Medical Microbiology Chapter 6: Antimicrobial Chemotherapy PDF

Kingdom of Saudi Arabia ‫اﻟﻣﻣﻠﻛﺔ اﻟﻌرﺑﯾﺔ اﻟﺳﻌودﯾﺔ‬ Ministry of Education ‫وزارة اﻟﺗﻌﻠﯾم‬ Qassim University ‫ﺟﺎﻣﻌﺔ اﻟﻘﺻﯾم‬ College of Me...

Kingdom of Saudi Arabia ‫اﻟﻣﻣﻠﻛﺔ اﻟﻌرﺑﯾﺔ اﻟﺳﻌودﯾﺔ‬ Ministry of Education ‫وزارة اﻟﺗﻌﻠﯾم‬ Qassim University ‫ﺟﺎﻣﻌﺔ اﻟﻘﺻﯾم‬ College of Medical Rehabilitation ‫ﻛﻠﯾﺔ اﻟﺗﺎھﯾل اﻟطﺑﻰ‬ Medical Microbiology [EDPT 211] Prof. Dr. Noha Mohammed Afifi Chapter 6 Antimicrobial Chemotherapy Antimicrobial Drugs are either: * Naturally produced from a living microorganism. This is known as (Antibiotic: that inhibits growth of other microorganisms) e.g. antibiotic Penicillin is produced from the fungus Penicillium fungi Streptomycin is produced from the bacteria Streptomyces. * Synthetic; prepared in the lab., known as (Chemotherapeutic). Antibacterial agents are divided into 2 Classes: (I) Bactericidal drugs (Irreversible killing): These drugs have a rapid lethal action (kill the microorganisms) e.g. Penicillin, Vancomycin and Cephalosporins. They inhibit “Cell Wall” formation in bacteria. (II) Bacteriostatic drugs (Reversible stoppage): These drugs inhibit the division (i.e. the growth of microorganisms) e.g. Tetracyclines, Chloramphenicol and Erythromycin. They inhibit protein synthesis in bacteria. Prof. Noha Afifi 39  Range of Action of Antimicrobial Drugs Antibiotics fall into 3 categories according to Activity Spectrum: 1. Active mainly against gram positive organisms e.g. Penicillin & Erythromycin. [Limited Spectrum] 2. Active mainly against gram negative organisms e.g. Nalidixic acid and Polymyxin. [Limited Spectrum] 3. Active against BOTH gram positive and gram negative organisms e.g. Ampicillin, Tetracyclines & Chloramphenicol. [Broad Spectrum]. Therapeutic Index (TI) of Antimicrobial Drugs Therapeutic Index is the Ratio between: Blood concentration of the drug to be: Toxic (Lethal) Dose / Therapeutic (Effective ) Dose. “High Therapeutic Index = Less Toxic” = Safe drug If the TI is small (the difference between the two concentrations is very small), the drug must be dosed carefully and the person receiving the drug should be monitored closely for any signs of drug toxicity. Prof. Noha Afifi 40  Mechanism of Action of Antimicrobial Drugs - An ideal antimicrobial agent should have Selective Toxicity i.e. it can kill or inhibit the growth of a microorganism in concentrations that are NOT harmful to the cells of the host. Thus, the mechanism of action of an antimicrobial drug must depend on the inhibition of a metabolic channel or a structure that is present in the microbe, but NOT in the host cell. Several Mechanisms of Action of Antimicrobial Drugs:  1) Inhibition of Cell Wall synthesis: (due to its unique structure) e.g. Penicillin, Vancomycin and Cephaolsporins [Bactericidal; mainly on gram +ve organisms].  2) Inhibition of Cytoplasmic Membrane function: (with subsequent leakage of cellular proteins and nucleotides leading to cell death i.e. Cidal) e.g. Polymyxins; act mainly on the fungi as its cytoplasmic membrane is formed of Ergesterol. Prof. Noha Afifi 41  3) Inhibition of Protein synthesis: (by acting on the 30s or 50s subunits of the bacterial ribosome) e.g. Chloramphenicol, Tetracycline and the Aminoglycosides e.g. Tobramycin, Gentamycin and Streptomycin. [Static]  4) Inhibition of Nucleic Acid synthesis: (by acting on any of the steps of DNA or RNA replication) e.g. Quinolones, Nalidixic acid and Metronidazole. [Static]  5) Competitive Inhibition: (Many organisms use para-aminobenzoic acid (PABA) in folic acid synthesis which is essential for protein synthesis. [Static] Sulphonamides are structural analogues to PABA, so they enter the reaction instead of PABA, thus inhibiting folic acid synthesis. [static] Mechanism of Resistance to Antimicrobial Agents  1) The organism produces enzymes that destroy the drug e.g. production of beta-lactamase (Penicillinase) enzyme- that destroys penicillin—by penicillin- resistant staphylococci (MRSA).  2) Gram-negative bacteria develop resistance to Polymyxins by modification of LPS in the outer bacterial membrane, thus impairing active transport of Polymyxin into the cell. [Polymyxins are highly Nephrotoxic and Neurotoxic, so they are used only topically as ointment].  3) The organism changes the antibiotic receptor site: resistance to Aminoglycosides is associated with alteration of a specific protein in the 30s subunit of the bacterial ribosome, that serves as a binding site for the organism.  