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Antimicrobial Agents and Chemotherapy, March 2003, p. 863-868, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.863-868.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Low-Level Resistance to Rifampin in Streptococcus pneumoniae

Institute for Infectious Diseases, University of Bern, University Hospital Bern, Bern, Switzerland

Received 29 July 2002/ Returned for modification 23 September 2002/ Accepted 21 November 2002

Rifampin is recommended for combination therapy of meningitis due to ß-lactam-resistant Streptococcus pneumoniae. High-level rifampin resistance (MIC, 4 mg/liter) has been mapped to point mutations in clusters I and III of rpoB of the pneumococcus. The molecular basis of low-level resistance (MICs, 0.5 and <4 mg/liter) was analyzed. Spontaneous mutants of clinical pneumococcal isolates were selected on Columbia sheep blood agar plates containing rifampin at 0.5, 4, 10, or 50 mg/liter. Low-level resistance could be assigned to mutations in cluster II (I₅₄₅N, I₅₄₅L). Sensitive (MIC, <0.048 mg/liter) wild-type strains acquired low-level resistance at a rate approximately 10 times higher than that at which they acquired high-level resistance (average mutation frequencies, 2.4 x 10^-7 for low-level resistance versus 2.9 x 10^-8 for high-level resistance [P < 0.0001]). In second-step experiments, the frequencies of mutations from low- to high-level resistance were over 10 times higher than the frequencies of mutations from susceptibility to high-level resistance (average mutation frequencies, 7.2 x 10^-7 versus 5.0 x 10^-8 [P < 0.001]). Mutants with low-level resistance were stable upon passage. Sequencing of a clinical isolate with low-level resistance (MIC, 0.5 mg/liter) revealed a Q₁₅₀R mutation upstream of cluster I. The frequencies of mutations to high-level resistance for this strain were even higher than the rates observed for the in vitro mutants. Therefore, a resistance-mediating mutation located outside clusters I, II, and III has been described for the first time in the pneumococcus. In vitro low-level rifampin resistance in S. pneumoniae could be mapped to cluster II of rpoB. Mutants of pneumococcus with low-level resistance may be selected in vivo during therapy in tissue compartments with low antibiotic concentrations and play a role in the development of resistance.

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