45th Interscience Conference on Antimicrobial Agents: Posaconazole Effective Against Zygomycosis

In: Main

11 Apr 2010

Antimicrobial AgentsSpeaker: Dimitrios P. Kontoyiannis, MD, ScD, Professor, Section of Infectious Diseases, Department of Internal Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Posaconazole (Noxafil, Schering-Plough), a novel, extended-spectrum triazole antifungal agent, may offer an attractive oral treatment alternative for patients with zygomycosis who cannot tolerate or do not respond to IV amphotericin B formulations (e.g., Amphotericin B, Bristol-Myers Squibb; Ambisome, Gilead).

A total of 91 patients with either proven (69) or probable (22) zygomycosis caused by immunosuppression, poorly controlled diabetes mellitus, or disruption of the skin or mucosal membranes, were enrolled into a “compassionate-use” study; 48 patients had infection that was refractory to previous anti-fungal therapy, 10 patients were intolerant of the previous therapy, and 33 patients had infection that was both refractory to and intolerant of the therapy. Treatment with lipid ampho-tericin B had failed in 85% of these patients.

Posaconazole was administered in divided doses of 400 mg twice daily or 200 mg four times a day either orally or enter-ally with meals and/or nutritional supplements. canadian pharmacy viagra

In July 2004, questionnaires were sent to investigators who were then treating or who had previously treated patients with zygomycosis under the compassionate-use protocol. Overall, patients received the antifungal agent from August 31, 2001, through November 29, 2004; thus, some patients were receiving ongoing therapy at the time the questionnaires were completed.

The primary efficacy variable—clinical response—was evaluated at the test-of-cure (TOC) point of 12 weeks or earlier after the initiation of posaconazole therapy.

The success rate with posaconazole among patients with zygomycosis refractory to or intolerant to amphotericin B therapy was high (60% at 12 weeks). Of the 91 patients evaluated, 13 had a complete response and 42 had a partial response. An additional 21% had stable disease at week 12.

Success was similar when findings were stratified by site of infection, predisposing conditions, the reason for enrollment, or the infecting Zygomycetes species. These results compared favorably with patients who tolerated amphotericin B agents. For these patients, the rate of survival was 61% with ampho-tericin deoxycholate and 69% with its lipid formulations. (Conventional amphotericin B is supplied in combination with sodium deoxycholate for IV administration; hence, it is referred to as amphotericin B deoxycholate.)

Valacyclovir Beneficial Against Infectious Mononucleosis

Speaker: Henry Balfour, MD, Professor of Pediatrics and Professor of Laboratory Medicine and Pathology, Division of Infectious Diseases, University of Minnesota School of Medicine; and Laboratory Director, University of Minnesota Fairview Virology Laboratory, Minneapolis, Minnesota

Valacyclovir (Valtrex canadian, GlaxoSmithKline), a well-known antiviral agent indicated for the treatment of herpes zoster and genital herpes, has been found to be beneficial for young adults with infectious mononucleosis (IM) and may help to reduce person-to-person spread. Because antiviral therapy has not been effective against Epstein-Barr virus (EBV), the causative agent of IM, a randomized controlled study with valacyclovir was conducted to reassess antiviral therapy for IM.

Twenty students with IM volunteered during the first week of a laboratory-confirmed diagnosis of primary EBV infection. The students were randomly assigned to receive 3 g/day for 14 days; the controls did not receive any antiviral agents. The volunteers visited the clinic about eight times over a period of six months. Patients were examined, their symptoms were evaluated, and specimens were collected for viral analysis at each visit.

Results showed that the severity of IM was significantly lessened by valacyclovir. The proportion of patients with a decrease of 2 logw quantity of EBV in oral washes from study days 1 to 14 (the primary endpoint) was 7 of 10 (70%) in the valacyclovir group and 1 of 10 (10%) in controls. A clinical benefit was also documented: illness severity scores were significantly lower in the valacyclovir patients than in the controls.

Because the students who received drug valacyclovir had a significantly reduced quantity of EBV in their saliva and throat cells compared with the controls, it is possible that this antiviral agent might be used to treat IM and to limit person-to-person spread. Relatively few persons were studied; therefore, these results need to be confirmed by testing more patients. The amounts of EBV in the mouth increased after therapy ended, suggesting that a longer period of treatment or the use of an antiviral agent that stays in the body longer might have an even greater benefit.

Trizivir/Viread Combination Valuable in Antiretroviral Therapy-Naive Patients with HIV Infection

Speaker: Calvin Cohen, MD, MS, Research Director, Community Research Initiative and Clinical Instructor, Harvard Medical School, Boston, Massachusetts

Because of its efficacy as antiretroviral therapy (ART) and its improved fasting lipid parameters, the nucleoside analogue combination of abacavir, lamivudine (TZV, Trizivir, GlaxoSmithKline) plus tenofovir disoproxil fumarate (TDF, Viread, Gilead Sciences) once daily may be useful as a protease inhibitor (PI) and non-nucleoside reverse transcrip-tase (NNRTI)-sparing regimen in patients with human immunodeficiency virus infection (HIV) who are ART-naive.

Data suggest that zidovudine medication has increased activity against HIV by incorporating the H65R gene. A zidovudine-containing regimen composed of TZV and TDF, therefore, might be able to provide a greater genetic barrier to resistance and also be a more potent treatment.

To evaluate the safety and efficacy of using three-tablet, once-daily TZV/TDF therapy over 48 weeks, 123 ART-naive patients with a viral load of HIV-1 RNA of 30,000 copies/ml or greater at the study’s entry received the drug combination once daily.

The primary endpoints included the percentage of patients with HIV-1 RNA below 50 copies/ml at week 48 and the percentage of patients with grade 3 or 4 ADEs and laboratory toxicities. Other endpoints included the percentage of individuals with HIV-1 RNA below 400 copies/ml; CD+ lymphocyte responses; fasting lipid levels; development of phenotypic and genotypic resistance in nonresponders; and changes from baseline fat distribution, bone density, and mitochondrial DNA.

In these ART-naive patients, TZV/TDF once daily provided virological suppression for those who continued therapy. At 48 weeks, the virological response rates for the intent-to-treat population (ITT) was 41% with fewer than 50 copies/ml and 50% with fewer than 400 copies/ml. The rates were low because of the high rate of premature discontinuation of the study.

Unlike the poor virological response documentation in previous studies that used and TDF, only 11% of patients withdrew from the study because of virological nonresponse. Of particular interest, TZV/TDF had a favorable effect on fasting lipid parameters, suggesting a synergistic effect. Further study with a longer follow-up period is needed.

In a subset of patients studied, neither lipoatrophy nor bone loss was observed.

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