Chemotherapy: this term is refers to treatment of disease by chemicals that kill cells, specifically those of micro-organism (virus ,bacteria, fungi, protozoa, and parasites) or cancer. *1877: Louis Pasteur, discovered bacterial diseases . *1900:Ehrlish was working on tissue dyes with in Arsenic derivatives (salvarsan) which effective against trypanosoma (sphlis) ,but later they found that arsenic causes hepatotoxicity or nephrotoxicity . ** selective toxicity ( S.T) : The substance or drug which inhibit or kill the M.O selectively with no or little effect on host . *1929:Fleming discover penicillin *1939:Domagk developed the prontosil from red tissue dye . prontosil sulfonamide *1940:Florey used the penicillin as drug . *1942:Waksmas ,define the antibiotic substance produce from the living M.O which inhibit or kill the another living M.O Waksmas Streptomycin Antibacterial not antibiotic. Antibacterial include chemical drug and antibiotic . *Antibiotic :is a substance or compound (made from a living source) that kill or inhibit the growth of bacteria . *Antibacterial : is a substance or compound that kills or inhibit the growth of bacteria 1 Classification of Antibacterials : There are -4- ways to classify the antibacterial they are : 1-according to the nature: a-synthetic chemical e.g. sulfonamide. b-antibiotic e.g. penicillin G. c-semi synthetic ( modified the antibiotic ) e.g. ampicillin, carbenicillin 2-according to the effectiveness: a- Bactericidal : (agent that destroys or kills bacteria ) e.g. penicillin, amino glycoside , cephalosporin (narrow spectrum) b- Bacteriostatic: (agent that inhibits the growth or reproduction of bacteria) . e.g. tetracycline , chloramphenicol ,erythromycin ,sulfonamide. (broad spectrum) 3- according to the spectrum : a- narrow spectrum : (agent acting only on single or limited group of micro-organisms ) . e.g. penicillin G, amino glycoside like streptomycin . b- broad spectrum :(agent that effective against G+ also against G- bacteria). e.g.ampicillin , chloramphenicol , tetracycline c- extend spectrum : (agent that effect on a wide range arity of M.O ) e.g. enrofloxacin , sulfa and trimethoprim . 4- according to the mechanism of action : a- antibacterial which inhibit cell wall synthesis. β – lactum ring b- antibacterial which inhibit protein synthesis they effect on ribosome which effect to 30s and 50s : 1- binding irreversibly to 30s, e.g. aminoglycosides , streptomycin 2 2-binding reversibly to 30s , e.g. tetracycline 3- binding reversibly to 50s , e.g. chloramphenicol , macrolides , erythromycin , lincocins. c- antibacterial which effect on permeability of cell membrane they act as detergent cell membrane . e.g. polymyxins d- antibacterial which inhibit synthesis of folic acid (antimetabolites) e.g. sulfonamides and trimethoprim. e- antibacterial which inhibit RNA synthesis e.g. rifampin ( (for tuberculosis ). f- antibacterial which inhibit DNA synthesis e.g. 1- fluroquinolone : enrofloxacin ,flumequine 2- nitrofurans : furaltidone. ** Resistance of M.O to antibacterial : - Drug resistance :temporary or permanent capacity of micro-organism to remain viable or multiplying in presence of certain concentration of antibacterial which would destroy another similar M.O. - type of resistance : 1-intrinsic ( natural ) resistance : It is naturally resistant to antibacterial without prior exposure to the antibacterial because of the lack of receptor on the M.O. e.g. mycoplasma . naturally resistance to penicillin because of lack the cell wall . 2- acquired resistance : It is resistance of M.O which due to prior exposure to certain antibacterial or transferred from another M.O. *acquired res. Consist by- 2- ways: 1-either from using sub lethal or sub inhibitory concentration for long time and become resistance . 2-transfer from other resistance M.O (more common ) 3 *Transferable resistance : It is an extra chromosomal piece of DNA which carry genes (code)for resistance is called resistance factor . Resistant factor consist of 2 parts : 1- resistance determent (RD) 2- resistance transfer (RTS) *mechanism of resistance : 1-codes for enzymes which destroy or change the structure of antibacterial -penicillinase only for penicillin . -acetyl transferase for chloramphenicol. -adenylase , phosforylase , acetylase for amino glycosides . 2-codes for decrease or prevent entry (uptake ) of antibacterial in side of M.O e.g. aminoglycosides 3- decrease the affinity of binding of antibacterial to it is binding site e.g. tetracycline 4-change the shape or structure of binding site . *method of transfer bacterial resistance : 1-conjugation : transfer the R.F from R.M.O (donor) to non R.M.O by direct contact through piles (bridge). 