[Federal Register Volume 65, Number 76 (Wednesday, April 19, 2000)]
[Notices]
[Pages 20992-20995]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-9696]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 98D-0969]
Risk Assessment of the Public Health Impact of Streptogramin
Resistance in Enterococcus faecium Attributable to the Use of
Streptogramins in Animals; Request for Comments and for Scientific Data
and Information
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; request for comments and for scientific data and
information.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA), Center for Veterinary
Medicine (CVM), is announcing plans to develop a prototypic risk
assessment (RA) model that accounts for the transfer of resistance
determinants from bacteria in food-producing animals to bacteria in
humans. The agency requests comments on their approach to the RA model
and requests that scientific data and information relevant to the
conduct of the RA be submitted. This model will be applied to assess
the association between the development of streptogramin (quinupristin/
dalfopristin (QD)) resistant Enterococcus faecium in humans and the use
of virginiamycin in food-producing animals. The center will attempt to
use the RA model to quantify the human health impact attributable both
to direct acquisition of resistant E. faecium from food-producing
animals and to the transfer of resistance determinants from E. faecium
in food-producing animals to E. faecium in humans.
DATES: Submit written comments, scientific data, and information by
June 19, 2000.
ADDRESSES: Single copies of ``A Proposed Framework for Evaluating and
Assuring the Human Safety of the Microbial Effects of Antimicrobial New
Animal Drugs Intended for Use in Food-Producing Animals'' (hereinafter
referred to as the Framework Document) is discussed in the
Supplementary Information section of this document and may be obtained
by writing to the Communications Staff (HFV-12), Center for Veterinary
Medicine, Food and Drug Administration, 7500 Standish Pl., Rockville,
MD 20855. Send one self-addressed adhesive label to assist the office
in processing your request. This document is also available through
CVM's homepage on the Internet at http://www.fda.gov/cvm/fda/mappgs/antitoc.html. Submit written comments, scientific data, and information
to the Dockets Management Branch (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Nicholas E. Weber, Center for
Veterinary Medicine (HFV-150), Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855, 301-827-6986, FAX 301-594-2298, or
e-mail [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
In theFederal Register of January 6, 1999 (64 FR 887), FDA
published a notice of availability of a discussion paper (the Framework
Document). This Framework Document sets out a conceptual risk-based
process for evaluating the microbial safety of antimicrobial drugs
intended for use in food-producing animals. The proposed RA furthers
the tenets of the Framework Document by developing a RA model to
quantify the potential human health impact of resistant bacteria
acquired from animals via food.
Thus, CVM proposes to conduct its second antimicrobial resistance
RA. A draft of CVM's first antimicrobial resistance RA model and
associated documents are available on CVM's homepage on the Internet at
http://www.fda.gov/cvm/fda/mappgs/ra/risk.html. The first RA modeled
the human health impact of fluoroquinolone resistant Campylobacter
infections associated with the consumption of chicken. CVM proposes to
develop a second RA that will account for both the acquisition of
resistant bacteria and the transfer of resistance determinants from
bacteria in food-producing animals to bacteria in humans. This model
will be applied to assess the association between the presence of
streptogramin (QD) resistant Enterococci faecium in humans and the use
of streptogramins (virginiamycin) in food-producing animals as an
example of risk attributed to transference of resistance determinants.
In September 1999, FDA's Center for Drug Evaluation and Research
approved SynercidTM, a streptogramin (QD), for use in human
medicine for treatment of vancomycin resistant E. faecium (VREF)
bacteremias as well as for treatment of Staphylococcus aureus and
Streptococcus pyogenes skin and soft tissue infections. At the current
time, QD is considered to be the last line of therapy for VREF. Another
streptogramin, virginiamycin, has been used in food-producing animals
for 26 years. The initial approval was for chickens, but virginiamycin
was subsequently approved for use in turkeys, swine, and most recently
in cattle. This RA will seek to quantify the public-health risk
attributable to the use of virginiamycin in food-producing animals.
Enterococcus faecium that develop resistance due to exposure to
virginiamycin also demonstrate reduced susceptibility to QD. These
resistant strains of E. faecium can contaminate meat products and
thereby enter the human intestine. It is thought that these resistant
strains contaminating meat products may cause problems for the human in
two major ways: By becoming host-adapted or by transferring resistance
determinants to endogenous human E. faecium.
