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By Carol A. Kemper, MD, FACP
An Oral Agent for Smallpox?
Source: Aldern KA, et al. Mol Pharmacol. 2003;63:678-681.
Cidofovir (CDV), which was licensed in the United States in 1996 for the treatment of cytomegalovirus retinitis, has been used successfully in a number of other viral infections, including those due to drug-resistant herpes simplex, varicella-zoster, and adenovirus. Furthermore, as reported previously in Infectious Disease Alert,* CDV may be the only licensed agent available with efficacy against smallpox virus. When administered parenterally, it protected against lethal poxvirus challenge in a murine model. Finding an orally bioavailable drug with similar efficacy is a priority.
Aldern and colleagues have been investigating 2 orally active derivatives of CDV and cyclic CDV, called HDP-CDV and HDP-cCDV. Compared with the parent compounds, the derivatives demonstrate greater than 100-fold increased activity against cells infected with orthopoxvirus, cowpox, and vaccinia virus. The basis for this tremendous increase in antiviral activity may be due to an unusual characteristic of the 2 derivatives, which appear to be rapidly taken up by human cells, possibly by associating with the cellular membrane phospholipids. When MRC-5 human fibroblasts were exposed in vitro to HDP-CDV compared with CDV, their intracellular half-lives were 10 vs 2.7 days. In addition, intracellular concentrations of the cellular metabolites of these agents were more than 100 times greater with HDP-CDV than with CDV. Intracellular uptake of CDV and cCDV, which appears to occur as the result of fluid endocytosis, was considerably slower.
*Kemper CA. Infectious Disease Alert. 2003;22(12):96.
Diagnostic Testing for SARS
Source: ProMEDmail, June 4, 2003; the WHO WER and Epidemiological Bulletin, http://www.who.int/csr/don.
As of june 2, the Weekly Epidemiological Record is reporting a cumulative total of 8384 probable cases of SARS and 770 deaths from 29 countries. The 27 new deaths were reported from China and Hong Kong. The development of commercially available diagnostic tests for SARS have been slower than hoped. Indirect immunofluorescence assays for IgM and IgG antibodies, as well as PCR tests, directed against the SARS virus are being developed. The accuracy and diagnostic sensitivity of these tests have been hampered by several unusual and unexpected features of the SARS virus infection itself. Whereas a greater amount of viral shedding typically occurs during the initial phase of most viral illnesses, SARS appears to be different. It turns out that viral shedding is fairly low during the initial phase of SARS but then peaks in respiratory and stool specimens about 10 days after the onset of symptoms. Serologic response to infection does not appear until the fifth or sixth day of symptomatic illness, and current antibody tests can not reliably detect antibodies until about day 10. The WHO continues to advocate that use of the SARS case definition for management and isolation of suspect cases, at least until such time as better testing is available. Based on the current situation, officials are anticipating that SARS is here to stay, although the incidence of infection may eventually prove to be more seasonal. In the United States, we may be moving toward a need for better containment policies and the designation of specific facilities for care for possible cases.
Itraconazole Prophylaxis in CGD
Source: Gallin JI, et al. N Engl J Med. 2003;348:2416-2422.
Patients with chronic granulomatous disease are especially vulnerable to bacterial and fungal infections. Although the administration of trimethoprim-sulfamethoxazole and interferon gamma reduces the incidence of bacterial infections in these patients, fungal infections, especially those due to the filamentous fungi, remain a significant problem. Gallin and associates evaluated the efficacy and tolerance of itraconazole administered as primary prophylaxis to 39 children (at least 5 years old) and adults in a randomized, double-blind, placebo-controlled trial. Patients were randomly assigned to receive 100 mg of itraconazole daily (or 200 mg daily if 13 years or older or weight > 50 kg) or placebo, which was then alternated on an annual basis. Six females and 33 males were enrolled, with an average age of 15 years (range, 5-57 years). They received a total of 61 courses of itraconazole and 63 courses of placebo. Eight patients were withdrawn due to serious fungal infection, including 1 patient receiving itraconazole and 7 patients receiving placebo (P = .10). The specific infections included aspergillus pneumonia in 6, 1 unidentified fungal pneumonia, and 1 soft-tissue abscess due to Paecilomyces spp. The single patient receiving itraconazole, who developed aspergillus pneumonia, reportedly had significant problems with adherence and had likely discontinued study drug (total time on study, 3.7 years).
Patients receiving itraconazole also had fewer superficial fungal infections. Five placebo recipients developed superficial fungal infections compared with none in the treatment group (P = .06). During the study, 19 serious bacterial infections occurred, 1 of which was fatal. There was no evidence that the use of itraconazole affected the frequency of bacterial infection. Three patients receiving itraconazole were withdrawn for other reasons, including headache, rash, and liver function abnormalities in 1 each. Itraconazole levels, obtained in a subset of patients, were undetectable in 50 of 95 plasma samples; levels of the principal metabolite were also undetectable in 39 samples. This is consistent with other data, indicating that blood levels of itraconazole do not necessarily correlate with clinical benefit, and suggests that routine monitoring of itraconazole blood levels is not useful. Based on the results of this study, itraconazole should be considered for use as a long-term primary prophylactic agent in any patient with CGD.