Penicillin resistance occurred soon after the discovery of penicillin, first in the test tube and subsequently in patients. The prevalence of invasive pneumococcal disease has been estimated to be as high as 15-18/100,000 in the elderly population and even higher in AIDS patients, children and the very old. While prevention with pneumococcal vaccine seems the most reasonable solution, under-utilization of the vaccine and an increase in the number of immuno-compromised individuals has limited the success of this approach. Streptococcus pneumoniae is conventionally classified as penicillin-susceptible (MIC < 0.125 mg/l), penicillin-intermediate (MIC 0.125-1.0 mg/l) and penicillin-resistant (MIC > or = 2 mg/l). In many countries, penicillin resistance in pneumococci is on the increase and in some areas penicillin intermediate and resistant isolates reach 60%. As a consequence, a switch of therapy from penicillin to other agents is mandatory in infections caused by penicillin-resistant strains. Benzyl-penicillin, however, can be used for most infections caused by penicillin-intermediate and all infections caused by penicillin-sensitive strains. Third generation cephalosporins, and in particular cefotaxime, are an optional alternative, particularly in view of their low MICs against penicillin-susceptible and -intermediate and some penicillin-resistant strains, and the easily achievable therapeutic concentrations in serum, pulmonary tissues and other compartments in which pneumococcal infections occur. Third generation cephalosporins have a high safety record and can be administered to children, pregnant women and the elderly.(ABSTRACT TRUNCATED AT 250 WORDS)