVES: This study assessed the roles of various exposures and personal protective equipment (PPE) use on healthcare workers' (HCWs) risk of COVID-19 working in primary care, long-term-care facilities or hospitals. METHODS: We conducted a matched case-control (1:1) study (10 April through 9 July 2021). Cases (HCWs with confirmed COVID-19) and controls (HCWs without any COVID-19-positive test or symptoms) were invited by E-mail to complete an online questionnaire on their exposures and PPE use over the 10-day period preceding inclusion. Risk factors were analysed using multivariable conditional logistic regression. RESULTS: A total of 2076 cases and 2076 matched controls were included. The analysis retained exposure to an infected person outside work (adjusted OR 19.9 (95% CI, 12.4-31.9)), an infected colleague (OR 2.26 (95% CI, 1.53-3.33)) or COVID-19 patients (OR 2.37 (95% CI, 1.66-3.40)), as independent predictors of COVID-19 in HCWs, while partial (OR 0.30 (95% CI, 0.22-0.40)) or complete (OR 0.19 (95% CI, 0.14-0.27)) immunisation was protective. Eye protection (OR 0.57 (95% CI, 0.37-0.87)) and wearing a gown (OR 0.58 (95% CI, 0.34-0.97)) for COVID-19 patient care were protective, while wearing an apron slightly increased the risk of infection (OR 1.47 (95% CI, 1.00-2.18)). Protection of N95 respirators and surgical face masks did not differ. Compared to medical professions, being a nurse (OR 3.79 (95% CI, 2.50-5.76)) or a nurse's aide (OR 9.08 (95% CI, 5.30-15.5)) was associated with COVID-19. Results were consistent across all healthcare settings. DISCUSSION: HCWs were more likely to get COVID-19 in their personal sphere than during occupational activities. Our results suggest that eye protection for HCWs during patient care should be actively promoted.

Diagnostic accuracy of non-invasive detection of SARS-CoV-2 infection by canine olfaction.

BACKGROUND: Throughout the COVID-19 pandemic, testing individuals remains a key action. One approach to rapid testing is to consider the olfactory capacities of trained detection dogs. METHODS: Prospective cohort study in two community COVID-19 screening centers. Two nasopharyngeal swabs (NPS), one saliva and one sweat samples were simultaneously collected. The dog handlers (and the dogs…) were blinded with regards to the Covid status. The diagnostic accuracy of non-invasive detection of SARS-CoV-2 infection by canine olfaction was assessed as compared to nasopharyngeal RT-PCR as the reference standard, saliva RT-PCR and nasopharyngeal antigen testing. RESULTS: 335 ambulatory adults (143 symptomatic and 192 asymptomatic) were included. Overall, 109/335 participants tested positive on nasopharyngeal RT-PCR either in symptomatic (78/143) or in asymptomatic participants (31/192). The overall sensitivity of canine detection was 97% (95% CI, 92 to 99) and even reached 100% (95% CI, 89 to 100) in asymptomatic individuals compared to NPS RT-PCR. The specificity was 91% (95% CI, 72 to 91), reaching 94% (95% CI, 90 to 97) for asymptomatic individuals. The sensitivity of canine detection was higher than that of nasopharyngeal antigen testing (97% CI: 91 to 99 versus 84% CI: 74 to 90, p = 0.006), but the specificity was lower (90% CI: 84 to 95 versus 97% CI: 93 to 99, p = 0.016). CONCLUSIONS: Non-invasive detection of SARS-CoV-2 infection by canine olfaction could be one alternative to NPS RT-PCR when it is necessary to obtain a result very quickly according to the same indications as antigenic tests in the context of mass screening.

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.

Antimicrobial stewardship in high-risk febrile neutropenia patients.

BACKGROUND: The 2011 4th European Conference on Infections in Leukemia (ECIL4) guidelines recommend antibiotics de-escalation/discontinuation in selected febrile neutropenia (FN) patients. We aimed to assess the impact of an antimicrobial stewardship (AMS) program based on these guidelines on antibiotics use and clinical outcomes in high-risk FN patients. METHODS: We conducted an observational study in the hematology department of Cochin University Hospital in Paris, France. An ECIL4-based antibiotics de-escalation and discontinuation strategy was implemented jointly by the hematologists and the AMS team. The pre-intervention (January-October 2018) and post-intervention (January-October 2019) periods were compared. We retrospectively collected clinical and microbiological data. We compiled antibiotics consumptions via hospital pharmacy data and standardized them by calculating defined daily doses per 1000 patient-days. We analyzed the two-monthly antibiotic consumption using an interrupted time series method and built a composite endpoint for clinical outcomes based on transfer to the intensive care unit (ICU) and/or hospital death. RESULTS: Overall, 273 hospital stays (164 patients) in the pre-intervention and 217 (148 patients) in the post-intervention periods were analyzed. Patients were mainly hospitalized for intensive chemotherapy for acute leukemia or autologous stem-cell transplant for myeloma. Patients were slightly younger in the pre-intervention compared to the post-intervention period (median age 60.4 vs 65.2 years, p = 0.049), but otherwise comparable. After implementation of the AMS program, glycopeptide and carbapenem use decreased by 85% (p = 0.03) and 72% (p = 0.04), respectively. After adjustment on confounders, the risk of transfer to the ICU/death decreased significantly after implementation of the AMS program (post-intervention period: odds-ratio = 0.29, 95% Confidence Interval: 0.15-0.53, p < 0.001). CONCLUSION: Implementation of a multidisciplinary AMS program for high-risk neutropenic patients was associated with lower carbapenem and glycopeptide use and improved clinical outcomes.

Oral levofloxacin: population pharmacokinetics model and pharmacodynamics study in bone and joint infections.

