Elaboration of type b capsule by Haemophilus influenzae as a determinant of pathogenicity and impaired killing by trimethoprim-sulfamethoxazole.
In vitro, Haemophilus influenzae strains have two distinct patterns of susceptibility to trimethoprim-sulfamethoxazole (TMP/SMZ); strains with low minimum inhibitory concentration and high minimum bactericidal concentration (tolerant) and those with both low minimum inhibitory concentration and minimum bactericidal concentration (kill-sensitive). Tolerant H. influenzae strains were found to elaborate significantly more type b capsular polysaccharide, a linear polymer of ribosyl ribose phosphate (PRP), than kill-sensitive strains. Tolerant strains became susceptible to killing by TMP/SMZ when type b capsule was physically removed, but reacquired tolerance following growth and reversion to original (mucoid) phenotype. Susceptibility of wild (type a, b, c), isogenic (type b and untypable), and transformed (type b and d) strains indicated that elaboration of type b capsule was associated with TMP/SMZ tolerance. In a second series of studies, virulence of H. influenzae in the infant rat model was correlated with in vitro tolerance. Tolerant strains (13/13) caused systemic disease while none (0/7) of kill-sensitive strains were pathogenic. The efficacy of TMP/SMZ in the treatment of invasive infection was evaluated in rats with established bacteremia and meningitis. TMP/SMZ failed to eradicate H. influenzae b from the blood in 85% (17/20) or from the cerebrospinal fluid in 95% (19/20) of infected animals. Thus, in vitro tolerance correlated with therapeutic failure in vivo.
D000818:Animals; D004338:Drug Combinations / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D004361:Drug Tolerance; D006192:Haemophilus Infections / Q000188:drug therapy; D006193:Haemophilus influenzae / Q000187:drug effects / Q000472:pathogenicity*; D006801:Humans; D011135:Polysaccharides, Bacterial / Q000276:immunology*; D051381:Rats; D011919:Rats, Inbred Strains; D013420:Sulfamethoxazole / Q000494:pharmacology*; D014295:Trimethoprim / Q000494:pharmacology*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination
D004338:Drug Combinations; D011135:Polysaccharides, Bacterial; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014295:Trimethoprim; D013420:Sulfamethoxazole