The aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed.

IntroductionCefepime has been associated with a greater risk of mortality than other beta-lactams in patients treated for severe sepsis. Hypotheses for this failure include possible hidden side-effects (for example, neurological) or inappropriate pharmacokinetic/pharmacodynamic (PK/PD) parameters for bacteria with cefepime minimal inhibitory concentrations (MIC) at the highest limits of susceptibility (8 mg/l) or intermediate-resistance (16 mg/l) for pathogens such as Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus. We examined these issues in a prospective non-interventional study of 21 consecutive intensive care unit (ICU) adult patients treated with cefepime for nosocomial pneumonia.MethodsPatients (median age 55.1 years, range 21.8 to 81.2) received intravenous cefepime at 2 g every 12 hours for creatinine clearance (CLCr) ≥ 50 ml/min, and 2 g every 24 hours or 36 hours for CLCr < 50 ml/minute. Cefepime plasma concentrations were determined at several time-points before and after drug administration by high-pressure liquid chromatography. PK/PD parameters were computed by standard non-compartmental analysis.ResultsSeventeen first-doses and 11 steady states (that is, four to six days after the first dose) were measured. Plasma levels varied greatly between individuals, from two- to three-fold at peak-concentrations to up to 40-fold at trough-concentrations. Nineteen out of 21 (90%) patients had PK/PD parameters comparable to literature values. Twenty-one of 21 (100%) patients had appropriate duration of cefepime concentrations above the MIC (T>MIC ≥ 50%) for the pathogens recovered in this study (MIC ≤ 4 mg/l), but only 45 to 65% of them had appropriate coverage for potential pathogens with cefepime MIC ≥ 8 mg/l. Moreover, 2/21 (10%) patients with renal impairment (CLCr < 30 ml/minute) demonstrated accumulation of cefepime in the plasma (trough concentrations of 20 to 30 mg/l) in spite of dosage adjustment. Both had symptoms compatible with non-convulsive epilepsy (confusion and muscle jerks) that were not attributed to cefepime-toxicity until plasma levels were disclosed to the caretakers and symptoms resolved promptly after drug arrest.ConclusionsThese empirical results confirm the suspected risks of hidden side-effects and inappropriate PK/PD parameters (for pathogens with upper-limit MICs) in a population of ICU adult patients. Moreover, it identifies a safety and efficacy window for cefepime doses of 2 g every 12 hours in patients with a CLCr ≥ 50 ml/minute infected by pathogens with cefepime MICs ≤ 4 mg/l. On the other hand, prompt monitoring of cefepime plasma levels should be considered in case of lower CLCr or greater MICs.

Using the rabbit endocarditis model, we compared the activity of a new broad-spectrum cephalosporin, ceftaroline, with those of linezolid and vancomycin against methicillin-resistant Staphylococcus aureus. After a 4-day treatment, ceftaroline exhibited superior bactericidal in vivo activity against resistant S. aureus strains and appeared to be the most effective drug against a heterogeneous glycopeptide-intermediate S. aureus strain.Ceftaroline is a novel broad-spectrum cephalosporin with potent activity against methicillin-resistant Staphylococcus aureus (MRSA) strains due to its strong affinity for S. aureus penicillin-binding proteins (PBPs), including PBP 2A, the additional protein responsible for the methicillin resistance mechanism (6, 15). Ceftaroline acetate (PPI-0903) is an Nphosphono water-soluble prodrug rapidly metabolized in vivo into the bioactive metabolite ceftaroline . No study has been performed by using a challenging rabbit infection model of experimental endocarditis, which has proved to be highly valuable in evaluating the in vivo effectiveness of antibiotics. The aim of the present study was to evaluate the in vivo activity of ceftaroline compared with those of other antistaphylococcal drugs by using a rabbit model of aortic valve endocarditis with doses projected to be therapeutic for humans.We studied two MRSA strains isolated from blood cultures. The MRSA strain (originally designated SA-2) was a strain with heterogeneous high-level methicillin resistance (methicillin MIC ϭ 128 mg/liter) (7), and the heterogeneous glycopeptide-intermediate S. aureus strain (hGISA) exhibited homogeneous resistance to methicillin (methicillin MIC Ͼ 1,024 mg/ liter) and heterogeneous resistance to glycopeptides (8). The MICs were determined in cation-supplemented Mueller-Hinton broth by the microdilution technique (1, 11). Bactericidal activity was assessed on the basis of the determination of minimal bactericidal concentrations (MBCs) by the microdilution method and on the basis of the results of time-kill experiments with an inoculum of 5 ϫ 10 6 CFU/ml (12). High-performance liquid chromatography was used to determine the concentrations of linezolid (13) (lower detection limit, 0.1 mg/liter; coefficient of variation, Ͻ10%). Assays with vancomycin were performed by an immunoenzymatic method with a COBAS MIRA unit and EMIT reagents (Behring Diagnostics Inc., Cupertino, CA) (detection threshold, 2.5 mg/ liter; coefficient of variation, 4.1 to 6.9%). Active ceftaroline concentrations were determined by a microbiologic assay with Bacillus subtilis as the test organism and antibiotic medium 2 (Difco Laboratories, Detroit, MI) as the diffusion medium (lower detection limit, 0.25 mg/liter; intraday and interday variations, Ͻ10%). Simulation of the pharmacokinetics of linezolid was performed as validated previously (7). For ceftaroline, blood samples were taken from six healthy rabbits after administration of a ceftaroline acetate bolus of 10 and 30 mg/kg of body weight in order to determine the spontaneous drug ...

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Indifference or moderate antagonism of linezolid combined with other antibiotics in vitro and in vivo have mainly been reported in the literature. We have assessed the in vitro activities of linezolid, alone or in combination with imipenem, against methicillin-resistant Staphylococcus aureus (MRSA) strains using the dynamic checkerboard and time-kill curve methods. Linezolid and low concentrations of imipenem had a synergistic effect, leading us to evaluate the in vivo antibacterial activity of the combination using the rabbit endocarditis experimental model. Two MRSA strains were used for in vivo experiments: one was a heterogeneous glycopeptide-intermediate clinical S. aureus strain isolated from blood cultures, and the other was the S. aureus COL reference strain. Animals infected with one of two MRSA strains were randomly assigned to one of the following treatments: no treatment (controls), linezolid (simulating a dose in humans of 10 mg/kg of body weight every 12 h), a constant intravenous infusion of imipenem (which allowed the steady-state concentration of about 1/32 the MIC of imipenem for each strain to be reached in serum), or the combination of both treatments. Linezolid and imipenem as monotherapies exhibited no bactericidal activity against either strain. The combination of linezolid plus imipenem showed in vivo bactericidal activity that corresponded to a decrease of at least 4.5 log CFU/g of vegetation compared to the counts for the controls. In conclusion, the combination exhibited synergistic and bactericidal activities against two MRSA strains after 5 days of treatment. The combination of linezolid plus imipenem appears to be promising for the treatment of severe MRSA infections and merits further investigations to explore the mechanism underlying the synergy between the two drugs.