Antimicrobial Chemotherapy PDF

Prepared by Dr Ayat Mostafa Chemotherapy is the treatment of infectious diseases by administration of drugs which are lethal or inhibitory to the causative organisms. Antimicrobial agents include: 1-Chemotherapeutics: A) Antibiotics e.g. penicillins is an antimicrobial substance produced by...

Prepared by Dr Ayat Mostafa Chemotherapy is the treatment of infectious diseases by administration of drugs which are lethal or inhibitory to the causative organisms. Antimicrobial agents include: 1-Chemotherapeutics: A) Antibiotics e.g. penicillins is an antimicrobial substance produced by a living microorganism to kill or inhibit the growth of another microorganism Synthetic modifications of previously discovered drugs allowed the development of several new antimicrobial agents. B) Synthetic chemicals e.g. sulphonamides, trimethoprim, quinolones…. 2-Antiseptics and disinfectants.  Criteria of ideal chemotherapeutic agent: 1- selective toxicity: It means that the chemotherapeutic agent produces toxic effect only against the microbial cells but not on the host cells. This selective toxicity depends on: A. The presence of biochemical and structural differences between microbial cells and host cells e.g. chemotherapeutic agents acting via inhibition of bacterial cell wall show selective toxicity due to absence of cell wall in mammalian cells. B. The presence of specific receptors for drug action. NB. Disinfectants, e.g. phenol and antiseptics, e.g. alcohol and iodine, destroy bacteria but they are highly toxic to tissue cells and are unsuitable for use as chemotherapeutic agents. 2- Bactericidal rather than bacteriostatic. 3- Broad spectrum rather than narrow spectrum. 4- Minimal side effects and no allergy. 5- Remain active in different body fluids. 6- High chemotherapeutic index. Chemotherapeutic index = Maximum tolerated dose Maximum curative dose The higher the Chemotherapeutic index, the better the drug. Classification of chemotherapeutic agents: I-According to antimicrobial spectrum: A- Broad-spectrum agents: Include agents which are active against several types of microorganisms, both gram positive and gram negative e.g. tetracyclines, chloramphenicol and cephalosporins. B- Narrow-spectrum agents: include Agents acting mostly against G+ve baceria e.g. vancomycin, penicillin G, erythromycin….. Agents acting mostly against G-ve baceria e.g. aminoglycosides, polymyxins….  II- According to antibacterial action: Bactericidal drugs Bacteriostatic drugs -Rapid killing action of bacteria. -Inhibit bacterial multiplication, but do not kill them. -Action is irreversible. -Action is reversible. The bacteria can grow again when the drug is withdrawn. In this case, host defense mechanisms, such as phagocytosis, are required to kill bacteria. -E.g. penicillins, cephalosporins and -E.g. sulphonamides, tetracyclines aminoglycosides. III- According to their source of origin: A-Natural: include * Antibiotics produced by bacteria e.g. polymyxin, bacitracin. * Antibiotics produced by fungi e.g. penicillins, cephalosporins * Antibiotics produced by actinomyces e.g. streptomycin, tetracyclines, chloramphenicol. B-Synthetic chemicals: E.g. sulphonamides, trimethoprim, quinolones. IV- According to their chemical structure: Chemotherapeutic agents can be classified into different groups according to differences in their chemical structure. E.g. β-lactam antibiotics.  A) Agents that inhibit cell wall synthesis: B) Agents that inhibit functions of cell membrane: V- According to their mechanisms of action: C) Agents that inhibit nucleic acid synthesis D) Agents that inhibit protein synthesis E) Agents that act as metabolic antagonists A) Agents that inhibit cell wall synthesis: Include 1-β-lactam antibiotics: *penicillins. *chephalosporins. *monobactams. *carbapenems. 2-glycopeptides: *vancomycin. *tiecoplanin. 3-polypeptides: *bacitracin. 4-cycloserine.  1-β-lactam antibiotics Mechanism of action: The cell wall is a rigid structure that surrounds the cytoplasmic membrane and protects the cell. The rigidity of the cell wall is due to the presence of peptidoglycan in its structure which is formed of a backbone of alternating N-acetyl glucosamine and N-acetyl muramic acid to which tetrapeptide side chains are attached. Its final rigidity is completed by cross linking of the peptide chains through transpeptidation reactions which are mediated by a group of enzymes known collectively as PBPs (penicillin binding proteins). B-lactam antibiotics inhibits cross-linking of peptidoglycan and preventing new cell wall formation that destroys the cell wall that leads to bacterial cell death Mechanism of bacterial resistance to B-lactam antibiotics: 1-inability of the drug to penetrate to its site of action. 