Lecture 3 Antimicrobials - Tagged PDF

Module 2: Antimicrobials Antimicrobials are drugs that kill or inhibit the growth of microorganisms such as bacteria, protozoa, viruses, and fungi. - technically an antibiotic is a substance produced by one microorganism that suppresses the growth of another microorganism - the term antimicrobial...

Module 2: Antimicrobials Antimicrobials are drugs that kill or inhibit the growth of microorganisms such as bacteria, protozoa, viruses, and fungi. - technically an antibiotic is a substance produced by one microorganism that suppresses the growth of another microorganism - the term antimicrobial includes antibiotics and all drugs chemically synthesized to control microorganisms Types of Antimicrobials Can be classified according to: 1. the type of microorganism it fights Antifungal vs antibacterial 2. whether it kills the microorganism or only prevents it from replicating and proliferating the suffix –cidal denotes drugs that kill the microorganism (e.g. bactericidal, fungicidal) the suffix –static denotes drugs that inhibit replication, but do not directly kill the microorganism Antimicrobials -cidal vs -static drugs generally have the potential to both kill and inhibit pathogens (disease causing organisms) Lower concentrations or short duration of treatment result in a sub-lethal inhibiting effect (-static) Higher concentrations or long durations of treatment result in death of the pathogenic organisms (- cidal) Goal of Antimicrobial Therapy To kill or disable pathogens without killing the host  Successful antimicrobial therapy requires: 1 2 3 microorganism is the antimicrobial the animal must be susceptible to the must be able to able to tolerate high drug reach the site of concentrations of infection in high the drug enough concentrations to kill or inhibit the microorganism When an animal has a bacterial infection, how do we determine which antimicrobial to use? Educated Guess Culture and Susceptibility Results Educated Guess Where is the infection? What type of bacteria did we see on cytology (rods/cocci) What’s the most common type of bacterial infection for the above? Bacterial Culture Collect fluid, tissue, or swab from site of infection Send to lab in culture medium Lab will then take your sample and place it onto a bacterial culture medium and incubate this, to grow what you have sent. If growth occurs, the bacteria are identified (PCR- testing) The bacteria that is most concerning for resistance will be put through susceptibility testing Antibacterial susceptibility Testing the measurement of susceptibility of a bacterial strain to the effects of an antimicrobial is represented by the drug’s minimum inhibitory concentration (MIC) against the bacterial strain The MIC represents the lowest concentration of drug at which the growth of the bacterium is inhibited The standard culture test plate used to assess which antibiotic inhibits the growth of a microbe is Mueller-Hinton  Standard Susceptibility Testing Based on the tolerated blood drug concentrations If a bacterial strain has an MIC for an antimicrobial that is low enough not to produce significant side effects in the host animal, the bacteria is said to be sensitive to the drug If the concentration required to kill or inhibit the pathogen is so high that significant side effects would occur in the host animal, the bacteria is said to be resistant to the drug Susceptibility Testing for Local/Topical Therapies Appropriate for determining appropriate antimicrobial for eye or ear infections Recognizes that the concentrations we can use locally is much higher than that we can safely introduce into the blood stream  Resistance of Microorganisms to Antimicrobial Therapy - Occurs when bacteria and other microorganisms develop the ability to survive in the presence of antimicrobial drugs designed to kill them - Resistance develops from Genetic changes arising through: - Inheritance from previous generations of bacteria - Spontaneous mutations of chromosomes - An additional piece of DNA called an R plasmid being acquired Resistance of Microorganisms to Antimicrobial Therapy - one example is the ability of bacteria to produce enzymes that render antibiotics useless (beta-lactamases produced by bacteria inactivate penicillins and cephalosporins) - inappropriate use of antimicrobials does not necessarily cause bacteria to become resistant, however it may allow a resistant population to propagate more readily than other bacteria in the population  To help prevent antimicrobial resistance veterinary professionals should: * administer the appropriate dose at * educate clients