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					                                                                  ADVICE SUMMARY
                                    APPLICATION FOR REGISTRATION OF A CHEMICAL PRODUCT
Product name:               NUFLOR PIG PREMIX
Applicant:                  SCHERING-PLOUGH PTY LIMITED
Product number:             60369
Application number:         38049

Purpose of Application and Description of Use:       Registration of a 40 g/kg florfenicol premix for the treatment of respiratory infections in pigs.

Active Constituent(s):      FLORFENICOL



Regulatory Decision:
To grant the application subject to the following conditions:

Standard Conditions of Registration/Approval


For full conditions, refer to http://www.apvma.gov.au/advice_summaries/adv_summaries.shtml.




38049                                                                       Page 1 of 13                                              KP25S_F39 Version: 2 Issued: 14/08/2007
ADVICE
Australian Government Department Of Health And Ageing, Office Of Chemical Safety
Additional toxicology data were not provided. Based on the extrapolated toxicology profile of Nuflor Pig Premix, OCS advised that the product is likely to have
low acute oral, dermal and inhalation toxicity. The premix is unlikely to be a skin irritant or sensitiser, but is likely to be a moderate eye irritant. OCS
established new safety directions for the product, but did not recommend changes to the existing acceptable daily intake of 0.001 mg/kg bw/day and S4
scheduling for florfenicol.

APVMA Residues Section
Residues data were provided from an overseas study in which crossbred pigs were administered Nuflor Pig Premix in feed at a rate of 200 mg florfenicol/kg
feed for five consecutive days. This rate equated to 10 mg florfenicol/kg bw (1x label dose rate) based on the assumption that pigs consume 5% of their body
weight in feed. Liver, kidney, muscle and skin/fat samples were taken from treated pigs after the medicated feed was withdrawn, and were analysed for
florfenicol residues. Statistical analysis of the decline residues data for liver and kidney indicated that florfenicol residues would comply with the Australian
MRLs of both tissues 11 and 7 days post-treatment respectively. For muscle and skin/fat, compliance with the MRLs would occur at all times after treatment.
These results supported a 12-day withholding period for meat. Changes to the existing MRLs and residues definition for florfenicol were not required.
Consequently, the estimated dietary exposure to florfenicol is unchanged and is unlikely to exceed the existing acceptable daily intake.
In the study described above, the EU MRLs for florfenicol were used as the endpoints for the ESI determination of the test product. Statistical analysis of the
residues decline data indicated that florfenicol residues in liver and kidneys would comply with the EU MRLs for these tissues 14 and 13 days post-treatment
respectively. For muscle and skin/fat, compliance with their EU MRLs will occur at all times after treatment. These results therefore supported a 15-day ESI.
Data relied on to provide the advice
                                                                                                                                                                             Inherited
Data    Data            Author(s)                             Title                              Date         Data Type       Data Sub-type              Authorising        Application
No      Source*                                                                                                                                            Party                No.
5646    S         Cortez C             SCH 25298 (Florfenicol): Storage stability of         1999       Residues          Fate - Storage,             Applicant
                                       the marker residue, florfenicol amine, in swine                                    Processing and
                                       liver tissue.                                                                      Cooking
5647    S         Mushtaq M            SCH 25298 (Florfenicol): A final residue              2003       Residues          Animal Commodity            Applicant
                                       depletion study of the marker residue, florfenicol                                 Residues Direct
                                       amine, in swine following administration of                                        Application
                                       florfenicol in feed.
5648    S         Bova A               SCH 25298: Development and validation of a            1998       Residues          Analytical Methods          Applicant
                                       determinative assay for the marker residue in
                                       swine tissue.



