An Introduction to Antimicrobials
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Transcript of 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
Pyrazinamide Ethambutol
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
Pyrazinamide Ethambutol
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
Pyrazinamide Ethambutol
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
Pyrazinamide Ethambutol
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