Download Antimicrobial Agents (General Considerations) [PPT]

Antimicrobial Agents
(General Considerations)
Prof. R. K. Dixit
Pharmacology and Therapeutics
K.G.M.U. Lucknow
[email protected]
Objectives
• After this lecture you will be able to answer
– What are antimicrobials, antibiotics,
chemotherapeutic agents (Terminologies used in
antimicrobial treatment)
– Classification of antimicrobials
• Chemicals
• Mechanism
• Spectrum
– Mechanisms of action of antimicrobials
– Resistance development in antimicrobials
– Multidrug resistant microorganisms
A naturopath tells
“One should never take antibiotics
Except in
Pneumonia, a kidney infection, boils, meningitis,
encephalitis, osteomyelitis, occular infections, or
other serious
illness………………………………………………….”
Allopath is Lucky to have the help of Antimicrobials
But This Luck may not last long due to reasons……
– Inappropriate use,… Overuse…..
– Antimicrobial resistance
– Reduced immunity and worsening of environment
– patients having co morbid illnesses like diabetes,
malnutrition………………..
– Less interest of pharmaceuticals in this field
– Costly new antimicrobials
Antimicrobials , Antimicrobials , Antimicrobials ,
Antimicrobials, Antimicrobials , Antimicrobials
Antimicrobials!!!
Penicillin, ampicillin, amoxycillin, ticarcillin, piperacillin,
flucloxacillin, dicloxacillin, oxacillin, methicillin, nafcillin,
carbenicillin, eryhtromycin, clindamycin, roxythromycin
clarithromycin, tetracycline, doxycycline, minocycline,
vancomycin, teicoplanin, augmentin, gentamicin, tobramycin,
amikacin, streptomycin, azithromycin, aztreonam, cephalexin,
cefotaxime, cephamandole, cefepime, ceftriaxone,
ceftazidime, cefpirome, imipenem, chloramphenicol,
cotrimoxazole, ciprofloxacin, norfloxacin, trimethoprim,…….
………………………………………………………………………………………………
………………………………………………….. hundreds of different
antimicrobial agents on the market.
Chemotherapy –
Terminology
Use of drugs to treat infections and malignancy. (Antimicrobials and
Antineoplastic agents)
Pharmacodynamic agentsDrugs regulating physiological process of body and act on the body cells.
Chemotherapeutic agentsSelectively acting against microbes or malignant cells. (Don’t touch body
cells)
Antimicrobials –
Used in treating infectious diseases.
Antibiotics –
Produced from microbes to inhibit or kill other microbes. (Antimicrobials from
microbes)
All antibiotics are antimicrobials but all antimicrobials are not
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antibiotics
 Bacteriostatic Stop the growth of bacteria
 Bactericidal Kill the bacteria
 PAE Post antibiotic effect
 Minimum Inhibitory Concentration (MIC) Which stops the growth
 Minimum Bactericidal Concentration (MBC) Which kills by 99.99%
(Bactericidal -less value of MBC-MIC,
Bacteriostatic - more value of MBC-MIC)
• Prebiotics– Stimulate the growth of intestinal commensals and
prevent multiplication and establishment of pathogenic
bacteria.
– Lactulose, Lactitol, Inulin
• Probiotics– Live microbial substances used as supplements to
maintain or improve the intestinal bacterial flora.
