Escherichia coli bacteraemia in adults: age-related differences in clinical and bacteriological characteristics, and outcome.

To explore the specificities of Escherichia coli bacteraemia in the elderly, the demographic, clinical and bacteriological characteristics and in-hospital mortality rate of 'young' (18-64 years, n = 395), 'old' (65-79 years, n = 372) and 'very old' (⩾80 years, n = 284) adult patients of the multicentre COLIBAFI cohort study were compared. Clinical and bacteriological risk factors for death were jointly identified by logistic regression and multivariate analysis within each group. 'Young' and 'old' patients had more comorbidities than 'very old' patients (comorbidity score: 1·5 ± 1·3 and 1·6 ± 1·2 vs. 1·2 ± 1·2, respectively; P < 0·001), and were more frequently nosocomially infected (22·3% and 23·8% vs. 8·8%, respectively; P < 0·001). 'Old' patients had the poorest prognosis (death rate: 16·4% vs.10·4% for 'young' and 12·0% for 'very old' patients, respectively; P = 0·039). Risk factors for death were age group-specific, suggesting a host-pathogen relationship evolving with age.

Effect of adherence as measured by MEMS, ritonavir boosting, and CYP3A5 genotype on atazanavir pharmacokinetics in treatment-naive HIV-infected patients.

We investigated population pharmacokinetics and pharmacogenetics of ritonavir-boosted atazanavir (ATV), using drug intake times exactly recorded by the Medication Event Monitoring System. The ANRS 134-COPHAR 3 trial was conducted in 35 HIV-infected treatment-naive patients. ATV (300 mg), ritonavir (100 mg), and tenofovir (300 mg) + emtricitabine (200 mg), in bottles with MEMS caps, were taken once daily for 6 months. Six blood samples were collected at week 4 to measure drug concentrations, and trough levels were measured bimonthly. A model integrating ATV and ritonavir pharmacokinetics and pharmacogenetics used nonlinear mixed effects. Use of exact dosing data halved unexplained variability in ATV clearance. The ritonavir-ATV interaction model suggested that optimal boosting effect is achievable at lower ritonavir exposures. Patients with at least one copy of the CYP3A5*1 allele exhibited 28% higher oral clearance. We provide evidence that variability in ATV pharmacokinetics is defined by adherence, CYP3A5 genotype, and ritonavir exposure.

Bacteraemia caused by third-generation cephalosporin-resistant Escherichia coli in France: prevalence, molecular epidemiology and clinical features.

Escherichia coli is one of the major pathogens responsible for bactaeremia. Empirical antibiotherapy of these infections usually relies on third-generation cephalosporins (3GCs). Thus, the occurrence and epidemiology of 3GC-resistant strains have to be monitored. The French prospective multicentre study COLIBAFI collected 1081 strains of E. coli responsible for bacteraemia in 2005. In the present work, the prevalence of resistance to 3GCs was evaluated, and the implicated molecular mechanisms were characterized by specific PCR and sequencing. Phylogenetic grouping, O-typing, pulsed-field gel electrophoresis and virulence factor analysis were used to investigate the genetic background of the 3GC-resistant (3GC-R) strains. Clinical features of the patients with documented data (n = 1051) were analysed. Decreased susceptibility to 3GCs was observed in 41 strains (3.8%): 19, 18 and four had extended-spectrum ß-lactamase (ESBL), AmpC cephalosporinase and OXA-type penicillinase phenotypes, respectively. Pulsed-field gel electrophoresis revealed that the 3GC-R strains constitute a diverse population. All but one of the strains with an ESBL phenotype produced a CTX-M-type enzyme, and six of them belonged to the widespread intercontinental clone O25b:H4-ST131. AmpC phenotype strains harboured various chromosomal ampC promoter and coding region mutations and/or the bla(CMY-2) plasmidic gene. 3GC-R strains carried fewer virulence factors and were more co-resistant to other antibiotics than 3GC-susceptible (3GC-S) strains. Infections with 3GC-R strains were mostly community-acquired and, as compared with those caused by their 3GC-S counterparts, were more severe. Underlying chronic disease and prior use of antibiotics were independent risk factors for development of a 3GC-R strain bacteraemia. The fact that the molecular support of 3GC resistance is mainly plasmid-mediated represents a potentially epidemic threat.

Genetic background of Escherichia coli isolates from patients with spontaneous bacterial peritonitis: relationship with host factors and prognosis.

