Antimicrobials Flashcards
(119 cards)
0
Q
What are the mechanisms of action of the antimicrobials?
A
- Inhibition of protein synthesis - tendency to be bacteriostatic, act at the site of the bacterial ribosome. 2. Inhibition of nucleic acid synthesis 3. Disruption of cell walls 4. Disruption of cell membranes. 5. Interfere with metabolic pathways.
1
Q
What are the antimicrobials?
A
Antibiotics - substances produced by a micro organism that kills or inhibits other micro organisms. Antibacterial - Synthetic agents which have activity against bacteria eg sulphonamides. Antimicrobial - any substance synthetic or natural that kills or inhibits growth of a micro organism without damaging the host.
2
Q
What are the different types of resistance that may develop to the antimicrobials?
A
Inherent resistance - E.g mycoplasma resistance to the Beta lactams, anaerobic organisms resistance to the aminoglycosides. Chromosomal mediated resistance -a daughter cell with a mutation may lead to a change which confers resistance to that organism. Transferable drug resistance - conjugation - mediated by plasmids, transduction, transformation. May contain genes that allow transfer from one bacteria to another. May contain genes encoding for antimicrobial resistance to one or several different drugs.
3
Q
What are the potential results of resistance?
A
Production of enzymes with inactive drug e.g B-lactamase. Alteration in drug binding site e.g amino glycosides, reduction in drug uptake - e.g tetracycline. Development of enzymes with low drug affinity e.g trimethoprim. Increased production of competitive metabolites e.g sulphonamides.
4
Q
What is the MIC?
A
Minimal inhibitory concentration - the highest dilution at which there is no growth after incubation. It is a quantitative value that defines susceptibility and is used to determine drug dose. Determination of susceptibility under laboratory conditions is problematic.
5
Q
What is post antibiotic effect?
A
For time dependent antimicrobials the parameter that best correlates with efficacy is the time that the serum concentration of the antimicrobial remains above the MIC. E.g Beta lactams. For concentration dependent antimicrobials the parameter that best correlates with efficacy is the peak serum concentration. - examples include the aminoglycosides and fluoroquinolones.
6
Q
What are the Beta Lactam antimicrobials?
A
They consist of; Narrow spectrum penicillins Broad spectrum penicillins Antipseudomonal penicillins Monobactams Carbapenems 1st,2nd,4d and 4th generation cephalosporins.
7
Q
What is the mechanism of action of the penicillins?
A
They inhibit transpeptidase enzymes (penicillin binding prooteins). They disrupt cross linking of glycopeptide polymer in bacterial cell wall and prevent bacterial cell wall formation and lyse the cell wall in growing cells. (bactericidal)
8
Q
What does the activity of the penicillins depend on?
A
Penicillin binding proteins (transpeptidase), ability to penetrate lipopolysaccharide of gram negative bacterial cell membrane, resistance to beta lactamase, amount of peptidoglycan in the cell wall.
9
Q
What is beta lactamase?
A
An enzyme produced by certain bacteria which can cleave the beta lactam ring. It is produced by gram positive bacteria such as staphylococci and is exogenously released and plasmid mediated. It is also produced by gram negative bacteria in a periplasmic location.
10
Q
Describe the pharmacokinetics of the penicillins?
A
Organic acids (pKa 2.7), low volume of distribution (0.), short half lives, exclusion from CSF and aqueous humor, ionised at plasma PH, penetration enhanced by inflammation. They have renal excretion therefore there are high levels here, undergo glomerular filtration and tubular secretion. They have a slow kill rate and not much post antibiotic effect. It is important to maintain drug levels above the MIC.
11
Q
Describe penicillin G?
A
Gram positive spectrum only, acid labile, beta lactamase susceptible. Unstable in gastric acid, inactive against gram negative bacteria (relatively.
12
Q
Describe penicillin V?
A
Gram positive only, acid stable, beta lactamase susceptible.
13
Q
Describe Nafcillin and the beta lactamase resistant penicillins?
A
Gram positive only, acid and beta lactamase stable - resistant to gram positive beta lactamases e.g staphylococci. Have minimal activity against gram negative organisms.
14
Q
What is the spectrum of activity of the narrow spectrum penicillins G and V?
A
Gram positive - staphylococcus aureus, beta haemolytic streptococci, corynebacterium, ersipelothrix spp, bacillus spp. Gram negative - fastidious spp such as haemophilus, pasteurella, actinobacillus. Anaerobes - clostridium, fusobacterium.
15
Q
Describe the broad spectrum penicillins - aminopenicillins?
A
Gram positive and gram negative, acid stable, beta lactamase susceptible e.g ampicillin, amoxicillin. Amoxicillin is more orally bioavailable than ampicillin, may be used with clavulanate (synulox = amoxicillin with clavulanic acid) Broader spectrum. Administered in sodium salts, Trihydrate salts or depot preparations containing aluminium monostearate.
16
Q
Describe the antispeudomonal penicillins?