38049                                                                             Page 2 of 13                                                KP25S_F39 Version: 2 Issued: 14/08/2007
External Efficacy Reviewer
Nuflor Pig Premix claims to be effective against respiratory infections caused by Actinobacillus pleuropneumoniae, Pasteurella multocida, and Streptococcus
suis Type 2 in pigs when incorporated in finished rations at 5 kg premix per tonne feed (200 ppm) to give the recommended label dose rate of 10 mg florfenicol/kg
body weight. Data were provided from five studies to support these claims.
A dose rate study assessed in-feed rates of 5, 10 and 15 mg/kg bw fed for 5 days to pigs inoculated with Actinobacillus pleuropneumoniae and Pasteurella
multocida. Successful treatment was measured by reduction of rectal temperature to <104oF, and dyspnoea and depression scores ≤1. The 10 mg/kg bw dose rate
improved all assessed parameters compared to non-medicated controls.
In two confirmatory studies, the premix was tested in pigs at the label dose rate during the treatment of natural challenge infections from which isolates of
Actinobacillus pleuropneumoniae, Pasteurella multocida, and Streptococcus suis Type 2 were obtained from lung swabs. Florfenicol-treated pigs showed significant
improvement in test parameters when compared to untreated controls (p = <0.0001 to 0.0353), and a higher proportion showed improvement when compared to
amoxicillin-treated pigs.
The bioavailability of the label dosage of florfenicol given intravenously to one group of pigs and by gavage of the premix to a second group of pigs was compared
over a 24-hour period. Treatments were reversed after a 14-day washout. Florfenicol concentrations via the oral route exceeded the MIC90 for Actinobacillus
pleuropneumoniae and Pasteurella multocida (MIC90 = 0.5-1 μg/mL). There was total bioavailability of florfenicol from the premix.
In a 5-day in-feed pharmacokinetic study, serum florfenicol concentrations were maintained above the MIC90 of 1 μg/mL of the target pathogens for greater than
13 hours each day. Peak concentrations of florfenicol of 1.92 and 2.40 μg/mL were realised on days 0 and 4 respectively.
The results of these studies demonstrate that treatment of pigs for 5 days with Nuflor Pig Premix at the recommended label dose rate will successfully reverse
symptoms caused by the target pathogens.
Results from a multidose trial were submitted to support that Nuflor Pig Premix is safe for administration in the diet of pigs. Test subjects were exposed to 1x,
3x and 5x the label dose rate for 15 days, and 10x the label dose rate for 5 days. Increased serum calcium was observed for all treatments. Other product-related
effects included feed spillage, decreased food and water intake at rates higher than the recommended label rate. In the clinical studies, there was a higher
incidence of perianal inflammation, which was transient. At the label dose rate, the product has demonstrated that it is well tolerated by pigs.




38049                                                                       Page 3 of 13                                             KP25S_F39 Version: 2 Issued: 14/08/2007
Data relied on to provide the advice
                                                                                                                                                                                      Inherited
Data    Data             Author(s)                             Title                                  Date         Data Type           Data Sub-type              Authorising        Application
No      Source*                                                                                                                                                     Party                No.
5649    S         Jackson J &           Florfenicol Actinobacillus pleuropneumoniae               2001       Efficacy and Safety   Efficacy                    Applicant
                  Lechtenberg K         (APP) and Pasteurella multocida (PM) mixed
                                        model feed medication dose selection study in
                                        swine.
5650    S         R Zolynas             Efficacy of a florfenicol (Nuflor) feed premix            2004       Efficacy and Safety   Efficacy                    Applicant
                                        for the control of Swine Respiratory Disease
                                        (SRD) in the US
5651    S         Etore F & de Haas V   Efficacy and safety of a florfenicol (Nuflor) feed        2004       Efficacy and Safety   Efficacy                    Applicant
                                        premix in comparison to amoxicillin feed premix
                                        in the treatment of Porcine Respiratory Disease
                                        (PRD) in Europe.
5652    S         TerHune T             SCH 25298 (Florfenicol) Medicated Feed                    2003       Efficacy and Safety   Target Animal Safety        Applicant
                                        Premix: Oral target animal safety study in swine                                           Studies
5653    S         Zolnas R              Bioavailability of florfenicol in swine following         2003       Efficacy and Safety   Pharmacological             Applicant
                                        intravenous and oral gavage administration.                                                Data/Studies
5654    S         Zolnas R              Pharmacokinetics of florfenicol in swine                  2004       Efficacy and Safety   Pharmacological             Applicant
                                        following administration of Nuflor Swine                                                   Data/Studies
                                        Premix in feed for 5 days.



NHMRC/EAGAR
NHMRC considered that the risk of antimicrobial resistance posed by the reference product was characterised as being low, but raised concerns about
prophylactic use of antibiotics in-feed for treating large number of pigs. Given that Nuflor Oral Premix provides an alternate method of administering
florfenicol and is applied at the same dose rate (10 mg/kg bw for 5 consecutive days) against the same bacteria as the in-water reference preparation, the
APVMA concluded that the risk of antimicrobial resistance developing as a result of treatment with premix is no greater than the risk posed by reference
product.
Data relied on to provide the advice
                                                                                                                                                                                      Inherited
Data    Data             Author(s)                             Title                                  Date         Data Type           Data Sub-type              Authorising        Application
No      Source*                                                                                                                                                     Party                No.


