Search

Objectives: In this study, we aimed to assess the efficacy of different ways of administration and types of beta-lactams for hospitalized community-acquired pneumonia (CAP)., Methods: In this post-hoc analysis of randomized controlled trials (RCT) on patients hospitalized for CAP (pneumonia short treatment trial) comparing 3-day vs. 8-day durations of beta-lactams, which concluded to non-inferiority, we included patients who received either amoxicillin-clavulanate (AMC) or third-generation cephalosporin (3GC) regimens, and exclusively either intravenous or oral treatment for the first 3 days (followed by either 5 days of oral placebo or AMC according to randomization). The choice of route and molecule was left to the physician in charge. The main outcome was a failure at 15 days after the first antibiotic intake, defined as temperature >37.9°C, and/or absence of resolution/improvement of respiratory symptoms, and/or additional antibiotic treatment for any cause. The primary outcome according to the route of administration was evaluated through logistic regression. Inverse probability treatment weighting with a propensity score model was used to adjust for non-randomization of treatment routes and potential confounders. The difference in failure rates was also evaluated among several sub-populations (AMC vs. 3GC treatments, intravenous vs. oral AMC, patients with multi-lobar infection, patients aged ≥65 years old, and patients with CURB65 scores of 3-4)., Results: We included 200 patients from the original trial, with 93/200 (46.5%) patients only treated with intravenous treatment and 107/200 (53.5%) patients only treated with oral therapy. The failure rate at Day 15 was not significantly different among patients treated with initial intravenous vs. oral treatment [25/93 (26.9%) vs. 28/107 (26.2%), adjusted odds ratios (aOR) 0.973 (95% CI 0.519-1.823), p 0.932)]. Failure rates at Day 15 were not significantly different among the subgroup populations., Discussion: Among hospitalized patients with CAP, there was no significant difference in efficacy between initial intravenous and exclusive oral treatment., Trial Registration: This trial is registered with ClinicalTrials.gov, NCT01963442., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Asymptomatic and paucisymptomatic infections account for a substantial portion of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmissions. The value of intensified screening strategies, especially in emergency departments (EDs), in reaching asymptomatic and paucisymptomatic patients and helping to improve detection and reduce transmission has not been documented. The objective of this study was to evaluate in EDs whether an intensified SARS-CoV-2 screening strategy combining nurse-driven screening for asymptomatic/paucisymptomatic patients with routine practice (intervention) could contribute to higher detection of SARS-CoV-2 infections compared to routine practice alone, including screening for symptomatic or hospitalized patients (control)., Methods and Findings: We conducted a cluster-randomized, two-period, crossover trial from February 2021 to May 2021 in 18 EDs in the Paris metropolitan area, France. All adults visiting the EDs were eligible. At the start of the first period, 18 EDs were randomized to the intervention or control strategy by balanced block randomization with stratification, with the alternative condition being applied in the second period. During the control period, routine screening for SARS-CoV-2 included screening for symptomatic or hospitalized patients. During the intervention period, in addition to routine screening practice, a questionnaire about risk exposure and symptoms and a SARS-CoV-2 screening test were offered by nurses to all remaining asymptomatic/paucisymptomatic patients. The primary outcome was the proportion of newly diagnosed SARS-CoV-2-positive patients among all adults visiting the 18 EDs. Primary analysis was by intention-to-treat. The primary outcome was analyzed using a generalized linear mixed model (Poisson distribution) with the center and center by period as random effects and the strategy (intervention versus control) and period (modeled as a weekly categorical variable) as fixed effects with additional adjustment for community incidence. During the intervention and control periods, 69,248 patients and 69,104 patients, respectively, were included for a total of 138,352 patients. Patients had a median age of 45.0 years [31.0, 63.0], and women represented 45.7% of the patients. During the intervention period, 6,332 asymptomatic/paucisymptomatic patients completed the questionnaire; 4,283 were screened for SARS-CoV-2 by nurses, leading to 224 new SARS-CoV-2 diagnoses. A total of 1,859 patients versus 2,084 patients were newly diagnosed during the intervention and control periods, respectively (adjusted analysis: 26.7/1,000 versus 26.2/1,000, adjusted relative risk: 1.02 (95% confidence interval (CI) [0.94, 1.11]; p = 0.634)). The main limitation of this study is that it was conducted in a rapidly evolving epidemiological context., Conclusions: The results of this study showed that intensified screening for SARS-CoV-2 in EDs was unlikely to identify a higher proportion of newly diagnosed patients., Trial Registration: Trial registration number: ClinicalTrials.gov NCT04756609., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JLG reports personal fees for symposia presentations organized by Abbott Rapid Diagnosis SAS in 2021 and Qiagen Inc in 2022. TS reports grants or contracts from AstraZeneca, Bayer, Boehringer, Daiichi-Sankyo, Eli-Lilly, GSK, Novartis, Sanofi, payment or honoraria for lectures from Servier, Novartis, participation on a Data Safety Monitoring Board or Advisory Board from Ablative Solutions, Air Liquide, AstraZeneca, Sanofi, Novartis, 4Living Biotech., (Copyright: © 2023 Leblanc et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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 bla OXA-48 and bla CTX-M15 inserts, both susceptible to gentamicin, colistin, fosfomycin, and ceftazidime-avibactam. Osteomyelitis was induced in rabbits by tibial injection of 2 × 10 8 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., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Background: While the treatment of ESBL-producing Enterobacterales osteomyelitis relies on carbapenems, the optimal regimen for OXA48 types remains unclear. We evaluated the efficacy of ceftazidime/avibactam in different combinations in an experimental model of OXA-48-/ESBL-producing Escherichia coli osteomyelitis., Methods: E. coli pACYC184 is a clinical strain harbouring blaOXA-48 and blaCTX-M-15 inserts, with 'increased exposure susceptibility' to imipenem (MIC, 2 mg/L), gentamicin (MIC, 0.5 mg/L), colistin (MIC, 0.25 mg/L), ceftazidime/avibactam (MIC, 0.094 mg/L) and fosfomycin (MIC, 1 mg/L), and resistance to ceftazidime (MIC, 16 mg/L). Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 cfu of OXA-48/ESBL E. coli. Treatment started 14 days later for 7 days in six groups: (1) control, (2) colistin 150.000 IU/kg subcutaneously (SC) q8h, (3) ceftazidime/avibactam 100/25 mg/kg SC q8h, (4) ceftazidime/avibactam + colistin, (5) ceftazidime/avibactam + fosfomycin 150 mg/kg SC q12h, (6) ceftazidime/avibactam + gentamicin 15 mg/kg intramuscularly (IM) q24h. Treatment was evaluated at Day 24 according to bone cultures., Results: In vitro, time-kill curves of ceftazidime/avibactam in combination showed a synergistic effect. In vivo, compared with controls, rabbits treated with colistin alone had similar bone bacterial density (P = 0.50), whereas ceftazidime/avibactam alone or in combinations significantly decreased bone bacterial densities (P = 0.004 and P < 0.0002, respectively). Bone sterilization was achieved using ceftazidime/avibactam in combination with colistin (91%) or fosfomycin (100%) or gentamicin (100%) (P < 0.0001), whereas single therapies were not different from controls. No ceftazidime/avibactam-resistant strains emerged in rabbits treated, regardless of the combination., Conclusions: In our model of E. coli OXA-48/ESBL osteomyelitis, ceftazidime/avibactam in combination was more effective than any single therapy, whatever the companion drug used (gentamicin or colistin or fosfomycin)., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: Lower respiratory tract infections are one of the most common indications for antibiotic use in community and hospital settings. Usual guidelines for adults with community-acquired pneumonia (CAP) recommend 5-7 days of antibiotic treatment. In daily practice, physicians often prescribe 9-10 days of antibiotic treatment. Among available strategies to decrease antibiotic use, possibly preventing the emergence of bacterial resistance, reducing treatment durations is the safest and the most acceptable to clinicians. We aim to review data evaluating the efficacy of short antibiotic duration in adult CAP and which criteria can help clinicians to reduce antibiotic treatment., Recent Findings: Several studies and meta-analyses demonstrated that the treatment duration of 7 days or less was sufficient for CAP. Two trials found that 3-day treatments were effective, even in hospitalized CAP.To customize and shorten duration, clinical and biological criteria have been studied and reflect patient's response. Indeed, stability criteria were recently shown to be effective to discontinue antibiotic treatment. Procalcitonin was also studied but never compared with clinical criteria., Summary: Treatment duration for CAP is still under debate, but several studies support short durations. Clinical criteria could be possibly used to discontinue antibiotic treatment., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Optimal treatment of carbapenemase-producing Enterobacterales (CPE) bone infections is poorly defined. This study evaluated the efficacy of the novel beta-lactam-beta-lactamase inhibitor-ceftazidime-avibactam (CAZ-AVI)-with different antibiotic combinations in an experimental model of CPE osteomyelitis., Methods: KPC-99YC is a clinical strain of Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae with intermediate susceptibility to meropenem (MIC 4 mg/L), gentamicin (MIC 0.25 mg/L), colistin (MIC 0.25 mg/L), fosfomycin (MIC 4 mg/L) and ceftazidime-avibactam (MIC 1 mg/L). Time-kill curves were performed at 4x MIC. Osteomyelitis was induced in rabbits by tibial injection of 2×10 8 CFU of KPC-99YC. Six groups started treatment 14 days later for 7 days: control, colistin, CAZ-AVI, CAZ-AVI plus gentamicin, CAZ-AVI plus colistin and CAZ-AVI plus fosfomycin. Antibiotic dosages were selected to simulate plasma concentrations obtained in humans. Treatment was evaluated according to bone cultures quantified in log 10 CFU., Results: In vitro, CAZ-AVI plus colistin or gentamicin were rapidly bactericidal in contrast with CAZ-AVI plus fosfomycin. In vivo, compared with controls, colistin alone (P = 0.045) and CAZ-AVI alone or in combination significantly lowered bone bacterial counts (P < 0.001). Bone sterilisation was achieved in 67% and 100% of animals with combinations of CAZ-AVI plus colistin or gentamicin (P = 0.001 and P < 0.001, respectively) whereas other treatments were no different from controls. CAZ-AVI plus gentamicin provided greater bone bacterial reduction than CAZ-AVI plus colistin (P = 0.033). No CAZ-AVI-resistant strains emerged in treated rabbits, regardless of combination., Conclusions: CAZ-AVI plus gentamicin was the best effective combination therapy. Combinations with CAZ-AVI appear to be a promising treatment of KPC-producing Klebsiella pneumoniae osteomyelitis., (Copyright © 2022 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Importance: Failure of treatment is the most serious complication in community-acquired pneumonia (CAP)., Objective: To assess the potential risk factors for treatment failure in clinically stable patients with CAP., Design, Setting, and Participants: This secondary analysis assesses data from a randomized clinical trial on CAP (Pneumonia Short Treatment [PTC] trial) conducted from December 19, 2013, to February 1, 2018. Data analysis was performed from July 18, 2019, to February 15, 2020. Patients hospitalized at 1 of 16 centers in France for moderately severe CAP who were clinically stable at day 3 of antibiotic treatment were included in the PTC trial and analyzed in the per-protocol trial population., Interventions: Patients were randomly assigned (1:1) on day 3 of antibiotic treatment to receive β-lactam (amoxicillin-clavulanate [1 g/125 mg] 3 times daily) or placebo for 5 extra days., Main Outcomes and Measures: The main outcome was failure at 15 days after first antibiotic intake, defined as a temperature greater than 37.9 °C and/or absence of resolution or improvement of respiratory symptoms and/or additional antibiotic treatment for any cause. The association among demographic characteristics, baseline clinical and biological variables available (ie, at the first day of β-lactam treatment), and treatment failure at day 15 among the per-protocol trial population was assessed by univariate and multivariable logistic regressions., Results: Overall, 310 patients were included in the study; this secondary analysis comprised 291 patients (174 [59.8%] male; mean [SD] age, 69.6 [18.5] years). The failure rate was 26.8%. Male sex (odds ratio [OR], 1.74; 95% CI, 1.01-3.07), age per year (OR, 1.03; 95% CI, 1.01-1.05), Pneumonia Severe Index score (OR, 1.01; 95% CI, 1.00-1.02), the presence of chronic lung disease (OR, 1.85; 95% CI, 1.03-3.30), and creatinine clearance (OR, 0.99; 95% CI, 0.98-1.00) were significantly associated with failure in the univariate analysis. When the Pneumonia Severe Index score was excluded to avoid collinearity with age and sex in the regression model, only male sex (OR, 1.92; 95% CI, 1.08-3.49) and age (OR, 1.02; 95% CI, 1.00-1.05) were associated with failure in the multivariable analysis., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, among patients with CAP who reached clinical stability after 3 days of antibiotic treatment, only male sex and age were associated with higher risk of failure, independent of antibiotic treatment duration and biomarker levels. Another randomized clinical trial is needed to evaluate the impact of treatment duration in populations at higher risk for treatment failure.

