Objectives: Because the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of colistin against Enterobacteriaceae are not well explored, we studied the activity of colistin against K. pneumoniae in an in vitro PK/PD model simulating different dosing regimens.Methods: Three clinical isolates of K. pneumoniae with MICs of 0.5, 1 and 4 mg/L were tested in an in vitro PK/PD model following a dose-fractionation design over a period of 24 h. A high and low inoculum of 10 7 and 10 4 cfu/mL with and without a heteroresistant subpopulation, respectively, were used. PK/PD indices associated with colistin activity were explored and Monte Carlo analysis was performed in order to determine the PTA for achieving a bactericidal effect (2 log kill). Results:The fAUC/MIC (R 2 " 0.64-0.68) followed by fC max /MIC (R 2 " 0.55-0.63) best described colistin's 24 h log 10 cfu/mL reduction for both low and high inocula. Dosing regimens with fC max /MIC !6 were always associated with a bactericidal effect (P " 0.0025). However, at clinically achievable concentrations, usually below fC max /MIC " 6, an fAUC/MIC !25 was more predictive of a bactericidal effect. Using a dosing regimen of 9 MU/ day, the PTA for this pharmacodynamic target was 100%, 5%-70% and 0%, for isolates with MICs of 0.5, 1 and !2 mg/L, respectively. Dosing regimens that aim for a trough level of 1 mg/L achieve coverage of strains up to 0.5 mg/L (target trough/MIC " 2 mg/L).Conclusions: Characterization of the pharmacodynamics of colistin against Enterobacteriaceae in an in vitro model of infection indicates that a revision of current susceptibility breakpoints is needed. Therapeutic drug monitoring of colistin to achieve pharmacodynamic targets in individual patients is highly recommended.

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Background. Extended spectrum beta-lactamase (ESBL) producing strains are increasing worldwide limiting therapeutic options. Taniborbactam (VNRX-5133) is a newly developed beta-lactamase inhibitor with a wide spectrum of activity covering both serine and metallo enzymes. We therefore, evaluated cefepime-taniborbactam activity against ESBL-producing isolates and determined the concentrations to be used in MIC determinations in the clinical laboratory. Methods. The in vitro activity of cefepime (0.06-256 mg/l) combined with taniborbactam (0.03-32 mg/l) against 129 clinically and molecularly well-documented ESBL producing isolates (42 Escherichia coli, 39 Klebsiella pneumoniae, 28 Pseudomonas aeruginosa, 16 Enterobacter cloacae, 2 Citrobacter freundii, 2 Enterobacter aerogenes) was tested with a broth microdilution checkerboard method based on ISO standard. The MICs of cefepime alone and in combination together with % of resistance at different concentrations of taniborbactam was calculated for each species and resistance mechanism. Results. The median (range)/MIC90 of cefepime were 32(0.125-256)/256 mg/l for all Enterobacterales isolates (n=101) with 72% being resistant and 32(8-256)/128 mg/l for the 28 P. aeruginosa isolates with 86% being resistant. The median(range)/90th percentile concentration of taniborbactam required to restore Enterobacterales susceptibility to cefepime (MIC ≤1 mg/l) was 0.06(≤0.03-32)/4 mg/l and P. aeruginosa susceptibility to increased exposure to cefepime (MIC ≤8 mg/l) 1(≤0.032-32)/32 mg/l. At a fixed concentration of 4 mg/liter of taniborbactam, cefepime median(range)/MIC90 were reduced to 0.125(0.06-4)/1 mg/l for Enterobacterales with no resistance detected and to 8(2-64)/16 mg/liter for P. aeruginosa isolates where 36% remained resistant. Conclusion. The combination cefepime/taniborbactam demonstrated a potent activity against ESBL isolates restoring susceptibility of all Enterobacterales and 2/3 of P. aeruginosa isolates.

The functional significance of cannabinoids in ocular physiology and disease has been reported some decades ago. In the early 1970s, subjects who smoked Cannabis sativa developed lower intraocular pressure (IOP). This led to the isolation of phytocannabinoids from this plant and the study of their therapeutic effects in glaucoma. The main treatment of this disease to date involves the administration of drugs mediating either the decrease of aqueous humour synthesis or the increase of its outflow and thus reduces IOP. However, the reduction of IOP is not sufficient to prevent visual field loss. Retinal diseases, such as glaucoma and diabetic retinopathy, have been defined as neurodegenerative diseases and characterized by ischemia-induced excitotoxicity and loss of retinal neurons. Therefore, new therapeutic strategies must be applied in order to target retinal cell death, reduction of visual acuity, and blindness. The aim of the present review is to address the neuroprotective and therapeutic potential of cannabinoids in retinal disease.

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