Veterinary Pharmaceuticals

By Craig Kohn, Waterford, WIBased on Kirkhams Animal Health Management.Veterinary Pharmaceuticals 1DrugsDrugs used by veterinarians and producers may be classified in one of two categories:1. Pharmaceuticals: mainly used for the treatment of a disease or infection (this week)2. Biologicals: used to prevent a disease (next week)Both are necessary for proper management of herd health.Pharmaceuticals should only be used for their approved and intended purposes. Use of a pharmaceutical in a way not intended by a producer is called off-label usage A licensed medical professional can prescribe a use of a pharmaceutical in a way not originally intended; this is call extra-label usage 2PharmaceuticalsPharmaceuticals are very specific in their action and effectivenessA pharmaceutical should never be used without a solid diagnosis that requires that particular treatmentPharmaceuticals can come in a variety of forms, including:DrenchesBolusesLiquids Feed AdditivesPowders

3Pharmaceuticals: In GeneralFor a pharmaceutical to work, a sufficient dosage level must be reached and maintained for a specific length of timeThe route of administration, dosage, and frequency of dosage are all important factors in sustaining an adequate dosage level for fighting a diseaseThe ideal pharmaceutical shouldHave selective and effective antimicrobial activityShould kill bacteria, not just slow its growthShould not cause the buildup of microbial resistanceShould reach a dosage level quickly and maintain it4Drug ResistanceIn some cases, not all the bacteria that caused the original infection are destroyed by the pharmaceutical; this can lead to drug resistance.Resistance: when a pharmaceutical becomes ineffective against its intended pathogen due to overuse, abuse, or inappropriate use. Resistance is where the surviving bacteria pass on genes for invulnerability to a drug when they divide into daughter cells or interact with other bacterial cells. The drug that was used to treat this infection is now ineffective against the new strain of bacteria and does not kill it. Why does this occur?5Bacterial GeneticsThe bacterial chromosome is a double stranded DNA molecule that forms a loop (like a donut)Because bacteria lack a nucleus, they are more susceptible to mutation, or a change, deletion, or addition of nucleotidesUsually mutations are very bad, but very rarely a beneficial mutation can arise that gives that particular bacterial cell an advantage in its environmentA mutation could cause a Chromosomal Resistance

6Bacterial Genetic TransferPharmaceutical resistance is more likely to occur when a beneficial mutation is transferred from one bacterial cell to another via plasmidsI.e. Plasmid ResistanceIn order for plasmid resistance to occur, genes must be transferred from one cell to anotherBacteria are able to exchange genes in one of 4 ways:1. transformation2. transduction3. conjugation4. transposon insertion 7

Transformation Transformation occurs when DNA fragments from one bacterium (released when the cell is lysed) are absorbed by other bacterial cellsThe absorbed DNA can then be incorporated into the recipient bacterial cells DNA This can only occur if the DNA of the recipient bacteria is very similar to the donor bacteriaThis is why transformation usually only occurs among bacteria of the same species8

TransductionTransduction occurs when a virus that infects bacteria (bacteriophages) carry DNA from one bacterial cell to another. Again a virus is a crystalline-protein structure that surrounds a molecule of DNA or RNA; it is not alive and reproduces by hijacking other cells Some bacterial cells have repressors that stop the action of a bacteriophageIn the process of fighting these viruses, the bacterial genes may become replicated and released with the virus particlesThe virus particles, when infecting other cells, may release these genes.9

ConjugationConjugation = Bacterial SexIn conjugation, DNA is transferred by cell-to-cell contactFor conjugation to occur, a bacterium must have a plasmid that lies outside of its regular chromosomesWe call these F-plasmidsCells with F-plasmids are called F(+) DonorsCells without the plasmids that receive are called F(-) Recipients

10Bacterial PenisesThe F-plasmid has genes that encode for proteins that form the microbial equivalent of a penis on the cells surfaceWhen a F(+) donor wishes to, ahem, donate it activates these proteins which forms a sex pilus on its surface.Sex pilus = microbial penisThe sex pilus forms a bridge between the two cells, and the F(+) cell donates a F-plasmid strand potentially carrying the genes for pharmaceutical resistanceBecause the F-plasmid is double stranded, each cell gets one strandThe single strand must again be doubled, but each cell now has these genesF-plasmids are responsible for actions such as creating enzymes that degrade penicillin or the release of certain exotoxins

11TransposonsTransposons are the equivalent of DNA with legsTransposons are also known as jumping genesThey have special sequences that enable themselves to be inserted anywhere in a bacterial genomeTransposons are not plasmids and cannot reproduce on their own; transposons can only jump into new genomesOnce they insert themselves into a plasmid, they can be spread via conjugation.

