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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 141-101 PREEMPT™ - original approval

Approval Date: March 13, 1998

I. GENERAL INFORMATION:

NADA141-101
Sponsor:BioScience
Division of Milk Specialties Company
P.O. Box 278
Dundee, Illinois 60118
Generic Name:competitive exclusion culture
Trade Name:PREEMPT™
Marketing Status:Over the Counter (OTC)

 

II. INDICATIONS FOR USE

PREEMPTTM is indicated for the early establishment of intestinal microflora in chickens to reduce Salmonella colonization.

 

III. DOSAGE

A.DOSAGE FORMPREEMPTTM is available as frozen pellets in foil packages of 2000 and 5000 dosages.
B.ROUTE OF ADMINISTRATIONReconstituted PREEMPTTM is administered as a topical spray via a spray box.
C.RECOMMENDED DOSAGES:Twenty-five (25) mL of reconstituted PREEMPTTM is sprayed onto each tray of 100 chicks (approximately 0.25 mL/chick).

 

IV. EFFECTIVENESS

A. Dose Determination Study

  1. Purpose: The purpose of the study was to determine an effective dose of PREEMPTTM for the reduction of Salmonella colonization in chickens.
  2. Investigator: Dr. Don Corrier, USDA/ARS, College Station, Texas 77845
  3. Study Design: Three replicate studies were conducted in which one-day-old broiler chicks were treated (topical spray) with various doses of PREEMPTTM (104, 105, 106, 107, and 108 colony forming units (CFU)/chick) to determine the optimal dose of PREEMPTTM for prevention of cecal Salmonella colonization in chickens. An untreated control group and a control group treated with the diluent used to resuspend PREEMPTTM were also included in the studies. PREEMPTTM was administered by using a commercial spray box to spray each tray of 100 chicks with 25 mL of PREEMPTTM(approximately 0.25 mL/chick).

    Each treatment group contained 100 chicks of both sexes. On Day 3 of age, one-half the chicks in each group (Seeders) received a crop gavage of Salmonella typhimurium culture (104 CFU/chick). The other half (Contacts) did not receive Salmonella , but were housed in contact with Salmonella-treated birds. The use of Seeders and Contacts was intended to determine the ability of PREEMPTTM to reduce horizontal transmission of Salmonella from infected (seeder) to uninfected (contact) birds.

    On Day 3 of age, 10 chicks per pen (Rep. 1 and 2) or 20 chicks/pen (rep. 3) were sacrificed and samples of cecal material were collected for measurement of cecal volatile fatty acid (VFA) concentrations (propionate and total VFA, µmol/g). Cecal VFAs were measured to determine the correlation between total VFA concentration, propionate concentration, and protection from Salmonella. On Day 10 of age, 20 chicks per pen were sacrificed and cecal material was collected for measurement of Salmonella population (Log10 CFU/g) and determination of the percentage of chickens testing positive for Salmonella.

  4. Results: The results are presented in Tables 4.1 and 4.2. Table 4.1. Effect of increasing doses of PREEMPTTM on Day 3 on total VFA and propionic acid concentrations
    Treatment groupReplications (n)Total VFA concentration (µmol/g)¹Propionic acid concentration (µmol/g)¹
    Control3730.91a2.09a
    Diluent3941.38b2.76a
    PREEMPTTM @ 1041835.25*3.44*
    PREEMPTTM @ 10520td>38.33*4.29*
    PREEMPTTM @ 1064042.99b4.46b
    PREEMPTTM @ 107td>3939.75b6.26c
    PREEMPTTM @ 1084041.53b8.00d
    n = number of chicks used for the determinations.
    1 means within a column that have a common letter superscript do not differ (a=0.05).
    * group not included in third replicate or final statistical analysis
    Table 4.2. Effect of increasing doses of PREEMPTTM on Salmonella
    Treatment
    CFU/chick
    Replications (n)Salmonella population
    Log10 CFU/g
    Seeder
    Salmonella population
    Log10 CFU/g
    Contact
    Salmonella positive % SeederSalmonella positive % Contact
    Control604.12a1.62a90a57a
    Diluent603.51a 1.62a1.62a83a50a
    PREEMPTTM @ 104403.58*1.63*73*63*
    PREEMPTTM @ 105401.91*0.43*65*23*
    PREEMPTTM @ 106601.82b0.15b53b12b
    PREEMPTTM @ 107601.38b0.19b47b,c10b
    PREEMPTTM @ 108601.16b0.34b35c13b
    n = number of chicks used for the determinations.
    1 means within a column that have a common letter superscript do not differ (a=0.05).
    * group not included in third replicate or final statistical analysis
  5. Conclusions: The results of this study indicated that:
    1. a. A PREEMPTTM dose of 107 CFU/chick was sufficient to provide significant protection against Salmonella colonization.
    2. b. Elevations in Day 3 cecal propionic acid were indicative of protection against Salmonella colonization
    3. c. Elevations in Day 3 cecal total VFA were not a sensitive measure of protection against Salmonella colonization.
    4. d. Treatment with PREEMPTTM was able to reduce transfer of Salmonella from infected (seeder) to uninfected (contact) birds.

