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Basic Principles
of Antimicrobial Therapy
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Penicillin became available in quantitiessufficient for clinical use in 1941.
After that, streptomycin, chloramphenicol,and tetracycline were discovered. Since then,numerous classes of antimicorabial agentshave been identified, and a lot of drugs areavailable for use today.Antimicrobials are among the mostcommonly used drugs.
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Selective toxicity of antimicrobial (AM)
Ability to kill invading m.o without harming hosts cells
Effective treatment in infectious disease
BUT it requires an appropriate concentration to attackthe m.o while tolerabled by the host
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Chemotheraphy : Drugs with selective toxicity against invading
parasites (virus, bacteria, protozoa, fungi andhelminth)
Antibiotics :
Substances produced by some microorganism(or by pharmaceutical chemists) that kill/inhibitthe growth of other microorganism (m.o)
= antimicrobial
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Fig 1. The relationship of Host-Drug-Pathogen in chemotherapy
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Molecular Basis of Chemotherapy
Chemotherapeutic drugs should be toxic for invadingm.o in the host
Selective toxicity depends on biochemical differences
between parasite host Biochemical reaction as potential targets:
Class I: glucose & other carbon source
Class II: energy and class I compound to make amino acid,nucleotides, etc Class III: small molecules are built into larger molecules,
e.g. proteins, nucleic acid, peptidoglycan
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Biochemical Reactions as Potential Targets
Class I: poor targets
Folate synthesis inhibited by sulfonamides Folate utilisation inhibited by folate antagonist Pyrimidine & purine analogues produce fraudulent
nucleotides
Class II: better targets
Peptidoglycan synthesis B-lactam Protein synthesis work though tRNA (T-S); mRNA (AMG) Nucleic acid synthesis work though DNA (quinolon,
rifampicin)
Class III: important targets
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Formed Structure of the Cell
Amphotericine, azole (antifungal)Plasma membraneaffected by:
Anticancer, antihelminthicsMicrotubule functiondisrupted by:
Antihelminthics increase Cl- permeability Pyrantel (antihelminthics) causing
paralysis
Muscle fibresaffected by:
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Identity of m.oand itssensitivity to AM
Where is site ofinfection?
How is the safetyof AM well use?
Any patientsfactors?
Availability?
What about costof th/?
We need information about:
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For C.I. P pts cant wait the result ofm.o identification [gram (+) / (-)] andDST
Immunocompromised patients When? Take the specimen for lab first!! choose broad spectrum administration: ivHow?
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Empiric therapy
Coverage by a combination ofantibiotics such as, clindamycin plus gentamicin , effective against gr ( ),
gr (-) and anaerobes, or a singlebroad spectrum antibiotic, such asimipenem cilastatin
If Grampositive
onlyIf Gram
negative only
If mixed
If anaerobic only
Receive culture reportwith sensitivities
Cont. gr (+) coverage.
discontinue gram (-) &anaerobic coverage
Cont. gr (-) coverage
Discontinue gr (+) andanaerobic coverage
Cont. anaerobic coverage
Discontinue gr (+) & (-)coverage
Continue therapyas initiated
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Renaldysfunction
Liverdysfunction
For AM excretedthrough kidney
toxicity adjustthe dosage
orchange thedrugs
Dont give drugsconcentrated/eliminated by the liver(macrolides, sulfa)
toxicity
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Poor perfusion
Exp: diabeticfoot with PAD
difficult totreat infection
Pregnancyand lactation
Some AM crossplacenta & excreted in
the breast milkteratogenic or riseproblems (toxicity)
Exp: pyrimetamin(for toxoplasma),
AMG
Age
Newborn:immaturation oforgans function
Children: deal withgrowth process
Geriatric pts :alteration organs
function
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Both drugs and patients factors B-lactam is least toxic compared to
other AM Pts factors: age, co -morbiditySafety
Consider the efficacy AND the cost In EMG case: efficacy is the mostimportant!
Feasibility !
Cost-benefit
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BUT, some AM is -statics for certain m.o while its -cidal toanother m.o (chloramphenicol)
Bactericidal:
kills the m.o decreases the amount of m.o
Bacteriostatic:
Only stop growth &replication of m.o
So, it limits the spread ofinfection
Wait for immune systemto solve the rest
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narrow
single/limited group ofm.o
exp. INH only form.TB
extended Gram (+), (-) exp; ampicillin
broad
Not only to gr (+), (-) But also to other m.o Exp. TS,
chloramphenicol
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Select if possible only single AMIt prevents: Superinfections emerge of drug resistance Minimize toxicity the cost
BUT sometimes wee need drug combination Synergism more effective (B-lactam + AMG) Wider coverage
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1. Hypersensitivity Ag-Ab complex reaction Mild (urticaria) severe (anaphylaxtic reaction)
Exp: penicillin
2. Direct toxicity Toxic directly to the cellular
Related to the plasma conc. Exp: AMG (nepfro & oto-toxicity)
3. Superinfection
Broad spectrum AM alter Normal flora OI
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Resistance to AB
a. Nature of m.o (exp: gr (-) m.o areresistant to vancomycin)
b. Acquired resistance Spontaneous mutation DNA transfer
If with max doseof AM (toleratedby the host)
the growth ofm.o is not halted.
inappropriate use of the drugs Why its happen?
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Can be spread
From bacteria bacteria (byplasmid)
From plasmid plasmid (bytransposons)
Plasmid:extrachromosomal
genetic element
Can replicateindependently,
Can carry genescoding forresistance to AB
Transposons:stretches of DNA
can betransported frompalsmid - another
Also from plasmidto chromosom &v.v
Resistance to AB
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Resistance to AB: Mechanism ?
Altered expression of proteins in DR-organismModification of target sites MRSA, quinolon resistance
Decreased accumulation Decrease permeability OR
increase Efflux system that pumpout the drug
Enzymatic inactivation B-lactamase
Genetic alterations DR
Spontaneous mutation of DNA DNA transfer of DR (through plasmid)
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Multidrug Resistance (MDR)
Resistance to commonly used ABMDR-TB (resistant to > 2 anti-TB drugs)
Some strains of Staph. & enterococc. (resistant to most all AB)
Lead to serious untreatable infection
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B-lactams AM (B-lactam ring): 1 st , 2nd , 3rd, 4 th generation AMG : AMK, KNM, STREPT
a. Chemical structure
Anti viral Antifungal Antibacterial !!!
b. Activity against certain m.o
Inhibitors of metabolism Inhibitors of cell wall synthesis Inhibitors of protein synthesis
Inhibitors of nucleic acid fct/synthesis
c. Mechanism of action
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