General Principles of Antimicrobial Therapy lecture

7/27/2019 General Principles of Antimicrobial Therapy lecture

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Antibacterial

Antiviral

Antifungal

Antiparasitic Pharmacophore: active chemical moiety of

the drug which binds to the microbialreceptor


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Biochemical processes commonly inhibited: Cell wall synthesis in bacteria/fungi

Cell membrane synthesis

Synthesis of 30s and 50s ribosomal subunits

Nucleic acid metabolism

Function of topoisomerases, viral proteases,viral integrases, viral envelope fusionproteins

Folate synthesis in parasites

Parasitic chemical detoxification processes


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Classification of antibiotic based on: Class and spectrum of microorganism it kills

Biochemical pathway it interferes with

Chemical structure of its pharmacophore


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PHARMACOKINETIC BASIS OFANTIMICROBIAL THERAPY

Ability of drug to penetrate the site ofinfection = crucial consideration in choosing

an antimicrobial agent for therapy Penetration of a drug depends on:

Physical barriers

Chemical properties of the drug

Presence of multi-drug transporters


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Physical barriers Layers of epithelial and endothelial cells

Type of junctions formed between thesecells

Octanol-water partition coefficient ofantimicrobial agent Measure of the hydrophilicity/hydrophobicity

of the agent

Hydrophobic agents-concentrate in the bi-

lipid cell membrane bi-layer Hydrophilic agents-concentrate in the blood,

cytosol and other aqueous compartments


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octanol-water partition coefficient

>likelihood of crossing physical barrierserected by layers of cells

More charged/larger moleculepoorerpenetration

CNS

Guarded by BBB Tight junctions that connect endothelial cells

of cerebral microvessels to one another

Protein transporters Antibiotics that are polar at physiologic

pHpoor penetration


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integrity during active bact.Infectionsmarked in penetration

Eye : poor penetration of drug from plasma

Standard Tx: direct instillation

Other compartments requiring specialpenetration

Endocardial vegetations/biofilm on artificialheart valves, IV caths, artificial hips, ORIF

devices


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Variability in Drug Response Between-patient variability

Same dose of drug given to multiplepatientsdifferent pharmacokinetic

parameters Inter-occasion/within-patient variability

Same dose administered to same patient ondifferent occasionsdifferent conc.-timeprofile of the drug


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Causes: Genetic variability

Weight, height, age

Comorbid conditions renal/liver

dysfunction Residual variability due to unexplainable

factors


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Susceptibility Testing ID and isolation of organism choice of

antibioticsusceptibility testing done tonarrow down the list of antimicrobials to be

used Bacteria

Dilution tests

MIC (minimum inhibitory conc.): lowest conc.Of the agent that prevents visible growth after18-24 hrs of incubation


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Fungi Same as used for bacteria

MIC-depends on drug and type of yeast

Viruses

HIV phenotypic assaysgenotypic tests Parasites

Similar to bacteria, fungi, viruses


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Basis for selection of dose and dosingschedule

Susceptibility of the organism to theantimicrobial agent

Ex. Vancomycin

Resistance MIC >2.0 mg/L MRSA 61% success rate w/ MIC 0.5 mg/L

28% for MIC 1.0

11% for MIC 2.0

Actual drug concentration achieved at siteof action-most impt Dose-poor measure due to between-patient

and w/in-patient variability


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Optimal dose of antibiotic for a patient=dosethat achieves IC80 to IC90 exposures at site ofinfection

Optimal microbial kill by the antibiotic may bebest achieved by maximizing antimicrobial

effect Some classes of antimicrobials kill best when

concentration persists above MIC for longerdurations of dosing interval

Beta-lactams 5-fluorocytosine

Drug should be dosed more frequently or t prolonged by other drugs


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Some drugs depend on peak concentration Aminoglycosides

Highly effective once daily

Rifampin

Long duration of post-antibiotic effect

Administer combined doses on a >intermittentbasis(OD)maximize effect

Also toxicity


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TYPES AND GOALS OF ANTIMICROBIALTHERAPY

Prophylactic

Preemptive

Empirical Definitive/suppressive


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Prophylactic therapy Treating patients not yet infected/not yet

developed the disease

Goal: prevent infection

Prevent devt of a potentially dangerous dsein those w/ evidence of infection

Main principle: targeted therapy

Used in immunocompromised patients

Therapy based on pathogens that are majorcauses of morbidity

AIDS-CD4 count


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Chemoprophylaxis

Prevent wound infection after surgery

Antimicrobial activity must bepresent at the wound site at thetime of its closure

1st dose begun w/in 60 minbefore surgical incision, D/C w/in

24 hrs

Antibiotic must be active againstthe most likely contaminatingmicroorganisms for that type ofsurgery