B. Dose Confirmation Study

  1. Purpose: The purpose of the study was to confirm the dosage that was obtained in the dose determination study.
  2. Investigator: Dr. David Nisbet, USDA/ARS, College Station, Texas 77845
  3. Study Design: This was a floor pen challenge study conducted at the USDA facilities in College Station, Texas, to evaluate the ability of 107 CFU/chick dosage of PREEMPTTM to protect chicks challenged with Salmonella typhimurium (a controlled variable) from cecal Salmonella colonization through the end of growout.

    One-day-old chicks (n=600) were sprayed with PREEMPTTM(107 CFU/chick). Control chicks (n=600) were sprayed with deionized water. Chicks were then placed in separate houses, each containing 6 pens of 100 chicks/pen. Separate houses were necessary because protection from PREEMPTTM may be transferable from treated to untreated chicks that are in contact with each other.

    On Day 3, 20 chicks per pen from each treatment group were sacrificed to measure cecal propionic acid concentration. Then 50% of the chicks in each pen received a crop gavage dose of 104 CFU Salmonella typhimurium per chick (seeders). The remaining chicks (contacts) served to examine the transmission of Salmonella from infected to uninfected chicks. On Days 21 and 43, samples were collected to measure Salmonella in cecal contents (15 chicks/pen) and floor litter (6 litter samples/pen). Mortality was monitored throughout the study, and weights of the remaining PREEMPTTM treated and control chickens were compared on Day 43.

    Cecal colonization data (percent positive birds and cecal Salmonella population) were analyzed separately for seeder and contact birds. Percent Salmonella positive cecal samples and floor litter samples were analyzed by Chi-square analysis. Salmonella population data, propionic acid concentration and Salmonella population in litter samples were analyzed by analysis of variance using mixed models.

  4. Results: The results are presented in Tables 4.3, 4.4, and 4.5.

    Table 4.3. Cecal Salmonella data in seeder birds

    TreatmentPens (n)Percent Salmonella-positive birds¹
    Day 21
    Percent Salmonella-positive birds¹
    Day 43
    Cecal Salmonella population
    (Log10 CFU/g)
    Day 21²
    Cecal Salmonella population
    (Log10 CFU/g)
    Day 43³
    Control687.8a11.1a3.84±1.62a0.32±0.35a
    PREEMPTTM617.0b0b0.63±0.95b0b
    n = number of pens
    ¹unlike letters within a column differ at p<0.001
    ²unlike letters within a column differ at p<0.01
    ³unlike letter within a column differ at p<0.0501
    Table 4.4. Cecal Salmonella data in contact birds
    TreatmentPens (n)Percent Salmonella-positive birds¹
    Day 21
    Percent Salmonella-positive birds¹
    Day 43
    Cecal Salmonella population
    (Log10 CFU/g)
    Day 21²
    Cecal Salmonella population
    (Log10 CFU/g)
    Day 43³
    Control686.7a6.7a3.90±1.45a0.19±0.24a
    PREEMPTTM610.0b0b0.43±0.67b0b

    n = number of pens used for the determination
    ¹unlike letters within a column differ at p<0.001
    ²unlike letters within a column differ at p<0.01
    ³unlike letter within a column differ at p<0.0840

    Table 4.5. Floor litter data

    Day 21¹ Day 43 Treatment Samples (n) Salmonella population (Log10 CFU/g) Salmonella-positive samples (%) Salmonella population (Log10 CFU/g)2 Salmonella-positive samples (%)3 Control 36 2.78±0.78a 91.7a 0.66±0.84 33.3a PREEMPTÔ 36 0.96±0.58b 47.2b 0.28±0.68 13.9b

    n = number of samples used for the determination
    ¹values with unlike letters within a column differ at p<0.001
    ²not significantly different between groups
    ³values with unlike letters within a column differ at p<0.052

  5. Conclusions: The results of this study indicated that PREEMPTTM at a dosage of 107 CFU/chick, when applied as a single topical spray, was effective in reducing cecal Salmonella colonization in birds directly or indirectly challenged with Salmonella typhimurium.
  6. No adverse reactions were noted during this study.

C. Field Study (96-1) A series of three, paired-house field studies on separate farms (Farms 1, 2, and 3) within one operation unit was conducted to determine the efficacy of PREEMPTTM culture in reducing Salmonella in broiler chickens. Upon completion of the study, it was discovered that chicks on two of the farms (Farm 2 and 3) had been sprayed with a solution containing gentamicin immediately prior to receiving PREEMPTTM. These two farms were excluded from analysis. The results from the remaining farm, Farm 1, were analyzed and are reported here.