4) The organism switches to an altered metabolic pathway that bypasses the reaction inhibited by the drug e.g. Sulphonamide-resistant bacteria acquire the ability to use preformed folic acid, with no need for extracellular PABA. Prof. Noha Afifi 42  Origin of Resistance to Antimicrobial Agents (Genetic or Non-Genetic) (A) Non-Genetic Drug Resistance: 1- Metabolic inactivity: Most antimicrobial agents act effectively ONLY on replicating cells. - Tubercle bacilli survive for years in tissues, yet they are restrained by the host’s defenses and don’t multiply (DORMANCY). - Such persisting organisms are resistant to anti-tuberculous drugs, due to their metabolic inactivity. - When they start to multiply, they become susceptible to the drugs. 2- Loss of target structure: - L-forms of bacteria are penicillin-resistant, having lost their cell wall which is the structural target site of the drug. - When these organisms revert to their parent bacterial forms, and resume cell wall production, they are again susceptible to Penicillin. (B) Genetic Drug Resistance: Prof. Noha Afifi 43 1- Chromosomal-drug resistance: this develops as a result of spontaneous mutation in a gene that controls susceptibility to an antimicrobial agent. For example, Streptomycin resistance can result from mutation in the chromosomal gene that controls the receptor for streptomycin, located in the 30s bacterial ribosome. 2- Extra-Chromosomal-drug resistance: a) Plasmid-Mediated b) Transposon-Mediated Prof. a) Plasmid-mediated resistance: Resistance (R) factors are a class of plasmids that mediate resistance to one or more antimicrobial agents. Plasmids carry genes that code for the production of beta-lactamase which destroys the β-lactam ring in Penicillin and Cephalosporins. b) Transposon-mediated resistance: - Simple transposons carry only information concerned with transposition. - Complex transposons carry additional genetic material unrelated to transposition, such as drug-resistance genes e.g. as Penicillin, Streptomycin and Chloramphenicol. Prof. Noha Afifi 44  Complications of Antimicrobial Chemotherapy 1- Development of Drug Resistance: - This may occur due to inadequate dosage, prolonged treatment and the abuse of antibiotics without susceptibility testing. - The condition is more serious in hospitals (Nosocomial Infections) where 90% of strains of Staph. aureus are resistant to penicillin (MRSA). 2- Drug Toxicity: This may occur due to overdosage, prolonged use or narrow margin of Selective Toxicity e.g. - Streptomycin affects the 8th cranial nerve leading to deafness. - Polymyxins are Nephrotoxic & Neurotoxic. - Tetracyclines inhibit growth of bones and teeth of the developing fetus and infants (Permanent Yellow-brown discoloration of teeth), so should be avoided during pregnancy. 3- Superinfection: Suppression of normal flora by the antibiotic used and their replacement with drug-resistant organisms which cause disease. For example, i- Overgrowth of Candida albicans in the vagina causing vaginitis or in the mouth causing oral thrush (Oral Candidiasis). ii- Prolonged oral chemotherapy leading to suppression of intestinal flora and overgrowth of Clostridium difficile which causes colitis. 45  4- Hypersensitivity: The drug may act as a hapten, binds to tissue proteins, and stimulates an exaggerated immune response leading to tissue damage i.e. hypersensitivity. The most serious hypersensitivity reaction is Anaphylactic shock, this may occur with Penicillin or Cephalosporins. Milder manifestations may be urticaria, skin rash, diarrhea and vomiting. Chemoprophylaxis Chemoprophylaxis is the use of antimicrobial agents to prevent rather than to treat infectious diseases. Prophylactic Antibiotics are positively indicated in the following conditions: 1) The use of Penicillin G injections every 4 weeks to prevent reinfection with Strept. Pyogenes in Rheumatic patients. 2) A single dose of Amoxicillin given immediately prior to dental procedures is recommended for patients with Congenital or Rheumatic heart disease to prevent Endocarditis. 3) Chemoprophylaxis in Surgery indicated in: Major orthopedic or cardiac surgery & Large bowel surgery. Combined Use of Antibiotics - For initial (blind/ Empiric) therapy when the patient is seriously ill and results of culture are pending. - Two or more antibiotics are required in some conditions e.g.: a- Serious resistant infections e.g. Infective Endocarditis. b- In treatment of Tuberculosis 2 or 3 drugs are given in combination ?? Rationale for Combined Therapy in Tuberculosis: 1- Synergy (additive) effect. 2- To prevent emergence of resistant mutants. 3- To decrease toxic effects of the drugs by lowering the dose of each. Prof. Noha Afifi 46  Prof. Noha Afifi 47