– Lactobacilli and Bifidobacteria
Gram positive & Gram Negative
• Gram positive bacteria have
– thick cell wall
– Peptidoglycan directly accessible from environment
• Gram negative bacteria have
– Thin cell wall
– Surrounded by inner and outer membrane
– Of lipopolysaccharide, phospholipids, and proteins
– Outer membrane is a barrier to diffusion of antibiotics
• Limited antibiotics may diffuse through porins
Historical Perspectives
• Chenopodium– for intestinal worms
• Mouldy curd –
– for boils
• Chaulmoogra oil– for Leprosy
• Mercury –
– for Syphilis
• Cinchona Bark– for Malaria
Historical perspectives
• Pasteur- (1877)
– Phenomenon of antibiosis
• Paul Ehrlich- (1906)
– Father of Chemotherapy, Coined term chemotherapy
• Domagk- (1935)
– Discovery of sulfonamides (Prontosil to sulphanilamide)
• Fleming, Chain, Florey– Penicillin (1929, 39, 41) from penicillium
• Waksman– Streptomycin, from actinomycetes,
– Coined term antibiotic
Introduction of Class of antimicrobial agents (SPECTM)
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1935 - Sulphonamides
1941 - Penicillins
1944 - Aminoglycosides
1945 - Cephalosporins
1949 - Chloramphenicol
1950 - Tetracyclines
1952 - Macrolides
1956 - Glycopeptides
1957 - Rifamycins
1959 - Nitroimidazoles
1962 - Quinolones
1968 - Trimethoprim
2000 - Oxazolidinones
2003 - Lipopeptides
Antimicrobial Classification
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Chemical structure
Mechanism of Action
Organism type
Spectrum of activity
Static or Cidal
Origin of antimicrobials
Chemical Classification (Public Loves GOOD Quality BATSMAN)
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Polypeptides- Polymyxin, Colistin, Bacitracin
Poyene antibiotics- Nystatin, Amphotericin-B, Hamycin
Lincosamide- Lincomycin, Clindamycin
Glycopeptides- Vancomycin, Teicoplanin
Oxazolidinone- Linezolid
Others-----------------Riampicin, Griseofulvin, etc
Diaminopyrimidines- Trimethoprim, Pyrimethamine
Quinolones- Nalidixic acid, ciprofloxacin
Beta-lactam- Penicillins, Cephalosporins, Monobactams, Carbapenems
Aminoglycosides- Streptomycin, Gentamycin
Tetracyclines- Oxytetracycline, Doxycycline
Sulphonamides- Sulfadiazine, Sulfamethoxazole,
Macrolides- Erythromycin, Clarithromycin
Azoles- Fluconazole, Clotrimazole
Nitroimidazoles- Metronidazole, Tinidazole
Nicotinic acid derivatives- Isoniazide, Pyrizinamide, Ethionamide
Nitrobenzene derivaties- Chloramphenicol
Nitrofuran derivatives- Nitrofurantoin, Furazolidone
Organism affected
Sources
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• Fungi-
Anti-viral
Anti-bacterial
Anti-fungal
Anti-protozoal
Anthelmintic
– Penicillin
– Cephalosporins
– Griseofulvin
• Bacteria– Polymyxin B
– Colistin
– Bacitracin
• Actinomycetes– Most common
– Aminoglycosides,
Tetracyclines,
Chloramphenicol
– Macrolides
Spectrum
• Narrow
– Penicillin G
– Streptomycin
– Erythromycin
• Broad
– Tetracycline
– Chloramphenicol
• Extended
– Ampicillin
– Amoxicillin
– Most……..
Bacteristatic
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Sulfonamides and Trimethoprim
Tetracyclines
Macrolides (Erythromycin)
Chloramphenicol
Ethambutol
Nitrofurantoin
Bactericidal
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Cotrimoxazol
Penicillins
Cephalosporins
Aminoglycosides
Vancomycin, Daptomycin
Fluroquinolones (ciprofloxacin)
INH, Rifampicin, Pyrazinamide
Polymixins, Bacitracin
Metronidazole
Spectrum
(Narrow, Broad, Extended)
Mechanism of action
• Cell Wall synthesis inhibition– Beta-lactams, Vancomycin, Cycloserines
• Cell membrane Leakage–
Polypeptides, Polyenes
• Folate Synthesis inhibition–
Sulfonamides, Pyrimethamine, Cotrimaxazole, PAS, Ethambutol
• DNA gyrase and Topoisomerase inhibition– Fluroquinolones
• RNA polymerase inhibition– Rifampicin,,
• Protein Synthesis Inhibition- (ATT)
– Aminoglycosides, tetracyclines, Chloramphenicol, Macrolides,
Clindamycin, Linezolid
Differences between human cells Vs Bacterial Cells
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(Makes the antibacterial selective)
Human cells don’t posses wall
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– (Peptidoglycans = peptides + sugar)
Human cell membrane is different 2
– ( Bacteria Contain Hypanoids in place of Sterol)
Human cells take preformed dihydrofolic acid 3
– (no need of PABA in human)
Dihydrofolic acid reducatase enzyme is different 4
– (thousand time affinity)
Topoisomerase II are different 5
– (in bacteria IV, DNA Gyrase)
DNA dependent RNA polymerase is different 6
Ribosome 60S subunit (in bacteria 50S) 7
Ribosome 40S subunit (in bacteria 30S) 8
Cell Wall
Beta Lactams
Protein Synthesis
ChloramphenicolMacrolidesErythromycin, Azithromycin
etc.
