Antibiotic Selection and Use - University of Nebraska ...



Antimicrobial groups approved for cattle:(See for more information)Antibiotic ClassMechanismAntibiotic Within ClassAminocoumarinsGRNovobiocin / AlbamycinAminocyclitolsPSSpectinomycinAminoglycosidesPSGentamicin, Neomycin, Dihydrostreptomycin Beta-lactamsCWAmoxicillin, Ampicillin, Ceftiofur, cephapirin, cloxicillin, Hetacillin, Penicillin GPhenicols PSFlorfenicolFluoroquinolonesGREnrofloxacin, DanofloxacinLincosamidesPSLincomycin, PirlimycinMacrolidesPSErythromycin, Gamithromycin, Tildipirosin, Tilmicosin, Tulathromycin, TylosinSulfonamidesMPSulfachloropyridazine, Sulfadimethoxine, Sulfamethazine, StreptograminsPSVirginiamycinTetracyclinesPSOxytetracycline, ChlortetracyclineAntibiotic Mechanisms: Conjugation & MutationCWcrippling production of the bacterial cell wall that protects the cell from the external environmentPSinterfering with protein synthesis by binding to the machinery that builds proteins, amino acid by amino acidMPwreaking havoc with metabolic processes, such as the synthesis of folic acid, that bacteria need to thriveGRblocking genetic replication by interfering with synthesis of DNA and RNAAntibiotic Resistance MechanismsDecrease Cell Wall Uptake / Perm: ?AminoglycosidesEfflux: ?Macrolides, fluoroquinolones, tetracyclinesEnzymes Induced: ?Aminoglycosides, florfenicol, beta-lactamsAltered Target Binding Sites: ?Ribosome …macrolides, Lincosamides ?Wall Protein … beta-lactams, glycopeptides ?DNA … fluoroquinolones Gene Resistance: ?Plasmids (b-lact, tetra, macro, linco, fluro, sulfa), ?Transposons (b-lactams, glycopeptides), ?Chromosome (b-lactams, FQs)PK / PD Relationships (See for more information)PK to PD Predictive RelationshipsAntibiotic ClassExamplesT (50%) > MICBeta-lactamsAmpicillin, Amoxicillin, Ceftiofur, PenGT (50 to 100%) > MICMacrolidesErythromycin, Lincomycin, Tilmicosin?, TylosinT (100%) > MICPhenol, Lincosa, Tetracy, SulfasFlorfenicol, Lincomycin, Oxytetracycline, SulfasPeak or Cmax (10x) / MICAminoglycosidesGentamicin, NeomycinAUC/MIC (>100 x = efficacy) Cmax/MIC (< 4 to 8 x = resistance)FluoroquinolonesDanofloxacin, EnrofloxacinAUC/MIC (>100 x)MacrolidesTulathromycin, Gamithromycin, Tildipirosin No Information Available … PK/PD not predictive AminocyclitolsSpectinomycin59753546189900059753566040001524001352550037465031750041910012065Craig, W, Pharmacokinetic/pharmacodynamic parameters; rational antibiotic dosing. Clin Infect Dis 26;1-12, 1998Jumbe N. Applications of mathematical model to prevent ab. resist. pop. amp. J Clin Invest 112(2)275-285, 200300Craig, W, Pharmacokinetic/pharmacodynamic parameters; rational antibiotic dosing. Clin Infect Dis 26;1-12, 1998Jumbe N. Applications of mathematical model to prevent ab. resist. pop. amp. J Clin Invest 112(2)275-285, 2003center1270000center1435100051689000063500405828500Key Cattle Antibiotic Pharmacodynamic and Pharmacokinetic ParametersGeneric NameNADA#PK/PDACTLSVdTMCMAUCT?DosePB %MIC90 MhMIC90 PmMIC90 HsWDAmpicillin (Polyflex)055-030T>MICCLL*10*1.210< 10320.250.256Ceftiofur Na (Naxcel)140-338T>MICCLL1.21411510180-900.03 (0.2)tt0.03 (0.2)tt0.03 (0.2)tt4Ceftiofur HCl (Excenel)140-890T>MICCLL2.51116012180-900.03 (0.2)tt0.03 (0.2)tt0.03 (0.2)tt3Ceftiofur cryst acid (Excede)141-209T>MICCLL196.437650380-900.03 (0.2)tt0.03 (0.2)tt0.03 (0.2)tt13Chlortetracycline (feed) CTC048-761T>MICSMM10.20.4+4.315.71047-544420Danofloxacin ** (Advocin)141-207AUC/MICCM?H3.21.394.52.740-500.060.020.064Enrofloxacin ** (Baytril)141-068AUC/MICCMH5.81.8196.45.754-610.060.030.0328Florfenicol (Nuflor/Gold)141-063T>MICSHH5.35.47118.31815-20110.538/44Gamithromycin (Zactran)141-328AUC/MIC*HH1~0.5189.25160750.890.42.726110.535Gentamicin ** Do Not