regarding the appropriate levels, for the importance of following instructions appropriate time, and in the appropriate manner Concern Over Antimicrobial Residues a residue is the presence of a drug, chemical, or its metabolites in animal tissues or food products exposure to low levels of antimicrobials in food can cause two effects in human beings: selection of resistant bacteria in the intestinal tract allergic reaction Concern Over Antimicrobial Residues - Protocols are in place when using drugs in animals intended for food, to prevent residues Veterinarian & Producer confirm and abide by proper withdrawal times post drug administration in an animal Cannot be shipped for slaughter prior to this time Milk produced by this animal does NOT go into the tank during withdrawal time Milk Tanks are ALWAYS tested before they are processed and shipped to stores Meat is tested at random AND whenever there is an index of suspicion that antibiotics have been used recently  antimicrobials exert their effects at one of five sites to kill or inhibit bacteria and other microorganisms: cell wall cell membrane ribosomes critical enzymes or metabolites nucleic acids  Mechanisms of Antimicrobial Action [+ denotes only effective if bacteria are replicating/dividing] 2. 1. 3. + 4. 5. + Classes of Antimicrobials Penicillins Cephalosporins Aminoglycosides Fluoroquinolones Tetracyclines Macrolides Sulfonamides Lincosamides  PENICILLINS among the most used antibiotics in veterinary medicine most contain a –cillin suffix Bactericidal Interfere with cell wall development Effective against most gram-positive bacteria and a lesser number of gram-negative bacteria  Penicillin Groups natural penicillin: penicillin-G (injectable only*) Broad spectrum aminopenicillins: ampicillin, and amoxicillin B-lactamase-resistant penicillins: cloxacillin, dicloxacillin and oxacillin Penicillin combined with clavulanic acid to effectively treat beta- lactamase producing bacteria: amoxicillin+clavulanic acid Extended-spectrum penicillins: rare in vet medicine Penicillin Group Spectra of Activity - each penicillin group has a slightly different bacterial spectrum; some strains of bacteria are resistant to one group and highly susceptible to another - some bacteria (e.g. Staphylococci) acquire resistance to many penicillins by producing an enzyme that attacks a particular part of the penicillin molecule called the β-lactam ring - these enzymes are called β-lactamases and render the penicillin ineffective  Penicillin Pharmacokinetics Well absorbed from injections sites and the GI tract Exception: penicillin G cannot be given by mouth Well distributed to most tissues in the body Exception: do not reach therapeutic concentrations in the globe of the eye, the brain or the prostate gland Excreted largely unchanged by the kidneys, and can achieve higher concentrations in urine than in blood Precautions for Use of Penicillins - allergic reactions are the most common adverse reaction; which can range from a mild skin rash to anaphylactic shock (should be clearly marked in the animal record) DO NOT USE ORALLY IN HINDGUT FERMENTERS (RABBITS, G.P.s, HORSES) - when given orally, penicillins may destroy beneficial bacteria in the intestinal tract, allowing more pathogenic bacteria to grow. This condition is called superinfection or suprainfection and can produce severe or fatal diarrhea in guinea pigs, ferrets, hamsters and rabbits. - a bacteriostatic drug should not be used in conjunction with penicillin (e.g. tetracyclines, such as doxycycline)  CEPHALOSPORINS the ceph- or cef- prefix identifies most members classified by generations Interferes with cell wall development contain Beta-lactam ring in their structure - susceptible to β-lactamase enzymes produced by bacteria, but less than penicillins Different Generations of Cephalosporins First generations Most effective against gram-positive bacteria (most comparable to penicillins) Include: Cephalexin, Cefazolin, Cephapirin (intramammary infusion for cattle with mastitis) Second and third generations more effective against gram-negative bacteria Include: Cefovecin sodium (Convenia), Ceftiofur (Excede) Pharmacokinetics of Cephalosporins Very similar to Penicillins -Distribute well throughout most tissues in the body, but also do not readily pass through blood-brain-barrier - Also excreted in the urine Precautions for Use of Cephalosporins - Oral formulations may cause anorexia, vomiting, diarrhea. Lessened by feeding with meal - potential for hypersensitivity reactions - Rarely – resistance issues, superinfections with oral administration - bacteriostatic drugs