From January 1979 to December 1990 we studied the susceptibility of 1,492 pneumococcal strains isolated from adult patients in Bellvitge Hospital, Barcelona, Spain, to nine antimicrobial agents. Among clinically significant pneumococci, the incidence of penicillin-resistant strains increased from 4.3% in 1979 to 40% in 1990, and that of erythromycin-resistant strains also rose from 0% in 1979 to 9.4% in 1990. On the other hand, the incidence of strains resistant to tetracycline decreased from 76.1% to 37.6%, as did that of chloramphenicol-resistant strains, from 56.5% to 29.4%. The incidence of co-trimoxazole-resistant strains was about 40% throughout the study. Even more alarming was the finding that about 70% of penicillin-resistant strains showed multiple resistance to non-beta-lactam antibiotics. All pneumococci were susceptible to vancomycin, and all but six were susceptible to rifampin. We observed that isolates from cerebrospinal fluid and the respiratory tract were significantly more resistant to penicillin than were isolates from blood. The majority of strains (95%) belonged to serogroups or serotypes included in the 23-valent pneumococcal vaccine and 77.6% of penicillin-resistant strains belonged to groups 23, 6, 9, and 19.

The in-vitro activity of 24 beta-lactam antibiotics was compared using three groups of pneumococci and an agar dilution method comprising 100 penicillin-susceptible, 100 intermediately penicillin-resistant, and 100 highly penicillin-resistant pneumococcal strains. Our results show that intermediately penicillin-resistant and highly penicillin-resistant pneumococci had decreased sensitivity to other beta-lactam agents. According to their relative in-vitro activity, the antimicrobials were classified into three groups. The first group included drugs more active than penicillin (imipenem, meropenem, cefotaxime, ceftriaxone, and cefpirome), which could be useful for the treatment of infections due to penicillin-resistant strains. The second group showed slightly lesser activity than did penicillin, and included: ampicillin, cefdinir, cefuroxime, cefoperazone, azlocillin, mezlocillin, piperacillin, cephalothin, and cefamandole. The remaining antibiotics (oxacillin, cefixime, ceftizoxime, cefetamet, cefaclor, ceftazidime, cefoxitin, cefonicid, and latamoxef) showed poor activity against penicillin-resistant strains, precluding their use for empirical treatment in areas with a high prevalence of penicillin-resistant strains.

The role ofras proteins in signal transduction was assessed by studying inositol phospholipid metabolism and inositol phospholipid-mediated cellular responsiveness to agonists in cells transformed by ras and other oncogenes. Specific alterations were observed in the inositol phospholipid cycle of ras-transformed fibroblasts, but similar changes were also produced by spontaneous transformation or transformation mediated by either membrane-associated oncogenes, such as src, met, or trk, or cytoplasmic oncogenes, mos and raf; the nuclear oncogenesfos and myc did not produce these changes. The alterations included (i) stimulation of phospholipase A2 activity as indicated by elevated levels of glycerophosphoinositol and nonesterified arachidonic acid and (ii) specific uncoupling between surface receptor-mediated stimulation by platelet-derived growth factor, bombesin, or serum and activation of intracellular phospholipase C. These findings suggest the existence of common biochemical pathways for transformation by cytoplasmic and membrane-associated oncogenes and are not consistent with the hypothesis that 21-kDa ras proteins (p21) are direct or distinct regulatory elements of phospholipase C or phospholipase A2 in inositol phospholipid signal transduction pathways.ras genes belong to a multigene family with a high degree of conservation, suggesting that they have essential cellular functions. It has been suggested that ras proteins play a role in signal transduction (for a review, see ref. 1). A direct relation with the mammalian adenylate cyclase system has been rejected (2). Other studies have investigated a possible role of 21-kDa ras proteins (p21) in inositol phospholipid signaling pathways (3-8), but these reports appear to be at least partially inconsistent. Thus, although some reports suggested that p21 ras proteins mediate stimulation of phospholipase C (3-5), others pointed to stimulation of phospholipase A2 (6) and yet others described inhibition of both phospholipases C and A2 in ras-transformed cells (7,8).In view of the conflicting reports, we have assessed the specificity of ras action by analyzing the inositol phospholipid cycle in normal and malignant NIH 3T3 and Rat-1 cells transformed either spontaneously or by the action of oncogenes other than ras. When available, normal revertant cell lines were also compared to their transformed counterparts.Also, in an effort to distinguish transformation-specific from proliferation-specific events, quiescent and actively proliferating normal cells were compared. In this communication we report that specific alterations were observed in the inositol phospholipid pathway of ras-transformed cells, but similar changes were also found in cells transformed spontaneously or by the action of other cytoplasmic and membraneassociated oncogenes. The alterations of inositol phospholipid metabolism included specific stimulation of phospholipase A2-like activity and specific uncoupling of intracellular phospholipase C activity from extracellular signals. These find...