Program Brief
The mission of the Centers for Education and Research on Therapeutics (CERTs)
is to conduct research and provide education that will advance the best use of therapeutics. This Program Brief highlights CERTs activities related to infectious disease in three areas: advancing knowledge, informing patients and providers, and improving the system.
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Contents
Background
CERTs Research on Infectious Disease
Advancing Knowledge
Informing Patients and Providers
Improving the System
Looking to the Future
For More Information
References
Background
The mission of the Centers for
Education and Research on
Therapeutics (CERTs) is to conduct
research and provide education that will
advance the best use of therapeutics
(drugs, medical devices, and biological
products). The CERTs seek to increase
awareness of the benefits and risks of
new, existing, and combined uses of
therapeutics, thereby improving the
effectiveness and safety of their use.
The program is administered as a
cooperative agreement by the Agency
for Healthcare Research and Quality
(AHRQ), in consultation with the U.S.
Food and Drug Administration (FDA).
The CERTs receive funds from both
public and private sources, with AHRQ
providing core financial support. The
CERTs network currently comprises 11
research centers, a
Coordinating Center, a Steering
Committee, and numerous
partnerships with public and private
organizations. Each CERTs center
focuses its educational and research
efforts on therapies in a particular
population, therapeutic area, or topic.
| CERTs Research Centers |
Emphasis |
Arizona CERT at The Critical Path Institute (C-Path), Tucson, AZ (HS10385)
Principal investigator: Raymond L. Woosley, M.D., Ph.D. |
Detection and prevention of adverse drug interactions |
Duke University Medical Center, Durham, NC (HS10548)
Principal investigator: Judith M. Kramer, M.D., M.S. |
Therapies for disorders of the heart and blood vessels |
HMO Research Network, Boston, MA (HS10391)
Principal investigator: Richard Platt, M.D., M.Sc. |
Use, safety, and effectiveness studies of therapeutics, using health plans that serve defined populations |
Rutgers, The State University of New Jersey,* New Brunswick, NJ (HS16097)
Principal investigator: Stephen Crystal, Ph.D. |
Therapies for mental health |
University of Alabama at Birmingham, Birmingham, AL (HS10389)
Principal investigator: Kenneth G. Saag, M.D., M.Sc. |
Therapies for musculoskeletal disorders |
University of Iowa,* Iowa City, IA (HS16094)
Principal investigator: Elizabeth A. Chrischilles, Ph.D.
|
Therapies for older adults and the effects of aging |
University of North Carolina at Chapel Hill, Chapel Hill, NC (HS10397)
Principal investigator: Alan D. Stiles, M.D. |
Therapies for children |
University of Pennsylvania School of Medicine, Philadelphia, PA (HS10399)
Principal investigator: Brian L. Strom, M.D., M.P.H. |
Therapies for infection; reduction in antibiotic resistance |
University of Texas MD Anderson Cancer Center and
Baylor College of Medicine,* Houston, TX (HS16093)
Principal investigator: Maria E. Suarez-Almazor, M.D., Ph.D. |
Risk and health communication; patient, consumer, and professional education; health decisionmaking and decision support; therapeutic adherence |
Vanderbilt University Medical Center, Nashville, TN (HS10384)
Principal investigator: Wayne A. Ray, Ph.D. |
Prescription drug use in Medicaid and veteran populations |
Weill Medical College of Cornell University,* New York, NY (HS16075)
Principal investigator: Alvin I. Mushlin, M.D., Sc.M. |
Therapeutic medical devices |
*New center as of April 2006.
|
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CERTs Research on Infectious Disease
Science has made great progress in
controlling or even eliminating many
infectious diseases; however, we remain
vulnerable to newly recognized and
resurgent organisms. Every day it seems
the media announce a new threat to the
public. While antibiotics and other
antimicrobials have played an important
role in the fight against infectious
diseases, some microorganisms have
developed resistance to the drugs used
against them. In addition, factors such
as population crowding, easy worldwide
travel, large-scale agriculture, and the
threat of bioterrorism have raised
concerns about the spread of infectious
agents.
Since the inception of the program,
CERTs researchers have tackled a variety
of important questions related to
infectious diseases, resulting in dozens
of published research studies. These
researchers have examined diverse areas
such as the overuse and misuse of
antibiotics, infection prevention and its
associated costs, side effects of
commonly used antiinfectives, physician
prescribing patterns, and factors
affecting patient adherence to treatment
regimens, just to name a few. In
addition, the CERTs program has
conducted several studies aimed at
understanding and improving our
Nation's bioterrorism preparedness.
The CERTs research efforts fall into
three main categories: advancing
knowledge, informing patients and
providers, and improving the system.
Here are a few of the program highlights
related to infectious disease.