It is generally believed that the indigenous intestinal microflora
of healthy humans inhibit colonization by bacteria from exogenous
sources. In the case of illness requiring antibiotic therapy however,
associated perturbations due to drug treatment may result in
colonization by organisms not included in the flora of healthy
individuals. This scenario could result in the intestinal colonization
and proliferation of antibiotic resistant bacteria from the external
environment. Enterococcal infections comprise 20 to 30 percent of over
2 million hospital-acquired infections per year in the United States
(Ref. 1). VREF infections are almost exclusively hospital infections
and account for about 14 percent of all enterococcal infections,
although this varies widely (5 to 70 percent) from hospital to
hospital, according to hospital vancomycin use, teaching versus
nonteaching hospital status, and hospital size (number of beds) (Refs.
1 and 2). This translates to about 70,000 VREF infections per year
which will most likely be treated with QD . Among VREF bacteremic
patients treated with QD, emerging resistance
[[Page 20993]]
has been documented in about 4 percent of cases (Ref. 3).
QD is a mixture of streptogramin A (SA) and
streptogramin B (SB) compounds. Resistance to Type B
streptogramins is widespread among enterococci and other organisms.
SB resistance is due to hydrolysis of the antibiotic
mediated by the vgb gene (Ref. 4), or more commonly, by ribosomal
methylation mediated by the ermB gene product (Ref. 5). Expression of
erm confers collateral resistance to macrolides, lincosamides, and
streptogramin B (MLSB) antimicrobials. Expression of
SB resistance determinants is not sufficient to confer
resistance either to SA or to the combination of compounds
(Ref. 6). SA resistance has been linked to two genes in E.
species, satA (Ref. 7) and satG (Ref. 8). These genes encode related
enzymes that inactivate the drug by acetylation, and expression imparts
resistance to the mixture of SA and SB. Both
genes have been found on plasmids and shown to be transferable in vitro
to susceptible strains. However, a number of SA resistant
enterococci carry neither locus (Ref. 9), indicating that the complete
complement of streptogramin resistance determinants has not been
identified in enterococci.
Data on the prevalence of QD resistance in hospitals, the
environment, and the community is sparse. QD-resistant E. faecium has
been detected in the stools of healthy adults in the community. Because
these individuals had not received QD therapy, some have assumed that
the resistant strain entered the human population from an agricultural
food production environment where virginiamycin is used or, possibly,
following exposure to other drugs that conferred cross-resistance to
streptogramins.
The prevalence of streptogramin resistant enterococci in the animal
production environment and on animal derived food is largely unknown.
For the purpose of this RA, data on human exposure to enterococci
through the food supply and the rate at which these organisms possess
determinants conferring resistance to streptogramin antibiotics is
critical. Preliminary data collected on isolates from the poultry
production environment suggest that about 65 percent of E. faecium are
resistant to streptogramins (MIC4g mg/ml) (Ref.
10). Data on the prevalence of these organisms and their antibiotic
resistance phenotypes associated with retail products are very limited
but critical to the RA process.
II. Objectives of the Risk Assessment
FDA is planning to conduct a RA of the potential harm to
hospitalized patients by E. faecium resistant to the streptogramin
combination drug (QD) associated with the use of virginiamycin in food-
producing animals. A RA is a systematic and comprehensive collection
and analysis of information that promotes an understanding of the
interactions of various factors in a complex situation and provides a
basis for making decisions. One goal of this RA is to organize a broad
array of information and to study the complex set of interactions
necessary to review the current uses of virginiamycin and their impact
on public health in an effort to make sound science-based decisions. An
underlying goal of this RA is to provide experience and a method for
modeling risk involving transfer of resistance determinants from
strains of bacteria found in food-producing animals to those found in
people. It is anticipated that the RA will reveal data gaps and help
guide the industry, FDA, and related agencies in setting research
priorities.
III. Risk Assessment Plan
FDA's RA plan will attempt to determine the relationship between
the use of virginiamycin in food-producing animals, and the development
and dissemination of QD-resistant E. faecium in contaminated meat
products. Examination of this relationship will be used to describe
health effects in humans resulting from exposure to meat contaminated
with QD resistant E. faecium. To accurately assess human exposure to
QD-resistant E. faecium from contaminated meat, the RA will seek and
analyze the following four types of information concerning the
epidemiology of foodborne QD-resistant E. faecium. Information
concerning the molecular epidemiology and associated carriage of
resistance determinants of E. faecium with respect to the on-farm
environment, carcass/retail meat contamination, other foods, and to the
human community (both within and outside of the hospital setting) will
be collected and analyzed.
1. Concerning the on-farm component of the RA, CVM will analyze
epidemiological evidence pertaining to the following areas in each
animal species studied: The prevalence of E. faecium colonization, the
proportion of animals exposed to virginiamycin, the rate of selection
of QD resistance in E. faecium, the emergence and dissemination of QD
resistance determinants in virginiamycin exposed live animals and in
their environment (including the level of fecal shedding).