Background: Shortening the duration of antibiotic therapy for patients admitted to hospital with community-acquired pneumonia should help reduce antibiotic consumption and thus bacterial resistance, adverse events, and related costs. We aimed to assess the need for an additional 5-day course of β-lactam therapy among patients with community-acquired pneumonia who were stable after 3 days of treatment., Methods: We did this double-blind, randomised, placebo-controlled, non-inferiority trial (the Pneumonia Short Treatment [PTC]) in 16 centres in France. Adult patients (aged ≥18 years) admitted to hospital with moderately severe community-acquired pneumonia (defined as patients admitted to a non-critical care unit) and who met prespecified clinical stability criteria after 3 days of treatment with β-lactam therapy were randomly assigned (1:1) to receive β-lactam therapy (oral amoxicillin 1 g plus clavulanate 125 mg three times a day) or matched placebo for 5 extra days. Randomisation was done using a web-based system with permuted blocks with random sizes and stratified by randomisation site and Pneumonia Severity Index score. Participants, clinicians, and study staff were masked to treatment allocation. The primary outcome was cure 15 days after first antibiotic intake, defined by apyrexia (temperature ≤37·8°C), resolution or improvement of respiratory symptoms, and no additional antibiotic treatment for any cause. A non-inferiority margin of 10 percentage points was chosen. The primary outcome was assessed in all patients who were randomly assigned and received any treatment (intention-to-treat [ITT] population) and in all patients who received their assigned treatment (per-protocol population). Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT01963442, and is now complete., Findings: Between Dec 19, 2013, and Feb 1, 2018, 706 patients were assessed for eligibility, and after 3 days of β-lactam treatment, 310 eligible patients were randomly assigned to receive either placebo (n=157) or β-lactam treatment (n=153). Seven patients withdrew consent before taking any study drug, five in the placebo group and two in the β-lactam group. In the ITT population, median age was 73·0 years (IQR 57·0-84·0) and 123 (41%) of 303 participants were female. In the ITT analysis, cure at day 15 occurred in 117 (77%) of 152 participants in the placebo group and 102 (68%) of 151 participants in the β-lactam group (between-group difference of 9·42%, 95% CI -0·38 to 20·04), indicating non-inferiority. In the per-protocol analysis, 113 (78%) of 145 participants in the placebo treatment group and 100 (68%) of 146 participants in the β-lactam treatment group were cured at day 15 (difference of 9·44% [95% CI -0·15 to 20·34]), indicating non-inferiority. Incidence of adverse events was similar between the treatment groups (22 [14%] of 152 in the placebo group and 29 [19%] of 151 in the β-lactam group). The most common adverse events were digestive disorders, reported in 17 (11%) of 152 patients in the placebo group and 28 (19%) of 151 patients in the β-lactam group. By day 30, three (2%) patients had died in the placebo group (one due to bacteraemia due to Staphylococcus aureus, one due to cardiogenic shock after acute pulmonary oedema, and one due to heart failure associated with acute renal failure) and two (1%) in the β-lactam group (due to pneumonia recurrence and possible acute pulmonary oedema)., Interpretation: Among patients admitted to hospital with community-acquired pneumonia who met clinical stability criteria, discontinuing β-lactam treatment after 3 days was non-inferior to 8 days of treatment. These findings could allow substantial reduction of antibiotic consumption., Funding: French Ministry of Health., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Optimizing care continuum entry interventions is key to ending the HIV epidemic. Offering HIV screening to key populations in emergency departments (EDs) is a strategy that has been demonstrated to be effective. Analyzing patient and provider perceptions of such screening can help identify implementation facilitators and barriers., Objectives: The aim of this study was to investigate the acceptability of offering nurse-driven HIV screening to key populations based on data collected from patients, nurses, and other service providers., Methods: This convergent mixed-methods study was a substudy of a cluster-randomized two-period crossover trial conducted in eight EDs to evaluate the effectiveness of the screening strategy. During the DICI-VIH (Dépistage Infirmier CIblé du VIH) trial, questionnaires were distributed to patients aged 18-64 years. Based on their responses, nurses offered screening to members of key populations.Over 5 days during the intervention period in four EDs, 218 patients were secondarily questioned about the acceptability of screening. Nurses completed 271 questionnaires pre- and posttrial regarding acceptability in all eight EDs. Descriptive analyses were conducted on these quantitative data. Convenience and purposeful sampling was used to recruit 53 providers to be interviewed posttrial. Two coders conducted a directed qualitative content analysis of the interview transcripts independently., Results: The vast majority of patients (95%) were comfortable with questions asked to determine membership in key populations and agreed (89%) that screening should be offered to key populations in EDs. Nurses mostly agreed that offering screening to key populations was well accepted by patients (62.2% pretrial and 71.4% posttrial), was easy to implement, and fell within the nursing sphere of competence. Pretrial, 73% of the nurses felt that such screening could be implemented in EDs. Posttrial, the proportion was 41%. Three themes emerged from the interviews: preference for targeted screening and a written questionnaire to identify key populations, facilitators of long-term implementation, and implementation barriers. Nurses were favorable to such screening provided specific conditions were met regarding training, support, collective involvement, and flexibility of application to overcome organizational and individual barriers., Discussion: Screening for key populations was perceived as acceptable and beneficial by patients and providers. Addressing the identified facilitators and barriers would help increase screening implementation in EDs., Competing Interests: The authors have no conflict of interest to report., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pneumonia, skin and soft tissue infections are more frequent in obese patients and are most often treated by co-amoxiclav, using similar dosing regimens to those used for non-obese subjects. No data are available on amoxicillin pharmacokinetics among obese subjects receiving co-amoxiclav., Materials and Methods: Prospective, single-centre, open-label, non-randomized, crossover pharmacokinetic trial having enrolled obese otherwise healthy adult subjects. A first dose of co-amoxiclav (amoxicillin/clavulanate 1000/200 mg) was infused IV over 30 min, followed by a second dose (1000/125 mg) administered orally, separated by a washout period of ≥24 h. We assayed concentrations of amoxicillin by a validated ultra HPLC-tandem MS technique. We estimated population pharmacokinetic parameters of amoxicillin by non-linear mixed-effect modelling using the SAEM algorithm developed by Monolix., Results: Twenty-seven subjects were included in the IV study, with 24 included in the oral part of the study. Median body weight and BMI were 109.3 kg and 40.6 kg/m2, respectively. Amoxicillin pharmacokinetics were best described by a two-compartment model with first-order elimination. Mean values for clearance, central volume, intercompartmental clearance and peripheral volume were, respectively, 14.6 L/h, 9.0 L, 4.2 L/h and 6.4 L for amoxicillin. Oral bioavailability of amoxicillin was 79.7%. Amoxicillin Cmax after oral administration significantly reduced with weight (P = 0.013). Dosing simulations for amoxicillin predicted that most of the population will achieve the pharmacodynamic target of fT>MIC ≥40% with the regimen of co-amoxiclav 1000/200 mg (IV) or 1000/125 mg (oral) q8h for MICs titrated up to 0.5 mg/L (IV) and 1 mg/L (oral)., Conclusions: Pharmacokinetic/pharmacodynamic goals for amoxicillin can be obtained in obese subjects., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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 × 10 8 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., (Copyright © 2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Background: The microbiological diagnosis of bone and joint infections (BJI) currently relies on cultures, and the relevance of molecular methods is still debated. The aim of this study was to determine whether polymerase chain reaction (PCR) could improve the etiological diagnosis of BJI., Methods: A prospective study was conducted during a 4-year period at Lariboisiere University Hospital (Paris, France), including patients with suspicion of infectious spondylodiscitis, septic arthritis, prosthetic joint infections, and respective noninfected groups. Clinical and radiological data were collected at inclusion and during follow-up. All samples were analyzed by conventional cultures and 16S ribosomal deoxyribonucleic acid (rDNA) gene (16S-PCR). Specific cultures and PCR targeting Mycobacterium tuberculosis were also performed for spondylodiscitis samples. Case records were subsequently analyzed by an independent expert committee to confirm or invalidate the suspicion of infection and definitively classify the patients in a case or control group. The sensitivity of the combination of culture and PCR was compared with culture alone., Results: After expert committee analysis, 105 cases of BJI cases and 111 control patients were analyzed. The most common pathogens of BJI were staphylococci (30%), M tuberculosis (19%), and streptococci (14%). Adding PCR enhanced the sensitivity compared with culture alone (1) for the diagnosis of M tuberculosis spondylodiscitis (64.4% vs 42.2%; P < .01) and (2) for nonstaphylococci BJI (81.6% vs 71.3%; P < .01). It is interesting to note that 16S-PCR could detect BJI due to uncommon bacteria such as Mycoplasma and fastidious bacteria., Conclusions: Our study showed the benefit of 16S-PCR and PCR targeting M tuberculosis as add-on tests in cases of suspected BJI., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: In countries with concentrated HIV epidemics, optimizing screening to reach individuals with undiagnosed infection is essential. The DICI-VIH study, a cluster-randomized crossover trial conducted in eight French emergency departments (EDs), found that a strategy combining nurse-driven targeted HIV screening with routine diagnostic testing was effective., Aim: The aim was to investigate factors associated with the implementation of HIV screening targeting key populations in EDs., Methods: A self-administered questionnaire was distributed at registration to patients aged 18-64 years and able to give consent during the DICI-VIH intervention. Based on their responses, those belonging to key populations were offered a rapid test by triage nurses. Two key stages of the process were evaluated: questionnaire distribution by providers and test acceptance by patients. Patient information, daily workload, and ED characteristics were collected. The associations between these variables and (a) the proportion of questionnaires distributed and (b) the proportion of tests accepted were evaluated using multilevel modeling in order to examine differences in screening implementation between EDs., Results: Questionnaire distribution proportions varied from 23% to 48% across EDs. They were higher on weekdays than weekends (odds ratio, OR: 3.77; 95% CI: 3.57-3.99) and when research staff participated (OR: 1.31; 95% CI: 1.26-1.37). They decreased over time (OR: 0.76; 95% CI: 0.71-0.82; 4th [Q3] vs. 1st quartile [Q0] of intervention days) and with increased patient flow (OR: 0.61; 95% CI: 0.56-0.67; Q3 vs. Q0 of eligible patients). Test acceptance varied from 64% to 77% across EDs, increased with research staff participation (OR 1.20; 95% CI: 1.03-1.40), and decreased over time (OR: 0.75; 95% CI: 0.60-0.92; Q3 vs. Q0). Patients who accepted were more likely to be younger (OR: 0.76; 95% CI: 0.61-0.96; 50-64-year-old vs. 30-39-year-old patients)., Linking Evidence to Action: Patient flow, intervention duration, weekdays, and research staff participation were important determinants of targeted screening implementation. These findings could help guide future implementation in similar settings., (© 2019 Sigma Theta Tau International.)

