Protein Synthesis Inhibitors

• Protein synthesis inhibitors target either the 30S or 50S ribosomal subunit
• Selectivity for bacterial protein synthesis is achieved because bacterial ribosomal subunits differ from mammalian ones
• Drugs must enter bacteria, so entry inhibition can lead to resistance

Classification

• Aminoglycosides
• Tetracyclines
• Macrolides
• Lincosamides (clindamycin)
• Chloramphenicol

Aminoglycosides

• Inhibit the 30S ribosomal subunit and are bactericidal
• Effective against Gram-negative bacteria like P. aeruginosa, Proteus, Klebsiella, E. coli, and Enterobacter
• Synergistic when combined with penicillins, spectrum of activity is synergistic for endocarditis
• Poor oral absorption due to polarity necessitates parenteral or topical administration
• Narrow therapeutic index is associated with side effects
  • Ototoxicity
  • Nephrotoxicity
  • Neuromuscular toxicity: Blockage of presynaptic ACh release, contraindicated in MG, may cause respiratory suppression; calcium gluconate and neostigmine can reverse
• Elimination occurs almost completely via glomerular filtration, so impaired kidney function leads to increased aminoglycoside concentration and toxicity

Specific Aminoglycosides

• Streptomycin sulphate is used with isoniazid for T.B and is drug of choice for plague and tularemia
• Gentamicin is used for serious Gram-negative infections like pneumonia, UTI, osteomyelitis, and septicemia, and topically for burns, wounds, and skin lesions; sometimes used with ampicillin or other penicillins
• Amikacin treats infections caused by Gram-negative bacteria resistant to other aminoglycosides
• Tobramycin is used topically for eye infections
• Neomycin is an exception for topical eye and skin applications and oral use as an intestinal antiseptic before intestinal operations and for hepatic coma

Important Considerations for Aminoglycosides

• Contraindicated and used in combination with other B-lactams
• Penicillins weaken the cell wall to promote aminoglycoside uptake by facilitating its diffusion
• Penicillins may inactivate aminoglycosides if mixed together in the same solution due to chemical incompatibility, so they should be used separately

Tetracyclines

• Inhibit the 30S ribosomal subunit (bacteriostatic) and decrease sebum secretion in acne treatment
• Limited use due to resistance
• Still the first choice for Chlamydia, Rickettsial infections like Rocky Mountain spotted fever, and Mycoplasma pneumonia
• Chlamydia cause nongonococcal urethritis (NGU)
• Examples include tetracycline, doxycycline, and minocycline
• Cannot be taken with meals containing milk, cheese, antacids, or multivitamins due to chelation with calcium
• Contraindicated in pregnancy and children under 8
  • Cause teeth and bone abnormalities (permanent yellow discoloration and deformity of bone with inhibition of growth)

Adverse Reactions of Tetracyclines

• Hypersensitivity
• Photosensitivity
• Gastric discomfort: Anorexia, heartburn, nausea, vomiting, flatulence, and diarrhea
• Super infection: Overgrowth of Candida
• May affect calcified tissues, may cause dysgenesis, staining, and caries in teeth during tooth development Tooth discoloration varies from yellowish blown to dark gray
• Intra-cranial hypertension
• May form non-absorbable complexes with divalent cations (Fe, Ca, Al, and Mg).
• Doxycycline is less toxic than tetracycline
• In case of renal impairment, give doxycycline as it is excreted in feces not in urine
• If pregnant with NGU, give Erythromycin

Tetracycline Doses

• Tetracycline requires 4 times per day dosing
• Doxycycline requires twice per day dosing

Tetracycline Drug Interactions

• Tetracyclines increase the effects of coumarin anticoagulants and seriously interfere with blood clotting

Macrolides

• Examples include Erythromycin, Clarithromycin, and Azithromycin
• Inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing elongation of the peptide chain
• Low toxicity as they do not bind to mammalian ribosomes
• Effective against Gram-positive cocci and bacilli, Neisseria, and Chlamydia
• Used for respiratory tract infections, rheumatic fever, and toxoplasmosis
• Erythromycin is effective against the same organisms as penicillin G but not H. influenzae; used in patients allergic to penicillins (Syphilis)
• The drug of choice for uro-genital infections of Chlamydia during pregnancy, atypical pneumonia caused by Mycoplasma, and Legionnaires' disease

Erythromycin Adverse Reactions and Contraindications

• Relatively safe antibiotic
• Epigastric distress is minimized by enteric-coated tablets and ester derivatives taken with food
• Cholestatic jaundice (hepatitis) can occur
• Ototoxicity (Transient)
• Contraindicated in patients with hepatic dysfunction
• Macrolides (erythromycin) inhibit hepatic enzymes, increasing the concentration of warfarin

Other Macrolides

• Clarithromycin is stable in gastric acid and well absorbed, and has a long half-life enabling twice-daily dosing, inhibits P-450 enzymes
• Azithromycin is more active against Gram-negative bacteria and is frequently used to treat respiratory infections and non-gonococcal urethritis
• It inhibits P 450, increasing the concentration of theophylline and antihistamines (astemizole or terfenadine), which may cause life-threatening arrhythmias

Additional Notes

• Penicillins are ineffective against pneumonia caused by mycoplasma because mycoplasma has no cell wall. It is treated by Tetracyclines in adults and erythromycin for children

Lincosamine

• Clindamycin is concentrated in bone and teeth and used in anaerobic infections

Chloramphenicol

• It has broad-spectrum activity but limited use due to its toxicity
• It inhibits bacterial protein synthesis by binding to 50S ribosomal subunits
• In certain microorganisms, it is preferred for the treatment of Samonella infection, Haemophilus influenza, meningitis, or pneumonia
• It can be given orally or parenterally and crosses the BBB

Chloramphenicol Adverse Reactions

• Gl upsets, overgrowth of Candida on mucous membranes
• Anaemias
• Haemolytic anaemia (in patient lacks glucose-6-posphate dehydrogenase)
• Aplastic anaemia (irreversible) and reversible bone marrow suppression
• Gray baby syndrome: Newborn infants are deficient in glucuronyl transterase, the enzyme that metabolizes chloramphenicol in the liver
• Large doses will precipitate gray baby syndrome, characterized by vomiting, hypothermia, gray skin, and shock

Chloramphenicol Interactions

• It inhibits mixed function oxidases and can block the metabolism of drugs like warfarin, phenytoin, tolbutamide, and chlorpropamide