A
Gram positive and gram negative, beta lactamase susceptible, effective against pseudomonas e.g carbenicillin, ticarcillin. They are synergistic with aminoglyosides e.g gentamicin. They are sensitive to beta lactamase of P. aueruginosa and gastric acid. Also the Ureidopenicillins .g piperacillin - broader spectrum than ticarcillin.
17
Q
What are the Beta lactamase inhibitors?
A
Clavulanic acid, tazobactam and sulbactam are suicide inhibitors. They bind irreversibly to beta lactamase enzymes and synergise beta lactam antibiotics. They are weak antibacterials.
18
Q
Describe the toxicity of penicillins?
A
They are very safe - occasional anaphylaxis or mild hypersensitivity. Toxicity may be associated with the salt formulation. Can cause fatal clostridial colitis in small furries.
19
Q
What are the interactions of the penicillins?
A
Synergism with the amino glycosides - against some bacteria only. Synergism with Clavulanic acid and other B lactamase inhibitors. Synergy with cloxacillin and other penicillins - beta lactamase producers.
20
Q
What are the cephalosporins & what are the characteristics of each generation?
A
Resistant to beta lactamase enzymes. First generation - good vs gram positive including penicillinase producing bacteria and anaerobes. Moderate vs gram negative. E.g cefadroxil.
Second generation - similar to first generations but better vs Ecoli, klebsiella, proteus. e.g Cefuroxime. Third generation - reduced activity vs gram positive, excellent vs enterobacteriaceae, fair vs pseudomonas. e.g ceftiofur. (binds to acute phase proteins, does not readily cross into milk.). Fourth - broad spectrum, not destroyed by beta lactamase producing klebsiella or pseudomonas.
21
Q
What is the mechanism of action of the cephalosporins?
A
Same mechanism of action as the penicillins - they inhibit transpeptidase enzymes & disrupt cross linking of glycopeptide polymer in the bacterial cell wall. They are bactericidal antibiotics and time dependent.
22
Q
Describe the pharmacokinetics of the cephalosporins:
A
Distribution similar to penicillins, high concentrations in urine and bile, excluded from CSF, prostate and aqeous humor except later generations, half life such that need to administer every 6-8 hours, no post antibiotic effect, subsequent generations less oral bioavailability, renal excretion (glomerular excretion and tubular secretion) some of the cephalosporins are de-acetylated in the liver.
23
Q
Describe some of the cephalosporins used in companion animal species?
A
Cephalexin - 1st generation, oral and parenteral. Cefovecin (convenia) - 3rd generation - parenteral administration only, every 14 days, very long half life, highly bound to plasma protein.
24
Describe some of the cephalosporins used in food producing species?
Ceftiofur (excenel) - 3rd generation cephalosporin, good gram negative activity, highly bound to plasma protein, hepatic metabolism to desfuroylceftiofur (active). Cefquinome - 4th generation, good gram negative activity.
25
What are the carbapenems and monobactams?
Developed to deal with Beta lactamase producing gram negative organisms, they are not licensed in vet med. Carbapenem imipenem - is given with cilistatin to inhibit renal hydrolysis which prevents the imipenem metabolism to potential toxic compounds.
26
What is the structure of the aminoglycosides?
Polar organic bases: similar structure. Structure is complex; 2 amino sugars attached to a hexose nucleus by glycosidic linkages. Polarity accounts for pharmacokinetic properies.
27
What is the mechanism of action of the aminoglycosides?
They inhibit protein synthesis - they penetrate through bacterial cell membrane (02 - dependent active transport by a polamine carrier) they bind to a non enzymatic site on the ribosome (30s subunit and other sites) - they alter codon: anticodon recognition and defective bacterial proteins are produced. Other effects include induction of RNA breakdown, inhibition of translation, damage to cell membranes, effects on DNA metabolism. Rapid dose related bactericidal action - abnormal cell membrane channels due to misread proteins. Their post antibiotic effect is concentration dependent. Drug penetration enhanced by drugs that interfere with bacterial cell wall synthesis - synergism with B lactam antibiotics. O2 dependent active transport is blocked by divalent cations, hyperosmolar conditions, low pH and anaerobic conditions - drugs don't work well in pus, inflamed tissue, abscesses etc.
28
What is the antimicrobial activity/spectrum of the aminoglycosides?
Narrow/moderate spectrum of activity - they are active primarily against gram-ve, aerobic bacteria. Some activity against gram +ve bacteria, mycoplasma and some mycobacteria. Little activity vs anaerobes or facultative anaerobes. Amikacin> tobramycin> gentamicin> neomycin>kanamycin>streptomycin.
29
What are the pharmacokinetics of the aminoglycosides?
Poor absorption from the GIT. Well absorbed after IM or SC administration. Poor penetration across cell membranes. Small volumes of distribution - do not readily achieve therapeutic concentrations in Transcellular fluids. Low plasma protein binding. Short half lies, elimination by renal excretion of unchanged drug - glomerular filtration, impaired renal function decreases their rate of excretion - must adjust dose or dosing interval.