Background: Infections complicate a minority of orthopaedic arthroplasties but are the leading cause of malpractice claims. The basis for the claims is unclear. The objective of this study was to identify the main deviations from current recommendations by reviewing patient files recorded by a major French medical liability-specialized insurance company for private practitioners (MACSF [Mutuelle d'Assurance du Corps de Santé Français]) and to analyze legal claims and outcomes of litigation., Methods: All claims data for periprosthetic joint infections were analyzed retrospectively from 2010 to 2014. Treatment strategies were compared with therapeutic guidelines published by medical societies., Results: Forty-five claims for periprosthetic joint infection were recorded; 82% of patients were men and the mean patient age was 63 years. Twenty-one patients (47%) had a knee arthroplasty, 21 had a hip arthroplasty, 2 had a shoulder arthroplasty, and 1 had an ankle arthroplasty. Twenty-three infections (51%) occurred within 1 month postoperatively. Staphylococcus aureus was isolated from intraoperative samples in 36% of the cases (including 25% of these with methicillin-resistant strains), and coagulase-negative staphylococci were isolated in 51% (44% methicillin-resistant strains) of the cases. Treatment lasted for a median of 9.5 months (range, 1.5 to 96 months), with a median of 6 months (range, 1.5 to 20 months) of antibiotics and 3 surgical procedures (range, 0 to 7 surgical procedures). A total of 18% of patients had antibiotic-related side effects, 2% of patients died, and 76% of patients had persistent sequelae. An infectious disease specialist's advice was required for 56% of the patients. Discordances with therapeutic guidelines were found in 76% of the patient files, including delay in diagnosis (44%) and inadequate medical treatment (18%) or medico-surgical treatment (13%)., Conclusions: Late diagnosis of early postoperative infections appears to be the major cause of inappropriate management and malpractice litigation. Discordance with current guidelines was identified. Early consultation with an infectious disease specialist may help to reduce malpractice claims., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Objectives: In a new experimental model of carbapenemase-producing Klebsiella pneumoniae osteomyelitis we evaluated the efficacy of colistin alone and in various combinations and examined the emergence of colistin-resistant strains and cross-resistance to host defence peptides (HDPs)., Methods: KPC-99YC is a clinical strain with intermediate susceptibility to meropenem (MIC = 4 mg/L) and full susceptibility to gentamicin, colistin and tigecycline (MICs = 1 mg/L) and fosfomycin (MIC = 32 mg/L). Time-kill curves were performed at 4× MIC. Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 cfu. Treatment started 14 days later for 7 days in seven groups: (i) control; (ii) colistin; (iii) colistin + gentamicin; (iv) colistin + tigecycline; (v) colistin + meropenem; (vi) colistin + meropenem + gentamicin; and (vii) colistin + fosfomycin., Results: In vitro, colistin was rapidly bactericidal, but regrowth occurred after 9 h. Combinations of colistin with meropenem or fosfomycin were synergistic, whereas combination with tigecycline was antagonistic. In vivo, colistin alone was not effective. Combinations of colistin with meropenem or fosfomycin were bactericidal (P < 0.001) and the addition of gentamicin enhanced the efficacy of colistin + meropenem (P = 0.025). Tigecycline reduced the efficacy of colistin (P = 0.007). Colistin-resistant strains emerged in all groups except colistin + fosfomycin and two strains showed cross-resistance to HDP LL-37., Conclusions: In this model, combinations of colistin plus meropenem, with or without gentamicin, or colistin plus fosfomycin were the only effective therapies. The combination of colistin and tigecycline should be administered with caution, as it may be antagonistic in vitro and in vivo., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Clostridium is a diverse genus including more than 200 species involved in varied clinical presentations in infectious diseases. Septic arthritis caused by Clostridium sp. are however uncommon. We report here the first septic arthritis due to Clostridium tarantellae, formerly called Eubacterium tarantellae, in a patient under anti-TNF therapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Study Objective: This study compares the effectiveness and cost-effectiveness of nurse-driven targeted HIV screening alongside physician-directed diagnostic testing (intervention strategy) with diagnostic testing alone (control strategy) in 8 emergency departments., Methods: In this cluster-randomized, 2-period, crossover trial, 18- to 64-year-old patients presenting for reasons other than potential exposure to HIV were included. The strategy applied first was randomly assigned. During both periods, diagnostic testing was prescribed by physicians following usual care. During the intervention periods, patients were asked to complete a self-administered questionnaire. According to their answers, the triage nurse suggested performing a rapid test to patients belonging to a high-risk group. The primary outcome was the proportion of new diagnoses among included patients, which further refers to effectiveness. A secondary outcome was the intervention's incremental cost (health care system perspective) per additional diagnosis., Results: During the intervention periods, 74,161 patients were included, 16,468 completed the questionnaire, 4,341 belonged to high-risk groups, and 2,818 were tested by nurses, yielding 13 new diagnoses. Combined with 9 diagnoses confirmed through 97 diagnostic tests, 22 new diagnoses were established. During the control periods, 74,166 patients were included, 92 were tested, and 6 received a new diagnosis. The proportion of new diagnoses among included patients was higher during the intervention than in the control periods (3.0 per 10,000 versus 0.8 per 10,000; difference 2.2 per 10,000, 95% CI 1.3 to 3.6; relative risk 3.7, 95% CI 1.4 to 9.8). The incremental cost was €1,324 per additional new diagnosis., Conclusion: The combined strategy of targeted screening and diagnostic testing was effective., (Copyright © 2017 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