5710    S         Keyes K et al         Detection of florfenicol resistance genes in              2000       Special Data          Antibiotics                 Public




38049                                                                                  Page 4 of 13                                                    KP25S_F39 Version: 2 Issued: 14/08/2007
                                 Escherichia coli isolated from sick chickens.                Requirements
5711    S   Kim E & Aoki T       Drug resistance and broad geographical                1993   Special Data   Antibiotics           Public
                                 distribution of identical R plasmids of                      Requirements
                                 Pasteurella piscicida isolated from cultured
                                 yellowtail in Japan.
5657    S   de Haas V            Expert report: Pre-clinical and clinical              2004   Special Data   Antibiotics           Applicant
                                 documentation. Nuflor Swine Premix                           Requirements
5712    S   Kim E & Aoki T       Sequence analysis of the florfenicol resistance       1996   Special Data   Antibiotics           Public
                                 gene encoded in the transferable R-plasmid of a              Requirements
                                 fish pathogen, Pasteurella piscicida.
5659    S   Anon                 Committee for Veterinary Medicinal Products -         2000   Special Data   Antibiotics           Public
                                 Florfenicol (extension to fish) - summary report             Requirements
                                 (5)
5713    S   Kloss P et al        Resistance mutations in 23 S rRNA identify the        1999   Special Data   Antibiotics           Public
                                 site of action of the protein synthesis inhibitor            Requirements
                                 linezolid in the ribosomal peptidyl transferase
                                 center.
5661    S   Anon                 Committee for Veterinary Medicinal Products -         1997   Special Data   Antibiotics           Public
                                 Florfenicol (extension to fish) - summary report             Requirements
                                 (2)
5714    S   Lautenbach E et al   The role of chloramphenicol in the treatment of       1998   Special Data   Antibiotics           Public
                                 bloodstream infection due to vancomycin-                     Requirements
                                 resistant Enterococcus.
5663    S   Anon                 Monitoring of the susceptibility to florfenicol       2002   Special Data   Antibiotics           Applicant
                                 (Nuflor) of various pathogenic organisms of                  Requirements
                                 cattle, swine and poultry
5715    S   Lee V & Lomovskaya   Efflux-mediated resistance to antibiotics in          1998   Special Data   Antibiotics           Public
                                 bacteria: challenges and opportunities.                      Requirements
5665    S   Cao J                Nuflor Swine Premix, Analysis of Feed                 2004   Special Data   Antibiotics           Applicant
                                 Consumption                                                  Requirements
5716    S   Lin C et al          Molecular characterization of a plasmid-borne         1996   Special Data   Antibiotics           Public
                                 (pTC82) chloramphenicol resistance determinant               Requirements
                                 (cat-TC) from Lactobacillus reuteri G4.
5667    S   Aarestrup F et al    Comparison of antimicrobial resistance                2000   Special Data   Antibiotics           Public
                                 phenotypes and resistance genes in Enterococcus              Requirements
                                 faecalis and Enterococcus faecium from humans
                                 in the community, broilers, and pigs in Denmark
5717    S   Lobell R             Post antibiotic effects of florfenicol. Report        1992   Special Data   Antibiotics           Applicant
                                 #25871.                                                      Requirements