reduce their effect (because their mechanism of action relies on active cell division/bacterial growth, just like penicillins)  Mechanisms of Antimicrobial Action [+ denotes only effective if bacteria are replicating/dividing] + Penicillin cephalosporins  AMINOGLYCOSIDES Can be identified with the suffix -micin or – mycin (exception: amikacin) Bactericidal Combine with ribosomes and prevents protein synthesis Ineffective against anaerobes (enter bacteria by oxygen-dependent pathway) Powerful group of antimicrobials used to combat serious (aerobic) bacterial infections This class is NOT utilized in food animals  Aminoglycosides used in Veterinary Medicine Examples: gentamicin*, amikacin, neomycin*, streptomycin, kanamycin, tobramycin* and netilmicin Commonly seen in topical preparations for eye & ear infections* Systemic use reserved for life threatening infections, seldom used in veterinary medicine (reserved for humans)  - hydrophilic at most physiologic pH levels and are therefore usually administered parenterally - not well absorbed through intact skin, but Pharmacokinetics well absorbed through abraded skin of Aminoglycosides - do not penetrate the blood-brain- barrier or the globe of the eye - they are found in high concentrations in bronchial secretions and therefore often used to treat pneumonia  - potentially nephrotoxic or ototoxic (inner ear) even at normal doses - cats are particularly sensitive to the vestibular toxic effects - nephrotoxicity from gentamicin has been reported in many species, Precautions for including exotic species, wildlife and Use of birds Aminoglycosides - cellular debris (pus) can make aminoglycosides ineffective, since they bind to the debris – purulent debris should be removed before application  Mechanisms of Antimicrobial Action [+ denotes only effective if bacteria are replicating/dividing] Aminoglycosides + Penicillin cephalosporins QUINOLONES/FLUOROQUINOLONES Identified by their –floxacin suffix Bactericidal Prevent coiling of bacterial DNA and subsequently disrupting DNA function Can treat prostate infections Damaging to cartilage in growing animals Banned for use in food animals in some countries, and more recently Quebec Example Enrofloxacin s of Quinolon Marbofloxac es used in in Veterinar Orbifloxacin y Medicine Ciprofloxaci n  Effective against common gram-negative Spectrum and gram-positive bacteria of Activity (Staph.,Pseudomonas, E.coli, Salmonella) of Ineffective against Streptococcus and Quinolone anaerobic bacteria s  Distributes very well throughout the body accumulate in high concentrations in the kidneys, liver, lungs, bone, joint fluid, aqueous humour of the eyeball Pharmacokin and respiratory tissues etics of Quinolones one of the few antimicrobials that effectively treats prostate infections Used to treat severe infections of the skin (deep pyoderma), respiratory tract, and urinary tract Precautions for Use of Quinolones Quinolones can adversely affect developing joint cartilage and therefore should not be used in small or medium sized dogs between 2 and 8 months, up to 12 months in large breed dogs and 18 months in giant breeds (now controversial) Higher doses 20 mg/kg+ have been found to cause retinal damage in cats, so dose now lowered to 5 mg/kg s.i.d (marbofloxacin safer than enrofloxacin) Precautions for Use of Quinolones may precipitate seizures in epileptic animals?? some issue with bacterial resistance and therefore fluoroquinolones should be reserved for more severe infections and when specific bacteria have been identified - not for use in dairy cattle (exception: females under 20 months, but second line choice), egg laying hens and horses - some countries and the province of Quebec have banned fluoroquinolones for use in food producing animals  Mechanisms of Antimicrobial Action [+ denotes only effective if bacteria are replicating/dividing] + Aminoglycosides Penicillin cephalosporins + Fluoroquinolone  TETRACYCLINES Recognized by the –cycline Bacteriostatic (therefore depend on a functional immune system to overcome microbial invasion) Bind to ribosomes and interrupt protein synthesis Have anti-inflammatory and immuno- modulatory effects Tetracyclines used in vet med: Oxytetracycline Chlortetracycline Doxycycline Minocycline Just remember a dachie cyclin' He's a tetra (4 footed) cyclist/cycline....a tetracycline Features of Doxycycline & Minocycline can cross the blood-brain barrier & penetrate the eye Better absorbed orally than oxytetracycline and tetracycline  Precautions for Use of Tetracyclines tetracycline and at high doses may slow bone oxytetracycline damage and development in young