The aim of this Research Article is to present three different techniques of poly(sodium styrene sulfonate) (polyNaSS) covalent grafting onto titanium (Ti) surfaces and study the influence of their architecture on biological response. Two of them are "grafting from" techniques requiring an activation step either by thermal or UV irradiation. The third method is a "grafting to" technique involving an anchorage molecule onto which polyNaSS synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization is clicked. The advantage of the "grafting to" technique when compared to the "grafting from" technique is the ability to control the architecture and length of the grafted polymers on the Ti surface and their influence on the biological responses. This investigation compares the effect of the three different grafting processes on the in vitro biological responses of bacteria and osteoblasts. Overall outcomes of this investigation confirmed the significance of the sulfonate functional groups on the biological responses, regardless of the grafting method. In addition, results showed that the architecture and distribution of grafted polyNaSS on Ti surfaces alter the intensity of the bacteria response mediated by fibronectin.

Background: Controlling antibiotic use in healthcare establishments limits their consumption and the emergence of bacterial resistance., Aim: To evaluate the efficiency of an innovative antibiotic stewardship strategy implemented over three years in a university hospital., Methods: An antimicrobial multi-disciplinary team (AMT) [pharmacist, microbiologist and infectious disease specialist (IDS)] conducted a postprescription review. Specific coding of targeted antibiotics (including broad-spectrum β-lactams, glycopeptides, lipopeptides, fluoroquinolones and carbapenems) in the computerized physician order entry allowed recording of all new prescriptions. The data [patient, antibiotic(s), prescription start date, etc.] were registered on an AMT spreadsheet with shared access, where the microbiologist's opinion on the drug choice, based on available microbiology results, was entered. When the microbiologist and pharmacist did not approve the antibiotic prescribed, a same-day alert was generated and sent to the IDS. That alert led the IDS to re-evaluate the treatment., Findings: From 2012 to 2014, 2106 targeted antibiotic prescriptions were reviewed. Among them, 389 (18.5%) generated an alert and 293 (13.9%) were re-evaluated by the IDS. Recommendations (mostly de-escalation or discontinuation) were necessary for 136 (46.4%) and the prescribers' acceptance rate was 97%. The estimated intervention time was <30 min/day for each AMT member. This system allowed correct use of targeted antibiotics for 91.8% of prescriptions, but had no significant impact on targeted antibiotic consumption., Conclusion: This computerized, shared access, antibiotic stewardship strategy seems to be time saving, and effectively limited misuse of broad-spectrum antibiotics., (Copyright © 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Introduction: In bone and joint infections (BJIs), bacterial toxins are major virulence factors: Panton-Valentine leukocidin (PVL) expression leads to severe local damage, including bone distortion and abscesses, while α-hemolysin (Hla) production is associated with severe sepsis-related mortality. Recently, other toxins, namely phenol-soluble modulins (PSMs) expressed by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strain USA300 (LAC WT) were shown to have ex vivo intracellular cytotoxic activity after S. aureus invasion of osteoblasts, but their in vivo contribution in a relatively PVL-sensitive osteomyelitis model remains poorly elucidated., Materials and Methods: We compared the outcomes of experimental rabbit osteomyelitises induced with pvl+hla+psms+ LAC WT and its isogenic Δpsm derivatives (LAC Δpsmα and LAC Δpsmαβhld) using an inoculum of 3 × 108 CFUs. Mortality, hematogenous spread (blood culture, spleen and kidney), lung and bone involvements were assessed in two groups (non-survivors of severe sepsis and survivors sacrificed on day (D) 14)., Results: Severe sepsis-related mortality tended to be lower for Δpsm derivatives (Kaplan-Meier curves, P = .06). Non-survivors' bone LAC-Δpsmα (6.9 log10 CFUs/g of bone, P = .04) or -Δpsmαβhld (6.86 log10 CFUs/g of bone, P = .014) densities were significantly higher than LAC WT (6.43 log10 CFUs/g of bone). Conversely, lung Δpsmαβhld CFUs were significantly lower than LAC WT (P = .04). LAC Δpsmα, Δpsmαβhld and WT induced similar bone damage in D14 survivors, with comparable bacterial densities (respectively: 5.89, 5.91, and 6.15 log10 CFUs/g of bone). Meanwhile, pulmonary histological scores of inflammation were significantly higher for LAC Δpsmα- and Δpsmαβhld-infected rabbits compared to LAC WT (P = .04 and .01, respectively) but with comparable lung bacterial densities., Conclusion: Our experimental results showed that deactivating PSM peptides significantly limited bacterial dissemination from bone during the early phase of infection, but did not affect local severity of USA300 rabbit osteomyelitis.

Background: In 2010, to reduce late HIV diagnosis, the French national health agency endorsed non-targeted HIV screening in health care settings. Despite these recommendations, non-targeted screening has not been implemented and only physician-directed diagnostic testing is currently performed. A survey conducted in 2010 in 29 French Emergency Departments (EDs) showed that non-targeted nurse-driven screening was feasible though only a few new HIV diagnoses were identified, predominantly among high-risk groups. A strategy targeting high-risk groups combined with current practice could be shown to be feasible, more efficient and cost-effective than current practice alone., Methods/design: DICI-VIH (acronym for nurse-driven targeted HIV screening) is a multicentre, cluster-randomized, two-period crossover trial. The primary objective is to compare the effectiveness of 2 strategies for diagnosing HIV among adult patients visiting EDs: nurse-driven targeted HIV screening combined with current practice (physician-directed diagnostic testing) versus current practice alone. Main secondary objectives are to compare access to specialist consultation and how early HIV diagnosis occurs in the course of the disease between the 2 groups, and to evaluate the implementation, acceptability and cost-effectiveness of nurse-driven targeted screening. The 2 strategies take place during 2 randomly assigned periods in 8 EDs of metropolitan Paris, where 42 % of France's new HIV patients are diagnosed every year. All patients aged 18 to 64, not presenting secondary to HIV exposure are included. During the intervention period, patients are invited to fill a 7-item questionnaire (country of birth, sexual partners and injection drug use) in order to select individuals who are offered a rapid test. If the rapid test is reactive, a follow-up visit with an infectious disease specialist is scheduled within 72 h. Assuming an 80 % statistical power and a 5 % type 1 error, with 1.04 and 3.38 new diagnoses per 10,000 patients in the control and targeted groups respectively, a sample size of 140,000 patients was estimated corresponding to 8,750 patients per ED and per period. Inclusions started in June 2014. Results are expected by mid-2016., Discussion: The DICI-VIH study is the first large randomized controlled trial designed to assess nurse-driven targeted HIV screening. This study can provide valuable information on HIV screening in health care settings., Trial Registration: ClinicalTrials.gov: NCT02127424 (29 April 2014).

Post-operative infection remains the main complication of prosthetic joint replacement, since its inception by Robert and Jean Judet in 1947. Because the number ofjoint prostheses implanted annually is increasing substantially, these infections are becoming more-and- more common and optimizing their management is an important issue for medical and economic reasons. Prosthetic joint infections are a good model for understanding the limitations of in vivo antibiotic eficacy. Antibiotic therapy faces a duel challenge: (i) the difficulty of eradicating the bacteria in contact with a prosthesis, partly due to the metabolic state of the bacteria enclosed within the biofilm ; (ii) the poor difusion of antibiotics into the infected cortical bone, as revealed autoradiographically in an experimental model of prosthetic joint infection due to staphylococcus, the main bacterium responsible for these infections. The " natural " emergence of antibiotic-resistant bacteria, even though they have not been subject to antibiotic-selection pressure, was observed more recently in the same model. The optimal management of these infections requires medico-surgical treat- ment using, whenever possible, antibiotics like rifampin combined with another antimicro- bial, whose remarkable efficacy was demonstrated in experimental models of staphylococ- cal infections.