Inject101-862CMax/MICCHL*<8*21~30?8416>730?Neomycin ** Do Not Inject200-113CMax/MICCLL*10*2.52~45646464>730?Oxytetracycline (LA)***ManyT>MICSMM1.83.67221918-2288836Oxytetracycline (feed)008-804T>MICSMM20.16491018-228880Pen G, Benzathine (LA Pen)ManyT>MICCLL*1.7*6010k2816816>180?Pen G, Procaine ManyT>MICCLL*3.4*5.210k~28?16816>60?Spectinomycin (Adspec)141-077?SLL120771.85.5~696969611Sulfa-diamethoxine (IV) Albon041-245T>MICSLL*64*13.12575-853503503505Sulfa-diamethoxine (oral)093-107T>MICSLL*8.9*13.162.575-8535035035021Sulfa-methazine140-270T>MICSLL*16*12.920075-8535035035012Tildipirosin (Zuprevo)141-334T>MICSHH1.84L240.7L3.521to3321025%21421Tilmicosin(LungCM)PulT/MicT140-929T>MICSHH1.41(9)x28~244.5x2~17?1632828/42Tulathromycin (Draxxin)141-244AUC/MIC*HH0.25L243.8+/-.416.7L1.2k90L1851.14021418Tylosin (Tylan 200)012-965T>MICSHH1.34.72924833-4432321628* No available data ** Not AMDUCA approved ELDU or BQA *** LA = long acting formulations designed for >72 hrs PTIACT: action listed as either (C) cidal or (S) static LS: lipid soluble (L = Low, M = Moderate, H = High)Vd: Volume of distribution (L = <0.5, M = 0.5-1.0, H = > 1.0) see LSDose: refers to typical dose (mg/lb body weight) and is listed as the maximum label approvalTM: TMAX- Time corresponding to concentration maximum CM: Cmax=Peak ppm concentrations (ppm=ug/Ml)AUC: Area Under the Curve (mcg x hr / ml) T: Time, T? Life: Half-life in hours (T?)MIC listings are all for concentrations greater than the values listed as MIC 90% http:// tt therapeutic thresholdRef: Dx lab data, Iowa State University 2000-2003 for 90% of isolates, FDA NADA FOI, & Shryock J Vet Diag Invest 8:337 (96)WD: withdrawal days before marketing for food. The longest label WD is listed. ? is estimate from FARAD information. AMDUCA ELDU requires the adjustment so that no violative residues would be detected. ? = WD adjustments of antibiotics for which ELDU has been practiced. NOTE: Use the PHARMACOKINETICS, PHARMACODYNAMICS, & MIC information only as a starting guide. Therapeutic regimen management requires response monitoring through accurate case definition, protocol adherence, record examination and outcome follow-up. Additional Info from Http: & (WD) Table for Common Cattle Animal Health ProductsAll WD times must be figured from the last day of treatment and for the longest WD of the list of products used. If multiple doses of a product designed for a single dose usage is given the WD time should be the sum of the WD days for each administration. Example; Consider an antibiotic intended for a single application that has a 13 day WD. If a 2nd dose is given 6 days after the 1st dose, the WD would be (13 - 6) + (13) = 20 days from the last injection. This WD estimate is very conservative.Giving greater than 10 CC per IM site will increase the potential for a violative residue.Off label use of non-feed medications requires as veterinary prescription and the withdrawal time must be extended to insure no violative residues will be found. Generally, the extended withdrawal a veterinarian may assign will be at least an additional 60 days above the label withdrawal. Off label use of feed additives violates federal law and is strictly forbidden.Animal Health Product NA = Not ApprovedWithdrawalAnimal Health Product NA = Not Approved WithdrawalMilk (hrs)Meat (days)Milk (hrs)Meat (days)All Non-Oil Adjuvant Vaccines 021AdspecNA11Oil Adjuvant Vaccines060AdvocinNA4Albon Injectable & Albon SR boluses60 / NA5 / 21All Growth Promotant Implants NA0Amoxi-inject9625Lutalyse (IM only in the neck)00Aureomycin (10mg/lb BW up to 5 days)NA10MGA and OptaflexxNA0Baytril 100NA28Zilmax NA3Bio-Mycin 2009628DraxxinNA18Antihistamine 244Excede (ear route of administration)013Banamine (Flunixin), Avoid IM, SubQ 10 days36IV = 4Excenel RTU03Steroids ( Azium or Predef )00 or 7GamithromycinNA35Therabloat 00Gentamicin (Never Inject) … 2 + years withdrawal !!!NA2+YrsVit A,D,E,K & B complex (5 cc/site)00Liquamycin LA 2009628Micotil 300NA28/42Corid (coccidia oral drench)NA1Naxcel04Curatrem (fluke oral drench)NA8Neomycin, ONLY ORAL, Never InjectNA1Cydectin (pour on)00Nuflor Gold / Resflor GoldNA44 / 38Cydectin (injectable)NA21Polyflex486Dectomax (pour on)NA45Penicillin G, Procaine … (ELDU “Off-Label” ~ 60+days)4810Dectomax (injectable)NA35Penicillin G, Benzathine (Long Acting)…(off label 180+)NA30Eprinex (pour on)00SulfamethazineNA12Ivomec (pour on)NA48Terramycin Soluble PowderNA5Ivomec (injectable)NA35Tetradure 300 / Noromycin 300NA28Ivomec Plus (Injectable)NA49Tylan 200NA21Levasole (injectable)NA7VetisulidNA7Levasole (oral)NA2Co-Ral 00Safeguard (oral)08Atroban, Boss, Cylence, Durasect00Syanthic (oral)NA7Saber, Permectrin, Ultra Boss00ValbazenNA27Elector02Spectramast LC720ToDAY / Cefa-Lak964Spectramast DC720+16ToMORROW / Cefa-Dri7242Quarter Master9660Pirsue369Albadry7230Dry-Clox030Biodry720+30Hetacin-K7210 Residue Avoidance StrategyIdentify all animals treated.Record all treatments: Date; animal’ ID; dose given; route of administration; person administering treatment; withdrawal time.Strictly follow label directions for product use.Use newer technology antibiotics when possible.Select antibiotics with short WD when equivalent.Never give more than 10 cc per IM injection site.Avoid Extra Label Drug Use (ELDU) of antibiotics.Avoid using multiple antibiotics at the same time.Don’t mix antibiotics in the same syringe.Check ALL medication/treatment records before marketing.Introduction to the PHAST (Pre-Harvest Antibiotic Screening Test)The PHAST is a microbial inhibition test (substances in the urine that inhibit the growth of the test microbe, Bacillus megaterium for the PHAST/FAST). Bacillus megaterium (ATCC 9885) is classified by the USDA among bacteria that are generally accepted as safe (GAAS). The organism will not cause disease in humans or domestic animals. Microbial inhibition tests are indirect assays that are dependent on a residue being passed in the urine in a chemical form that inhibit the growth of the test organism. Because Bacillus megaterium is frequently more sensitive to target antibiotics than the FDA established tolerance for the target antibiotic and because there are a number of microbial inhibition substances that are not antibiotics, false positives are the most common problem with these types of tests. False negatives are thought to be rare, but are dependent on the sensitivity of the test organism to the antibiotic relative to the FDA tolerance to the target antibiotic. Bacillus megaterium is very sensitive to penicillin type antibiotics and intermediate to aminoglycosides and sulfa drugs. The reliability of the PHAST for detecting violative residues in cattle has not been investigated. The most common false positives should be associated with antibiotics, such as Oxytetracycline and Naxcel, which has an established FDA tolerance level above the level detectable in the kidney or cleared in the urine. Specific Bacillus megaterium sensitivities to commonly used antimicrobials and their relationship to FDA tolerance are listed in the USDA-FSIS Bioassay Residue Screening Test Evaluation table located at the end of this paper. THE PHAST IS NOT A RELIABLE TEST TO EVALUATE THE RESIDUE STATUS OF AN ANIMAL WHICH HAS NOT MET THE WITHDRAWAL TIME SPECIFIED ON AN ANTIBIOTIC LABEL. Never use the PHAST test to evaluate the residue status of an animal, which has not met the withdrawal time specified on the label of an antibiotic. The