Chemotherapy Treatment in Pediatric Patients with Acute Myeloid Leukemia Receiving Antimicrobial Prophylaxis Leads to a Relative Increase of Colonization with Potentially Pathogenic Bacteria in the Gut

Abstract

BACKGROUND: Normally, humans are protected against infections by their anaerobic intestinal microorganisms providing colonization resistance. In immunocompromised patients, the endogenous intestinal gram-positive and gram-negative pathogens often cause infectious complications. Therefore, we analyzed the effect of chemotherapy treatment and antimicrobial prophylaxis on intestinal bacterial populations (microbiota) among pediatric patients with acute myeloid leukemia who are prone to intestinal mucositis and infections. METHODS: During 36 chemotherapy cycles, fecal samples were collected from pediatric patients with acute myeloid leukemia. Fecal bacterial populations were analyzed by polymerase chain reaction denaturing gradient gel electrophoresis fingerprinting. Fluorescent in situ hybridization analysis with specific bacterial oligonucleotide probes was used to quantify the fecal bacteria. RESULTS: During chemotherapy treatment, the total number of bacteria in fecal samples was 10(9) per gram of dry weight feces, which was 100-fold lower than than in healthy control samples. Fluorescent in situ hybridization analysis showed that this decrease was the result of an up to 10,000-fold decrease in anaerobic bacteria, partly compensated for by a 100-fold increase in potentially pathogenic enterococci. Additional experiments showed that both prophylactic and therapeutic use of antibiotics could not sufficiently explain the tremendous changes in intestinal microbial composition. In vitro tests showed a direct bacteriostatic effect of chemotherapeutics. CONCLUSIONS: Patients with acute myeloid leukemia treated with chemotherapy and prophylactic antibiotics are unable to maintain colonization resistance because of a decrease in anaerobic bacteria and an increase in potentially pathogenic aerobic enterococci. We hypothesize that this disturbance in the balance between anaerobic and aerobic bacteria will further increase the risk of gram-positive aerobic infections among immunocompromised patients with cancer.