2-transduction : transfer of RD after multiplication by bacteriofage from R.M.O to non R.M.O 3-transformation :transfer of RF from R.M.O after lyses to non R.M.O 4-transposon:part of plasmid which contain one gene cod which jumped from plasmid to plasmid or from plasmid to chromosome or from chromosome to plasmid inside the organism. 4 Penicillin -discovered by Fleming 1929 ,produced by penicillinum natatum , contain β –lactam ring (6- amino pencillinic acid) - - -mechanism of action : Inhibit the cell wall synthesis by inhibiting the rigidity of peptidoglycan layer by inhibiting the transpeptidase. enzyme . • Penicillins can be divided to four groups they are:- 1- Natural(Basic) Penicillins: - They are narrow spectrum, bactericidal, and penicillinase sensitive (Penicillinase is specific type of -lactamase, affect the penicillins by hydrolysing the -lactam ring). - There are two types of natural penicillins they are: a- Penicillin G: (Benzyl penicillin, Procain penicillin, Benzathine penicillin): It was the first of the penicillins, and remains an important and useful antibiotic,it is particularly active against Gram-positive bacteria, sensitive micro-organisms include Gram positive streptococci, Gram-positive Bacilli, Gram-negative cocci (Neisseria), most anaerobic bacteria including Clostridium and Spirochetes. -Staphylococcus aureus resist natural penicillins because of its ability to produce penicillinase (β-lactamase) Penicillin G is inactivated by gastric juice (Acid labile) so that it not administrated orally but used via other routes like intravenous and 5 Intramuscular. b-Penicillin V: (Phenoxymethyl penicillin) - Semi synthetic penicillin, it has similar bacterial effect to Penicillin G. Penicillin V is acid stable in contrast to Penicillin G therefore it can be administred orally. 2- Antistaphylococcal (penicillinase resistant) Penicillins: They are semi-synthetic, narrow spectrum, acid stable (can be administrated orally) and penicillinase resistant penicillins. These antibiotics are effective against streptococci and most community- acquired Penicillin-resistant staph. infection (drug of choice). Examples; Nafcillin, oxacillin, cloxacillin, and dicloxacillin 3-Aminopencillins (extended spectrum pencillins): Semi –synthetic ,extended spectrum ,acid stable and penicillinase sensitive penicillins .they have an antibacterial spectrum similar to penicillin G but more effective against Gram-negative bacilli ,they have given orally and paraenterally . Examples : Ampicillin , Amoxicillin and Pivampicillin. 4-Antipseudomonal penicillins: Semi-synthetic, broad spectrum, acid labile and penicillinase sensitive penicillins. Examples; Carbencillin, Mezlocillin, piperacillin, and ticarcillin. Clinical problems with penicillins : 1- Narrow spectrum: it corrected by administration of extended or broad spectrum penicillins instead of narrow spectrum penicillins 2- Acid lability: it corrected by administration of acid stable penicillins . 3- Short Half- life: it corrected by increase the half life of penicillins by using of probencid which blocks the tubular secretion of penicillin . thereby prolonging it is half-life. 4- Penicillinase sensitivity: it solved by using of Clavulanic- 6 suitable penicillin . Side effect of penicillins: 1-hypersensitivity : it range between skin rash to anaphylactic shock lead to death. 2-oral penicillin it cause GIT disturbance (diarrhea) due to effect to normal micro flora of the GIT , e.g. fungus and bacteria(E coli)and cause diarrhea. 3-slight nephrotoxicity . 4-neurotoxicity :penicillins irritant to the neural tissues so that they induce seizures . Dose : Penicillin G it is Biological I.U Substance which measure in I.U(international unit) but it is not equal in all time . I.U for penicillin G = 0.6 µg 1667 I.U = 1mg Cephalosporins: -the cephalosporins are semi-synthetic antibiotic because of very toxic ,derived from products of various micro-organism ,including cephalosporium and streptomyces. -all cephalosporins have a7- amino cephalosporanic acid and composed of dihydrothiazine ring fused to β – lactam ring -the cephalosporin β – lactam ring is the chemical group associated with 7 Mechanism of action : It is the same like penicillin. *cephalosporins can be divided into four generations they are: 1-First generation : example – oral (acid stable) I.M ,I.V (acid lable) The first generation drugs are active against of both G+ and G- ,pasteurella,E.coli ,actinobacillus actinomyces , haemophilus , clostridium and salmonella spp. 2-Second generation: Example oral I.V ,I.M Second generation have good activity against G+ and G- 3-Third generation : Third generation more active against the G-including β-lactamase producing strains and drug choice for pseudomonas . 4-Fourth generation -cefeprime . I.V 8 They are extremely broad spectrum being highly active