Antimicrobial Agents - PowerPoint Presentation

Slide1

Antimicrobial Agents(General Considerations)

Prof. R. K. DixitPharmacology and TherapeuticsK.G.M.U. Lucknowdixitkumarrakesh@gmail.comSlide2

Objectives

After this lecture you will be able to answerWhat are antimicrobials, antibiotics, chemotherapeutic agents (Terminologies used in antimicrobial treatment)Classification of antimicrobials ChemicalsMechanismSpectrumMechanisms of action of antimicrobialsResistance development in antimicrobials

Multidrug resistant microorganismsSlide3

A naturopath tells “One should never take antibiotics

Except in Pneumonia, a kidney infection, boils, meningitis, encephalitis, osteomyelitis, occular infections, or other serious illness………………………………………………….”Slide4

Allopath is Lucky to have the help of Antimicrobials

But This Luck may not last long due to reasons……Inappropriate use,… Overuse…..Antimicrobial resistanceReduced immunity and worsening of environment

patients having co morbid illnesses like diabetes, malnutrition………………..

Less interest of pharmaceuticals in this field

Costly new antimicrobialsSlide5

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. Slide6

Terminology

6

Chemotherapy

–

U

se of

drugs

to treat infections and malignancy. (Antimicrobials and

Antineoplastic

agents)

Pharmacodynamic

agents-

D

rugs 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 antibioticsSlide7

Bacteriostatic

- Stop the growth of bacteriaBactericidal- 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)Slide8

Prebiotics-

Stimulate the growth of intestinal commensals and prevent multiplication and establishment of pathogenic bacteria. Lactulose, Lactitol, InulinProbiotics-

Live microbial substances

used as supplements to maintain or improve the intestinal bacterial flora.

Lactobacilli and

BifidobacteriaSlide9
Slide10

Gram positive & Gram Negative

Gram positive bacteria have thick cell wallPeptidoglycan 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

antibioticsLimited antibiotics may diffuse through porinsSlide11

Historical Perspectives

Chenopodium- for intestinal wormsMouldy curd – for boilsChaulmoogra oil- for LeprosyMercury – for Syphilis

Cinchona Bark-

for MalariaSlide12

Historical perspectives

Pasteur- (1877)Phenomenon of antibiosisPaul Ehrlich- (1906)Father of Chemotherapy, Coined term chemotherapyDomagk- (1935)Discovery of sulfonamides (Prontosil to sulphanilamide)Fleming, Chain, Florey- Penicillin (1929, 39, 41) from

penicillium

Waksman-

Streptomycin, from

actinomycetes

,

Coined term antibioticSlide13

Introduction of Class of antimicrobial agents (SPECTM)

1935 - Sulphonamides1941 - Penicillins1944 - Aminoglycosides

1945 -

Cephalosporins

1949 -

Chloramphenicol

1950 -

Tetracyclines

1952 -

Macrolides

1956 - Glycopeptides

1957 -

Rifamycins

1959 - Nitroimidazoles1962 - Quinolones1968 - Trimethoprim2000 - Oxazolidinones2003 - LipopeptidesSlide14

Antimicrobial Classification

Chemical structureMechanism of ActionOrganism type Spectrum of activityStatic or CidalOrigin of antimicrobialsSlide15

Chemical Classification (Public

Loves GOOD Quality BATSMAN)

P

olypeptides

-

Polymyxin

,

Colistin

,

Bacitracin

P

oyene

antibiotics-

Nystatin, Amphotericin-B, HamycinLincosamide- Lincomycin, ClindamycinGlycopeptides- Vancomycin, TeicoplaninOxazolidinone- LinezolidOthers-----------------Riampicin, Griseofulvin, etcDiaminopyrimidines- Trimethoprim, PyrimethamineQuinolones- Nalidixic acid, ciprofloxacinBeta-lactam- Penicillins, Cephalosporins, Monobactams, CarbapenemsAminoglycosides- Streptomycin, GentamycinTetracyclines

