by Carol A. Kemper, MD, FACP

The Softer Side of Fluoroquinolones

Source: Johnstone TBC, et al. Nature Medicine. 2004;10:31-32.

Observing that some fluoroquinolones are associated with a lower incidence of seizures and anxiety, pharmacologists from California and the United Kingdom successfully modified norfloxacin to provide enhanced anxiolytic properties in rats without being overly sedating. Norfloxacin typically acts as an antagonist of the neurotransmitter g-aminobutyric acid (GABA) in the brain, at the a receptor site. By modifying the parent compound at the R6 and R7 positions, Johnstone and associates came up with a variety of compounds that enhanced the action of GABA at the receptor complex site. One compound in particular, "compound 4," induced anxiolytic effects in rats similar to diazepam, with about one-tenth the potency. Unlike diazepam, no sedative or depressant CNS effects were identified. Because fluoroquinolones are structurally distinct from other agents with activity against the GABA receptor site, Johnstone et al hope these or other fluoroquinolone derivatives may provide a unique and highly selective way to target the GABA receptor. n

Cycloserine for Phobics?

Source: Pilcher HR. Society for Neuroscience Annual Meeting. November 2003.

Earlier studies have shown that D-cycloserine (DCS), a drug occasionally used to treat tuberculosis, allowed rats to overcome previously learned fears. Behavioral researchers reported in November that DCS was successfully used in treating patients with acrophobia. Thirty acrophobics were treated with DCS plus virtual reality behavioral modification, with a 50% reduction in anxiety and fear, compared with a 10% reduction using behavioral modification alone. Two sessions with DCS were equivalent, in terms of being able to successfully ride in an elevator or drive over a bridge (in virtual reality), to 8 sessions without the drug. Pilcher and colleagues hope that DCS will get phobics through the first training sessions, if nothing else. Apparently, the fear associated with the behavioral modification alone is sufficient to cause many patients to drop out or refuse further therapy.

115-Year-Old Smallpox Scabs— A Literary Find

Source: ProMED-mail post. January 2, 2004. promed@promedmail.org.

A librarian at the sante fe Fogelson College Library made the surprise discovery of a sealed envelope containing what appear to be 115-year-old smallpox vaccination scabs. The enveloped was labeled "scabs from vaccination of W.B. Yarrington’s children," with the signature W.D. Kelly, and was found tucked between the pages of an 1888 Civil War medical text written by Kelly. After doing a quick literature search, the librarian discovered that Kelly had done research on childhood smallpox vaccination in the 1880s. She decided not to open the envelope. How the book made it to the library remains a mystery. Although the librarian initially inquired whether the Civil War Medicine Museum in Maryland would be interested in the specimens, the FBI quickly became involved. The scabs have since carefully made their way to the smallpox laboratory at the CDC in Atlanta. Based on the information on the envelope, the scabs were presumably obtained from someone variolated with smallpox virus, a common technique used to induce immunity in those days (first used in the United States by George Washington on troops during the Revolutionary War).

The hope is that the specimens may yield sufficient genetic material to shed light on the evolution of smallpox and vaccinia virus in the United States (vaccinia is a related but genetically distinct orthopox virus of uncertain origin, presently used for vaccination). It is believed (theoretically) possible to isolate smallpox virus, or at least genetic material, from well-preserved specimens, although past attempts have been fruitless. In the 1960s the WHO reportedly isolated variola virus from 13-year-old smallpox scabs. Analysis of tissues taken from the mummified corpse of a smallpox victim who died in Kentucky in the 1880s was unsuccessful. Similarly, although smallpox-like particles were visualized in the pox-like lesions of a mummified 16th century Italian child, no intact genetic material could be detected. The CDC intends to analyze the Fogelson College library samples sometime this spring.

Positive PPDs Due to M marinum Infection

Source: Lewis FM, et al. Clin Infect Dis. 2003;37:390-397.

