Retrospective Multicenter Study Comparing Infectious and Noninfectious Aortitis.

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.

Burden of influenza in the elderly: a narrative review.

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.

Necrotizing external otitis: analysis of relapse risk factors in 66 patients managed during a 12 year period.

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.

Outcomes of post-exposure vaccination by modified vaccinia Ankara to prevent mpox (formerly monkeypox): a retrospective observational study in Lyon, France, June to August 2022.

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.

Multimechanistic Monoclonal Antibody Combination Targeting Key Staphylococcus aureus Virulence Determinants in a Rabbit Model of Prosthetic Joint Infection.

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.

In vitro antibiotic activity against intraosteoblastic Staphylococcus aureus: a narrative review of the literature.

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.

Evaluation of intraosteoblastic activity of dalbavancin against Staphylococcus aureus in an ex vivo model of bone cell infection.

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.

Efficacy and Safety of Revaccination against Tetanus, Diphtheria, Haemophilus influenzae Type b and Hepatitis B Virus in a Prospective Cohort of Adult Recipients of Allogeneic Hematopoietic Stem Cell Transplantation.

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.

Antibiofilm and intraosteoblastic activities of rifamycins against Staphylococcus aureus: promising in vitro profile of rifabutin.

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.

Investigation of a Staphylococcus argenteus Strain Involved in a Chronic Prosthetic-Joint Infection.

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.

Evaluation of the ability of linezolid and tedizolid to eradicate intraosteoblastic and biofilm-embedded Staphylococcus aureus in the bone and joint infection setting.

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.

Genetic polymorphisms of ABCB1 (P-glycoprotein) as a covariate influencing daptomycin pharmacokinetics: a population analysis in patients with bone and joint infection.

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.

Subcutaneous suppressive antibiotic therapy for bone and joint infections: safety and outcome in a cohort of 10 patients.

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 ß-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.

Prospective Cohort Study of the Tolerability of Prosthetic Joint Infection Empirical Antimicrobial Therapy.

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.).

Population pharmacokinetics and probability of target attainment of ertapenem administered by subcutaneous or intravenous route in patients with bone and joint infection.

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.

A retrospective study of factors associated with treatment decision for nontuberculous mycobacterial lung disease in adults without altered systemic immunity.

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/m2 (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.

Pressure ulcer-related pelvic osteomyelitis: evaluation of a two-stage surgical strategy (debridement, negative pressure therapy and flap coverage) with prolonged antimicrobial therapy.

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.

Intraosteoblastic activity of daptomycin in combination with oxacillin and ceftaroline against MSSA and MRSA.

BACKGROUND: The Staphylococcus aureus intracellular reservoir is associated with bone and joint infection (BJI) chronicity. As daptomycin is increasingly prescribed in BJI, strategies for improving its reduced intracellular activity should be promoted. OBJECTIVES: Based on the known in vitro synergy of daptomycin with ß-lactams, the aim of the present study was to evaluate the intracellular activity of these combinations in an ex vivo osteoblast infection model. METHODS: Osteoblastic cells infected with an MRSA strain or its isogenic MSSA counterpart were incubated for 24 h with daptomycin, oxacillin or ceftaroline alone or in combination using usual intraosseous therapeutic concentrations. Intracellular bacteria were quantified by plating cell lysates. MICs for MSSA and MRSA were determined using the chequerboard method at pH 5 to mimic conditions expected within lysosomes, the foremost S. aureus intracellular location. RESULTS: Daptomycin failed to reduce the intracellular MSSA inoculum, and was weakly active against MRSA compared with untreated cells (-27.6%; P < 10-3). Oxacillin and ceftaroline revealed significant intracellular activity, including oxacillin against MRSA-infected cells (-43.2%; P < 10-3). The daptomycin/oxacillin combination was significantly more active against intracellular MSSA and MRSA compared with daptomycin and oxacillin alone (-44.4% and -57.2%, respectively; P < 0.05). In contrast, daptomycin/ceftaroline was not more efficient than ceftaroline alone. Interestingly, oxacillin MICs for MRSA decreased in vitro from >256 to 0.023 mg/L when the pH decreased from 7 to 5, and chequerboards showed an additive effect of the daptomycin/oxacillin combination against MRSA at pH 5. CONCLUSIONS: In acidic intracellular conditions, oxacillin enhances daptomycin activity against the intraosteoblastic reservoir of S. aureus, including MRSA.

Adaptive processes of Staphylococcus aureus isolates during the progression from acute to chronic bone and joint infections in patients.

Staphylococcus aureus bone and joint infection (BJI) is associated with significant rates of chronicity and relapse. In this study, we investigated how S. aureus is able to adapt to the human environment by comparing isolates from single patients with persisting or relapsing BJIs that were recovered during the initial and recurrent BJI episodes. In vitro and in vivo assays and whole-genome sequencing analyses revealed that the recurrent isolates induced a reduced inflammatory response, formed more biofilms, persisted longer in the intracellular compartments of host bone cells, were less cytotoxic and induced less mortality in a mouse infection model compared with the initial isolates despite the lack of significant changes at the genomic level. These findings suggest that S. aureus BJI chronicization is associated with an in vivo bacterial phenotypical adaptation that leads to decreased virulence and host immune escape, which is linked to increased intraosteoblastic persistence and biofilm formation.