38049                                                                       Page 5 of 13                                   KP25S_F39 Version: 2 Issued: 14/08/2007
5669    S   Arcangioli M et al     A new chloramphenicol and florfenicol                  1999   Special Data   Antibiotics           Public
                                   resistance gene flanked by two integron                       Requirements
                                   structures in Salmonella typhimurium DT104.
5718    S   Lovett R               Translation attenuation regulation of                  1996   Special Data   Antibiotics           Public
                                   chloramphenicol resistance in bacteria - a                    Requirements
                                   review.
5671    S   Arias C et al          Multicentre surveillance of antimicrobial              2003   Special Data   Antibiotics           Public
                                   resistance in enterococci and staphylococci from              Requirements
                                   Colombian hospitals, 2001-2002.
5719    S   Low D et al            Clinical prevalence, antimicrobial susceptibility,     2001   Special Data   Antibiotics           Public
                                   and geographic resistance patterns of                         Requirements
                                   enterococci: results from the SENTRY
                                   antimicrobial surveillance program, 1997-1999.
5673    S   Bager F et al          DANMAP 99 - Consumption of antimicrobial               2000   Special Data   Antibiotics           Public
                                   agents and occurrence of antimicrobial                        Requirements
                                   resistance in bacteria from food animals, food
                                   and humans in Denmark.
5720    S   Lynch C et al          Active efflux of antimicrobial agents in wild-         1997   Special Data   Antibiotics           Public
                                   type strains of enterococci.                                  Requirements
5675    S   Bissonenette L et al   Characterization of the nonenzymatic                   1991   Special Data   Antibiotics           Public
                                   chloramphenicol resistance (cmlA) gene of the                 Requirements
                                   In4 integron of Tn1696: similarity of the product
                                   to transmembrane transport proteins.
5721    S   Mankin A and Garrett   Chloramphenicol resistance mutations in the            1991   Special Data   Antibiotics           Public
            R                      single 23S rRNA gene of the archaeon                          Requirements
                                   Halobacterium halobium.
5677    S   Blais J et al          Bactericidal activity of florfenicol against           2003   Special Data   Antibiotics           Applicant
                                   Mannheimia haemolytica. Report for Study                      Requirements
                                   #E03-059-01..
5722    S   McDermott P et al      Multidrug resistance following expression of the       1998   Special Data   Antibiotics           Public
                                   Escherichia coli marA gene in Mycobacterium                   Requirements
                                   smegmatis.
5679    S   Bolton L et al         Detection of multidrug-resistant Salmonella            1999   Special Data   Antibiotics           Public
                                   enterica serotype typhimurium DT104 based on                  Requirements
                                   a gene which confers cross resistance to
                                   florfenicol and chloramphenicol.
5723    S   Miller M               Widespread emergence in the United States of           1997   Special Data   Antibiotics           Public
                                   multiple drug-resistant type of Salmonella                    Requirements
                                   typhimurium.




38049                                                                          Page 6 of 13                                   KP25S_F39 Version: 2 Issued: 14/08/2007
5681    S   Bonnier M et al      In vitro evaluation of the kinetics of the          2001   Special Data   Antibiotics           Applicant
                                 bactericidal effect of florfenicol against                 Requirements
                                 Escherichia coli. Report #39178.
5724    S   Mosher R et al       Inactivation of chloramphenicol by O-               1995   Special Data   Antibiotics           Public
                                 phosphorylation. A novel resistance mechanism              Requirements
                                 in Streptomyces venezuelae ISP5230, a
                                 chloramphenicol producer.
5683    S   Briggs C and         Molecular characterization of an antibiotic         1999   Special Data   Antibiotics           Public
            Fratamico P          resistance gene cluster of Salmonella                      Requirements
                                 typhimurium DT104.
5725    S   Mushtaq M & Crouch   Comparison of SCH 529752                            2003   Special Data   Antibiotics           Applicant
            L                    (florfenicol/flunixin combination drug) to                 Requirements
                                 NUFLOR in a single dose, bioequivalence,
                                 crossover study of florfenicol in cattle. Study
                                 #02436.
5685    S   Cloeckaert A et al   Plasmid-mediated florfenicol resistance encoded     2000   Special Data   Antibiotics           Public
                                 by the floR gene in Escherichia coli isolated              Requirements
                                 from cattle.
5726    S   Anon                 NARMS - Human. 1999. National Antimicrobial         1999   Special Data   Antibiotics           Public
                                 Resistance Monitoring System (NARMS) for                   Requirements
                                 Enteric Bacteria Participants (Human Isolates).
5687    S   Cloeckaert A et al   Nonenzymatic chloramphenicol resistance             2001   Special Data   Antibiotics           Public
                                 mediated by IncC plasmid R55 is encoded by a               Requirements
                                 floR gene variant.
5727    S   Anon                 NARMS - Human. 2001. National Antimicrobial         2001   Special Data   Antibiotics           Public
                                 Resistance Monitoring System (NARMS) for                   Requirements
                                 Enteric Bacteria Participants (Human Isolates).
5689    S   Crouch L             A total residue depletion study in swine            1998   Special Data   Antibiotics           Applicant
                                 following oral administration of 14C-SCH                   Requirements
                                 25298. Report P-6853.
5728    S   Anon                 NARMS - Veterinary. 1999. FDA/USDA/CDC              1999   Special Data   Antibiotics           Public
                                 National Antimicrobial Resistance Monitoring               Requirements
                                 System - Enteric Bacteria (NARMS-EB)
                                 Veterinary Isolates Final Report - 1999.
5691    S   Davis M et al        Changes in antimicrobial resistance among           1999   Special Data   Antibiotics           Public
                                 Salmonella enterica serovar Typhimurium                    Requirements
                                 isolates from humans and cattle in the
                                 northwestern United States, 1982-1997.
5729    S   Anon                 NARMS - Veterinary. 2001. FDA/USDA/CDC              2001   Special Data   Antibiotics           Public




