Antimicrobials PDF
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Ross University School of Veterinary Medicine
Kristen
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Summary
This presentation details various antimicrobials, including their mechanisms of action, side effects, and clinical applications. The presentation covers different classes of antimicrobials and their properties. It's aimed at a medical or veterinary audience.
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# Antimicrobials ## Remember | | Bactericidal | Bacteriostatic | |-------------|-----------------------------|-----------------------------| | **Concentration dependent** | Aminoglycosides | Tetracycline | | | Flur...
# Antimicrobials ## Remember | | Bactericidal | Bacteriostatic | |-------------|-----------------------------|-----------------------------| | **Concentration dependent** | Aminoglycosides | Tetracycline | | | Fluroquinolone | | | | Nitroimidazoles | | | | Polymyxin (F NAP) | | | **Time dependent** | B-lactam | Tetracycline | | | Ansamycin | Sulfonamide/diaminopyrimidine | | | Glycopeptides (BAG) | Amphenicol | | | | Macrolide | | | | Lincosamide (MALTS) | ## Beta Lactams - Beta lactamase inhibitor - Penicillin - Aminopenicillin - Antistaphylococcal Penicillin - Antipseudomonal Penicillin - Cephalosporins - Penems and Monobactams ## General info - Chemistry: Major target for bacterial resistance mechanisms - Gastric pH deactivates most beta lactams except aminopenicillins and some cephalosporins - MOA: Inhibits penicillin binding protein (PBP) – synthesis of bacterial cell wall peptidoglycan - Acetylation of transpeptidase - Effective against rapidly multiplying organisms. - Poor membrane penetration: little use for intracellular pathogens - Susceptibility G+ > G- except aminopenicillin, extended spectrum penicillins, cephalosporins, penem, monobactams - Time dependent bactericidal ## General info - Resistance: bacteria produce beta-lactamases that hydrolyze the beta lactam ring - Synergist with aminoglycosides (other than aminopenicillin) and beta lactams - Do not use with bacteriostatic antimicrobials (remember, needs multiplying organism to work) ### Aminoglycoside Monotherapy - Gentamicin (NFL Running back) ### Synergistic Drug Combination - Gentamicin (NFL Running back) - Peptidoglycan (Defensive Line) - Cell Wall Synthesis Inhibitor (NFL Offensive Front Line) : B-lactam or vancomycin induced gaps in growing cell wall ## Beta Lactamase Inhibitor - Clavulanic acid: No WHO rank ### PK - **Absorption:** Oral and IM bioavailability is variable - **Distribution:** Penetrates tissue body fluids - **Vd:** moderate - **Metabolization:** Extensively in dog - **Elimination:** Renal excretion of unchanged drug via glomerular filtration - Feces - High levels in urine ### PD - **Spectrum of activity:** Very little antibacterial properties - Inhibit bacterial beta lactamases: only assist in destruction of resistant bacteria that produce beta lactamases - Inactivates penicillinase and some cephalosporinases - Does NOT inactivate all G- beta lactamases - Most beta lactamase is synthesized by anaerobes - **Formulations:** Amoxicillin-clavulanic acid oral formulation for humans and small animals. Human formula has different ratio than vet formula. - Sodium ampicillin-sulbactam and acarcillin disodium-clavulanic acid - **Clinical indications:** Treatment of sepsis in small animals or foals ### Gram + - Staphylococcus spp ### Gram - - Klebsiella - Enterobacteriaceae ### Anaerobes - Bacteroides fragilis ## Penicillin - Penicillin G: WHO: HI, Time dependent ### PK - **Absorption:** Oral penicillin V only - IM/SQ quickly absorbed – depending on injection site - Flip flop kinetics - **Distribution:** Distributed in ECF and may not reach therapeutic concentration - **Vd:** low to moderate - **Elimination:** Renal excretion of unchanged drug