Post by shoreman on May 5, 2006 10:33:00 GMT -5
Bad Bugs, Few Drugs
Miller Op-Ed in TCSDaily
Op-Eds & Articles
by Henry I. Miller
May 4, 2006
www.cei.org/gencon/019,05301.cfm
During the late 1960's, my college roommate suffered a seemingly minor skin infection on a finger, which quickly turned into blood poisoning and resulted in a hip abscess. The infection resolved completely after a few weeks of therapy with a penicillin derivative and repeated aspirations of pus.
That success story is less likely to be repeated today. Especially if the infection is one contracted in a hospital—in a surgical wound, for example, or in the form of pneumonia—there is a high probability that the bacteria responsible will be resistant to one or more antibiotics.
As many as two million patients nationwide contract infections in hospitals each year, and 90,000 die, according to the Centers for Disease Control and Prevention (CDC). The death rate in such cases is alarmingly high not because the patients initially are gravely ill, but because hospital germs increasingly are resistant to multiple antibiotics: about 70 percent of those infections are resistant to at least one drug, so the infections are hard to treat. In many cases, we're already out of good second- or third-line alternatives that are effective, can be administered by mouth and have few side effects, so we must resort to drugs that are inconvenient to administer or are toxic.
Antibiotic-resistant pathogens lead to higher health care costs because they often require more expensive drugs and extended hospital stays. The total cost to U.S. society is nearly $5 billion annually, according to the Infectious Diseases Society of America.
The trends toward increasing numbers of infections and increasing drug resistance show no sign of abating, and formerly unusual bacteria are gaining prominence. An example is Acinetobacter baumannii, outbreaks of which are plaguing hospitals in the United States, Europe and elsewhere. It evolves resistance to multiple antibiotics unusually quickly and also survives on dry surfaces for many weeks.
Many bad bugs are spreading beyond our hospitals into the greater community. Bacteria are masters of evolutionary adaptation: Given sufficient time and exposure, they use a variety of enormously clever genetic and metabolic tricks to resist any drug we invent. There is no antibiotic in clinical use today to which resistance has not developed. A future with few effective antibiotics would be treacherous; and many of today's routine medical procedures, from surgical operations to chemotherapy, would be far more dangerous if we permit the bacteria to outwit us.
Federal agencies are acutely aware of the importance of this issue. "Unless antibiotic resistance problems are detected as they emerge, and actions are taken to contain them, the world could be faced with previously treatable diseases that have again become untreatable, as in the days before antibiotics were developed," according to the FDA. An example that supports this pessimistic view is our waning ability to treat the common pathogen Staphylococcus aureus, which causes pustules and abscesses on the skin and can spread to the bloodstream, lungs, brain, bones, or heart, causing severe organ damage and death. Nearly all S. aureus strains have now become resistant to penicillin, and many have become resistant to methicillin and other similar drugs that used to comprise the second line of treatment for S. aureus infections.
Vancomycin was long considered to be the only uniformly effective drug for methicillin-resistant S. aureus (MRSA). However, a decade ago, strains of S. aureus with decreased susceptibility to vancomycin were reported for the first time in Japan and the United States. Since then, resistance to vancomycin has become common, which has largely removed our last bulwark against MRSA. Officials at the CDC are appropriately concerned about this development; echoing the quote from the FDA, above, the website of the National Center for Infectious Diseases contains this warning: "If we are unable to limit the emergence and spread of resistance—and to replace drugs like vancomycin as they lose their effectiveness—S. aureus and other similar common bacterial infections may become untreatable, as they were 60 years ago."
To combat this public health emergency, important initiatives are underway by both government and the private sector to promote more sparing and intelligent use of antibiotics. Regulators and livestock producers are collaborating to reduce the amounts of antibiotics used to prevent disease in livestock, and many HMOs have adopted policies that restrict antibiotics to infections that seem unequivocally to be caused by bacteria. (In other words, patients should not routinely get antibiotics for colds, which are caused not by bacteria, but by viruses.)
The CDC is conducting a campaign to prevent antibiotic resistance in healthcare centers that consists of four main strategies: prevent infection, diagnose and treat infection, use antimicrobials wisely, and prevent transmission. However, federal officials have paid little attention to the flip side of the problem: the shortage of new antibiotics. Twenty years ago, approximately a half-dozen new antibiotics would appear on the market each year; now it's at most one or two. For decades we've relied largely on new variations on old tricks to combat rapidly evolving pathogens: Most antibiotics in use today are chemically related to earlier ones discovered between 1941 and 1968. During the last 37 years, only two antibiotics with truly novel modes of action have been introduced—Zyvox in 2000 and Cubicin in 2003, the latter of which is used only against skin infections.
