Elizabeth Davis; Week 12 MED1011; Pharmacology
Targets of antibacterials are cell wall synthesis, protein synthesis, nucleic acid synthesis and other metabolic processes. Choice of antibacterial depends on bacterial factors, host factors and drug factors.
Cell wall synthesis inhibitors are beta lactams such as penicillins (amoxycillin), cephalosporins (cephalexin), carbapenams and monobactam; glycopeptides such as vancomycin; and polypeptides such as bacitracin. Beta lactams inhibit synthesis of peptidoglycan wall by inhibition of polymer crosslinking (by inhibiting transpeptidases). Causes lysis and cell death in growing cells. Spectrum of activity is determined by ability to bind transpeptidases, ability to penetrate cell to reach target (gram +ve hydrophilic and phobic drugs cross; -ve hydrophilic pass through porins more readily). Hydrophilic is broad spectrum therefore and hydrophobic is narrower. Beta lactams act synergistically with other antibacterials (increased penetration of cell wall by aminoglycosides). Can react with amino groups on proteins and make them antigenic causing an immune response, dose dependant, and can cross react. Beta lactamase is produced by some bacteria, is inactivated by clavulanic acid, it cleaves the beta lactam ring and inactivates the drug.
Penicillins have 4 groups based on spectrum of activity and sensitivity to beta lactamase, used for a range of infections caused by sensitive organisms, inihbits transpeptidases and has selectivity for bacterial transpeptidases. Amoxycillin is moderate spectrum but becomes broad spectrum with clavulanic acid. It has few adverse effects, nausea, diarrhoea, can have hypersensitivity rash. Anaphylaxis is rare but can be fatal. Superinfection can occur especially if treatment is prolonged. Excreted by kidneys. Safe in pregnancy and breast feeding.
Cephalosporins are classified by spectrum of activity and sensitivity to beta lactamases. Rarely first choice, used for penicillin allergies. Selective for bacterial transpeptidases. Cephalexin is moderate spectrum, common adverse effects are diarrhoea, nausea, vomiting. Rare is neurotoxicity. Can cause hypersensitivity reactions and opportunistic infection. Precautions are renal excretion (reduce dose if renally impaired), safe in pregnancy and breastfeeding. Cephalexin is given orally.
Glycopeptides such as vancomycin are used only for severe infections resistant to other drugs (endocarditis). Inhibits transglycosidase and polymerisation as well as cell wall synthesis. Vancomycin is lipophilic, large, not well absorbed orally and has renal excretion. Side effects are common and include nausea, vomiting, 'red man syndrome', associated with nephrotoxocity and ototoxicity. Resistance is common so used sparingly.
Agents that inhibit protein synthesis are aminoglycosides (gentamicin), macrolides (erythromycin), tetracyclines (doxycycline), lincosamides eg clindamycin. Gentamicin is used for serious gram -ve infections, serious systemic enterococcal infections/endocarditis, surgical prophylaxis, eye infections. It binds irreversibly to 30S ribosomal subunit to inhibit protein synthesis (bactericidal at therapeutic levels) and is broad spectrum. It enters through an oxygen dependant mechanism so is not effective against anaerobes. It is also highly polar so has limited movement, poor oral absorption, t1/2 is 2-3 hours (short). It has a low therapeutic index and can cause nephrotoxicity and ototoxicity.
Macrolides e.g. erythromycin reversibly bind 50S subunit and blocks movement of ribosome along mRNA. It is broad spectrum and used in penicillin sensitive patients. It can be used in UR infection and sinusitis. It is broad spectrum, with serious adverse effects rare. It can be the drug of choice for some infections. Allergic responses can occur and it may prolong QT interval, can also have drug interactions and should be avoided in first trimester.
Tetracyclines such as doxycycline have a broad spectrum of activity, reversibly bind to 30S subunit and is used for acne and URT. Prevents protein translation. Adverse effects are GI disturbances, chelate calcium deposited in bones and teeth, hepatotoxic, renal damage, photosensitivity. Resistance is a problem, not recommended in hepatic impairment or children/pregnancy. Used for malaria.
Chloramephincol binds to 50S like erythromycin, not first line, orally active and widely distributed. Can cause nausea, vomiting, bone marrow suppression (reversible usually), causes 'grey baby syndrome' in some neonates.
Agents which affect nucleic acid synthesis are fluoroquinolones (ciprofloxacin), nitroimidazoles (metronidazole), rifampicin inhibits RNA synthesis. Fluoroquinolones like ciprofloxacin are broad spectrum against gram negative, limited use usually. Inhibits topsoisomerase (DNA gyrase) which is involved in DNA supercoiling. It is well absorbed from the gut and has good distribution. Adverse effects are infrequent and mild (cartilage and tendon damage, phototoxicity can occur). Precautions are hepatic metabolism, increasing resistance.
Nitroimidazoles such as metronidazole are gram positive and negative anaerobic infections, work on some protozoal infections. Can cause a headache, nausea, dry mouth, metallic taste and can interfere with alcohol metabolism.
Rifampicin inhibits DNA polymerase enzyme, used as part of TB combined treatment and staph aureus. Has significant drug interactions and is always used in combination. Isonazid is antimycobacterial, activated by tuberculosis and inhibits synthesis of mycolic acids (constituents of cell wall), Always used in combination due to resistance. Can cause allergic reactions, fever, hepatotoxicity, haematological changes.
Agents affecting other pathways are sulphonamides which inhibit folate synthesis by resembling PABA, are bacteriostatic but have decreased effect in the presence of pus. Can cause allergic reactions and GI disturbances. Allergenic and resistance is common. Used in combination with trimethoprim which inhibits dihydrofolate reductase in bacteria. Is bacteriostatic. Used for UTI, prostatitis, some resp infections, high doses possibly for megaloblastic anaemia.