Antimicrobial drugs Can be defined as the use of chemicals in infectious disease to destroy microorganisms without damaging the host

tissues. Antibiotics Are substances that suppress the growth of or destroy microorganisms.

Most Common Microbial Organisms Causing Infectious Disease

Bacteria Fungi Viruses Protozoa Helminths

Antimicrobial Agents 1. Antibiotics: natural antimicrobial substances produced by certain microorganisms. 2. Chemotherapeutic Agents: chemically synthesized antimicrobial agents. 3. Semi-synthetic Antibiotics: antimicrobial agents of natural origin, but modified synthetically to improve pharmacological properties. A Clinically Useful Antimicrobial Agent: Should have as many of these characteristics as possible: 1. 2. 3. 4. 5. 6. 7. Low incidence of side effects and toxicity to patient. Non-allergenic to patient. Minimal effect on normal flora of patient (intestinal bacteria). Ability to access the site of infection. Inexpensive and easy to produce. Chemically stable. Low incidence of existing microbial resistance and low probability of future development of resistance.

Factors that influence the successful of chemotherapy of an infection are: Site: the drug should reach the site of infection. Concentration: it should attain adequate concentration at the site. Host defence: active host defences reduce the antibiotic requirement. Sensitivity: the microorganism should be sensitive to the antimicrobial agents.

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General considerations (principles) - Selective toxicity Most Desirable Property of an Antimicrobial Agent kills/inhibits pathogens with little or no host toxicity. - Susceptibility MIC (minimum inhibitory concentration) Lowest concentration of antibiotic that stops growth. MBC Required resuspending the bacteria in fresh media without antibiotics to see if the bacteria re grow. - Antimicrobial action Bacteriostatic Inhibits growth.e.g Chloramphenicol, erythromycin, clindamycin, and tetracycline. Bacteriocidal Causes cell death.Aminoglycosides, cephalosporins, and vancomycin. cidal vs. -static Ex. Ampicillin cidal against S. pneumonia and static against Enterococcus. - Combination of antimicrobial drugs 1. To obtain synergism usually recommended in bacterial endocarditis (penicillin+streptomycine), pseudomonas infection (carbincillin+gentamicine), pneumocyctis carini pneumonia (trimethoprim+sulphamethexazole). 2. Treatment of mixed infections like intra abdominal infections, brain abscess, genitourinary infection. 3. Initial treatment of severe infections: drugs covering both grampositive and gram-negative pathogens may be used initially till the culture report is available. 4. To prevent the emergence of resistance example in the treatment of tuberculosis and leprosy. - Spectrum of activity o Broad spectrum e.g Tetracyclines, Chloramphenicol o Narrow spectrum e.g Penicillin G, Aminoglycosides. o Extended spectrum e.g ampicillin

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- Resistance Is the unresponsiveness of a microorganism to the antimicrobial agent. 1. Natural (the organisms have never responded to the antimicrobial, may be due to the absence of a particular enzyme or target site affected by the drug) e.g gram negative bacilli to penicillin G 2. Acquired (the microbes which were previously sensitive to the antimicrobial agents become resistant to it) and the bacteria acquire resistance by a change in their DNA. Such DNA changes may occur by: - Mutation: is a genetic change that occurs spontaneously. In any population of bacteria. A few resistant mutants may be present. When the sensitive organisms are destroyed by the antibiotic, the resistant mutants freely multiply. - Transfer of genetic material: many bacteria contain extrachromosomal genetic material called plasmids in the cytoplasm. These carry genes coding for resistance called (R factors). These R-factor are transferred to other bacteria and spread the resistance. This may take place by: Transduction: plasmid DNA is transferred through bacteriophage, i.e virus which infects bacteria. Transformation: resistant bacteria may release genetic material into the medium which is taken up by other bacteria. Conjugation: is the most important mode of resistance. The Rfactor is transferred from cell to cell by direct contact through a sex pilus or bridge. The resistance acquired by the bacteria may be exhibited: 1. Altered cell permeability 2. Enzymatic inactivation of the antibiotic 3. Modification of antibiotic target site 4. Synthesis of a resistant metabolic pathways Altered cell permeability Decreased uptake o Altered proteins in the membrane decrease the overall membrane permeability, resulting in decreased uptake of antibiotics o E.g., Mutations of E. coli porin are associated with decreased sensitivity to various fluoroquinolones, tetracycline and chloramphenicol Active efflux (increased outflow) Pumps (transporters) in the outer membrane actively export the antibiotic back out, reducing the intracellular concentration.

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Enzymatic inactivation of the antibiotic o Beta-lactamase (bla) inactivates penicillin derivatives by cleavage of the betalactam ring. o Aminoglycoside inactivating enzymes, such as acetyltransferases, adenyltransferases, phosphotransferases). Modification of antibiotic target site o Penicillin binding protein (transpeptidase) mutants o Mutations in rpoB (RNA polymerase -subunit) confer resistance to rifampin. Prevent binding of the drug. Synthesis of resistant metabolic pathways o Hyperproduction of para-aminobenzoic acid (PABA). o A mutation in dihydropteroate synthetase results in a lower affinity for sulphonamides. o A mutation in dihydrofolate reductase results in lower affinity for trimethoprim.

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