An Introduction to Antimicrobials

7/30/2019 An Introduction to Antimicrobials

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22/10/2012 2000 9/10 batchFoundation Year 3 Semester 1

ANTIMICROBIAL AGENTS

Introduction

Dr. N. P. Senanayake

Senior Registrar in Microbiology

Department of Microbiology

Faculty of MedicinePeradeniya


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Antimicrobial agents

Antibacterial

Antiviral

Antifungal

Antiparasitic


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ANTIBIOTICSDefinition

Natural metabolic products of fungi,actinomycetes and bacteria that kill or

inhibit the growth of microorganisms

Current usage includes:

natural and chemically modified andtotally synthetic products


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Organism / antimicrobial agent interaction

Minimum inhibitory concentration(MIC)

Minimum concentration of antibioticrequired to inhibit growth of

organisms

Principles underlying use of

antimicrobial agents


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Serum & tissue

concentration of antibiotic

Bio-availability of active component at siteof infection

Absorption and distribution

Protein bindingExcretion

Serum and tissue levels of

antibiotic


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Factors affecting effectiveness ofantibiotic in a given infection

Serum / Tissue levels in relation to MIC(Therapeutic ratio)

Intrinsic and acquired resistance of micro-organism to antibiotic

extracellular vs intracellular site of microorganimsand antibiotic

Pharmacokinetics of antibiotic in particular patient

(kidney, liver disease, other drugs etc)


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ABST and Therapeutic ratio

Sensitive - antibiotic in able to inhibit

microorganism when given innormal dosage

Resistant - antibiotic not able to inhibit

the growth of organism whengiven in normal dosage

Intermediate sensitive- antibiotic able to inhibitgrowth of organism whengiven in increased dosage or

if concentration occurs at a

particular site


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Classification of antibiotics

(antibacterial agents) bactericidal or bacteristatic

by target site by chemical structure


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Classification of Antibiotics

Bacteriostatic Bactericidal


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Mechanism of Action


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What do we need to knowabout antibiotics

What is it? Chemical structureNatural or synthetic?

What does it do? Target site

Mechanism of action

Where does it go? Pharmacokinetics

When is it used? Spectrum of activity

Clinical indications

What are the limitations? Toxicity Cost?


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Peptidoglycans - vital component of cell wall

unique to bacterial cell

found in both Gram positive and negativebacteria- different quantities and in differentlocations

Penicillin Binding Proteins )

carboxy-peptidases & transpeptidases

PBPs

Antibiotics acting on cell wall


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Cell Wall Characteristics

Gram Positive Gram Negative


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Inhibitors of Cell Wall Synthesis


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Beta Lactam Antibiotics

Penicillins

Cephalosporins Carbapenems

Monobactams


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Pencillins

BenzylPencillin

Gram positive organisms

Staphylococcus aureus

Streptococci

Corynebacteria

Clostridia

Gram negative cocci

Neisseria gonorrhoea

Neisseria meningitidis

Spirochaetes

Treponema pallidum


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Benzyl Penicillin

1936

Parenteral

Short half life

Pencillins


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Oral preparationPhenoxy methyl pencillin

Lengthen half lifeProcaine penicillinBenzathine penicillin

Improvepharmacokinetics

Pencillins


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Include Gram negative bacilliAminopenicillins

AmpicillinAmoxycillin

Include pseudomonasCarboxypenicillins

Carbenicillin

Increase spectrumof activity

Pencillins


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Deal withresistance

Beta-lactamase stablepenicillins

Ureido pencillinsPencillin + beta lactamaseinhibitor

Carbapenems /Monobactams

Pencillins


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Beta-lactamase stable pencillins Penicillinase stable penicillins

>90% of S aureusPenicillinase

producing strainsMethicillin - first penicillinase

stable penicillin (parenteral)

only used for laboratory testingCloxacillin, Flucloxacillin and

Oxacillin -oral and parenteral- in

current use

Pencillins


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Beta lactamase producing Gram negative bacilli

Major clinical problem in severalcountries

ESBL induced by use of beta lactams

multi-resistance emerges whichlimits therapeutic options

Extended spectrum penicillins,

carbapenems , monobactams andbeta-lactamase inhibitors to combatthis problem

Pencillins


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Extend spectrum of penicillins