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Pts at risk for infective endocarditis for w/c

prophylaxis is recommended

Those w/ prosthetic material used for heart

valve repair/replacement

Previous infective endocarditis

CHD(unrepaired cyanotic heart dse, w/in 6 mos

of repair of heart dse w/ prosthetic material,

residual defects adjacent to prosthetic material)

Postcardiac transplant patients w/ heart valve

defects


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Prophylaxis recommended for abovepatients if:

Dental procedures

Manipulation of gingival tissue/periapicalregion of teeth

Perforation of oral mucosa

Single dose of oral Amoxicillin 30 min 1hour before procedure

IV Ampicillin or Ceftrixone

Macrolide /Clindamycin - allergic


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Post-exposure prophylaxis Meningococcal meningitis prevention after

exposure: Rifampin

Prevention of Gonorrhea/Syphilis

Macrolides after contact w/ Pertussis HIV exposure-4 weeks therapy


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Pre-emptive therapy Delivery of therapy prior to development of

symptomsaborts impending dse

Short and defined duration of therapy

Tx for CMV after hamatopoietic stem celltransplants and after solid organtransplantation


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Empirical Tx in symptomatic patient 1st determine if drug is indicated

Gram staining of infected secretion/bodyfluid

Most valuable and time tested method for IDof bacteria

Definitive Tx w/ Known Pathogen

Monotherapy-preferred

risk of toxicity and selection ofantimicrobial-resistant pathogens


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Combination Tx Prevent resistance to monoTx

Accelerating rapidity of microbial kill

Enhance therapeutic efficacy by use of

synergistic interactions or enhancing kill Reducing toxicity


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MECHANISMS OF RESISTANCE TOANTIMICROBIAL AGENTS

2 major factors

Evolution

For survival

Aided by poor therapeutic practices

Indiscriminate use of antibiotics

Clinical/environmental practices


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Resistance due to: Reduced entry of antibiotic into pathogen

Enhanced export of antibiotic

Release of microbial enzymes that destroy

antibiotic Alteration of microbial proteins that

transform prodrugs to active

Alteration of target proteins

Development of alternative pathways tothose inhibited by antibiotic


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Resistance due to reduced entry of drug intopathogen

Porins-protein channels through whichantibiotics pass through outer membrane of

gm bacteria Absence

Mutation porin channel slow/prevent

Loss drug entry into cell

resistance


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Resistance due to drug efflux 5 major systems of efflux pumps

Multidrug and toxic compound extruder(MATE)

Major facilitator superfamily (MFS)transporters

Small multidrug resustance (SMR) system

Resistance modulation division (RND)exporters

ATP binding cassette (ABC) transporters


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Efflux pumps-prominent mech. Of resistancefor parasites, bacteria and fungi

Ex. P. falciparum resistant to chloroquine,quinine, mefloquine, halofantrine,

lumefantrine Mediated by ABC transporter encoded by P.

falciparum multidrug resistance gene 1(Pfmdr1)


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Resistance due to destruction of antibiotic

Drug inactivation

Ex. Drug resistance to aminoglycosides and-lactam antibiotics

due to production of an

aminoglycoside-modifying enzyme or

lactamase


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Resistance due to affinity of drug toaltered target structure

Single point or multiple point mutations

affinity of drug for its targetDue to:

mutation of natural target(fluoroquinoloneresistance)

Target modification (macrolides andtetracyclines)


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Acquisition of a resistant form of the native,susceptible target (MRSA due to productionof low affinity PCN-binding protein)

Resistance due to Incorporation of drug

Org not only becomes resistant but startsrequiring it for growth

Ex-Vancomycin resistant Enterococcus

Due to prolonged exposure to Vancomycin


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Resistance due to Enhanced Excision ofincorporated drug

Zidovudine

Hetero-resistance and Viral Quasi species

Subset of total microbial population isresistant, despite susceptibility of totalpopulation on testing


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Evolutionary Basis of Resistance Emergence

Mutation selection

Occur in the gene encoding:

Target protein no longer binds the drug

Protein involved in drug transport Protein impt for drug activation/inactivation

Regulatory gene or promoter affectingexpression of the target

Not caused by drug alone Random events that give a survival

advantage when drug is present


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Hypermutable phenotypes

Ability to protect genetic information fromdisintegrating

Flexibility to allow genetic changes leading

to adaptation

essential for life


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Accomplished by:

Insertion of correct base pair by DNApolymerase III

Proofreading by the polymerase

Postreplicative repair Defect in any of these repair mechanisms

high degree of mutations

May include mutations in genes causing

antibiotic resistance Ex - MDRTB


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Resistance by External Acquisition of GeneticElements

