Gram-negative septicemia remains one of the most serious forms of hospital-acquired infection. The most consistently virulent component of the gram-negative lipopolysaccharide (endotoxin) appears to be lipid A. Elucidation of the structure-function relationships of lipid A and the biochemical configurations required for endotoxicity makes possible the design of lipopolysaccharide antagonists and/or the production of poly- or monoclonal antibodies that may abrogate the biologic effects of endotoxin. The mechanisms of activity of lipopolysaccharide and the pathophysiologic events it triggers are now better understood than in the recent past. Lipid A triggers the release of mediators such as cachectin (tumor necrosis factor), thereby initiating a cascade of potentially lethal events. Although recent studies indicate no routine role for corticosteroids in gram-negative septic shock or acute respiratory distress syndrome, considerable progress has been made in the development of effective antibiotics. Recent studies of septicemia in neutropenic patients show survival rates significantly higher than those reported more than two decades ago.

Animals↗

PubMedDate not supplied

Interactions of rifampin and trimethoprim in vitro.

Combination of rifampin and trimethoprim (TMP) has been suggested as a means of preventing the emergence of bacterial resistance to the individual agents and of achieving synergistic antimicrobial activity. By means of standard techniques of antimicrobial susceptibility testing, combinations of rifampin and TMP were tested against clinical isolates of a variety of aerobic bacteria. Synergism was defined as a fourfold or greater decrease in the minimal inhibitory concentration (MIC) of the more active agent in the combination. Antagonism was defined as a fourfold or greater increase in the MIC of the more active agent. No change or, at most, a twofold change was considered to represent indifference. Combinations of rifampin and TMP in ratios of 7:1, 7:2, and 1:1 demonstrated synergistic activity against 12%, 13%, and 28% of 440 isolates, respectively. Antagonism was observed in 10%, 9%, and 8% of strains tested against the above ratios. Killing curves determined with selected organisms failed to demonstrate synergistic antibacterial activity. Combinations of rifampin and TMP failed to prevent the emergence of resistance to both drugs when selected strains of various bacteria were exposed to serial, subinhibitory concentrations. Thus, synergism of rifampin and TMP was observed in only a minority of strains tested, and combination of the two agents failed to prevent the emergence of drug resistance in vitro.

Bacteria↗

PubMedDate not supplied

Empiric therapy for bacterial meningitis.

Population studies from three counties indicate that meningitis occurs with a frequency of approximately 10 episodes per 100,000 population annually in the United States. Estimates based on this prevalence and a population of 2.3 X 10(8) suggest that approximately 23,000 episodes of meningitis occur annually in the United States. Available studies indicate that rapid and reasonably accurate identification of the etiologic agent can be made in greater than or equal to 75% of patients with meningitis by gram-staining of the cerebrospinal fluid, counterimmunoelectrophoresis, or other antigen detection techniques. These means of rapid diagnosis theoretically leave only approximately 7,000 episodes of meningitis annually in the United States in which empiric, as opposed to specific, therapy is necessary. Age-dependent variation in etiologic agents of meningitis markedly influences selection of therapeutic regimens. The preponderance of Enterobacteriaceae and group B streptococci as causes of meningitis in neonates has resulted in utilization of a penicillin (often ampicillin) combined with an aminoglycoside for empiric therapy. Continued high morbidity and mortality, especially in neonatal meningitis caused by Enterobacteriaceae, have been felt to reflect inadequate penetration of aminoglycosides into the cerebrospinal fluid, but careful prospective randomized studies of intrathecal and intraventricular administration of aminoglycosides failed to demonstrate any enhancement of therapeutic results. Ampicillin appeared to be an ideal agent for empiric therapy in older children, in whom meningitis is usually caused by Haemophilus influenzae, with Streptococcus pneumoniae and Neisseria meningitidis being less frequently implicated as etiologic agents. The occurrence of beta-lactamase-mediated resistance to ampicillin in as high as 15% of isolates of H. influenzae has resulted in combined use of ampicillin and chloramphenicol for meningitis in children. This approach is complicated by evidence of clinically important antagonism between ampicillin and chloramphenicol. Since almost all community-acquired meningitis in otherwise healthy adults is caused by meningococci and pneumococci, penicillin remains the agent of choice. In contrast, meningitis following trauma to and surgery involving the central nervous system and in the elderly is often caused by gram-negative bacilli and other "unusual" organisms; therapeutic problems in this group parallel those observed in neonatal meningitis.

Anti-Bacterial Agents↗