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Latest multidrug-resistant bacterial diarrheas raise questions
Gastroenterology News John H. Walsh, Section Editor
How Helicobacter pylori Defends Its Turf
The authors speculate that these peptides may be released by bacterial lysates to prevent other faster-growing microorganisms from colonizing the stomach. Thomas Ganz of the University of Califor-
nia, Los Angeles, an expert on defensins (antibacterial peptides produced by mammalian white blood cells and epithelial cells), feels that this article is provocative elicobacter pylori is uniquely but not conclusive until such peptides adapted to survive in the acid pH of are isolated directly from inthe stomach. Intracellular urefected human stomachs, but bease in the organism creates amlieves that this article repremonia to provide a halo of parsents ‘‘a good opening move.’’ tial neutralization of acid pH Another paper published last around each organism. Howyear in the July 1998 Journal of ever, even under conditions of Clinical Investigation by Mattspartial gastric neutralization by son et al. from Go ¨ teborg, Sweantisecretory drugs or chronic den, found that subjects with H. gastritis, coinfection of the stompylori infection responded to ach by other organisms is unoral cholera vaccine with incommon. Two recent articles tense antral immune response offer possible explanations. characterized by production of In the April 22nd issue of immunoglobulin A, whereas unNature, a group from the Karoinfected subjects had little or linska Institute in Sweden reno response. Thus, the H. pyloported that H. pylori lysates ri–infected human antrum may contained antibacterial activity. be primed to produce antibodA search of the H. pylori geies against foreign bacteria. nome revealed a peptide seThese two articles suggest quence that resembled cecrothat H. pylori may not simply pins, known antibacterial have the means to defend itself peptides produced by insects. A 19–amino acid peptide synthe- H. pylori may repel bacterial invasion of the stomach by against acid, but it may also sized from this sequence other organisms by release of antibacterial peptides and by participate in an active defense to prevent invasion of the stomshowed strong antibacterial ac- stimulation of antral immune responses. ach by other bacteria. tivity against Escherichia coli.
H
Latest Multidrug-Resistant Bacterial Diarrheas Raise Questions hree articles were recently published in the same week in JAMA and the New England Journal of Medicine describing separate outbreaks of multidrugresistant bacterial diarrheas. Which raises the question: What is causing the apparent increase in antimicrobial resistance in the United States? In the May 19 issue of JAMA, Cody et al. described two outbreaks in Northern California of multidrug-resistant Salmonella typhimurium definitive type 104, the most common multidrug-resistant Salmonella strain in the United States. In the same issue, Mead et al. reported an outbreak of the same strain in Washington state. Previously, illnesses from this strain in the United States hadn’t been definitively tied to a source, but both the California outbreaks and the Washington outbreak were linked to the consumption of raw milk products. Meanwhile, Smith et al. at the Minne-
T
sota Department of Health, reporting in the May 20 New England Journal of Medicine, described an increase in the proportion of quinolone-resistant Campylobacter jejuni infections from 1.3% in 1992 to 10.2% in 1998. They attributed the increase in domestically acquired quinolone-resistant infections to the use of fluoroquinolones in poultry, which began in the United States in 1995. The immediate implication, noted by the lead authors of the Salmonella articles, is that clinicians should obtain cultures from patients presenting with diarrhea, and that the increasingly common antimicrobial-resistant strain of Salmonella, as well as the growing possibility of other drug-resistant pathogens, may complicate treatment. ‘‘Physicians should be aware that drug resistance is looming, and should probably assume that the bug they’re seeing is resistant and treat accordingly until they get antibiotic sensitivity patterns back from the lab,’’ says Sara Cody of the Santa Clara County Public Health Department, the lead author on the Northern California article. But Paul Mead of the Centers for Disease Control
and Prevention, the lead author of the article on the strain in Washington state, is concerned that a trend toward empiric diagnoses in the era of managed care might cause the pathogen to be overlooked in some cases. Mead urges gastroenterologists not only to obtain cultures, but also to pay attention to their patients’ eating practices so that they are aware of the risks. Perhaps more troubling is the growing sense that multidrug-resistant pathogens are resulting from the way antibiotics are used in animal populations. Salmonella lives in the intestines of animals, and one of the concerns is that the use of antibiotics for growth-promoting reasons may also be promoting resistance to antibiotics. ‘‘We don’t want to discount the legitimate needs for therapeutic antimicrobial use on farms, but clearly we need to know more about the ecology of these organisms,’’ says Mead. ‘‘The use of antibiotics in livestock is the obvious thing to look into,’’ adds Cody. ‘‘We need to understand the downstream effects, as a possible impetus for making changes.’’
