New faces of an old pathogen: emergence and spread of multidrug-resistant Streptococcus pneumoniae.

The image of Streptococcus pneumoniae is split between the world of infectious diseases and the world of the science laboratory. In the eyes of medical practitioners and clinical microbiologists, this bacterium is a dangerous pathogen capable of causing potentially life-threatening community-acquired diseases. In the eyes of the microbiologist, S. pneumoniae is the microbe that has provided some of the most important insights into molecular biology. It was laboratory studies with S. pneumoniae that led to the identification of the first polysaccharide antigen, the unique recombinational mechanism of genetic transformation, and identification of DNA as the genetic material; the first bacterial quorum-sensing polypeptide, a microbial hormone inducing and controlling the physiological state of competence, and the first bacterial autolysin, were also first identified in pneumococci. The novel feature of our era is that these two images of the pneumococcus, the disease-causing pathogen and the source of unique insights into molecular biology, are becoming fused through the introduction of molecular fingerprinting techniques that allow one to observe molecular-level interactions among these bacteria in their natural habitat, which is the human host. There is little doubt that the appearance and massive geographic spread of penicillin-resistant and multidrug-resistant pneumococcus among clinical isolates in the 1980s and 1990s were major motives for the development and application of the molecular techniques that began to play an increasingly important role in the identification of the novel genetic elements, new physiologic, biochemical, and epidemiologic features that constitute the new face of S. pneumoniae in the 1990s. Analysis of penicillin-resistant strains of S. pneumoniae isolated from the clinical environment revealed a remarkable number of changes in these bacteria: Genetic determinants of cell wall synthetic enzymes were shown to contain patches of nucleotide sequence mosaics, indicating the acquisition of extraspecies DNA; penicillin-resistant bacteria contained membrane proteins of altered catalytic properties and altered molecular size; the chemical composition of the cell wall peptidoglycan was changed; the control of autolytic enzymes was changed; and clear-cut evidence for the change of capsular type through the replacement of large pieces of DNA was obtained. Directly or indirectly, most, if not all, of these changes were related to the appearance of antibiotic-resistant pneumococcus. The first report describing a penicillin-resistant S. pneumoniae isolate that caught the attention of the world of infectious diseases was a capsular type 4 S. pneumoniae isolated from the throat of a healthy 3-year-old boy in the village of Anguganak, New Guinea (population 507) on April 15, 1969. The isolate had an increased minimum inhibitory concentration (MIC) for penicillin (0.5 mg/ mL) but was susceptible to chloramphenicol, tetracycline, erythromycin, and sulfa drugs. The putative selective pressure in operation in this part of New Guinea was the extensive use of prophylactic procaine penicillin. The publication of this report prompted an editorial in The New England Journal of Medicine in 1970, which recognized the implication: the specter of a potential problem in the treatment of serious pneumococcal infections. However, the editorial continued with the statement that the particular epidemiologic circumstances and the special properties of the strain involved made the prospect of spread of the resistant pneumococcus extremely remote. This, of course, turned out to be more wishful thinking than a correct prediction of things to come. The next report with major impact came in 1977, from South Africa, with an epidemic pneumococcal disease caused by strains with greatly increased penicillin MIC values and carrying resistance traits to tetracycline, macrolides, and chloramphenicol as well. A comparison of the antibiotic susceptibilities of a prepenicillin era S. pneumoniae and one of the multidrug-resistant South African strains illustrates the magnitude of change (Table 1). In between and after these two dramatic reports, detection of penicillin-resistant pneumococci among clinical isolates began to be reported with increasing frequency in the clinical and microbiologic literature. Careful surveillance in Spain showed the increasing geographic spread and also the increasing penicillin resistance level of the pneumococcal strains from a mean MIC of 0.1– 0.2 mg/mL in the 1970s to a mean of 1–2 mg/mL in the 1980s. In most parts of the world where surveillance for resistant pneumococci was performed at several time inFrom the Laboratory of Microbiology, The Rockefeller University, New York, New York. This article was written during the tenure of a grant from the National Institutes of Health (RO1 AI37275). Requests for reprints should be addressed to Alexander Tomasz, Laboratory of Microbiology, The Rockefeller University, 1230 York Avenue, New York, New York 10021.