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Advancing Knowledge
Understanding the dangers of
antibiotic resistance
Antibiotics constitute an essential
weapon in the arsenal against infectious
diseases, and yet the widespread use of
these drugs can undermine their
effectiveness. The more broadly
antibiotics are used, the more likely it is
that resistant strains of microorganisms
will emerge.
In order to understand the possible
consequences of antibiotic resistance,
researchers studied a group of patients
who had taken antibiotics for an
extended period of time—patients
treated for acne. Researchers wanted to
know if those who had taken antibiotics
long term suffered a higher incidence of
upper respiratory tract infections than
those who had not.
Although upper respiratory tract
infections are generally viral in nature
and of limited clinical consequence, they
have significant public health
implications. Previous studies have
shown that more than 200 million
episodes occur per year in the United
States, and that the economy suffers a
loss of more than $25 billion in annual
revenue due to them.
The General Practice Research Database
(GPRD) houses information on patients
in the United Kingdom who are
assigned to some of the National Health
Service's general practitioners who
maintain their clinical records
electronically. Using GPRD data, the
CERTs team identified more than
118,000 people diagnosed with acne.
Of these, 72 percent received some type
of antibiotic treatment for more than 6
weeks, while 28 percent did not. The
study found that patients receiving
antibiotics were twice as likely to
develop an upper respiratory tract
infection as were patients who did not
use antibiotics.1
While these results are not proof that
the antibiotics caused the increased
infections, there are theories to explain
the connection. Perhaps antibiotics
change the bacterial flora at the back of
the throat, making people more
vulnerable to infections. Or perhaps the
antibiotics lead to changes in the
immune system—changes that could
make patients more vulnerable to upper
respiratory tract infections. Until
physicians have more information with
concrete guidelines to follow, research in
this area should continue.
Finding ways to reduce postoperative
infections in children
Children with life-threatening
congenital heart disease often face
surgery within the first few weeks of life.
After surgery, a chest infection, also
called mediastinitis, can develop. While
this complication is rare, it is serious and
can be fatal. A CERTs research team
designed a study to find out how often
this problem occurs and to find ways to
reduce the risk of developing this
infection.
CERTs researchers found the attack rate
of mediastinitis to be about 1.4 percent,
which was similar to the rate found in
previous studies of adults. However,
one-third of the infections were due to
gram-negative bacilli (GNB), a higher
percentage than previously found in
children. Researchers believe the higher
number of GNB infections was due, at
least in part, to the fact that the study
included infants—a group often
exposed to GNB immediately before or
after birth. Additionally, researchers
found that when physicians delayed
surgically closing the patient's sternum
(sometimes done due to swelling after
surgery), there was an even greater risk
of GNB infection. These results were
alarming to the investigators because
GNB are some of the most antibiotic-resistant
strains of bacteria.2
Exposing the dangers of the antibiotic
erythromycin
Erythromycin has been on the market
for 50 years and is commonly
prescribed to treat conditions such as
strep throat, certain types of
pneumonia, and other infections. While
it is generally accepted as safe and
effective, some reports have associated
its use with serious arrhythmias
(irregular heartbeats) and sudden cardiac
death. Because previous reports focused
on the intravenous form of
erythromycin, many have presumed
that the oral form of the drug was not
associated with serious arrhythmias.
CERTs researchers designed a study to
test this theory and to find out whether
taking certain medications in addition
to erythromycin could increase the risk
of sudden cardiac death.
CERTs researchers reviewed the
electronic records of 4,404 Medicaid
patients from Tennessee who died of
sudden cardiac death from 1988
through 1993. The researchers
confirmed 1,476 cases and then studied
Medicaid's records of each patient's
medication use.
The research team found an association
between the use of erythromycin and
the risk of sudden death from cardiac
arrest with both the oral and
intravenous forms of erythromycin.
Even more concerning, they found an
increased risk associated with taking
erythromycin in combination with
medications that inhibit a specific type
of enzyme in the body known as
CYP3A. The risk of death for people
using both erythromycin and a CYP3A
inhibitor was five times as high as the
risk for those who were not using any of
the antibiotic drugs from the study or a
CYP3A inhibitor.
Commonly used medications that
inhibit the CYP3A enzyme include the
antibiotic clarithromycin (Biaxin);
certain antifungal drugs used to treat
toenail fungus and yeast infections, such
as fluconazole (Diflucan), ketoconazole
(Nizoral), and itraconazole (Sporanox);
and calcium channel blockers prescribed
for high blood pressure such as
verapamil (Verelan) and diltiazem
(Cardizem).
