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Principles of Antimicrobial Therapy
Selective toxicity is achieved by exploiting the differences between the metabolism and structure of the microorganism and the corresponding features of human cells. There are four major sites in the bacterial cell that are sufficiently different from the human cell that they serve as the basis for the action of clinically effective drugs: cell wall, ribosomes, nucleic acids, and cell membrane. Broad-spectrum antibiotics are active against several types of microorganisms (e.g., tetracyclines are active against many gram-negative rods, chlamydiae, mycoplasmas, and rickettsiae). Narrow-spectrum antibiotics are active against one or very few types (e.g., vancomycin is primarily used against certain gram-positive cocci, namely, staphylococci and enterococci). Inhibition of bacterial cell wall synthesis can be done by following drugs:
- Cycloserine & Bacitracin
Inhibition of Protein Synthesis
Several drugs inhibit protein synthesis in bacteria without significantly interfering with protein synthesis in human cells. This selectivity is due to the differences between bacterial and human ribosomal proteins, RNAs, and associated enzymes. Bacteria have 70S ribosomes with 50S and 30S subunits, whereas human cells have 80S ribosomes with 60S and 40S subunits. Chloramphenicol, erythromycin, clindamycin, and linezolid act on the 50S subunit, whereas tetracyclines and aminoglycosides act on the 30S subunit. Aminoglycosides are bactericidal drugs especially useful against many gram-negative rods. Chloramphenicol is active against a broad range of organisms, including gram positive and gram-negative bacteria (including anaerobes).
Inhibition of Nucleic Acid Synthesis
Sulfonamides are inexpensive and infrequently cause side effects. However, drug-related fever, rashes, photosensitivity (rash upon exposure to sunlight), and bone marrow suppression can occur. They are the most common group of drugs that cause erythema multiforme and its more severe forms, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Fluoroquinolones are bactericidal drugs that block bacterial DNA synthesis by inhibiting DNA gyrase (topoisomerase). Another important adverse effect of fluoroquinolones is peripheral neuropathy, e.g., pain, burning, numbness, or tingling in the arms or legs.
Rifampin is used primarily for the treatment of tuberculosis in combination with other drugs and for prophylaxis in close contacts of patients with meningitis caused by either N. meningitidis or H. influenzae. The selective mode of action of rifampin is based on blocking mRNA synthesis by bacterial RNA polymerase without affecting the RNA polymerase of human cells. Rifampin is red, and the urine, saliva, and sweat of patients taking rifampin often turn orange; this is disturbing but harmless. Rifampin is excreted in high concentration in saliva, which accounts for its success in the prophylaxis of bacterial meningitis since the organisms are carried in the throat.
Alteration of Cell Membrane Function
There are few antimicrobial compounds that act on the cell membrane because the structural and chemical similarities of bacterial and human cell membranes make it difficult to provide sufficient selective toxicity. Polymyxins are a family of polypeptide antibiotics of which the clinically most useful compound is polymyxin E (colistin). Amphotericin B, the most important antifungal drug, is used in the treatment of a variety of disseminated fungal diseases. Nystatin is another polyene antifungal agent, which, because of its toxicity, is used topically for infections caused by the yeast Candida. Terbinafine blocks ergosterol synthesis by inhibiting squalene epoxidase. It is used in the treatment of dermatophyte infections of the skin, fingernails, and toenails. Azoles are antifungal drugs that act by inhibiting ergosterol synthesis.
Additional Drug Mechanisms
Isoniazid inhibits the synthesis of mycolic acid, a long-chain fatty acid found in the cell wall of mycobacteria. Isoniazid is a prodrug that requires a bacterial peroxidase (catalase) to activate isoniazid to the metabolite that inhibits mycolic acid synthesis. Isoniazid is the most important drug used in the treatment of tuberculosis and other mycobacterial diseases. Metronidazole is effective against anaerobic bacteria and certain protozoa because it acts as an electron sink, taking away the electrons that the organisms need to survive. It also forms toxic intermediates that damage DNA. Antimicrobial drugs are used to prevent infectious diseases as well as to treat them. Chemoprophylactic drugs are given primarily in three circumstances: to prevent surgical wound infections, to prevent opportunistic infections in immunocompromised patients, and to prevent infections in those known to be exposed to pathogens that cause serious infectious diseases.
Probiotics are live, non-pathogenic bacteria that may be effective in the treatment or prevention of certain human diseases. For example, the oral administration of live Lactobacillus rhamnosus strain GG significantly reduces the number of cases of nosocomial diarrhea in young children.