Aminoglycosides.
Gentamicin, Amikacin,
etc.
• DNA gyrase (Gyrase) belongs to DNA
topo-isomerases
• DNA gyrase, referred to simply as gyrase,
• DNA gyrase also known as DNA
topoisomerase IV (In bacteria).
• In human Topoisomerase II
Quinolones
Sulphonamides (PABA analogue and inhibitor of DHFAS)
Dihydro-folic acid Synthetase
PABA
Dihydrofolic acid
Dihydro-folic acid reductase
Tetrahydrofolic acid
Purines and Pyrimidines
DNA And RNA
Trimethoprim and Pyrimethamine (inhibitor of
DHFAR)
Quinolones
(Inhibitor of DNA gyrase and Topoisomerase IV)
DNA unwinding (DNA gyrase)
DNA multiplication
Threads sepeartion (Topoisomerase IV)
Rifampicin
(inhibitor of DNA dependant RNA Polymerase)
Ribosome unit (50S) Chloramphenicol, Macrolides (50S)
DNA dependent RNA Polymerase
Protein Synthesis
mRNA
tRNA + Amino Acids Ribosome unit (30S)Aminoglycosides, Tetracyclines (30S)
Sulphonamides (PABA analogue and inhibitor of DHFAS)
Dihydro-folic acid Synthetase
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PABA
Dihydrofolic acid
Dihydro-folic acid reductase
Tetrahydrofolic acid
Purines and Pyrimidines
DNA And RNA
DNA unwinding (DNA gyrase)
Trimethoprim and Pyrimethamine (inhibitor of
DHFAR)
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Quinolones
(Inhibitor of DNA gyrase and Topoisomerase IV)
5
Threads sepeartion (Topoisomerase IV)
RNA Polymerase
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Rifampicin (inhibitor of DNA dependant RNA Polymerase)
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Ribosome unit (50S) Chloramphenicol, Macrolides (50S)
Protein Synthesis
mRNA
8 Aminoglycosides, Tetracyclines (30S)
tRNA + Amino Acids Ribosome unit (30S)
Cell Wall synthesis inhibition-
1
Beta-lactams, Vancomycin, Cycloserines
Cell membrane Leakage-
2
Polypeptides, Polyenes
PABA
Dihydro-folic acid Synthetase
3
Sulphonamides (PABA analogue and inhibitor of DHFAS)
Dihydrofolic acid
Dihydro-folic acid reductase
Tetrahydrofolic acid
Purines and Pyrimidines
DNA And RNA
DNA unwinding (DNA gyrase)
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Trimethoprim and Pyrimethamine (inhibitor of DHFAR)
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Quinolones
(Inhibitor of DNA gyrase and Topoisomerase IV)
DNA multiplication
Threads sepeartion (Topoisomerase IV)
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RNA Polymerase
mRNA
tRNA + Amino Acids
Ribosome unit (50S)
Ribosome unit (30S)
Rifampicin (inhibitor of RNA Polymerase)
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Chloramphenicol, Macrolides (50S)
Protein Synthesis
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Aminoglycosides, Tetracyclines (30S)
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ANTIBIOTICS
Dose-dependent (With PAE)
Time-dependent
Antibacterial effect directly
depends on their concentrations
in the locus of infection
(high doses 1-2 times/24h)
Effectiveness depends on a
period of time, during which
concentration
in
blood
overwhelms MIC for a particular
causative agent
(constant i.v. infusion or 3-6
times/24h)
•Aminoglycosides
•Fluoroqinolones
•Metronidazol
•Amphotericin
B
•Beta-lactames
•Glycopeptides
•Macrolides
•Tetracyclines
•Vancomycin
Post-Antibiotic Effect
• The capacity to inhibit the growth of bacteria
after removal of the drug from the culture
(body)
• Provides additional time for the immune
system to remove bacteria that might have
survived antibiotic treatment before they can
eventually regrow after removal of the drug.