38049                                                                     Page 7 of 13                                   KP25S_F39 Version: 2 Issued: 14/08/2007
                                   National Antimicrobial Resistance Monitoring                 Requirements
                                   System - Enteric Bacteria (NARMS-EB)
                                   Veterinary Isolates Preliminary Report - 2001.
5693    S   Dorman C and Foster    Nonenzymatic chloramphenicol resistance               1982   Special Data   Antibiotics           Public
            T                      determinants specified by plasmids R26 and                   Requirements
                                   R55-1 in Escherichia coli K-12 do not confer
                                   high-level resistance to fluorinated analogs.
5730    S   Neu H and Fu K         In vitro activity of chloramphenicol and              1980   Special Data   Antibiotics           Public
                                   thiamphenicol analogs.                                       Requirements
5695    S   Fines M and Leclercq   Activity of linezolid against Gram-positive cocci     2000   Special Data   Antibiotics           Public
            R                      possessing genes conferring resistance to protein            Requirements
                                   synthesis inhibitors.
5731    S   Nilsen I et al         Isolation of cmr, a novel Escherichia coli            1996   Special Data   Antibiotics           Public
                                   chloramphenicol resistance gene encoding a                   Requirements
                                   putative efflux pump.
5697    S   Galimand M et al       High-level chloramphenicol resistance in              1998   Special Data   Antibiotics           Public
                                   Neisseria meningitidis.                                      Requirements
5732    S   Norris A et al         Chloramphenicol for the treatment of                  1995   Special Data   Antibiotics           Public
                                   vancomycin-resistant enterococcal infections                 Requirements
5699    S   Graham R et al         In vitro activity of florphenicol.                    1988   Special Data   Antibiotics           Public
                                                                                                Requirements
5733    S   Okusu H et al          AcrAB efflux pump plays a major role in the           1996   Special Data   Antibiotics           Public
                                   antibiotic resistance phenotype of Escherichia               Requirements
                                   coli multiple-antibiotic-resistance (Mar)
                                   mutants.
5701    S   Guerra B et al         Phenotypic and genotypic characterization of          2003   Special Data   Antibiotics           Public
                                   antimicrobial resistance in German Escherichia               Requirements
                                   coli isolates from cattle, swine and poultry.
5734    S   Osawa S et al          Chloramphenicol resistant mutants of Bacillus         1973   Special Data   Antibiotics           Public
                                   subtilis.                                                    Requirements
5703    S   Hansen L               The macrolide-ketolide antibiotic binding site is     1999   Special Data   Antibiotics           Public
                                   formed by structures in domains II and V of 23S              Requirements
                                   ribosomal RNA.
5735    S   Park C et al           Low rates of spontaneous resistance emergence         2004   Special Data   Antibiotics           Public
                                   to florfenicol among bovine and swine                        Requirements
                                   respiratory pathogens.
5705    S   Heggers J et al        Alternate antimicrobial therapy for vancomycin-       1998   Special Data   Antibiotics           Public
                                   resistant enterococci burn wound infections.                 Requirements
5736    S   Pegues D et al         Salmonella including S. typhi                         1995   Special Data   Antibiotics           Public




