1. Antimicrobials CHAPTER 10-2 Dr. Dipa Brahmbhatt VMD MpH dbrahmbh@yahoo.com

2. Objectives Mechanisms of action of antibiotics Adverse drug reactions and how to mitigate these Selection of antibiotics: Ab resistance, drug absorption, distribution, location of bacteria and drug elimination Antifungal drugs: Advantages, Disadvantages and side effects

4. Cell Wall Agents Bacitracin Bacitracin – Disrupts the bacterial cell wall and is effective against gram-positive bacteria – Used topically (skin, mucous membranes, eyes) and as a feed additive – Nephrotoxic Vancomycin Vancomycin – Bacteriocidal; effective against many gram- positive bacteria; used for resistant infections – Useful in treatment of Staphylococcus aureus

5. Cell Membrane Agents Polymyxin B Polymyxin B – Works by attacking the cell membrane of bacteria (remember that animal cells have cell membranes too) – Is a narrow-spectrum, gram- positive antibiotic Not absorbed when taken orally or applied topically Used as an ointment or wet dressing – Often combined with neomycin and bacitracin = triple ABX ointment

7. Protein Synthesis Agents Aminoglycosides Aminoglycosides – Interfere with the production of protein in bacterial cells – Are a specialized group of antibiotics with a broad spectrum of activity, used for gram-negative bacteria. Pneumonia – Aerobic bacteria, bactericidal – Are not absorbed well from the GI tract, so are given parenterally – Suffix –micin or –mycin (but are not the only group to use these suffixes e.g. clindamycin, erthromycin) – T1/2 = 2-5 hours still SID for safety – Penicillin's (cell wall) will enhance their activity – Cross resistance not as common as penicillins

8. Protein Synthesis Agents Aminoglycosides Aminoglycosides – Pharmacokinetics – Hydrophilic mostly parenterally – Well absorbed in GI through neonates, haemorrhagic, necrotic intestine – Well absorbed locally if skin is denuded/ abraded – Parenterally > ECF: volume of distribution is larger in neonates/ young animals > low drug conc. Most diluted in ECF – Not good for brain/ eye infections systematically – Accumulate: bronchioles, kidneys, inner ear, cross placenta – Eliminated in Kidney – Not effective with cellular debri e.g pus, dirt, fecal material, anaerobic conditions: deep wounds, abscess

9. Protein Synthesis Agents Aminoglycosides Aminoglycosides – Side effects are nephrotoxicity and Ototoxicity: cats sensitive, vestibular signs; circling, head tilt, nystagmus – Increase dosage interval for safety – Monitor: BUN and serum creatine (70-75% kidney damage), urine sediment, urine SPG – Early signs: casts or increased protein - urine – Examples include gentamicin, neomycin, amikacin, streptomycin, kanamycin, netilmicin, tobramycin, and dihydrostreptomycin – Don’t use in pregnant animals, geriatric patients, dehydration, shock or kidney disease – NOT approved for use in food-producing animals. Granular casts

10. Protein Synthesis Agents Tetracyclines ( Tetracyclines ( Oral and parenteral forms) – Are a group of bacteriostatic antibiotics with a broad spectrum Ab. – Rickettsial agents: Treats Lyme disease (borreliosis), Ehrlichia - dogs, Hemobartonella – dogs/ cats, RMSF – Salmon poisoning – dogs – Mycoplasma pneumonia – Chlamydial infections: ocular infections – feline – Psittacosis – birds – Epiphora: canine? – Are recognized by –cycline suffix – Examples include – Older tetracyclines: hydrophilic - tetracycline, oxytetracycline – Newer tetracyclines: lipophilic - chlortetracycline, doxycycline, and minocycline. Longer t1/2, more broad spectrum, better penetration

11. Protein Synthesis Agents Tetracyclines: Don’t use with penicillins/ cephalosporins Tetracyclines: Don’t use with penicillins/ cephalosporins Pharmacokinetics Pharmacokinetics Doxy/minocycline: lipophilic better oral absorption Only 20% not absorbed with chelators, not significant Penetrate brain, eye and prostate better than older drugs Doxycycline uses: CNS signs related to Lyme disease/ excreted in GI hence ok to use in kidney cases. GIVE WITH FOOD IV Doxycycline: DON’T GIVE TO HORSES, cardiac arrhythmias, collapse, death Oxt/tetracycline: hydrophilic. Expired products > FANCONI syndrome (glycosuria) Readily chelated (bound and ppt. out of solution) by minerals with divalent cations Ca ++, Mg ++, Fe ++, Cu ++ If given with milk products, antacids (Mg ++ ), Fe ++ supplementation, andidiarrheal: kaolin/ pectin, bismuth subsalicylate (Pepto-Bismal): chelate drug in GI and drug is not absorbed Oxytetracycline: IM – LA 200 q 2-3 days Tetracycline: PO – SE: superinfection, v/d, anorexia. Cat’s tolerate this less: fever, depression, abdominal pain Excreted mostly by kidney than liver Young animals: chelate Ca ++ yellow, mottled teeth also combine with Ca ++ and slow bone development

