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Flashcards in M10: Antimicrobial Resistance Mechanisms Deck (29)
1

Antimicrobial Resistance:

Antibiotic resistance is (a major / not a) problem for contemporary medicine.

The annual cost of bacterial drug resistance is estimated to run between $100 million and $30 billion.

It is important to note that antimicrobial resistance in bacteria is a (local / global) problem.

The problem is even more critical as we face the emergence of some _ organisms for which there are no effective antimicrobial regimens.

a major

global

multi-resistant

2

Where Does Antibacterial Resistance Come From?

There are several potential sources of antimicrobial resistance in bacteria.

One common source is via the introduction of _ from _.

An important example of this is the introduction of the USA 300 clone of _ which is the prominent strain associated with the epidemic of community-associated _ in the USA.

resistant strains
outside the “community”

Staphylococcus aureus
MRSA

3

Where Does Antibacterial Resistance Come From?

There are several potential sources of antimicrobial resistance in bacteria.

A second important source is the acquisition of _ from _.

This may be accomplished through the acquisition of _ elements such as _ or _.

antimicrobial resistance
another strain

mobile DNA
plasmids or transposons

4

Where Does Antibacterial Resistance Come From?

There are several potential sources of antimicrobial resistance in bacteria.

Emergence of resistance can also occur as a consequence of a _ in the _.

An example of this would be development of a mutation in the _ which alters the affinity of macrolide antibiotics to _ and _, rendering them essential inactive.

spontaneous mutation
bacterial genome

23s ribosome
bind to their target
block protein synthesis

5

Where Does Antibacterial Resistance Come From?

There are several potential sources of antimicrobial resistance in bacteria.

The last important source of resistance is the selection of _ via _.

This differs slightly from mutation alone as it combines the natural occurrence of _ with the selective pressure of _.

resistant strains
antibiotic pressure

genetic mutation
broad exposure to antibiotics

6

Mechanisms of Antibacterial Resistance:

There are 4 major mechanisms of antibacterial resistance.

Together, these 4 mechanisms essentially account for (all / most) of the methods that bacteria manifest antimicrobial resistance.

These mechanisms include:

1) the presence of _ that _ or _ antibiotics

2) synthesis of _ which maintain their biologic function but are not _ (typically through loss of affinity of the antibiotic for the _)

3) alterations in _ resulting in a decreased ability of the drug to _ and to have _

4) the presence of _ which _ from the cell and hence decrease the amount of drug present at the site of _.

all

enzymes
destroy or inactivate

substitute proteins
targeted by the antimicrobial agent
target site

permeability of bacterial cell
enter the cell
access to its target

pumps
remove antibiotics
antimicrobial action

7

Enzymes That Destroy or Inactivate Antibiotics (Example: Beta-Lactamases):

There are a wide variety of beta-lactamases.

These enzymes can have either a _ or _-spectrum.

The presence of beta-lactamases is very (common / rare) among pathogens.

Greater than 35% of middle ear isolates of H. influenzae and nearly 100% of M. catarrhalis synthesize a beta-lactamase enzyme rendering these organisms resistant to _.

Another very prominent and prevalent beta-lactamase is the _ enzyme of S. aureus which is found in nearly all strains of this bacterium and emerged shortly after the introduction of _.

narrow
extended

common

amoxicillin

penicillinase
penicillin

8

Enzymes That Destroy or Inactivate Antibiotics (Example: Beta-Lactamases):

The presence of beta-lactamase enzymes mediate antibiotic resistance through the _ of the _.

As a consequence of this action, the hydrolyzed product is unable to _, one or more of the _, resulting in resistance.

The genes that code for beta-lactamase enzymes may be located on acquired _ or on the bacterial chromosome.

hydrolysis
beta-lactam ring

bind to its target
penicillin binding proteins

plasmids

9

Enzymes That Destroy or Inactivate Antibiotics (Example: Beta-Lactamases):

Extended spectrum beta-lactamases are an increasingly important class of beta-lactamase enzymes.

These enzymes are notable for their ability to affect _ beta-lactams, including 3rd and 4th generation _.

The genes for ESBLs can be found on _ or they may have been inserted into a _ location.

To date, hundreds of these ESBL enzymes have been reported, many of which have been derived through serial mutations of _ genes.

ESBL enzymes had initially been recovered most frequently from _ and _.

However, these enzymes have now been identified in many other _.

advanced generation
cephalosporins

plasmids
chromosomal

preexisting ESBL

Klebsiella
E. coli

GNR

10

Enzymes That Destroy or Inactivate Antibiotics (Example: Beta-Lactamases):

An increasing number of broad spectrum beta-lactamases are now recognized.

In addition to ESBLs, a number of bacteria carry _ genes in their chromosomes.

These genes tend to be inducible and can code for (broad / extended)-spectrum beta-lactamase activity which can destroy penicillins and cephalosporins (except for _) and are not fully inhibited by _.

In addition to cefepime, _ are the only beta-lactams that are resistant to hydrolysis by the ampC beta-lactamases.

Finally, the most recent and perhaps most concerning emerging classes of beta-lactamases are the _.

A number of these, related and unrelated, have now been recognized and are being identified with increasing frequency.

ampC

broad
cefepime
beta-lactamase inhibitors

carbapenems

carbapenemases

11

Development of Altered Targets:

The evolution of altered targets as a mechanism of antibiotic resistance results in a modification of the _ with resultant diminished affinity of the antibiotic for the _ without loss of the target’s _.

