The Oct. 17 estimate from the Centers for Disease Control and Prevention of the burden of invasive MRSA infections nationwide comes just as U.S. hospitals are starting to conduct preadmission rapid screening of patients for MRSA, or methicillin-resistant Staphylococcus aureus. Some state legislatures have even begun to require that screening.
Another laboratory test was pushed into the limelight
on Aug. 16 when the Food and Drug Administration encouraged wider use
of genetic testing to predict patients' response to warfarin, and approved
the first commercial genetic test for warfarin sensitivity on Sept. 17.
With such strong signs that laboratories could be dealing
with a long-term increase in both MRSA and warfarin genotyping test orders,
some especially timely help is arriving from the CAP in the form of Surveys
for those two screening tests.
Recently announced as additions to the 2008 Surveys
catalog, these two Surveys will make it possible for hospital and reference
laboratories to assess and improve their performance as they meet critical
testing demands in infection control and anticoagulant therapy. "We're
implementing these Surveys in anticipation of customer demand," says Kathleen
Beavis, MD, chair of the College's Microbiology Resource Committee.
Though MRSA is not yet a reportable condition, the
CDC has estimated the pathogen caused 94,000 U.S. infections and nearly
19,000 deaths in 2005. That compares to 17,011 people the CDC says died
from the AIDS virus in the same year.
The MRSA figures, published in the Journal
of the American Medical Association (2007;298:1763-1771), establish
the first national baseline by which to assess future trends in invasive
MRSA infection, the CDC says. Denise Cardo, MD, director of the CDC's
Division of Healthcare Quality Promotion, said in an Oct. 16 statement
that health care facilities need to make MRSA prevention a higher priority.
"The closer we get to 100 percent compliance with CDC recommendations,"
she said, "the greater the impact on patient health and safety."
Though the CDC promotes "active surveillance" of patients
to reduce MRSA infections, it has not recommended mandatory screening
of all patients. However, the Veterans Health Administration has begun
phasing in MRSA testing at all 155 of its medical centers, and it plans
to test all patients starting next year.
The proper approach to MRSA infection control can be
controversial, and many pathologists are wary of mandates to screen all
patients. "The primary problem is transmission of nosocomial infections
within the hospitals, and one of the organisms that has been implicated
is MRSA. In the past it was predominantly an organism found in hospitals,
but more and more often it's being found in the community," says Dr. Beavis,
director of the microbiology and virology laboratory at Stroger Hospital
of Cook County, Chicago.
Illinois, which passed a bill in August, is one of
14 states that require hospitals to identify people coming in who are
carrying a MRSA infection and either segregate them or have infection
control procedures made available to them. At Stroger Hospital, however,
Dr. Beavis says, "we have plenty of challenges in infection control but
nosocomial transmission of MRSA is not one of them. A hospital that knows
it has a problem with nosocomial transmission of MRSA might want to adopt
a screening program targeting its problem."
"Many hospitals have a totally different issue, such
as transmission of VRE [vancomycin-resistant enterococci] or Clostridium
difficile, and this special treatment for MRSA ties our hands. It
doesn't give us the flexibility to put our resources where they would
be of better use."
In an ideal world, in her view, state legislatures
would not take away the judgment that pathologists, infection control
specialists, and infectious disease physicians should be exercising. But
the Surveys program is geared to respond to realities in the field.
"We did have an item in one of our Surveys testing
the relatedness of strains; this item was geared toward laboratories that
do epidemiologic investigations. This new Survey will address the needs
of laboratories that screen for MRSA. We wanted to anticipate the demand
for this type of Survey, and with the recent flurry in mandating MRSA
screening, it made sense to break it out into its own Survey."
Warfarin genotyping testing challenges are included
in the CAP's pharmacogenetics Survey (PGx), a new CAP product delivering
proficiency evaluation for molecular diagnostic tests that predict patients'
About 2 million people start taking the oral anticoagulant
warfarin each year in the U.S., yet warfarin is the second most common
drug linked to emergency room visits. "It's one of the most common drugs
associated with adverse drug reactions," says Charles S. Eby, MD, associate
professor in the Department of Pathology and Immunology at Washington
University, St. Louis. "Frankly, it's dangerous."