OBJECTIVES: This study aimed at characterizing the pharmacokinetics (PK) of oral levofloxacin in adult patients in order to optimize dosing scheme and explore the PK/pharmacodynamics (PD) of levofloxacin in bone and joint infections (BJIs). METHODS: From November 2015 to December 2019, all patients hospitalized in Cochin Hospital, treated with levofloxacin and who had at least one dosage for therapeutic drug monitoring were included. PK was described using non-linear mixed-effect modelling. In a subgroup of patients with BJIs, the association between PK, MIC for the isolated pathogen and clinical outcome was investigated. Monte Carlo simulations investigated dosing regimens to achieve the PK/PD target (AUC/MIC ratio >100). RESULTS: One hundred and two patients were included (199 measurements), including 32 treated for BJI. A one-compartment model with first-order absorption and elimination best described the data. Effects of estimated creatinine clearance (eCLCR) and age were significant on levofloxacin clearance. In BJI patients, no significant association was found between levofloxacin PK/microbiological parameters and either clinical outcome or adverse events. Based on our model, we proposed optimized oral levofloxacin dosing regimens according to renal function, to reach the PK/PD target AUC/MIC ratio >100 for three frequent causative pathogens (Staphylococcus aureus, Enterobacterales and Pseudomonas aeruginosa). CONCLUSIONS: Our results reinforce the need of determining the MIC and using therapeutic drug monitoring in complex infections caused by P. aeruginosa.

Osteitis in Systemic Sclerosis: A Nationwide Case-Control Retrospective Study.

OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by skin fibrosis, vasculopathy, and dysimmunity. Data regarding osteitis in SSc are scarce. METHODS: We performed a nationwide multicenter, retrospective, case-control study including patients with SSc, according to the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification, with a diagnosis of osteitis. The objectives of the study were to describe, to characterize, and to identify associated factors for osteitis in patients with SSc. RESULTS: Forty-eight patients were included. Twenty-six patients (54.1%) had osteitis beneath digital tip ulcers. Physical symptoms included pain (36 of 48, 75%), erythema (35 of 48, 73%), and local warmth (35 of 48, 73%). Thirty-one (65%) patients had median (interquartile range) C-reactive protein levels >2 mg/liter of 8 (2.7-44.3) mg/liter. On radiography, computed tomography, or magnetic resonance imaging, osteitis was characterized by swelling or abscess of soft tissues, with acro-osteolysis or lysis in 28 patients (58%). Microbiological sampling was performed in 45 (94%) patients. Most pathogens were Staphylococcus aureus (43.8%), anaerobes and Enterobacteriaceae (29.1%), and Pseudomonas aeruginosa (10.4%). Management comprised antibiotics in 37 (77.1%) patients and/or surgery in 26 (54.2%). Fluoroquinolones were used in 22 (45.8%) patients, and amoxicillin plus ß-lactamase inhibitor in 7 (14.6%). Six (12.6%) patients relapsed, 6 (12.6%) patients had osteitis recurrence, 15 (32%) sequelae, and 2 patients had septic shock and died. CONCLUSION: This study confirmed digital tip ulcers as an associated factor for osteitis and revealed a high rate of functional sequelae. Antimicrobial therapy with oral fluoroquinolone or intravenous amoxicillin and ß-lactamase inhibitor are used as first-line antibiotic therapy in SSc patients with osteitis.

Prevention of SARS-CoV-2 transmission during a large, live, indoor gathering (SPRING): a non-inferiority, randomised, controlled trial.

BACKGROUND: Mass indoor gatherings were banned in early 2020 to prevent the spread of SARS-CoV-2. We aimed to assess, under controlled conditions, whether infection rates among attendees at a large, indoor gathering event would be similar to those in non-attendees, given implementation of a comprehensive prevention strategy including antigen-screening within 3 days, medical mask wearing, and optimised ventilation. METHODS: The non-inferiority, prospective, open-label, randomised, controlled SPRING trial was done on attendees at a live indoor concert held in the Accor Arena on May 29, 2021 in Paris, France. Participants, aged 18-45 years, recruited via a dedicated website, had no comorbidities, COVID-19 symptoms, or recent case contact, and had had a negative rapid antigen diagnostic test within 3 days before the concert. Participants were randomly allocated in a 2:1 ratio to the experimental group (attendees) or to the control group (non-attendees). The allocation sequence was computer-generated by means of permuted blocks of sizes three, six, or nine, with no stratification. The primary outcome measure was the number of patients who were SARS-CoV-2-positive by RT-PCR test on self-collected saliva 7 days post-gathering in the per-protocol population (non-inferiority margin <0·35%). This trial is registered with ClinicalTrials.gov, NCT04872075. FINDINGS: Between May 11 and 25, 2021, 18 845 individuals registered on the dedicated website, and 10 953 were randomly selected for a pre-enrolment on-site visit. Among 6968 who kept the appointment and were screened, 6678 participants were randomly assigned (4451 were assigned to be attendees and 2227 to be non-attendees; median age 28 years; 59% women); 88% (3917) of attendees and 87% (1947) of non-attendees complied with follow-up requirements. The day 7 RT-PCR was positive for eight of the 3917 attendees (observed incidence, 0·20%; 95% CI 0·09-0·40) and three of the 1947 non-attendees (0·15%; 0·03-0·45; absolute difference, 95% CI -0·26% to 0·28%), findings that met the non-inferiority criterion for the primary endpoint. INTERPRETATION: Participation in a large, indoor, live gathering without physical distancing was not associated with increased SARS-CoV-2-transmission risk, provided a comprehensive preventive intervention was implemented. FUNDING: French Ministry of Health. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.