Horizontal transfer of resistancedeterminants from a donor cell(anotherbact. Species)


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SUMMARY

Success of antimicrobial tx

Proper selection of drug based onmicrobiological results and susceptibilitytesting

Knowledge of drug penetration into infectedcompartment

Knowledge of compartmentalpharmacokinetics


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PENICILLIN

Thiazolidine ring connected to a -lactamring, attached to a side chain

PCN nucleus chief structural requirementfor biological activity

Side chain-determines many antibacterial andpharmacological char. Of a particular type ofPCN

PCN G-greatest antimicrobial activity

Only natural PCN used clinically


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MOA:

Inhibition of bacterial cell wall synthesis Mech. Of Bacterial Resistance

Structural differences in PBPs(PCN-bindingproteins)targets of drug

Found in bacterial cell wall

Development of high-molecular-weight PBPsw/ decreased affinity for PCN

Inability to penetrate site of action

Active efflux pumpsremove antibioticfrom its site of action before it can act


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Enzymatically ( lactamases)

4 classes Class A: extended spectrum (ESBLs)

Degrade PCN, some cephalosporins,carbapenems

Most worrisome: KPCcarbapenemase inEnterobacteriaceaeresistant toCarbapenems, PCN all extendedspectrum cephalosporins

Class B: Zn+ dependent enzymes Destroy all - lactams except

Aztreonam


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Class C: active against cephalosporins

Class D: Cloxacillin-degrading enzymes Gm + bacteria-produce and secrete a large

amount of lactamase

Most enzymes: penicillinases


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Other factors that influence activity

Microorganisms adhering to implantedprosthetic devices (catheters, artificial joints,prosthetic heart valves)producebiofilmsmuch < sensitive to antibiotic Tx

Density of bacterial population influence Age of infection activity of -

lactams

Presence of proteins/other constituents of

pus, low pH, low O2 tensiondoes notdecrease ability of - lactams to kill bacteria


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Classification of PCN Table 53-1

Penicillin G and V Readily hydrolyzed by PCNase

Active against sensitive strains of gm + cocci

Ineffective against most S. aureus

PCNase resistant PCNs

Nafcillin, oxacillin, cloxacillin, dicloxacillin

1st line for PCNase producing S. aureus and S.

epidermidis


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Ampicillin, Amoxicillin

Extended spectrum including gm (-) org: H.influenzae, E. coli, P. mirabilis

Ther. Conc of PCN-achieved readily in tissuesand secretions (joint, pleural fluid and bile)

Low conc-prostatic secretions, brain tissue,intraocular fluid


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PENICILLIN G and V

Antimicrobial activity Similar for aerobic gm + org

PCN G-5-10> more active against Neisseria sp

Many bacteria previously sensitive to PCN G

are now resistant Viridans streptococci

S. pneumoniae

S. aureus

S. epidermidis

PCNase producing gonococci

Not effective against amebae, plasmodia,rickettsiae, fungi or viruses


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Absorption

Oral admin of PCN G 1/3 of dose absorbed

pH 2 of gastric juice destroys antibiotic

Rapid absorption

Max conc in bld achieved in 30-60 min Ingestion of food interferes w/ absorptionadministered 30 min before meals or 2hours after


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Oral admin of PCN V

More stable in acidic medium Better absorbed from GIT

Parenteral admin of PCN G

Peak plasma conc. w/in 15-30 min

PCN G benzathine

Releases PCN G slowly from area of injection

Produces low but persistent conc. In theblood


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Distribution

Conc. Vary in different fluids and tissues Sig. amounts = liver, bile, kidney, semen,

joint fluid, lymph and intestine

Penetration into CSF

Normal meninges-does not readily enter CSF Acutely inflamed meninges-penetrates into

CSF easilytherapeutically effective againstsusceptible org

Probenecid-elevates conc. Of PCN in CSF byinhibiting active transport processnosecretion of PCN from CSF into bloodstream


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Excretion

Mainly by kidney Small part-bile and other routes


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Therapeutic Uses

Pneumococcal infections DOC for sensitive strains of S. pneumoniae

Pneumococcal pneumonia

3rd gen cephalosporin/20-24 M units PCN G

daily by continuous IV infusion Tx continued for 7-10 days

Pneumococcal meningitis

Only if sensitive to PCN

Strep pharyngitis

Caused by S. pyogenes

PCN V 500 mg q 6H x 10D


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Infections caused by other Streptococci