GASTROENTEROLOGY 1999;117:3–4
Gastroenterology News continued
New Fat-Preventing Pill Likely to Yield Slim Benefits ith obesity increasing and millions of Americans looking for a simple way to shed pounds, no one will be surprised to see Xenical (orlistat), the fat-absorption-preventing pill that hit the pharmacies in May, to fulfill its marketing promise. Hoffman-La Roche expects sales to reach $3 billion a year, which, at an annual cost of roughly $1400 a person, translates to several million takers. But at least one expert who sat on the FDA Advisory Panel for the drug believes it’s being oversold. Jules Hirsch of Rockefeller University recommended against FDA approval based on his conviction that Xenical’s relatively minor benefits are outweighed by the potential hazards inherent in introducing any new drug, particularly one
W
New COX-2 Inhibitors Look for the GI-Safe Label DA approval in May of the cyclooxygenase 2 (COX-2)-inhibiting arthritis drug Vioxx pits Merck, the drug’s manufacturer, against fellow pharmaceutical giant Searle and its own COX-2 inhibitor, Celebrex, for market share in what is projected to be a $3-billion-a-year industry. Vioxx and Celebrex are the first in a new class of drugs that block the COX-2 enzyme, which is activated during inflammation, while leaving alone the COX-1 enzyme that protects the lining of the gastrointestinal tract. The drugs arrive amid great fanfare based on their ability
F
Budget Bickering Is Bad News for NIH t press time, the prospect continued to loom that a budget shortfall would force the congressional subcommittees that handle funding for the National Institutes of Health to make fiscal year (FY) 2000 cuts of as much as $10 billion in health, education, and labor programs. The source of the potential cuts–and of
A
4
with such a large customer base. ‘‘There’s only a 4% difference in weight loss between the drug and placebo in the first year,’’ he says. ‘‘And in the 2-year studies, it looks as if the subjects in both the placebo and treated groups are coming back toward their previous weights. This drug is coming across in the media as though it’s some amazing new thing, and it really isn’t that effective.’’ Xenical decreases absorption of dietary fat by about 30% by coating the lining of the gut with lipase inhibitors. Initially, the drug seemed to be associated with a small increase in breast cancer risk. An independent panel determined that almost all of the cancers existed before the women began taking Xenical, though Hirsch is not convinced the issue has been completely resolved. The drug can cause less serious side effects, including oily spotting, fatty or
oily stools, and frequent bowel movements. Other concerns range from the potential impact of the reduction in levels of fat-soluble vitamins to the possibility of long-term inflammatory bowel disease risk. In addition, Hirsch points out that the drug is being sold over the Internet. ‘‘It clearly should be under a physician’s supervision,’’ he says. The FDA approved Xenical for individuals with body mass indexes of 30 or more, but Hirsch suspects that it will be used by people with lesser degrees of obesity. Considering the rapid pace at which scientists are learning about the mechanisms whereby fat is controlled in the body, Hirsch doesn’t discount the possibility of a ‘‘magic bullet’’ for obesity one day emerging. But, he concludes, those who are looking for such magic in a Xenical capsule are bound to be disappointed.
to kill pain while producing fewer ulcers and stomach problems than aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDS), which are not COX-specific. But so far, neither Merck nor Searle has been allowed to use the two words that would render the greatest competitive advantage of all: GI-safe. Both are required by the FDA to carry the standard NSAID warning about potential gastrointestinal toxicity on their labels –at least for now–despite the fact that clinical trials have found that the drugs, which are as effective as NSAIDs at relieving pain, produce a dramatically lower rate of endoscopic ulcers, with rates comparable to placebo.
The question that still needs to be answered before the warnings are modified or removed is whether one can extrapolate from endoscopic ulcers to clinical events, notes Loren Laine of the USC School of Medicine. Laine presented results at this year’s DDW from a study comparing endoscopic ulcer rates among patients taking Vioxx with those taking ibuprofen. ‘‘Everything we know at this point suggests that the COX-specific inhibitors should be significantly safer in terms of clinically important ulcers,’’ Laine says. ‘‘But we still need the large, prospective clinical-outcome studies to confirm what we suspect.’’