via glomerular filtration - High levels in urine - Short half life if IV, long acting formulas have longer half lives due to flip flop kinetics - **Formulations:** - Pen G: water soluble salt – not stable IV, IM, SQ - Procaine pen G/Benzathine Pen G: long acting, less soluble IM ### PD - **Spectrum of activity:** Narrow, gram + and anaerobes - Little efficacy against beta lactamase producers - **Drug residues:** Procaine is slowly eliminated, violative residues in race horses, food animals. Give < 10mLs per injection site - Pen G: Found in injection site long after label withdrawal period - **Side effects:** - Hypersensitivity reaction (Types I, II, and III) - Procaine reaction: IV – CNS stimulation. Keep it in fridge and administer carefully IM - Electrolyte imbalances, cardiac arrythmias. Administer slow IV - GI upset, floral alterations. Clostridium in g. pigs, hamsters, rabbits - **Clinical indications:** Anaerobic infection, streptococcal diseases, life threatening situation - Swine and poultry local treatment of enteritis - Mastitis in dry cow - First line: septic pneumonia ### Gram + - Streptococci - Erysipelothrix rhusiopathiae - Trueperella pyogenes - Corynebacterium - Clostridium ### Gram - - Anaerobes - Fusobacterium necrophorum ### Mycoplasma - Intrinsic resistance: No cell wall ## Aminopenicillin - Ampicillin, Hetacillin, Amoxicillin: WHO: HI, Time dependent ### PK - **Absorption** - PO: amoxicillin 2x bioavailability of ampicillin - Amoxicillin bioavailability not affected by food - PO don't reach therapeutic concentration - horses and ruminants - Ampicillin sodium – IM/SQ vs ampicillin trihydrate with flip flop kinetics - **Distribution:** Most body fluids – synovial fluid. Meninges when inflamed - **Vd:** low to moderate - **Elimination:** Renal excretion of unchanged drug via glomerular filtration - Short half life ### PD - **Spectrum of activity:** Broad spectrum, G+ and G-, especially amoxicillin - Beta-lactamase inhibitors extend spectrum - **Drug reactions:** Precipitates with aminoglycosides - **Side effects:** Same as Penicillin G. - **Formulations:** - Amoxicillin: oral tablet and suspensions - Ampicillin: oral capsules - Amoxi-clav: oral formulations - Sodium ampicillin: IV, IM, SQ - Ampicillin trihydrate: IM, SQ - Hetacillin: intramammary infusion for dairy cattle ### Gram + - Aerobes and anaerobes - Enterococci - S. Aureus resistant ### Gram - - Aerobes and anaerobes - E. coli, salmonella, Pasteurella - Pseudomonas, Bacteroides are resistant. ### Mycoplasma - Intrinsic resistance: No cell wall ## Antistaphylococcal Penicillin - Cloxacillin, methicillin: WHO: HI, Time dependent ### PK - **Absorption:** PO: low and inconsistent - **Distribution:** Vd: low to moderate - **Elimination:** Renal excretion of unchanged drug via glomerular filtration - Short half life ### PD - **Spectrum of activity:** Narrow spectrum, G+ - Do not penetrate outer layer of G- - Used as indicators of multi-drug resistance, if resistant to methicillin – resistant to all beta lactams. - May be resistant to fluoroquinolones, sulfonamides/diamino, macrolides, lincosamides - MRSA and MRSP - **Formulations:** Cloxacillin: intramammary infusion ### Gram + - Resistant to beta lactamase of staphylococcus spp. - No intracellular bacteria ### Gram - - Minimal activity ### Mycoplasma - Intrinsic resistance: No cell wall ## Antipsuedomonal Penicillin - Extended spectrum: WHO: Human Use Only, Time dependent ### PK - **Absorption:** PO: Carbenicillin only one sufficiently absorbed - Ticarcillin and Piperacillin must be injected - Neonates have high bioavailability than older foals. - **Distribution:** Vd: low to moderate (similar to other penicillins) ### PD - **Spectrum of activity:** Narrow spectrum, G- and anaerobes - Can penetrate wall of Pseudomonas and other G- - Decreased activity against G+ - Beta lactamase producers can inactivate - **Drug interactions:** Synergist with aminoglycosides - **Formulations:** Cloxacillin: intramammary infusion ### Gram + - Resistant to beta lactamase of staphylococcus spp. - No intracellular bacteria ### Gram - - Minimal activity ### Mycoplasma - Intrinsic resistance: No cell wall ## Cephalosporins 1st and 2nd gen - 1st: Cefadroxil, cephalexin, cephapirin, cefazolin - 2nd: cefoxitin - ELDU: Restricted - WHO: HI, Time dependent ### PK - **Absorption:** PO: dogs, cats, horse neonates - Erratic in older foals, ruminants, horses. - IM/SQ rapid absorption - **Distribution:** Vd: low - Penetrates bone - Primarily ECF: pleural, pericardial, synovial - **Elimination:** Renal excretion of unchanged drug via glomerular filtration - Very short half life ### PD - **Spectrum of activity:** Broad, G+ and G- ### Side effects - Same as Penicillin G - Coagulopathies, blood dyscrasias – vitamin K antagonism - Gl upset from oral administration (give with food) - Nephrotoxic: do not give with aminoglycosides - **Formulations:** - Cefadroxil and cephalexin: oral - Cephapirin (human formulation): intramammary and intrauterine ### Gram + - Aerobic and anaerobic - Corynebacterium, strep and staph - MRSA, MRSP, enterococci, - Rhodococcus equi resistant ### Gram - - Aerobic, anaerobic - Enterobacteria, Pasteurella, - Haemophilus, Histophilus - 1st: Bacteroides is resistant ### Mycoplasma - Intrinsic resistance: No cell wall ## Cephalosporins 3rd and 4th gen - 3rd: Ceftiofur, cefovecin, cefotaxime, cefpodoxime, ceftazidime - 4th: Cefquinome - ELDU: Restricted - WHO: HPCI, Time dependent ### PK - **Absorption:** PO: dogs, cats, horse neonates - Erratic in older foals, ruminants, horses - IM/SQ rapid absorption - Ceftiofur crystalline free acid and cefovecin: flip flop kinetics - **Distribution:** Vd: low - Penetrates bone - Primarily ECF: pleural, pericardial, synovial - 3rd: Highly protein bound - **Elimination:** Renal excretion of unchanged drug via glomerular filtration - Very short half life, longer when protein bound ### PD - **Spectrum of activity:** Broad, G+ and G- ### Side effects - Same as Penicillin G - Coagulopathies, blood dyscrasias – vitamin K antagonism - Gl upset from oral administration (give with food) - Nephrotoxic: do not give with aminoglycosides - Injection site inflammation with cetiofur - **Formulations:** - Ceftiofur: injectable formulations including a slow release. - Intramammary for lactating or dry cows - Cefovecin (convenia): SC use in dogs and cats – 14 day duration - Cefpodoxime: tablets for dogs ### Gram + - Restricted to patients with multiple drug resistant strains - Used for skin infections and UTI - Aerobic and anaerobic - Corynebacterium, strep and staph (ceftiofur less active against) - MRSA, MRSP, enterococci, - Rhodococcus equi resistant ### Gram - - Aerobic, anaerobic - Enterobacteria (ceftiofur less active against), Pasteurella, Haemophilus, - Histophilus, Bacteroides, Pseudomonas ### Mycoplasma - Intrinsic resistance: No cell wall ## Penems - Imipenem, Meropenem: WHO: Human Use Only, Time dependent ### PK - **Absorption:** Meropenem SQ good b/a in dogs - **Distribution:** Penetrates inflamed meninges - **Elimination** - Imipenem: metabolized by renal tubule – toxic compound - Short half life ### PD - **Spectrum of activity:** Last resort drug in human med - Stable against most beta lactamases - Bactericidal G- - **Sid effects with Imipenem:** - Nephrotoxic: renal injury - Seizure: diluted and slow CRI ### Gram + - MRSA ### Gram - - Anaerobes and Aerobes ### Mycoplasma - Intrinsic resistance: No cell wall ## Monobactams - Aztreonam: WHO: Human Use Only, Time dependent ### Clinical indications: Avoid use in vetmed ### Gram + - ---- ### Gram - - Aerobes only ### Mycoplasma - Intrinsic resistance: No cell wall ## Aminoglycoside and Aminocyclitols - Oxygen dependent (aerobes only) - MOA: Bind to 30s ribosomal sub