Ultrasonography-driven combination antibiotic therapy with tigecycline significantly increases survival among patients with neutropenic enterocolitis following cytarabine-containing chemotherapy for the remission induction of acute myeloid leukemia

Abstract

Neutropenic enterocolitis (NEC) is an abdominal infection reported primarily in patients with acute myeloid leukemia (AML) following chemotherapy, especially cytarabine, a notable efficacious cytotoxic agent for AML remission. Specific data regarding the impact of different cytarabine schedules and/or antibacterial regimens for NEC are sparse. The aim of the study was to identify the predictors of outcome within 30 days of NEC onset. NEC episodes were retrospectively pinpointed among 440 patients with newly diagnosed AML hospitalized in our Institution, over a 10-year period, for receiving chemotherapy protocols with 100-6000 mg/m² daily of cytarabine. Two subgroups, survivors versus nonsurvivors, were compared by using logistic regression analysis. NEC was documented in 100 of 420 (23.8%) analyzed patients: 42.5% had received high-dose cytarabine, whereas 19% and 15% intermediate-dose and standard-dose cytarabine, respectively (P < 0.001). The 30-day NEC attributable mortality rate was 23%. In univariate analysis, antileukemic protocols containing robust dosages of cytarabine were significantly associated with high mortality (P < 0.001); whereas, standard-dose cytarabine and prompt initiation (at the ultrasonographic appearance of intestinal mural thickening) of NEC therapy with antibiotic combinations including tigecycline were significantly associated with low mortality. In multivariate analysis, high-dose cytarabine-containing chemotherapy was the independent predictor of poor outcome (odds ratio [OR]: 0.109; 95% confidence interval [CI]: 0.032-0.364; P < 0.001), whereas ultrasonography-driven NEC therapy with antibiotic regimens including tigecycline was associated with a favorable outcome (OR: 13.161; 95% CI: 1.587-109.17; P = 0.017). Chemotherapy schedules with robust dosages of cytarabine for AML remission are associated with a high rate of NEC incidence and attributable. Vigorous antibacterial therapy, triggered off pathologic ultrasonographic findings, with drug combinations which have broad antimicrobial coverage and good gut penetration, specifically those also including tigecycline, may be effective in improving 30-day survival rate after NEC onset.

Keywords: Acute myeloid leukemia; cytarabine; neutropenic enterocolitis; tigecycline.

Figure 1

Study flowchart based on ultrasonography and microbiology evaluation. AML, acute myeloid leukemia; NEC, neutropenic enterocolitis; US, ultrasonography.

Figure 2

A‐B‐C‐D. Ultrasonographic features of neutropenic enterocolitis. (A) Transverse scan with 5‐1‐MHz convex probe showing a rounded mass due to severe bowel wall thickening (16 mm) of the cecum. (B) Transverse scan with 9‐3‐MHz linear probe identifying different wall layers, in particular hypoechoic central portion (virtual lumen and mucosa), wide hyperechoic submucosal, and hypoechoic periphery (muscularis mucosa) in the same case. (C) Longitudinal scan with 5‐1‐MHz convex probe showing >4 mm thickness for at least 30 mm in length, in the same case. (D) Median bowel wall thickness (12 mm; range, 6–20 mm) of the entire patient population with neutropenic enterocolitis.

Figure 3

Subgroup analyses of overall survival for several variables associated with death among the entire patient population with neutropenic enterocolitis. Rates and absolute differences in the risk of mortality are given. L‐AMB, liposomal amphotericin B; G‐CSF, granulocyte colony‐stimulating factors; Ultrasonography‐driven antibiotic treatment of NEC = antibacterial regimens, promptly given at ultrasonographic appearance of pathologic intestinal mural thickening. Azoles =  fluconazole in 6 cases and voriconazole in 4 cases. Enterococcus spp. included 3 cases of Streptococcus mutans infections and 3 cases of Enterococcus faecium infections.

Figure 4

Incidence of NEC in the subgroups of patients according to the schedules of cytarabine included in the induction protocols for hematological remission. The numbers of patients affected and not affected are inside the columns.

Figure 5

Kaplan–Meier curves. The impact of tigecycline‐including combination regimens (dotted line) versus tigecycline‐sparing combination regimens (solid line) on 30‐day mortality of patients with neutropenic enterocolitis. Days = days from neutropenic enterocolitis onset.