Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains have emerged as serious health threats in the last 15 years. They are associated with large numbers of atopic dermatitis skin and soft tissue infections, but also originating from skin and mucous membranes, have the capacity to produce sepsis and highly fatal pulmonary infections characterized as necrotizing pneumonia, purpura fulminans, and post-viral TSS. This review is a discussion of the emergence of three major CA-MRSA organisms, designated CA-MRSA USA400, followed by USA300, and most recently USA200. CA-MRSA USA300 and USA400 isolates and their methicillin-sensitive counterparts (CA-MSSA) typically produce highly inflammatory cytolysins α-toxin, γ-toxin, δ-toxin (as representative of the phenol soluble modulin family of cytolysins), and Panton Valentine leukocidin. USA300 isolates produce the superantigens enterotoxin-like Q and a highly pyrogenic deletion variant of toxic shock syndrome toxin-1 (TSST-1), whereas USA400 isolates produce the superantigens staphylococcal enterotoxin (SE) B or SEC. USA200 CA-MRSA isolates produce small amounts of cytolysins but produce high levels of TSST-1. In contrast, their MSSA counterparts produce various cytolysins, apparently in part dependent on niche occupied in the host, and levels of TSST-1 expressed. Significant differences seen in production of secreted virulence factors by CA-MRSA versus hospital-associated MRSA and CA-MSSA strains appear to be due to the need to specialize as the result of energy drains from both virulence factor production and methicillin-resistance.

S. aureus isolates from patients with steroid-resistant atopic dermatitis appear to be selected on the basis of greater production of superantigens, compared with that of isolates from control groups. Superantigens may offer selective advantages for colonization of patients.

Glycerol monolaurate (GML) is a fatty acid monoester that inhibits growth and exotoxin production of vaginal pathogens and cytokine production by vaginal epithelial cells. Because of these activities, and because of the importance of cytokine-mediated immune activation in human immunodeficiency virus type 1 (HIV-1) transmission to women, our laboratories are performing studies on the potential efficacy of GML as a topical microbicide to interfere with HIV-1 transmission in the simian immunodeficiency virus-rhesus macaque model. While GML is generally recognized as safe by the FDA for topical use, its safety for chronic use and effects on normal vaginal microflora in this animal model have not been evaluated. GML was therefore tested both in vitro for its effects on vaginal flora lactobacilli and in vivo as a 5% gel administered vaginally to monkeys. In vitro studies demonstrated that lactobacilli are not killed by GML; GML blocks the loss of their viability in stationary phase and does not interfere with lactic acid production. GML (5% gel) does not quantitatively alter monkey aerobic vaginal microflora compared to vehicle control gel. Lactobacilli and coagulase-negative staphylococci are the dominant vaginal aerobic microflora, with beta-hemolytic streptococci, Staphylococcus aureus, and yeasts sporadically present; gram-negative rods are not part of their vaginal flora. Colposcopy and biopsy studies indicate that GML does not alter normal mucosal integrity and does not induce inflammation; instead, GML reduces epithelial cell production of interleukin 8. The studies suggest that GML is safe for chronic use in monkeys when applied vaginally; it does not alter either mucosal microflora or integrity.Glycerol monolaurate (GML), a fatty acid monoester, is generally recognized as safe by the Food and Drug Administration for topical skin and mucous membrane uses at doses up to 100 mg/ml; this is based on many years of experience with GML as an additive to cosmetics and foods. Previously, the compound was shown in vitro to inhibit exotoxin production by gram-positive bacteria, including production of staphylococcal toxic shock syndrome (TSS) toxin-1 and alpha-toxin, at concentrations of Ն20 g/ml, acting at the level of transcription (24,28,35). Streptococci and other gram-positive cocci, which do not produce glycerol ester hydrolases (lipases), are killed by GML at concentrations of Ն10 g/ml, but production of their exotoxins is inhibited at even lower GML doses (28). Staphylococcus aureus and coagulase-negative staphylococci secrete lipases, and thus, the organisms are resistant to killing by GML except at concentrations approaching 500 g/ml (28). Studies to assess the effect of GML on normal vaginal microflora lactobacilli have not been performed.Unlike gram-positive cocci, gram-negative Enterobacteriaceae are resistant to GML at even very high concentrations (Ͼ2,000 g/ml); however, rough mutants, lacking intact lipopolysaccharide (LPS), are highly susceptible to the bactericidal effects of GML (at concentrations of...

