Abstract Background Ceftolozane (C/T) is widely used in clinical practice to treat difficult and/or multidrug resistant Pseudomonas aeruginosa (Pa). However, clinical data is absent on the use of C/T therapy to treat Pa strains with C/T MICs ≥ 4mg/L, that is outside the wild type population. To address this, we simulated 7-day courses of C/T against 8 strains of Pa C/T MICs 4-64mg/L as monotherapy and in combination with tobramycin (T) or fosfomycin (F) using an in vitro pharmacokinetic model. Methods A single compartment dilutional in vitro model was used, volume central chamber 360mL, inoculum 106 CFU/mL. Differing drugs t½ were simulated using add back. Pa strain C/T MICs were 4-64mg/L, T 0.25-8mg/L and F 4-1024mg/L. C/T doses of 2-1g, 8h (Cmax 112-32mg/L, t½ 2.5-1h), T doses 7mg/Kg 24h (Cmax 22mg/L, t½ 2.5h) and F doses 4g 8h (Cmax 250mg/L, t½ 2.5h) were simulated for 7 days. Endpoints were changes in bacterial load (log CFU/ml) and population profiles (growth on C/T containing media at MICx4 and MICx8 concentrations). Results C/T alone resulted in rapid clearance of all strains after 4-12h exposure, with the antibacterial effect being poorest with strains with the highest C/T MICs. Regrowth occurred with 7/8 strains after 24-48h, counts reaching 6-8 logs by 7 days. Combination of C/T plus T increased the rate of initial clearance and suppressed regrowth with all strains. Combination of C/T plus F did not increase the rate of initial clearance except in the strains with the highest C/T MICs but resulted in suppression of regrowth with final bacterial counts of 3-4 logs at day 7. Changes in C/T population profiles occurred after 7 days exposure with growth on C/T MICx8 containing media in 6/8 strains exposed to C/T alone, but 0/8 strains exposed to C/T plus T and 1/8 strains exposed to C/T plus F. Conclusion Combinations of C/T plus T or F resulted in long term suppression of Pa bacterial load and minimised emergence of resistance in Pa strains with C/T MICs on or just above the epidemiological cut off value (MIC 4mg/L-64mg/L). Disclosures Alasdair P. MacGowan, MD, GSK: Grant/Research Support|InfectoPharm: Grant/Research Support|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Venatorx: Advisor/Consultant.