Efficacy of generic meropenem products in combination with colistin in carbapenemase-producing Klebsiella pneumoniae experimental osteomyelitis.

Guidelines for the management of carbapenemase-producing Enterobacterales (CPE) infections recommend a combination of two active agents, including meropenem if the minimum inhibitory concentration (MIC) is ≤8 mg/L. The therapeutic equivalence of meropenem generics has been challenged. We compared the bactericidal activity of meropenem innovator (AstraZeneca) and four generic products (Actavis, Kabi, Mylan and Panpharma), both in vitro and in vivo, in association with colistin. In vitro time-kill studies were performed at 4 × MIC. An experimental model of KPC-producing Klebsiella pneumoniae osteomyelitis was induced in rabbits by tibial injection of a sclerosing agent followed by 2 × 108 CFU of K. pneumoniae KPC-99YC (meropenem MIC = 4 mg/L; colistin MIC = 1 mg/L). At 14 days after inoculation, treatment for 7 days started in seven groups of ≥10 rabbits, including a control group, a colistin group, and one group for each meropenem product (i.e. the innovator and four generics), in combination with colistin. In vitro, meropenem + colistin was bactericidal with no viable bacteria after 6 h, and this effect was similar with all meropenem products. In the osteomyelitis model, there was no significant difference between meropenem generics and the innovator when combined with colistin. Colistin-resistant strains were detected after treatment with colistin + meropenem innovator (n = 3) and generics (n = 3). The efficacy of four meropenem generics did not differ from the innovator in vitro and in an experimental rabbit model of KPC-producing K. pneumoniae osteomyelitis in terms of bactericidal activity and the emergence of resistance.

Colistin-containing cement spacer for treatment of experimental carbapenemase-producing Klebsiella pneumoniae prosthetic joint infection.

Carbapenemase-producing Enterobacteriaceae (CPE) are emerging multidrug-resistant bacteria responsible for invasive infections, including prosthetic joint infections (PJIs). Local administration of colistin may provide bactericidal concentrations in situ. This study evaluated the efficacy of a colistin-impregnated cement spacer, alone and in combination with systemic antibiotics, in a rabbit model of CPE-PJI. Elution of 3 MIU of colistimethate sodium (CMS) in 40 g of poly(methyl methacrylate) cement was studied in vitro. In vivo, 5 × 108 CFU of KPC-producing Klebsiella pneumoniae (colistin and meropenem MICs of 1 mg/L and 4 mg/L, respectively) were injected close to a prosthetic knee. Surgical debridement and prosthesis removal were performed 7 days later, and rabbits were assigned to six treatment groups (11-13 rabbits each): drug-free spacer; colistin-loaded spacer; colistin intramuscular (i.m.); colistin i.m. + colistin spacer; colistin i.m. + meropenem subcutaneous (s.c.); and colistin i.m. + meropenem s.c. + colistin spacer. Systemic treatment was administered at doses targeting pharmacokinetics in humans, and rabbits were euthanised 7 days later to evaluate bacterial counts in infected bones. In vitro, CMS elution was low (<0.1% at 24 h) but reached a local concentration of ≥20 mg/L (>20 × MIC). In vivo, combinations of local and systemic colistin, with or without meropenem, were the only regimens superior to the control group (P ≤ 0.05) in terms of viable bacterial counts and the proportion of rabbits with sterile bone, with no emergence of colistin-resistant strains. Colistin-loaded cement spacer in combination with systemic antibiotics were the most effective regimens in this CPE-PJI model.

Late Functional Changes Post-Severe Traumatic Brain Injury Are Related to Community Reentry Support: Results From the PariS-TBI Cohort.

OBJECTIVES: To explore late functional changes after a traumatic brain injury and their relation to patients' characteristics and reentry support. DESIGN: Prospective follow-up of an inception cohort of adults with severe traumatic brain injury recruited in 2005-2007 in the Parisian area, France. One and 4-year assessments were performed by trained neuropsychologists. One-to-4-year change in the Glasgow Outcome Scale-Extended defined 3 groups: "improvement," "stability," and "worsening." Relationships between these groups and patients' characteristics were analyzed. RESULTS: Among 504 recruited patients and 245 four-year survivors, 93 participated in both evaluations. Overall Glasgow Outcome Scale-Extended improved by 0.4. Forty percent of the sample improved, 44% were stable, and 16% worsened. Being in a more unfavorable group was related to preinjury alcohol abuse and to higher anxiety and depression at 4 years. Attendance to a specialized community reentry unit was related to higher chances of being in the "improvement" group in univariate analyses and after adjustment for age, time to follow command, preinjury alcohol and occupation, and mood disorders (adjusted odds ratio [OR] = 4.6 [1.1-20]). CONCLUSION: Late functional changes were related to psychosocial variables and to reentry support. The effect of reentry support on late recovery needs to be confirmed by further investigations.