30
Describe the resistance that occurs with the aminoglycosides.
Plasmid mediated resistance occurs - code for enzymes that inactivate the aminoglycosides and consequently prevent ribosomal binding. Include phosphotransferases, acetyltransferases and adenyltransferases.
31
Describe how ototoxicity can occur with the aminoglycosides?
Vestibular toxicity - damage to the sensory cells of the labyrinth leads to vestibular signs, disturbance of balance, ataxia, incoordination, nystagmus, it is reversible. Streptomycin and dihydrostreptomycin most likely to interfere. Cochlear toxicity - damage to sensory cells of the cochlea, deafness, irreversible - streptomycin, neomycin. Ototoxicity is potentiated by loop diuretics and probably other diuretics.
32
How does nephrotoxicity occur with the aminoglycosides?
Acute tubular necrosis, proteinuria, hyaline and granular casts in urine. Reversible, caused by neomycin, gentamicin. Consider TDM.
33
What other types of toxicity can occur with the aminoglyosides?
Neuromuscular blockage (non depolarizing)- generally not a problem in conscious animals - prolongation of effects of NMBs. Collapse after IV injection - due to decreased heart rate and cardiac output, administer slowly. Hypersensitivity.
34
What are the aminocyclitols?
Apramycin - active vs gram negative bacteria, S aureus and some mycoplasma. REsist most R plasmid mediated degradative enzymes, used to treat gram -ve infections in calves, piglets.
Spectinomycin - lacks much of the toxicity of the aminoglycosides, acts by inhibiting protein synthesis at the translocation step, chromosomal mutation to resistance occurs readily, used to treat diarrhoea in piglets, control of mycoplasma in poultry.
35
What are the sulphonamides?
Antibacterials- They are antimetabolites - they are competitive inhibitors of para aminobenzoic acid (PABA), they are bacteriostatic, broad spectrum. Sulphonamides compete with Paba for Dihydropteroate synthetase.
36
What is the spectrum of activity of the sulphonamides?
Gram positive staphylococci and streptococci. Gram negative - pasteurella, E. coli, salmonella. Protozoa - coccidia, toxoplasma. No activity against mycoplasma, enterococci or pseudomonas.
37
Describe the resistance seen with the sulphonamides?
Chromosomal mutation - impaired penetration, insensitive Dihydropteroate enzyme, increased production of PABA. Plasmid mediated - impaired penetration, insensitive dihydropteroate enzymes. R factor resistance commonly linked with streptomycin resistance.
38
Describe the absorption of the sulphonamides?
Most sulphonamides are weak acids (absorbed from the stomach). Gut active sulphonamides have substituted amino nitrogen and must be hydrolysed to become active. Hydrolysis of gut active sulphonamides takes place in lower gut from which they are poorly absorbed.
39
Describe the distribution of the sulphonamides?
Distribution is relatively good - some reach significant CSF levels, generally penetrate milk and synovial fluids - have variable protein binding 20-90%.
40
Describe the metabolism of the sulphonamides?
Mostly metabolised by acetylation, glucuronidation and hydroxylation in the liver. Metabolites are inactive. Acetylated metabolites are less soluble than the parent compounds.
41
Describe the excretion of the sulphonamides?
Partially excreted unchanged in the urine. Principally excreted as metabolites in the urine. Excretion by filtration and active tubular secretion. Gut active sulphonamides are excreted in the gut.
42
Describe renal crystalluria seen with the sulphonamides?
Urine solubility exceeded. Principally acetylated metabolites (less soluble). Crystallisation greater in acidic urine. Alkalisation of the urine enhances elimination and decreases precipitation. Renal crystalluria may be reduced by using longer acting compounds, more potent drugs, combinations of sulphonamides.
43
What kind of toxicity may occur with the sulphonamides?
Diarrhoea, (disturb rumen flora, irritate intestine). Haemorrhaghic syndrome, non specific polyarthritis, dobermanns, keratoconjunctivitis sicca, fatal arrhythmias in horses in conjunction with alpha 2 agonists, soft shelled eggs, diuresis.
44
What local factors can affect efficacy of the sulphonamides?
Pus: free thymidine and purines provide nucleotide precursors. Necrotic and purulent material gives nucleotide precursors so the bacteria can overcome folic acid inhibition. Local anaesthetics are esters of PABA which compete with the sulphonamides.
45
What preparations are the sulphonamides found in?
rapid onset short duration. Rapid onset long duration (1-4 days) Sulfacetamide - occular preparation. Sulfasalazine - treatment of colitis hydrolysed to 5 amino salicylate. Gut preparations Phthalylsulfathiazole.
46
Name some Diaminopyrimidines and describe their mechanism of action?
Trimethoprim, ormetoprim, baquiloprim, pyrimethamine. Mechanism of action - weak bases, anti metabolites - inhibit dihydrofolate reductase. Their selectivity varies. Trimethoprim, aditoprim and baquiloprim are selective for bacterial DHFR. They are bacteriostatic and broad spectrum. Diaveridine, pyrimethamine are selective for protozoal coccidial DHFR. Mammalian DHFR is targetted by anti cancer drugs.