  1. Purpose: The purpose of this field evaluation was to determine the safety and effectiveness of a characterized continuous flow bacterial culture (PREEMPTTM) in preventing Salmonella colonization in commercially reared broiler chickens.
  2. Investigator: Dr. Don Corrier, USDA/ARS, College Station, Texas 77845
  3. Product manufacturing site:
    BioScience Division of Milk Specialties Co.,
    Fermentation Facility #1,
    3802 Packers Ave.,
    Madison, WI 53704
  4. Product lot number: Lot #196248, expiration date - April 1997
  5. Trial Locations: The study was conducted at the broiler hatcheries, growout houses, and processing plant located in the Nashville, Arkansas area.
  6. Number of birds used: Farm 1 (approximately 13,600 chicks/rearing house).
  7. Study Design: The study was initiated at the beginning of an 8-week growout cycle. Newly-hatched chicks were assigned to treatment groups at the hatchery, where they were administered, as a single spray treatment, either PREEMPTTM (107 CFU/chick) or deionized water and then placed in rearing houses.

    The experiment was designed to compare data from treated chicks to data from control chicks.

    Approximately 2 weeks prior to study initiation, baseline Salmonella testing and litter sampling were conducted to identify Salmonella positive houses. Only houses with litter that tested positive for Salmonella were used to ensure that both control and PREEMPTTM treated chicks were exposed to natural Salmonella challenge.

    On Day 3 (48 hours after spray treatment either with PREEMPTTM or water), propionic acid concentration in cecal contents obtained from 100 control and 100 PREEMPTTM-treated chicks was determined with a gas chromatograph.

    Effectiveness was determined by measuring the incidence of Salmonella-positive chickens at the end of growout, prior to processing. Salmonella-positive chickens were identified by culturing the cecal contents. Salmonella incidence in the environment was monitored by testing hatchery tray liners (Day 1), floor litter, feed and water (Day 1, Day 22, and end of growout). Mortality was also determined.

  8. Results: Birds treated with PREEMPTTM had lower end-of-growout cecal Salmonella incidence than untreated control birds in all testing methods as shown in Table 4.6.

    Table 4.6. Cecal Salmonella incidence at the end of growout

    Method of testingSalmonella-positive birds¹ (%)
    PREEMPTTM
    Salmonella-positive birds¹ (%)
    Control
    Serial dilution and/or tetrathionate broth incubation07.2
    Serial dilution04.1
    Tetrathionate broth incubation05.2
    ¹(Number of positive samples)/n; nPREEMPT = 99, nControl = 97.
  9. Conclusions: The results of this field study demonstrated that a single spray administration of PREEMPTTM culture to day-old chicks was effective in reducing Salmonella colonization in chickens at the end of growout.
  10. Adverse Reactions: No adverse reactions were noted during this field study.

 

V. ANIMAL SAFETY

PREEMPTTM consists of live bacteria, originally obtained from healthy, specific-pathogen-free (SPF) chickens, and maintained under controlled manufacturing conditions. The lack of adverse effects in the dose titration study (summarized under EFFECTIVENESS, page 2) and in the field study were considered adequate to determine that PREEMPTTM is safe when used in day-old chicks at the approved dose of 107 CFU/chick.

 

VI. HUMAN FOOD SAFETY

PREEMPTTM culture consists of normal chicken cecal microflora, free of known pathogens. Administration of PREEMPTTM to newly hatched chicks will not create exposure to bacteria and bacterial products not already present in the poultry environment. Since the use of PREEMPTTM in chickens produces no residues in edible tissues or products, the residue chemistry testing requirements that are specified in 21 CFR 514.1(b)(7) are waived.

 

VII. AGENCY CONCLUSIONS

The data submitted in support of this NADA satisfy the requirements of Section 512 of the Federal Food, Drug, and Cosmetic Act and 21 CFR Part 514 of the implementing regulations. The data demonstrate that PREEMPTTM, a competitive exclusion product, when administered as a single spray to newly hatched chicks, is safe and effective for the early establishment of intestinal microflora to reduce Salmonella colonization.

PREEMPTTM is a characterized bacterial culture, originally derived from the ceca of adult healthy chickens. It is free of known pathogens. Since its use in chickens produces no residues in edible tissues or products, the agency has waived the residue chemistry testing requirements that are specified in 21 CFR 514.1(b)(7).

The product will be available as an over-the-counter drug. This decision is based on the following factors: (a) the product contains live non-pathogenic bacteria that are intended only for the establishment of gut microflora in newly hatched chicks at a time when they are vulnerable to colonization with Salmonella, and (b) adequate directions are written to enable lay persons to appropriately use the product on chicks at the hatchery before the chicks are transferred to the rearing facilities.

The agency has determined, under 21 CFR 25.33(c), that this action is of a type that does not individually or cumulatively have a significant impact on the human environment. Therefore, neither an environmental assessment nor an environmental impact statement is required.

Under section 512(c)(2)(F)(i) of the FFDCA, this approval qualifies for FIVE years of marketing exclusivity beginning on the date of approval because no active ingredient (including any ester or salt of the active ingredient) has been approved in any other application.

PREEMPTTM is under patent number U.S. 5,478,557 expiring December 13, 2013.

 

VIII. LABELING (Attached)

Copies of applicable labels may be obtained by writing to the:

Freedom of Information Office
Center for Veterinary Medicine, FDA
7500 Standish Place
Rockville, MD 20855