Search

Objectives: To describe the set-up in 2022 of the PHAGEinLYON Clinic program dedicated to improve access to phage therapy in France using pharmaceutical-grade phages., Methods: We described the process, prospectively collected all phage therapy requests received during 2022 and reviewed them retrospectively to analyze the decision and also the patient care pathway (NCT05883995)., Results: Among 143 phage therapy requests, the indication was confirmed by multidisciplinary team meetings for 57 (40%) of them, and 44 were infected with bacteria that could be easily targeted by phages in France. Finally, 33 patients were treated, including 26 at our institution as compassionate use or in a clinical trial. Main indications were complex bone and joint infections, endovascular infections and lung infections. To manage these patients, 172 pharmaceutic phage cocktails targeting S. aureus and/or P. aeruginosa were prepared; 57 were dedicated to local, and 99 to intravenous injections. During the follow-up, 18 (69%) patients had a favorable clinical evolution, 6 (23%) required subsequent phage therapy, with the same phages with a greater phage exposition, or with different phages from elsewhere., Conclusions: The implementation of the PHAGEinLYON Clinic program in 2022 was associated with a groundbreaking access of phage therapy in France., (Copyright © 2024. Published by Elsevier Ltd.)

Pseudomonas aeruginosa is one of the main causes of healthcare-associated infection in Europe that increases patient morbidity and mortality. Multi-resistant pathogens are a major public health issue in burn centers. Mortality increases when the initial antibiotic treatment is inappropriate, especially if the patient is infected with P. aeruginosa strains that are resistant to many antibiotics. Phage therapy is an emerging option to treat severe P. aeruginosa infections. It involves using natural viruses called bacteriophages, which have the ability to infect, replicate, and, theoretically, destroy the P. aeruginosa population in an infected patient. We report here the case of a severely burned patient who experienced relapsing ventilator-associated pneumonia associated with skin graft infection and bacteremia due to extensively drug-resistant P. aeruginosa . The patient was successfully treated with personalized nebulized and intravenous phage therapy in combination with immunostimulation (interferon-γ) and last-resort antimicrobial therapy (imipenem-relebactam).

Background: New drugs targeting antimicrobial resistant pathogens, including Pseudomonas aeruginosa , have been challenging to evaluate in clinical trials, particularly for the non-ventilated hospital-acquired pneumonia and ventilator-associated pneumonia indications. Development of new antibacterial drugs is facilitated by preclinical animal models that could predict clinical efficacy in patients with these infections., Methods: We report here an FDA-funded study to develop a rabbit model of non-ventilated pneumonia with Pseudomonas aeruginosa by determining the extent to which the natural history of animal disease reproduced human pathophysiology and conducting validation studies to evaluate whether humanized dosing regimens of two antibiotics, meropenem and tobramycin, can halt or reverse disease progression., Results: In a rabbit model of non-ventilated pneumonia, endobronchial challenge with live P. aeruginosa strain 6206, but not with UV-killed Pa6206, caused acute respiratory distress syndrome, as evidenced by acute lung inflammation, pulmonary edema, hemorrhage, severe hypoxemia, hyperlactatemia, neutropenia, thrombocytopenia, and hypoglycemia, which preceded respiratory failure and death. Pa6206 increased >100-fold in the lungs and then disseminated from there to infect distal organs, including spleen and kidneys. At 5 h post-infection, 67% of Pa6206-challenged rabbits had PaO 2 <60 mmHg, corresponding to a clinical cut-off when oxygen therapy would be required. When administered at 5 h post-infection, humanized dosing regimens of tobramycin and meropenem reduced mortality to 17-33%, compared to 100% for saline-treated rabbits ( P <0.001 by log-rank tests). For meropenem which exhibits time-dependent bactericidal activity, rabbits treated with a humanized meropenem dosing regimen of 80 mg/kg q2h for 24 h achieved 100% T>MIC, resulting in 75% microbiological clearance rate of Pa6206 from the lungs. For tobramycin which exhibits concentration-dependent killing, rabbits treated with a humanized tobramycin dosing regimen of 8 mg/kg q8h for 24 h achieved C max /MIC of 9.8 ± 1.4 at 60 min post-dose, resulting in 50% lung microbiological clearance rate. In contrast, rabbits treated with a single tobramycin dose of 2.5 mg/kg had C max /MIC of 7.8 ± 0.8 and 8% (1/12) microbiological clearance rate, indicating that this rabbit model can detect dose-response effects., Conclusion: The rabbit model may be used to help predict clinical efficacy of new antibacterial drugs for the treatment of non-ventilated P. aeruginosa pneumonia., Competing Interests: Authors BZ, LC, CS, AD and BS are or were employed by AstraZeneca. Author BD previously received funding from AstraZeneca, Pfizer, Merck, Arsanis, ContraFect, and Integrated Biotherapeutics for preclinical studies using earlier iterations of the rabbit model of non-ventilated pneumonia. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gras, Vu, Nguyen, Tran, Mao, Tran, Mai, Dong, Jung, Iorio, Povoa, Pinheiro, Aguiar-Alves, Weiss, Zheng, Cheng, Stover, Sellman, DiGiandomenico, Gibault, Valour and Diep.)

Objectives: We aimed to describe diagnostic, management, and outcome of bone flap-related osteomyelitis after cranioplasty., Methods: Patients followed up in our tertiary care hospital for bone flap-related osteomyelitis after cranioplasty were included in a retrospective cohort (2008-2021). Determinants of treatment failure were assessed using logistic regression and Kaplan-Meier curves analysis., Results: The 144 included patients (81 [56.3%] males; median age 53.4 [interquartile range [IQR], 42.6-62.5] years) mostly presented wound abnormalities (n = 115, 79.9%). All infections were documented, the main pathogens being Staphylococcus aureus (n = 64, 44.4%), Cutibacterium acnes (n = 57, 39.6%), gram-negative bacilli (n = 40, 27.8%) and/or non-aureus staphylococci (n = 34, 23.6%). Surgery was performed in 140 (97.2%) cases, for bone flap removal (n = 102, 72.9%) or debridement with flap retention (n = 31, 22.1%), along with 12.7 (IQR, 8.0-14.0) weeks of antimicrobial therapy. After a follow-up of 117.1 (IQR, 62.5-235.5) weeks, 37 (26.1%) failures were observed: 16 (43.2%) infection persistence, three (8.1%) relapses, 22 (59.5%) superinfections and/or two (1.7%) infection-related deaths. Excluding superinfections, determinants of the 19 (13.4%) specific failures were an index craniectomy for brain tumor (odds ratio = 4.038, P = 0.033) and curettage of bone edges (odds ratio = 0.342, P = 0.048)., Conclusion: Post-craniectomy bone flap osteomyelitis are difficult-to-treat infection, necessitating prolonged antimicrobial therapy with appropriate surgical debridement, and advocating for multidisciplinary management in dedicated reference centers., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose of Review: This review provides an update on specificities of influenza in older adults (≥65-year-old), including epidemiology, burden in terms of hospitalization and mortality, extra-respiratory complications and specific challenges of prevention., Recent Findings: In the past 2 years, influenza activity was drastically reduced by barrier measures implemented during the COVID-19 pandemic. A recent French epidemiological study covering 2010-2018 epidemic seasons estimated that 75% of costs induced by influenza-associated hospitalizations and complications were attributable to older adults, a population bearing more than 90% of influenza-associated excess mortality.In addition to their age, comorbidities and reduced vaccine response, long-term facility residents are at risk for nosocomial outbreaks. Beyond respiratory complications, influenza triggers acute myocardial infarction and ischemic stroke. Influenza might drive significant functional loss in frail older adults, which can lead to "catastrophic" or severe disability in up to 10% of patients. Vaccination remains the cornerstone of prevention, with enhanced immunization strategies (i.e., high-dose or adjuvanted formulations) to be largely implemented in older adults. Efforts to increase influenza vaccination uptake during the COVID-19 pandemic should be consolidated., Summary: Burden of influenza in the elderly is largely under-recognized, especially the cardiovascular complications and the impact on functional status, justifying more effective preventive strategies., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Determining the etiology of aortitis is often challenging, in particular to distinguish infectious aortitis (IA) and noninfectious aortitis (NIA). This study aims to describe and compare the clinical, biological, and radiological characteristics of IA and NIA and their outcomes., Methods: A multicenter retrospective study was performed in 10 French centers, including patients with aortitis between 1 January 2014 and 31 December 2019., Results: One hundred eighty-three patients were included. Of these, 66 had IA (36.1%); the causative organism was Enterobacterales and streptococci in 18.2% each, Staphylococcus aureus in 13.6%, and Coxiella burnetii in 10.6%. NIA was diagnosed in 117 patients (63.9%), mainly due to vasculitides (49.6%), followed by idiopathic aortitis (39.3%). IA was more frequently associated with aortic aneurysms compared with NIA (78.8% vs 17.6%, P < .001), especially located in the abdominal aorta (69.7% vs 23.1%, P < .001). Crude and adjusted survival were significantly lower in IA compared to NIA (P < .001 and P = .006, respectively). In the IA cohort, high American Society of Anesthesiologists score (hazard ratio [HR], 2.47 [95% confidence interval {CI}, 1.08-5.66]; P = .033) and free aneurysm rupture (HR, 9.54 [95% CI, 1.04-87.11]; P = .046) were significantly associated with mortality after adjusting for age, sex, and Charlson comorbidity score. Effective empiric antimicrobial therapy, initiated before any microbial documentation, was associated with a decreased mortality (HR, 0.23, 95% CI, .08-.71]; P = .01)., Conclusions: IA was complicated by significantly higher mortality rates compared with NIA. An appropriate initial antibiotic therapy appeared as a protective factor in IA., Competing Interests: Potential conflicts of interest. P. R. reports payment or honoraria from Celgene, Novartis, and AdLiva and support for attending meetings and/or travel from Janssen-Cilag, Amgen, Roche, Takeda, Mylan, and Celgene. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To describe Staphylococcus lugdunensis prosthetic joint infection (PJI) management and outcome., Methods: Adults with proven S. lugdunensis PJI were included in a multicentric retrospective cohort. Determinants for failure were assessed by logistic regression and treatment failure-free survival curve analysis (Kaplan-Meier)., Results: One hundred and eleven patients were included (median age 72.4 [IQR, 62.7-79.4] years), with a knee (n = 71, 64.0%) or hip (n = 39, 35.1%) PJI considered as chronic in 77 (69.4%) cases. Surgical management consisted in debridement, antibiotic with implant retention (DAIR; n = 60, 54.1%), two-stage (n = 28, 25.2%) or one-stage (n = 15, 13.5%) exchange. Total duration of antimicrobial therapy was 13.1 (IQR, 11.8-16.9) weeks. After a median follow-up of 99.9 (IQR, 53.9-178.1) weeks, 22 (19.8%) S. lugdunensis-related treatment failures were observed. Independent determinants for outcome were diabetes (OR, 3.741; p = 0.036), sinus tract (OR, 3.846; p = 0.032), DAIR (OR, 3.749; p = 0.039) and rifampin-based regimen (OR, 0.319; p = 0.043). Twenty-four (40.0%) of the 60 DAIR-treated patients experienced treatment failure, with hip location (OR, 3.273; p = 0.048), delay from prosthesis implantation (OR, 1.012 per month; p = 0.019), pre-surgical CRP level >115 mg/L (OR, 4.800; p = 0.039) and mobile component exchange (OR, 0.302; p = 0.069) constituting additional determinants of outcome., Conclusions: Staphylococcus lugdunensis PJI are difficult-to-treat infections, with pivotal roles of an optimal surgical management., Competing Interests: Conflict of interest None of the authors has commercial or other associations that might pose a conflict of interest for this manuscript., (Copyright © 2022. Published by Elsevier Ltd.)

