pharm 7 (30S protein synthesis inhibitors)

Aminoglycosides

Antibacterial class acting at the 30S ribosomal subunit (protein synthesis inhibitors); Exam 2 focus

Systemic aminoglycosides

Gentamicin, amikacin (focus on these two), and tobramycin; also used intra-articularly (IA) and for regional limb perfusion (RLP)

Local aminoglycosides

Neomycin and streptomycin; not absorbed orally, so used orally to treat GI lumen infections

Aminoglycoside mechanism of action

Irreversibly bind a specific receptor protein on the 30S subunit; immature proteins are released and aberrant proteins are inserted in the cell wall, causing altered permeability and cell death (may also affect 50S)

Aminoglycoside bactericidal activity

The only bactericidal protein synthesis inhibitor class; kills rapidly

Aminoglycoside post-antibiotic effect (PAE)

Altered membrane proteins increase drug permeability, so effects last long after the drug has left the plasma

Aminoglycoside spectrum

Gram-negative aerobes (primary), staphylococci (including some MRSA/MRSP); no activity against streptococci or strict anaerobes

Why aminoglycosides don’t work on anaerobes

They require oxygen for active transport into the bacterial cell

Aminoglycoside clinical uses

Severe gram-negative infections/sepsis, systemic MRSP, pleuropneumonia, peritonitis, neonates; use limited by adverse effects

Why combine aminoglycosides with beta-lactams

Synergism and broader spectrum (beta-lactams cover streptococci and anaerobes)

Amikacin vs gentamicin

Amikacin is more active, less toxic, and less prone to resistance (least affected by aminoglycosidases) but much more expensive; amikacin is preferred in dogs and cats

Aminoglycoside oral absorption

Poor for all drugs in the class (water soluble)

Aminoglycoside routes of administration

IM absorption is almost 100%; IV is the most common route; SC is used in dogs and cats

Aminoglycoside distribution

High water solubility, low protein binding, and highly polar give a low volume of distribution; they stay in plasma and extracellular fluid

Aminoglycoside protected sites and intracellular bacteria

Do not penetrate the CNS, eye, prostate, abscesses, or cells; ineffective against intracellular organisms like R. equi

Aminoglycoside volume of distribution in neonates

Higher because of more body water, so the drug is diluted and the Cmax is lower, which can make it ineffective

Aminoglycoside elimination

Excreted unmetabolized by the kidney via glomerular filtration (tubular reabsorption also occurs; fluids help prevent it); half-life 1-2 hr with normal renal function

Aminoglycoside PK/PD pattern

Concentration-dependent killing; target Cmax:MIC of 8-10x (e.g., MIC 2 ug/mL needs Cmax >16-20 ug/mL); dose ranges are age-dependent (neonates vs adults)

Why aminoglycosides are dosed once daily

Higher dose gives higher Cmax (8-10x MIC) and uses the PAE; it lowers nephrotoxicity because trough stays low (Cmin <2-3 ug/mL) and renal tubular active transport saturates at high doses

Most clinically relevant aminoglycoside adverse effect

Dose-dependent nephrotoxicity (risk greatly decreased with q24h dosing)

Aminoglycoside nephrotoxicity ranking

Gentamicin > tobramycin > amikacin

Risk factors for aminoglycoside nephrotoxicity

Dehydration, fever, and pre-existing renal disease

Aminoglycoside nephrotoxicity reversibility and protection

Often reversible, but treatment is prolonged because the kidney eliminates the drug slowly; calcium is protective (competes with the drug in tubules), so add calcium to fluids

Aminoglycoside ototoxicity

Drug accumulates in the perilymph and organ of Corti; deafness in horses (often not clinically relevant: reversible, unilateral vs bilateral); increased risk in cats and with topical otic products and a ruptured ear drum

Aminoglycoside vestibular toxicity signs

Head tilt, ataxia, impaired righting reflexes, and cochlear toxicity

Aminoglycoside neuromuscular blockade

Competes with calcium transport at the motor endplate; avoid with certain anesthetics and skeletal muscle relaxants, and in neuromuscular junction diseases such as botulism

Aminoglycoside reproductive safety

Considered teratogenic in humans

Aminoglycoside drug interactions

Beta-lactams (synergy), bacteriostatic drugs (possible antagonism), other nephrotoxic drugs, NSAIDs, and furosemide/diuretics unless the patient is well hydrated (increased nephrotoxicity risk)