the impasse through the first half of this year–is implementation of the GOPauthored FY 2000 budget agreement, which retains the caps on discretionary spending implemented in the balanced budget deal of 1997. The FY 1999 budget stand-off was resolved with Republicans and Democrats agreeing to essentially ignore the caps and use a variety of budget gimmicks, including declaring billions of dollars in ‘‘emergency spend-
ing.’’ This time, those same tricks would probably not be enough, sources say. Stories by Dan Gordon The section editor can be sent suggestions for articles at [email protected]
How Helicobacter pylori Defends Its Turf
The authors speculate that these peptides may be released by bacterial lysates to prevent other faster-growing microorganisms from colonizing the stomach. Thomas Ganz of the University of Califor-
nia, Los Angeles, an expert on defensins (antibacterial peptides produced by mammalian white blood cells and epithelial cells), feels that this article is provocative elicobacter pylori is uniquely but not conclusive until such peptides adapted to survive in the acid pH of are isolated directly from inthe stomach. Intracellular urefected human stomachs, but bease in the organism creates amlieves that this article repremonia to provide a halo of parsents ‘‘a good opening move.’’ tial neutralization of acid pH Another paper published last around each organism. Howyear in the July 1998 Journal of ever, even under conditions of Clinical Investigation by Mattspartial gastric neutralization by son et al. from Go ¨ teborg, Sweantisecretory drugs or chronic den, found that subjects with H. gastritis, coinfection of the stompylori infection responded to ach by other organisms is unoral cholera vaccine with incommon. Two recent articles tense antral immune response offer possible explanations. characterized by production of In the April 22nd issue of immunoglobulin A, whereas unNature, a group from the Karoinfected subjects had little or linska Institute in Sweden reno response. Thus, the H. pyloported that H. pylori lysates ri–infected human antrum may contained antibacterial activity. be primed to produce antibodA search of the H. pylori geies against foreign bacteria. nome revealed a peptide seThese two articles suggest quence that resembled cecrothat H. pylori may not simply pins, known antibacterial have the means to defend itself peptides produced by insects. A 19–amino acid peptide synthe- H. pylori may repel bacterial invasion of the stomach by against acid, but it may also sized from this sequence other organisms by release of antibacterial peptides and by participate in an active defense to prevent invasion of the stomshowed strong antibacterial ac- stimulation of antral immune responses. ach by other bacteria. tivity against Escherichia coli.
H
Latest Multidrug-Resistant Bacterial Diarrheas Raise Questions hree articles were recently published in the same week in JAMA and the New England Journal of Medicine describing separate outbreaks of multidrugresistant bacterial diarrheas. Which raises the question: What is causing the apparent increase in antimicrobial resistance in the United States? In the May 19 issue of JAMA, Cody et al. described two outbreaks in Northern California of multidrug-resistant Salmonella typhimurium definitive type 104, the most common multidrug-resistant Salmonella strain in the United States. In the same issue, Mead et al. reported an outbreak of the same strain in Washington state. Previously, illnesses from this strain in the United States hadn’t been definitively tied to a source, but both the California outbreaks and the Washington outbreak were linked to the consumption of raw milk products. Meanwhile, Smith et al. at the Minne-
T
sota Department of Health, reporting in the May 20 New England Journal of Medicine, described an increase in the proportion of quinolone-resistant Campylobacter jejuni infections from 1.3% in 1992 to 10.2% in 1998. They attributed the increase in domestically acquired quinolone-resistant infections to the use of fluoroquinolones in poultry, which began in the United States in 1995. The immediate implication, noted by the lead authors of the Salmonella articles, is that clinicians should obtain cultures from patients presenting with diarrhea, and that the increasingly common antimicrobial-resistant strain of Salmonella, as well as the growing possibility of other drug-resistant pathogens, may complicate treatment. ‘‘Physicians should be aware that drug resistance is looming, and should probably assume that the bug they’re seeing is resistant and treat accordingly until they get antibiotic sensitivity patterns back from the lab,’’ says Sara Cody of the Santa Clara County Public Health Department, the lead author on the Northern California article. But Paul Mead of the Centers for Disease Control
and Prevention, the lead author of the article on the strain in Washington state, is concerned that a trend toward empiric diagnoses in the era of managed care might cause the pathogen to be overlooked in some cases. Mead urges gastroenterologists not only to obtain cultures, but also to pay attention to their patients’ eating practices so that they are aware of the risks. Perhaps more troubling is the growing sense that multidrug-resistant pathogens are resulting from the way antibiotics are used in animal populations. Salmonella lives in the intestines of animals, and one of the concerns is that the use of antibiotics for growth-promoting reasons may also be promoting resistance to antibiotics. ‘‘We don’t want to discount the legitimate needs for therapeutic antimicrobial use on farms, but clearly we need to know more about the ecology of these organisms,’’ says Mead. ‘‘The use of antibiotics in livestock is the obvious thing to look into,’’ adds Cody. ‘‘We need to understand the downstream effects, as a possible impetus for making changes.’’
