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Chemotherapeutic Agent
= are compounds that destroys pathogenic microorganism
or inhibit their growth.= one of the most valuable method of treating infection= most common agents used are: antibiotics, microbial
products or their derivatives that are capable ofkilling susceptible microorganism or inhibiting their
growth
Antibiotics:= are naturally occurring metabolic products of primarily
soil bacteria & fungi= these substances functions to limit microbial growth in
soil environment by killing or inhibiting their growth= some are semi-synthetic in which the natural active
component in the molecule is combined with asynthetic group
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Desirable Properties of Chemotherapeutic Agent:
1. Selective toxicity2. Bactericidal rather than bacteriostatic3. Should not be allergenic4. It should remain active in the presence of plasma,
body fluids and exudates5. Should have broad-spectrum activity6. Water soluble and stable7. Susceptible organism should not become resistant
8. Cheap
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Antibiotic producing organism:A) Bacteria
a.1. Bacillus
a.2. Streptomyces
B) Fungib.1. Penicillium
b.2. Cephalosporiumb.3. Micromonospora
Mech. of action:1. Interfere with cell wall synthesis2. Interfere with cell membrane function3. Interfere with Protein synthesis4. Interfere with nucleic acid metabolism
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I. Cell Wall Inhibitors:
1.1. B lactam antibiotics
A. Penicillin= product of the green mold penicillium notatum= basic structure consist of thiazolidine ring joined
to a B-lactam ring= MOA: affect bacteria by interfering with the
normal maintenance and synthesis ofbacterial cell wall
= inhibit the transpeptidation enzyme involve in cellwall synthesis
= have a B-lactam ring structure that is inactivatedby B-lactamase which are genetically coded insome bacterial DNA and some R plasmid
= reacts with penicillin-binding protein= active against both gram positive and gram
negative bacteria
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a.1. Natural occurring Penicillin
Benzylpenicillin / Penicillin G= first antibiotic to be widely used in medicine= administered parenterally= inactivated by acidic pH of gastric juice= destroyed by B-lactamase
= highly effective against gram positive and lesseffective against gram negative bacteria
Phenoxymethylpenicillin / Penicillin V= similar to penicillin G= more stable in acid medium= can be given orally
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a.2. Semisynthetic Penicillin= are derivative of 6-aminopenicillamic acid
= most crucial feature is the B-lactam ring which
appears to be essential for biologic activity1) Penicillinase-resistant penicillin
1.1. Includes: Methicillin and Nafcillin= drug of choice for penicillinase-resistant organism
= penicillinase, the enzyme synthesized by manypenicillin-resistant bacteria which destroysactivity by hydrolyzing a bond in the ring
= less active than penicillin G= acid-labile
1.2. Isoxazolyl PCN (Oxacillin, Cloxacillin & Dicloxacillin)= resistant to B-lactamase and gastric acid= drug of choice for PCN-resistant S. aureus and
S. epidermides
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2) Extended-spectrum penicillin
2.1. Ampicillin, Amoxicillin, Aminopenicillin= administered orally= has a broad-spectrum of activity= highly active against gram positive and
gram negative bacteria
= acid-stable and B-lactamase sensitive
2.2. Carbenicillin and Ticarcillin= both have broad spectrum activity
= active against gram negative bacteriaincluding (P. aeruginosa & Proteus)= acid-stable= not well tolerated by the intestine
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B. Cephalosporins= isolated from fungus cephalosporium= mechanism of action similar to penicillin in inhibiting
the transpeptidation reaction during peptidoglycan
synthesis= all these drugs are derivatives of the 7-amino-
cephalosporamic acid= contain a B-lactam ring structure similar to penicillin
= inactivated by B-lactamaseFirst GenerationCephalothin, Cefazolin and Cephalexin
bactericidal against most gram (+) bacteria
Second GenerationCefamandole, Cefuroxime and Cefaclor bactericidal against gram negative bacilli
Third GenerationCefotaxime, Ceftazidime and Cefoperazoneless active against gram (+) but more active
against gram (-) bacteria
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C. Other B-lactam antibodies= MOA similar to penicillin= have a B-lactam ring and is resistant to B-lactamase
a) Monobactam - Aztreonam= has excellent activity against aerobic gram (-)
organism such as the Enterobacteriaceae,
Pseudomonas, Gonococci and Hemophilus
b) Thienamycin - Carbapenem compounds= active against all medically important organism
including organism frequently resistant to
other B-lactam antibiotics
c) B-lactamase inhibitors - Clavulamic acid, Sulbactam
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II. Cycloserine= produced by specie of steptomyces= broad-spectrum antibiotic used to treat patient with TB= inhibit peptidoglycan synthesis