PHAST is useful in evaluating cattle that have: undergone prolonged treatment, been treated with multiple antibiotics, and/or have failed to perform normally following therapy or have suspected organ (kidney or liver) damage that might interfere with excretion and elimination of an antibiotic. Avoiding violative residues is dependent on: 1) using FDA approved medications, 2) following label directions when possible, 3) ELDU must have withdrawal times appropriate for the dose, medication and route of administration, 4) not exceeding dose per injection site recommendations, and 5) screening cattle which may not have cleared the antibiotics normally.4114354-571500PHAST TEST OUTLINE: A Muller-Hinton agar plate is streaked to carpet with B. megaterium spores. A sterile swab dipped in urine is placed on the inoculated agar plate along with a neomycin antibiotic sensitivity disc as a positive control. Incubate the test plate containing the test urine swab agar side down at 37° C for 12 to 24 hours. The zone of inhibition for the positive control antibiotic sensitivity disc must be within the limits set for the disc used. If there is any inhibition of bacterial growth around the urine swab the test is considered positive for urine antibiotic residues and the animal should be withheld from marketing (See PHAST Sensitivity Table) JNote: From the USDA-FSIS Domestic Residue Plan “Blue Book” page 10. “beta-lactams (quantitated as penicillin-G; penicillins and cephalosporins are not differentiated within this category). Therefore ceftiofur will be false positive and not differentiated from penicillin. (last publication released 2005) Cattle Antibiotic Residue Tolerance and Detection Estimates for theSTOP (B.sub), FAST / PHAST (B.meg), & Charm KIS/DSM PremiTest (B.stearo)Dee Griffin, UNL-GPVEC, 2009Generic Name NADA#Maximum Residue Limit (MRL) in Cattle Tissues(Previously termed “Tolerance”)B. subDetectB.megDetectB.stearo DetectAmpicillin 055-0300.1ppm edible>0.1 b0.2 a0.005 cAmoxicillin 055-0890.1ppm edible>0.1 b0.2 a0.005 cCeftiofur sodium 140-3380.4 ppm kidney, 1.0 ppm muscle>0.1 b~0.1 b0.1 cCeftiofur hydrochloride 140-8900.4 ppm kidney, 1.0 ppm muscle>0.1 b~0.1 b0.1 cCeftiofur crystalline acid 141-2090.4 ppm kidney, 1.0 ppm muscle>0.1 b~0.1 b0.1 cChlortetracycline (feed) 048-76112.0 ppm kidney, 2.0 ppm muscle>10 b~0.1 b0.05 cDanofloxacin ** 141-2070.2 ppm liver, 0.2 ppm muscle>0.1 b>0.1 b0.6?Dihydrostreptomycin NDC2 ppm kidney, 0.5 ppm edible??3.0Enrofloxacin ** 141-0680.1 ppm liver, 0.1 ppm muscle>0.1 b>0.1 b0.6 cFlorfenicol 141-06312.0 ppm kidney, 3.7 ppm liver>1 b~5.0 b0.1 cGamithromycin141-3280.5 ppm liverGentamicin ** 101-862No residue tolerance>1 b0.13 a0.1 cNeomycin ** 200-1130.25 ppm edible~10 b0.06 a0.3 cOxytetracycline (LA)*** Many12.0 ppm kidney, 2.0 ppm muscle>10 b0.8 a0.05 cPen G, Benzathine Many0.05 ppm edible>0.1 b<0.01 a0.005 cPen G, Procaine Many0.05 ppm edible>0.1 b<0.01 a0.005 cSpectinomycin 141-0774.0 ppm kidney, 0.25 ppm edible>10 b6.2 a1.5 dSulfa-diamethoxine (IV) 041-2450.1 ppm edible>100 b~1 b0.1 cSulfa-diamethoxine (oral) 093-1070.1 ppm edible>100 b~1 b0.1 cSulfa-methazine 140-2700.1 ppm edible>100 b?0.1 cTilmicosin (Lung CM) 140-92914.4 ppm kidney, 1.2 ppm liver>10 b~5.0 b005 cTulathromycin 141-2445.5 ppm liver, 18.0 ppm kidney>0.1 b>0.1 b18?Tylosin 012-9650.2 ppm kidney, 0.2 ppm liver>1 b~5.0 b0.05 cVirginiamycin0.5 ppm distiller’s grains, 0.4 edible pork??2.0False PositiveFalse NegativeU.S. Tolerance: FDA permissible tolerance for the antibiotic in ppm (mg/kg) for target marker tissue listed 21 CFR 556 and CODEX Tolerance (Max. Residue Limits (MRL)) @ FAST (Fast Antibiotic Screening Test), a microbial inhibition test used by USDA-FSIS