Modified vaccinia virus Ankara vaccine (MVA-BN; Bavarian Nordic) is recommended to contacts of mpox cases up to 14 days post-exposure but the effectiveness of this strategy is unknown. Among 108 adults (≥ 18 years old) who received one dose of MVA-BN after exposure to mpox, 11 (10%) cases of breakthrough mpox were observed. Sexual exposure was associated with the risk of breakthrough mpox (p = 0.0179). Samples taken from vaccinated breakthrough mpox cases had similar rates of infectious virus isolation than unvaccinated mpox cases.

Background: Necrotizing external otitis (NEO) is a severe infection of the skull base that occurs generally in the elderly and/or in diabetic recipients. There are few data in the literature about the therapeutic management of this complex bone infection., Objectives: To analyse relapses after NEO treatment completion, and to describe the clinical features of NEO., Methods: We performed a retrospective cohort study in the Lyon regional reference centre for the management of complex bone and joint infections. Consecutive cases of NEO from 1 January 2006 to 31 December 2018 were included. The primary outcome was the relapse of NEO. Variables were analysed using Cox regression survival analysis with adjusted hazard ratio (aHR) and Kaplan-Meier curve., Results: Sixty-six patients were included. Median age was 75 (IQR 69-81) years and 46 (70%) patients were diabetic. Eleven patients (17%) had temporomandibular arthritis, 10 (15%) cranial nerve paralysis, 2 (3%) cerebral thrombophlebitis, and 2 (3%) contiguous abscess. Microbiological documentation was obtained in 56 patients and revealed Pseudomonas aeruginosa in 44/56 patients (79%). Nine (14%) cases had no microbiological documentation. Antibiotic therapy was dual for 63 (95%) patients. During a median follow-up of 27 (IQR 12-40) months, 16 out of 63 (25%) patients experienced a relapse. Fungal infection was significantly associated with relapse [aHR 4.1 (95% CI 1.1-15); P = 0.03]., Conclusions: NEO is a severe bone infection, mainly (but not exclusively) caused by P. aeruginosa, which occurs in elderly and diabetic recipients. Fungal infections at baseline significantly impact the outcome., (© The Author(s) 2022. 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.)

Objectives: Nocardiosis is a rare opportunistic infection that is frequently associated with dissemination (i.e. involvement of several body sites). Identifying the factors associated with Nocardia spp. dissemination may help improving the management of patients with nocardiosis., Methods: This 10-year (2010-2020) retrospective multicenter cohort study included adult patients with Nocardia-confirmed infections. The first objective was to determine the factors associated with disseminated nocardiosis. The secondary endpoints were to determine and compare the management and the 12-month overall mortality in patients with localized and disseminated nocardiosis. Univariate and multivariate logistic regression analyses were used., Results: Nocardia spp. infection was confirmed in 110 patients, of whom 38 (34.5%) had disseminated nocardiosis. In univariate analysis, the factors associated with dissemination were immunosuppressive conditions: having an auto-immune disease and receiving high-dose corticosteroid (31.5% vs 8.3%, P = 0.003 and 52.6% vs 26.3%, P = 0.007, respectively). Absolute lymphocyte count <1 G/L at diagnosis was the only biomarker associated with dissemination (57.2% vs 26.3%, P = 0.007). Nocardia farcinica was not only the most frequent species identified in patient specimens (n = 22, 20%) but was also associated with a higher rate of dissemination (36.8% vs 11.1%, P = 0.002). Multivariate analysis confirmed the association between auto-immune diseases, lymphopenia, N. farcinica species and the higher rate of dissemination. Even though patients with disseminated nocardiosis were treated longer and more often with an antibiotic combination therapy, their 12-month overall mortality was significantly higher than that of patients with localized nocardiosis (36.8% vs 18%)., Conclusions: Dissemination of Nocardia spp. is favoured by auto-immune diseases, lymphopenia, and infection with N. farcinica., Competing Interests: Declaration of Competing Interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest or financial conflict with the subject matter or materials discussed in the manuscript. Production of this manuscript did not require writing assistance., (Copyright © 2022 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Herpes zoster, which is due to the reactivation of Varicella zoster virus (VZV), is a leading cause of morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). While cell-mediated immunity (CMI) is critical to inhibiting VZV reactivation, CMI is not routinely assessed due to a lack of reliable tests. In this study, we aimed to evaluate VZV-specific CMI among allo-HSCT recipients (n = 60) and healthy individuals (HI, n = 17) through a panel of three immune functional assays after ex vivo stimulation by VZV antigen: quantification of (i) IFN-γ release in the supernatants, (ii) T-cell proliferation after a 7-day stimulation of peripheral blood mononuclear cells (PBMC), and (iii) measurement of the ifn - γ mRNA gene expression level after 24 h of stimulation of a whole-blood sample. VZV responsiveness was defined according to IFN-γ release from VZV-stimulated PBMC. Upon VZV stimulation, we found that allo-HSCT recipients at a median time of 6 [5-8] months post-transplant had lower IFN-γ release (median [IQR], 0.34 [0.12-8.56] vs. 409.5 [143.9-910.2] pg/ml, P <.0001) and fewer proliferating T cells (0.05 [0.01-0.57] % vs. 8.74 [3.12-15.05] %, P <.0001) than HI. A subset of allo-HSCT recipients (VZV-responders, n = 15/57, 26%) distinguished themselves from VZV-non-responders (n = 42/57, 74%; missing data, n = 3) by higher IFN-γ release (80.45 [54.3-312.8] vs. 0.22 [0.12-0.42] pg/ml, P <.0001) and T-cell proliferation (2.22 [1.18-7.56] % vs. 0.002 [0.001-0.11] %, P <.0001), suggesting recovery of VZV-specific CMI. Interestingly, VZV responders had a significant fold increase in ifn-γ gene expression, whereas ifn-γ mRNA was not detected in whole blood of VZV-non-responders ( P <.0001). This study is the first to suggest that measurement of ifn-γ gene expression in 24-h-stimulated whole blood could be an accurate test of VZV-specific CMI. The routine use of this immune functional assay to guide antiviral prophylaxis at an individual level remains to be evaluated., Competing Interests: WM has a PhD grant CIFRE 2019 (conventions industrielles de formation par la recherche, Ministère de l’Enseignement supérieur, de la Recherche et de l’Innovation, Paris, France) half-funded by Lyon University and half-funded by bioMerieux SA. KB-P is an employee of bioMérieux SA, an in vitro diagnostic company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Boccard, Conrad, Mouton, Valour, Roure-Sobas, Frobert, Rohmer, Alcazer, Labussière-Wallet, Ghesquières, Venet, Brengel-Pesce, Trouillet-Assant and Ader.)

