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1.
J Antimicrob Chemother ; 74(9): 2666-2675, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263884

RESUMO

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

3.
Am Heart J ; 214: 69-76, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31174053

RESUMO

BACKGROUND: Left ventricular assist device (LVAD)-associated infections may be life-threatening and impact patients' outcome. We aimed to identify the characteristics, risk factors, and prognosis of LVAD-associated infections. METHODS: Patients included in the ASSIST-ICD study (19 centers) were enrolled. The main outcome was the occurrence of LVAD-associated infection (driveline infection, pocket infection, or pump/cannula infection) during follow-up. RESULTS: Of the 652 patients enrolled, 201 (30.1%) presented a total of 248 LVAD infections diagnosed 6.5 months after implantation, including 171 (26.2%), 51 (7.8%), and 26 (4.0%) percutaneous driveline infection, pocket infection, or pump/cannula infection, respectively. Patients with infections were aged 58.7 years, and most received HeartMate II (82.1%) or HeartWare (13.4%). Most patients (62%) had implantable cardioverter-defibrillators (ICDs) before LVAD, and 104 (16.0%) had ICD implantation, extraction, or replacement after the LVAD surgery. Main pathogens found among the 248 infections were Staphylococcus aureus (n = 113' 45.4%), Enterobacteriaceae (n = 61; 24.6%), Pseudomonas aeruginosa (n = 34; 13.7%), coagulase-negative staphylococci (n = 13; 5.2%), and Candida species (n = 13; 5.2%). In multivariable analysis, HeartMate II (subhazard ratio, 1.56; 95% CI, 1.03 to 2.36; P = .031) and ICD-related procedures post-LVAD (subhazard ratio, 1.43; 95% CI, 1.03-1.98; P = .031) were significantly associated with LVAD infections. Infections had no detrimental impact on survival. CONCLUSIONS: Left ventricular assist device-associated infections affect one-third of LVAD recipients, mostly related to skin pathogens and gram-negative bacilli, with increased risk with HeartMate II as compared with HeartWare, and in patients who required ICD-related procedures post-LVAD. This is a plea to better select patients needing ICD implantation/replacement after LVAD implantation.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31235630

RESUMO

High dosages of ceftriaxone are used to treat central nervous system (CNS) infections. Dosage adaptation according to the glomerular filtration rate is currently not recommended. Ceftriaxone pharmacokinetics (PK) was investigated by a population approach in patients enrolled in a French multicenter prospective cohort study who received high-dose ceftriaxone for CNS infection as recommended by French guidelines (75 to 100 mg/kg of body weight/day without an upper limit). Only those with suspected bacterial meningitis were included in the PK analysis. A population model was developed using Pmetrics. Based on this model, a dosing nomogram was developed, using the estimated glomerular filtration rate (eGFR) and total body weight as covariates to determine the optimal dosage allowing achievement of targeted plasma trough concentrations. Efficacy and toxicity endpoints were based on previous reports, as follows: total plasma ceftriaxone concentrations of ≥20 mg/liter in >90% of patients for efficacy and ≤100 mg/liter in >90% of patients for toxicity. Based on 153 included patients, a two-compartment model including eGFR and total body weight as covariates was developed. The median value of the unbound fraction was 7.57%, and the median value of the cerebral spinal fluid (CSF)/plasma ratio was 14.39%. A nomogram was developed according to a twice-daily regimen. High-dose ceftriaxone administration schemes, used to treat meningitis, should be adapted to the eGFR and weight, especially to avoid underdosing using current guidelines. (This study has been registered at ClinicalTrials.gov under identifier NCT01745679.).

5.
Int J Cardiol ; 288: 102-106, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31056415

RESUMO

BACKGROUND: Streptococcus pneumoniae is responsible for <2% of infective endocarditis (IE). The aim of this study was to assess the prognosis of pneumococcal IE. METHODS: This multicentric observational retrospective study included adult patients presenting with definite S. pneumoniae IE according to modified Dukes criteria from four French university hospitals over a 15-year period, January 2000-December 2015. Survival rate at 90 days and 2 years after diagnosis, appropriateness of antibiotherapy, and pneumococcal vaccination status were determined. Risk factors for mortality were studied by univariate analysis. RESULTS: Of 3886 patients admitted with IE during the study period, 50 (1.3%) had pneumococcal IE, mostly males (n = 38, 76%), with a mean age of 60 ±â€¯14 years. Predisposing conditions for IE or for invasive pneumococcal disease (IPD) involved 24% and 78% of the cases, respectively. Only 2 patients were vaccinated against pneumococcus before IE and 13 (26%) after IE. Antimicrobial strategy was in accordance with the 2015 ESC Guidelines in 28%. Cardiac surgery was performed in 56%, and was associated with better survival (p = 0.012). In the 40 patients followed until 2 years, the survival rate was 67%, deaths occurring mostly before 90 days. Age ≥ 65 was a risk factor for mortality (p = 0.011). CONCLUSION: Pneumococcal IE remains rare but with a poor prognosis. Resort to surgery is yet to be determined. Predisposing conditions for IPD are the main factors leading to pneumococcal IE. They could be prevented by vaccine coverage improvement.

