Determinants of clinical response to empirical antibiotic treatment in patients with cirrhosis and bacterial and fungal infections- Results from the ICA 'Global study' [EABCIR-Global Study]

Background and aims: The administration of an appropriate empirical antibiotic treatment is essential in cirrhosis and severe bacterial infections. We aimed to investigate the predictors of clinical response of empirical antibiotic treatment in a prospective cohort of patients with cirrhosis and bacterial and fungal infections included in the International Club of Ascites(ICA) "Global Study". Methods: Hospitalized patients with cirrhosis and bacterial/fungal infection were prospectively enrolled at 46 centers. Clinical response to antibiotic treatment was defined according to changes in markers of infection/inflammation, vital signs, improvement of organ failure, and results of cultures. Results: From October 2015 to September 2016, 1302 patients were included at 46 centres. A clinical response was achieved only 61% of cases. Independent predictors of lack of clinical response to empirical treatment were C-reactive protein (OR=1.16;95%CI=1.02-1.31),blood leukocyte count (OR=1.39;95%CI=1.09-1.77), serum albumin (OR=0.70;95%CI=0.55-0.88), nosocomial infections (OR=1.96;95%CI=1.20-2.38), pneumonia (OR=1.75;95%CI=1.22-2.53),and ineffective treatment according to antibiotic susceptibility test (OR=5.32;95%CI=3.47-8.57). Patients with lack of clinical response to first-line antibiotic treatment had a significantly lower resolution rate of infections (55%vs. 96%;p<0.001), a higher incidence of second infections (29%vs. 15%;p<0.001),shock (35%vs. 7%;p<0.001) and new organ failures (52%vs. 19%;p<0.001) than responders. Clinical response to empirical treatment was an independent predictor of 28-day survival (sHR=0.20;95%CI=0.14-0.27). Conclusion: Four out of 10 patients with cirrhosis do not respond to the first-line antibiotic therapy, leading to lower resolution of infections and higher mortality. Broader-spectrum antibiotics and strategies targeting systemic inflammation may improve prognosis in patients with high degree of inflammation, low serum albumin levels and severe liver impairment. Lay summary: In a large, hospitalized cohort of patients with cirrhosis and infection at 46 multinational sites, lack of clinical response to empirical antibiotics was noted in four out of each ten patients. The non-response varied according to the geographic area and prevalence of multidrug/extensively drug resistant organisms with lowest response noted in the Asian countries particularly the Indian subcontinent. Severe systemic inflammation, as indicated by high white cell count, serum C-reactive protein levels low serum albumin concentration, presence of pneumonia, nosocomial infection and ineffective treatment were independent predictors of lack of clinical response to empirical antibiotic regimens. Patients with non-response to empirical regimen had worse clinical outcomes and this was identified as an independent predictor of higher in-hospital and 28-day mortality. Additional care and novel antibiotic protocols are an unmet need in cirrhosis patients, especially those with higher degree of inflammation, lower serum albumin levels and more severe liver impairment.