12Antibiotic Resistance Mechanisms Decrease Cell Wall Uptake / PermE.g. Gram Negative cells are mostly impermeable to chemical attack by antibiotics Efflux PumpsSome bacterial cells literally pump the chemical out of their cellFound in both Gram Positive and NegativeDeactivating Enzymes (e.g. Penicillin Binding Protein)The cells produce enzymes the inactivate/degrade the antibiotic Altered Target Binding SitesThe antibiotic binds to a non-critical portion of the cellIts activity is limited by this binding Ribosome macrolides, lincosamidesWall Protein beta-lactams, glycopeptidesDNA fluoroquinolones Slide courtesy of the Great Plains Vet Education Center13

Slide courtesy of the L. Dyner, MD, Standford University 14Factors that Promote ResistanceExposure to lower levels of antimicrobials than prescribedExposure to broad-spectrum antibiotics (which arent specific to a microbe)Exposure to microbes carrying resistant genesLack of hygiene in clinical environmentsOveruse of antibiotics in foods/agricultureInappropriate antimicrobial use, including:Prescriptions not used/taken for a total duration of therapyAntibiotics for viral infectionsAntibiotics sold without medical supervision15

Slide courtesy of the L. Dyner, MD, Standford University 16.Types of Pharmceuticals17AntibioticsThe word antibiotic means against lifeIn the case of veterinary medicine it means against bacteriaSome antibiotics are specific in killing only a certain strain of bacteriaOthers are effective against a wide range of bacteriaThese are called broad spectrum antibioticsExamples of antibiotics:PenicillinTetracyclinesNeomycin

18AntibioticsAntibiotics are chemical substances that kill bacterial cells by interrupting a key cellular functionThey originally came from fungi (molds)They have no effect on viral diseases Different bacteria often require different antibiotics

19Antibiotic MechanismsThere are 4 mechanisms that can make an antibiotic effective:Breached bacterial cell wallsBacterial cells need their cell walls to be protected from their environmentInterruption of protein manufacturing (ribosomes)When the ribosomal function is impaired, proteins cannot be produced by the bacterial cellDisrupted metabolic processesFor example, bacterial cells need to produce folic acid to surviveThis class of antibiotics prevents this from occurringBlocked DNA / RNA synthesisDNA in a cell must continuously be replicated and transcripted (copied) into RNA for translation Without instructions from its DNA or RNA, a cell cannot function and will shutdown20Antimicrobial groups approved for cattle:Antibiotic ClassAntibiotic Within ClassResistanceMechanismLipid Solubility~ Protein Binding %AminocyclitolsSpectinomycinPSLowLowAminoglycosidesGentamicin, NeomycinPSLow20-25%Beta-lactamsPenicillin G, Ampicillin, CeftiofurCWLowP&A 20, Cef 80+ Chloramphenicol derivativesFlorfenicolPSHigh60FluoroquinolonesEnrofloxacin, DanofloxacinGRHighLowLincosamidesLincomycinPSHigh55-75MacrolidesErythromycin, Tilmicosin, TylosinPSHigh70-80SulfonamidesSulfa - dimethoxine, methazine, chlorpyridazineMPLowSM 70, SDM 80-85TetracyclinesOxytetracycline, ChlortetracyclinePSIntermediateOTC 20-25, CTC 65CWcrippling production of the bacterial cell wall that protects the cell from the external environment PSinterfering with protein synthesis by binding to the machinery that builds proteins, amino acid by amino acid MPwreaking havoc with metabolic processes, such as the synthesis of folic acid, that bacteria need to thrive GRblocking genetic replication by interfering with synthesis of DNA and RNASlide courtesy of the Great Plains Vet Education Center21Sulfa CompoundsSulfa-based drugs work by preventing the reproduction of bacteria, allowing the hosts immune system to get a fighting chanceSulfa drugs are considered broad-spectrum treatments they work against a variety of bacterial speciesBacterial resistance is a big problem with this class of drugWater intake must be increased in treated animalsToxicity can be a problem with prolonged use

22NitrofuransThese are broad-spectrum drugs that inhibit the growth of pathogenic bacteriaThey are very effective in digestive infectionsThey also have low toxicity These are an effective treatment in many ear, skin, eye, and genital infections

23SteroidsSteroids are commonly used to reduce inflammationRemember septic shock?However, steroids can also compromise the function of the immune systemSteroid-use is complex and should only be used under the careful watch of a veterinarian24