Market forces and regulatory costs have exacerbated the antibiotics drought. Until about a decade ago, all the major pharmaceutical makers had antibacterial research programs, but they have dramatically trimmed or eliminated these efforts, focusing instead on more lucrative drugs that treat chronic ailments and other issues. Think Lipitor and Levitra, for example. Whereas antibiotics cure a patient in days, and may not be required again for years, someone with high cholesterol or erectile dysfunction might pop expensive pills every day for decades. Moreover, drug development has become hugely expensive, with the direct and indirect costs to bring a drug to market now averaging more than $800 million.
We need both legislative and FDA-initiated remedies. In 2005, Senators Joe Lieberman (D-Connecticut) and Orrin Hatch (R-Utah) introduced BioShield II, legislation that if enacted, would have created tax incentives for companies that develop new antibiotics and would limit their liability for side effects, as has been done for vaccines. It would also have extended patents on antibiotics to compensate for time lost while awaiting FDA approval.
The bill's most controversial provision was "wild-card exclusivity," which would have allowed a drug company that markets a new antibiotic to extend the patent on any product in its portfolio by up to two years, with the approval of federal officials. If Pfizer were to discover a new antibiotic, for example, the company might be granted more time to market Viagra before generic manufacturers were permitted to produce that drug.
Although the wild-card idea offers the best hope of fostering antibiotics research, it was a little too wild in its proposed form. It would have permitted federal officials to grant a wild-card patent extension whenever a pharmaceutical maker developed an antibiotic that met the FDA's broad definition of a "new chemical entity." Under this language, if Bayer were to chemically alter its already-marketed antibiotic ciprofloxacin (Cipro), for example, the company might qualify for a lucrative patent extension on Levitra, even if the new antibiotic wasn't significantly better than its precursor.
A more appropriate standard would be that in order to qualify for wild-card exclusivity, a drug company's new antibiotic would have to meet FDA's criteria for "fast track" designation during development—a product that "is intended for the treatment of a serious or life-threatening condition and [that] demonstrates the potential to address unmet medical needs." Thus, a new antibiotic would qualify if it were intended for serious infections; and if it were active against bacteria widely resistant to existing antibiotics, or if it were more easily administered—for example, orally—or had fewer side effects than alternatives. Arguably, a chemically altered Cipro should qualify for the wild-card only if it met these criteria.
In order to stimulate the development of new antibiotics, other aspects of public policy will need attention as well. It has been said that when the FDA sneezes, the pharmaceutical industry gets pneumonia. A chilling example is the delay of an injectable antibiotic called Tigecycline, for infections caused by antibiotic-resistant pathogens. Its manufacturer, Wyeth-Ayerst Laboratories, had done two human studies to show that the drug was safe and effective, and was planning a third and final one. However, in 2000 the FDA changed the rules for measuring efficacy in trials of antibiotics, which required the company to double the number of patients in the trials from 4,000 to 8,000. That made the investment required by Wyeth much greater in both time and money. The drug was finally approved in 2005.
This kind of policy decision has a pernicious ripple effect. "As a result [of FDA's change in policy], we've got fewer companies involved in the antibiotic discovery business at a time when antibiotic resistance to existing drugs is becoming more of a problem," according to Dr. Robert C. Moellering, Jr., chairman of the department of medicine at Beth Israel Deaconness Medical Center in Boston.
We need also to adopt the kinds of critical FDA reforms suggested by the Infectious Diseases Society of America. Among them: expediting the publication of updated guidelines for clinical trials of antibiotics, including a clear definition of what constitutes acceptable surrogate markers as endpoints; encouraging "imaginative clinical trial designs that lead to a better understanding" of antibiotics' efficacy; the exploration of animal models of infection, in vitro technologies, and microbiologic surrogate markers to reduce the number of efficacy studies required; and the FDA's granting of accelerated review status to priority antibiotics.
The two novel antibiotics introduced since 2000 won't be enough to keep rapidly mutating pathogens at bay for long, and once resistance appears, it will spread rapidly. Unless we create economic and regulatory incentives for companies to develop antibiotics, it's unlikely that we'll see many more wonder drugs in the near future. That's something to think about next time you contract bronchitis, or are hospitalized with a flesh-eating bacterial infection.