Extended spectrum

penicillins

Carbapenems

Monobactams

Beta-lactamaseinhibitors

Ticarcillin

Piperacillin

Imipenem

MeropenemAztreonam

Clavulanic acidSulbactam

Amoxycillin + Clavulanic acid


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Change in PBP

Results in resistance to all beta lactams In S aureus: expressed as Methicillin

Resistant S aureus(MRSA)

Other important pathogens where

resistance due to this mechanismclinically important

S pneumoniae

Enterococcus


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Resistance due to

inaccessibility of PBP Dependent on porins

In several species (eg

Pseudomonas), results in intrinsicresistance

Change in porins contributes to

acquired resistance in severalspecies


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Cephalosporins

Classification more difficult than withpencillins

Generation -First, Second, Third and Fourth

Oral , Parenteral

Spectrum of activity


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Cephalosporins

Structurally similar topenicillins

Therapeuticconcentration in manytissues, 3rd and 4thgeneration into CSF

Renal Excretion

Side Effects allergy

disulfiram-like effect

anti-Vitamin K

G ti f C h l i


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Generations of Cephalosporins

C h l i


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CephalosporinsS aureus

Pen R

Streptococci Enterobacteria Pseudomonas

Cephalexin (O)Cephradine (O/P)Cefaclor (O)

Variable

(V)

OK V No

Cefuroxime (O/P) good good V No

Cefotaxime (P)

Ceftriaxone (P)

good good good No

Ceftazidime (P) No good good good

Cefepime (O/P) good good good good


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Carbapenems

Meropenem/Imipenem broad spectrum

active against MRSA

given IV

penetrates CSF

renal metabolism andexcretion

addition of cilastin

side effects: GI upset,eosinophilia,neutropenia, loweringof seizure threshold


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GLYCOPEPTIDES Vancomycin & Teicoplanin

Large molecules -do not penetrate porinsin Gram negative cell wall

Activity against Gram positive organisms

Main clinical use:

resistance due to alteration in PBP inGram positive bacteria (S aureus-MRSA; pencillin resistantStreptococcus pneumoniae)

Major current concern: Vancomycinresistance in Enterococcus


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Human Ribosome

80S 40S

60S

BacterialRibosome

70S 30S

50S

Protein Synthesis Inhibitors


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Aminoglycosides

Derived from Streptomyces and Micormonospora

Irreversible binding to 30S subunit

Actively transported into bacterial cells Variable tissue penetration, unreliable CSF levels

Concentrate within perilymph

Renal elimination Nephrotoxicity, ototoxicity, neurotoxicity


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Aminoglycosides

Includes pseudomonas

Useful in immune dysfunction

Poor penetration(jncluding CSF)

Nephrotoxic and Oto-toxic

Levels need to be assayed as low therapeutic index

Spectrum

Bactericidal

Problems for use

Gentamicin, Tobramycin, Netilmicin, Amikacin

Resistance by inactivating enzymes

T t li


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Tetracyclines

Isolated from Streptomyces aureofaciens

Reversibly bind 30S ribosomal subunit

Penetrate sinus mucosa, saliva and tears

Metabolized in liver-->excreted in bile-->reabsorbed-->eliminated in urine

Side effects: GI upset, hepatotoxicity,

photosensitivity, bony deposition Contraindicated in pregnant or breast

feeding women, children under 8 y/o

Chl h i l


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Chloramphenicol

Excellent absorption when given orally and verygood tissue penetration and intra cellular activity

Broad (excluding pseudomonas)

Typhoid (10-25% resistance in SL)

Meningitis -rarely, resistant

H influenzae (mediatedbyacetyltransferase)

Blocks peptidyl transferase & inhibits peptide bond synthesis

(selective binding to bacterial 50S subunit)

Nitrobenzene nucleus, which is responsible for sideeffects (bone marrow suppression)

Spectrum

Clinicaluses

M lid d Li id


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Macrolides and Licosamides

Macrolides

Erythromycin New macrolides -

Azithromycin andClarithromycin

Spectrum: Grampositive cocci & cellwall free organisms

resistance common

among bacteria Useful alternative to

penicillins ifhypersensitive

Lincosamides

Clindamycin &Lincomycin

Useful activity againstS aureus

Side effect: antibioticassociated colitis &pseudomembranous

colitis

I hibit f N l i A id


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Inhibitors of Nucleic Acidsynthesis