12. Protein Synthesis Agents Chloramphenicol: bacteriostatic Chloramphenicol: bacteriostatic – Is a broad-spectrum antibiotic that penetrates tissues and fluids well (including the prostate, eyes and CNS) and rickettsiae – Has toxic side effects (bone marrow depression: myelosuppression) that extremely limit use: aplastic anemia – human – In cats kidney function is essential to use this drug – Use caution when handling this product – Chloramphenicol is the only drug in this category – Also available in ophthalmic solution – Banned from use in food-producing animals. – Don’t use in pregnant animals and use with caution in neonate kittens – Concurrent use with phenobarbital and primidone will make them toxic in the body – Not considered a first-line drug

13. Protein Synthesis Agents Florfenicol (Nuflor®): Newer. Bacteriostatic Florfenicol (Nuflor®): Newer. Bacteriostatic – Is a synthetic, broad-spectrum antibiotic – Injectable solution – Used to treat bovine respiratory disease complex (shipping fever)and foot rot. – 2 injections: IM every 48 hrs. apart – Drug withdrawal: 28 days – Side effects include local tissue reaction (possible loss of tissue at slaughter), in appetence, decreased water consumption, and diarrhea – Florfenicol is the only drug in this category – Don’t use in breeding animals

14. Protein Synthesis Agents Macrolides Macrolides – Interfere with the production of protein in bacterial cells – Are broad-spectrum antibiotics that have a large molecular structure. Don’t penetrate CNS. – Used to treat penicillin-resistant infections or in animals that have allergic reactions to penicillins – May cause stomach upset in animals Erythromycin (oral or ointment): In foals – respiratory disease can get superinfection hence add probiotics. Label – foal Rhodococcus Equi. In adult horses and ruminants (oral): diarrhea Tylosin (used mainly in livestock even though labeled by dogs/cats - can cause fatal diarrhea in horses) Tilmicosin (Micotil: SQ: used to treat bovine respiratory disease – single injection). Can cause death IV and irritating IM. Toxic: horses, primates, swine, humans (farmers who inject themselves accidentally or in the eyes) Azithromycin (Human drug: Zithromax): Mycoplasma - FRDC SE: Intestinal cramping, abdominal pain, diarrhea, suprainfection (erythromycin and Azithromycin)

15. Protein Synthesis Agents Lincosamides: -cidal/static Lincosamides: -cidal/static – Interfere with the production of protein in bacterial cells – Are narrow-spectrum, gram-positive aerobic cocci antibiotics e.g. Staphylococcus aureus – Side effects include GI problems Veterinarians typically use erythromycin instead. – Examples – Clindamycin (Antirobe): Label – dogs. Anaerobic bacteria, deep pyoderma, abscess, dental infections, bite wounds, osteomyelitis – Pirlimycin (Pirsue): 36 hrs - milk; 28 days - meat – Lincomycin: Label – dogs, cats, swine, poultry – DON’T USE rabbits, hamsters, guinea pigs, horses, ruminants: severe GI effects and also death – SE: v/d and bloody diarrhea – Nursing kittens/ pups: DIARRHEA – With Kaopectate (antidiarrheal) cannot absorb drug: hence give lincomycin first than 2 hours later antidiarrheal.

17. Nucleic Acid Agents Fluoroquinolones/ Quinolones: -cidal Fluoroquinolones/ Quinolones: -cidal – Are antibiotics with fluorine bound to the quinolone base, which increases the drug’s potency, spectrum of activity, and absorption – Disrupt DNA gyrase of bacteria – Are broad-spectrum antibiotics (gram + and gram -): Staphylococcus, Pseudomonas (better than Gentamicin), Klebsiella, Escheria coli, Salmonella spp. DON’T use for Streptococcus spp. Or anaerobes – –floxacin suffix – Examples – Enrofloxacin (Baytril): 1 st. Label: dog/cat. 5mg/kg – Ciprofloxacin: Label – human. – Marbofloxacin (Zeniquin). Label: dog/cat – Orbifloxacin (Orbax). Label: dog/cat – Difloxacin (Dicural) – Sarafloxacin (Saraflox). Label – poultry, REMOVED – Nalidixic acid (older) and norfloxacin (human): not often used in vet medicine