Aminoglycoside resistance mechanisms

1 enzymatic modification by aminoglycosidases (mostly plasmid-mediated; amikacin least affected); lesser mechanisms are altered ribosome binding and reduced uptake (active transport)

Aminoglycosides in food animals

“Voluntary ban” because of prolonged kidney residues; US withdrawal recommendations 10 days milk and 18 months meat (Canada: 7 years for meat)

The 4 Nos of aminoglycosides

Nephrotoxic/ototoxic, protein synthesis inhibitor, no anaerobic spectrum, no oral absorption

Tetracyclines

Antibacterial class acting at the 30S ribosomal subunit (protein synthesis inhibitors)

Tetracycline mechanism of action

Reversibly bind the 30S subunit and block amino acids from being added to the peptide chain, preventing protein elongation

Tetracycline bactericidal vs bacteriostatic

Bacteriostatic at all relevant concentrations (always)

Tetracycline drugs and species

Oxytetracycline (horses, food animals), chlortetracycline (food animals), minocycline and doxycycline (horses, dogs, cats)

Most active tetracyclines

Doxycycline and minocycline

Tetracycline spectrum

Very broad: gram-positive and gram-negative, aerobes and anaerobes, Chlamydia, Rickettsia, spirochetes, Mycoplasma, L-form (cell wall deficient) bacteria, some protozoa; resistance is common

Tetracycline uses in dogs and cats

Ehrlichia, Rickettsia, Mycoplasma haemofelis, Borrelia, and Bartonella; treatment of choice for tick-borne diseases and intracellular organisms

Tetracycline use in birds

Chlamydophila psittaci

Tetracycline uses in horses

Neorickettsia risticii and Anaplasma phagocytophilum (rickettsial diseases), and Lawsonia intracellularis

Tetracycline use in food animals

Injectable extended-release products (BRDC, foot rot, diphtheria, bacterial enteritis, wooden tongue, leptospirosis, wound infections, acute metritis, anaplasmosis, anthrax) and feed/water additives (E. coli enteritis, P. multocida pneumonia, combined with other drugs)

Tetracycline oral absorption

Good in small animals; poor to moderate in horses and ruminants (still used orally); can be erratic, so minocycline is given on an empty stomach

Tetracycline chelation

Cations in the stomach (e.g., calcium in milk or diets) bind the drug and decrease absorption

Tetracycline distribution

Distribute well to most tissues; minocycline is best for protected sites (CNS, eye, prostate) because it is more lipophilic with lower protein binding; doxycycline is as lipophilic but has higher protein binding, which limits protected-site penetration

Tetracycline intracellular accumulation

Accumulate intracellularly, especially in neutrophils

Tetracycline elimination

Oxytetracycline mainly renal; doxycycline via bile and kidneys; minocycline mainly via bile

Tetracycline common adverse effects

GI signs (mild to severe; regional in horses) and esophageal strictures in cats

Doxycycline esophageal stricture in cats

Tablets or capsules cause direct mucosal ulceration and stricture, especially when broken; follow with about 6 mL water or a small amount of food

Rapid IV tetracycline administration

Causes hypotension and collapse in any species (possibly from calcium chelation or propylene glycol vehicles)

IV doxycycline in horses

Fatal

Tetracycline minor adverse effects

Dental discoloration and inhibition of long bone growth in young animals or offspring of treated pregnant animals (doxycycline less likely); photosensitization, particularly with doxycycline

Tetracycline rare adverse effects

Nephrotoxicity only at high oxytetracycline doses (propylene glycol formulations; not reported with chlor/doxy/mino); idiosyncratic hepatotoxicity (foals: doxycycline/rifampin)

Tetracycline resistance

Widespread; mainly drug efflux (pumps), plasmid-mediated; oxytetracycline = chlortetracycline > doxycycline > minocycline

Tetracycline non-antibacterial uses

Heartworm treatment in dogs and cats (kills Wolbachia, a bacterial endosymbiont); anti-inflammatory effects via MMP inhibition (topical in the eye for melting ulcers, systemic for synovitis/laminitis in horses)

Tetracycline key concepts

Bacteriostatic, 30S protein synthesis inhibitor, broad spectrum, accumulates intracellularly, drug of choice for tick-borne diseases, doxycycline can cause esophageal strictures in cats and is fatal IV in horses, skeletal and dental issues in young animals