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Given the changing epidemiology of disease due to Staphylococcus aureus (SA), including the emergence of drug-resistant organisms such as methicillin-resistant SA, investigators may wish to evaluate the effects of antimicrobials in disease due to SA as well as in disease due to other organisms in the same trial. Here we discuss issues that investigators should address in trial design, conduct, and analysis to evaluate overall effects or effects within subgroups according to causative organisms.

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Antimicrobial resistance has been an issue since the introduction into clinical use of the first agents in the 1940s. Although the discovery and development of new classes of antimicrobials through the 1960s presented an array of treatment options, these options for some serious and life-threatening infectious diseases may now be more limited. This paper examines the history of antimicrobial development, showing how the challenges in discovering new classes of drugs have been with us for the last 40 years. The present state of antimicrobial discovery and development is shaped by these challenges as well as by the economic realities of the pharmaceutical industry. This paper also discusses some of the regulatory considerations in antimicrobial drug development, and presents some potential solutions to the challenges inherent in antimicrobial drug development, including steps taken by the US Food and Drug Administration to streamline the drug review process for antimicrobial agents while maintaining the standards necessary to protect and promote the health of the public.

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Since the introduction of antimicrobial agents, there has been an association between antibiotic use and the development of antimicrobial resistance. Antibiotic therapy eradicates not only pathogenic organisms but also the protective normal flora. This so-called "selective pressure" results in colonization with bacteria that are resistant to the original therapy. The result has been an increase over the past two decades in antibiotic resistance among common bacterial causes of outpatient infections. Several studies have demonstrated that a substantial portion of the antibiotics prescribed in the outpatient setting are given for viral illnesses or bacterial diseases where the benefit of antibacterial therapy is marginal. The reasons for prescribing antibiotics in these situations are related to medical and social factors. Physicians should be familiar with the clinical situations in which they should provide antibiotics and those in which they may safely be withheld. Physicians should understand the motivations of patients who are seeking antibiotics and provide education, empathy and alternative treatments.

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In the sense that the brain houses the central mechanism for the regulation of body temperature, almost all illnesses that cause fever must interact with the central nervous system. There are far fewer diseases, however, in which the nervous system symptomatology is of prime diagnostic importance. A helpful way to view fever in association with neurologic disease is to roughly divide these disease entities into four broad categories: (1) neurologic impairment resulting from fever itself, (2) fever as the sole manifestation of a central nervous system infection, (3) systemic febrile disorders with central nervous system signs and symptoms, and (4) primary neurologic diseases, either central or peripheral in origin, with fever as a presenting sign. This article discusses the clinical presentation of disorders in each of these categories as an aid to the clinician in diagnosing and differentiating between these syndromes.

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Under certain circumstances, soluble antigens, particulate antigens, and/or microorganisms have been shown to bind to primate erythrocytes via complement receptor 1 (CR1) in the presence of specific antibodies and complement. This immune adherence reaction, specific for CR1, can lead to neutralization of antigens in the circulation and their subsequent clearance from the blood. The present experiments utilized cross-linked monoclonal antibody complexes (heteropolymers) with specificity for both CR1 and either 35S-labeled herpes simplex virus capsid or Haemophilus influenzae as prototype viral and bacterial particulate antigens, respectively. In each case, the respective specific heteropolymers facilitated binding of the target antigens (> or = 70 to 90%) in vitro to erythrocytes in the absence of complement. Several experimental protocols were employed to demonstrate that heteropolymers mediate specific, rapid (> or = 30 s), and quantitative binding of prototypical particulate pathogens to human and monkey erythrocytes but not to sheep erythrocytes, which lack CR1. These results extend the potential use of the erythrocyte-heteropolymer system to the neutralization and clearance of particulate viral and bacterial pathogens from the blood.

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The molecular basis for the receptorless (r-) and activation-labile (act1) phenotypes of glucocorticoid-resistant mutants isolated from glucocorticoid-sensitive human leukemic CEM-C7 cells was determined. Clones isolated from a complementary DNA library prepared from r- ICR27TK.3 cells, in which one glucocorticoid receptor (GR) gene has been deleted, contained a single adenosine to thymidine transversion in the third position of codon 753, resulting in the substitution of phenylalanine for leucine. This mutant gene (GR753F) had only 13% of the trans-activating activity of the normal gene and produced a M(r) 92,000 receptor protein with the same r- phenotype seen in ICR27TK.3 cells. Analysis of complementary DNA clones isolated from a library prepared from parental glucocorticoid-sensitive 6TG1.1 cells showed that these cells express both a normal GR gene (GR+) and the GR753F gene. Thus, their genotype is GR+/GR753F. Analysis of clones isolated from a complementary DNA library prepared from glucocorticoid-resistant activation-labile 3R7. 6TG.4 cells revealed the presence of the GR753F gene and a second mutant gene (GR421Y) containing a guanosine to adenosine transition in the second position of codon 421, resulting in the replacement of the first cysteine of the proximal zinc finger of the DNA-binding domain by tyrosine. This mutant had no trans-activating activity but normal ligand-binding characteristics. Thus, the genotype of act1 3R7.6TG.4 cells is GR421Y/GR753F. Consequently, the sequence-specific DNA-binding activity of receptors in act1 cells is attributable to the GR753F gene, while the ligand-binding activity seen in intact cells is attributable to the GR421Y gene. These results provide a direct explanation for the r- and act1 phenotypes of glucocorticoid-resistant cells and demonstrate that glucocorticoid-sensitive cells derived from CEM-C7 cells contain a heterogeneous population of normal and mutant receptors.

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Previous studies have identified a nucleosome near a potential late boundary for the nuclease-hypersensitive region in simian virus 40 chromatin. We have performed in vitro reconstitution analysis to determine whether the underlying DNA sequence encodes for the assembly of this nucleosome and applied hydroxyl radical and DNase I footprinting techniques to examine the structure of the reconstituted nucleosome. Both methods revealed the formation of a precisely positioned nucleosome in vitro, on a fragment spanning the strong in vivo nucleosome location site determined previously in the viral chromatin. The center of the positioned nucleosome maps between nucleotide 384 and 387 on simian virus 40 DNA. The corresponding nucleosome core includes the major-late transcription site (12 base-pairs within the core), the MspI site, and a segment shown previously to adopt a bent structure in the absence of proteins. The hydroxyl radical produces a strikingly well-defined cleavage pattern over the bent DNA incorporated in nucleosomes. The dominant periodicity of DNA in this nucleosome is 10.26 base-pairs per turn. The distribution of the .OH cut sites in the positioned nucleosome provides strong support for models in which the minor grooves of the A/T-rich tracts are oriented toward the histone core while the minor grooves of the G/C-rich sequences are facing outward.

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