-

Oxytetracycline

, Doxycycline

S

ulphonamides

- Sulfadiazine,

Sulfamethoxazole

,

M

acrolides

-

Erythromycin,

Clarithromycin

A

zoles-

Fluconazole

,

Clotrimazole

N

itroimidazoles

-

Metronidazole

,

Tinidazole

N

icotinic acid derivatives-

Isoniazide

,

Pyrizinamide

,

Ethionamide

N

itrobenzene

derivaties

-

Chloramphenicol

N

itrofuran

derivatives-

Nitrofurantoin

,

FurazolidoneSlide16

Organism affectedAnti-viral

Anti-bacterialAnti-fungalAnti-protozoalAnthelminticSources

Fungi-

Penicillin

Cephalosporins

Griseofulvin

Bacteria-

Polymyxin

B

Colistin

Bacitracin

Actinomycetes

-

Most commonAminoglycosides, Tetracyclines, ChloramphenicolMacrolidesSlide17

SpectrumNarrow

Penicillin GStreptomycinErythromycinBroadTetracyclineChloramphenicolExtendedAmpicillinAmoxicillinMost……..

Bacteristatic

Sulfonamides and

Trimethoprim

Tetracyclines

Macrolides

(Erythromycin)

Chloramphenicol

Ethambutol

Nitrofurantoin

Bactericidal

Cotrimoxazol

PenicillinsCephalosporinsAminoglycosidesVancomycin, Daptomycin Fluroquinolones (ciprofloxacin)INH, Rifampicin, PyrazinamidePolymixins, BacitracinMetronidazoleSlide18

Spectrum

(Narrow, Broad, Extended)Slide19

Mechanism of action

Cell Wall synthesis inhibition- Beta-lactams, Vancomycin, CycloserinesCell membrane Leakage- Polypeptides, Polyenes

Folate

Synthesis inhibition-

Sulfonamides,

Pyrimethamine

,

Cotrimaxazole

, PAS,

Ethambutol

DNA

gyrase

and Topoisomerase inhibition- FluroquinolonesRNA polymerase inhibition- Rifampicin,, Protein Synthesis Inhibition- (ATT)Aminoglycosides, tetracyclines, Chloramphenicol, Macrolides, Clindamycin, LinezolidSlide20

Differences between human cells Vs Bacterial Cells (Makes the antibacterial selective)

Human cells don’t posses wall (Peptidoglycans = peptides + sugar)Human cell membrane is different ( Bacteria Contain Hypanoids in place of Sterol)

Human cells take preformed

dihydrofolic

acid

(no need of PABA in human)

Dihydrofolic

acid reducatase enzyme is different

(thousand time affinity)

Topoisomerase

II

are different

(in bacteria IV, DNA

Gyrase)DNA dependent RNA polymerase is differentRibosome 60S subunit (in bacteria 50S)Ribosome 40S subunit (in bacteria 30S)12345678Slide21

Cell Wall

Beta

LactamsSlide22

Protein Synthesis

Chloramphenicol-Macrolides- Erythromycin,

Azithromycin

etc.

Aminoglycosides

.

Gentamicin

,

Amikacin

, etc.Slide23

DNA gyrase (Gyrase) belongs to DNA

topo-isomerasesDNA gyrase, referred to simply as gyrase, DNA gyrase also known as DNA topoisomerase

IV (In bacteria).

In

human

Topoisomerase

IISlide24

Enzyme that relieves strain while double-strand DNA is being unwound by helicase. Causing negative super coiling of the DNA.

DNA gyrase is particularly unique because it is the only Topoiosmerase that can both relax positively super coiled DNA and introduce negative supercoils into the DNA (most Topoiosmerase only relieve the positively super coiled DNA)This process occurs in prokaryotes (in particular, in bacteria), whose single circular DNA is cut by DNA gyrase and the two ends are then twisted around each other to form super coilsSlide25

There are three main types of topology: supercoiling,

knotting, and catenation. (Outside of the essential processes of replication or transcription, DNA must be kept as compact as possible, and these three states help this cause. However, when transcription or replication occurs, DNA must be free, and these states seriously hinder the processes. In addition, during replication, the newly replicated duplex of DNA and the original duplex of DNA become intertwined and must be completely separated in order to ensure genomic integrity as a cell divides

.) Slide26

As a transcription bubble proceeds, DNA ahead of the transcription fork becomes over wound, or positively super coiled, while DNA behind the transcription bubble becomes under wound, or negatively super coiled.