A comprehensive picture of 4-year outcome of severe brain injuries. Results from the PariS-TBI study.

OBJECTIVES: Survivors of severe traumatic brain injury have a great variety of impairments and participation restrictions. Detailed descriptions of their long-term outcome are critical. We aimed to assess brain injury outcome for subjects with traumatic brain injury in terms of the International classification of functioning, disability and health. MATERIALS AND METHODS: Four-year follow-up of an inception cohort of adults with severe traumatic brain injury by using face-to-face interviews with patients and proxies. RESULTS: Among 245 survivors at 4 years, 147 were evaluated (80% male, mean age: 32.5±14.2 years at injury); 46 (32%) presented severe disability, 58 (40%) moderate disability, and 40 (28%) good recovery. Most frequent somatic problems were fatigue, headaches, other pain, and balance. One quarter of subjects had motor impairments. Rates of cognitive complaints ranged from 25 to 68%, the most frequent being memory, irritability, slowness and concentration. With the Hospital Anxiety and Depression Scale, 43% had anxiety and 25% depression. Overall, 79% were independent in daily living activities and 40 to 50% needed help for outdoor or organizational activities on the BICRO-39. Most had regular contacts with relatives or close friends but few contacts with colleagues or new acquaintances. Subjects spent little time in productive activities such as working, studying, looking after children or voluntary work. Quality of life on the QOLIBRI scale was associated with disability level (P<0.0001). CONCLUSION: Management of late brain injury needs to focus on cognitive difficulties, particularly social skills, to enhance patient participation in life.

A genome-wide DNA methylation study in azoospermia.

The objective of this study was to assess genome-wide DNA methylation in testicular tissue from azoospermic patients. A total of 94 azoospermic patients were recruited and classified into three groups: 29 patients presented obstructive azoospermia (OA), 26 displayed non-obstructive azoospermia (NOA) and successful retrieval of spermatozoa by testicular sperm extraction (TESE+) and 39 displayed NOA and failure to retrieve spermatozoa by TESE (TESE-). An Illumina Infinium Human Methylation27 BeadChip DNA methylation array was used to establish a testicular DNA methylation pattern for each type of azoospermic patient. The OA and NOA groups were compared in terms of the relative M-value (the log2 ratio between methylated and non-methylated probe intensities) for each CpG site. We observed significantly different DNA methylation profiles for the NOA and OA groups, with differences at over 9000 of the 27 578 CpG sites; 212 CpG sites had a relative M-value >3. The results highlighted 14 testis-specific genes. Patient clustering with respect to these 212 CpG sites corresponded closely to the clinical classification. The DNA methylation patterns showed that in the NOA group, 78 of the 212 CpG sites were hypomethylated and 134 were hypermethylated (relative to the OA group). On the basis of these DNA methylation profiles, azoospermic patients could be classified as OA or NOA by considering the 212 CpG sites with the greatest methylation differences. Furthermore, we identified genes that may provide insight into the mechanism of idiopathic NOA.

Predictive factors for 1-year outcome of a cohort of patients with severe traumatic brain injury (TBI): results from the PariS-TBI study.

OBJECTIVES: To assess outcome and predicting factors 1 year after a severe traumatic brain injury (TBI). METHODS: Multi-centre prospective inception cohort study of patients aged 15 or older with a severe TBI in the Parisian area, France. Data were collected prospectively starting the day of injury. One-year evaluation included the relatives-rating of the Dysexecutive Questionnaire (DEX-R), the Glasgow Outcome Scale-Extended (GOSE) and employment. Univariate and multivariate tests were computed. RESULTS: Among 257 survivors, 134 were included (mean age 36 years, 84% men). Good recovery concerned 19%, moderate disability 43% and severe disability 38%. Among patients employed pre-injury, 42% were working, 28% with no job change. DEX-R score was significantly associated with length of education only. Among initial severity measures, only the IMPACT prognostic score was significantly related to GOSE in univariate analyses, while measures relating to early evolution were more significant predictors. In multivariate analyses, independent predictors of GOSE were length of stay in intensive care (LOS), age and education. Independent predictors of employment were LOS and age. CONCLUSIONS: Age, education and injury severity are independent predictors of global disability and return to work 1 year after a severe TBI.

Comparison of six generic vancomycin products for treatment of methicillin-resistant Staphylococcus aureus experimental endocarditis in rabbits.

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