Resistance of S. pneumoniae to penicillin G and other useful antibiotics has sharply increase during the last years in many countries and especially in France. Resistance to penicillin G is due to an unpredictable qualitative and quantitative modification of several penicillin binding proteins. All the beta-lactams are affected but the level of cross-resistance depends upon the affinity of the beta-lactam for the modified penicillin binding proteins. As a consequence, the minimal inhibitory concentration of penicillin G and other useful beta-lactams have to be determined against S. pneumoniae isolated from serious infection, responsible for a clinical failure or resistant to penicillin G.