Antimicrobials Flashcards
What are the mechanisms of action of the antimicrobials?
- 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.
What are the antimicrobials?
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.
What are the different types of resistance that may develop to the antimicrobials?
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.
What are the potential results of resistance?
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.
What is the MIC?
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.
What is post antibiotic effect?
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.
What are the Beta Lactam antimicrobials?
They consist of; Narrow spectrum penicillins Broad spectrum penicillins Antipseudomonal penicillins Monobactams Carbapenems 1st,2nd,4d and 4th generation cephalosporins.
What is the mechanism of action of the penicillins?
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)
What does the activity of the penicillins depend on?
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.
What is beta lactamase?
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.
Describe the pharmacokinetics of the penicillins?
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.
Describe penicillin G?
Gram positive spectrum only, acid labile, beta lactamase susceptible. Unstable in gastric acid, inactive against gram negative bacteria (relatively.
Describe penicillin V?
Gram positive only, acid stable, beta lactamase susceptible.
Describe Nafcillin and the beta lactamase resistant penicillins?
Gram positive only, acid and beta lactamase stable - resistant to gram positive beta lactamases e.g staphylococci. Have minimal activity against gram negative organisms.
What is the spectrum of activity of the narrow spectrum penicillins G and V?
Gram positive - staphylococcus aureus, beta haemolytic streptococci, corynebacterium, ersipelothrix spp, bacillus spp. Gram negative - fastidious spp such as haemophilus, pasteurella, actinobacillus. Anaerobes - clostridium, fusobacterium.
Describe the broad spectrum penicillins - aminopenicillins?
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.
Describe the antispeudomonal penicillins?
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.
What are the Beta lactamase inhibitors?
Clavulanic acid, tazobactam and sulbactam are suicide inhibitors. They bind irreversibly to beta lactamase enzymes and synergise beta lactam antibiotics. They are weak antibacterials.
Describe the toxicity of penicillins?
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.
What are the interactions of the penicillins?
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.
What are the cephalosporins & what are the characteristics of each generation?
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.
What is the mechanism of action of the cephalosporins?
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.
Describe the pharmacokinetics of the cephalosporins:
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.
Describe some of the cephalosporins used in companion animal species?
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.
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.
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.
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.
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.
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.
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.
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.
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.
How does nephrotoxicity occur with the aminoglycosides?
Acute tubular necrosis, proteinuria, hyaline and granular casts in urine. Reversible, caused by neomycin, gentamicin. Consider TDM.
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.
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.
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.
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.
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.
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.
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%.
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.
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.
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.
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.
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.
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.
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.
