Covid-19: FDA approves use of convalescent plasma to treat critically ill patients

Abstract

<h3>Abstract</h3> Fosfomycin-tromethamine activity is well established for oral treatment of uncomplicated lower urinary tract infections but little is known about its potential efficacy in pyelonephritis. Ascending pyelonephritis was induced in mice infected with 6 strains of <i>Escherichia coli</i> (fosfomycin MICs: 1 μg/ml to 256 μg/ml). Urine pH was 4.5 before infection and 5.5-6.0 during infection. Animals were treated for 24h with fosfomycin (100 mg/kg subcutaneously every 4 hours) and CFU were enumerated in kidneys 24h after the last fosfomycin injection. Peak (20.5 μg/ml at 1h) and trough (3.5 μg/ml at 4h) levels in plasma were comparable to those obtained in human after an oral dose of 3 grams. Fosfomycin treatment significantly reduced bacterial loads in kidneys (3.65 log₁₀CFU/g [min-max=1.83-7.03] and 1.88 log₁₀CFU/g [1.78-5.74] in start-of-treatment control mice and treated mice, respectively, <i>P</i> &lt; 10^-6). However, this effect was not found to differ across the 6 study strains (P = 0.71) and between the 3 susceptible and the 3 resistant strains (P=0.09). Three phenomena may contribute to explain this unexpected <i>in vivo</i> activity: i) in mice, fosfomycin kidney/plasma concentrations ratio increased from 1 to 7.8 (95% CI, 5.2; 10.4) within 24 hours; <i>in vitro</i>, when pH decreased to 5: (ii) fosfomycin MICs for the 3 resistant strains (64-256 μg/ml) decreased into the susceptible range (16-32 μg/ml) and: iii) maximal growth rates significantly decreased for all strains and were the lowest in urine. These results suggest that local fosfomycin concentrations and physiological conditions may favour fosfomycin activity in pyelonephritis, even against resistant strains.