Viridans grp-most common cause ofinfectious endocarditis

PCN-sensitivedaily doses of 12-20 M unitsof IV PCN G for 2 weeks + Gentamicin 1

mg/kg q 8H Infections w/ Anaerobes

Sensitive to PCN G exceptB. fragilis


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Staphylococcal Infections

Resistant due to penicillinase Meningococcal Infections

PCN G-DOC

High doses IV

Does not eliminate carrier stateineffectivefor prophylaxis

Gonococcal Infections

> resistant

Ceftriaxone


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Syphilis

1o

, 2o

, and latent syphilis of


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Due to release of spirochetal antigens withsubsequent host reactions to the products

Persist for a few hours, rash begins to fadew/in 48 hrs

Tx: Aspirin, do not D/C Tx

Actinomycosis PCN G-DOC

20 M units IV daily for 6 weeks

Clostridial Infections

DOC for gas gangrene 12-20 M units/day IV + antitoxin +

debridement


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Recurrences of Rheumatic Fever

200,000 units PCN G/V q 12H orally 1.2 M units PCN G benzathine IM once

monthly for 1 year


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PENICILLINASE-RESISTANT PENICILLINS

Use restricted to treatment of infectionsknown/suspected to be caused by Staphelaborating penicillinase

Oxacillin, Cloxacillin, Dicloxacillin Stable in acidic medium

Not substitutes for PCN G, not active againstenterococci or Listeria

Potent inhibitors of the growth of mostPCNase-producing Staph

Dicloxacillin-most active Absorption more effective on an empty

stomach


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Administered 1 hour before or 2 hours aftermeals

Nafcillin

>active than Oxacillin against PCN-resistant S.aureus


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AMINOPENICILLINS

Ampicillin, Amoxicillin Bactericidal for both gm+ and gm- bacteria

Meningococci, L. monocytogenes-sensitive

Salmonella, Shigella(most strains),

Pseudomonas, Klebsiella, Serratia,Acinetobacter, indole+ Proteus resistant

Ampicillin

Stable in acid

Well absorbed after oral administration Intake of food prior to ingestion diminishes

absorption


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Amoxicillin

Absorbed more rapidly and completely fromGIT than Ampicillin (major difference)

Similar antimicrobial spectrum to Ampicillin

< effective for Shigellosis


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Therapeutic Indications

URTI Active against S. pyogenes, S. pneumoniae,

H. influenzae

Sinusitis, OM, acute exacerbations of chronic

bronchitis, epiglottitis Most active against both PCN-sensitive and

PCN-resistant S. pneumoniae

Addition of beta lactamase inhibitor-extendsspectrum to beta lactamase producing H.influenzae and Enterobacteriaceae


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UTI

Ampicillin-effective but w/ inc. resistance Meningitis

S. pneumoniae or N. meningitidis

20-30%-resistant

Ampicillin + Vancomycin + 3rd genCephalosporin

L. monocytogenes-Ampicillin (excellentactivity)


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Salmonella infections

Fluoroquinolone/Ceftriaxone-DOC High doses Ampicillin (12 g/day) for adults


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ANTIPSEUDOMONAL PCNs

Carboxypenicillins Carbenicillin

Ticarcillin

Active against P. aeruginosa and Proteus w/care resistant to Ampicillin

Ineffective against S. aureus, E. faecalis,Klebsiella, L. monocytogenes

Ureidopenicillins

Mezlocillin

Piperacillin

Superior activity vs P. aeruginosa

klebsiella


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Carbenicillin

1st

PCN w/ activity vs P. aeruginosa and someProteus strains resistant to Ampicillin

Contains 5 mEq Na+ per gram of drug

May produce CHF due to excess Na+

Carbenicillin Indanyl Sodium Acid stable, avail. For oral admin

Only use is for mgt of UTI caused by Proteusspp other than P. mirabilis and P. aeruginosa

Active component excreted rapidly inurine=therapeutic conc.


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Piperacillin

Extends spectrum of Ampicillin to includeP.aeruginosa, Enterobacteriaceae,Bacteroides spp and E. faecalis

+ lactamase inhibitor(Piperacillin-

Tazobactam) Broadest antibacterial spectrum of PCNs

Tx of pts w/ serious infections caused by gm-bacteria

Bacteremia, pneumonias, infections ff. burns,UTI caused by P. aeruginosa, Proteus,Enterobacter spp


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UNTOWARD REACTIONS TO PCNs

Hypersensitivity reactions Most common

Maculopapular rash, urticarial rash, fever,bronchospasm, vasculitis, serum sickness,

exfoliative dermatitis, Stevens-Johnsonsyndrome, anaphylaxis

Extends to other beta-lactams

Management

Careful Hx

Desensitizations

Gradually increasing doses


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Pts w/ life-threatening infections

Continued on PCN despite rash

oftenresolves as Tx is D/C

Give antihistamines or glucocorticoids


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Documents

General Principles of Antimicrobial Therapy lecture