Topical microbicides designed to prevent acquisition of sexually transmitted infections are urgently needed. Nonoxynol-9, the only commercially available spermicide, damages epithelium and may enhance human immunodeficiency virus transmission. The observation that herpes simplex virus (HSV) and human immunodeficiency virus bind heparan sulfate provided the rationale for the development of sulfated or sulfonated polymers as topical agents. Although several of the polymers have advanced to clinical trials, the spectrum and mechanism of anti-HSV activity and the effects on soluble mediators of inflammation have not been evaluated. The present studies address these gaps. The results indicate that PRO 2000, polystyrene sulfonate, cellulose sulfate, and polymethylenehydroquinone sulfonate inhibit HSV infection 10,000-fold and are active against clinical isolates, including an acyclovir-resistant variant. The compounds formed stable complexes with glycoprotein B and inhibit viral binding, entry, and cell-to-cell spread. The effects may be long lasting due to the high affinity and stability of the sulfated compound-virus complex, as evidenced by surface plasmon resonance studies. The candidate microbicides retained their antiviral activities in the presence of cervical secretions and over a broad pH range. There was little reduction in cell viability following repeated exposure of human endocervical cells to these compounds, although a reduction in secretory leukocyte protease inhibitor levels was observed. These studies support further development and rigorous evaluation of these candidate microbicides.

section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA) for AVYCAZ (ceftazidime-avibactam) Injection.

The female genital tract is immunologically unique because it must be tolerant to spermatozoa, pregnancy, and vaginal flora, but also protect the host from pathogen challenge. The mucosal response to herpes simplex viruses (HSV), a major cause of genital ulcerative disease and critical co-factor in the HIV/AIDS epidemic, is complex and consists of the normally acidic vaginal environment, constitutively secreted and induced antimicrobial peptides, complement, and cellular responses mediated by epithelial and immune cells. This review summarizes our current understanding of the mucosal response to HSV focusing on those factors that may prevent initial infection. Understanding how each of these components contribute to innate immunity, mechanisms of antiviral activity, and whether the virus has evolved strategies to evade their effects may lead to the development of novel vaginal microbicides.