Antibiotic resistance criteria - PowerPoint Presentation

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Antibiotic resistance criteria

Komal Pareek

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Key Terms

Antibiotic = A drug that kills or inhibits the growth of microorganisms

Resistant = Somewhat arbitrary designation that implies that an antimicrobial will not inhibit bacterial growth at clinically achievable concentrations

Susceptible = Somewhat arbitrary designation that implies that an antimicrobial will inhibit bacterial growth at clinically achievable concentrations

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Key Terms

MIC = Minimal

inhibitory

concentration. Lowest concentration of antimicrobial that inhibits growth of bacteria. Commonly used in clinical lab

MBC = Minimal bactericidal concentration. Concentration of an antimicrobial that kills bacteria. Used clinically only in special circumstances

Breakpoint = The MIC that is used to designate between susceptible and resistant. Arbitrarily set by a committee

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MIC = 6.25 mcg/mL

Minimum Inhibitory Concentration

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Well Plate for MIC Testing

Many Labs Use Automated Testing

Automated Methods

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Other Methods for Determining Susceptibility

E-test®

Kirby-Bauer

Disk Diffusion

Agar dilution

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Concept of Breakpoint to Determine Susceptibility

Antibiotic

MIC

Breakpoint

Susceptibility

Ampicillin

>16

8

Resistant

Gentamicin

2

4

Susceptible

Cephalothin

>16

N/A

Resistant

Cefepime

8

32

Susceptible

Cefotaxime

16

16/32

Intermediate

Ceftazidime

2

32

Susceptible

Aztreonam416SusceptibleCiprofloxacin22ResistantAmp/Sulbactam>168ResistantMeropenem44/8IntermediatePip/tazo832-64/128Susceptible

EXAMPLE: Susceptibility testing for a single isolate of Pseudomonas aeruginosa

-Breakpoint for intermediate resistance for meropenem is 4 and for piperacillin/tazobactam (pip/tazo) 32-Pip/tazo is the better choice between the two -Ciprofloxacin is a poor choice even though the MIC is lowest of the three

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Agriculture

Inpatient

Outpatient

Antibiotic Use Leads to

Antibiotic Resistance

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Reasons for Antibiotic Overuse :

Conclusions from 8 Focus Groups

Patient Concerns

Want clear explanation

Green nasal dischargeNeed to return to work

Physician Concerns

Patient expects antibiotic

Diagnostic uncertaintyTime pressure

Barden L.S. Clin Pediatr 1998;37:665

Antibiotic Prescription

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Antimicrobial Resistance

Natural (Inherent)

G(-) LPS

Lack target or transport

AcquiredMutationHorizontal transferVertical HorizontalTransformationTransductionConjugation

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Plasmids

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AB resistance

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“Super Bugs”

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Resistance to Antimicrobial Drugs

Mechanisms of resistance

Enzymes that

cleave or otherwise inactivate

antibioticsβ-lactamasesChanges in bacterial permeabilitiesPrevents entry of antibiotic into cellMutation in target moleculeAlter binding characteristics of the antibioticsAlteration of metabolic pathways

Some resistant bacteria can acquire PABA from the environment

Molecular

pumps (efflux systems)Secretion systems that export antibiotics faster than the rate of import14

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Nongenetic Origins of Drug Resistance

Low replication rates

Antibiotic is metabolized or neutralized before it act

Mycobacteria

spp.Alteration of cellular physiologyBacterial L forms are cell wall-freeStreptococcus spp., Treponema spp., Bacillius spp., othersColonization of sites where antibiotics cannot reach

Gentamicin cannot enter cells

Salmonella

are thus resistant to gentamicin15

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Chromosomal Resistance

Genes that regulate susceptibility

Often found in

enzymes,

rRNA and secretion system genesMutations in RNApol render it resistant to the effects of rifampinEfflux pumps with specificity for antibioticsFound in all bacteriaAll possess large hydrophobic cavity for binding antibiotics

Genetic Origins of Drug Resistance

Five efflux pumps (“

antiporters

”) that regulate antibiotic resistance (Paulsen, 2003)

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Extrachromosomal Resistance

Often account for interspecies acquisition

of resistance

Contribute to

multi-drug resistance (MDR)Genetic elements are:PlasmidsTransposonsConjugationTransductionTransformationGenetic Origins of Drug Resistance

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Drug Resistance

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Antimicrobial Activity In Vivo

Drug-Pathogen Relationships

Environment

State of metabolic activity

: slow-growing or dormant bacteria less susceptibleDistribution of drug: CNS is often exclusionary Location of organisms: Some drugs do not enter host cellsInterfering substances: pH, damaged tissues, etc.ConcentrationAbsorption

: some cannot be taken orally

Distribution

: some accumulate in certain tissuesVariability of concentration: peaks and troughsPostantibiotic effect: delayed regrowth of bacteria

