Introduction

            Chemotherapeutic agents:  chemical substances used for the treatment of

infectious diseases or the prevention of disease

            Chemotherapy--Chemoprophylaxis

            Origin--Natural-microbial and botanical (antibiotics)

                          Synthetic-semisynthetic

            Characteristics

                        Selective toxicity

                                    inhibit or kill with little or no damage to the host cells

                        Penetration

                        Alteration to host’s defense mechanism

Historical Review

            Plasmodium vivax  1630  bark of cinchona tree

                        Quinine

                        Synthetics--quinacrine, chloroquine, paludrine, and primaquine

            Treponema pallidium  1495  mercuric compounds

                        Arsenical compounds  1910  Ehrlich--Salvarsan

            Streptococcus spp.  1935  Prontosil (dye)  Domagk

                        Sulfanilamide  1908  Gelmo

                        5488 derivatives by 1945

            Antibiotics:  metabolic product of one organism which is detrimental or

inhibitory to other microbes

Actinomycetes   Gratia and Dath 1924

            actinomycetin--vaccine preparation--lysis

Staphylococcus aureus  1929  Fleming--Penicillium

            “contaminant mold”

Bacillus brevis  1939  exude toxin to gram +

            gramicidin and tyrocidine

Antibiotic Chemotherapeutic Agents

            Qualities

            Penicillins (side chains provide unique activities)

Common core--beta lactam thiazolidine ring

                                    6-aminopenicillanic acid

Natural penicillins

                                    Penicillium notatum & P. chrysogenum

                                                Penicillin V and G

                                    Commercially prepared as sodium, potassium, or procaine salts

                                    Water soluble

                                    Inactivated by heat, cysteine, sodium hydroxide, penicillinase and

hydrochloric acid

                        Semisynthetic penicillin

                                    Core compound produced naturally in quantity

                                    Side chains added by chemical reactions

                                    Phenethicillin--best of Penicillin V and G

                                    Penicillinase resistant

                                                methicillin--oxacillin

                                    Broad spectrum

                                                ampicillin

                                                strong bactericide and lacks toxicity

Mode of Action

            Inhibits bacterial cell-wall formation

            Prevents incorporation of N-acetylmuramic acid

            Affects only growing bacteria

            Cephalosporins--produced by Cephalosporium acremonium

            Aminoglycosides--amino-sugars

                        Streptomycin

                        Spectinomycin

                        Gentamicin

                        Neomycin

            Tetrocyclines--produced by Streptomyces spp.

            Macrolide--lactone rings linked to aminoglycosides

                        Erythromycin

            Chloramphenical

            Polymyxin--produced by Bacillus polymyxa

            Bacitracin--produced by Bacillus subtilis

            Nystatin--antifungal antibiotics--Candida albicans

Synthetic Chemotherapeutic Agents

            Sulfonamides--side chain varies activities

                        Sulfadiazine and sulfamerazine

            Nitrofurans--derivatives of furfural--broad spectrum

            Isonicotinic acid hydroxide  (Isoniazide)

            Nalidixic acid

Resistance to Antibiotics--tolerance development--natural

            Transmission of drug resistance

                        conjugation    transformation    transduction

E. coli may transfer R factor to Enterobacter, Klevsiella, Salmonella, and Shigella

E. coli may occasionally transfer to Pasteurilla, Proteus, and Serratia

Development of Resistance may be minimized by:

1)      avoiding indiscriminate use of antibiotics

2)      avoidance of general antibiotics

3)      use appropriate dosage

4)      use combinations of antibiotics

5)      use alternatives when resistance is encountered

Effectiveness of Chemotherapeutics

            Tube dilution (MIC) :  minimum inhibitory concentration

            Paper disk plate

Assay of Antibiotics

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