Sulphonamides(dihydropteroic synthetase)

Trimethoprim(dihydrofolate reductase)

PABA Dihydrofolic acid

Tetrahydrofolic acidPurines &Pyrimidines


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Co-Trimoxazole (TMP/SMX)

Combination gives synergisticantibacterial action

Quinolones


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Quinolones Synthetic agents

prevent supercoiling of bacterial chromasome byinhibiting activity of DNA gyrase

DNA

(chromosome in helices)

GYRASE

Supercoiled DNA

RNA Core

RNA Core

Quinolones


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Staphylococci

Enterobacteria ; Pseudomonas

Norfloxacin, Ofloxacin, Ciprofloxacin (oral and IV)

Many new quinolones : Perfloxacin, Grapafloxacin...Extend spectrum to include streptococci

Resistance developing

Side effects: ? Toxic effects on cartilagedevelopment

Spectrum:

Currently available quinolones

Gap in spectrumAnaerobes

Quinolones


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Antimycobacterial Therapy

Must address two distinct populations of

tubercle bacilli

First-line treatment: regimens of 3-4drugs for 6 months to 2 years

Second-line therapy: reserved for multi-

drug resistant organisms or unresponsiveinfection


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First-Line Agents

Isoniazide

Rifampin

Pyrazinamide Ethambutol

Streptomycin

Isoniazide

most potent drug

inhibits formation of

outer mycolic acid widely distributes and

penetrates CSF

metabolized in liver,

excreted in urine,saliva, and sputum

side effects:

hypersensitivity,

neruopathy,

hepatotoxicity


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First-Line Agents

Isoniazide

Rifampin


Streptomycin

Rifampin from Streptomyces

antibacterial and anti-

tubercule

interferes with RNA

transcription

wide distribution, penetrates

CSF

metabolized in liver

gives orange-red color to

stool, urine and tears

side effects: rash, GI upset,

hepatotoxicity


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First-Line Agents

Isoniazide

Rifampin


Streptomycin

Pyrazinamide

hydrolyzed to

pyrazinoic acid

unclear mechanism

widely distributed,

including CSF

side effects: GI upset,

hepatotoxicity,

hyperuricemia


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First-Line Agents

Isoniazide

Rifampin


Streptomycin

Ethambutol

inhibits cell wall

synthesis and

maintenance

widely distributed,

penetrates CSF

partially metabolized,

excreted in urine

potential for optic

neuritis


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First-Line Agents

Isoniazide

Rifampin


Streptomycin

Streptomycin

aminoglycoside

binds 30S subunit

penetrates synovial,pleural, pericardial, and

ascitic fluids but not CSF

renal excretion

side effects:hypersensitivity,

paraesthesias, auditory

or vestibular dysfunction,

nephrotoxicity


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Antimycobacterials for Leprosy

Dapsone structurally related to

sulfonamides

PABA antagonist

activity against M. leprae

also effective for

pneumocystis and brown

recluse spider bites

wide distribution

acetylated in liver, eliminated

in urine

side effects: erythema

nodosum leprosum,

peripheral neuropathy,methemoglobinemia

Clofazimine synthetic phenazine dye

binds DNA and inhibits

replication and transcription

activity against M. leprai and

MAI

wide distribution, does not

penetrate CSF

partially metabolized,

excreted in bile

side effects: GI upset,

red/purple discoloration of

skin and body fluids

New antibiotics


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New antibiotics

Several reasons for developing new antibiotics

To overcome the development of resistance(improve spectrum)

MRSA

ESBL producing Gram negative bacilli

Mycobacterium tuberculosis

Improved pharmacokinetics

Daily or BD dosing

Oral as well as parenteral preparations Better access (respiratory tract, CNS, prostate, bone)

Many problems in developing new antibiotics

Effective against resistance in Gram


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Effective against resistance in Grampositive cocci

MRSA Penicillin resistant pneumococci

Vancomycin resistant enterococci (VRE) & S aureus(VRSA)

Oxazolidinones Linezolid

Streptogramins Dalfopristin -Quinipristin

Lipopeptides Daptomycin

Effective against resistance in Gram


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Effective against resistance in Gramnegative bacilli

Extended spectrum lactamase producers

Much less development

Carbapenems

Quinolones

4th generation cephalosporins

lactam + lactam inhibitors

An Introduction to Antimicrobials

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