Ecological disturbances and emergence of resistance in the oral and gastrointestinal microflora after drug exposure

Abstract

The exposure of antimicrobial agents and antacids may disturb the ecological balance of the normal microflora. This influence often leads to decreased colonization resistance due to repression of sensitive bacteria and selection of resistant bacteria which have acquired resistance during therapy. The predominant resistant mechanism to B-lactam agents in anaerobic bacteria is production of 13-lactamase, which can be either inducible or constitutive. The purpose of this investigation was to study ecological disturbances and emergence of resistance in the oral and gastrointestinal normal microflora after exposure of different drugs and its relationship with B-lactamase production. The resistance pattern in the oral and intestinal anaerobic microflora was investigated in outpatients and hospitalized patients with and without antimicrobial treatment. The oral microflora was not resistant to any of the antimicrobial agents tested. The intestinal microflora contained a large number of resistant bacteria that mainly belong to the Bacteroides fragilis group in both outpatients and hospitalized patients regardless of previous treatment with antimicrobial agents.

Hospitalization or intake of antimicrobial agents promoted an increase in the relative number of resistant anaerobic microorganisms in the intestinal tract. The relation between B-lactamase activity, drug concentration and ecological disturbances was recorded in volunteers perorally treated with amoxicillin and cephalosporins. Administration of amoxicillin resulted in an overgrowth with new amoxicillin-resistant enterobacteria. Administration of cefpodoxime proxetil, ceftibuten, and cefuroxime axetil resulted in moderate ecological disturbances of the intestinal microflora and lead to significant increases in 13-lactamase activity and to degradation of the cephalosporins. High B-lactamase activity corresponded to low cephalosporin levels in faeces and to minimal disturbance of the ecology whereas the converse was true for low or undetectable enzyme activities. The ecological effects on the normal oral, gastric and intestinal microflora were determined after oral administration of omeprazole in combination with amoxicillin or placebo in patients with Helicobacter pylori infection.

Treatment with omeprazole and amoxicillin caused ecological disturbances in the oral, gastric and intestinal microflora selected for antibiotic resistant enterococci and enterobacteria and caused an increase in 13-lactamase production in the intestinal microflora. Treatment with omeprazole caused ecological disturbances in the gastric and intestinal microflora. All isolated H. pyloristrains were susceptible to amoxicillin. The induction ability in anaerobic bacteria was investigated. Anaerobic bacteria were able to increase the production of B-lactamases after induction with cefoxitin, although to a lesser extent than aerobic bacteria. The combination of inducer, inducible strains and faecal suspension resulted in no or strongly repressed B-lactamase activities. The potential of an antimicrobial agent to have an impact on the normal microflora is related to the agent's antibacterial spectrum, route of administration, pharmacokinetic properties and the degree of inactivation in vivo. This should be considered when antimicrobial agents are used for treatment and prophylaxis of infections.