47
Describe the pharmacokinetics of the diaminopyrimidines?
They are lipid soluble. Trimethoprim is rapidly reduced in ruminants so has a much shorter elimination half life than sulphonamides however combinations are effective. Baquiloprim has a more appropriate half life. Most diaminopyrimidines are degraded by Ruminal flora. Oral administration in ruminants is not useful. Baquiloprim exception - not degraded by ruminal flora, longer half life in cattle, can be given as a bolus in cattle.
48
Describe the toxicity seen with the diaminopyrimidines?
Uncommon. Prolonged therapy may lead to erythrocyte dysfunction associated with folic acid deficiency. Treated with folic acid.
49
What are the clinical applications of the diaminopyrimidines?
Diaminopyrimidines used in combination with sulphonamides in animals. Ratio 5:1 sulphonamide: diaminopyrimidine. The combinations are synergistic and bactericidal. Allow sulphonamide to be used at about 1/ normal dose. Resistance to combinations is low. Use e.g trimethoprim and sulfadoxine.
50
What are the Fluoroquinolones?
Broad spectrum activity, bactericidal, good oral bioavailability, large volume of distribution. Resistance develops more slowly - no plasmid mediated resistance? Toxicity - arthropathy in growing animals.
51
How does the structure affect the activity of the fluoroquinolones?
All have acidic group but are generally amphoteric. The 6 fluoro group confers broad spectrum activity. The 7 piperazine group confers pseudomonas activity. the 1 alkyl or ring group improves distribution.
52
What is the mode of action of the Fluoroquinolones?
They inhibit bacterial DNA gyrase. DNA gyrase is responsible for breaking DNA which is essential for negative supercoiling and essential during transcription. It is much less effective against the equivalent mammalian enzyme. Bacterial DNA gyrase contains 4 subunits - fluoroquinolones inhibit the A subunits. Post antibiotic effect - concentration dependent. The fluoroquinolones enter bacteria through porins. Reduction in the permeability of porins to quinolones may confer resistance.
53
What is the spectrum of activity of the fluoroquinolones?
They are active against gram-negative bacteria (aerobes), gram positive bacteria (aerobes), intracellular bacteria, mycoplasma, relatively inactive against anaerobes. Ciprofloxacin - activity vs mycobacteria.
54
Which bacteria have good susceptibility to fluoroquinolones?
Good susceptibility (MIC <1ug/ml) - Enterobacteriacea ( E. coli, klebsiella, proteus, salmonella), Actinobacilllus, brucella, haemophilus, pasteurela, manheima, leptospira, aeruginosa. Moderate susceptibility 1-4ug/ml - streptococci.
55
Describe the resistance which occurs to the Fluoroquinolones?
Resistance develops by chromosomal mutation (change in cell permeability or gyrase structure - develops slowly - generally unstable and low level). Plasmid mediated resistance used to not occur but is an emerging mechanism of resistance.
56
What are the pharmacokinetics of the fluoroquinolones?
They are highly orally bioavailable. They have low protein binding, a large volume of distribution, and concentrate in some tissues - lung, urine, prostate, bone. Good penetration into the CSF and bronchial secretions. They are partially metabolised in the liver. The parent drug and metabolites are excreted in the urine and bile. There are high urinary concentrations of the parent drug. Enterohepatic recycling may occur.
57
What kind of toxicity and interactions occur with the fluoroquinolones?
Considered to be relatively safe. Erosion of weight bearing cartilage may occur dogs appear to be most susceptible. Contraindicated in growing cats and dogs. Clearance of other drugs metabolised in the liver may be reduced. Neurotoxicity with enrofloxacin and cats.
58
Give a summary of the fluorooquinolones?
Excellent for infections due to gram-negative aerobes. Good for UTI. Good penetration into tissues. May be suitable for skin/soft tissue infections. Good activity in respiratory and enteric infections in ruminants, pigs and poultry. They have a long half life. They should not be used as first line agents.
59
What is a mutant prevention concentration?
A wild type bacterial population will be susceptible to an FQ. however first step mutants are not completely resistant but show decreased susceptibility hence the MIC shifts upward. A level of FQ which will still kill the first step mutants is called the MPC.
60
Name some common macrolides and their mechanism of action?
Erythromycin, tylosin, tilmicosin, tiamulin, spiramycin, tulathromycin. They inhibit protein synthesis - bind to ribosome (50s sunbunit) and inhibit translocation - so small truncated peptides are produced. They bind when the 50s subunit is free from tRNA molecules. Small peptides are produced. They are bacteriostatic but can be bacteriocidal depending on drug concentration and organism.
61
What is the spectrum of activity of the macrolides?
Moderate spectrum - Gram positive bacteria. Gram positive staphs, streps, corynebacterium, listeria. Anaerobes - prevotella, clostridium, fusobacterium. Mycoplasma and some chlamydophila. Non tubercular mycobacterial organisms. Some G-ve bacterial (pasteurella, manheimia, actinobacillus, campylobacter spp).