2-altered PBPs with decreased affinity to β-lactam antibiotics. 3-different microorganisms produce β-lactamases that inactivate the antibiotic. 4-lack of peptidoglycan in bacterial cells e.g. L-forms and mycoplasma. Clinical applications of β-lactam antibiotics: Penicillins: 1-short acting penicillin G is used for pneumococcal, meningococcal, streptococcal meningitis and gonococcal infection (with sensitive strain) also used in syphilis, anthrax, clostridia infection and in diphtheria to eliminate carrier state. 2-long-acting penicillin G is used for prophylaxis against streptococcal infection and recurrence of rheumatic fever and syphilis. 3-penicillinase resistant penicillins are used in most of staphylococcal infections (vancomycin is used for resistant strains). Undesired reactions to penicillins: Allergy is the main serious reaction as penicillin act as a hapten that binds to host proteins leading to allergic reactions up to anaphylactic shock. β-lactamase inhibitors clavulanic acid and sulbactam. They protect hydrolyzable penicillins and are incorporated with them in many preparations. Cephalosporins: They are effective against both G+ve and G-ve (especially 3ed and 4th generations) bacteria as staphylococcal infection (but not MRSA), streptococcal infections, E.coli, kl.Pneuminae… they are destroyed by cephalosporinases. Monobactams: They are resistant to β-lactamases and active mainly against G-ve bacteria (mainly pseudomonas and serratia). They can be used in patients with allergy to penicillin. Carbapenems: They are resistant to β-lactamases and active against G+ve and G-ve anaerobes. They are used in UTI, LRTI, intraabdominal infections, skin and soft tissues infections, nosocomial infections and in pseudomonas infections.  2-Glycopeptides 1-Vancomycin: Mechanism of action: It inhibits cell wall elongation by inhibition of peptidoglycan synthesis via interaction with terminal D-alanine D-alanine bonds present in the side chains → block cross linking of PG subunits It is used for G+ve infections as staphylococcal infections (including MRSA) Resistance: Develops due to alteration of D-alanine D- alanine bonds leading to decreased affinity to vancomycin. Side effects: The most serious are ototoxicity and nephrotoxicity.  3-polypeptides Bacitracin: Obtained from B.subtilis. Mechanism of action: It inhibits early steps of cell wall synthesis by interfering with dephosphorylation and recycling of the lipid carrier (Bacto prenol phosphate BPP) responsible for moving peptidoglycan precursors through the cytoplasmic membrane to the cell wall. Clinical uses: It is used topically for skin infections caused by G+ve bacteria including MRSA alone or in combination with polymyxin B Side effects: The most serious is nephrotoxicity. 4-cycoserine It is a structural analogue of D-alanine so its incorporation into the cell wall leads to the formation of cell wall with abnormal function. B) Agents that inhibit functions of cell membrane: Include 1- polymyxins. 2- ionophores e.g. valinomycin. 3- daptomycin. Mechanism of action: The cell membrane is the osmotic barrier surrounding the cell which is responsible for constant internal environment of the cell by control of ion movement in and out of the cell. Any drug that disrupts the cell membrane functions will lead to ion leakage and cell death. there is no marked differentiation between the cell membrane of bacterial and animal cells, these drugs show no reliable selective toxicity and intended mainly for topical use. polymyxins Formed of detergent like cyclic peptide e.g. polymyxin B and polymyxin E. Mechanism of action: It binds to the surface of the cell membrane interfering with its selective permeability leading to cell death. Clinical uses: Active against G-ve aerobic bacilli including pseudomonas and serratia. -Used topically for eye, ear and skin infections. -Used for pseudomonas urinary tract infection. Disadvantages: 1-No selective toxicity. 2-Poor distribution to the tissues.  C) Agents that inhibit nucleic acid synthesis: Include 1-inhibitors of RNA synthesis: *Rifampicin. 2-inhibitors of DNA synthesis: *quinolones & flouroquinolones e.g. nalidixic acid, ofloxacin, norfloxacin, ciprofloxacin. *novobiocin. *metronidazole.  I-Inhibitors of RNA synthesis 1-Rifampicin Mechanism of action: inhibition of RNA synthesis by binding to DNA dependent RNA polymerase so inhibits transcription of DNA to mRNA so inhibits protein synthesis. Clinical uses: Mainly used for treatment of TB but can be used also for prophylaxis of CS meningitis. Resistance to rifampicin: develops mainly due to chromosomal mutations that lead to change in DNA dependant RNA polymerase.  