Background: The incidence of skin cancer has reached epidemic proportions in the white population and is significantly elevated in agricultural populations, who are exposed to ultraviolet radiation during their professional activities. In 2014, the Agricultural Social Insurance Mutual Benefit Fund (MSA) offered its customers who work in agriculture and live in rural areas with reduced access to dermatologists the ability to participate in a 1-day teledermoscopic (TDS) screening event., Objective: This study's aim was to assess the feasibility of real-time mobile TDS triage of a large number of agricultural workers by trained medical officers and occupational physicians., Methods: Fifteen TDS screening centres were located in different areas of France. Individuals older than 18 years who worked in agriculture and lived in rural area near a TDS screening centre were invited to participate in a 1-day screening event and were examined by an MSA physician. In cases of suspicious skin lesions, clinical and dermoscopic images were obtained and transferred immediately to four dermatologists who were simultaneously present at the tele-platform for diagnosis and decision-making. Low-quality images were retaken., Results: Two-hundred eighty-nine patients underwent skin cancer screening. Among 199 patients (69%), 390 suspicious lesions were identified and generated 412 pictures. All lesions were analysed by dermatologists. For 105 patients (53%), no follow-up was required. Seventeen patients were referred to local dermatologists for rapid examination, including 12 cases of suspected malignant melanocytic lesions. Among the 12 patients with suspected melanoma, face-to-face visits were conducted within 10 days for 11 of them, and 1 case of melanoma was confirmed by histopathology., Conclusions: Our study suggests that teledermoscopy performed in the context of occupational medicine and targeted to agricultural populations is feasible and could be useful for improving skin cancer screening in at-risk populations while avoiding face-to-face examinations by a dermatologist in 53% of cases., (© 2015 European Academy of Dermatology and Venereology.)

Introduction: Because the extreme diversity of clinical situations makes formal clinical trials difficult to carry out, animal models of periprosthetic infection in orthopaedics are needed to understand the aetiology and pathology of these infections, and to test new treatment methods. These experimental models must reproduce the features of the infections encountered in clinical practice. One of the model variables is the method of inoculation: local (intra-articular), intravenous or intra-arterial. Another is the timing of the inoculation: intra-operative or postoperative. Together, these options simulate the different contamination methods: direct, by proximity or blood-borne. However, the chosen inoculation route can also affect the infection rate and severity in the various models, and in some cases do not accurately reproduce the postoperative infections encountered clinically., Hypothesis: The direct inoculation method is the most effective for inducing a local infection on a foreign body in a joint, and the least iatrogenic., Methods: A critical analysis of published studies was carried out to evaluate each model against three endpoints, according to the type of inoculation. The primary endpoint was the infection rate, which should be as close as possible to 100%. The secondary endpoints were the mortality rate and rate of spontaneous healing, both of which should be as low as possible. Twenty-one articles were reviewed., Results: Intra-articular and intra-medullary inoculations had induction rates between 70 and 100%; intra-arterial inoculations had an induction rate of 100%, while intravenous inoculation had a rate of 47 to 77%. The mortality rates were lower with the intra-articular and intramedullary inoculations (5 to 23%) than for the intra-arterial inoculations (37%) and intravenous inoculations (28 to 56%). The spontaneous healing rate was 0 to 30% for intra-articular and intramedullary inoculations, 30 to 53% for intravenous inoculations and 0% for intra-arterial inoculations., Conclusion: Direct inoculation methods are most effective at reproducing chronic periprosthetic joints infections, without putting the animal's life at risk or allowing for spontaneous healing. The simulation of blood-borne infections is more random., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Objective: To examine nurse-driven HIV screening in various health care settings in terms of its impact on test offering, acceptance and delivery rates, nursing responsibilities, staff perceptions and long-term implementation., Design: Systematic review., Review Methods: The systematic review conducted in September 2014 adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Two independent reviewers extracted and summarised the eligible studies using a standardised form., Study Eligibility Criteria: All studies published from 2004 to 2014 that explored nurse-driven HIV screening practice in health care facilities in countries with comparable concentrated HIV epidemics were included., Data Sources: MEDLINE, EBSCO CINAHL., Results: Overall, 30 quantitative, qualitative and mixed methods studies fulfilled the eligibility criteria. The studies showed a trend in higher test offering, better acceptance and higher delivery rates with the implementation of nurse-driven HIV screening. However, among the 23 studies (77%) that evaluated these aims, only 13 studies (56%) had a control group, and 4 studies (17%) were randomised controlled trials (RCT) in few centres (i.e., 1 or 2). In 2 studies that compared nurse-driven HIV test offering to physician intervention, the participation of nurses was higher than that of physicians (85% vs. 54%, p<0.001; 47% vs. 28%, p<0.05). In a third study, the intervention of a dedicated nurse increased the test offering from 96.5% to 99.5% (OR=7.27, 95% CI=1.02-316.9). Acceptance rates increased with the nurse intervention in 2 RCTs (75% vs. 71%, p=0.025; 45% vs. 19%, p<0.05) and in a cohort study (74.8% vs. 84.3%, OR=1.82, 95% CI=1.14-2.88), whereas it decreased in 2 other studies. The testing rates increased in 7 out of 10 studies, with a maximum absolute increase of 65.9%. Nurse-driven HIV screening was evaluated at the time of routine HIV screening implementation in 27 studies (90%) and provided nurses with new responsibilities in 9 studies (30%). The few studies (23%) that explored how health care professionals, including nurses, perceived the strategy showed that this approach was well received. However, several operational barriers, such as lack of time, prevented its long-term implementation., Conclusion: The review supports the implementation of nurse-driven HIV screening. However, the evaluation of the impact of the nurse approach by RCTs was scarce, calling for additional research to better evaluate the impact of the nursing profession's contribution to HIV screening. Moreover, the perceptions of nurses and health care staff were seldom evaluated and require further exploration to improve nurse-driven HIV screening implementation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Ceftaroline (CPT), the active metabolite of the prodrug ceftaroline-fosamil (CPT-F), demonstrates in vitro bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and is effective in rabbit models of difficult-to-treat MRSA endocarditis and acute osteomyelitis. However, its in vivo efficacy in a prosthetic joint infection (PJI) model is unknown. Using a MRSA-infected knee PJI model in rabbits, the efficacies of CPT-F or vancomycin (VAN) alone and combined with rifampin (RIF) were compared. After each partial knee replacement with a silicone implant that fit into the tibial intramedullary canal was performed, 5 × 10(7) MRSA CFU (MICs of 0.38, 0.006, and 1 mg/liter for CPT, RIF, and VAN, respectively) was injected into the knee. Infected animals were randomly assigned to receive no treatment (controls) or CPT-F (60 mg/kg of body weight intramuscularly [i.m.]), VAN (60 mg/kg i.m.), CPT-F plus RIF (10 mg/kg i.m.), or VAN plus RIF starting 7 days postinoculation and lasting for 7 days. Surviving bacteria in crushed tibias were counted 3 days after ending treatment. Although the in vivo mean log10 CFU/g of CPT-treated (3.0 ± 0.9, n = 12) and VAN-treated (3.5 ± 1.1, n = 12) crushed bones was significantly lower than those of controls (5.6 ± 1.1, n = 14) (P < 0.001), neither treatment fully sterilized the bones (3/12 were sterile with each treatment). The mean log10 CFU/g values for the antibiotics in combination with RIF were 1.9 ± 0.5 (12/14 were sterile) for CPT-F and 1.9 ± 0.5 (12/14 were sterile) for VAN. In this MRSA PJI model, the efficacies of CPT-F and VAN did not differ; thus, CPT appears to be a promising antimicrobial agent for the treatment of MRSA PJIs., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Background: Severe sepsis, combining acute osteomyelitis and lung involvement, has been described increasingly in healthy children with the spread of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA)., Methods: Outcomes (mortality, hematogenous spread, lung and bone involvements) of rabbit osteomyelitis caused by CA-MRSA LAC(WT) USA300 and its Panton-Valentine leukocidin (PVL)- and α-hemolysin (Hla)-negative isogenic derivatives (LACΔpvl and LACΔhla, respectively) were compared., Results: Three days after inoculation (D3), all LAC(WT)- and LACΔpvl-, and 72% of LACΔhla-infected rabbits had no hematogenous spread and similar lung and bone bacterial densities. LACΔpvl and LACΔhla caused less severe histological lung lesions than LAC(WT) (P ≤ .01). Between D3 and D9, 10 (53%) LAC(WT)-, 11 (55%) LACΔpvl-, but no LACΔhla-infected rabbits (P < .005) died of severe sepsis with disseminated infection. Unlike deceased animals, most LAC(WT), LACΔpvl, and LACΔhla D14 survivors had no hematogenous spread (P < .001). LAC(WT) (88%) caused more bone abscesses than LACΔpvl (0, P = .001) or LACΔhla (30%, P = .01)., Conclusion: In this model, both PVL and Hla seemed to be required for early lung involvement via hematogenous spread. Hla, but not PVL, significantly impacted severe sepsis-related mortality. PVL was the predominant factor determining late-stage bone abscesses.