Spontaneous bacterial peritonitis (SBP) is a severe complication in patients with cirrhosis and ascites. It is predominantly caused by Escherichia coli. The phylogenetic group and virulence genotype of E. coli isolates causing SBP were investigated, and the association of these characteristics with host factors and prognosis was examined. Seventy-six episodes of E. coli SBP that occurred over a 9-year period were studied. The phylogenetic group of the isolates and the presence of 36 virulence factor genes were investigated. The influence of bacterial and host factors on in-hospital mortality was assessed by multiple logistic regression. Phylogenetic groups A, B1, B2 and D were found in 26%, 4%, 46% and 24% of the isolates, respectively. Virulence factor genes were more frequent in B2 isolates than in non-B2 isolates (mean virulence score 15.4 vs. 7.3, p <10(-4)). Ciprofloxacin resistance was significantly associated with non-B2 groups and a low virulence score. Host factors independently associated with a shift from B2 to non-B2 isolates were norfloxacin prophylaxis (OR 13.01, p 0.0213) and prothrombin ratio (OR 1.04 for a 10% decrease, p 0.0211). The model for end-stage liver disease (MELD) score (OR 1.83, p 0.0007) and hospital-acquired SBP (OR 4.13, p 0.0247) were independent predictors of in-hospital mortality. In contrast, outcome was not influenced by the phylogenetic group or the virulence profile. These findings indicate that the characteristics of E. coli isolates causing SBP vary with the severity of liver disease and with fluoroquinolone prophylaxis. Host factors are more important than bacterial factors in predicting in-hospital mortality.

Population pharmacokinetic analysis for nelfinavir and its metabolite M8 in virologically controlled HIV-infected patients on HAART.

AIMS: To describe the pharmacokinetics of nelfinavir and its main metabolite M8 in HIV-infected patients with a sustained virological response, to characterize the effect of covariates and to estimate inter- and intra-individual variability in the pharmacokinetics. METHODS: Three hundred and twenty concentrations of both nelfinavir and M8 were measured in 46 patients enrolled in the COPHAR 1-ANRS 102 study. Blood samples were taken at a first visit (one sample before drug administration and four samples at fixed times after) and at a second visit 1 to 3 months later (one before and one 3 h after drug administration). The data from both visits on nelfinavir and M8 were modelled jointly in all patients using a population approach. RESULTS: A one-compartment model with first-order absorption and elimination best described nelfinavir data, with an additional compartment incorporating a first order rate-constant describing the metabolism of the drug to M8. For nelfinavir, the apparent volume of distribution (V/F ) (95% confidence interval for the mean), was 309 l (185, 516), the absorption rate constant (k(a)) was 0.4 h(-1) (0.2, 0.8), and the apparent clearance (CL/F ) was 37.3 l h(-1) (32, 44). For M8, V(m) /(Fk(m)) and CL(m)/(Fk(m)) were 866 l h(-1) (351, 2161) and 1670 l (965, 2894), respectively. The interindividual variabilities were 34.9%, 34.3% and 62.2% for V/F, CL/F and CL(m)/(Fk(m)), respectively. The interoccasion variability was 27.8% for CL/F. The mean half-lives were 05.38 h and 00.44 h for nelfinavir and M8, respectively. Significant but opposite effects of comedication with zidovudine were found on nelfinavir CL/F and M8 CL(m)/(Fk(m)), but they were not considered to be clinically relevant. CONCLUSIONS: A joint model was found to describe adequately nelfinavir and M8 concentrations and was used to estimate pharmacokinetic parameters for M8. The model can be used to build reference pharmacokinetic profiles for therapeutic drug monitoring of the drug.

Assessment of the cough reflex after propofol anaesthesia for colonoscopy.

BACKGROUND: Dysfunction of the cough reflex as a result of the lingering effects of anaesthetics may lead to aspiration pneumonia or retained secretions after general anaesthesia. It is unknown whether low concentrations of propofol alter the cough reflex in the early period after anaesthesia. The objective of this study was to investigate the effect of low concentrations of propofol on the cough reflex sensitivity as assessed by the cough reflex threshold to an inhaled irritant. METHODS: Fifteen, ASA I-II, non-smoking patients undergoing elective colonoscopy were studied. Anaesthesia was induced and maintained with a blood target-controlled propofol infusion. Cough reflex threshold was measured with citric acid. Increasing concentrations of nebulized citric acid (2.5, 5, 10, 20, 40, 80, 160, 320, and 640 mg ml(-1)) were delivered during inspiration until a cough was evoked. The citric acid concentration eliciting one cough (C1) was defined as the cough reflex threshold. C1 was log transformed for statistical analysis (Log C1). Log C1 was measured before anaesthesia and during the recovery period with estimated decreasing propofol concentrations of 1.2, 0.9, 0.6, and 0.3 microg ml(-1). RESULTS: Log C1 (median; interquartile range) measured with propofol concentrations of 1.2, 0.9, 0.6, 0.3, and 0 microg ml(-1) were 1.9 (0.6), 1.9 (1.0), 1.9 (1.1), 1.9 (0.6), and 1.9 (0.7) mg ml(-1) (NS), respectively. However, light sedation was observed with propofol concentrations of 1.2 and 0.9 microg ml(-1). CONCLUSION: This study indicates that residual sedation after propofol anaesthesia for colonoscopy does not adversely affect the cough reflex.