As replication occurs, DNA ahead of the replication bubble becomes positively super coiled, while DNA behind the replication fork becomes entangled forming pre-catenanes. One of the most essential topological problems occurs at the very end of replication, when daughter chromosomes must be fully disentangled before mitosis occurs. Topoiosmerase IIA plays an essential role in resolving these topological problemsSlide27

QuinolonesSlide28

PABA

Dihydrofolic acidTetrahydrofolic acid

Purines

and

Pyrimidines

DNA

And RNA

DNA unwinding

(DNA

gyrase

)

Threads

sepeartion

(Topoisomerase IV)DNA dependent RNA PolymerasetRNA +Amino AcidsRibosome unit (50S)Ribosome unit (30S)Protein SynthesisDihydro

-folic acid

Synthetase

Dihydro

-folic acid

reductase

DNA multiplication

mRNA

Sulphonamides

(PABA analogue and inhibitor of DHFAS)

Trimethoprim

and

Pyrimethamine

(inhibitor of DHFAR)

Quinolones

(Inhibitor of DNA

gyrase

and

Topoisomerase

IV)

Rifampicin

(inhibitor of DNA dependant RNA Polymerase)

Chloramphenicol

,

Macrolides

(50S)

Aminoglycosides

,

Tetracyclines

(30S)Slide29

DNA unwinding

(DNA gyrase)Threads sepeartion

(

Topoisomerase

IV)

PABA

Dihydrofolic

acid

Tetrahydrofolic

acid

Purines

and

Pyrimidines

DNAAnd RNADihydro-folic acid SynthetaseDihydro-folic acid reductase

RNA Polymerase

tRNA

+

Amino Acids

Ribosome unit (50S)

Ribosome unit (30S)

Protein Synthesis

mRNA

Sulphonamides

(PABA analogue and inhibitor of DHFAS)

Trimethoprim

and

Pyrimethamine

(inhibitor of DHFAR)

Quinolones

(Inhibitor of DNA

gyrase

and

Topoisomerase

IV)

Rifampicin

(inhibitor of DNA dependant RNA Polymerase)

Chloramphenicol

,

Macrolides

(50S)

Aminoglycosides

,

Tetracyclines

(30S)

3

4

5

6

7

8Slide30

Cell Wall synthesis inhibition-

Beta-

lactams

,

Vancomycin

,

Cycloserines

Cell membrane Leakage-

Polypeptides,

Polyenes

PABA

Dihydrofolic

acidTetrahydrofolic acidPurines and PyrimidinesDNAAnd RNADNA unwinding (DNA gyrase)

Threads

sepeartion

(

Topoisomerase

IV)

RNA Polymerase

mRNA

tRNA

+

Amino Acids

Ribosome unit (50S)

Ribosome unit (30S)

Protein Synthesis

Dihydro

-folic acid

Synthetase

Dihydro

-folic acid

reductase

DNA multiplication

Sulphonamides

(PABA analogue and inhibitor of DHFAS)

Trimethoprim

and

Pyrimethamine

(inhibitor of DHFAR)

Quinolones

(Inhibitor of DNA

gyrase

and

Topoisomerase

IV)

Rifampicin

(inhibitor of RNA Polymerase)

Chloramphenicol

,

Macrolides

(50S)

Aminoglycosides

,

Tetracyclines

(30S)

1

2

3

4

5

6

7

8Slide31

1

2

3

4

5

6

7

8Slide32

ANTIBIOTICS

Dose-dependent

(With PAE)

Time-dependent

Antibacterial effect directly depends on their concentrations in the

locus

of in

fection

(high doses 1-2 times/24h)