Mycobacterium marinum, originally isolated from dead fish in 1926, is a well-recognized cause of soft-tissue infection in persons with contact with swimming pools and fish tanks. Recent efforts to enhance chlorination of public pools and spas has decreased the risk from these sources, but the organism remains ubiquitous in aquatic environments, including both fresh and brackish waters and fish tanks. Lewis and associates reviewed 8 cases of M marinum soft-tissue infection, 6 of which had a positive culture, one of which had characteristic skin lesions and a positive smear, and one of which had characteristic skin lesions and fish tank exposure. Six patients had cutaneous disease, and 2 patients had deeper infection, including tenosynovitis in one and lymphadenitis in the other. Three patients had significant underlying disease, including rheumatoid arthritis (on plaquenil), melanoma and psoriasis (on prednisone), and diabetes mellitus.

Six patients (including 5 with cutaneous disease and one patient with tenosynovitis) responded to 3-6 months of chemotherapy, with or without debridement. Treatment consisted of clarithromycin and ethambutol in 4 patients, and ethambutol and rifampin in 2 patients. (The 2 individuals lacking confirmatory cultures responded to treatment within 2-6 months). Of the remaining 2 patients, the patient with rheumatoid arthritis eventually responded to 14 months of ethambutol and rifampin. The other patient with psoriasis who was receiving corticosteroid therapy failed to respond to ~2 years of treatment with clarithromycin, ethambutol, rifampin, and amikacin, despite repeated attempts at debridement and excision of infected lymph nodes.

Lewis et al suggest that current recommendations more strongly stress the avoidance of fish tanks and suspect waters for persons with open wounds or immune suppression. While no controlled trials exist, treatment with at least 3 agents (clarithromycin, ethambutol, and rifampin) should be considered for initial therapy. The duration of therapy is variable but should be continued for a minimum of 3-4 months, and for at least 1-2 months after resolution of clinically apparent disease.

Interestingly, all 6 patients tested had tuberculin skin tests positive at > 10 mm (2 had reactions > 15 mm). Although it is known that nontuberculous mycobacterial infections can result in positive tuberculin skin test reactions, we don’t usually think of this when confronted with a patient with a positive PPD. One report found that patients with M marinum infection may have positive skin tests up to 60% of the time. Lewis et al found that 100% of their patients with M marinum had positive skin tests. Treatment for latent TB may not be indicated in such patients, especially if they lack risk factors for TB.

Cost-Effectiveness of Influenza Treatment

Source: Rothberg MB, et al. Ann Intern Med. 2003;139:321-329.

Using decision analysis, the cost-effectiveness of rapid diagnostic testing and antiviral therapy for influenza-like illness was evaluated in older adults (older than 65). The model was based on several key assumptions, including that neuraminidase inhibitors would decrease hospitalizations by 33%, along with a comparable reduction in complications and antibiotic use, although zanamivir would be somewhat less effective than oseltamivir because ~50% of older adults would have difficulty loading and administering the medication. In addition, it was assumed that amantadine and rimantadine were less effective because they would not reduce hospitalization and are only effective against influenza A virus. The model was not sensitive to the prevalence or severity of medication side effects.

Not surprisingly, in adults at greatest risk for influenza—unvaccinated, institutionalized, nursing home residents, etc—empiric treatment with oseltamivir without diagnostic testing was the most cost-effective strategy. In patients at lower risk (eg, those who have been vaccinated), rapid diagnostic testing followed by appropriate therapy with oseltamivir was the most cost-effective approach. Empirical amantadine was less cost effective in either circumstance, but could be used if patients had to pay for drug out of their own pocket and couldn’t afford the more expensive agent. (This sounds a bit like backward logic to me: Oseltamivir is cost-effective as long as someone else is paying for it?)

While these conclusions largely make sense, one wonders how the model would perform in the current year when the predominant circulating strain of influenza virus (eg, A/Fujian/411/2002) is not included in (although may be partially covered by) the current vaccine.

Dr. Kemper, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center Section Editor, Updates Section Editor, HIV.