8.
J Antimicrob Chemother ; 74(4): 1078-1085, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30698733

RESUMO

BACKGROUND: Ceftriaxone is widely used to treat community-acquired CNS bacterial infections. French guidelines for meningitis in adults promote 75-100 mg/kg/day ceftriaxone without an upper limit for dosage, yet little is known about the pharmacology and tolerability of such regimens. PATIENTS AND METHODS: A multicentre prospective cohort study was conducted in adult patients to assess the adverse drug reactions (ADRs) of high-dose ceftriaxone (i.e. daily dosage ≥4 g or ≥75 mg/kg) in CNS infections and to analyse their related factors. Drug causality was systematically assessed by an expert committee who reviewed the medical charts of all included patients. RESULTS: A total of 196 patients were enrolled over a 31 month period. Median dosage and duration of ceftriaxone were 96.4 mg/kg/day (7 g/day) and 8 days, respectively. Nineteen ceftriaxone-related ADRs (mainly neurological) occurred in 17 patients (8.7%), with only one case of treatment discontinuation (biliary pseudolithiasis). In univariate analysis, older age, male gender, renal impairment and high trough ceftriaxone plasma concentration were associated with ceftriaxone-related ADRs. CONCLUSIONS: High-dose ceftriaxone for CNS infection administered as recommended by French guidelines in adults was well tolerated overall, suggesting these recommendations could be applied and generalized. In patients with advanced age or renal insufficiency, prescription should be done with caution and therapeutic drug monitoring could be useful.

9.
Hellenic J Cardiol ; 2019 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-30690140

RESUMO

BACKGROUND: The accuracy of surgical scores in predicting in-hospital mortality for nonsurgically treated patients with infective endocarditis (IE) has not yet been explored. METHODS: Patients with definite IE who did not undergo valve surgery were selected from the database of seven French administrative areas (Association pour l'Étude et la Prévention de l'Endocardite Infectieuse [AEPEI] Registry, 2008). The patients were scored using (a) six systems specifically devised to predict in-hospital mortality after surgery for IE, (b) three commonly used risk scores for heart surgery, and (c) a risk score for predicting six-month mortality in IE after either surgery or medical therapy. Calibration (Hosmer-Lemeshow test) and discriminatory power (receiver operating characteristic [ROC] analysis) were assessed for each score. Areas under ROC curves were compared one-to-one (Hanley-McNeil method). RESULTS: A total of 192 patients (mean age, 65.2±15.2 years) were considered for analysis. There were 38 (19.8%) in-hospital deaths. Age >70 years (p=0.001), Staphylococcus aureus as causal agent (p=0.05), and severe sepsis (p=0.027) were independent predictors of in-hospital mortality. Despite many differences in the number and type of variables, all but two of the investigated scores showed good calibration (p>0.66). However, discriminatory power was satisfactory (area under ROC curve >0.70) only for three of the scores specific for IE and two of the scores used to predict mortality after cardiac surgery. CONCLUSIONS: Among the 10 surgical scores evaluated in this study, five could be adopted to predict in-hospital mortality even for IE patients receiving medical treatment only.

11.
PLoS One ; 14(1): e0210253, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30650119

RESUMO

We examined trends in the MI incidence and age at MI diagnosis among adults living with HIV-1 between 2000 and 2009, by comparison with the French MI registries, by gender. Age standardized incidence rates and standardized incidence-ratios (SIRs) were estimated for individuals included in the French hospital database on HIV (n = 71 204, MI = 663) during three periods: 2000-2002, 2003-2005 and 2006-2009. Median ages at MI diagnosis were compared using the Brown-Mood test. Over the study periods, the absolute rate difference and relative risks were higher in women than in men in 2000-2002 and 2006-2009, with respective SIRs 1.99 (1.39-2.75) and 1.12 (0.99-1.27) in 2006-2009. The trends were different for men and women with a decreasing trend in SIRs in men and no change in women. In both sexes, among individuals with CD4 ≥500/µL and controlled viral-load on cART, the risk was no longer elevated. Age at MI diagnosis was significantly younger than in the general population, especially among women (-6.2 years, p<0.001; men: -2.1 years, p = 0.02). In HIV-1-positive adults, absolute rate difference and relative risks and trends of MI were different between men and women and there was no additional risk among individuals on effective cART.