Osteocutaneous flap (OCF) mandible reconstruction is at high risk for surgical site infection. This study aimed to describe diagnosis, management, and outcome of OCF-related osteomyelitis. All patients managed at our institution for an OCF-related osteomyelitis following mandible reconstruction were included in a retrospective cohort study (2012-2019). Microbiology was described according to gold-standard surgical samples, considering all virulent pathogens, and potential contaminants if present on at least two samples. Determinants of treatment failure were assessed by logistic regression and Kaplan-Meier curve analysis. The 48 included patients (median age 60.5 (IQR, 52.4-66.6) years) benefited from OCF mandible reconstruction mostly for carcinoma ( n = 27 / 48 ; 56.3 %) or osteoradionecrosis ( n = 12 / 48 ; 25.0 %). OCF-related osteomyelitis was mostly early ( ≤ 3 months post-surgery; n = 43 / 48 ; 89.6 %), presenting with local inflammation ( n = 28 / 47 ; 59.6 %), nonunion (wound dehiscence) or sinus tract ( n = 28 / 47 ; 59.6 %), and/or bone or device exposure ( n = 21 / 47 ; 44.7 %). Main implicated pathogens were Enterobacteriaceae ( n = 25 / 41 ; 61.0 %), streptococci ( n = 22 / 41 ; 53.7 %), Staphylococcus aureus ( n = 10 / 41 ; 24.4 %), enterococci ( n = 9 / 41 ; 22.0 %), non-fermenting Gram-negative bacilli ( n = 8 / 41 ; 19.5 %), and anaerobes ( n = 8 / 41 ; 19.5 %). Thirty-nine patients (81.3 %) benefited from surgery, consisting of debridement with implant retention (DAIR) in 25 / 39 (64.1 %) cases, associated with 93 (IQR, 64-128) days of antimicrobial therapy. After a follow-up of 18 (IQR, 11-31) months, 24 / 48 (50.0 %) treatment failures were observed. Determinants of treatment outcomes were DAIR (OR, 3.333; 95 % CI, 1.020-10.898) and an early infectious disease specialist referral (OR, 0.236 if ≤ 2  weeks; 95 % CI, 0.062-0.933). OCF-related osteomyelitis following mandibular reconstruction represents difficult-to-treat infections. Our results advocate for a multidisciplinary management, including an early infectious-disease-specialist referral to manage the antimicrobial therapy driven by complex microbiological documentation., Competing Interests: The contact author has declared that neither they nor their co-authors have any competing interests., (Copyright: © 2022 Clément Javaux et al.)

Objectives: Beyond intracellular penetration, acidic lysosomal pH might affect the intracellular activity of some antimicrobials. This study evaluated the ability of lysosomotropic alkalizing agents to potentiate the antimicrobial eradication of an intra-osteoblastic Staphylococcus aureus reservoir in the setting of bone and joint infection (BJI)., Methods: MICs of 16 anti-staphylococcal molecules active against methicillin-sensitive S. aureus (MSSA) were evaluated at pH 5 and pH 7. Additionally, the lysosomal alkalizing potential (spectrofluorometry) and cytotoxicity (MTT assay) of hydroxychloroquine, amantadine and ammonium chloride were assessed. The results led to further investigation of clindamycin, cotrimoxazole, daptomycin and levofloxacin-alone or in combination with hydroxychloroquine-in an in vitro model of osteoblast infection. The impact of hydroxychloroquine on autophagy was finally investigated using Western blot detection of two autophagic flux indicators, the LC3 membrane protein and the SQSTM1 cargo protein., Results: Daptomycin, cotrimoxazole, clindamycin and levofloxacin alone significantly decreased the intracellular staphylococcal reservoir (5.12 log 10  CFU/100 000 cells) by 0.14 (95%CI 0.01-0.34), 0.25 (95%CI 0.12-0.43), 0.16 (95%CI 0.004-0.39) and 1.18 (95%CI 1.04-1.38) log 10  CFU/100 000 cells, respectively (p < 10 -3 ). Adding hydroxychloroquine (20 mg/L) increased intralysosomal pH from 4.8 to 7, and concomitantly the inoculum of each antimicrobial was reduced by 0.50 (95%CI 0.30-0.84), 0.73 (95%CI 0.59-0.96), 0.59 (95%CI 0.46-0.78) and 1.8 (95%CI 1.66-2.1) log 10  CFU/100 000 cells, respectively (p < 10 -4 ). Cellular levels of LC3II and SQSTM1 showed that hydroxychloroquine has direct activity on the autophagic flux, fostering the eradication of intracellular S. aureus by antimicrobials., Conclusion: At high concentrations, hydroxychloroquine used as an adjuvant to antimicrobials improves eradication of an S. aureus intra-osteoblastic reservoir in our in vitro cell infection model. These findings advocate further in vivo evaluation of alkalization efficacy and tolerance in S. aureus BJI., (Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Staphylococcus aureus - a major aetiological agent of bone and joint infection (BJI) - is associated with a high risk of relapse and chronicity, in part due to its ability to invade and persist in non-professional phagocytic bone cells such as osteoblasts. This intracellular reservoir protects S. aureus from the action of the immune system and most antibiotics. To date, the choice of antimicrobial strategies for BJI treatment mostly relies on standard susceptibility testing, bone penetration of antibiotics and their 'antibiofilm' activity. Despite the role of intracellular persistent S. aureus in the development of chronic infection, the ability of antibiotics to target the S. aureus intraosteoblastic reservoir is not considered in therapeutic choices but might represent a key determinant of treatment outcome. This review provides an overview of the intracellular pharmacokinetics of antistaphylococcal drugs used in the treatment of BJI and of their ability to target intraosteoblastic S. aureus. Thirteen studies focusing on the intraosteoblastic activity of antibiotics against S. aureus were reviewed, all relying on in vitro models of osteoblast infection. Despite varying incubation times, multiplicities of infection, bacterial strains, and the types of infected cell lines, rifamycins and fluoroquinolones remain the two most potent antimicrobial classes for intraosteoblastic S. aureus eradication, consistent with clinical data showing a superiority of this combination therapy in S. aureus orthopaedic device-related infections., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Objectives: Long-acting lipoglycopeptides are promising therapeutic options in Staphylococcus aureus bone and joint infections (BJIs). This study evaluated the ability of dalbavancin to eradicate the intraosteoblastic reservoir of S. aureus, associated with BJI chronicity., Methods: Osteoblastic cells were infected with a standardized inoculum of the S. aureus reference strain HG001 and incubated for 24 h with dalbavancin, vancomycin or rifampicin using the MIC, 10×MIC, 100×MIC and/or the intraosseous concentrations reached using standard therapeutic doses (i.e. vancomycin, 10 mg/L; rifampicin, 2 mg/L; and dalbavancin, 6 mg/L). The remaining intracellular bacteria were quantified by plating cell lysates., Results: MICs of dalbavancin, vancomycin and rifampicin were 0.125, 1 and 0.004 mg/L, respectively. Dalbavancin significantly reduced the intracellular inoculum of S. aureus starting at a concentration equal to the MIC, with a significant dose effect, ranging from a reduction of 31.4% (95% CI = 17.6%-45.2%) at MIC to 51.6% (95% CI = 39.8%-63.4%) at 100×MIC compared with untreated cells. Of note, dalbavancin was the only molecule to significantly reduce the intraosteoblastic inoculum at low concentration (MIC). At intraosseous concentrations, dalbavancin reduced the intracellular inoculum by 49.6% (95% CI = 45.1%-54.1%) compared with untreated cells (P < 0.001), with no significant difference compared with vancomycin (38.1%; 95% CI = 19.2%-57.0%; P = 0.646), and was less efficient than rifampicin (69.0%; 95% CI = 63.2-74.8; P < 0.001)., Conclusions: Dalbavancin was able to decrease the intraosteoblastic S. aureus inoculum by 50% at intraosseous concentrations reached during standard human therapeutic dosing, with no difference compared with vancomycin, and remained less efficient than rifampicin. However, it was the only molecule significantly active at low concentration., (© The Author(s) 2021. 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.)