Because CYP3A inhibitors slow down
erythromycin's breakdown in the body,
its concentration in the bloodstream is
significantly increased. At high levels, it
traps salt inside muscle cells and can
interrupt normal heart muscle
contraction, triggering serious heart
rhythms or even sudden death. With
safer antibiotics, such as amoxicillin,
readily available, researchers recommend
that physicians avoid prescribing
erythromycin in conjunction with
CYP3A inhibitors.3
This study illustrates that it is important
for patients to keep a list of medications
that they can share with all their
doctors. It also shows the need for
continuing research on the safety of
older medicines, including how they
interact with newer drugs.
Finding risk factors associated with
resistant urinary tract infections in
children
The research community has limited
data on the extent of antibiotic
resistance in bacteria that cause urinary
tract infections (UTIs) in children. This
information is needed to help optimize
the use of antibiotics for such infections.
A CERTs study has investigated recent
changes in the frequency of different
types of bacteria that cause UTIs, the
extent of antibiotic resistance, the
association of ethnicity with resistance,
and experience-based therapy in
pediatric UTIs.
During the study period, CERTs
investigators found that isolates of
Escherichia coli (the most common
bacteria causing UTIs) obtained from
Hispanic children were less likely to be
pan-susceptible (or treatable by a variety
of antibiotics) than were isolates from
other children. Bacteria from Hispanic
children were more likely to exhibit
poor susceptibility to TMP-SMX, an
antimicrobial combination commonly
used for UTI treatment, as well as
resistance to two or more drugs.
The
choice of empirical therapy varied
during the study period, and higher
resistance rates in Hispanic children
may correlate with a greater risk of a
poor response to initial antibiotic
therapy. CERTs investigators are
conducting additional research to
characterize further associated risk
factors for resistance and to optimize
experienced-based therapy in these
children.
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Informing Patients and Providers
Education campaign works to
decrease antibiotic prescriptions in
children
The use of antibiotics in children greatly
increased between the mid 1970s and
early 1990s. Unfortunately, with this
trend, rates of bacterial resistance also
increased. Public health officials grew
increasingly worried for a number of
reasons—rising rates of resistant
organisms were making a number of
antibiotics less useful, and
pharmaceutical companies were doing
only limited research to develop new
antibiotics.
In 1999, 10 Federal agencies and
departments, led by the Department of
Health and Human Services, formed a
task force to tackle the problem of
antimicrobial resistance. Cochaired by
the Centers for Disease Control and
Prevention, the FDA, and the National
Institutes of Health, the task force
issued a plan of action in 2001.
To better understand the latest
antibiotic-prescription patterns, CERTs
researchers designed a study to look for
prescribing changes between 1996 and
2000. The study found that antibiotic
prescriptions for children ages 3 months
to18 years dropped significantly
between 1996 and 2000, suggesting
that the combination of public health
campaigns and attention by the lay press
and other groups was effective in
shaping public attitudes toward these
drugs.
Although such educational campaigns
are beneficial, public health officials
warn that antimicrobial resistance
continues to be a serious threat.
Researchers agree that intensive
educational efforts must continue.4
Published guidelines decrease
dangerous drug combinations in HIV
patients
The biggest news and greatest benefit to
people with human immunodeficiency
virus (HIV) came in the winter of
1995-96 with the introduction of
protease inhibitors, a new class of drugs.
Patients started taking protease
inhibitors in combination with other
drugs, and the number who became ill
from opportunistic infections or died
from AIDS dropped by about 70
percent in the United States.
Unfortunately, protease inhibitors can
cause elevated levels of cholesterol,
putting patients at risk of heart disease,
so sometimes they are given
prescriptions for lipid-lowering
medications such as statins. However,
some statin drugs interact with protease
inhibitors and increase the risk of
dangerous side effects.
CERTs researchers examined the use of
protease inhibitors and statins in a large
group of HIV patients to determine
how often physicians prescribed
dangerous combinations of these drugs.
Specifically, researchers wanted to see if
health care providers changed their
prescribing habits after the publication
of preliminary guidelines for combining
these drugs.
The study found that the number of
dangerous combinations prescribed
decreased significantly after the release
of the preliminary guidelines but still
remained relatively high. CERTs
researchers believe that continued
education will help physicians reduce
the use of dangerous combinations of
protease inhibitors and statins.5
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Improving the System
Drug used to prevent infection in
preterm infants does not reduce costs
The Medicaid program provides care for
approximately 46 million people. In
most States, it is the fastest growing
category of spending and has already
surpassed education as the largest
portion of the State budget. With these
cost increases, there is increased public
scrutiny—each potential medical
treatment must be weighed against its
cost and benefit.
CERTs researchers designed a cost
analysis of palivizumab, an expensive
antibody preparation used by the North
Carolina Medicaid Program to prevent a
serious viral infection of the lung in
premature infants. In 2003 the program
spent more than $12 million on
palivizumab.
