Updates By Carol A. Kemper, MD, FACP
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.
Scrub That Lettuce!
Sposton EL, Macrae M, Ogden ID, et al. Slugs: Potential Novel Vectors of Escherichia coli 0157. Appl Environ Microbiol. 2006;72:144-149.
On my first walk through a redwood forest after moving to California, I came across numerous slimy yellow creatures along the trail that looked like snails without shells. These were banana slugs, creatures that are currently the official mascots of the University of Califonia, Santa Cruz.
Slugs, like snails, are molluscs, but they lack shells and come in a variety of sizes, including some which make their presence much less obvious than that of the banana slug. Instead, they are soft, slimy creatures that necessarily hang out in dark, moist places, such as the underside of lettuce leafs in the field. Lettuce and other leafy vegetables commonly retain a complement of these creatures and, unless removed by vigorous cleaning, they and their feces may be ingested along with the arugula and other raw items in modern salads. Vegetables such as these may also be carry snails, and these fellow gastropods are known to be intermediated hosts for a number of parasitic infections affecting humans, such as fascioliasis.
Sposton and colleagues have now provided evidence demonstrating the potential for slugs to transmit at least one enteric pathogen, Escherichia coli 0157. The major reservoir for these enteropathogens is the gastrointestinal tract of farm ruminants who shed the organism in their feces. Slugs, which are ubiquitous agricultural pests that continuously infest soil and its associated bacteria. Sposton et al identified verotoxin gene-positive E. coli 1057 in 0.21% of gray field slugs, a frequent contaminant of leafy salad vegetables, from a farm in Aberdeenshire, Scotland. The bacteria were genetically indistinguishable from those recovered from sheep on the farm, 7% of whom were estimated to be carrying it. They demonstrated that the slug, which can travel up to 12 meters a night, could carry viable E. coli on its external surface for as long as 14 days, and the microorganism persisted for up to 3 weeks in excreted slug feces.
Thus, slugs have the potential to act as vectors of transmission of verotoxin positive E. coli 0157. This, however, could be prevented by careful cleaning of leafy salad vegetables before ingestions.
An aside: Slugs are hermaphroditic, having the "unenviable task of being a father and a mother at the same time."1 Some slugs enhance their reproductive success by the use of love darts, which are hard, needle-like structures produced in the dart-sac for the express purpose of dart shooting, which results in increased success in spermatozoa reaching their trarget.1 This raises the bizarre question: could E. coli 0157 infection be a sexually transmitted disease in slugs?
Reference
- Schilthuizen M. The Darting Game in Snails and Slugs. Trends Ecol Evol. 2005;20:581-584.
Ketek's Troubled History
Wall Street Journal, Monday May 1, 2006, page A1; Response Statement from Sanofi Aventis dated May 10, 2006.
Reports of severe, life threatening and even fatal cases of severe liver damage in patients receiving telithromycin (Ketek®, Sanofi Aventis), some of which were recently reviewed in the Annals of Internal Medicine, has prompted a deeper analysis of events leading up to FDA approval of this agent in the United States. According to the FDA, they are presently aware of 10 cases of hepatic failure following administration of telithromycin, although the relationship to drug is under investigation.
Telithromycin was first submitted to the FDA for approval in 2000, and eventually received formal approval for use in sinusitis, bronchitis and community acquired pneumonia in April 2004. During the FDA's initial drug evaluation, it was felt that there was insufficient data regarding the risks of visual blurring, hepatic toxicity, and other side events, and drug interactions and requested additional data. The company complied, embarking on a large clinical trail in 24,000 adult outpatients (Study 3014). The study was performed in the usual care setting, with more than 400 sites throughout the United States.
Unfortunately, subsequent events have shed doubt on the validity of Study 3014 data provided by at least 3 of the investigators (these 3 sites enrolled a total of 872 patients). The most egregious case was a female physician in Alabama who "enrolled" 407 patients, who is subsequently serving a 4-year sentence in Federal prison for defrauding the company (in an interesting twist, she pled guilty to mail fraud for sending falsified data through the mail). Another physician lost his license for gross negligence and drug possession shortly after enrolling the final patient at his site. And another physician admitted to inadequate record keeping.
The hullabaloo surrounds the issue of whether and when the parent company may have recognized irregularities and deficiencies at some sites, and whether this was adequately reported to the FDA. Only an independent FDA audit of these sites, conducted simply because of the large numbers of patients enrolled, revealed serious problems, including patients who received study drug for inappropriate indications (eg, weight loss), patients who reported never receiving study drug, fabrication of data, and failure to report adverse events.
Despite suspicions and concerns raised about Study 3014 sites in ongoing FDA investigations, an FDA Advisory Committee Panel convened in January 2003 to-re-evaluate telithromycin for approval. Inexplicably, the panel was not made aware of the above concerns, and recommended the drug for approval. The FDA rejected the Advisory Committee's recommendation, indicating that additional data from Study 3014 and overseas post-marketing experience was still needed.
In the meantime, increasingly available post-marketing data from Europe and other countries suggested the drug had an adequate safety record. The FDA ultimately decided that Study 3014 was too flawed to be relied upon, but nonetheless approved the drug in April 2004 for the treatment of sinusitis, bronchitis and community acquired pneumonia.
The Senate Finance Committee and 2 congressmen are now examining these events. While the company admits that "deviations occurred at some sites, and in one case, actual fraud by one the site investigators was ultimately identified in an FDA criminal investigation", they continue to vigorously defend Study 3014 data as reflecting the broader experience of community based research, and believe it provides useful safety data. They "remain confidant that Ketek is a safe and effective first-line therapy" for respiratory tract infections. Indeed, the drug has broader activity against many respiratory bacterial pathogens than many other currently available agents, and continues to be evaluated in clinical trails of pediatric otitis.
The company is to be credited for their efforts at new drug development in the face of increasing bacterial resistance, something that few pharmaceutical companies have elected to pursue.
None of this addresses many primary care physicians concerns regarding the potential drug interactions with this telithromycin, including agents commonly received by many elderly. These include interactions with CYP 3A4 inducers, such as rifampin, coumadin (with an increased risk of bleeding), some of the statins, several antiarrhythmic agents, and drugs with the potential to prolong the QT interval. Feedback from physicians in the community suggests that concerns regarding drug interactions (and just trying to remember them all) may be the more material limitation to the broader use of this agent.
However, it may be telling that a local dermatologist scared the beejeebers out of patient recently seen in consultation for disabling chronic bronchiectasis. Although he had received telithromycin without problem on at least one prior occasion, the dermatologist urged him to stop his current course of therapy before it "damaged his liver."
On my first walk through a redwood forest after moving to California, I came across numerous slimy yellow creatures along the trail that looked like snails without shells. These were banana slugs, creatures that are currently the official mascots of the University of Califonia, Santa Cruz.Subscribe Now for Access
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