unit - Bactericidal - Concentration dependent ### Therapeutic Drug Monitoring - Accumulate in renal tubular cells – renal failure - Continuous exposure leads to adaptive resistance - Concentration of at least 8-10x MIC should be achieved for efficacy ## Aminoglycoside - Gentamicin, amikacin, streptomycin, neomycin, kanamycin, apramycin: WHO: CI, Concentration dependent ### PK - **Absorption:** - IM/SQ: Rapidly and well absorbed - PO: not well absorbed - **Distribution:** - Vd low to moderate in ECF, higher in neonates - Effective concentrations in synovial, perilymph, pleural, peritoneal, and pericardial fluid - Renal tubular epithelium accumulation - **Elimination:** - Glomerular filtration - Short half life – increased in neonates or with renal dysfunction ### PD - **Spectrum of activity:** Narrow spectrum, G- and some G+ aerobes - Efficacy decreased in purulent debris or acidic environments - **Drug reactions:** - Precipitates with aminopenicillin - Avoid nephrotoxic drugs - Anesthesia: neuromuscular blockade - **Side effects:** - Nephrotoxic - Ototoxic: vestibular or cochlear damage - Neuromuscular block: ACh or calcium inhibitor - Cardiotoxic - **Formulations:** - Gentamicin/Amikacin: small animal and intrauterine infusions in mares - Commonly used IV, IM, SQ, intra-articular, and IO routes - Gentamicin: topical and ophthalmic formulation - Neomycin: oral formulation or part of triple antibiotic ### Gram + - Somewhat effective against aerobes ### Gram - - Aerobes including pseudomonas ### Mycoplasma - May be susceptible ## Aminocyclitols - Spectinomycin: WHO: Important, Bacteriostatic unless 4x MIC ### PK - **Absorption:** IM/SQ: Rapidly and well absorbed - PO: not well absorbed - **Distribution:** Vd low to moderate in ECF, higher in neonates - Effective concentrations in synovial, perilymph, pleural, peritoneal, and pericardial fluid - **Elimination:** Glomerular filtration - Short half life ### PD - **Spectrum of activity:** Narrow spectrum, G- aerobes (rods unpredictable) - Efficacy decreased in purulent debris or acidic environments - **Drug reactions:** Anesthesia: neuromuscular blockade - **Side effects:** Neuromuscular block: ACh or calcium inhibitor ### Formulations: - Oral and parenteral - Spectinomycin + lincomycin ### Gram + - Little anaerobic activity ### Gram - - Aerobes including - Pseudomonas is resistant ### Mycoplasma - Susceptible ## Tetracyclines - Tetracycline (TTC), oxytetracycline (OTC), chlortetracycline (CTC), doxycycline (DXC): WHO: HI ### PK - **Absorption:** - PO: poor, though oral formulations exist - IM and SQ bioavailability is high - Long acting formulation (flip flop kinetics), lost if given IV - **Distribution:** - Vd large: well distributed: milk, synovial, peritoneal fluid, endometrial tissue - OTC high concentration in urine - Not in CNS unless inflammation - DXC highly protein bound - **Elimination:** - Glomerular filtration and enterohepatic circulation - Long half life ### PD - **Spectrum of activity:** Broad spectrum, G-, G+, and mycoplasma - Widespread acquired resistance - plasmid mediated - **Drug reactions:** Calcium chelation: avoid calcium containing products. Interferes with absorption. - **Side effects:** - Gl upset in horses and small animals - Nephrotoxic - Cardiovascular collapses: - Rapid IV: hypotension and collapse - IV DXC – death in horses - Musculoskeletal effects: swelling at injection site - Fever: cats - Esophageal stricture: follow drug with water to avoid - Discolored teeth in fetuses - **Formulations:** - Injectable OTC: slow IV - Oral OTC, TTC, CTC: use in food animals including fish - Oral TTC and OTC for small animals - Ophthalmic ointment - Feed additives - DXC oral and IV ### Gram + - Aerobe, anaerobe, intracellular - Listeria ### Gram - - Aerobes, anaerobes, intracellular - Enterobacteriales and - pseudomonas are resistant ### Mycoplasma - Susceptible