Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis.

Cryptococcus neoformans is an encapsulated yeast responsible for approximately a quarter of a million deaths worldwide annually despite therapy, and upwards of 11% of HIV/AIDS-related deaths, rivaling the impact of tuberculosis and malaria. However, the most effective antifungal agent, amphotericin B, requires intravenous delivery and has significant renal and hematopoietic toxicity, making it difficult to utilize, especially in resource-limited settings. The present studies describe a new nanoparticle crystal encapsulated formulation of amphotericin B known as encochleated amphotericin B (CAmB) that seeks to provide an oral formulation that is low in toxicity and cost. Using a 3-day delayed model of murine cryptococcal meningoencephalitis and a large inoculum of a highly virulent strain of serotype A C. neoformans, CAmB, in combination with flucytosine, was found to have efficacy equivalent to parental amphotericin B deoxycholate with flucytosine and superior to oral fluconazole without untoward toxicity. Transport of fluorescent CAmB particles to brain as well as significant brain levels of amphotericin drug was demonstrated in treated mice, and immunological profiles were similar to those of mice treated with conventional amphotericin B. Additional toxicity studies using a standardized rat model showed negligible toxicity after a 28-day treatment schedule. These studies thus offer the potential for an efficacious oral formulation of a known fungicidal drug against intrathecal cryptococcal disease.IMPORTANCECryptococcus neoformans is a significant global fungal pathogen that kills an estimated quarter of a million HIV-infected individuals yearly and has poor outcomes despite therapy. The most effective therapy, amphotericin B, is highly effective in killing the fungus but is available only in highly toxic, intravenous formulations that are unavailable in most of the developing world, where cryptococcal disease in most prevalent. For example, in Ethiopia, reliance on the orally available antifungal fluconazole results in high mortality, even when initiated as preemptive therapy at the time of HIV diagnosis. Thus, alternative agents could result in significant saving of lives. Toward this end, the present work describes the development of a new formulation of amphotericin B (CAmB) that encapsulates the drug as a crystal lipid nanoparticle that facilitates oral absorption and prevents toxicity. Successful oral absorption of the drug was demonstrated in a mouse model that, in combination with the antifungal flucytosine, provided efficacy equal to a parental preparation of amphotericin B plus flucytosine. These studies demonstrate the potential for CAmB in combination with flucytosine to provide an effective oral formulation of a well-known, potent fungicidal drug combination.

The human immunodeficiency virus.

HIV is a complex retrovirus. Like some other viruses it infects host cells for life, but unlike other viruses it appears to do so every time. Its elaborate genetic regulation enables it to remain relatively dormant, replicating steadily but slowly. On appropriate stimulation, it is capable of explosive up-regulation, releasing high numbers of new infectious virus. It replicates in an error-prone way, constantly changing its structure to improve its infectivity while presenting the host's immune system with a constantly moving target.

Seronegative secondary syphilis in a patient infected with the human immunodeficiency virus (HIV) with Kaposi sarcoma. A diagnostic dilemma.

Reagin and treponemal antibody tests are highly reliable in diagnosing secondary syphilis. However, patients infected with the human immunodeficiency virus (HIV) respond abnormally to antigenic stimulation and may fail to develop typical serologic responses to infections. We report the case of an HIV-infected man with Kaposi sarcoma and secondary syphilis whose VDRL test and fluorescent treponemal antibody-absorbed test were repeatedly nonreactive. Correct diagnosis required biopsy of a skin lesion with silver staining to show spirochetes. Clinicians treating HIV-infected patients should be aware of the problems of serologic diagnosis of syphilis in these patients. Biopsy samples of appropriate tissues and staining for spirochetes may be needed to arrive at the correct diagnosis.

The Walter Reed staging classification for HTLV-III/LAV infection.

PIP: Patients with acquired immunodeficiency syndrome (AIDS) represent a minority of those who have been infected with human T-lymphotropic virus type III (HTLV-III). The clinical presentation of patients with HTLV-III infections can range from asymptomatic through chronic generalized lymphadenopathy, to subclinical and clinical T-cell deficiency. The US Army has recently adopted a staging classification for HTLV-III infection. The purpose of the Walter Reed (WR) staging Classification is to provide uniformity for routine clinical evaluation of military personnel with HTLV-III infection, to facilitate understanding of the natural history of these infections, and to help evaluate the clinical response to antiviral treatment regimens. Stage WR0 designates high-risk contacts, while stages WR1-6 require documentation of HTLV-III infection. Stages WR1-6 show ascending degrees of disease, so that those classified in WR6 manifest antibodies to HTLV-III, chronic lymphadenopathy, T helper cell counts below the normal limit, delayed hypersensitivity, thrush, and opportunistic infection. HTLV-III infections with symptoms are designated by the addition of the letter B, while the occurrence of Kaposi's sarcoma is designated by adding the letter K. This classification scheme is based on the fact that the T helper cell is the principal target cell of HTLV-III and the clinical observation that the functional integrity of the T helper cell determines the clinical presentation. Preliminary studies in 39 sequential patients followed for over 18 months found that patients who entered in stages WR3-WR6 had a slow but progressive course to the next stage or death. Many questions about clinical progression remain, but it is hoped that this staging classification will facilitate their resolution.^ieng

Variations in buccal cell adhesion of Neisseria gonorrhoeae.

Human buccal cells were found to vary in their day-to-day capacity to support attachment of certain strains of gonococci. Gonococci serially cultured in vitro also differed in their day-to-day ability to attach to buccal cells.

Specificity of inhibition of epithelial cell adhesion of Neisseria gonorrhoeae.

Inhibition of epithelial cell adhesion (attachment) for individual strains of Neisseria gonorrhoeae is antigenically distinct.