Background: Concerns have recently emerged about the efficacy and the quality of antibacterial generic products approved for use in humans., Methods: We searched Medline and Embase for original research articles on antibacterial generic products published in English or French before July 2013., Results: We selected 37 original research articles: 15 on β-lactams, 10 on glycopeptides, and 12 on other antibacterial agents. The majority of articles (73.0%) were published during 2008-2012. Study designs included analytical chemistry (n = 9), in vitro susceptibility studies (n = 14), animal experiments (n = 6, including 5 using the neutropenic mouse thigh infection model), and clinical studies in humans (n = 15). Of the 37 studies, 14 (37.8%) suggested that some generic products may be inferior to the innovator in terms of purity (n = 2), in vitro activity (n = 3), in vivo efficacy in experimental models (n = 4), clinical efficacy (n = 2), taste (n = 2), or compliance and acceptability in children (n = 1). The majority of in vitro studies (78.6%) found no significant difference between generic products and the innovator. Most (5/6) in vivo studies suggesting a difference between generic products and the innovator were performed in an animal model that is not validated for the evaluation of the efficacy of antibacterial agents. The level of evidence was constantly low in clinical studies., Conclusions: Published data on antibacterial generic products are limited and heterogeneous, thus precluding any attempt to generalize the study results. This systematic review suggests that additional evidence would be needed before considering a revision of the marketing authorization process for antibacterial generic products.

We report Campylobacter fetus meningitis associated with endocarditis in a 75-year-old diabetic man after he consumed raw liver. C. fetus was isolated from blood samples and cerebrospinal fluid. Cure was obtained with combined intravenous imipenem-gentamicin for 4 weeks; no relapse occurred after 6 months of follow-up.

Background: Previous studies of both clinically-derived and in vitro passage-derived daptomycin-resistant (DAP-R) Staphylococcus aureus strains demonstrated the coincident emergence of increased DAP MICs and resistance to host defense cationic peptides (HDP-R)., Methods: In the present investigation, we studied a parental DAP-susceptible (DAP-S) methicillin-resistant Staphylococcus aureus (MRSA) strain and three isogenic variants with increased DAP MICs which were isolated from both DAP-treated and DAP-untreated rabbits with prosthetic joint infections. These strains were compared for: in vitro susceptibility to distinct HDPs differing in size, structure, and origin; i.e.; thrombin-induced platelet microbicidal proteins [tPMPs] and human neutrophil peptide-1 [hNP-1]; cell membrane (CM) phospholipid and fatty acid content; CM order; envelope surface charge; cell wall thickness; and mprF single nucleotide polymorphisms (SNPs) and expression profiles., Results: In comparison with the parental strain, both DAP-exposed and DAP-naive strains exhibited: (i) significantly reduced susceptibility to each HDP (P<0.05); (ii) thicker cell walls (P<0.05); (iii) increased synthesis of CM lysyl-phosphatidylglycerol (L-PG); (iv) reduced content of CM phosphatidylglycerol (PG); and (v) SNPs within the mprF locus No significant differences were observed between parental or variant strains in outer CM content of L-PG, CM fluidity, CM fatty acid contents, surface charge, mprF expression profiles or MprF protein content. An isolate which underwent identical in vivo passage, but without evolving increased DAP MICs, retained parental phenotypes and genotype., Conclusions: THESE RESULTS SUGGEST: i) DAP MIC increases may occur in the absence of DAP exposures in vivo and may be triggered by organism exposure to endogenous HDPs: and ii) gain-in-function SNPs in mprF may contribute to such HDP-DAP cross-resistance phenotypes, although the mechanism of this relationship remains to be defined.

Objective: We assessed the EDs' characteristics associated with the offer and acceptance rates of a nontargeted HIV rapid-test screening in 29 Emergency Departments (EDs) in the metropolitan Paris region (11.7 million inhabitants), where half of France's new HIV cases are diagnosed annually., Methods: EDs nurses offered testing to all patients 18-64-year-old, able to provide consent, either with or without supplemental staff (hybrid staff model or indigenous staff model). The EDS' characteristics collected included structural characteristics (location, type, size), daily workload (patients' number and severity, length of stay in hours), staff's participation (training, support to the intervention, leadership), type of week day (weekends vs weekdays) and time (in days). Associations between these variables and the staff model, the offer and acceptance rates were studied using multilevel modeling., Results: Indigenous staff model was more frequent in EDs with a lower daily patient flow and a higher staff support score to the intervention. In indigenous-model EDs, the offer rate was associated with the patient flow (OR = 0.838, 95% CI = 0.773-0.908), was lower during weekends (OR = 0.623, 95% CI = 0.581-0.667) and decreased over time (OR = 0.978, 95% CI = 0.975-0.981). Similar results were found in hybrid-model EDs. Acceptance was poorly associated with EDs characteristics in indigenous-model EDs while in hybrid-model EDs it was lower during weekends (OR = 0.713, 95% CI = 0.623-0.816) and increased after the first positive test (OR = 1.526, 95% CI = 1.142-2.038). The EDs' characteristics explained respectively 38.5% and 15% of the total variance in the offer rate across indigenous model-EDs and hybrid model-EDs vs 12% and 1% for the acceptance rate., Conclusion: Our findings suggest the need for taking into account EDs' characteristics while considering the implementation of an ED-based HIV screening program. Strategies allowing the optimization of human resources' utilization such as HIV targeted screening in the EDs might be privileged.