19. Nucleic Acid Agents Fluoroquinolones/ Quinolones: -cidal Fluoroquinolones/ Quinolones: -cidal Pharmacokinetics Pharmacokinetics Effectively absorbed from GI tract dogs/cats Effectively absorbed from GI tract dogs/cats Uses: severe skin infections (pyoderma), respiratory tract, urinary tract, prostate infections Uses: severe skin infections (pyoderma), respiratory tract, urinary tract, prostate infections Extralabel use in horses: caution in foals Extralabel use in horses: caution in foals Avoid with antacids and sucralfate or give 4 hours later Avoid with antacids and sucralfate or give 4 hours later They can exacerbate seizures They can exacerbate seizures – SE: – bubble-like cartilage lesions in growing dogs (X5 times higher dosage): contraindicated in small/medium size dogs of 2-8 months age Large breeds: 12 months; giant breeds: 18 months – Crystalluria – Quinolone-induced blindness in cats (>20mg/kg). – Indiscriminate use may result in bacterial resistance: Staphylococcus and Pseudomonas spp. Hence reserve for severe infections – Can’t use in food animals

21. Antimetabolites Sulfonamides and Potentiated sulfonamides: -static/cidal Sulfonamides and Potentiated sulfonamides: -static/cidal – Are broad-spectrum antibiotics that inhibit the synthesis of folic acid (needed for the growth of many bacteria) – Enteric forms or systemic forms – Examples; Bactericidal when potentiated with trimethoprim or ormetoprim; gram + organisms: Streptococci, Staphylococci, Nocardia, Coccidia, Toxoplasma and Chlamydia – sulfadimethoxine/ormetoprim (Primor) – sulfadiazine/trimethoprim (Tribrissen) – sulfadimethoxale/trimethoprim (human drug: Septra) – Sulfachlorpyridazine (livestock and poultry) – Sulfasalazine (Azulfidine: IBD). Enteric. More antiinflammatory effect esp in colon as aminosalicyclic acid. Caution in cat

22. Antimetabolites Sulfonamides and Potentiated sulfonamides: -static/cidal Sulfonamides and Potentiated sulfonamides: -static/cidal – Pharmacokinetics – Absorbed in monogastric GI tract – Mostly lipophilic: prostate, pleura, CSF, ocular, UTI – Don’t use in pregnant/ lactating animals – Excreted: kidney – SE: crystalluria (esp. older drugs), KCS (dry eye): can be irreversible, and skin rashes (most common): pruritus, hives, swelling – face esp. Doberman pinschers, thrombocytopenia, leukopenia, anemia, cats: profuse salivation – Precipitate in kidneys of animals that are dehydrated or have acidic urine; Adequate water intake = very important! – Antibiotic resistance

23. Miscellaneous Agents Nitrofurans Nitrofurans – Are broad-spectrum antibiotics that include furazolidone, nitrofurantoin (Furadantin), and nitrofurantoin – Used to treat wounds (topically) and urinary tract infections (not 1 st choice) – Filtered unchanged through kidneys – Carcinogenic residues in animal tissues Nitroimiazoles Nitroimiazoles – Have antibacterial and antiprotozoal activity; work by disrupting DNA and nucleic acid synthesis – An example is metronidazole, which is considered by some the drug of choice for canine diarrhea

24. Metronidazole (Flagyl®) Metronidazole (Flagyl®) is drug of choice for canine diarrhea – Disrupt syn. of DNA and nucleic acids. Works with anaerobic bacteria – Used to treat Giardia, Entamoeba histolytica, Balantidium and Trichomonas infections, deep puncture wounds – Also used for amoebiasis and anaerobic bacteria – Oral or intravascular administration – No approved veterinary form of metronidazole (used off-label) – Do not use in pregnant animals – SE: Can cause neurologic signs: vestibular signs, tremors, seizures with oversose/ long periods of time

25. Miscellaneous Agents Rifampin: -cidal/static Rifampin: -cidal/static – Disrupts RNA synthesis by inhibiting RNA polymerase – Is broad-spectrum; used in conjunction with other antibiotics (usually erythromycin) for Corynebacterium equi (Rhodococcus equi), Staphylococcus infections, Fungi?: Histoplasma, Aspergillus, Blastomyces with amphotericin B – May impart a reddish color to urine, tears, sweat, and saliva. – Increases metabolism of: propranolol, quinidine, chloramphenicol, diazepam, zolazepam (Telazol), phenobarbital, pentobarbital, prednisone and dexmathasone

26. References Romich, J.A. Pharmacology for Veterinary Technicians, 2 nd edition. 2010. Bill, R.L. Clinical Pharmacology and Therapeutics for the Veterinary Technician, 3 rd edition. 2006. http://ahdc.vet.cornell.edu/clinpath/modules/ua -rout/castssed.htm