Investigations on In Vivo Pharmacokinetic/Pharmacodynamic Determinants of Fosfomycin in Murine Thigh and Kidney Infection Models.

Background: Amidst the era of widespread resistance, there has been a renewed interest in older antibiotics such as fosfomycin, owing to its activity against certain resistant Gram-negative pathogens, including multidrug-resistant variants expressing extended spectrum ß-lactamases or carbapenemases. The goal of the study was to investigate pharmacokinetic/pharmacodynamic (PK/PD) index and PK/PD targets of fosfomycin in murine thigh and kidney infection models, employing clinical isolates of Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae). Methods: Seven isolates of E. coli (one wild-type and six clinical isolates) and five isolates of K. pneumoniae (one wild-type and four clinical isolates) were utilized for in vivo PK/PD studies. Single-dose plasma PK studies were conducted in infected mice by subcutaneous route. PD index was determined from exposure-response analysis employing 24-hr dose fractionation studies in neutropenic murine thigh infection model, while pharmacodynamic targets (PDTs) were derived from both thigh and kidney infection models. Results: Dose fractionation studies demonstrated that in vivo efficacy of fosfomycin best correlated with AUC/MIC for E. coli (R2 = 0.9227) and K. pneumoniae (R2 = 0.8693). The median AUC/MIC linked to 1 log10 kill effects were 346.2 and 745.2 in thigh infection model and 244.1 and 425.4 in kidney infection model for E. coli and K. pneumoniae, respectively. The mice plasma protein binding of fosfomycin was estimated to be 5.4%. Conclusions: The in vivo efficacy of fosfomycin against Enterobacterales was best described by AUC/MIC. The PDTs derived from this study may help define the coverage potential of fosfomycin at the clinical doses approved.

In Vitro Activity of Fosfomycin and Nitrofurantoin Against Contemporary Enterobacterales Pathogens Isolated from Indian Tertiary Care Hospitals.

Background: In India, multidrug resistance in community and hospital associated Gram-negative pathogens has increased sharply over the past few years. In the absence of novel oral multidrug resistant-pathogen active therapies, the therapeutic situation with regard to community infections is even more challenging. Hence, the focus is now shifting toward potentially expanding the utility of older antibiotics such as fosfomycin and nitrofurantoin beyond their approved pathogen coverage. The current study was undertaken to assess the activity of fosfomycin and nitrofurantoin against Enterobacterales pathogens through minimum inhibitory concentration (MIC) determination to facilitate monitoring future shifts in susceptibility to these agents. Materials and Methods: The present study used 1,350 Enterobacterales, recently collected from various Indian tertiary care hospitals and preserved at Wockhardt Strain Repository. The MIC50/90 for fosfomycin and nitrofurantoin and the comparator antibiotics was determined for Escherichia coli (N = 470), Klebsiella pneumoniae (N = 429), Enterobacter spp., (N = 144), Proteus spp. (N = 262), and Citrobacter spp. (N = 45), using Clinical and Laboratory Standards Institute recommended agar dilution method. Results: Applying E. coli breakpoints, the susceptibility rates of fosfomycin for E. coli, K. pneumoniae, Enterobacter spp., Proteus spp., and Citrobacter spp., were 95.5%, 53.2%, 71.5%, 76.7%, and 91.1%, respectively. Applying respective breakpoints, the susceptibility rates of comparator drugs, including meropenem, were lower than fosfomycin. Susceptibility of nitrofurantoin for E. coli and Citrobacter isolate was 83%, while limited coverage (<13.2% susceptibility) was observed for other genera. Conclusion: Amidst widespread resistance, a > 70% fosfomycin susceptibility observed for clinical isolates, including strains expressing carbapenemases, is encouraging and supports conducting additional susceptibility and pharmacokinetic/pharmacodynamic studies to explore its potential for expanded therapeutic use. Nitrofurantoin activity spectrum was restricted to E. coli and Citrobacter spp. and, therefore, offers a relatively limited therapeutic scope.

Studies on monitoring the heavy metal contents in water, sediment and snail species in Latipada reservoir.

The concentrations of zinc, copper, cadmium and lead in surface water, sediments and two native snail species, Bellamya bengalensis and Melanoides tuberculata from Latipada reservoir were determined. The concentrations of cadmium and lead in surface water were higher than the WHO recommended limits for drinking water standards; where as those of zinc and copper were within the permissible limits. The concentrations of zinc, copper, cadmium and lead were higher in sediments than in water. The observed bioaccumulated level of zinc, copper, cadmium and lead in Bellamya bengalensis were Zn- 197.22, Cu- 172.14, Cd- 11.59 and Pb- 112.57 µg g(-1), while in Melanoides tuberculata were Zn- 136.59, Cu- 132.04, Cd- 13.25 and Pb- 27.69 µg g(-1). The metal concentrations in both species of snails were higher than those of the water and sediment. Bioaccumulated metal concentrations, Bio-Water Accumulation Factor (BWAF) and Bio-Sediment Accumulation Factor (BSAF) values indicated that Bellamya bengalensis had high potential for zinc, copper and lead bioaccumulation than Melanoides tuberculata, while Melanoides tuberculata had high potential for cadmium than Bellamya bengalensis. Therefore, Bellamya bengalensis is proposed as sentinel organism for monitoring zinc, copper and lead, while Melanoides tuberculata for monitoring cadmium in freshwater.

Evaluation of bivalves as bioindicators of metal pollution in freshwater.

The fresh water bivalves, Lamellidens corrianus, Lamellidens marginalis, and Indonaia caeruleus were exposed to chronic concentration of arsenic (0.1719 ppm), cadmium (0.1284 ppm), copper (0.033 ppm), lead (1.50 ppm), mercury (0.0443 ppm) and zinc (1.858 ppm) separately up to 30 days in laboratory. Dry weight of each animal was used to calculate metal concentrations (µg/g) and the metal body burden (µg/individual). It was observed that lead (1235.4 µg/g) and arsenic (37.9 µg/g) concentration were highest in Lamellidens corrianus, zinc (3,032.3 µg/g) was highest in Lamellidens marginalis, while mercury (5.87 µg/g), cadmium (142 µg/g) and copper (826.7 µg/g) was highest in Indonaia caeruleus.

Assessment of the metal bioaccumulation in three species of freshwater bivalves.

The metal concentration and body burden of three species of fresh water bivalves, Parreysia cylindrica, Parreysia corrugata and Corbicula striatella were estimated in laboratory experiment after exposure to chronic concentration of arsenic (0.1719 ppm), cadmium (0.23 ppm), copper (0.13 ppm), mercury (0.06 ppm), lead (2.4 ppm) and zinc (5.1 ppm) separately up to 30 days. Dry weight of each animal was used to calculate metal concentrations (µg/g) and the metal body burden (µg/individual). It was observed that zinc, lead and copper concentration and metal body burden was highest in the Corbicula striatella, mercury and arsenic was highest in Parreysia corrugata and cadmium was highest in Parreysia cylindrica. Therefore, Corbicula striatella is being proposed as sentinel organism for monitoring of zinc, lead and copper, Parreysia corrugata for mercury and arsenic, and Parreysia cylindrica for cadmium in fresh water ecosystem.