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Cell mebrane
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– Polypeptides and Polyenes
– Polymyxin, Colistin, Bacitracin, Nystatin, Amphotericin-B, Hamycin
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Cell Wall synthesis by acting on cross linking
2
– Penicillins, Cephalosporins, Monobactams, Carbapenems, Vancomycin, Teicoplanin,
Cell wall synthesis by acting on inhibition of mycolic acid (Long Fatty acid present in
mycobacterial family)
2
– Isoniazide, Pyrizinamide, Ethambutol
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Interfering with folic acid metabolism
– Sulphonamides- Sulfamethoxazole, Sulfadoxine,
– Diaminopyrimidines- Trimethoprim, Pyrimethamine
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DNA gyrase and topoisomerase IV inhibitors
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Antibacterial - Co-trimoxazole
Antimalarial- Co-trimazine
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– Quinolones- Nalidixic acid, ciprofloxacin, Ofloxacin, Pfloxacin, Gatifloxacin, Sparfloxacin
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Inhibition of DNA dependeant RNA Polymerase
– Rifampicin,
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Acting on 50S ribosome
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– Macrolides- Erythromycin, Clarithromycin, Azithromycin, Roxithromycin,
– Chloramphenicol, Lincomycin, Clindamycin, Linezolid
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Acting on 30 S ribosome
– Aminoglycosides- Streptomycin, Gentamycin, Kanamycin, Amikacin, Tobramycin
– Tetracyclines- Oxytetracycline, Doxycycline
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Mechanisms Of Resistance
Resistance
Intrinsic
Acquired
Not Dangerous/
less clinical importance
Mutation
Dangerous/
clinical importance
Transferred
Conjugation
Transformation
Transduction
Inherent Resistance
(Not Much of clinical importance)
• Bacteria naturally resistant
– e.g., Gram-negative bacteria resistant to penicillins
– Genes transferred to the bacterial progeny.
• Bacteria may be resistant because
– No mechanism to transport the drug into the cell.
– Do not contain antibiotic’s target process or protein.
Acquired Resistance
• Due to exposure of antimicrobials
• Horizontal evolution:
– Resistance genes pass from resistant to
nonresistant strain,
– Antibiotics- a selective pressure.
– Gene transfer mechanisms:
• Conjugation.
• Transduction.
• Transformation.
Cellular Resistance
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ATTACK OF THE SUPERBUGS: ANTIBIOTIC RESISTANCE By Grace Yim, Science Creative
Quarterly. Jan 07
Mechanisms of Resistance
• Enzyme-based resistance–
– Break down of antimicrobials.
• Ribosomal modifications–
– Methylation of ribosome interferes with antibiotic binding.
• Protein modifications–
– Mutations leave target protein unrecognizable to antibiotic
• Metabolic resistance–
– Overcome competitive inhibition by alternate pathway.
• Efflux–
– Pumps antimicrobials out.
Resistance to Antibiotics
Resistance in some antibiotics
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Beta-lactams: Tetracycline:
AminoglycosidesSulfonamidesFluoroquinolonesChloramphenicolMacrolides -
Hydrolysis , mutant PBP
Active efflux from the cell
Inactivation by enzymes
Alternate pathway,
Mutant DNA gyrase
Reduced uptake into cell
RNA methylation, drug efflux
Factors favoring Resistance
•Prescription related factors:
•Overuse
•Early discontinuation
•Over continuation
•Less dose, duration
•Livestock doping:
•Animals exposure
Superbugs
(Microorganisms with multiple resistance)
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MRSA - Methicillin-resistant Staphylococcus aureus
VISA - Vancomycin intermediate resistant Staphylococcі
VRE - Vancomycin-resistant enterococci
ESBLs - Extended-spectrum beta-lactamases
(microorganisms – resistant to cephalosporins and
monobactams)
• PRSP - Penicillin-resistant Streptococcus pneumoniae
• MRPA (MDR-PA)- Multidrug resistant Pseudomonas
aeruginosa
• MRAB (MDR-AB) - Multidrug resistant Acinetobacter
baumannii
Why worry?
 MDRO are dangerous
– Difficult to treat
– More virulent
– Increase mortality and morbidity
 Resource-intensive
– More expensive and toxic antibiotics
– Increase length of hospitalization
– Increase demand for isolation-facilities
Thanks