The study compared costs related to this
infection in two groups of infants born
5 to 8 weeks prematurely. One group
received palivizumab as a preventive
measure, while the other group did not.
Although the group receiving the drug
had fewer hospitalizations during this
period, the study found that the cost of
palivizumab outweighed the money
saved from treating fewer infections.
Medicaid programs across the United
States may want to reconsider the
criteria used to determine which infants
should receive this product and look for
less expensive ways of reducing the
number of babies at high risk of this
infection.6
Bioterrorism concerns place demands
on the health care system
The 2001 anthrax attacks occurred over
the course of several weeks beginning on
September 18, 2001. Letters containing
anthrax bacteria, mailed to several news
media offices and two U.S. Senators,
killed five people. In the days that
followed, many Americans who feared
anthrax exposure requested prophylactic
doses of antimicrobials.
To understand better how such a
situation affects our health care system,
CERTs researchers surveyed emergency
physicians in Pennsylvania to find out
whether they had received patient
requests for antimicrobials because of
the fear of anthrax exposure and, if so,
whether they had prescribed them.
A majority of the respondents received
requests for antimicrobials, and one-quarter
prescribed them due to a
request. Although antimicrobials are an
important tool for treating anthrax
exposure, prescribing them
inappropriately is a public health
concern. Overuse of antimicrobials can
have serious consequences, ranging from
potential adverse effects on individual
patients to the increased risk of drug
resistance, depletion of supplies, and
increased costs to insurers and patients.
This study demonstrated gaps in our
current understanding of how to handle
public demands for medications after
perceived exposure to biological agents.
The study respondents suggest that
improving public communication to
reduce fear could help.
This study underscores the importance
of a strong working relationship
between public health officials and
health care providers in responding to
demands for treatment of possible
exposure after a bioterrorist incident.7
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Looking to the Future
The CERTs program conducts research
and develops educational projects that
study and report the efficacy, safety, and
use of various medical therapies. The
studies highlighted in this Program Brief
demonstrate our progress in the area of
infectious disease, but additional
research is needed.
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For More Information
More information on the CERTs program is available from:
Anne Trontell, M.D., M.P.H.
Program Director, Centers for Education and Research in Therapeutics
Center for Outcomes and Effectiveness Research, AHRQ
Phone: (301) 427-1607
Fax: (301) 427-1640
E-mail: Anne.Trontell@ahrq.hhs.gov
Carmen Kelly, Pharm.D.
Project Officer, CERTs Coordinating Center
Center for Outcomes and Effectiveness Research, AHRQ
Phone: (301) 427-1513
E-mail: Carmen.Kelly@ahrq.hhs.gov
In addition, the CERTs program welcomes input about the types of research and education that Medicaid programs need to better address costs, effectiveness, and safety issues related to the use of therapeutics. Comments may be sent to CERTs program staff at AHRQ, or to:
Judy Donald
Project Manager
CERTs Coordinating Center
Kaiser Foundation Center for Health Research
E-mail: Judy.L.Donald@kpchr.org
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References
1. Margolis DJ, Bowe WP, Hoffstad O,
et al. Antibiotic treatment of acne
may be associated with upper
respiratory tract infections. Arch
Dermatol 2005;141:1132-6.
2. Long CB, Shah SS, Lautenbach E, et
al. Postoperative mediastinitis in
children: epidemiology,
microbiology and risk factors for
Gram-negative pathogens. Pediatr
Infect Dis J 2005;24:315-9.
3. Ray WA, Murray KT, Meredith S, et
al. Oral erythromycin and the risk of
sudden death from cardiac causes. N
Engl J Med 2004;351:1089-96.
4. Finkelstein JA, Stille C, Nordin J, et
al. Reduction in antibiotic use
among US children, 1996-2000.
Pediatrics 2003;112:620-7.
5. Hulgan T, Sterling TR, Daugherty J,
et al. Prescribing of contraindicated
protease inhibitor and statin
combinations among HIV-infected
persons. J Acquir Immune Defic
Syndr 2005;38:277-82.
6. Wegner S, Vann JJ, Liu G, et al.
Direct cost analyses of palivizumab
treatment in a cohort of at-risk
children: evidence from the North
Carolina Medicaid Program.
Pediatrics 2004;114:1612-9.
7. M'ikanatha NM, Julian KG,
Kunselman AR, et al. Patients'
request for and emergency
physicians' prescription of
antimicrobial prophylaxis for anthrax
during the 2001 bioterrorism-related
outbreak. BMC Public Health
2005;5:2.
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AHRQ Publication No. 07-P008
Current as of May 2007
Internet Citation:
CERTs Research: Infectious Disease. AHRQ Publication No. 07-P008, May 2007. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/certsinfect.htm
540 Gaither Road Rockville, MD 20850