2. The RA will also seek to collect and analyze information on the
frequency of occurrence of post-slaughter contamination with QD
resistant E. faecium to include carcass and retail sampling, and, where
data are available, the impact of other agricultural sources of QD
resistant E. faecium on food products destined for human consumption.
Modeling may be used when data are collected at slaughter and retail
outlets to estimate actual human exposure.
3. Human exposure is a function of QD-resistant E. faecium
prevalence in the food supply and the consumption patterns of the
population. The level of QD-resistant E. faecium contamination of meat
destined for human consumption is very critical exposure information.
Thus, the RA will evaluate information on the level of QD-resistant E.
faecium in retail meat classes where data are available and combine
this information with food consumption patterns. The RA will then
produce estimates of QD-resistant E. faecium gut flora colonization
likely given the levels of meat consumption by different
subpopulations.
4. The RA will include an examination of the number of people who
may enter the hospital colonized with QD-resistant E. faecium, and the
proportion of those who are likely to develop VREF infections and
require QD treatment. In addition, the RA will seek to evaluate the
rate of emergence of QD-resistant E. faecium in the hospital
environment and its dissemination within the hospital setting.
The RA process will seek to quantify the risk associated with
virginiamycin use in animals utilizing data and information in a number
of areas including: Prevalence of QD-resistant E. faecium pre- and
post-slaughter contamination; molecular epidemiology of E. faecium
carriage of resistance determinants in animal, community, and human
clinical isolates; epidemiology of community and hospital sources of
QD-resistant E. faecium; and prevalence of QD-resistant VREF
infections, and molecular fingerprinting and epidemiology of QD
resistance transfer to VREF in humans. All uncertainties and
assumptions will be identified and documented. The RA process will also
include an evaluation of the adequacy of current scientific knowledge,
data, and information. This will be used to suggest where future
research could be directed to reduce the uncertainty in the risk
estimate.
[[Page 20994]]
IV. Data and Information Requested
FDA requests comments on the RA approach outlined in the RA plan
and the submission of any information relevant to the RA. The purpose
of the request for comments and data is to gather relevant information
from a broad base of stakeholders to help the agency develop a science-
based RA model. While some preliminary data are available, as indicated
in section I of this document, the agency specifically requests data
that would help to quantify the steps outlined in section III of this
document. A list of requested information is presented below; however,
the list is not exhaustive, and the agency encourages submission of any
additional data relevant to this RA. The requested information
includes, but is not limited to the following:
1. The prevalence of E. faecium and the prevalence of QD resistant
E. faecium among all E. faecium in food-producing animals;
2. Virginiamycin use information, including the proportion of food-
producing animals in each class that receive virginiamycin;
3. The prevalence of carcasses contaminated with E. faecium and
among those, the prevalence of carcasses contaminated with QD-resistant
E. faecium;
4. Procedures during slaughtering and food processing which modify
enterococcal contamination and load on the carcass or product;
5. The prevalence and load of QD-resistant E. faecium in humans in
the community acquired from contaminated meat products of each class;
6. Consumption and food preparation patterns that would aid in
apportioning potential E. faecium ingestion among chicken, turkey,
pork, beef, and other sources;
7. The prevalence of colonization by E. faecium and infection rates
due to E. faecium in humans, for: (a) All E. faecium, (b) vancomycin
resistant E. faecium, (c) QD-resistant E. faecium, and (d) QD-
resistant/vancomycin resistant E. faecium;
8. The rate at which QD resistance and vancomycin resistance will
be transferred among E. faecium in humans;
9. The enterococcal disease infection rate among humans harboring
vancomycin resistant E. faecium;
10. Genetic fingerprinting for molecular epidemiology of E. faecium
strains and details of the mechanisms of associated resistance,
including gene identification; and
11. Other pertinent data.
FDA's CVM requests that reports of data include a description of
the population from which samples were taken and a description of
sampling and culture procedures used. All prevalence information or
rates need to be provided with numerators and denominators. Likewise,
count data is most useful if it is provided with information about the
distribution of counts, such as with a range or with the mean and
standard deviation. For the RA to become a useful regulatory tool for
protection of public health in the United States, it must be based on
good quality, contemporaneous data gathered in the United States, or
from populations demonstrated to be representative of the U.S.-
population.
FDA believes that the credibility and validity of the RA requires
that the process for the conduct of the RA be transparent, and all data
and information evaluated in the context of the RA and utilized in the
RA should be publicly available. Accordingly, any data or information
submitted in response to this document should be in a form that permits
public disclosure. Submitters of data and information should not mark
any information as ``Confidential'' and should fully expect that any
data or information submitted will be made available to the public.