62
What type of resistance can occur?
Chromosomal resistance can occur during treatment - tends to be unstable. Plasmid mediated resistance is common - methylation of binding site, decreased permeability, esterases which hydrolyse the drug.
63
What are the pharmacokinetics of the macrolides?
They are large macrocyclic ring, to which sugars are attached. They are highly lipid soluble. They have a large Vd. In particular, spiramycin, tilmicosin. They are basic - ion trapping in milk, prostate, high intracellular concentrations. They have variable half lives (erythromycin cf tilmicosin. Proportion metabolised in liver to inactive metabolites) some active drug excreted in bile.
64
Describe erythromycin and its uses.
Given by oral administration, parenteral administration, stearate hydrolysed in GT to free base. Free base is well absorbed from the GIT (upper SI). Esters are absorbed as such, hydrolysed in tissues. It is relatively safe. Highly irritant given - oral, IV thromophlebitis, IM, intramammary. some serious GIT disturbances may occur in horses, rabbits. May induce vomiting in dogs. Used for staph aureus infections. C jejuni enteritis, and R equi pneumonia with rifampicin.
65
What is tylosin and what are its uses?
It has a short half life, large VD, less active vs bacteria than erythromycin but good activity vs mycoplasma and treponema. Similar toxicity to erythromycin, irritant to tissues, should not be used in horses. Its uses are to treat leptospirosis, alternative to tetracyclines for rickettsia infections, mastitis, bovine pneumonia, foot rot, mastitis. Used in the management of mycoplasma in poultry and pigs. Not commonly used in small animals.
66
What is spiramycin used for?
Not as effective vs mycoplasma as tylosin or tiamulin. Less active than erythromycin in vitro. Long persistence of drug in tissues - residues - long half life. Excellent ability to concentrate in tissue. Good activity in vivo despite in vitro comparison.
67
What is tiamulin?
A pleuromutilin - lipophilic, penetrates cell walls, high concentrations in lung and milk, excellent activity vs mycoplasma and anaerobes, rapidly absorbed, also available as parenteral preparation, one way cross resistance with tylosin. Used in pigs vs swine dysentry, enzootic pneumonia and leptospirosis. Cannot be given with ionophore antibiotics in pigs, poultry. It precipitates primary ionophore toxicity. It probably interferes with cyto p450 mediated metabolism. Skin lesions have been reported in pigs - avoid in horses, rabbis , guinea pigs.
68
What is tilmicosin?
It is toxic in humans, horses, sheep goats and pigs. Main indication pasteurella pneumonia. It has a long duration of action, therapy only required every 48 hours. It has good penetration and persistence in the lungs.
69
What is tulathromycin?
Very closely related to azithromycin. Licensed specifically in cattle and pigs. It has a long half life and more importantly long persistence in tissues. Respiratory disease - mycoplasma, pasteurella, manheimia, haemophillus.
70
What are the lincosamides?
Basic compounds - structurally distinct from the macrolides but share many properties. Lincomycin, clindamycin - semisynthetic derivative of lincomycin with greater activity.
71
What is the mechanism of action of the lincosamides?
They inhibit bacterial protein synthesis. They bind to 50S subunit and inhibit peptidyl transferase. They are similar to chloramphenicol therefore they can inhibit each other. They are bacteriostatic can be 'cidal' to some anaerobes.
72
What is their spectrum of antimicrobial activity.
They have a moderate spectrum. Active vs gram +ve bacteria, anaerobes and mycoplasma. Clindamycin active vs toxoplasma, some malarial parasites. They have little activity vs gram -ve bacteria. Many gram negative bacteria resistant because of impermeability and methylation of ribosomal binding site.
73
Describe the bacterial resistance to the lincosamides?
Chromosomal mutation - can emerge during treatment but not common. Plasmid mediated is common - methylation of adenine residues in ribosomal RNA of the 50S ribosomal subunit inhibits drug binding. cross resistance between the lincosamides and the macrolides is common.
74
What are the pharmacokinetics of the lincosamides?
Basic compounds - pKA values 7.6. Oral administration - good absorption in non herbivores. Food can decrease the absorption of lincomycin. Parenteral administration; good bioavailability. Highly plasma protein bound; rapid elimination. They have a large vd due to high lipid solubility. Tissue concentrations generally exceed serum concentrations several fold. ion trapping occurs - relevant potentially in udder, prostate, lung. CSF levels not as high as other tissues. Good penetration into bone, eye, synovial fluid. Eliminated mainly through hepatic metabolism.
75
What toxicity occurs with the lincosamides?
Gastrointestinal signs probably due to the destruction of anaerobic bacteria in the colon. Contraindicated in horses - haemorrhagic colitis and diarrhoea. highly toxic to rabbits, guinea pigs and hamsters. Cattle - inappetance, diarrhoea, Dogs & cats: relatively non toxic.
76
What are the interactions of the lincomycins?