GASTROENTEROLOGY 1999;117:3–4
Gastroenterology News continued
New Fat-Preventing Pill Likely to Yield Slim Benefits ith obesity increasing and millions of Americans looking for a simple way to shed pounds, no one will be surprised to see Xenical (orlistat), the fat-absorption-preventing pill that hit the pharmacies in May, to fulfill its marketing promise. Hoffman-La Roche expects sales to reach $3 billion a year, which, at an annual cost of roughly $1400 a person, translates to several million takers. But at least one expert who sat on the FDA Advisory Panel for the drug believes it’s being oversold. Jules Hirsch of Rockefeller University recommended against FDA approval based on his conviction that Xenical’s relatively minor benefits are outweighed by the potential hazards inherent in introducing any new drug, particularly one
W
New COX-2 Inhibitors Look for the GI-Safe Label DA approval in May of the cyclooxygenase 2 (COX-2)-inhibiting arthritis drug Vioxx pits Merck, the drug’s manufacturer, against fellow pharmaceutical giant Searle and its own COX-2 inhibitor, Celebrex, for market share in what is projected to be a $3-billion-a-year industry. Vioxx and Celebrex are the first in a new class of drugs that block the COX-2 enzyme, which is activated during inflammation, while leaving alone the COX-1 enzyme that protects the lining of the gastrointestinal tract. The drugs arrive amid great fanfare based on their ability
F
Budget Bickering Is Bad News for NIH t press time, the prospect continued to loom that a budget shortfall would force the congressional subcommittees that handle funding for the National Institutes of Health to make fiscal year (FY) 2000 cuts of as much as $10 billion in health, education, and labor programs. The source of the potential cuts–and of
A
4
with such a large customer base. ‘‘There’s only a 4% difference in weight loss between the drug and placebo in the first year,’’ he says. ‘‘And in the 2-year studies, it looks as if the subjects in both the placebo and treated groups are coming back toward their previous weights. This drug is coming across in the media as though it’s some amazing new thing, and it really isn’t that effective.’’ Xenical decreases absorption of dietary fat by about 30% by coating the lining of the gut with lipase inhibitors. Initially, the drug seemed to be associated with a small increase in breast cancer risk. An independent panel determined that almost all of the cancers existed before the women began taking Xenical, though Hirsch is not convinced the issue has been completely resolved. The drug can cause less serious side effects, including oily spotting, fatty or
oily stools, and frequent bowel movements. Other concerns range from the potential impact of the reduction in levels of fat-soluble vitamins to the possibility of long-term inflammatory bowel disease risk. In addition, Hirsch points out that the drug is being sold over the Internet. ‘‘It clearly should be under a physician’s supervision,’’ he says. The FDA approved Xenical for individuals with body mass indexes of 30 or more, but Hirsch suspects that it will be used by people with lesser degrees of obesity. Considering the rapid pace at which scientists are learning about the mechanisms whereby fat is controlled in the body, Hirsch doesn’t discount the possibility of a ‘‘magic bullet’’ for obesity one day emerging. But, he concludes, those who are looking for such magic in a Xenical capsule are bound to be disappointed.
to kill pain while producing fewer ulcers and stomach problems than aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDS), which are not COX-specific. But so far, neither Merck nor Searle has been allowed to use the two words that would render the greatest competitive advantage of all: GI-safe. Both are required by the FDA to carry the standard NSAID warning about potential gastrointestinal toxicity on their labels –at least for now–despite the fact that clinical trials have found that the drugs, which are as effective as NSAIDs at relieving pain, produce a dramatically lower rate of endoscopic ulcers, with rates comparable to placebo.
The question that still needs to be answered before the warnings are modified or removed is whether one can extrapolate from endoscopic ulcers to clinical events, notes Loren Laine of the USC School of Medicine. Laine presented results at this year’s DDW from a study comparing endoscopic ulcer rates among patients taking Vioxx with those taking ibuprofen. ‘‘Everything we know at this point suggests that the COX-specific inhibitors should be significantly safer in terms of clinically important ulcers,’’ Laine says. ‘‘But we still need the large, prospective clinical-outcome studies to confirm what we suspect.’’
the impasse through the first half of this year–is implementation of the GOPauthored FY 2000 budget agreement, which retains the caps on discretionary spending implemented in the balanced budget deal of 1997. The FY 1999 budget stand-off was resolved with Republicans and Democrats agreeing to essentially ignore the caps and use a variety of budget gimmicks, including declaring billions of dollars in ‘‘emergency spend-
ing.’’ This time, those same tricks would probably not be enough, sources say. Stories by Dan Gordon The section editor can be sent suggestions for articles at [email protected]