Introduction : Costs related to bone and joint infection (BJI) management are increasing worldwide, particularly due to the growing use of off-label antibiotics that are expensive treatments (ETs), in conjunction with increasing incidence of multi-drug-resistant pathogens. The aim of this study was to evaluate the whole costs related to these treatments during the patient route, including those attributed to the rehabilitation centre (RC) stay in one regional referral centre in France. The total annual cost of ETs for managing complex BJIs in France was then estimated. Material and methods : A prospective monocentric observational study was conducted from 2014 to 2019 in a referral centre for BJI management (CRIOAc - Centre de Référence des Infections OstéoArticulaires complexes). Costs related to expensive treatments ("old" ETs, i.e. ceftaroline, ertapenem, daptomycin, colistin, tigecycline, and linezolid and "new" ETs, defined as those used since 2017, including ceftobiprole, ceftazidime-avibactam, ceftolozane-tazobactam, tedizolid, and dalbavancin) were prospectively recorded. In all cases, the use of these ETs was validated during multidisciplinary meetings. Results : Of the 3219 patients treated, 1682 (52.3 %) received at least one ET, and 21.5 % of patients who received ET were managed in RCs. The overall cost of ETs remained high but stable (EUR 1 033 610 in 2014; EUR 1 129 862 in 2019), despite the increase of patients treated by ETs (from 182 in 2014 to 512 in 2019) and in the cumulative days of treatment (9739 to 16 191 d). Daptomycin was the most prescribed molecule (46.2 % of patients in 2014 and 56.8 % in 2019, with 53.8 % overall), but its cost has decreased since this molecule was genericized in 2018; the same trend was observed for linezolid. Thus, costs for old ETs decreased overall, from EUR 1 033 610 in 2014 to EUR 604 997 in 2019, but global costs remained stable due to new ET utilization accounting for 46.5 % of overall costs in 2019. Tedizolid, used as suppressive antimicrobial therapy, represented 77.5 % of total new ET costs. In our centre, dalbavancin was never used. The cost paid by RCs for ETs and the duration of ET remained stable overall between 2016 and 2019. Conclusions : A high consumption of off-label ET is required to treat patients with BJIs in a CRIOAc, and the consequence is a high cost of antimicrobial therapy for these patients, estimated to be almost EUR 10 million in France annually. Costs associated with ET utilization remained stable over the years. On the one hand, the introduction of the generic drugs of daptomycin and linezolid has significantly decreased the share of old ETs, but, on the other hand, the need for new ETs to treat infections associated with more resistant pathogens has not led to decrease in the overall costs. A drastic price reduction of generic drugs is essential to limit the costs associated with more complex BJIs., Competing Interests: The contact author has declared that neither they nor their co-authors have any competing interests., (Copyright: © 2021 Truong-Thanh Pham et al.)

A prospective cohort study was conducted to evaluate long-term safety of tedizolid as suppressive antimicrobial treatment in patients with implant-associated bone and joint infection caused by multidrug-resistant gram-positive pathogens. Seventeen patients received tedizolid with a median duration of treatment of 6 months. No patients developed a serious adverse event., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

In a rabbit model of methicillin-resistant Staphylococcus aureus prosthetic joint infection (PJI), prophylaxis with AZD6389*-a combination of three monoclonal antibodies targeting alpha-hemolysin, bicomponent cytotoxins (LukSF/LukED/HlgAB/HlgCB), and clumping factor A-resulted in significant reductions in joint swelling, erythema, intra-articular pus, and bacterial burden in synovial tissues and biofilm-associated prosthetic implants compared with isotype-matched control IgG. Targeting specific staphylococcal virulence factors may thus have potential clinical utility for prevention of PJI.

Objectives: To analyse functional outcome parameters according to antimicrobial treatments after respiratory syncytial virus (RSV)-confirmed infection in adult lung transplant recipients., Methods: A 9-year retrospective multicentre cohort study (2011-19) included adult lung transplant recipients with RSV-confirmed infection. The first endpoint determined new allograft dysfunction (acute graft rejection and chronic lung allograft dysfunction (CLAD)) 3 months after infection. Then baseline and 3 months' postinfection forced expiratory volume in 1 second (FEV 1 ) values were compared according to antimicrobial treatment. Univariate logistic regression analysis was performed., Results: RSV infection was confirmed in 77 of 424 lung transplant recipients (estimated incidence of 0.025 per patient per year; 95% confidence interval 0.018-0.036). At 3 months, 22 recipients (28.8%) developed allograft dysfunction: ten (13%) possible CLAD, six (7.9%) acute rejection and six (7.9%) CLAD. Recipients with the lowest preinfection FEV 1 had a greater risk of developing pneumonia (median (interquartile range) 1.5 (1.1-1.9) vs. 2.2 (1.5-2.4) L/s, p 0.003) and a higher odds of receiving antibiotics (1.6 (1.3-2.3) vs. 2.3 (1.9-2.5) L/s, p 0.017; odds ratio 0.52, 95% confidence interval 0.27-0.99). Compared to tracheobronchitis/bronchiolitis, RSV-induced pneumonia led more frequently to hospitalization (91.7%, 22 vs. 58.0%, 29, p 0.003) and intensive care unit admission (33.3%, 8 vs. 0, p < 10 -3 ). For ribavirin-treated recipients (24.7%, 19) and azithromycin prophylaxis (50.6%, 39), 3-month FEV 1 values were not different from untreated recipients. The overall mortality was 2.5% at 1 month and 5.3% at 6 months, unrelated to RSV., Conclusions: At 3 months after RSV-confirmed infection, 22 recipients (28.8%) had new allograft dysfunction. Ribavirin treatment and azithromycin prophylaxis did not prevent FEV 1 decline., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Suppressive parenteral antibiotic therapy with beta-lactams may be necessary in patients with Gram-negative bone and joint infection (BJI). Subcutaneous drug administration can facilitate this therapy in outpatient setting, but there is limited information about this practice. We have developed an original approach for drug dosing in this context, based on therapeutic drug monitoring (TDM) and pharmacokinetic/pharmacodynamic (PK/PD) principles. The objective of this study was to describe our approach and its first results in a case series. We analyzed data from patients who received suppressive antibiotic therapy by subcutaneous (SC) route with beta-lactams as salvage therapy for prosthetic joint infection (PJI) and had TDM with PK/PD-based dose adjustment. Ten patients (six women and four men with a mean age of 77 years) were included from January 2017 to May 2020. The drugs administered by SC route were ceftazidime ( n = 4), ertapenem ( n = 4), and ceftriaxone ( n = 2). In each patient, PK/PD-guided dosage individualization was performed based on TDM and minimum inhibitory concentration (MIC) measurements. The dose interval could be prolonged from twice daily to thrice weekly in some patients, while preserving the achievement of PK/PD targets. The infection was totally controlled by the strategy in nine out the 10 patients during a median follow-up of 1,035 days (~3 years). No patient acquired carbapenem-resistant Gram-negative bacteria during the follow-up. One patient presented treatment failure with acquired drug resistance under therapy, which could be explained by late MIC determination and insufficient exposure, retrospectively. To conclude, our innovative approach, based on model-based TDM, MIC determination, and individualized PK/PD goals, facilitates, and optimizes suppressive outpatient beta-lactam therapy administered by SC route for PJI. These encouraging results advocate for larger clinical evaluation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Goutelle, Conrad, Pouderoux, Braun, Laurent, Gagnieu, Cohen, Guitton, Valour and Ferry.)

Introduction: Corynebacteria represent often-neglected etiological agents of post-traumatic and/or post-operative bone and joint infection (BJI). We describe here clinical characteristics and bacteriological determinants of this condition. Methods: A retrospective cohort study described characteristics, outcome and determinants of treatment failure of all patients with proven Corynebacterium spp. BJI (i.e., ≥2 culture-positive gold-standard samples). Available strains were further characterized regarding their antibiotic susceptibilies, abilities to form early (BioFilm Ring Test®) and mature (crystal violet staining method) biofilms and to invade osteoblasts (gentamicin protection assay). Results: The 51 included BJI were mostly chronic (88.2%), orthopedic device-related (74.5%) and polymicrobial (78.4%). After a follow-up of 60.7 weeks (IQR, 30.1-115.1), 20 (39.2%) treatment failures were observed, including 4 Corynebacterium -documented relapses, mostly associated with non-optimal surgical management (OR 7.291; p = 0.039). Internalization rate within MG63 human osteoblasts was higher for strains isolated from delayed (>3 months) BJI ( p < 0.001). Infection of murine osteoblasts deleted for the β1-integrin resulted in a drastic reduction in the internalization rate. No difference was observed regarding biofilm formation. Conclusions: Surgical management plays a crucial role in outcome of BJI involving corynebacteria, as often chronic and device-associated infections. Sanctuarisation within osteoblasts, implicating the β1 cellular integrin, may represent a pivotal virulence factor associated with BJI chronicity., Competing Interests: Biofilm Control provided support in the form of salaries for JT but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chauvelot, Ferry, Tafani, Diot, Tasse, Conrad, Chidiac, Braun, Lustig, Laurent and Valour.)