II-Inhibitors of DNA synthesis 1-Quinolones and flouroquinolones E.g. ciprofloxacin, ofloxacin, norfloxacin and nalidixic acid. Mechanism of action: They inhibit the action of DNA gyrase by binding to its α-subunit. This enzyme is responsible for relaxation of positively supercoiled DNA. Clinical uses: 1-UTI 2-Entritis 3-LRTI 4-Venerial diseases caused by N.gonorrohoae and clamydia tracomatis. NB: these drugs are not used in children as they may lead to joint damage. Resistance: Develops due to: -chromosomal mutations with subsequent changes in α-subunit of DNA gyrase. -Decreased uptake of the drug due to alteration of the outer membrane permeability. -Active pump of the drug out (efflux pump). 2-Metronidazole Metronidazole is selectively absorbed then activated (reduced) by the microbial proteins (flavodoxins and ferredoxins) found in anaerobic bacteria and certain protozoa. Once activated, the reduction product of the drug oxidizes DNA causing cell death. NB: Mammalian cells are unharmed because they lack flavodoxins and ferredoxins that reduce the nitro group of metronidazole. It is used as antiprotozoal and in anaerobic bacterial infections. D-Inhibitors of protein synthesis Inhibitors of translation They inhibit translation of mRNA to proteins. These drugs show selective toxicity due to difference between mammalian ribosomes (80s) and bacterial ribosomes (70s). a-inhibitors of 30s ribosomal subunit: aminoglcosides. tetracyclins. b-inhibitors of 50s ribosomal subunit: chloramphenichol. lincomycin. clindamycin. macrolides (as erythromycin). linezolid  Linezolid: E.g. erythromycin, Azithromycin and It is an inhibitor of protein synthesis by clarithromycin binding to 50s ribosomal subunit. It is used mainly for treatment of multidrug resistant enterococci, VRSA e.g. streptomycin, kanamycin, neomycin, gentamycin, tobramycin, amikacin. Mechanism of Resistance: Mutation of ribosomal binding sits (chromosomally mediated). Enzymatic modification of the drug (plasmid mediated). Decreased uptake of the drug by the bacterial cell or active pump of the drug outside the cell. E) Agents that act as metabolic antagonists: These agents have structural similarity to metabolites essential for bacterial growth. So when incorporated into metabolic pathways lead to the formation of non functioning units and stop bacterial growth i.e. bacteriostatic. include sulphonamides. trimthoprim. PASA,isoniazide (INH), ethambutol→ used in treatment of TB dapsone sulfons.→ used in treatment of leprosy.  1-Sulphonamides and trimethoprim Mechanism of action: PABA (para-amino benzoic acid) is used by the bacterial cells to sensitize folic acid which is used as a precursor of nucleic acid formation. Sulphonamides compete with PABA. Trimethoprim inhibit folate reductase enzyme Selective toxicity: It is due to the fact that animal cells do not sensitize folic acid and depend only on exogenous source. Only bacterial cells synthesize folic acid. Resistance: Develops when the microorganism either: -Takes exogenous folic acid. -Produces excess PABA. -Alter dihydrofolate reductase and synthetase with decreased affinity to the drug. Clinical uses: Combination is used for - G-ve bacilli e.g. E.coli, shigella…. G-ve cocci → N.gonorrhoae and N.meningitidis. -G+ve bacilli → cl.difficile. Trimethoprim+ sulfamethoxazole = co-trimoxazole. These two drugs are given in combination which has the following advantages: Enhanced activity of both drugs. Increased antibacterial spectrum of both drugs. Combination is bactericidal for some bacterial strains rather than bacteriostatic. Decreased frequency of drug resistance  Limitation of Resistance to Antimicrobial Agents: It can be achieved by 1- Implementation of antibiotic policy through control, reduce, or cycle antibiotic usage 2-limition of empirical use of antibiotics. 3-use of the proper dose of the drug, at the proper time for enough duration. 4- Combination therapy by using two or more drugs that do not give cross resistance. 5-application of proper infection control measures to limit spread of resistant strains. 6-expensive and valuable drugs should be of limited use especially in hospitals. 7-developpment of new antibiotics. 8-modification of the existing drugs to overcome the resistance mechanism. 9-devlopment of agents that overcome the resistance mechanisms e.g. inhibitors of drug modifying enzymes, agents that cure resistance plasmids  Complications of Antibacterial Chemotherapy: 1- Development of drug resistance: The emergence of resistant mutants is encouraged by inadequate dosage, prolonged treatment, the presence of a closed focus of infection and the abuse of antibiotics without in vitro susceptibility testing. 