Aminoglycosides

F

lu

or

oq

inolones

Metronidazol

Amphoter

i

cin B

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)

Beta-lactames

Glycopeptides

Macrolides

Tetracyclines

VancomycinSlide33

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. Slide34
Slide35

Cell mebrane

Polypeptides and PolyenesPolymyxin, Colistin, Bacitracin, Nystatin, Amphotericin

-B,

Hamycin

Cell Wall synthesis by acting on cross linking

Penicillins

,

Cephalosporins

,

Monobactams

,

Carbapenems

,

Vancomycin, Teicoplanin, Cell wall synthesis by acting on inhibition of mycolic acid (Long Fatty acid present in mycobacterial family)Isoniazide, Pyrizinamide, EthambutolInterfering with folic acid metabolismSulphonamides- Sulfamethoxazole, Sulfadoxine, Diaminopyrimidines- Trimethoprim, PyrimethamineDNA gyrase and topoisomerase IV inhibitorsQuinolones- Nalidixic acid, ciprofloxacin, Ofloxacin, Pfloxacin, Gatifloxacin, SparfloxacinInhibition of DNA dependeant RNA PolymeraseRifampicin,

Acting on 50S ribosome

Macrolides

- Erythromycin,

Clarithromycin

,

Azithromycin

,

Roxithromycin

,

Chloramphenicol

,

Lincomycin

,

Clindamycin

,

Linezolid

Acting on 30 S ribosome

Aminoglycosides

- Streptomycin,

Gentamycin

,

Kanamycin

,

Amikacin

,

Tobramycin

Tetracyclines

-

Oxytetracycline

,

Doxycycline

Antibacterial - Co-

trimoxazole

Antimalarial

- Co-

trimazine

1

2

3

4

5

6

7

8

2Slide36

Mechanisms Of Resistance

ResistanceIntrinsic Acquired Mutation TransferredConjugation

Transformation

Transduction

Not Dangerous/

less clinical importance

Dangerous/

clinical importanceSlide37

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. Slide38

Acquired Resistance

Due to exposure of antimicrobialsHorizontal evolution:Resistance genes pass from resistant to nonresistant strain,

Antibiotics-

a selective pressure.

Gene transfer mechanisms:

Conjugation.

Transduction.

Transformation.Slide39

Cellular Resistance

ATTACK OF THE SUPERBUGS: ANTIBIOTIC RESISTANCE By Grace Yim, Science Creative Quarterly. Jan 07 Slide40

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.Slide41

Resistance to AntibioticsSlide42

Resistance in some antibiotics

Beta-lactams: - Hydrolysis , mutant PBPTetracycline: - Active efflux from the cell

Aminoglycosides

-

Inactivation

by enzymes

Sulfonamides-

Alternate pathway,

Fluoroquinolones

-

Mutant DNA

gyrase

Chloramphenicol- Reduced uptake into cell Macrolides - RNA methylation, drug effluxSlide43

Factors favoring Resistance

Prescription related factors:OveruseEarly discontinuation

Over continuation

Less dose, duration

Livestock

doping

:

Animals exposure

Slide44
Slide45
Slide46

Superbugs

(Microorganisms with multiple resistance)

MRSA

-

Methicillin

-

resistant

Staphylococcus

aureus

VISA

- Vancomycin intermediate resistant StaphylococcіVRE - Vancomycin-resistant enterococciESBLs - Extended-spectrum beta-lactamases (microorganisms – resistant to cephalosporins and monobactams)PRSP - Penicillin-resistant Streptococcus pneumoniaeMRPA (MDR-PA)- Multidrug resistant Pseudomonas aeruginosaMRAB (MDR-AB) - Multidrug resistant Acinetobacter baumanniiSlide47

Why worry?

MDRO are dangerousDifficult to treatMore virulentIncrease mortality and morbidity

Resource-intensive

More expensive

and toxic antibiotics

Increase length of hospitalization

Increase demand for

isolation-facilitiesSlide48

The number of new antibiotics is fallingSlide49

Thanks