III. Vancomicin= produced by specie of streptomyces= used as alternative drug for serious infection in patient
who are allergic to B-lactam agents caused bymethicillin resistant S. aureus
= drug of choice for antibiotic-associated colitissecondary to Cl. defficile infection
IV. Bacitracin=polypeptide antibiotic produced by strain of B. subtilis= bactericidal for many gram (+) organism and pathogenic
neisseria
= highly toxic: used for topical application only
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II. Protein Synthesis Inhibitors= protein synthesis is the end results of 2 major processes
1) DNA dependent RNA synthesis (transcription)
2) RNA dependent protein synthesis (translation)Inhibitors of transcription:1) Actinomycin
= active against gram (+) and gram (-) bacteria aswell as mammalian cells
= toxic; with limited clinical use2) Rifampicin
= are compounds which contain an aromatic ringsystem
Rifampin = most useful member of the group= effective against gram (+) organism
and mycobacteria= major drug for the treatment of
tuberculosis, leprosy & as prophylaxisagainst meningococcal meningitis
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Inhibitors of translation:= translation of mRNA into protein are divided into 3
major phases
a) initiation- starts with association of mRNA in the 30sribosomal subunit to form a 30s initiation
complex
b) elongation- ribosome is the target site for proteinsynthesis
c) termination of polypeptide chain-enzyme catalyzingpeptide formation (peptidyl transferase)
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Inhibitors of the 30s Ribosomal subunit:1) Aminoglyside antibiotics
(Streptomycin, Neomycin, Kanamycin, Tobramycin)Gentamicin and Amikacin
Streptomycin - bactericidal for gram (+), gram (-)bacteria and M. tuberculosis
- drug of choice F. tularensis andY. pestis infection
Gentamicin, Tobramycin and Amikacin - activeagainst gram (-) bacteria incl. Pseudomonas
= synthesized by the genus streptomyces= Gentamicin synthesized by micromonospora purpuriae
= MOA: binds to 30s ribosomal subunits and inhibitprotein synthesis= may irriversively block initiation of translation or
cause mRNA misreading or both= toxic and can cause renal and eight cranial nerve
damage, neuromuscular paralysis
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2)Tetracylines
= Oxytetracycline and Chlortetracycline,Demethylchlotetracycline
= naturally produce by specie of the genusstreptomyces
= inhibit protein synthesis by combining with the 30ssubunits of the ribosome= active against gram (+) and gram (-) bacteria
including Mycoplasma, Rickettsia and Chlamydia= Semi-synthetic: Doxycycline, Minoccycline
- both are lipophilic and are absorbed completelyin the GIT
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3) Nitrofurans
Nitrofurantoin (synthetic derivative)= used clinically to treat urinary tract infection
especially patient unable to tolerateSulfonamide
= most active against E. coli, Klebsiella,Enterobacter and S. faecalis
= at present, it is recommended only foruncomplicated UTI
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Inhibitors of the 50s Ribosomal Subunit:
1) Chloramphenicol
= produce from cultures of streptomyces venezuelae= binds to the 23s RNA on the 50s ribosomal
subunits and inhibit peptide bond formation(similar to erythromycin)
= bacteriostatic for gram positive and gram negativebacteria including Rickettsia and Chlamydia
= maybe inactivated by the enzyme chloramphenicolacetyltransferase which is carried by the Rplasmid
= very toxic, can cause allergic & neurotoxic reaction= used only in serious and life-threathening situation= most common side effect is bone marrow
depression leading to aplastic anemia and
decreased blood leukocytes
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2) Macrolide antibiotics (Erythromycin)= synthesize by streptomyces erythraeus= binds to the 50s ribosomal unit to inhibit peptide
chain elongation during protein synthesis= most frequently used antibiotic in patient allergic
to penicillin= primarily bacteriostatic, but may be bactericidal for
some organism= effective against gram positive bacteria, mycoplasmaand few gram negative organism
3) Clindamycin / Lincomycin
= similar activity spectrum with Erythromycin butchemically unrelated= active against group A strept., Pneumococci and
Penicillinase producing staphylococci
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4. Puromycin= not clinically useful but has an inhibiting effect on
growth of both procaryotic and eucaryoticorganism
5. Fusidic acid= steroidal antibiotic with narrow antibacterial spectrum= active against gram (+) bacteria= no significant activity against gram (-) organism
Fucidin (salt of fusidic acid)
= used in the treatment of various seriousstaphylococcal infection
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Inhibitors of Protein Assembly
Griseofulvin= a fungistatic agent specific for fungi whose cell
wall contains chitin
= no effect on fungi with cellulose cell wall bacteriaand yeast
=given orally and clinically useful in treating chronicdermatophyte infection