13.
Artigo em Inglês | MEDLINE | ID: mdl-30395988

RESUMO

OBJECTIVE: We analyze factors influencing the treatment outcome of patients with Gram negative (GNB) multi-drug (MDR) and extensively-drug (XDR) resistant prosthetic joint infection (PJI). METHODS: Data were collected from 2000-2015 by 18 centers, endorsed by ESGIAI (European Study Group for Implant Associated Infections). Treatment success was analyzed by the type of surgery for PJI, the type of resistance (MDR/XDR) and antimicrobials (colistin vs non-colistin) through logistic regression and survival analysis. RESULTS: One hundred thirty one patients (mean age 73 years, male 36%, comorbidities 58.8%) with MDR(n=108) or XDR(n=23) GNB PJI were assessed. Most frequent pathogens were E.coli (33.5%) followed by P.aeruginosa (25.1%), K.pneumoniae (21.3%) and E.cloacae (17.5%). P.aeruginosa predominated in XDR cases (n=15).Resistance referred to carbapenems(n=12),fluoroquinolones(n=63) and ESBL(n=94). Treatment outcome was worse in XDR than in MDR cases (p=0.018). Success rates did not differ in colistin vs non-colistin antimicrobials in XDR cases (p=0.657), but in MDR ones colistin was less successful (p=0.018). DAIR (Debridment, Antibiotics and Implant Retention) (n=67) was associated with higher rates of failure vs Non-DAIR (any other procedure with implant removal,n=64) [(OR=3.57,95%CI 1.68-7.58,(p<0.001)]. The superiority of Non-DAIR was confirmed by Kaplan-Meir analysis (HR:0.36,(95%CI 0.20-0.67) and remained unchangeable from the time of infection (early/late), the type of resistance (MDR/XDR) and the antimicrobial treatment (colistin vs non colistin) (Breslow-Day, p=0.737). CONCLUSION: DAIR is associated with higher rates of failure even in early MDR/XDR GNB PJI compared to implant removal. Colistin should be preserved only for XDR cases as its use is detrimental in MDR ones.

14.
Infection ; 2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30341638

RESUMO

Chronic meningococcemia is defined by blood culture(s) positive for Neisseria meningitidis, symptoms duration > 7 days, and neither meningitis nor shock on admission. This series of 26 consecutive cases illustrates that this is a rare disease (< 5% of meningococcemia, < 0.05 cases per 100,000 inhabitants per year), mostly affecting young adults, males, with no predisposing condition. Major symptoms include fever, rash, and arthralgia. Median time between symptoms onset, and diagnosis is 28 days. Most patients fully recover with a 1-week course of parenteral betalactams.

15.
Artigo em Inglês | MEDLINE | ID: mdl-30368740

RESUMO

Neurosyphilis (NS) has different clinical manifestations and can appear during any stage of syphilis. We aimed to identify the factors affecting poor outcome in NS patients. Patients with positive cerebrospinal fluid Venereal Disease Research Laboratory test, and positive serological serum treponemal or nontreponemal tests were classified as definite NS. The data of 141 patients with definite NS were submitted from 22 referral centers. Asymptomatic NS, syphilitic meningitis, meningovascular syphilis, tabes dorsalis, general paresis, and taboparesis were detected in 22 (15.6%), 67 (47.5%), 13 (9.2%), 10 (7%), 13 (9.2%), and 16 patients (11.3%), respectively. The number of HIV-positive patients was 43 (30.4%). The most common symptoms were headache (n = 55, 39%), fatigue (n = 52, 36.8%), and altered consciousness (50, 35.4%). Tabetic symptoms were detected in 28 (19.8%), paretic symptoms in 32 (22.6%), and vascular symptoms in 39 patients (27.6%). Eye involvement was detected in 19 of 80 patients (23.7%) who underwent eye examination and ear involvement was detected in eight of 25 patients (32%) who underwent ear examination. Crystallized penicillin was used in 109 (77.3%), procaine penicillin in seven (4.9%), ceftriaxone in 31 (21.9%), and doxycycline in five patients (3.5%). According to multivariate regression analysis, while headache was a protective factor in NS patients, double vision was significantly associated to poor outcome. We concluded that double vision indicated unfavorable outcome among NS patients. A high clinical suspicion is needed for the diagnosis NS. As determined in our study, the presence of headache in syphilitic patients can help in early diagnosis of central nervous system disease.

