crippling production of the bacterial cell wall that protects the cell from the external environment PS

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1 Antibiotic Selection and Use in Cattle Dee Griffin DVM MS, Texas A&M Veterinary Medical Center, Canyon, TX Antibiotic use in food animals is increasingly scrutinized Much of the world s antibiotic resistance concerns are being laid at the door step of food animals The Center for Disease Control (CDC) started the National Antibiotic Resistance Monitoring System (NARMS) in 1996 Thousands of samples are collected from hundreds of laboratories Much of the antibiotic resistance focus is on coliforms such as E coli, Salmonella sp and Campylobacter jejuni which could potentially be transferred through fecal contamination of food from animal origin We have a great responsibility to thoughtfully and responsibly select and use antibiotics This especially applies to food animal practitioners and as a cattle practitioner, a personal mission has become to understand to the best of my ability how to step beyond the pharmacodynamic (PD) S-I-R (sensitive, intermediate or resistance) reporting to include applying pharmacokinetic (PK) properties of antibiotics (and other medications) in my treatment protocol development I will attempt to condense the use of PK concepts as related to meeting PD requirements in protocols in the remainder of this paper by summarizing these in tables and graphic images The following tables outline the key PK elements to consider: Antibiotic Mechanisms of Actions CW crippling production of the bacterial cell wall that protects the cell from the external environment PS interfering with protein synthesis by binding to the machinery that builds proteins, amino acid by amino acid MP wreaking havoc with metabolic processes, such as the synthesis of folic acid, that bacteria need to thrive GR blocking genetic replication by interfering with synthesis of DNA and RNA Antimicrobial Groups Approved or Legally Available for Cattle: Antibiotic Class Mechanism Example Antibiotics Within Class Aminocoumarins GR Novobiocin / Albamycin Aminocyclitols PS Spectinomycin Aminoglycosides PS Gentamicin, Neomycin, Dihydrostreptomycin, Beta-lactams CW Ampicillin, Ceftiofur, Cephapirin, Cloxicillin, Hetacillin, Penicillin G Phenicols PS Florfenicol Fluoroquinolones GR Enrofloxacin, Danofloxacin Lincosamides PS Lincomycin, Pirlimycin Macrolides PS Gamithromycin, Tildipirosin, Tilmicosin, Tulathromycin, Tylosin Sulfonamides MP Sulfachloropyridazine, Sulfadimethoxine, Sulfamethazine, Streptogramins PS Virginiamycin Tetracyclines PS Oxytetracycline, Chlortetracycline The following table outlines the efficacy predictive relationship between PK and PD

2 PK / PD Relationships (Go tohttp://wwwaavptorg for more information) PK to PD Predictive Relationships Antibiotic Class Antibiotic Examples Time (50%) > MIC Beta-lactams Ampicillin, Amoxicillin, Ceftiofur, PenG Time (50 to 100%) > MIC Time (100%)> MIC Peak or Cmax (10x) / MIC AUC/MIC (>100 x = efficacy) Cmax/MIC (< 4 to 8 x = resistance) AUC/MIC (>100 x) No Information Available PK/PD relationship is not predictive Macrolides Phenol, Lincosa, Tetracy, Sulfas Erythromycin, Lincomycin, Tilmicosin, Tylosin Florfenicol, Lincomycin, Oxytetracycline, Sulfas Aminoglycosides Gentamicin, Neomycin Fluoroquinolones Danofloxacin, Enrofloxacin Macrolides Aminocyclitols Tulathromycin, Gamithromycin, Tildipirosin Spectinomycin In appropriate selection and/or dosing, either medication level or delivery frequency, can lead to rapid development of resistance See the graphic below The graphic above illustrates the outcome when an antibiotic is dosed below an MIC needed to deal with resistant organisms, or is dosed at a frequency that allows the medication concentration to fall below the effective MIC before a subsequent dose An example can be found in the CDC s discussion of Community Acquired Pneumonia management in the elderly

3 The graphic below illustrates the concept proposed by W Craig for dosing concentration dependent antibiotics by using the relationship between the Area Under the Curve (AUC) to the MIC90 Craig s proposal that dosing indexes would remain above the MIC for sufficient amount of time if the ratio of the AUC to the MIC90 was greater than 125 This has become known as the AU-MIC and is accepted in the medical community See: Craig, W, Pharmacokinetic/pharmacodynamic parameters; rational antibiotic dosing Clin Infect Dis 26;1-12, 1998 Jumbe N Applications of mathematical model to prevent ab resist pop amp J Clin Invest 112(2) , 2003 It is important to remember that only unbound antibiotics moves between compartments and have antibacterial activity Therefore, when evaluating medication concentrations (Cmax for example), consider the unbound level of drug available from your protocol

4 PK information of a number of cattle antibiotics are listed in the table below Abbreviations used are explained below the table A few key observations: 1) Polyflex T½ dictates >4 times a day dosing, 2) Naxcel T½ suggests it s a superior long acting BRD drugthan LA 200, 3) CTC & Sulfas Cmax is >1/10 th BRD MIC90 Key Cattle Antibiotic Pharmacodynamic and Pharmacokinetic Parameters Generic Name ACT LS Vd TM CM AUC T½ Dose PB % MIC90 Mh MIC90 Pm WD Ampicillin (Polyflex) C L L * 10 * Ceftiofur Na (Naxcel) C L L (02) tt 003 (02) tt 4 Ceftiofur cryst acid (Excede) C L L (02) tt 003 (02) tt 13 Chlortetracycline (feed) CTC S M M Danofloxacin ** (Advocin) C M? H Enrofloxacin ** (Baytril) C M H Florfenicol (Nuflor/Gold) S H H /44 Gentamicin and Neomycin It is stupid to inject either of these the withdrawal is over 2 yrs Oxytetracycline (LA)*** S M M PenG, Benzathine (LA Pen) C L L * 17 * 60 10k >180? PenG, Procaine C L L * 34 * 52 10k ~28? 16 8 >60? Sulfa-diamethoxine(IV) S L L * 64 * Sulfa-diamethoxine (oral) S L L * 89 * Sulfa-methazine S L L * 16 * Tildipirosin (Zuprevo) S H H L24 L35 to % Tilmicosin(LungCM) 1(9) S H H 14 Pulmotil/Micotil x2 8 ~24 45x2 ~17? /42 Tulathromycin (Draxxin) * H H L24 +/-4 L12k L * No available data ** Not AMDUCA approved ELDU or BQA *** LA = long acting formulations designed for >72 hrs PTI ACT: action listed as either (C) cidal or (S) static LS: lipid soluble (L = Low, M = Moderate, H = High) Vd: Volume of distribution (L = <05, M = 05-10, H = > 10) see LS Dose: refers to typical dose (mg/lb body weight) and is listed as the maximum label approval

5 TM: 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, T½ Life: Half-life in hours (T½) MIC listings are all for concentrations greater than the values listed as MIC 90% wwwvadsorg tt therapeutic threshold Ref: Dx lab data, Iowa State University for 90% of isolates, FDA NADA FOI, &ShryockJVetDiag 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 Thoughtful, responsible use is not only our business, our future depends on it