Combined with aminoglycosides in umans. Clindamycin synergistic with metranidazole. Combinations of macrolides or chloramphenicols with lincosamides are antagonistic in vitro.
77
What is the mechanism of action of the tetracyclines?
They inhibit bacterial protein synthesis. They enter the bacteria by passive diffusion (outer cell wall) and active carrier-mediated transport (inner cell membrane). They bind to the ribosome (30S subunit) and prevent access of aminoacyl tRNA onto the ribosomal mRNA complex. They prevent elongation of the peptide chain. They are bacteriostatic.
78
What is the antimicrobial activity of the tetracyclines.
They are broad spectrum antibiotics. Gram+ve bacteria, Gram-ve bacteria, mycoplasma, chlamydia, rickettsia, protozoa, spirochaetes. Many staph and enterobacteriaceae are resistant. They are all approx equipotent. Minocycline has greater activity than other tetracyclines due to its kinetics. They exert greater activity at acidic pH.
79
Describe the pharmacokinetics of the tetracyclines?
Adequate absorption from the GIT in dogs and cats. Systemic availability depends on drug preparation, presence of food/milk in the stomach. Given orally to carnivores, omnivores and newborn herbivores. Adult herbivores - intestinal microflora is altered. Lipid solubility determines distribution and excretion. They are generally well distributed into most tissues except CSF. Minocycline penetrates tissue best. Metabolism is minimal. Most excreted unchanged in urine and bile. Minocycline is partly metabolised. Doxycycline is excreted almost entirely in faeces. May undergo enterhepatic recycling. Long half lives - 6-14hours.
80
What types of resistance occur with the tetracyclines?
Acquired resistance - developing among bacteria and mycoplasma. Plasmid mediated - interference with transport of tetracycline into and out of cell.
81
Describe the toxicity that may occur with tetracyclines?
Broad spectrum suppression of intestinal flora leads to superinfection with resistant pathogens. e.g colitis X in horses. They are irritant (by injection and orally) - oesophageal lesions in cats have been reported. Occasional anaphylaxis after IV administration. They are deposited at active sites of ossification - staining of teeth. Not such a problem with newer agents. They are nephrotoxic at high doses - dose related functional changes in renal tubules in some species. Exacerbated by dehydration, debility, haemoglobinuria and toxaemia.
82
What are the indications for use for tetracyclines?
Cattle: respiratory infections in calves, pneumonias, infectious keratoconjunctivitis. Sheep: Q fever (coxella burnetti), enzootic abortion (chlamydia psittaci). Pigs: Atrophic rhinitis (bordatella bronchiseptica). Dogs, cats chlamydophila infections, rickettsial infections. Doxycycline useful in cases with renal impairment.
83
Give a brief summary of the tetracyclines?
Broad spectrum antimicrobials. They act by inhibiting proteiin synthesis. They penetrate tissues well. They have reasonable absorption from the GIT . suitable for mixed infections. Considerable resistance has developed.
84
What is chloramphenicol?
A lipid soluble, neutral compound. It acts by inhibiting bacterial protein synthesis - penetration of the cell wall is by facilitated diffusion. It binds irreversibly to the bacterial ribosome (50S subunit) and blocks the action of peptidyl transferase. It is bacteriostatic.
85
What is the antimicrobial activity of chloramphenicol?
Broad spectrum of activity - gram +ve b acteria, gram -ve bacteria (good against salmonella, pasteurella, haemophilus), rickettsia, chlamydophila, anaerobes. Not very effective against mycoplasma. Pseudomonas is increasingly resistant.
86
What are the pharmacokinetics of the chloramphenicols?
Oral administration - well absorbed in monogastric animals, inactivated in the rumen. Moderately binding to plasma protein. Large Vd. Good penetration into tissues and body fluids. Wide variation in half life. Drug is metabolised in liver by glucuronidation. Glucuronide conjugate is excreted in urine and to a lesser extent in bile - enterohepatic recycling. Some drug is excreted by glomerular filtration unchanged in the urine. Inhibits microsomal enzymes - may prolong half life of other drugs.
87
What type of resistance occurs with chloramphenicol?
Plasmid mediated resistance is most common - mediated by multiple resistance genes. Intracellular enzymes acetylate chloramphenicol. Resistance may occur by mutation - slow process.
88
What types of toxicity occur with chloramphenicol?
Depression of bone marrow - inhibits protein synthesis in mammalian bone marrow cells. Reversible in cats. In humans it can cause fatal aplastic anaemia. May precipitate phenytoin toxicity in epileptic animals.
89
What are the indications for use of chloramphenicol?
Concern: that chloramphenicol resistance might be acquired by enteric commersals or pathogens in animals, contaminate carcases and pass along the food chain to colonise the human gut. Potential source of resistance factors which could be transferred to human enteric organisms. Recommendations: use chloramphenicol only as an exceptional measure e.g in opthalmic infections; CNS infections. Not to be used in food producing animals.
90
Describe Florfenicol and thiamphenicol pharmacokinetics?
