In vitro activity of fosfomycin, and synergy in combination, against Gram negative bloodstream infection isolates in a UK hospital

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Background: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 Enterobacteriaceae. 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 UTIs. Materials/methods: 1. We evaluated, in 100 consecutive Gram-negative bloodstream infections (BSI), the in-vitro activity of fosfomycin. Disc diffusion and MIC test strip methods applying revised EUCAST guidelines for fosfomycin were used. 2. A secondary objective was testing for synergy in combination with 10 further antibiotics. Isolates were selected if: a) Fosfomycin resistant b) AMP-C/ESBL/carbapenemase producers (or carbapenem resistant) c) ‘MDR’: defined as ‘resistance to ≥3 classes of antibiotics’ (based on prior routine sensitivity testing). For eligible isolates, MICs were determined individually, and subsequently in combination using the MTS ‘cross’ synergy method. Results:96/100 isolates were susceptible to fosfomycin by MIC test strip. 30/100 isolates were eligible for synergy testing. Synergy was most commonly detected between fosfomycin and piperacillin/tazobactam (32.1%), ceftazidime/avibactam (30%), and temocillin (28.5%). An additive effect was most commonly detected with aztreonam (85.7%) and meropenem (82.1%), but 100% indifference was found with tigecycline. No antagonism was identified. Conclusions:Synergistic or additive effects were detected for beta-lactam/fosfomycin combinations in a high proportion of isolates; >80% for all suggesting such combinations should be preferred when using fosfomycin combination therapy. Agents with a different site of antibiotic action, were more likely to result in indifference.

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