It takes advance planning and work to launch a new
CAP Survey, and the College started to look into a warfarin genotyping
Survey well before the FDA's recent relabeling decision, says Dr. Eby,
who is one of the members of the College's Coagulation Resource Committee
and Pharmacogenetics Working Group.
"When a new proficiency testing proposal is made, it
is reviewed by the appropriate Survey committees, marketing department,
and Council on Scientific Affairs," he says. Since new Surveys are usually
launched only once a year, the planning process has to be completed in
time for the catalog released in August.
"Another challenge is identifying a provider for the
material we're sending out for the proficiency test," says Dr. Eby, who
notes that the Surveys program often relies on the diagnostics industry
to provide material. For the genetic Surveys, the CAP has tended to use
the nonprofit Coriell Institute for Medical Research in Camden, NJ. "It
provides a valuable function by storing cell lines for research as well
as human DNA that is annotated for many clinically relevant polymorphisms,"
Dr. Eby explains. In addition, members of the Biochemical and Molecular
Genetics Resource Committee confirm the expected genotypes in their clinical
laboratories before Survey material is distributed.
Warfarin is not the first drug for which the FDA has
changed the labeling to indicate a role for genetic testing before a person
begins to take a medication, but the impact is likely to be greater since
it is a commonly prescribed medication, Dr. Eby explains. For example,
FDA labeling for Irinotecan, a chemotherapeutic for colon cancer, contains
pharmacogenetic information and highlights the increased risk for severe
neutropenia in patients who are homozygous for UDP-glucuronosyltransferase
1A1 (UGT1A1)*28 allele and are slower metabolizers of the active form
of the drug.
The updated FDA labeling of warfarin provides similar
pharmacogenetic information about warfarin and does not require that genetic
testing be performed.
One of the problems with warfarin is that one dose
does not fit all. "The dose has to be readjusted based on frequent monitoring
of the International Normalized Ratio," Dr. Eby says.
"While clinical studies have helped define the therapeutic
ranges for INR to minimize thrombotic and hemorrhagic complications, where
there's been minimal progress until recently is in the ability to predict
a therapeutic dose for individual patients when you're starting them on
Determining the therapeutic dose at this point is a
trial-and-error process, he says. "You typically start patients on 5 mg
a day, then monitor the INR frequently and make adjustments as needed
up or down. Therapeutic warfarin doses can vary from 0.5 mg up to 15 mg
a day. That's a wide variability of dose in a drug that when you're over
the therapeutic target, you increase the patient's risk of bleeding complications,
and when you're under the target, you increase the risk of clotting complications."
Until now, the main approach to improving clinicians'
ability to predict the patient's dose has been to identify clinical variables,
including a person's age, weight or body surface area, and other medications
they're taking that are known to inhibit or accentuate anticoagulant effects
of warfarin. "These variables have been modestly helpful but probably
only explain about 20 percent of the variation in dosing," Dr. Eby says.
"Recent improvements in predicting a patient's therapeutic
warfarin dose are based on identification of polymorphisms in two genes
whose products affect warfarin metabolism and warfarin inhibition of vitamin
K cofactor activity," he says. Warfarin is predominantly metabolized by
cytochrome P450 2C9 (CYP2C9) enzyme. Two CYP2C9 polymorphisms, *2 and
*3, reduce the rate of warfarin clearance. The frequencies of *2 and *3
polymorphisms in Caucasians are approximately 11 percent and approximately
seven percent, respectively, Dr. Eby says.
People who inherit these polymorphisms will be slow
metabolizers of warfarin and will need a lower therapeutic dose, he adds.
Efficient synthesis of coagulation factors X, IX, VII,
and II (prothrombin) requires vitamin K as a cofactor in a chemical reaction
called gamma carboxylation. Vitamin K undergoes oxidation during this
enzymatic step and must be converted back to its reduced form by the enzyme
vitamin K reductase, or VKOR, in order to sustain coagulation factor production.
"Warfarin competes with oxidized vitamin K for VKOR, resulting in lower
levels of factors X, IX, VII, and II and a prolonged INR," Dr. Eby says.