Miller Op-Ed in TCSDaily
Op-Eds & Articles
by Henry I. Miller
May 4, 2006
www.cei.org/gencon/019,05301.cfm
During the late 1960's, my college roommate suffered a seemingly minor skin infection on a finger, which quickly turned into blood poisoning and resulted in a hip abscess. The infection resolved completely after a few weeks of therapy with a penicillin derivative and repeated aspirations of pus.
That success story is less likely to be repeated today. Especially if the infection is one contracted in a hospital—in a surgical wound, for example, or in the form of pneumonia—there is a high probability that the bacteria responsible will be resistant to one or more antibiotics.
As many as two million patients nationwide contract infections in hospitals each year, and 90,000 die, according to the Centers for Disease Control and Prevention (CDC). The death rate in such cases is alarmingly high not because the patients initially are gravely ill, but because hospital germs increasingly are resistant to multiple antibiotics: about 70 percent of those infections are resistant to at least one drug, so the infections are hard to treat. In many cases, we're already out of good second- or third-line alternatives that are effective, can be administered by mouth and have few side effects, so we must resort to drugs that are inconvenient to administer or are toxic.
Antibiotic-resistant pathogens lead to higher health care costs because they often require more expensive drugs and extended hospital stays. The total cost to U.S. society is nearly $5 billion annually, according to the Infectious Diseases Society of America.
The trends toward increasing numbers of infections and increasing drug resistance show no sign of abating, and formerly unusual bacteria are gaining prominence. An example is Acinetobacter baumannii, outbreaks of which are plaguing hospitals in the United States, Europe and elsewhere. It evolves resistance to multiple antibiotics unusually quickly and also survives on dry surfaces for many weeks.
Many bad bugs are spreading beyond our hospitals into the greater community. Bacteria are masters of evolutionary adaptation: Given sufficient time and exposure, they use a variety of enormously clever genetic and metabolic tricks to resist any drug we invent. There is no antibiotic in clinical use today to which resistance has not developed. A future with few effective antibiotics would be treacherous; and many of today's routine medical procedures, from surgical operations to chemotherapy, would be far more dangerous if we permit the bacteria to outwit us.
Federal agencies are acutely aware of the importance of this issue. "Unless antibiotic resistance problems are detected as they emerge, and actions are taken to contain them, the world could be faced with previously treatable diseases that have again become untreatable, as in the days before antibiotics were developed," according to the FDA. An example that supports this pessimistic view is our waning ability to treat the common pathogen Staphylococcus aureus, which causes pustules and abscesses on the skin and can spread to the bloodstream, lungs, brain, bones, or heart, causing severe organ damage and death. Nearly all S. aureus strains have now become resistant to penicillin, and many have become resistant to methicillin and other similar drugs that used to comprise the second line of treatment for S. aureus infections.
Vancomycin was long considered to be the only uniformly effective drug for methicillin-resistant S. aureus (MRSA). However, a decade ago, strains of S. aureus with decreased susceptibility to vancomycin were reported for the first time in Japan and the United States. Since then, resistance to vancomycin has become common, which has largely removed our last bulwark against MRSA. Officials at the CDC are appropriately concerned about this development; echoing the quote from the FDA, above, the website of the National Center for Infectious Diseases contains this warning: "If we are unable to limit the emergence and spread of resistance—and to replace drugs like vancomycin as they lose their effectiveness—S. aureus and other similar common bacterial infections may become untreatable, as they were 60 years ago."
To combat this public health emergency, important initiatives are underway by both government and the private sector to promote more sparing and intelligent use of antibiotics. Regulators and livestock producers are collaborating to reduce the amounts of antibiotics used to prevent disease in livestock, and many HMOs have adopted policies that restrict antibiotics to infections that seem unequivocally to be caused by bacteria. (In other words, patients should not routinely get antibiotics for colds, which are caused not by bacteria, but by viruses.)
The CDC is conducting a campaign to prevent antibiotic resistance in healthcare centers that consists of four main strategies: prevent infection, diagnose and treat infection, use antimicrobials wisely, and prevent transmission. However, federal officials have paid little attention to the flip side of the problem: the shortage of new antibiotics. Twenty years ago, approximately a half-dozen new antibiotics would appear on the market each year; now it's at most one or two. For decades we've relied largely on new variations on old tricks to combat rapidly evolving pathogens: Most antibiotics in use today are chemically related to earlier ones discovered between 1941 and 1968. During the last 37 years, only two antibiotics with truly novel modes of action have been introduced—Zyvox in 2000 and Cubicin in 2003, the latter of which is used only against skin infections.