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Mechanisms of Resistance

Overview

Specific Examples

Antibiotic Degrading Enzymes

Decreased PermeabilityEfflux Pumps

Target Alterations

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Mechanisms of Resistance

Antibiotic Degrading Enzymes

Sulfonation

, phosphorylation, or

esterifictation Especially a problem for aminoglycosides

β

-lactamases

Simple,

Extended

spectrum

β

-lactamases (ESBL),

cephalosporinases

,

carbapenemases

Confer resistance to some, many, or all beta-lactam antibiotics

May be encoded on

chromosome or plasmid

More potent in Gram-negative bacteriaExamples: S. aureus, H. influenzae, N. gonorrhoeae, E. coli, Klebsiella sp., Enterobacter sp., Serratia sp.,

other enteric bacteria, anaerobes

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Extended Spectrum



-lactamases



-lactamases capable of hydrolysing extended spectrum

cephalosporins

,

penicillins, and aztreonam

Most often associated with

E. coli

and

Klebsiella

pneumoniae

but spreading to other bacteria

Usually plasmid mediated

Aminoglycoside, ciprofloxacin and trimethoprim-sulfamethoxazole resistance often

encoded on same plasmid

Has become a significant resistance determinate in acute and long-term care facility enteric pathogens22

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Class A

Carbapenemases

Most common in

Klebsiella

pneumoniae (KPC)

Also seen in

E. coli, Enterobacter,

Citrobacter, Salmonella, Serratia

, Pseudomonas

and

Proteus spp.

Very often with multiple other drug resistance mechanisms, resistance profile similar to ESBL but also

carbapenem

resistant

Became problem in

New York City first in 2002-2003

and is being increasingly recognized in Mid-Atlantic US.

Spreading across species to other

Gram-negatives and EnterobacteriaceaeEmerging in long-term care facilities23

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Mechanisms

of Resistance

Decreased Permeability

Pseudomonas spp.

Affects many antibiotics including carbapenems

Efflux Pumps

Pseudomonas spp.

(multiple antibiotics)

Tetracyclines

Macrolides

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Mechanisms of Resistance

Target Alteration

DNA gyrase

Fluoroquinolones

Many Gram-negatives, S. pneumoniae

Penicillin-binding protein

Methicillin

-resistant S. aureus

(MRSA)

Penicillin-resistant

S.

pneumoniae

Gram positive cell wall

Vancomycin

Enterococcus

spp

.

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Mechanisms of Resistance

Target Alteration

Ribosome

Tetracyclines

Macrolides

S. pneumoniae

,

Staphylococcus sp., N. gonorrhoeae

, enteric

Gram-negative

rods

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VRE-Vancomycin resistant Enterococci

VRE- found first time in France,

1986

Vancomycin n

glycopeptide (avaporcin) used in feed-EuropeVRE found in horse, pigs, dogs and poulty- used avaporcin in feedUse of avaporcin – leads development of VREFood products from Europe contain VRE1996, use of avaporcin is banned and drop of VRE rateEnterococcus

faecium

and Enterococcus

faecalisVancomycin is the only antibiotic for

MRSA strain

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Increase in MRSA Prevalence in US

Comparison to Other Drug-Resistant Organisms

Wenzel et. al. ICHE 2008;29;1012

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Conclusion

Inappropriate and excessive use of antibiotics is a major factor contributing to emerging antibiotic resistance

Determinants of resistance are selected for by antibiotic use

Multiple mechanisms exist for bacteria to become resistant to antibiotics

Antibiotic resistance is a problem in outpatient and inpatient settings and is a factor in a wide variety of infectionsAntibiotic resistance continues to emerge as a serious threat to public health29

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First effective drug: Streptomycin 1946

Treatment

Long time ≥6 mnds

Combination of drugs

Different stages of bacterial growth

DOT: Directly observed therapy

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First-line drugs

Isoniazid

Isoniazid®

Mycolic acid

Long Chain ACP-Enoyl

Fatty Acid Reductase (inhA)

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First-line drugs

Rifampicin

Rimactan®

Broad spectrum antibiotic

From

Streptomyces

sp

Inhib bacterial RNA polymerase

(

p-p

intract. naphtalene rings aromatic AA?)

Induce CYP2C; increased metabol. of certain anti AIDS drugs

Pyrazinamide

Mechanism not known

Ethambutol

Mechanism not fully known

Synth of cell wall comp.:

Inhib. arabinocyl transferase?

Arabinose,

Arabinomannan

and Lipoarabinomannan

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Second-line drugs

Ethionamide

p-Aminosalicylic acid

Cycloserine

Isolated

Spreptomyces

sp

Mech. ≈ Isoniazide

PABA antimetabolite

Folic acid synth (≈antibact. sulfa

)

Inhib. alanine racemase

and alanine ligase;

Inhib. peptidoglycan synth

Kanamycin

(aminoglycoside antibiotics)

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Others

Quinolones

Oxazolidinones

Treatment of MAC infections

Clarithromycin

(Macrolide)

Other macrolides

Ethambutol

Quinolones

Rifabutin (Rifamycin)

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Inhibition of AFB

MOA

Disrupt cell wall synthesis

Cycloserine

Prevents replicationClofazimineDisrupt Waxy layerMycolic acid and ArabinogalactanExamplesIsoniazidEthambutalMycobacteriumMultidrug Therapies36

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TB resistance

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Antimycobacterium

antibiotics

Isoniazid

(INH)

Inhibits mycolic acid synthesisEthambutol Inhibits incorporation of mycolic acid

Antibacterial Antibiotics

Inhibitors of Cell Wall Synthesis

Multidrug-Resistant Tuberculosis Infection

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