Concerns have recently emerged about the potency and the quality of generic vancomycin (VAN) products approved for use in humans, based on experiments in a neutropenic mouse thigh infection model. However, other animal models may be more appropriate to decipher the bactericidal activities of VAN generics in vivo and to predict their efficacy in humans. We aimed to compare the bactericidal activities of six generic VAN products currently used in France (Mylan and Sandoz), Spain (Hospira), Switzerland (Teva), and the United States (Akorn-Strides and American Pharmaceutical Products [APP]) in a rabbit model of aortic valve endocarditis induced by 8 × 10(7) CFU of methicillin-resistant Staphylococcus aureus (MRSA) strain COL (VAN MIC, 1.5 μg/ml). In vitro, there were no significant differences in the time-kill curve studies performed with the six generic VAN products. Ten rabbits in each group were treated with intravenous (i.v.) VAN, 60 mg/kg of body weight twice a day (b.i.d.) for 4 days. Mean peak serum VAN levels, measured 45 min after the last injection, ranged from 35.5 (APP) to 45.9 μg/ml (Teva). Mean trough serum VAN levels, measured 12 h after the last injection, ranged from 2.3 (Hospira) to 9.2 (APP) μg/ml. All generic VAN products were superior to controls (no treatment) in terms of residual organisms in vegetations (P < 0.02 for each comparison) and in the spleen (P < 0.005 for each comparison). Pairwise comparisons of generic VAN products found no significant differences. In conclusion, a stringent MRSA endocarditis model found no significant differences in the bactericidal activities of six generic VAN products currently used in Europe and America.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) can cause osteomyelitis with severe sepsis and/or local complications in which a Panton-Valentine leukocidin (PVL) role is suspected. In vitro sub-MIC antibiotic effects on growth and PVL production by 11 PVL(+) MRSA strains, including the major CA-MRSA clones (USA300, including the LAC strain; USA400; and USA1000), and 11 PVL(+) methicillin-susceptible S. aureus (MSSA) strains were tested in microplate culture. Time-kill analyses with ceftobiprole at its MIC were also run with LAC. Efficacies of ceftobiprole (40 mg/kg of body weight subcutaneously [s.c.] four times a day [q.i.d.]) or vancomycin (60 mg/kg intramuscularly [i.m.] twice a day [b.i.d.]) alone or combined with rifampin (10 mg/kg b.i.d.) against rabbit CA-MRSA osteomyelitis, induced by tibial injection of 3.4 × 10(7) CFU of LAC, were compared. Treatment, started 14 days postinoculation, lasted 14 days. In vitro, 6/11 strains cultured with sub-MICs of ceftobiprole produced 1.6- to 4.8-fold more PVL than did the controls, with no link to specific clones. Rifampin decreased PVL production by all tested strains. In time-kill analyses at the LAC MIC (0.75 mg/liter), PVL production rose transiently at 6 and 8 h and then declined 2-fold at 16 h, concomitant with a 2-log(10)-CFU-count decrease. In vivo, the mean log(10) CFU/g of bone for ceftobiprole (1.44 ± 0.40) was significantly lower than that for vancomycin (2.37 ± 1.22) (P = 0.034), with 7/10 versus 5/11 bones sterilized, respectively. Combination with rifampin enhanced ceftobiprole (1.16 ± 0.04 CFU/g of bone [P = 0.056], 11/11 sterile bones) and vancomycin (1.23 ± 0.06 CFU/g [P = 0.011], 11/11 sterile bones) efficacies. Ceftobiprole bactericidal activity and the rifampin anti-PVL effect could play a role in these findings, which should be of interest for treating CA-MRSA osteomyelitis.

To estimate the 2009-2010 undiagnosed HIV prevalence in the Paris metropolitan region, where half of France's new HIV cases are diagnosed annually, we used a direct method based on a large sample of emergency department patients unaware of their HIV status. The overall expected prevalence was 0.09% (95% confidence interval 0.04-0.13). Undiagnosed infections were exclusively found in high-risk groups. This prevalence is below the 0.1% threshold suggested by regulatory authorities for implementing universal screening.

Background: To lower the number of undiagnosed infections and to improve early detection, international health agencies have promoted nontargeted human immunodeficiency virus (HIV) screening in health care settings, including emergency departments (EDs). This strategy remains controversial and has yet to be tested on a large scale. We assessed the public health impact of nontargeted HIV-rapid test (RT) screening among ED patients in the metropolitan area of Paris (11.7 million inhabitants), where half of France's new HIV cases are diagnosed annually., Methods: During a randomly assigned 6-week period for each of the 29 participating EDs, 18- to 64-year-old patients who were able to provide consent for HIV testing were offered a fingerstick whole-blood HIV RT. Main outcome measures were the number of patients tested for HIV and their characteristics vs those of the general metropolitan Paris population and the proportion of newly diagnosed HIV-positive patients among those tested and their characteristics vs those from the national HIV case surveillance., Results: Among 138,691 visits, there were 78,411 eligible patients, 20,962 of whom (27.0%) were offered HIV RT; 13,229 (63.1%) accepted testing and 12,754 (16.3%) were tested. The ED patients' characteristics reflected the general population distribution. Eighteen patients received new HIV diagnoses (0.14%; 95% confidence interval, 0.08%-0.22%). Like national HIV case surveillance patients, they belonged to a high-risk group (n = 17), were previously tested (n = 12), and were either symptomatic or had a CD4 lymphocyte count lower than 350/μL, suggesting late-stage infections (n = 8); 12 patients were linked to care., Conclusions: Nontargeted HIV testing in EDs was feasible but identified only a few new HIV diagnoses, often at late stages, and, unexpectedly, most patients belonged to a high-risk group. Our findings do not support the implementation of nontargeted screening of the general population in EDs.

Daptomycin is an attractive option for treating prosthetic joint infection, but the 6-mg/kg of body weight/day dose was linked to clinical failure and emergence of resistance. Using a methicillin-resistant Staphylococcus aureus (MRSA) knee prosthesis infection in rabbits, we studied the efficacies of high-dose daptomycin (22 mg/kg given intravenously [i.v.] once daily [o.d.]; equivalent to 8 mg/kg/day in humans) or vancomycin (60 mg/kg given intramuscularly [i.m.] twice daily [b.i.d.]), both either alone or with adjunctive rifampin (10 mg/kg i.m. b.i.d.). After partial knee replacement with a silicone implant, 10(7) MRSA CFU was injected into the knees. Treatment started 7 days postinoculation and lasted 7 days. Positive cultures were screened for the emergence of mutant strains, defined as having 3-fold-increased MICs. Although in vivo mean log(10) CFU/g of daptomycin-treated (4.23 ± 1.44; n = 12) or vancomycin-treated (4.63 ± 1.08; n = 12) crushed bone was significantly lower than that of controls (5.93 ± 1.15; n = 9) (P < 0.01), neither treatment sterilized bone (2/12 and 0/12 rabbits with sterile bone, respectively). Daptomycin mutant strains were found in 6/12, 3/12, and 2/9 daptomycin-treated, vancomycin-treated, and control rabbits, respectively; no resistant strains emerged (MIC was always <1 mg/liter). Adjunctive rifampin with daptomycin (1.47 ± 0.04 CFU/g of bone [detection threshold]; 11/11 sterile bones) or vancomycin (1.5 ± 0.12 CFU/g of bone; 6/8 sterile bones) was significantly more effective than monotherapy (P < 0.01) and prevented the emergence of daptomycin mutant strains. In this MRSA joint prosthesis infection model, combining rifampin with daptomycin was highly effective. Daptomycin mutant strains were isolated in vivo even without treatment, but adjunctive rifampin prevented this phenomenon, previously found after monotherapy in humans.

Background: Extensive spread of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in the United States, and the concomitant increase in severe invasive staphylococcal infections, including osteomyelitis, in healthy children, has led to renewed interest in Panton-Valentine leukocidin (PVL). However, the pathogenetic role of PVL in staphylococcal infections remains controversial, possibly because it depends on the site of infection., Methodology/principal Findings: We compared the course of experimental rabbit osteomyelitis due to the PVL-positive CA-MRSA strain USA 300 (LAC) and its PVL-negative isogenic derivative (LACDeltapvl), using a low and a high inoculum (8x10(5) and 4x10(8) CFU). With the low inoculum, bone infection was less frequent on day 7 (D7) and day 28 (D28) with LACDeltapvl than with LAC (respectively 12/19 and 18/19 animals, p = 0.042). With the high inoculum of both strains, all the animals were infected on D7 and the infection persisted on D28 in almost every case. However, tibial bacterial counts and the serum CRP concentration fell significantly between D7 and D28 with LACDeltapvl but not with LAC. Respectively 67% and 60% of LAC-infected rabbits had bone deformation and muscle/joint involvement on D7, compared to 0% and 7% of LACDeltapvl-infected rabbits (p = 0.001 and p = 0.005 respectively). Between D0 and D28, the anti-PVL antibody titer increased significantly only with the high inoculum of LAC., Conclusions/significance: PVL appears to play a role in the persistence and rapid local extension of rabbit osteomyelitis, in keeping with the greater severity of human bone infections due to PVL-positive S. aureus. The possible therapeutic implications of these findings are discussed.