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Inhibitors of Tetrahydrofolate Synthesis (Folic acid synthesis)
1) Sulfonamide (analogue of PABA)
= generic name for derivatives of para-aminobenzenesulfonamide or sulfanilamide
= first administered as a red dye Prontosil (Sulfanilanide)= effective chemotherapeutic agent used systematically
as prevention and cure of bacterial infection in huma = MOA: interfere with synthesis of folic acid (required for
the synthesis of purine & pyrimedine) precursor of
RNA and DNA= useful in the treatment of uncomplicated UTI
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2) Sulfones
= analogue of PABA and is most useful clinically= derivatives of the diaminodiphenylsulfone (dapsone)
= primarily used to treat leprosy
3) Para-aminosalicylic Acid (PAS)
= highly specific for M. tuberculosis
= used primarily as a second-line drug in the treatmentof tuberculosis
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Inhibitors of dihydrofolate reductase
1) Trimethoprim
= antifolic acid agent= very potent and a selective inhibitor of bacterial
dihydrofolate reductase= spectrum of activity similar to sulfonamide= are bactericidal and act synergistically with sulfonamide
or sulfamethoxazole
= useful in the treatment of recurrent or chronic UTIand Pneumocystis infection= also effective against bronchitis shigellosis and Ty fever
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2) Isoniazed (INH)= hydrazide of isonicotinic acid
= highly specific for M. tuberculosis= hepatotoxic= most potent anti-TB drug= never given as single drug
3. Flucytosine= flourine analogue of cytosine= an antifungal agent which is a true antimetabolite= effective against most systemic deep-seated fungal
infection= drug of choice for chromomycosis= toxic effect: skin rashes, diarrhea, liver damage and
aplastic anemia
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III. Cell Membrane Inhibitors
1) Polymixin= produced by Bacillus polymxa= MOA: binds specifically to the outer surface of cell
membrane, altering their structure and osmoticproperties
= spectrum of activity is restricted to gram (-) organism= reserved drug for the treatment of severe
Pseudomonas infection when organism is resistant
to other antibiotics
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2) Polyenes= macrolide antibiotics, most important antifungal agent:
Amphotericin B and Nystatin
= MOA: binds to sterol in fungal membrane causingdisruption of membrane permeability resulting toleakage of cell content
= active against yeast, fungi and other eucaryotic cellsbut inhibitory to procaryotic organism
= selectively inhibit org. whose membrane contain sterols
Amphotericin B - cornerstone of antifungal therapy= active agent most deep-seated fungi infection
= toxic and used only for serious life-threateninginfection
Nystatin - use to treat candida infection of the skin,vagina and alimentary tract
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3) Azoles
3.1) Imidazoles: Ketaconazole, Miconazole, Clotrimazole
= acts by interfering ergosterol synthesis by thefungal cell or disrupt fungal membranepermeability and inhibit sterol synthesis
= blocks demethylation of ergosterol precursor
lanosterol= broad-spectrum antifungal agent active against
dermatophytes, dimorphic fungi and yeast= Miconazole and Clotrimazole are administered
topically only as a treatment of cutaneousand vaginal candidiasis
= Ketoconazole given orally, very effective forsuperficial and deep mycotic infection inhuman
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3.2) Triazoles:Itaconazole, Fluconazole
= are substitute of imidazoles with antifungalspectrum
= MOA same with Imidazole
= better tolerated when given orally= effective in the treatment of deep mycosesand opportunistic infection
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Inhibitors of DNA Function= MOA: inhibit cross-linkage and intercalation between
the stacked bases of the double helix DNA
1) Mitomycin (synthetic antibacterial agent)= converted enzymatically to a highly reactive
hydroquinone derivatives that acts as a bifunctionalalkalyting agent
= acts on the guanine residues of DNA and under certaincondition blocks the synthesis of host cell DNA
2) Quinolones= all agents in the quinolone class are synthetic products
Nalidixic acid - first to be introduced as derivative ofnaphthyridine compound
= blocks DNA replication= bactericidal and use in the management of
uncomplicated UTI
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Newer QuinolonesNorfloxacin and Ciprofloxacin
= most useful flourinated compounds
= spectrum of activity includes Enterococci,Staphylococci and PseudomonasCiprofloxacin - most potent of the quinolones
= active against gram (-) and gram (+) bacteria= used to treat UTI
3) Metronidazole= effective antimicrobial agent for infection caused by
anaerobes and some protozoans= no effect on facultative and aerobic organism
4) Novobiocin= bactericidal especially among gram positive bacteria= target site is the subunit B component of the DNA gyrase
= no valid therapeutic used at present