to screen for antibiotic residues PHAST(Pre-Harvest Antibiotic Screening Test) utilizes the FAST test to screen cattle urine for antibiotic presence B. stearo (Bacillus stearothermophilus var.calidolactis (ATCC 10149) is the microbe used in the Premi-Test and Charm KIS antibiotic screening tests B.meg (Bacillus megaterium, ATCC 9885 ) is the microbe used in the FAST (meat) & PHAST (urine) antibiotic screening tests B.sub (Bacillus subtilis, ATCC 6633) is the microbe used in the STOP (meat) and LAST (urine) antibiotic screening tests a =Korsrud, J Food Protect. 51:1 43-46, 1988. b = Griffin, D.D. Univ of Neb, Great Plains Veterinary Educational Center, PO Box 148, Clay Center, NE 68933. c = Data from FOI provided by Charm Sci (KIS) and DSM (Premi-Test) d = Mohsendadeh,M and Bahrainipour, A., Detection Limits … Pak. J. Biol. Sci. vol 11(num18), pg2282-2285, 2008 USDA-CSREES Grant: WBS # 25-6239-0098-011 (Develop Pre-Harvest Version of the USDA-FSIS Fast Antibiotic Screening Test & Education). NOTE: Use the RESIDUE DETECTION information only as a starting guide. WD (Withdrawal) days listed are the maximum from product labels within product class. ? = FARAD published estimate.A Producers Guide for Judicious Use of Antimicrobials in Cattle (As Adopted by the NCBA, 2001.)Prevent Problems: Emphasize appropriate husbandry and hygiene, routine health examinations, and vaccinations.Select and Use Antibiotics Carefully: Consult with your veterinarian on the selection and use of antibiotics. Have a valid reason to use an antibiotic. Therapeutic alternatives should be considered prior to using antimicrobial therapy. Avoid Using Antibiotics Important In Human Medicine As First Line Therapy: Avoid using as the first antibiotic those medications that are important to treating strategic human or animal infections. Use the Laboratory to Help You Select Antibiotics: Cultures and susceptibility test results should be used to aid in the selection of antimicrobials, whenever possible. Combination Antibiotic Therapy Is Discouraged Unless There Is Clear Evidence The Specific Practice Is Beneficial: Select and dose an antibiotic to affect a cure. Avoid Inappropriate Antibiotic Use: Confine therapeutic antimicrobial use to proven clinical indications, avoiding inappropriate uses such as for viral infections without bacterial complication. Treatment Programs Should Reflect Best Use Principles: Regimens for therapeutic antimicrobial use should be optimized using current pharmacological information and principles. Treat the Fewest Number of Animals Possible: Limit antibiotic use to sick or at risk animals. Treat for the Recommended Time Period: To minimize the potential for bacteria to become resistant to antimicrobials. Avoid Environmental Contamination with Antibiotics: Steps should be taken to minimize antimicrobials reaching the environment through spillage, contaminated ground run off or aerosolization. Keep Records of Antibiotic Use: Accurate records of treatment and outcome should be used to evaluate therapeutic regimens and always follow proper withdrawal times.Follow Label Directions: Follow label instructions and never use antibiotics other than as labeled without a valid veterinary prescription. Extralabel Antibiotic Use Must follow FDA Regulations: Prescriptions, including extra label use of medications must meet the Animal Medicinal Drug Use Clarification Act (AMDUCA) amendments to the Food, Drug, and Cosmetic Act and its regulations. This includes having a valid Veterinary-Client-Relationship. Subtherapeutic Antibiotic Use Is Discouraged: Antibiotic use should be limited to prevent or control disease. ................
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