Introduction.
Fosfomycin has retained activity against many multi-
drug resistant (MDR) Gram-negatives, and may be useful against extended spectrum
beta-lactamase (ESBL) producing and
carbapenem-resistant Enterobacterales to improve clinical outcomes.Hypothesis/Gap Statement. There are few data from the UK on the susceptibility of invasive Gram-negative isolates to
fosfomycin, especially in the era of increasing use of oral
fosfomycin for
urinary tract infections (UTIs).Aim. We evaluated
fosfomycin susceptibility against 100 consecutive Gram-negative bloodstream isolates, both individually, and in combination with other mechanistically similar and differing
antibiotics. The aim was to investigate the synergy between
antibiotic combinations against several E. coli, K. pneumoniae and P. aeruginosa isolates with variable levels of resistance.Methodology. Disc diffusion and MIC test strip methods applying revised EUCAST guidelines for
Fosfomycin were used, followed by the MTS™ 'cross synergy' method for 'resistant' isolates as defined below: (a)
Fosfomycin resistant by MIC test strip; (b) MDR isolates defined as being resistant to ≥3 classes of
antibiotics (based on routine sensitivity testing;
beta lactams were considered as a single class), and/or (c)
AMP C or ESBL or
carbapenemase producers (or
carbapenem resistant). FIC Index (Fractional Inhibitory Concentration Index) calculations were used to interpret findings, whereby: FIC = (
MICA combination A+B/ MIC agent A) + (MICB combination A+B/ MIC agent B). A result of ≤0.5 was taken to indicate 'synergy', >0.5 and ≤1.0 to indicate 'additive' effect, >1.0 and ≤4.0 to indicate 'indifference', and >4.0 to indicate 'antagonism'.Results. We found that 95/100 isolates were susceptible to
fosfomycin by MIC test strip, with 88/100 isolates susceptible to
fosfomycin by disc, based on EUCAST guideline breakpoints. A total of 30/100 isolates (the more 'resistant' of the 100) were eligible for synergy testing according to our definitions (see Methodology), with the remaining 70 isolates not tested further. Seventeen out of 30 were MDR, 2/30 were
AMP C producers and 9/30 were ESBL producers. Overall, 34/300 (11 %) of all combination tests showed synergy and 161/300 (54 %) were additive. Synergy was most commonly detected between
fosfomycin and
beta-lactam antibiotics, including
piperacillin/tazobactam (10/30; 33 %),
ceftazidime/avibactam (10/30; 30 %), and
temocillin (8/30; 27 %). An additive effect was most commonly detected with
aztreonam (25/30; 83 %) and
meropenem (25/30; 83 %), but 100 % indifference was found with
tigecycline (30/30). No antagonism was identified with any
antibiotic combination.Conclusion.
Fosfomycin non-susceptibility by MIC test strip was unusual. Synergy was variable when combining
fosfomycin with other
antibiotics against the more 'resistant' isolates. Synergistic/additive effects were detected for
beta-lactam/
fosfomycin combinations in >80 % of all such combinations, suggesting
beta-lactams may be the preferred partner for
fosfomycin. Agents with a discordant site of action were more likely to result in indifference. Antagonism was not detected.