Preparing for the Possibility of a Bird Flu Pandemic
Pharmacology Watch

The possibility of a bird flu pandemic has health officials worldwide in a high state of alert. The highly pathogenic avian influenza A virus is responsible for the death of more than 100 million birds in Southeast Asia, but less than 100 cases have been documented in humans, and only 2 of those have been from human-to-human contact. Still, influenza A viruses are known to undergo an antigenic shift periodically, marking an abrupt change in the viral genome. It is the possibility of a mutation that has health officials concerned. If the virus suddenly became infectious in human populations, the resulting pandemic could kill millions, as similar avian influenza virus pandemics did in 1968, with one to four million deaths, and 1918, when the avian flu pandemic killed as many as 50 million people. The World Heath Organization is urging all countries to develop or update their influenza pandemic preparedness plans. From a pharmaceutical perspective, the WHO has singled out oseltamivir (Tamiflu) as the treatment of choice to reduce symptoms and prevent spread of avian influenza. Roche Holding AG, the makers of oseltamivir, recently announced that Britain and the United States are discussing large purchases of the drug, with the intent of stockpiling supplies for a potential avian influenza outbreak. Other governments around the world have been stockpiling the drug as well, and Roche is increasing its production capacity to meet the additional demand.

Amoxicillin-Clavulanate vs Ciprofloxacin

The search for effective antibiotics to treat common infections is a high priority, given increasing resistance patterns for many commonly used antibiotics. This was the basis for a new study by researchers at the University of Washington, in which they compared ciprofloxacin to amoxicillin-clavulanate in women with uncomplicated cystitis. The study was driven by an increasing rate of resistance to trimethoprim-sulfa and other antimicrobials among E. coli strains causing acute cystitis in women. While ciprofloxacin is a common alternative, amoxicillin-clavulanate has not been well studied. In a randomized, single-blinded trial, 370 women aged 18 to 45 with symptoms of acute uncomplicate cystitis with a positive urine culture were randomized to amoxicillin-clavulanate 500/125mg twice daily or ciprofloxacin to 250 mg twice daily for 3 days. Clinical cure was observed in 58% of women treated with amoxicillin-clavulanate, compared with 77% of women treated with ciprofloxacin (P < .001). Amoxicillin-clavulanate was not as effective as ciprofloxacin, even among women infected with E. coli strains susceptible to amoxicillin-clavulanate. At follow-up visits 2 weeks after treatment, 45% of women in the amoxicillin-clavulanate group had vaginal colonization with E. coli, compared to only 10% in the ciprofloxacin group (P < .001). The authors point out that E. coli resistance is an increasing problem worldwide, especially with trimethoprim-sulfa. However, resistance is also been seen with fluoroquinolones including ciprofloxacin. Amoxicillin-clavulanate was chosen in the study in the hopes of finding an effective fluoroquinolone-sparing antibiotic for the treatment of uncomplicated cystitis. Unfortunately, amoxicillin-clavulanate is not a reliable option and alternatives will need to be found (JAMA. 2005;293:949-955).

AD Therapy and Cognitive Function

Men with prostate cancer who note worsening cognitive function in the early stages of androgen deprivation (AD) therapy should consider that the change is due to the treatment not the disease, according to new study published online in the "Early View" section of Cancer. Researchers from Finland followed 23 men undergoing AD for prostate cancer. Thirty-one cognitive tests were performed at baseline, 6 months, and 12 months into therapy. Testosterone and estradiol locals were followed throughout treatment. Visual memory of figures in recognition speed of numbers were significantly impaired at 6 months. Surprisingly, some men with the lowest change in estradiol levels had an improvement in verbal fluency and 12 months. The author suggests that cognition may be adversely affected during androgen deprivation (Cancer-published online 2/16/05).

LDL Lowering in CHD Patients

An LDL target in the 70s for CAD patients may become the standard, as evidence continues to mount for the benefit of intensive cholesterol lowering. The latest study from the "Treating to New Targets" or TNT investigators looked at 10,000 patients with stable coronary disease and LDL levels less than 130. Patients were randomized to atorvastatin 10 mg/day (low dose) or 80mg/day (high dose) and were followed for an average of 4 years. Mean LDL cholesterol was lowered to 101 mg/dL in the low-dose group and to 77 mg/dL in the high-dose group. Persistent elevations in liver enzymes was more common in the high-dose group (0.2% low dose, 1.2 % high dose [P < .001]). The study end points were cardiovascular events including death from CHD, nonfatal MI, resuscitation after cardiac arrest, or stroke (fatal or nonfatal). A primary event occurred in 548 patients in the low-dose group (10.9%) and 434 patients in the high-dose group (8.7%) for a 2.2% absolute rate reduction (HR, 0.78; 95% CI, 0.69-0.89; P < .001). There was a higher death rate from noncardiovascular causes in the high-dose treatment group, and no difference in overall mortality. There were no trends in the noncardiovascular deaths, specifically no higher rate of cancer or violent deaths. The authors conclude that aggressive LDL lowering is warranted in CHD patients (N Engl J Med-published online March 2005). An accompanying editorial suggests more caution, stating, "Patients and their physicians will need to carefully weigh the benefits or a reduction in the risk of cardiovascular events. . . against the uncertainty of an increase in the risk of death from noncardiovascular causes" (N Engl J Med-published online March 2005).

FDA Actions

The FDA and federal marshals from the Department of Justice have seized Paxil CR and Avandamet tablets manufactured by GlazxoSmithKline at its plants in Knoxville, TN, and Puerto Rico. The FDA stated that the seizures were prompted by violations of manufacturing standards that resulted in the production of poor quality drug products, including tablets that could split apart and tablets that had inaccurate doses of the active ingredient.

In late February, the FDA issued a public health advisory regarding nataluzimab (Tysabri), Biogen’s recently approved drug for the treatment of relapsing forms of multiple sclerosis. Marketing of the drug has been suspended while the agency and the manufacturer evaluate 2 cases of progressive multifocal leukoencephalopathy in MS patients who were using the drug, one of which resulted in death. Nataluzimab received accelerated approval in November 2004, and 8000 patients have received the drug, including 3000 who received it during clinical trials.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5416. E-mail: