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Objectives To explore the association between MIC/EUCAST breakpoint ratio and 28 day mortality in patients with a Gram-negative bloodstream infection (BSI). Methods Using data from the Bloodstream Infection—Focus on Outcomes (BSI-FOO) observational study, we defined an average MIC/EUCAST breakpoint ratio that was updated daily to reflect changes in treatment in the first 7 days after blood culture. Cox regression analysis was performed to estimate the association between MIC/EUCAST breakpoint ratio and mortality, adjusting for organism and a risk score calculated using potential confounding variables. The primary outcome was 28 day all-cause mortality from the date of blood culture. Results Of the 1903 study participants, 514 met the eligibility criteria and were included in the analysis (n = 357 Escherichia coli, n = 6 Klebsiella and n = 151 Pseudomonas aeruginosa). The average age was 74.0 years (IQR 60.0–82.0). The mortality rate varied from 11.1% (in patients treated with an average MIC/EUCAST breakpoint ratio of 1) to 27.6% (in patients treated with antibiotics with an average MIC/EUCAST breakpoint ratio >1). After adjusting for risk score and organism, MIC/EUCAST breakpoint ratio was not associated with 28 day mortality (P = 0.148). Conclusions In an adjusted model controlling for potential confounding variables, there was no evidence to suggest a relationship between MIC/EUCAST breakpoint ratio and 28 day mortality in patients with a Gram-negative BSI.

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.

Objective To estimate the effect of treatment duration on in-hospital mortality in patients with Staphylococcus aureus blood stream infection and demonstrate the biases that can arise when immortal-time bias is ignored. Exposure We compared three treatment strategies: short therapy (18 days). Main outcome measures Twenty-eight-day all-cause in-hospital mortality. Methods Using data from the BSI-FOO study, we implemented an approach proposed by Hernán to overcome confounding and immortal-time biases. The first stage is to clone all participants, so that each participant is assigned to each treatment strategy. Second, observations are censored when their data becomes inconsistent with their assigned strategy. Finally, inverse-probability weights are applied to adjust for potential selection. We compared our results to a naïve approach where immortal-time bias is ignored. Results Of the 1903 participants in BSI-FOO, 587 were eligible and included in the analysis. After cloning, the weighted estimates of hazard ratio of mortality for short versus long therapy was 1.74 (95% CI 1.36, 2.24) and for intermediate versus long therapy was 1.09 (0.98, 1.22). In the naïve approach, the hazard ratios with reference to the long therapy group are 37.4 (95% CI 18.9 to 74.4) in the short therapy group and 4.1 (95% CI 1.9 to 8.9) in the intermediate therapy group. Conclusions Our findings suggest that duration of therapy >18 days is beneficial with respect to 28-day in-hospital mortality, however, there remains uncertainty around the efficacy of reducing duration of treatment to 10–18 days.