Market forces and regulatory costs have exacerbated the antibiotics drought. Until about a decade ago, all the major pharmaceutical makers had antibacterial research programs, but they have dramatically trimmed or eliminated these efforts, focusing instead on more lucrative drugs that treat chronic ailments and other issues. Think Lipitor and Levitra, for example. Whereas antibiotics cure a patient in days, and may not be required again for years, someone with high cholesterol or erectile dysfunction might pop expensive pills every day for decades. Moreover, drug development has become hugely expensive, with the direct and indirect costs to bring a drug to market now averaging more than $800 million.
We need both legislative and FDA-initiated remedies. In 2005, Senators Joe Lieberman (D-Connecticut) and Orrin Hatch (R-Utah) introduced BioShield II, legislation that if enacted, would have created tax incentives for companies that develop new antibiotics and would limit their liability for side effects, as has been done for vaccines. It would also have extended patents on antibiotics to compensate for time lost while awaiting FDA approval.
The bill's most controversial provision was "wild-card exclusivity," which would have allowed a drug company that markets a new antibiotic to extend the patent on any product in its portfolio by up to two years, with the approval of federal officials. If Pfizer were to discover a new antibiotic, for example, the company might be granted more time to market Viagra before generic manufacturers were permitted to produce that drug.
Although the wild-card idea offers the best hope of fostering antibiotics research, it was a little too wild in its proposed form. It would have permitted federal officials to grant a wild-card patent extension whenever a pharmaceutical maker developed an antibiotic that met the FDA's broad definition of a "new chemical entity." Under this language, if Bayer were to chemically alter its already-marketed antibiotic ciprofloxacin (Cipro), for example, the company might qualify for a lucrative patent extension on Levitra, even if the new antibiotic wasn't significantly better than its precursor.
A more appropriate standard would be that in order to qualify for wild-card exclusivity, a drug company's new antibiotic would have to meet FDA's criteria for "fast track" designation during development—a product that "is intended for the treatment of a serious or life-threatening condition and [that] demonstrates the potential to address unmet medical needs." Thus, a new antibiotic would qualify if it were intended for serious infections; and if it were active against bacteria widely resistant to existing antibiotics, or if it were more easily administered—for example, orally—or had fewer side effects than alternatives. Arguably, a chemically altered Cipro should qualify for the wild-card only if it met these criteria.
In order to stimulate the development of new antibiotics, other aspects of public policy will need attention as well. It has been said that when the FDA sneezes, the pharmaceutical industry gets pneumonia. A chilling example is the delay of an injectable antibiotic called Tigecycline, for infections caused by antibiotic-resistant pathogens. Its manufacturer, Wyeth-Ayerst Laboratories, had done two human studies to show that the drug was safe and effective, and was planning a third and final one. However, in 2000 the FDA changed the rules for measuring efficacy in trials of antibiotics, which required the company to double the number of patients in the trials from 4,000 to 8,000. That made the investment required by Wyeth much greater in both time and money. The drug was finally approved in 2005.
This kind of policy decision has a pernicious ripple effect. "As a result [of FDA's change in policy], we've got fewer companies involved in the antibiotic discovery business at a time when antibiotic resistance to existing drugs is becoming more of a problem," according to Dr. Robert C. Moellering, Jr., chairman of the department of medicine at Beth Israel Deaconness Medical Center in Boston.
We need also to adopt the kinds of critical FDA reforms suggested by the Infectious Diseases Society of America. Among them: expediting the publication of updated guidelines for clinical trials of antibiotics, including a clear definition of what constitutes acceptable surrogate markers as endpoints; encouraging "imaginative clinical trial designs that lead to a better understanding" of antibiotics' efficacy; the exploration of animal models of infection, in vitro technologies, and microbiologic surrogate markers to reduce the number of efficacy studies required; and the FDA's granting of accelerated review status to priority antibiotics.
The two novel antibiotics introduced since 2000 won't be enough to keep rapidly mutating pathogens at bay for long, and once resistance appears, it will spread rapidly. Unless we create economic and regulatory incentives for companies to develop antibiotics, it's unlikely that we'll see many more wonder drugs in the near future. That's something to think about next time you contract bronchitis, or are hospitalized with a flesh-eating bacterial infection.