Objective: To describe the epidemiology of pubic osteomyelitis (PO) and to look for factors associated with treatment failure., Method: Retrospective study describing PO according to outcome: success or failure of initial management. Factors associated with failure determined by univariate Cox analysis. Kaplan-Meier curve compared between groups by log-rank test., Results: Twenty-five patients were included over a 13-year period; 24% of PO had blood-borne infection. Failure (44%) was always observed in chronic postoperative presentations (76%). Fistula (32%) was only observed in postoperative presentations and was significantly associated with failure (HR 5.1; P=0.011). Other risk factors were pelvic malignant tumor history, abscess, infection due to extended-spectrum beta-lactamase-producing Enterobacteriaceae, and polymicrobial infection., Conclusion: PO is most often a chronic postoperative polymicrobial infection in patients with comorbidities at high risk of relapse. Studies in larger cohorts could assess the efficacy of more aggressive surgical strategies in patients at high risk of failure., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: P. aeruginosa implant-associated bone and joint infections (BJI) is considered to be one of the most difficult to treat BJI. The data focusing specifically on this pathogen are sparse, and it seems difficult to extrapolate the results obtained with Enterobacteriaceae . Methods: We performed a retrospective observation study of all P. aeruginosa implant-associated BJI diagnosed at our institution from 2011 to 2018. We defined failure as any type of relapse, including persistence of the same P. aeruginosa , superinfection by another organism(s) or any other cause of relapse such as the need for a subsequent surgery. Nonparametric statistical methods were used to compare the study groups and Kaplan-Meier curves and multivariate Cox analysis and were used to detect determinants associated with treatment failure. Results: A total of 90 patients (62% men, median age 60 years IQR 47-72) including 30 (33%) prosthetic-joint infections and 60 (66%) other implant-associated BJIs were studied. Most of them were acute (62%). During the prolonged follow-up, (median 20 months; IQR 9-37), 23 patients (26%) experienced treatment failure. Optimal surgical treatment (DAIR for acute forms, explantation, 1-stage or 2-stage exchange for others) was significantly associated with a higher success rate in the univariate analysis ( p = 0.003). Sixty-four (71%) patients received effective initial treatment against P. aeruginosa administered and 81 of them (90%) did for at least 3 weeks: both these parameters correlated with a higher success rate. In the multivariate Cox-analysis optimal surgical treatment, IV effective treatment of at least 3 weeks and treatment with ciprofloxacin for at least 3 months proved to be independently associated to a better outcome in patients with P. aeruginosa implant-associated BJI. Conclusion: P. aeruginosa implant-associated BJI is one of the most difficult-to-treat BJI, with a strong impact on the prognosis of the surgical strategy. An effective initial IV antibiotic treatment for at least 3 weeks seems to be required, followed by oral ciprofloxacin for a total duration of 3 months., (Copyright © 2020 Cerioli, Batailler, Conrad, Roux, Perpoint, Becker, Triffault-Fillit, Lustig, Fessy, Laurent, Valour, Chidiac, Ferry.)

Data on immunogenicity and safety of the recommended revaccination schedule against diphtheria, tetanus, poliomyelitis, pertussis, Haemophilus influenzae type b (Hib), and hepatitis B in adult allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients are limited. This prospective single-center cohort study (April 2014 to March 2018) included adult allo-HSCT recipients referred to a dedicated vaccinology consultation and vaccinated with the pediatric combined diphtheria, tetanus, acellular pertussis, hepatitis B virus, inactivated poliovirus, and Haemophilus influenzae type b (DTaP(±HB)-IPV-Hib) vaccine (3 doses 1 month apart, booster dose 1 year later). The proportion of responders to tetanus, diphtheria, Hib, and hepatitis B vaccine and geometric mean concentrations (GMCs) of antibodies were assessed before and up to 24 months after vaccination. A total of 106 patients were vaccinated at a median (interquartile range) time of 12.4 (10 to 18.4) months post-transplant. At 5.3 (4.8 to 6.6) and 23.1 (21.1 to 25.1) months after vaccine initiation, high and sustained rates of protective antibody titers were achieved for tetanus (97.8% [95% confidence interval (95% CI), 92.4% to 99.7%], n = 91/93 and 100% [95% CI, 92% to 100%], n = 44/44), diphtheria (94.6% [95% CI, 87.9% to 98.2%], n = 88/93 and 90.9% [95% CI, 78.3% to 97.5%], n = 40/44), Hib (96.6% [95% CI, 90.4% to 99.3%], n = 85/88 and 93% [95% CI, 80.9% to 98.5%], n = 40/43), and hepatitis B (83.5% [95% CI, 73.5% to 90.9%], n = 66/79 and 81.1% [95% CI, 64.8% to 92%], n = 30/37). Underlying disease, stem cell source, chronic graft-versus-host-disease, and extracorporeal photopheresis differentially influenced GMCs of tetanus, diphtheria, and hepatitis B antibodies after 3 doses but not in the long term (24 months). Six (5.7%) patients experienced mild side effects. The pediatric DTaP(±HB)-IPV-Hib vaccine was safe and effective in eliciting a sustained protective humoral response in adult allo-HSCT recipients. Hepatitis B revaccination might be optimized by using higher antigen doses., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Staphylococcus argenteus is an emerging species responsible for infections comparable to those induced by Staphylococcus aureus . It has been involved in few chronic or persistent infections so far. In this study, we described a case of a persistent prosthetic-joint infection (PJI) affecting a young woman. We investigated in vitro the virulence traits of the incriminated S. argenteus strain (bone cell invasion, biofilm formation and induction of inflammation) and analyzed its genome, in comparison with two other strains of S. argenteus and two S. aureus isolates. It appeared that this S. argenteus PJI strain combined biofilm formation, osteoblast invasion and intracellular persistence abilities together with genes potentially involved in the escape of the host immune defenses, which might explain the chronicization of the infection.

Introduction: Histopathological definition of bone and joint infection (BJI) is based on Mirra's criterion (≥ 5 polymorphonuclears (PMNs) per field in 5 high power fields (HPFs)). However, this definition does not seem appropriate for chronic BJIs caused by slow-growing germs such as Cutibacterium acnes ( C. acnes ). The aim of this study was to confirm that Mirra's criterion is not adequate for diagnosis of BJIs due to C. acnes . The second objective was to determine if plasma cell infiltration could be useful for the diagnosis of chronic BJIs due to C. acnes . Methods: We retrospectively selected 25 consecutive patients from 2009 to 2013 with chronic BJIs due to C. acnes . Histological analysis was performed on the 21 cases with at least two C. acnes positive cultures. In addition of Mirra's criterion, the number of plasma cells (≥5 plasma cells/5 HPFs, defined as "CRIOAc Lyon's criterion") was implemented in the histopathological analysis. Patients were defined as infected, if at least one of the two criteria were present. Results: According to Mirra's and CRIOAc Lyon's criteria, positive histopathology was observed in 12 (57.1%) and 15 (71.4%) cases respectively. Considering the 9 cases with negative Mirra's criterion, high plasma cell infiltration (≥5 plasma cells per field/5 HPFs) was observed in 5 cases (55.6%), and low plasma cells infiltration (2-5 plasma cells per field/5 HPFs) was observed in 4 other cases (44.4%). Conclusions: Adding CRIOAc Lyon's criterion to Mirra's criterion might restore some histopathological diagnosis of chronic BJIs due to C. acnes when a chronic BJI is clinically suspected., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Targeting biofilm-embedded and intraosteoblastic Staphylococcus aureus, rifampicin gained a pivotal role in bone and joint infection (BJI) treatment. Two other rifamycins, rifabutin and rifapentine, may represent better-tolerated alternatives, but their activity against bacterial reservoirs associated with BJI chronicity has never been evaluated., Objectives: To evaluate the activities of rifampicin, rifabutin and rifapentine in osteoblast infection models., Methods: Using three S. aureus isolates, rifamycins were compared regarding: (i) their intracellular activity in 'acute' (24 h) and 'chronic' (7 days) osteoblast infection models at 0.1× MIC, 1× MIC, 10× MIC and 100× MIC, while impacting infection-induced cytotoxicity (MTT assay), intracellular phenol-soluble modulin (PSM) secretion (RT-PCR), resistance selection and small colony variant (SCV) emergence; and (ii) their minimal biofilm eradication concentration (MBEC) and their MIC to prevent biofilm formation (bMIC)., Results: At 0.1× MIC, only rifabutin significantly reduced intracellular inoculum and PSM secretion. All rifamycins allowed a 50% reduction of intraosteoblastic inoculum at higher concentrations, with no difference between acute and chronic infection models, while reducing infection-induced cytotoxicity and PSM secretion. Dose-dependent emergence of intracellular SCVs was observed for all molecules. No intracellular emergence of resistance was detected. bMICs were equivalent for all molecules, but MBEC90s of rifapentine and rifabutin were 10- to 100-fold lower than those of rifampicin, respectively., Conclusions: All rifamycins are efficient in reducing the S. aureus intraosteoblastic reservoir while limiting infection-induced cytotoxicity, with a higher activity of rifabutin at low concentrations. All molecules prevent biofilm formation, but only rifapentine and rifabutin consistently reduce formed biofilm-embedded bacteria for all isolates. The activity of rifabutin at lower doses highlights its therapeutic potential., (© 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.)