2- Drug toxicity: Many of the antibacterial drugs have toxic side effects. This can be due to overdosage, prolonged use or narrow margin of selective toxicity Streptomycin affects the 8th cranial nerve leading to deafness. Chloramphenicol may cause bone marrow depression. Aminoglycosides, (e.g. gentamicin, tobramycin) are nephrotoxic. Tetracyclines inhibit growth and development of bones and teeth in the developing fetus and infants. 3- 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. Any type of hypersensitivity reaction can occur with several antibiotics. The most serious is anaphylactic shock, this may occur with penicillin or cephalosporins. Milder manifestations may be urticaria, purpural eruptions, skin rash, diarrhea, vomiting and jaundice. 4- Superinfection: Definition: It means bacteriological and clinical evidence of new infection during the treatment of the primary one. It is difficult to treat as it is caused by resistant strains. Mechanisms: Superinfection is due to suppression of normal flora by the antibiotic used and their replacement with drug resistant organisms which cause disease, e.g.: i-Overgrowth of Candida in the vagina causing vaginitis or in the mouth causing oral thrush. ii-Prolonged oral chemotherapy leading to suppression of intestinal flora and overgrowth of staphylococci causing staphylococcal enterocolitis or Cl. difficile which causes pseudomembranous colitis. Clinical Use of Antibiotics: I-treatment of already established infection: The objective of antibiotic therapy is to cure the patient with minimal complications. At the same time, it is important to discourage the emergence of drug-resistant organisms. The following principles should be observed: 1-Antibiotics should not be given for trivial infections. 2-Treatment should be based on a clear clinical and bacteriological diagnosis. Suitable specimens should be sent to the laboratory before treatment is begun. However, "empirical treatment" can be started after taking the sample; but should be modified later according to results of antibiotic sensitivity testing in vitro. 3-Antibiotics for systemic treatment should be given in full therapeutic doses, by the proper route of administration and for adequate periods. 4-Combined therapy with two or more antibiotics is required in some conditions, e.g.: a-Serious resistant infections e.g. infective endocarditis or meningitis. b-To delay emergence of resistant mutants and to decrease toxic effects of each drug by lowering the dose of each. E.g. In the treatment of tuberculosis 2 or 3 drugs are given in combination. c-Severe mixed infections e.g. peritonitis following perforation of the colon or compound fractures. II-Chemoprophylaxis: Chemoprophylaxis is the use of antimicrobial agents to prevent rather than to treat infectious diseases. The following are principal conditions for which prophylactic antibiotics are indicated: 1-The use of benzathine penicillin G injections every 3-4 weeks to prevent reinfection with Strept. pyogenes in rheumatic patients. 2-A single large dose of amoxycillin given immediately prior to dental procedures is recommended for patients with congenital or rheumatic heart disease to prevent endocarditis. 3-The oral administration of rifampicin 600 mg twice a day for 2 days to exposed persons during epidemics of meningo-coccal meningitis. 4-Oral administration of tetracycline to prevent cholera. 5-Women identified as vaginal carriers of Str. agalactiae should receive ampicillin intravenously at least 4 hours before delivery to prevent occurrence of neonatal sepsis and meningitis. 6-Chemoprophylaxis in surgery is indicated in the following conditions: a- Large bowel surgery. b- Major orthopedic and cardiac surgery. c- Amputation of an ischaemic limb. Combination of two drugs may result in one of several interactions: 1-Indifference, i.e., the combined action is no greater than that each agent when used alone (1 + 1 = 1) 2-Addition, i.e., the combined action is equivalent to the sum of the actions of each drug when used alone (1 + 1=2) 3-Synergism, i.e., the combined action is significantly greater than the sum of the two drugs acting separately, e.g. combination of penicillin and an aminoglycoside against enterococci, because penicillin damages the cell wall sufficiently to enhance the entry of the aminoglycoside (1 + 1= >2) 4-One drug may antagonize the action of the other e.g. the use of penicillin combined with the bacteriostatic drug tetracycline in the treatment of meningitis caused by pneumococci. Tetracycline inhibits the growth of the organism, thereby preventing the bactericidal effect of penicillin, which kills multiplying organisms only (1 + 1=