38049                                                                         Page 8 of 13                                   KP25S_F39 Version: 2 Issued: 14/08/2007
                                                                                                 Requirements
5707    S   Jones R et al          In vitro Gram-positive antimicrobial activity of       2001   Special Data   Antibiotics           Public
                                   evernimicin (SCH 27899), a novel                              Requirements
                                   oligosaccharide, compared with other
                                   antimicrobials: a multicentre international trial.
5737    S   Perreten V et al       Antibiotic resistance genes in coagulase-              1998   Special Data   Antibiotics           Public
                                   negative staphylococci isolated from food.                    Requirements
5709    S   Kehrenberg C &         A novel gene from Staphylococcus lentus, fexA,         2003   Special Data   Antibiotics           Public
            Schwarz S              encodes combined resistance to florfenicol and                Requirements
                                   chloramphenicol.
5738    S   Anon                   Physicians' Desk Reference. 1997.                      1997   Special Data   Antibiotics           Public
                                   Chloromycetin« sodium succinate.                              Requirements
5658    S   Barrigazzi G et al     Postantibiotic effect (PAE) of florfenicol on P.       2002   Special Data   Antibiotics           Public
                                   multocida strains from pigs                                   Requirements
5739    S   Priebe S and Schwarz   Monitoring of florfenicol susceptibility in            2003   Special Data   Antibiotics           Public
            S                      porcine respiratory pathogens collected at the                Requirements
                                   time of introduction of florfenicol into clinical
                                   veterinary use.
5662    S   Herrig B               Report on comparison of serum concentrations           2005   Special Data   Antibiotics           Applicant
                                   of florfenicol resulting from swine consuming                 Requirements
                                   either Nuflor Oral for Pigs or Nuflor Swine
                                   Premix according to label directions
5740    S   Sander P et al         Ribosomal and non-ribosomal resistance to              2002   Special Data   Antibiotics           Public
                                   oxazolidinones: species-specific idiosyncrasy of              Requirements
                                   ribosomal alterations.
5666    S   Aarestrup F et al      Resistance to antimicrobial agents used for            1998   Special Data   Antibiotics           Public
                                   animal therapy in pathogenic-, zoonotic- and                  Requirements
                                   indicator bacteria isolated from different food
                                   animals in Denmark: a baseline study for the
                                   Danish Integrated Antimicrobial Resistance
                                   Monitoring Program (DANMAP)
5741    S   Schafer T et al        Novel fluorine-containing analogs of                   1980   Special Data   Antibiotics           Public
                                   chloramphenicol and thiamphenicol:                            Requirements
                                   antibacterial and biological properties.
5670    S   Arcangioli M et al     Evolution of chloramphenicol resistance, with          2000   Special Data   Antibiotics           Public
                                   emergence of cross-resistance to florfenicol, in              Requirements
                                   bovine Salmonella Typhimurium strains
                                   implicates definitive phage type (DT) 104.
5742    S   Schmieger H &          Transduction of multiple drug resistance of            1999   Special Data   Antibiotics           Public




38049                                                                          Page 9 of 13                                   KP25S_F39 Version: 2 Issued: 14/08/2007
            Schicklmaier P        Salmonella enterica serovar typhimurium                    Requirements
                                  DT104.
5674    S   Barie P               Antibiotic-resistant Gram-positive cocci:           1998   Special Data   Antibiotics           Public
                                  implications for surgical practice                         Requirements
5743    S   Schouten M et al      Antimicrobial susceptibility patterns of            1999   Special Data   Antibiotics           Public
                                  enterococci causing infections in Europe.                  Requirements
5678    S   Blais J et al         Bactericidal activity of florfenicol against        2003   Special Data   Antibiotics           Applicant
                                  Streptococcus suis. Report for Study #E03-147-             Requirements
                                  01.
5744    S   Schuchat A et al      Bacterial meningitis in the United States in        1997   Special Data   Antibiotics           Public
                                  1995.                                                      Requirements
5682    S   Bourchardon A         Study of the pharmacodynamic action of              2002   Special Data   Antibiotics           Applicant
                                  florfenicol on Mycoplasma gallisepticum,                   Requirements
                                  Mycoplasma hyopneumoniae and Mycoplasma
                                  hyorhinis. Report for Study #X01-110-01.
5745    S   Schwarz S et al       Chloramphenicol resistance in Staphylococcus        1995   Special Data   Antibiotics           Public
                                  intermedius from a single veterinary centre:               Requirements
                                  evidence for plasmid and chromosomal location
                                  of the resistance genes.
5686    S   Cloeckaert A et al    Occurrence of a Salmonella enterica serovar         2000   Special Data   Antibiotics           Public
                                  Typhimurium DT104-like antibiotic resistance               Requirements
                                  gene cluster including the floR gene in S.
                                  enterica serovar Agona
5746    S   Schwarz S et al       Identification of a plasmid-borne                   2000   Special Data   Antibiotics           Public
                                  chloramphenicol-florfenicol resistance gene in             Requirements
                                  Staphylococcus sciuri.
5690    S   Anon                  DANMAP 2002. Use of antimicrobial agents            2002   Special Data   Antibiotics           Public
                                  and occurrence of antimicrobial resistance in              Requirements
                                  bacteria from food animals, food and humans in
                                  Denmark.
5747    S   Syriopoulou V et al   In vitro antibacterial activity of fluorinated      1981   Special Data   Antibiotics           Public
                                  analogs of chloramphenicol and thiamphenicol.              Requirements
5694    S   Ettayebi M et al      Chloramphenicol-erythromycin resistance             1985   Special Data   Antibiotics           Public
                                  mutations in a 23S rRNA gene of Escherichia                Requirements
                                  coli.
5748    S   Teale C et al         VLA antimicrobial sensitivity report.               2001   Special Data   Antibiotics           Public
                                                                                             Requirements
5698    S   Gilbert D et al       The Sanford Guide to Antimicrobial Therapy          2003   Special Data   Antibiotics           Public
                                  33rd Edition.                                              Requirements




