```

[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
```