In patients with chronic liver disease and liver transplant recipients, cirrhosis-associated immune dysfunction syndrome and immunosuppressant drug regimens required to prevent graft rejection lead to a high risk of severe infections, associated with acute liver decompensation, graft loss and increased mortality. In addition to maintain their global health status, vaccination represents a major preventive measure against specific infectious risks of particular concern in this population, such as invasive pneumococcal diseases, influenza or viral hepatitis A and B. However, immunization in this setting raises several issues: i) recommended vaccination schedules rely on sparse immunogenicity data without clinical efficacy and effectiveness trials designed for this specific population; ii) dynamics of immunosuppression makes timing of immunization challenging; iii) live attenuated vaccines are contraindicated after transplantation; and iv) vaccines tolerance is poorly known in cirrhotic patients. This review outlines the rational for vaccination in adult liver transplant candidates and recipients and available data regarding immunization in this specific population., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Introduction : In patients undergoing a « debridement, antibiotics, and implant retention » (DAIR) procedure for acute staphylococcal prosthetic joint infection (PJI), post-operative treatment with rifampin has been associated with a higher probability of success.(1,2) However, it is not known whether it is the total dose, delay of introduction or length of therapy with rifampin that is most strongly associated with the observed improved outcomes. Methods : A multicentric, retrospective cohort study of patients with acute staphylococcal hip and knee PJI treated with DAIR between January 2011 and December 2016. Failure of the DAIR procedure was defined as persistent infection, need for another surgery or death. We fitted logistic and Cox regression multivariate models to identify predictors of DAIR failure. We compared Kaplan-Meier estimates of failure probability in different levels of the 3 variables of interest - total dose, delay of introduction or length of therapy with rifampin - with the log-rank test. Results : 79 patients included (median age 71 years [63.5-81]; 55 men [70%]), including 54 (68%) DAIR successes and 25 (32%) DAIR failures. Patients observed for a median of 435 days [IQR 107.5-834]. Median ASA score significantly lower in DAIR successes than in DAIR failures (2 vs. 3, respectively p = 0.011). Bacterial cultures revealed 65 (82.3%) S. aureus and 16 (20.3%) coagulase negative staphylococci, with 2 patients being infected simultaneously with S. aureus and CNS. Among S. aureus isolates, 7 (10.8%) resistant to methicillin; 2 (3.1 %) resistant to rifampin. Median duration of antimicrobial therapy was 85 days [IQR 28.5-97.8]. Fifty-eight patients (73.4%) received rifampin at a median dose of 14.6 mg/kg/day |IQR 13-16.7], started at a median delay of 8.5 days [IQR, 4-7.5] after debridement surgery. Twenty-one patients (26.6%) developed a drug-related adverse event, leading to rifampin interruption in 6 of them (7.6% of total cohort). Determinants of DAIR failure were rifampin use (HR 0.17, IC [0.06, 0.45], p-value <0.001), association of rifampin with a fluoroquinolone (HR 0.19, IC [0.07, 0.53], p-value = 0.002) and duration of rifampin therapy (HR 0.97, IC [0.95, 1], p-value = 0.022). We did not observe a significant difference between DAIR successes and failures in rifampin use, dose and delay of introduction. In a multivariate Cox model, only duration of rifampin therapy was significantly associated with DAIR failure. Kaplan Meier estimate of DAIR failure probability was significantly higher in patients receiving less than 14 days of rifampin in comparison with those receiving more than 14 days of rifampin ( p = 0.0017). Conclusion : Duration of rifampin therapy is a key determinant of improved outcomes in early-onset acute prosthetic joint infection due to Staphylococcus treated with DAIR., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Small colony variants (SCV) of Staphylococcus aureus have been reported as implicated in chronic infections. Here, we investigated the genomic and transcriptomic changes involved in the evolution from a wild-type to a SCV from in a patient with prosthetic joint infection relapse. The SCV presented a stable phenotype with no classical auxotrophy and the emergence of rifampicin resistance. Whole Genome Sequencing (WGS) analysis showed only the loss of a 42.5 kb phage and 3 deletions, among which one targeting the rpoB gene, known to be the target of rifampicin and to be associated to SCV formation in the context of a constitutively active stringent response. Transcriptomic analysis highlighted a specific signature in the SCV strain including a complex, multi-level strategy of survival and adaptation to chronicity within the host including a protection from the inflammatory response, an evasion of the immune response, a constitutively activated stringent response and a scavenging of iron sources., (Copyright © 2019 Loss, Simões, Valour, Cortês, Gonzaga, Bergot, Trouillet-Assant, Josse, Diot, Ricci, Vasconcelos and Laurent.)

With the aging of population, the number of indications for total joint replacement is continuously increasing. However, prosthesis loosening can happen and is related to two major mechanisms: (1) aseptic loosening due to prosthesis micromotion and/or corrosion and release of wear particles from the different components of the implanted material and (2) septic loosening due to chronic prosthetic joint infection (PJI). The "aseptic" character of prosthesis loosening has been challenged over the years, especially considering that bacteria can persist in biofilms and be overlooked during diagnosis. Histological studies on periprosthetic tissue samples reported that macrophages are the principle cells associated with aseptic loosening due to wear debris. They produce cytokines and favor an inflammatory environment that induces formation and activation of osteoclasts, leading to bone resorption and periprosthetic osteolysis. In PJIs, the presence of infiltrates of polymorphonuclear neutrophils is a major criterion for histological diagnosis. Neutrophils are colocalized with osteoclasts and zones of osteolysis. A similar inflammatory environment also develops, leading to bone resorption through osteoclasts. Staphylococcus aureus , Staphylococcus epidermidis , and Staphylococcus lugdunensis are the main staphylococci observed in PJIs. They share the common feature to form biofilm. For S. aureus and S. epidermidis , the interaction between biofilm and immunes cells (macrophages and polymorphonuclear neutrophils) differs regarding the species. Indeed, the composition of extracellular matrix of biofilm seems to impact the interaction with immune cells. Recent papers also reported the major role of myeloid-derived suppressor cells in biofilm-associated PJIs with S. aureus . These cells prevent lymphocyte infiltration and facilitate biofilm persistence. Moreover, the role of T lymphocytes is still unclear and potentially underestimates. In this review, after introducing the cellular mechanism of aseptic and septic loosening, we will focus on the interrelationships between staphylococcal biofilm, immune cells, and bone cells.

Background: Optimal treatment of prosthetic joint infection and chronic osteomyelitis consists of surgical removal of biofilm-embedded bacteria, followed by a 6-12 week course of antimicrobial therapy. However, when optimal surgery is not feasible, oral prolonged suppressive antibiotic therapy (PSAT) is recommended to prevent prosthesis loosening and/or relapse of infection. Since 2010, we have used infection salvage therapy using off-label subcutaneous (sc) injection of a β-lactam as PSAT for patients in whom oral PSAT is not possible., Methods: A single-centre prospective cohort study (2010-18) reporting treatment modalities, efficacy and safety in all patients receiving sc PSAT. NCT03403608., Results: The 10 included patients (median age 79 years) had polymicrobial (n = 5) or MDR bacterial (n = 4) prosthetic joint infection (knee, n = 4; hip, n = 3) or chronic osteomyelitis (n = 3). After initial intensive therapy, seven patients received ertapenem, three patients received ceftriaxone and one patient received ceftazidime by sc injection (one patient received 8 days of ceftriaxone before receiving ertapenem). In one patient, sc PSAT failed with recurrent signs of infection under treatment. In three patients, sc PSAT had to be discontinued due to side effects; in only one of these was the sc route implicated (skin necrosis following direct sc injection and not gravity infusion). Median treatment duration was 433 days. In six patients, sc PSAT was successful with favourable outcome at the time of writing. Interestingly, three patients with MDR bacterial carriage at baseline lost this under PSAT during follow-up., Conclusions: As salvage therapy, sc PSAT delivered by gravity infusion is a safe and interesting alternative when an optimal surgical strategy is not feasible and no oral treatment is available., (© 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.)

