Updates

By Carol A. Kemper, MD, FACP, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, Section Editor, Updates; Section Editor, HIV, is Associate Editor for Infectious Disease Alert.

Teen Survives Rabies — And Doing Well 3 Years Later

Source: Hu WT, et al. Long-term follow-up after treatment of rabies by induction of coma. N Engl J Med 2007; 357:945-946.

Nothing short of a medical miracle occurred in 2004, when a 15-year old Wisconsin girl survived rabies encephalitis following a therapeutically induced coma, using a novel combination of ketamine, ribavirin, and amantadine. How and why she survived is not clear. Only 5 other humans have been reported to have survived rabies; most were presumed to have some degree of pre-existing immunity. An interesting question raised in the young woman's case was whether she had been infected with a less virulent or variant lyssavirus (there is speculation that other lyssaviruses may cause a rabies-like condition), but efforts to recover virus were unsuccessful. And, sadly, since this case was published in 2005,1 a similar therapeutic effort failed in a young man who died from rabies in Texas.2

Hu and colleagues report on her remarkable recovery over the past 3 years. Her initial recovery was complicated by generalized choreoathetosis, and speech and gait abnormalities. A trial of therapeutic carbidopa-levodopa worsened her gait. With intensive physical therapy, her speech and gait abnormalities significantly improved by 18 months post-rabies exposure, and her choreoathetosis completely resolved by 2006. MRI of the brain showed resolution of the earlier hyperintensities seen in the basal ganglia during her acute illness. Cerebrospinal fluid analysis showed 6 unique oligoclonal bands, mildly elevated levels of neopterin, and decreased levels of homovanillic acid and 5-hyroxyindoleacetic acid, suggestive of decreased turnover of dopamine and serotonin.

Twenty-seven months after exposure, she continued to have mild dysarthria and intermittent dysesthesias. She had no evidence of attention deficit, memory problems, or mood disorder. She took college-level math and physics in high school, scored above average on a national college achievement test, and is now attending college.

References:

  1. Willoughby RE Jr, et al. Survival after treatment of rabies with induction of coma. N Engl J Med 2005; 352:2508-2514.
  2. Hemachudha T, et al. Failure of therapeutic coma and ketamine for therapy of human rabies. J Neurovirol 2006; 12(5):407-409.

Antibiotic-Impregnated Urinary Catheters Reduce Infection Risk

Source: Stensballe J, et al. Infection risk with nitrofurazone-impregnated urinary catheters in trauma patients. Ann Intern Med 2007; 147:285-293.

Antibiotic impregnated catheters can reduce biofilm formation, bacterial colonization, and have the potential to reduce the frequency of UTI in hospitalized patients. However, their use has not met with broad acceptance. This may, in part, be due to a lack of convincing data from larger randomized clinical trials and proven cost-effectiveness. The cost of the newer antibiotic- or silver-impregnated catheters is 2 to 4 times as much as a standard silicone catheter.

These authors examined the risk of UTI in a large, randomized, double-blind, controlled clinical trial of 212 consecutive trauma patients requiring urinary catheterization. Patients were randomly assigned to receive a nitrofurazone-impregnated (Rochester Medical Corporation. Stewartville, Minnesota) or standard silicone catheter (nitrofurazone is a nitrofuran drug, similar to nitrofurantoin). Urine specimens were obtained immediately after insertion of the catheter and then daily until its removal. The primary end-point was the incidence of catheter-associated bacteruria or fungeria with at least 103 colony forming units/mL with ≥ 1 isolate; post-hoc analysis were also done using a cut-off ≥ 105 CFU/mL. Subjective symptoms could not be readily assessed as most patients had altered mental status and/or required ventilatory assistance. Patients who did not qualify for enrollment included those who were pregnant, HIV+, burn victims, or those with baseline bacteriuria. Most of the patients were hospitalized with blunt trauma or penetration injuries from car accidents (49%) or falls (32%).

A total of 1190 urine cultures were obtained over 1001 catheter days. Patients with nitrofurazone-catheters had a significantly lower incidence of catheter-associated bacteriuria and funguria compared with the control group (9.1% vs. 24.7%, adjusted relative risk 0.31, P -0.005). The incidence per 1000 catheter days was 13.8% vs 38.6, respectively, for the nitrofurazone vs. the control group. In the post-hoc analysis, using the cut-off of at least 105 CFU/mL, bacteriuria and funguria were still significantly lower in the nitrofurazone group (6.5% vs 19.5%, p = 0.014).

The presence of bacteriuria/funguria led to a change in or initiation of antimicrobial therapy in 5 of 7 patients (71%) in the nitrofurazone group compared with 18 of 19 patients in the control group (95%). Thus, the proportion of patients specifically treated for a UTI was 4.8% vs 17.5% of nitrofurazone vs. control subjects, respectively (p = 0.006). In addition, the onset of catheter-associated bacteriuria/funguria was significantly delayed in the nitrofurazone group (p = 0.01).