Questions regarding the public availability of data and information
submitted in response to this document, including questions on
maintaining confidentiality while maximizing the utility of the data,
should be directed to the contact person above.
As noted, the purpose of this request for data is to gather
relevant information to facilitate a valid RA of the human health
impact attributable both to direct acquisition of resistant E. faecium
from food-producing animals and to the transfer of resistance
determinants from E. faecium in food-producing animals to E. faecium in
humans. The larger goal is the development of a prototype quantitative
RA model that incorporates a segment modeling the transfer of
resistance determinants from animal bacteria to human bacteria. This
model along with CVM's first quantitative antimicrobial RA model for
acquisition of resistant food-borne bacteria will be used to help the
agency make appropriate risk management decisions about the use of
antimicrobials in food-producing animals. Accordingly, it is acceptable
that data submitted in response to this document be ``blinded'' in the
sense that the data need not identify the particular manufacturer,
animal producer, or processor that was the source of the samples
underlying the results. However, the agency must be assured of the
validity of the study design and data.
The RA team plans to present a summary of responses to this
document as part of the completed RA document.
Comments and scientific data and information should be addressed to
the Dockets Management Branch (address above) and identified with the
docket number found in brackets in the heading of this document.
Received materials may be seen in the Dockets Management Branch between
9 a.m. and 4 p.m., Monday through Friday.
V. References
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. The Centers for Disease Control and Prevention National
Nosocomial Infections Surveillance (NNIS) System, NNIS Report, data
summary from October 1986 to April 1996, issued May 1996, American
Journal of Infection Control, 24(5), pp. 380-388, 1996.
2. Moellering, R. C., P. K. Linden, J. Reinhardt, E. A.
Blumberg, et al., ``The Efficacy and Safety of Quinupristin/
dalfopristin for the Treatment of Infections Caused by Vancomycin-
resistant Enterococcus faecium,'' Synercid Emergency Use Study
Group, Journal of Antimicrobial Chemotherapy, 44(2), pp. 251-261,
1999.
3. Huycke, M., D. Sahm, and M. Gilmore, ``Multiple-Drug
Resistant Enterococci: The Nature of the Problem and an Agenda for
the Future,'' Emerging Infectious Diseases, 4(2), pp. 239-249, 1998.
4. Jensen, L. B., A. M. Hammerum, F. M. Aerestrup, A. E. Van Den
Gofaard, and E. E. Stobberingh, ``Occurrence of satA and vgb Genes
in Streptogramin-resistant Enterococcus faecium Isolates of Animal
and Human Origins in The Netherlands,'' Antimicrobial Agents and
Chemotherapy, vol. 42, pp. 3330-3331, 1998.
5. Leclercq, R., and P. Courvalin, ``Bacterial Resistance to
Macrolide, Lincosamide, and Streptogramin Antibiotics by Target
Modification,'' Antimicrobial Agents and Chemotherapy, 35(7), pp.
1267-1272, 1991.
6. Bozdogan, B., and R. Leclercq, ``Effects of Genes Encoding
Resistance to Streptogramins A and B on the Activity of
Quinupristin-Dalfopristin Against Enterococcus
faecium,''Antimicrobial Agents and Chemotherapy, 43(11), pp. 2720-
2725, 1999.
7. Rende-Fournier, R., R. Leclercq, M. Galimand, J. Duval, and
P. Courvalin, ``Identification of the satA Gene Encoding a
Streptogramin A Acetyltransferase in Enterococcus faecium BM4145,''
Antimicrobial Agents and Chemotherapy, 37(10), pp. 2119-2125, 1993.
8. Werner, G., and W. Witte, ``Characterization of a New
Enterococcal Gene, satG, Encoding a Putative Acetyltransferase
Conferring Resistance to Streptogramin A Compounds,'' Antimicribial
Agents and Chemotherapy, 43(7), pp. 1813-1814, 1999.
[[Page 20995]]
9. Soltani, M., D. Beighton, J. Philpott-Howard, N. Woodford,
``Mechanisms of Resistance to Quinupristin-dalfopristin among
Isolates of Enterococcus Faecium from Animals, Raw Meat, and
Hospital Patients in Western Europe,'' Antimicrobial Agents and
Chemotherapy, 44(2), pp. 433-436, 2000.
10. English, L. L., J. R. Hayes, D. G. White, S. W. Joseph, L.
E. Carr, and D. D. Wagner, ``Antibiotic Susceptibility Profiles of
Enterococcus Isolates from the Poultry Production Environment,''
Abstract J17, 2000 FDA Science Forum FDA and the Science of Safety:
New Perspectives, p. 73, 2000.
Dated: April 11, 2000.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 00-9696 Filed 4-14-00; 8:45 am]
BILLING CODE 4160-01-F