animals discolor developing chelate with minerals teeth of developing tooth enamel and dentin causing a yellow discolouration  Precautions for Use of Tetracyclines vomiting, diarrhea and anorexia with oral administration in dogs and cats (giving with food helps reduce these side effects) Esophagitis with dry pilling in cats doxycycline in particular is very irritating  Mechanisms of Antimicrobial Action [+ denotes only effective if bacteria are replicating/dividing] Aminoglycosides + Tetracyclines Penicillin cephalosporins + Fluoroquinolone Stopped here today SULFONAMIDES AND POTENTIATED SULFONAMIDES Recognized by the sulfa- prefix Bacteriostatic alone, bactericidal when potentiated interferes with synthesis of folic acid in bacteria necessary for protein and nucleic acid metabolism Potentiated by combining with trimethoprim or ormethoprim Resistance used for many years in Issues with human and veterinary Sulfonamid medicine and now es significant resistance issues. need to be potentiated Examples of Sulfonamides sulfadimethoxine (combined with ormethoprim) sulfadiazine (combined with trimethoprim = TMS) Uses of sulfonamides in Vet Medicine Treatment against: Coccidia Toxoplasma Chlamydia  used orally in small animals, but injectably in large animals due to nature of their metabolism Well distributed throughout the body including pleural fluid, peritoneal fluid, synovial fluid, ocular fluid, cerebrospinal fluid and Pharmacokinetics of Sulfonamides prostate gland achieve significant concentrations in the kidney and therefore can be used for urinary tract infections either excreted intact through the kidney or metabolized by the liver, then excreted via the kidney  Precautions for Use of Sulfonamides decreased tear production in dogs (keratoconjunctivitis sicca KCS) hypersensitivity skin reactions thrombocytopenia (decreased platelets) have been reported in dogs and cats some can produce crystalluria, particularly with dehydration or acidic urine. Crystals can damage renal tubules  Mechanisms of Antimicrobial Action [+ denotes only effective if bacteria are replicating/dividing] Aminoglycosides + Tetracyclines Penicillin cephalosporins + Sulfonamides Fluoroquinolone LINCOSAMIDES bacteriostatic or bactericidal, depending on the concentrations at the site of infection Bacterial protein inhibitors Effective against many gram-positive aerobic cocci Examples: lincomycin, clindamycin Cautions NEVER used in large animals Not used in pocket pets – guinea pigs, rabbits, hamsters (risk severe GI disease & death)  Mechanisms of Antimicrobial Action [+ denotes only effective if bacteria are replicating/dividing] Aminoglycosides + Tetracyclines Penicillin lincosamides cephalosporins + Sulfonamides Fluoroquinolone  Bacteriostatic MACROLIDES inhibit bacterial protein synthesis examples: erythromycin, azithromycin (Zithromax), tylosin (Tylan), tilmicosin (Micotil)  tilmicosin (Micotil) can cause tachycardia, cardiac arrhythmias and even death if accidentally injected into humans Til-mi-kill-me if I self inject  Mechanisms of Antimicrobial Action [+ denotes only effective if bacteria are replicating/dividing] Aminoglycosides + Tetracyclines Penicillin Macrolides cephalosporins lincosamides + Sulfonamides Fluoroquinolone METRONIDAZOLE - exact mode of action not entirely known - Used to treat anaerobic bacterial infections - IBD - Hemorrhagic Gastroenteritis - Used to treat Giardia (a protozoa!) Metronidazole Cautions can produce neurological side effects such as loss of balance, head tilt, nystagmus, tremors and seizures when overdosed CHLORAMPHENICOL AND FLORFENICOL Bacteriostatic or –cidal, depending on the dose used blocks bacterial protein synthesis  Chloramphenicol Use is uncommon in small Use is banned in food animals animals Cats & neonates cannot Risk of fatal aplastic anemia in metabolize it well – high toxicity people risk Used most often in rodents Florfenicol newer antibiotic that can be used safely in cattle for bovine respiratory diseases Brand name: Nuflor IM injection only No risk of aplastic anemia in people if accidental exposure occurs  Mechanisms of Antimicrobial Action [+ denotes only effective if bacteria are replicating/dividing] Aminoglycosides + Tetracyclines Penicillin Macrolides cephalosporins lincosamides Chloramphenicol florfenicol + Sulfonamides Fluoroquinolone MISCELLANEOUS ANTIBIOTICS -Polypeptide Antibacterials: bacitracin, polymyxin B, gramicidin -Recall we these in combo with one another and other antibiotics in eye preparations -Recall polymyxin b in several otic preparations?! -Recall these are ALSO in topical ointments/creams for pyoderma