Most S. pneumoniae strains gain penicillin resistance by altering the penicillin-binding proteins in their cell wall. Penicillin molecules that cannot find a penicillin binding site cannot interfere with cell wall synthesis. Several different types of penicillin binding proteins may be involved, explaining the various levels of intermediate resistance that may be encountered with different strains of S. pneumoniae.
Because different penicillin binding proteins may be involved, the level of penicillin resistance cannot be predicted by the oxacillin screening test. Infections caused by isolates of S. pneumoniae showing penicillin resistance in the intermediate range may be successfully treated by administering high doses of antibiotic. For this reason, the level of resistance with an accurate minimum inhibitory concentration (MIC) test must be determined for all clinically significant isolates of S. pneumoniae.