38049                                                                     Page 10 of 13                                   KP25S_F39 Version: 2 Issued: 14/08/2007
5749    S   Tennigkeit J &         Nucleotide sequence analysis of a                     1991   Special Data   Antibiotics           Public
            Matzura H              chloramphenicol-resistance determinant from                  Requirements
                                   Agrobacterium tumefaciens and identification of
                                   its gene product.
5702    S   Guerrant R et al       Practice guidelines for the management of             2001   Special Data   Antibiotics           Public
                                   infectious diarrhea.                                         Requirements
5750    S   Threlfall E et al      Multiresistant Salmonella typhimurium DT 104          1998   Special Data   Antibiotics           Public
                                   and salmonella bacteremia.                                   Requirements
5706    S   Hoban D et al          Worldwide prevalence of antimicrobial                 2001   Special Data   Antibiotics           Public
                                   resistance in Streptococcus pneumoniae,                      Requirements
                                   Haemophilus influenzae, and Moraxella
                                   catarhalis in the SENTRY antimicrobial
                                   surveillance program, 1997-1999.
5751    S   Thyssen A et al        Phenotypic characterization of the marine             1998   Special Data   Antibiotics           Public
                                   pathogen Photobacterium damselae subsp.                      Requirements
                                   piscicida.
5656    S   Shuster D              Safety assessment of the potential for resistance     2004   Special Data   Antibiotics           Applicant
                                   resulting from the use of Nuflor Swine Premix                Requirements
5752    S   Trieu-Cuot P et al     Study of heterogeneity of chloramphenicol             1993   Special Data   Antibiotics           Public
                                   acetyltransferase (CAT) genes in streptococci                Requirements
                                   and enterococci by polymerase chain reaction:
                                   characterization of a new CAT determinant.
5664    S   Coates K et al         Level of food borne pathogens on Australian pig       1997   Special Data   Antibiotics           Public
                                   meat and carcasses.                                          Requirements
5753    S   Vassort-Bruneau C et   CAT III chloramphenicol resistance in                 1996   Special Data   Antibiotics           Public
            al                     Pasteurella haemolytica and Pasteurella                      Requirements
                                   multocida isolated from calves.
5672    S   Ayling R et al         Comparison of in vitro activity of danofloxacin,      2000   Special Data   Antibiotics           Public
                                   florfenicol, oxytetracycline, spectinomycin and              Requirements
                                   tilmicosin against recent field isolates of
                                   Mycoplasma bovis.
5754    S   Vester B & Garrett R   The importance of highly conserved nucleotides        1988   Special Data   Antibiotics           Public
                                   in the binding region of chloramphenicol at the              Requirements
                                   peptidyl transfer centre of Escherichia coli 23S
                                   ribosomal RNA.
5680    S   Bonnier M et al        In vitro evaluation of the kinetics of the            2001   Special Data   Antibiotics           Applicant
                                   bacteriological effect of florfenicol against                Requirements
                                   swine pathogens. Report #31194.
5755    S   Wall P et al           A case control study of infection with an             1994   Special Data   Antibiotics           Public