17.
BMJ Open ; 8(8): e023151, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30173161

RESUMO

INTRODUCTION: Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a common and severe disease responsible for approximately 65 000 deaths every year in Europe. Intravenous antistaphylococcal penicillins (ASP) such as cloxacillin are the current recommended antibiotics. However, increasing reports of toxicity and recurrent stock-outs of ASP prompted healthcare providers to seek for alternative antibiotic treatment. Based on retrospective studies, cefazolin, a first-generation cephalosporin, is recommended in patients at risk of severe ASP-associated toxicity.We hypothesised that cefazolin has a non-inferior efficacy in comparison to cloxacillin, with a better safety profile for the treatment of MSSA bacteraemia. METHODS AND ANALYSIS: The CloCeBa trial is an open-label, randomised, controlled, non-inferiority trial conducted in academic centres throughout France. Eligible patients are adults with MSSA bacteraemia without intravascular device or suspicion of central nervous system infection. Patients will be randomised (1:1) to receive either cloxacillin or cefazolin by the intravenous route, for the first 14 days of therapy. The evaluation criteria is a composite criteria of negative blood cultures at day 5, survival, absence of relapse and clinical success at day 90 after randomisation. Secondary evaluation criteria include both efficacy and safety assessments. Three ancillary studies are planned to describe the epidemiology of ß-lactamase encoding genes, the ecological impact and pharmacokinetic/pharmacodynamic parameters of cefazolin and cloxacillin. Including 300 patients will provide 80% power to demonstrate the non-inferiority of cefazolin over cloxacillin, assuming 85% success rate with cloxacillin and taking into account loss-to-follow-up, with a 0.12 non-inferiority margin and a one-sided type I error of 0.025. ETHICS AND DISSEMINATION: This protocol received authorisation from the ethics committee Sud-Est I on 13 November 2017 (2017-87-PP)and French National Agency for Medicines and Health Products (170661A-43). Results will be disseminated to the scientific community through congresses and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03248063 and 2017-003967-36.

18.
J Infect ; 2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-30138639

RESUMO

OBJECTIVES: We aimed to characterize diagnosis, management, and outcome of Mycobacterium tuberculosis prosthetic joint infections (PJI). METHODS: Cases of M. tuberculosis PJI documented in 7 referral French centers were retrospectively reviewed. Data were collected from medical files on a standardized questionnaire. We performed a literature review using the keywords 'prosthetic joint', and 'tuberculosis'. RESULTS: During years 1997-2016, 13 patients (8 males, 5 females, median age 79 years [range, 60-86]) had documented M. tuberculosis PJI, involving hip (n = 6), knee (n = 6), or shoulder (n = 1). Median time from arthroplasty to diagnosis was 9 years [0.4-20]. The diagnosis was obtained on joint aspirates (n = 9), or synovial tissue (n = 4). PCR was positive in all cases tested (5/5). Median duration of antituberculosis treatment was 14 months [6-32]). Nine patients underwent surgery: debridement (n = 4), resection arthroplasty (n = 3), and revision arthroplasty (1-stage exchange, n = 2). PJI was controlled in 12 patients. Seventeen additional cases of documented M. tuberculosis PJI have been reported, with a favorable outcome in 79% (11/14) of patients with no surgery, 85% (11/13) with debridement, 86% (19/22) with revision arthroplasty, and 81% (17/21) with resection (NS). CONCLUSIONS: M. tuberculosis PJI can be controlled with prolonged antituberculosis treatment in most cases, with or without surgical treatment.

19.
J Neurovirol ; 24(6): 769-772, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30097971

RESUMO

Extrahepatic manifestations linked to hepatitis B Virus (HBV) are usually indirect consequences of immune-mediated mechanisms triggered by the virus replication. Strong evidence of brain HBV replication is missing and direct involvement of HBV in nervous system symptoms has been rarely reported. We report two cases of neurological manifestations contemporary to HBV infection. In both cases, HBV-DNA and HBsAg could be quantified in the cerebrospinal fluid (CSF) at relatively high levels. Differential quantification of HBsAg and HBV viral load both in CSF and in blood as well as phylogenic studies on HBV genomic sequences obtained from blood and CSF provided strong arguments for central nervous system viral replication in both cases. Direct causality of HBV replication in the central nervous system in these clinical situations is certainly not demonstrated but these findings could expand the list of hepatitis viruses possibly involved in neurological disorders. Further studies should be promoted to better document possible HBV replication in the brain tissues and its consequences.

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