Background The CDC et al. reported methicillin-resistant S. aureus (MRSA) are significant causes of serious human infections, including pulmonary illnesses. We investigated the role of superantigens (SAgs) in lung-associated lethal illness in rabbits. Methods A rabbit model was established to investigate the potential role of SAgs, staphylococcal enterotoxin (SE) B and SEC, and toxic shock syndrome toxin-1 (TSST-1). Rabbits received intra-bronchial community-associated (CA) MRSA strains USA200 (TSST-1+), MW2 (SEC+), or c99-529 (SEB+), or purified SAgs. Some rabbits were pre-immunized against SAgs or treated with soluble high-affinity T cell receptors (Vβ-TCR) to neutralize SEB and then challenged intra-bronchially with CA-MRSA or SAgs. Results Rabbits challenged with CA-MRSA or SAgs developed fatal, pulmonary illnesses. Animals pre-immunized against purified SAgs, or treated passively with Vβ-TCRs, and then challenged with CA-MRSA or SAgs, survived. Lung histology indicated non-immune animals developed lesions consistent with necrotizing pneumonia after challenge with CA-MRSA or purified SAgs. SAg immune animals or animals treated with soluble Vβ-TCRs did not develop pulmonary lesions. Conclusions SAgs contribute to lethal pulmonary illneses due to CA-MRSA; pre-existing immunity to SAgs prevents lethality. Administration of high-affinity Vβ-TCR with specificity for SEB to non-immune animals protects from lethal pulmonary illness due to SEB+ CA-MRSA and SEB.

We investigated the effects of glycerol monolaurate (GML) on Lactobacillus, Candida, and Gardnerella vaginalis human vaginal microflora. Our previous work demonstrated that 6 months of GML treatment vaginally does not alter lactobacillus counts in monkeys. Candida and G. vaginalis are commonly associated with vaginal infections in women, many becoming chronic or recurrent. In vitro growth inhibition studies determined the effects of GML (0 to 500 g/ml) against multiple Candida species and G. vaginalis. A randomized, double-blind study investigated the effects of GML on vaginal microflora Lactobacillus, Candida, and G. vaginalis in colonized or infected women (n ‫؍‬ 36). Women self-administered intravaginal gels containing 0% (n ‫؍‬ 14), 0.5% (n ‫؍‬ 13), or 5% (n ‫؍‬ 9) GML every 12 h for 2 days. Vaginal swabs were collected before and immediately after the first gel administration and 12 h after the final gel administration. Swabs were tested for Lactobacillus, Candida, G. vaginalis, and GML. In vitro GML concentrations of 500 g/ml were candicidal for all species tested, while a concentration of 10 g/ml was bactericidal for G. vaginalis. Control and GML gels applied vaginally in women did not alter vaginal pH or Lactobacillus counts. Control gels reduced G. vaginalis counts but not Candida counts, whereas GML gels reduced both Candida and G. vaginalis. No adverse events were reported by participating women. GML is antimicrobial for Candida and G. vaginalis in vitro. Vaginal GML gels in women do not affect Lactobacillus negatively but significantly reduce Candida and G. vaginalis.The human vagina is colonized by microbes, and infections occur when the balance is disturbed. Under healthy conditions, vaginal flora is dominated by lactobacilli, which maintain acidic pH through production of organic acids at times other than menstruation (1,8,13,30). Disruptions of vaginal pH or lactobacilli may allow potentially pathogenic microorganisms to grow and dominate.Bacterial vaginosis (BV) is a common chronic infection characterized by complex vaginal flora changes, which include elevations of vaginal pH and, when symptomatic, malodorous discharge and inflammation (2,5,11). BV is associated with preterm delivery, increased risk of HIV transmission, and risk of other infections (17). The prevalences of BV range from 4 to 40% of women, with the highest prevalence among patients at sexually transmitted infection clinics (25). During BV infection, there are reductions in lactobacilli and increases in bacterial groups such as the Gram-negative bacterium Gardnerella vaginalis (3,10,18,25). Additional bacterial groups that are associated with BV include Bacteroides fragilis and Peptostreptococcus (12, 28). Current treatment recommendations for BV include metronidazole and clindamycin (4).Vulvovaginal candidiasis (VVC) is also a common infection. VVC is caused by Candida species, most often Candida albicans (7,26). It is estimated that 70 to 75% of women experience VVC at least once during their reproductive years (14), and 5 to 8...