"Recent identification of the VKOR gene led to discovery of a common polymorphism
in the promoter region of the gene that reduces gene expression and enzymatic
activity, increases patients' sensitivity to warfarin, and lowers their
Knowing a patient's genetic status for three polymorphisms,
CYP2C9 *2 and *3 and VKORC1 promoter -1639, allows physicians to account
for about 30 percent of the variation of therapeutic dosage. Combining
pharmacogenetic information with clinical details about a patient, such
as age, body surface area, concurrent use of certain drugs such as amiodarone,
and INR target, makes it possible to predict a patient's therapeutic dose
with about 50 percent accuracy, Dr. Eby says.
Washington University and groups in Asia and Europe
have confirmed this finding. "I think it's this information that led the
FDA to make the decision to change the labeling," Dr. Eby says. Application
of this pharmacogenetic information can be demonstrated, he says, by using
a prospectively validated warfarin dosing algorithm, found at www.warfarindosing.org.
A physician enters clinical, demographic, and CYP2C9 and VKORC1 genotype
data, and the Web site estimates the therapeutic warfarin dose.
CYP2C9 and VKORC1 genetic testing will be of little
use to the millions already taking warfarin. "Once you've established
their dose, the genetic information is really not that important. We're
really interested in the 2 million new people starting warfarin for the
first time every year. The test makes prediction of the dose earlier and
But one piece of the puzzle is still missing, he says,
and the FDA has acknowledged this. "Using this genetic information to
better estimate a patient's warfarin dose has not been shown to improve
patient safety by reducing bleeding complications when starting warfarin,
or even to improve how quickly a patient reaches and stays in therapeutic
INR range compared to the trial-and-error method. Those studies have not
been done yet." However, he adds, several institutions are in competition
to lead a National Institutes of Health-sponsored prospective randomized
study to address those questions.
"The FDA has said we think it's important enough to
change the labeling to make clinicians aware they might want to test their
patients for the single nucleotide polymorphisms in these two genes and
start patients who have one or more of these SNPs on a lower warfarin
dose, but we don't have the FDA saying you must do it."
Of the new CAP PGx Survey, Dr. Eby says, "I think any
laboratory contemplating offering warfarin genotyping would want to participate
in this CAP Survey-not only for quality control but also because it will
be a great instrument to help laboratories learn how to report the information."
"On this Survey, obtaining the correct genotype is
only part of the game. We ask participants to interpret the impact of
the genotype on drug metabolism and activity and to make recommendations
to clinicians regarding dosing modifications."
The Survey will be ungraded. "But," says Dr. Eby, "it's
extremely helpful from an educational point of view for laboratories doing
this testing and will help them communicate results to clinicians in a
way most beneficial to the patient."
Further additions to the pharmacogenetics Survey are
in the planning stages. Says Corrine Cagney, CAP product manager for microbiology/molecular
diagnostics: "We're hoping to expand the PGx Survey to include other alleles
as the pharmaceutical companies determine which alleles are predictive
for their drugs. Abbott, GlaxoSmithKline, Pfizer, Roche, and Johnson and
Johnson are all collaborating to decide what other genetic alleles will
help determine drug response."
In addition to MRSA, mumps and Shiga toxin are two
other important public health and safety tests that were mid-year additions
to the College's Surveys catalog. The mumps Survey, designed for the new
rapid test, came out last March and now has 260 participants. Tests for
Shiga toxin, which is usually transmitted by undercooked contaminated
meats and spread through incorrect hand-washing, are often sent to reference
laboratories because few hospital labs perform the testing. The Shiga
toxin Survey came out in August and has 132 participants.
In 2008, the CAP plans to add a QuantiFeron-TB Survey
for tuberculosis. Like MRSA, Cagney notes, TB testing became high-profile
after stories surfaced this year about public health hazards—in
the case of TB, an infectious patient traveling by airplane.
All four Surveys are tied together as public health
issues, she says. "We grouped them together not so much because they're
differentiated, but because they are all things that affect the community."
And they're good examples, Dr. Beavis says, of "how quickly the College
can respond to the changing needs of the laboratory."
Anne Paxton is a writer in Seattle.