A lack of nitrofurazone susceptibility was found in 3 isolates (2 yeast and 1 Pseudomonas aeruginosa) in the nitrofurazone group, compared with 7 isolates in the control group (5 yeast and 2 Enterobacter spp).

There were no instances of bacteremia related to catheter-associated bacteriuria. There was no apparent affect on length of stay in the ICU, duration of stay in hospital, or 30-day mortality. Elevations of white blood counts, increased heart rate, or temperature did not significantly differ between groups. A large number of patients (n = 52) were not included in the per-protocol analysis, and a number of patients had missing values. However, examination of the data by intent-to-treat and sensitivity analyses (best case/worse case scenarios) did not appear to affect the conclusions.

There are some intriguing aspects to this study, and several limitations. One of the more compelling findings of this study is the less frequent administration of antibiotics specifically for "UTI" in the nitrofurazone group compared with controls. Presumably physicians prescribed antibiotics for what they believed was symptomatic urinary tract infection, and not just asymptomatic colonization. However, there is no evidence for this, and none of the patients evaluated had documentation of temperature greater than 38.2° C. The more frequent (daily) monitoring of urine specimens may have led to more frequent recognition of colonization and treatment than would have occurred in the clinical setting. Should physicians have been blinded to those results, except for those instances where urinary specimens were requested by the treating physicians, different results may have been obtained. In addition, most of the patients enrolled in this study were young (median age early 40s), and few had complicating conditions, such as diabetes, heart disease, or urologic disease. Thus, this data may not be generalizable to older, chronically ill patients in a critical care setting, or to those requiring non-critical hospital care, where the use of a catheter may be limited to a couple of days.

Direct Consumer Advertising — Is There Adequate Oversite?

Source: Donohue JM, et al. A decade of direct-to-consumer advertising of prescription drugs. N Engl J Med 2007, 357:673-681.

Direct consumer advertising was first approved by the Food and Drug Administration in 1996. Since then, direct pharmaceutical promotions within the United States, either through print, radio, or television ads, has increased from $985 million to more than $4 billion in 2005, and now accounts for 2.6% of drug sales. Almost every drug class has been affected, although drugs that are advertised to consumers tend to be new (expensive) agents for chronic conditions. For certain agents, such as the protocol pump inhibitors, erythropoietin, and the statins, about one-third of their marketing budget is designated for direct consumer advertising. In contrast, professional promotion to health care workers during this same period of time dropped 23%, although it still represents 4.4% of total drug costs (including $429,000 for journal advertising). In total, marketing dollars account for 18.2% of drug sales, and are heavily focused on newer agents.

As I scanned through the list of the top 20 pharmaceutical drugs in terms of spending, I breathed a sigh of relief; only 2 were antimicrobials (Valtrex and terbenafine). Total direct consumer advertising dollars for terbenafine alone was $110 million. Notably, Medical (California's version of Medicaid) pays for neither of these agents; and at the Santa Clara County hospital we've decided our limited ADAP budget can not afford them. (We'd happily take the $110 million to pay for other more necessary drugs). And yet, I am sure every ID physician has had their share of requests for other drugs on the top 20 list, including lunesta, ambien, Viagra and cialis, and even humara and neulasta (!).

This survey found that while the budget for consumer advertising continues to grow every year, adequate FDA regulation of those ads is not keeping pace. From 1999 to 2004, the number of ads reviewed prior to being aired decreased from 64% to 32%. Three FDA staff members were assigned in 2002 to review direct-to-consumers ads, but only 4 staff members were assigned in 2006, although the budget for consumer advertising grew 45% during that period of time, to a current value of 4.2 billion dollars.

The total number of letters for violating regulations for prescription advertising sent by the FDA to pharmaceutical manufacturers dropped 86% from 1997 to 2006 (only 21 letters were issued in 2006). Nearly half were for direct consumer advertising, 84% of which cited companies for minimizing risk, exaggerating effectiveness, or unsubstantiated claims of superiority, or all of the above.

Most direct consumer drug campaigns for the top 20 most heavily advertised agents all started within one year of FDA approval of the drug. This raises concerns that adequate regulatory oversite of these campaigns is not occurring (or possible) in this time frame, and that drugs are being heavily marketed even before there is much consumer experience with them or, for that matter, even before physicians have experience with them. Complicating the timely intervention of misleading or false advertising was a new policy instituted in 2002 whereby the FDA general counsel must first review and approve all FDA letters related to advertising violations. As a result, the number of letters issued by the FDA in 2002 dropped by half compared with one year earlier, many of which were issued after the advertising campaign had run its course. Several authorities have called for restrictions in advertising until at least one year after FDA approval, and perhaps even after regulatory bodies have had the opportunity to at least review the advertisements.

Obviously, pharmaceutical companies do not spend heavily without achieving their aims. But the next time a pharmaceutical company protests that drug development and research are responsible for high drug costs, you can suggest they could cut their marketing budgets for the top 20 drugs alone and save a bundle.

Thought for the day….

Are you aware that tap water is much more heavily regulated than bottled water, and is not only cheaper but cleaner? That is because tap water is regulated by the EPA, with fairly strict standards. Bottled water is monitored by the FDA.