Solid organ transplant candidates/recipients are at risk of mycobacterial infections. Although guidelines on the management of latent tuberculosis infection and active tuberculosis are available for solid organ transplant recipients, limited guidance focuses on end-stage liver disease or liver transplant recipients who require management in a referral center. Therapeutic challenges arise from direct antituberculosis drug-related hepatotoxicity, and substantial metabolic interactions between immunosuppressive and antituberculosis drugs. Another issue is the optimal timing of therapy with regards to the time of transplantation. This review focuses on the importance of tuberculosis screening with immunological tests, challenges in the diagnosis, management, and treatment of latent tuberculosis infection and active tuberculosis, as well as risk assessment for active tuberculosis in the critical peri-liver transplantation period. We detail therapeutic adjustments required for the management of antituberculosis drugs in latent tuberculosis infection and active tuberculosis, particularly when concomitantly using rifampicin and immunosuppressive drugs., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Daptomycin has been recognized as a therapeutic option for the treatment of bone and joint infection (BJI). Gene polymorphism of ABCB1, the gene encoding P-glycoprotein (P-gp), may influence daptomycin pharmacokinetics (PK)., Objectives: We aimed to examine population PK of daptomycin and its determinants, including genetic factors, in patients with BJI., Patients and Methods: We analysed data from patients who received daptomycin for BJI between 2012 and 2016 in our regional reference centre and who had measured daptomycin concentrations and P-gp genotyping. A population approach was used to analyse PK data. In covariate analysis, we examined the influence of three single nucleotide variations (SNVs) of ABCB1 (3435C > T, 2677G > T/A and 1236C > T) and that of the corresponding haplotype on daptomycin PK parameters. Simulations performed with the final model examined the influence of covariates on the probability to achieve pharmacodynamic (PD) targets., Results: Data from 81 patients were analysed. Daptomycin body CL (CLDAP) correlated with CLCR and was 23% greater in males than in females. Daptomycin central V (V1) was allometrically scaled to body weight and was 25% lower in patients with homozygous CGC ABCB1 haplotype than in patients with any other genotype. Simulations performed with the model showed that sex and P-gp haplotype may influence the PTA for high MIC values and that a dosage of 10 mg/kg/24 h would optimize efficacy., Conclusions: Daptomycin dosages higher than currently recommended should be evaluated in patients with BJI. Gender and P-gp gene polymorphism should be further examined as determinants of dosage requirements., (© 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.)

Objectives: Prolonged use of linezolid for bone and joint infection (BJI) is limited by its long-term toxicity. The better safety profile of tedizolid, a recently developed oxazolidinone, could offer an alternative. However, its efficacy against biofilm-embedded and intracellular Staphylococcus aureus, the two main bacterial reservoirs associated with BJI chronicity, is unknown., Methods: Using three S. aureus strains (6850 and two clinical BJI isolates), linezolid and tedizolid were compared regarding their ability: (i) to target the S. aureus intracellular reservoir in an in vitro model of osteoblast infection, using three concentrations increasing from the bone concentration reached with standard therapeutic doses (Cbone = 2.5 × MIC; Cplasm = 10 × MIC; Cmax = 40 × MIC); (ii) to eradicate mature biofilm [minimal biofilm eradication concentration (MBEC)]; and (iii) to prevent biofilm formation [biofilm MIC (bMIC) and confocal microscopy]., Results: Linezolid and tedizolid weakly reduced the intracellular inoculum of S. aureus in a strain-dependent manner despite the similar MICs for the tested strains, but improved cell viability even in the absence of an intracellular bactericidal effect. Conversely, linezolid and tedizolid were ineffective in eradicating mature biofilm formed in vitro, with MBEC >2000 and >675 mg/L, respectively. bMICs of tedizolid were 4-fold lower than those of linezolid for all strains., Conclusions: Linezolid and tedizolid alone are not optimal candidates to target bacterial phenotypes associated with chronic forms of BJI. Despite weak intracellular activity, they both reduce infection-related cytotoxicity, suggesting a role in modulating intracellular expression of staphylococcal virulence factors. Although inactive against biofilm-embedded S. aureus, both-but particularly tedizolid-are able to prevent biofilm formation., (© The Author(s) 2018. 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.)

Introduction: Immune reconstitution after haematopoietic stem cell transplantation (HSCT) is a complex and dynamic process, varying from a state of nearly complete immunosuppression to an expected full immune recovery. Specific vaccination guidelines recommend reimmunisation after HSCT but data regarding vaccine efficacy in this unique population are scarce. New immune functional assays could enable prediction of vaccine response in the setting of HSCT., Methods and Analysis: A prospective, longitudinal single-centre cohort study of autologous and allogeneic HSCT recipients was designed in order to determine the vaccine response to five vaccine targets (pneumococcus, hepatitis B virus, Haemophilus Influenzae type b, tetanus and diphtheria) and to correlate it to immune function parameters. A workflow was set up to study serological response to vaccines and to describe the functional immune status of 100 HSCT recipients (50 autologous and 50 allogeneic) before and 3, 12 and 24 months after primary immunisation. At each time point, 'basic' immune status recording (serology, immunophenotyping of lymphocyte subsets by flow cytometry) will be assessed. The immune response will furthermore be evaluated before and 3 months after primary vaccination by two ex vivo immune functional assays assessing: (1) tumour necrosis factor alpha, interferon gamma production and host messenger RNA expression on whole-blood stimulation by lipopolysaccharide or Staphylococcus aureus enterotoxin B and (2) T-lymphocyte proliferation in response to a standard mitogen (phytohaemagglutinin) or to selected recall antigens. Reference intervals will be determined from a cohort of 30 healthy volunteers. This translational study will provide data describing vaccine response, immune functionality of HSCT recipients over time and will allow mapping HSCT recipients with regard to their immune function., Ethics and Dissemination: Ethical approval has been obtained from the institutional review board (no 69HCL17&#95;0769). Results will be communicated at scientific meetings and submitted for publication in peer-reviewed journals., Trial Registration Number: NCT03659773; Pre-results., Competing Interests: Competing interests: KB-P is an employee of bioMérieux SA, an in vitro diagnostic company., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Nontuberculous mycobacteria (NTM) lung diseases are increasingly recognized as chronic opportunistic infections, occurring in individuals with a wide variety of underlying conditions. In the absence of systemic immunodeficiency, decision of NTM lung disease treatment must relies on a careful risk/benefit assessment, given the requirement of long-term administration of multidrug therapies supported by limited evidence. The primary objective was to identify the factors associated with anti-NTM treatment initiation. Clinical and radiological outcome upon treatment were studied., Methods: This retrospective, single center study (2013-2016, 45 months) addressed the criteria supporting treatment decision among adults with NTM lung disease without systemic immunodeficiency at our institution, with the assigned goal to harmonize the practice. All patients matched the current international definitions of NTM lung disease according to the American Thoracic Society criteria. Factors associated with anti-NTM treatment were investigated by conditional logistic regression. Clinical and radiological outcomes of treated and untreated NTM-disease cases were examined. Mortality rate was assessed. An expert radiologist conducted a blinded computed tomography (CT)-scan review of the treated and untreated patients., Results: Among 51 cases of NTM lung diseases, 25 (49%) received anti-NTM treatment. In univariate analysis, a body mass index (BMI) < 18 kg/m 2 (odds ratio (OR), 4.2 [95% confidence interval (CI) 1.2-15.2]; p = 0.042), hemoptysis (OR, 11.8 [95% CI 1.35-12.9]; p = 0.026), excavation(s) (OR, 4.8 [95% CI 1.4-16.4], p = 0.012), prior anti-NTM treatment (OR, 5.65 [95% CI 1.06-29.9]; p = 0.042), Aspergillus spp. co-infection (OR, 6.3 [95% CI 1.8-22.2]; p = 0.004) were associated with treatment initiation. In multivariate analysis, Aspergillus spp. co-infection was the only independent determinant of treatment initiation (OR, 5.3 [95% CI 1.1-25.4]; p = 0.036). Twenty-one (81%) patients received ≥3 anti-NTM drugs. Median treatment duration and follow-up were 36.3 (interquartile range [IQR], 13.1-64.4) weeks and 17.1 (IQR, 8.7-27.1) months, respectively. Regarding radiological outcome, 85 CT-scans were reviewed, showing similar rates of regression or stabilization in treated and untreated patients. Overall mortality rate was not different in treated and untreated patients., Conclusion: The most relevant variable associated with anti-NTM treatment initiation was Aspergillus spp. co-infection. Radiological regression or stabilization of pulmonary lesions was not different between the treated and untreated patients.

The empirical use of vancomycin in combination with a broad-spectrum beta-lactam is currently recommended after the initial surgery of prosthetic joint infection (PJI). However, the tolerability of such high-dose intravenous regimens is poorly known. Adult patients receiving an empirical antimicrobial therapy (EAT) for a PJI were enrolled in a prospective cohort study (2011 to 2016). EAT-related adverse events (AE) were described according to the common terminology criteria for AE (CTCAE), and their determinants were assessed by logistic regression and Kaplan-Meier curve analysis. The EAT of the 333 included patients (median age, 69.8 years; interquartile range [IQR], 59.3 to 79.1 years) mostly relies on vancomycin ( n = 229, 68.8%), piperacillin-tazobactam ( n = 131, 39.3%), and/or third-generation cephalosporins ( n = 50, 15%). Forty-two patients (12.6%) experienced an EAT-related AE. Ten (20.4%) AE were severe (CTCAE grade ≥ 3). The use of vancomycin (odds ratio [OR], 6.9; 95% confidence interval [95%CI], 2.1 to 22.9), piperacillin-tazobactam (OR, 3.7; 95%CI, 1.8 to 7.2), or the combination of both (OR, 4.1; 95%CI, 2.1 to 8.2) were the only AE predictors. Acute kidney injury (AKI) was the most common AE ( n = 25; 51.0% of AE) and was also associated with the use of the vancomycin and piperacillin-tazobactam combination (OR, 6.7; 95%CI, 2.6 to 17.3). A vancomycin plasma overexposure was noted in nine (37.5%) of the vancomycin-related AKIs only. Other vancomycin-based therapies were significantly less at risk for AE and AKI. The EAT of PJI is associated with an important rate of AE, linked with the use of the vancomycin and the piperacillin-tazobactam combination. These results corroborate recent findings suggesting a synergic toxicity of these drugs in comparison to vancomycin-cefepime, which remains to be evaluated in PJI. (This study has been registered at ClinicalTrials.gov under identifier NCT03010293.)., (Copyright © 2018 American Society for Microbiology.)

We reviewed all outpatients with bone and joint infection treated with cefoxitin in continuous intravenous infusion using mobile elastomeric infusors in our regional reference center between 2014 and 2017. The stability of cefoxitin provides an interesting and well-tolerated alternative for continuous infusion in outpatients with polymicrobial bone and joint infection., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Biofilm formation is a critical virulence factor responsible for treatment failure and chronicity in orthopaedic device-related infections (ODIs) caused by Staphylococcus aureus. Clonal lineages differ in terms of their biofilm forming capacities. The aim of this study was to investigate the correlation between the clonal complex (CC) affiliation and biofilm phenotype of 30 clinical S. aureus isolates responsible of ODI based on i) early biofilm formation using BioFilm Ring Test® and mature biofilm formation using crystal violet assays, ii) biofilm composition using DNase and proteinase K activity, and iii) prevention of biofilm formation by cloxacillin, teicoplanin and vancomycin using Antibiofilmogram® (biofilm minimal inhibitory concentration-bMIC). In terms of early biofilm formation, the CC30 strains were significantly slower than the CC5, CC15 and CC45 strains. CC45 strains produced significantly more mature biofilm than other group of strains did. The formation of biofilms was highly dependent on the presence of extracellular DNA in the CC5, CC15 and CC30 strains whereas it was mostly dependent on the presence of proteins in CC45. Finally, the CC30 group highlighted higher proportion of susceptible (bMIC < breakpoints of EUCAST guidelines) for cloxacillin, teicoplanin and vancomycin compared to the other CCs. These results demonstrate that the biofilm phenotype of clinical S. aureus isolates from ODIs is strongly related to their respective CC affiliation., Competing Interests: We have read the journal’s policy and we have commercial competing interests with Biofilm Control but this does not alter our adherence to PLOS ONE policies on sharing data and materials. Biofilm Control only provided a financial help for the present study.

Background: A two-stage surgical strategy (debridement-negative pressure therapy (NPT) and flap coverage) with prolonged antimicrobial therapy is usually proposed in pressure ulcer-related pelvic osteomyelitis but has not been widely evaluated., Methods: Adult patients with pressure ulcer-related pelvic osteomyelitis treated by a two-stage surgical strategy were included in a retrospective cohort study. Determinants of superinfection (i.e., additional microbiological findings at reconstruction) and treatment failure were assessed using binary logistic regression and Kaplan-Meier curve analysis., Results: Sixty-four pressure ulcer-related pelvic osteomyelitis in 61 patients (age, 47 (IQR, 36-63)) were included. Osteomyelitis was mostly polymicrobial (73%), with a predominance of S. aureus (47%), Enterobacteriaceae spp. (44%) and anaerobes (44%). Flap coverage was performed after 7 (IQR, 5-10) weeks of NPT, with 43 (68%) positive bone samples among which 39 (91%) were superinfections, associated with a high ASA score (OR, 5.8; p = 0.022). An increased prevalence of coagulase negative staphylococci (p = 0.017) and Candida spp. (p = 0.003) was observed at time of flap coverage. An ESBL Enterobacteriaceae spp. was found in 5 (12%) patients, associated with fluoroquinolone consumption (OR, 32.4; p = 0.005). Treatment duration was as 20 (IQR, 14-27) weeks, including 11 (IQR, 8-15) after reconstruction. After a follow-up of 54 (IQR, 27-102) weeks, 15 (23%) failures were observed, associated with previous pressure ulcer (OR, 5.7; p = 0.025) and Actinomyces spp. infection (OR, 9.5; p = 0.027)., Conclusions: Pressure ulcer-related pelvic osteomyelitis is a difficult-to-treat clinical condition, generating an important consumption of broad-spectrum antibiotics. The lack of correlation between outcome and the debridement-to-reconstruction interval argue for a short sequence to limit the total duration of treatment.

Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is a major curative treatment option for malignant and non-malignant hematological diseases, but is associated with an increased risk for infections, of which some are preventable by vaccination. Vaccination guidelines recommend repeated doses of most inactivated vaccines to achieve long-lasting immune responses. However, the efficacy of immunization is often hampered by graft-versus-host disease or severe opportunistic infections., Areas Covered: This review summarizes the vaccine recommendations for adult allogeneic HSCT recipients and discusses the challenges and future directions regarding vaccine immunization in these patients., Expert Commentary: Vaccination is a well-tolerated therapeutic intervention to prevent infections after allogeneic HSCT. Allogeneic HSCT recipients could benefit from experience regarding vaccine efficacy capitalized through specific data registries. An individualized immunization approach, modulating inception and intensity of vaccination schedule according to transplant characteristics, transplant-related complications and immune recovery status, might help to improve vaccine efficacy in this specific population. Identification of surrogate markers of the immune status and of vaccine efficacy, beyond antibody testing, as well as development of new vaccines are exciting fields of future research.

Background: Ertapenem is a therapeutic option in patients with Gram-negative bone and joint infection (BJI). The subcutaneous (sc) route of administration is convenient in the outpatient setting and has shown favourable pharmacokinetics (PK), but available data on ertapenem are limited., Objectives: To perform population PK analysis and pharmacokinetic/pharmacodynamic (PK/PD) simulation of ertapenem administered by the intravenous (iv) or sc route to patients with BJI., Patients and Methods: This was a retrospective analysis of PK data collected in patients with BJI who received iv or sc ertapenem. Measured ertapenem concentrations were analysed with a non-parametric population approach. Then, simulations were performed based on the final model to investigate the influence of ertapenem route of administration, dosage and renal function on the probability of achieving a pharmacodynamic (PD) target, defined as the percentage of time for which free plasma concentrations of ertapenem remained above the MIC (fT>MIC) of 40%., Results: Forty-six PK profiles (13 with iv and 33 with sc ertapenem) with a total of 133 concentrations from 31 subjects were available for the analysis. A two-compartment model with linear sc absorption and linear elimination best fitted the data. Creatinine clearance was found to significantly influence ertapenem plasma clearance. Simulations showed that twice daily dosing, sc administration and renal impairment were associated with an increase in fT>MIC and target attainment., Conclusions: Our results indicate that 1 g of ertapenem administered twice daily, by the iv or sc route, may optimize ertapenem exposure and achievement of PK/PD targets in patients with BJI.