Thiamphenicol is a derivative of chloramphenicol. Florfenicol is an analogue of thiamphenicol. They have advantages over chloramphenicol as they do not induce irreversible bone marrow aplasia in humans. They cause reversible haematopoietic depression in animals. Florfenicol is rapidly absorbed after IM injction and has good systemic availability. It has low binding to plasma proteins. Volume of distribution is 0.76L/kg - concentrations in CSF, b rain and aqueous humor < serum concentrations. Concentratios in bronchial secretions > serum concentrations. Some metabolism , remainder excreted unchanged in urine.
91
What are the Nitroimidazoles?
E.g Metranidazole. Dimetridazole now banned in food producing species. Used in veterinary medicine for their activity against anaerobic bacteria. They inhibit nucleic acid function - reduction of the nitro group yields unstable intermediates. Loss of helical structure of DNA and strand breakage leads to cell death.
92
What is the spectrum of activity of the nitroimidazoles?
Anaerobic G+ve and G-ve - very little against aerobes. Some protozoa e.g giardia and trichomonas fetus. Resistance is rare and involves reduced intracellular drug activation.
93
Describe the pharmacokinetics of the nitroimidazoles?
Well absorbed after oral administration, excellent tissue penetration, proportion metabolised in the liver (oxidation, conjugation) unchanged drug excreted in the urine.
94
What are the clinical applications of metranidazole?
Anaerobic infections - including acute gingivitis/periodontal disease in cats and dogs. OFten used in combinations to improve anaerobic spectrum. Note metranidazole is also banned in food producing species as is dimetridazole but has companion animal application.
95
What is Rifampin?
It inhibits RNA polymerase - enzyme that catalysis the transcription of DNA to RNA. It is bactericidal - gram+ve, anaerobes, chlamydophila, rickettsia. Some antifungal and antiviral activity. Resistanc does occur - chromosomal mutation, plasmid mediated uncommon. Used in combination with other drugs.
96
Describe the pharmacokinetics of Rifampin?
Can give orally. Highly lipid soluble therefore large volumes of distribution. Crosses blood brain barrier. Improved by inflammation. Enters abscess cavities. Penetrates phagocytic cells. EXcellent for intracellular pathogens. Used for rhodococcus equi infection in foals. Atypical mycobacterial lesions in cats. It is metabolised to desacetylrifampin. Ultimately glucuronidated. Little unchanged drug in urine. Increases cytochrome p450 activity.
97
What are the polymyxins and describe their antimicrobial activity?
They are products of bacillus polymixa. Simple basic peptides attached to a long chain FAs. heir mechanism is - surface active agents, disrupt cell membrane phospholipids - rapidly bactericidal. They are active against gram -ve organisms (not proteus) Resistance is rare- manifests as reduced bacterial permeability. Cross resistance within polymyxins occurs but not out with. can occur with pseudomonas. They are poorly absorbed from the GIT and have a small volume of distribution and diffuse poorly through membranes. Accumulation occurs with long term dosing. They are excreted unchanged in urine.
98
What possible toxicity occurs with the polymyxins and what are their therapeutic uses?
Nephrotoxic to the renal tubular epithelial cells. Neurotoxic - can cause a degree of neuromuscular blockade. May cause degranulation of mast cells - hypotensive episoode. They are mainly used topically in eye and ear preparations. Systemic administration at lower doses to bind endotoxin - actually binds LPS and in addition inhibits the production of cytokines by LPS induced macrophages.
99
What is novobiocin?
Mechanism of action: inhibits nucleic acid synthesis. Bactericidal. Antimicrobial activity: gram +ve. Resistance: chromosomal mutation can occur. Toxic if used parenterally. Therapeutic uses: used in local preparations e.g intramammary.
100
What is Bacitracin?
A polypeptide antibiotic Mechanism of action: inhibits foormation of bacterial cell wall peptidoglycan. It is bactericidal. Antimicrobial activity: narrow spectrum, gram+ve. Resistance not uncommon. It is not absorbed from the GIT. Toxicity : highly nephrotoxic. Too toxic to use parenterally. Used topically for superficial infections of skin, and may be combined with a g-ve active antibiotic. Banned as in feed growth promotant.
101
What is fusidic acid?
A lipophilic steroid antibiotic. Available as a soluble sodium salt. Mechanism of action: inhibits protein synthesis - inhibits binding of aminoacyl tRNA to ribosomal A site. Active against gram+ve bacteria - very effective against S aureus. Reasonable activity against M tuberculosis. Resistance can occur during therapy. Combination with penicillins delays considerably the resistance. It is relatively non toxic, used to treat ocular staph infections eg conjunctivitis. Used topically to treat g+Ve skin and ear infections.
102
What is thiostrepton?
Sulphur containing polypeptide antibiotic. Mechanism of action:inhibits protein synthesis. Bacteriostatic. most active against g+ve cocci. Used topically in ear preparations.
103
What is griseofulvin?