38049                                                                        Page 11 of 13                                   KP25S_F39 Version: 2 Issued: 14/08/2007
                                  epidemic strain of multiresistant Salmonella                 Requirements
                                  typhimurium DT104 in England and Wales.
5688    S   Cohen S et al         Genetic and functional analysis of the multiple       1993   Special Data   Antibiotics           Public
                                  antibiotic resistance (mar) locus in Escherichia             Requirements
                                  coli.
5756    S   Wang Y & Taylor D     Chloramphenicol resistance in Campylobacter           1990   Special Data   Antibiotics           Public
                                  coli: nucleotide sequence, expression, and                   Requirements
                                  cloning vector construction.
5696    S   Frech G et al         Resistance phenotypes and genotypes of                2003   Special Data   Antibiotics           Public
                                  multiresistant Salmonella enterica subsp.                    Requirements
                                  enterica serovar Typhimurium var. Copenhagen
                                  isolates from animal sources.
5757    S   Webber M & Piddock    The importance of efflux pumps in bacterial           2003   Special Data   Antibiotics           Public
            L                     antibiotic resistance.                                       Requirements
5704    S   Harrod R and Lovett   Leader peptides of inducible chloramphenicol          1997   Special Data   Antibiotics           Public
            P                     resistance genes from gram-positive and gram-                Requirements
                                  negative bacteria bind to yeast and Archaea
                                  large subunit rRNA.
5758    S   Werner G et al        Linkage of determinants for streptogramin A,          2000   Special Data   Antibiotics           Public
                                  macrolide-lincosamide-streptogramin B, and                   Requirements
                                  chloramphenicol resistance on a conjugative
                                  plasmid in Enterococcus faecium and
                                  dissemination of this cluster among
                                  streptogramin-resistant enterococci.
5660    S   Anon                  Committee for Veterinary Medicinal Products -         1999   Special Data   Antibiotics           Public
                                  Florfenicol (extension to chicken) - summary                 Requirements
                                  report (3)
5759    S   White D et al         Characterization of chloramphenicol and               2000   Special Data   Antibiotics           Public
                                  florfenicol resistance in Escherichia coli                   Requirements
                                  associated with bovine diarrhea.
5676    S   Blais J et al         MBC:MIC Determination for florfenicol against         2003   Special Data   Antibiotics           Applicant
                                  Pasteurella multocida and Mannheimia                         Requirements
                                  haemolytica. Report #JBCPDS2003-001
5760    S   Xiong L et al         Oxazolidinone resistance mutations in 23S             2000   Special Data   Antibiotics           Public
                                  rRNA of Escherichia coli reveal the central                  Requirements
                                  region of domain V as the primary site of drug
                                  action.
5692    S   Deshpande L et al     Accuracy of broth microdilution and E test            2001   Special Data   Antibiotics           Public
                                  methods for detecting chloramphenicol acetyl                 Requirements




38049                                                                       Page 12 of 13                                   KP25S_F39 Version: 2 Issued: 14/08/2007
                                       transferase mediated resistance in Streptococcus
                                       pneumoniae: geographic variations in the
                                       prevalence of resistance in The SENTRY
                                       Antimicrobial Surveillance Program (1999)
5761    S        Yang S et al          Journal of Antimicrobial Chemotherapy                  2003   Special Data   Antibiotics           Public
                                                                                                     Requirements
5708    S        Kaye K & Kaye D       Multidrug-resistant pathogens: mechanisms of           2000   Special Data   Antibiotics           Public
                                       resistance and epidemiology.                                  Requirements
5762    S        Yunis A               Comparative toxicity of chloramphenicol and            1981   Special Data   Antibiotics           Public
                                       thiamphenicol with particular reference to                    Requirements
                                       aplastic anemia.
5700    S        Guerra B et al        Characterization of a self-transferable plasmid        2002   Special Data   Antibiotics           Public
                                       from Salmonella enterica serotype Typhimurium                 Requirements
                                       clinical isolates carrying two integron-borne
                                       gene cassettes together with virulence and drug
                                       resistance genes.
5668    S        Aarestrup F et al     Antimicrobial susceptibility of Haemophilus            2004   Special Data   Antibiotics           Public
                                       parasuis and Histophilus somni from pigs and                  Requirements
                                       cattle in Denmark
5684    S        Butaye P et al        Mobile genes coding for efflux-mediated                2003   Special Data   Antibiotics           Public
                                       antimicrobial resistance in Gram-positive and                 Requirements
                                       Gram-negative bacteria.
5763    S        Yunis A               Chloramphenicol: relation of structure to activity     1988   Special Data   Antibiotics           Public
                                       and toxicity.                                                 Requirements
5655    S        Anon                  EAGAR Resistance Risk Assessment - Nuflor              2002   Special Data   Antibiotics           Applicant
                                       Oral for Pigs                                                 Requirements




* S = Data submitted with the application
  I = Data inherited (that is, referenced) from another application




38049                                                                             Page 13 of 13                                   KP25S_F39 Version: 2 Issued: 14/08/2007

				
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