An antifungal. A fungistatic antibiotic derived from pencillium griseofulvum. It is preferentially taken up into the fungal cell. It has an energy dependent mechanism and disrupts the mitotic spindle. Its spectrum - dermatophytosis , microsporum, tricophytan, epidermophytan. A fatty meal enhances its oral bioavailability. It distributes preferentially to the stratum corneum,hair and nails. It has a short plasma half life but binds tightly to the skin cells and stays there until cells are shed.
104
What is flucytosine?
A fluorinated pyrimidine. Its mechanism of action is fungicidal - the drug is taken into the fungal cell where it is converted to 5-flouracil by cytosine deaminase.. This then incorporates into mRNA and cases faulty protein synthesis. Other metabolites also disrupt DNA synthesis. Its spectrum activity is narrow: yeast - more specifically candida and cryptococcus neoformans. Well distributed into CNS and CSF.
105
Describe amphotericin B (a polyene)
It is a fungicidal - its main mechanism is binding to ergosterol in the fungal cell membrane causing disruption. Mammalian cells have cholesterol not ergosterol. It is broad spectrum. Poor oral bioavailability and poorly soluble, it is highly plasma protein bound and has biliary and some renal excretion. It is highly nephrotoxic. Combinations may reduce dose eg with flucytosine.
106
Describe Nystatin (a polyene)
A Broad spectrum polyene antibiotic which disrupts the fungal cell membrane by occupying ergosterol binding sites. It is fungicidal, used topically , no absorption rom the GI tract so used for alimentary candidiasis.
107
Describe Natamycin (A polyene)
Similar to nystatin, a fungicidal polyene antibiotic with broad spectrum activity. Used in topical preparations and only suitable for superficial mycoses as no absorption to deeper layers.
108
What is the mechanism of action of the Azole antifungal agents - the imidazoles and triazoles?
All in the grop inhibit the formation of ergosterol necessary in the structure of the fungal cell membrane (Cyctochrome P450 dependent). Toxicity depends on their selectivity for fungal versus mammalian cytochrome P450. Triazoles more specific than imidazoles. Generally they are fungistatic. Systemic use azoles - ketoconazole (imidazole), fluconazole, itraconazole (triazole). Topical use azoles - clotrimazole, miconazole, enilconazole.
109
Describe ketoconazole and its uses?
Broad spectrum - yeasts, dermatophytes, dimorphic fungi, malassezia. Pharmacokinetics - hydrophobic, lipophilic molecule, acid required or absorption, oral bioavailability good, limited distribution - does get into milk. High PPB. Hepatic metabolism with inactive metabolites, biliary excretion. Avoid use in breeding males, CI in pregnancy. Used for systemic fungal infections. May need prolonged treatment.
110
Describe the pharmacokinetics of fluconazole?
Hydrophilic and well distributed including in the CSF. Oral absorption not acid dependent, excreted unchanged in the urine, can give IV.
111
Describe clotrimazole, miconazole and enilconazole
All topical azole antifungals. Limited to topical use for a variety of reasons - clotrimazole rapidly inactivated, miconazole vehicle too toxic.
112
Describe the Allylamines?
Terbinafine - inhibits squalene epoxidase - reducing ergosterol production. Squalene accumulates in the cell membrane leading to cell death. Given orally for dermatophyte infections. Lipophilic and penetrates keratinized tissues where it persists. Has been used in the dog and cat although not licensed.
113
What are the iodides?
Antifungals - mechanism of action is unclear but may be applied topically or given orally. Potassium iodide used for cutaneous histoplasmosis.
114
Describe novel antifungal agents that target the fungal cell wall?
Echincandins: Caspofungin, micafungin and andilafungin. They target and inhibit an enzyme called glucan synthase which then prevents polysaccharide production.
115
What is acyclovir?
It is an acylic guanine nucleoside. It acts by inhibiting viral DNA polymerase, only clinically effective against herpes virus. It has greater affinity for viral enzymes versus mammalian enzymes. Can be administered orally or by iv injection. It is eliminated unchanged in the urine.
116
What is Zidovudine?
Phoosphorylateed by cellular enzymes to active form where it inhibits RNA dependent DNA polymerase it also causes chain termination. It is shown to have activity against HIV. Gets into the CSF. Metabolised to the 5 glucuronide, metabolites are active and drug excreted in the urine. May cause anaemia and granulocytopenia. May be useful in FIV.
117
What are omega interferons?
They are recombinant peptides of feline oriigin. Their mechanism of action is not entirely clear. They interfere with translational protein production and disrupt mRNA. As they are peptides they are not orally bioavailable. They are given i/v or s/c. They have a short half life, low volume of distribution and high clearance. They have a good margin of safety. They are marketed specifically for the treatment of canine parvovirus. Also been used for cases of FeLV and FIV.
118
What is amantadine?
A water soluble cyclic amine. It has a narrow spectrum of activity - myxoviruses, paramyxoviruses, toga viruses and influenza A. It is thought to involve disruption of virus assembly. it has good oral bioavailability, renal elimination and half life of about 15 hours. It is used in the management of influenza.