Examples of this mechanism of resistance include:

1) alterations in _ leading to beta-lactam resistance

2) the presence of mutant _, resulting in vancomycin-resistance

3) alteration of _ with consequent quinolone resistance

4) alteration of _ resulting in macrolide resistance

antibiotic target
antibiotic target
biologic function

penicillin binding proteins (PBPs)

peptidoglycan precursors

DNA gyrase

ribosome

12

Development of Altered Targets:

PBPs are found in all _.

The PBP is an enzyme which is responsible for _.

The PBPs covalently bind _; the bound PBP is (able / unable) to perform its essential biologic function causing _.

Antimicrobial resistance occurs through presence of PBPs with (high / low) affinity for beta-lactams which are able to catalyze all steps in _.

This mechanism is responsible for resistance in _, _, and _.

bacterial plasma membranes

cross-linking of cell wall

beta-lactams
unable
cell death

low
cell wall synthesis

S. aureus, E. faecium, and S. pneumoniae

13

Development of Altered Targets:

A second example is the presence of quinolone resistance secondary to alterations in the enzyme _.

Quinolones exert their antibacterial effect by binding to _ & preventing its normal function.

Mutation of _ gene can be selected by _.

These mutations can result in alterations of _ preventing the _ and hence, conveying resistance.

DNA gyrase

DNA gyrase

DNA gyrase
exposure to quinolones

DNA gyrase
binding of quinolones

14

Alterations in Permeability of Bacterial Cell:

Alterations in permeability of the bacteria cell impede _, limiting its ability to reach and interact with its site of action.

One of the most common ways that permeability is altered is via mutation or loss of a _.

Porins are proteins that facilitate the _ through the creation of _.

Many antibiotics enter Gram (positive / negative) bacteria via porins.

Modification of porins may prevent or slow _ entrance into cell.

Decreased rates of entrance favors enzymes which _

the entrance of the antimicrobial agent into the bacterial cell

porin

transfer of molecules across cell membranes
“tunnels” that “carry” the molecule from one surface to the other of the bacterial cell membrane

negative

antibiotic

modify antibiotics

15

Alterations in Permeability of Bacterial Cell:

Modifications of porins play a particularly important role in antibiotic resistance in Pseudomonas aeruginosa.

_ enter P. aeruginosa through a porin known as _.

Decreased expression of this porin results in (enhanced / diminished) permeability of quinolones and other antibiotics into the bacteria.

Alterations in the expression of this porin are easily selected for through the presence of _.

The ease of this selection process accounts in part for the relatively (high / low) prevalence of resistance to quinolones in strains of P. aeruginosa recovered from patients who are treated with quinolones.

Quinolones
OprD

diminished

antibiotic pressure

high

16

Presence of Pumps Which Remove Antibiotics:

The last mechanism of resistance is manifest through the presence of efflux pumps which _.

Removal of antibiotics from the cytoplasm before they are able to bind to their targets limits their ability to _.

Efflux pumps take on an even greater importance if there is also diminished susceptibility to the _ because of other mechanisms of resistance.

The presence of efflux pumps plays a role in antimicrobial resistance in many different bacteria.

Clinical examples include the presence of efflux pumps mediating _ resistance in Gram positive cocci and _ resistance in Pseudomonas spp.

remove antibiotics from cells

kill or inhibit the growth of bacteria

antimicrobial agent

macrolide
quinolone

17

The 4 mechanisms we have been discussing account for essentially all antimicrobial resistance currently described in the literature.

It is important to note that (only / more than) one of the resistance mechanisms may be present within a single bacterium at a time.

The presence of multiple resistance mechanisms may synergistically (enhance / diminish) the level of antibiotic resistance within a single bacterium.

The ability of existing resistance genes to undergo _ with consequent (broadening / narrowing) spectrum of resistance is another important concern to remember.

Finally, while these 4 major mechanisms characterize all of the changes currently recognized as being associated with antimicrobial resistance within the bacteria cell, there may be _ factors in the bacterial environment that can also result to “in (vitro / vivo)” resistance even when the bacteria appear to be susceptible to a given antimicrobial agent in (vitro / vivo).

The study of bacterial biofilms is a very active focus of research.

A great deal of effort is being spent to understand how living in a biofilm can protect bacterial pathogens from antimicrobial therapy that is typically active against a given pathogen.

more than

enhance

ongoing mutations
broadening

extrinsic
vivo
vitro

18

A Possible 5th Mechanism: Biofilms:

Organisms living in biofilms are “_” from effect of antibiotics both by the _ of antibiotics through biofilms as well as the very slow _ of organisms living in biofilm.

Consequently there are (high / low) levels of drug reaching the pathogens living in the biofilms and (higher / lower) MICs of organisms when they are in the sessile state.

protected
poor permeability
metabolic state

low
higher

19

Antimicrobial Resistance: Examples in Clinical Care:
Escherichia coli:

• Frequent pathogen in _ and _

• Cause of _, _, and _

• As many as 30% of community and 50% of hospital isolates are resistant to _ on the basis of a “simple” beta-lactamase

• Frequently resistant to _ and other agents

• Prevalence of extended-spectrum beta-lactamases on the rise

nosocomial and community-acquired infection

cystitis, pyelonephritis and bacteremia

amoxicillin

TMP/SMZ

20

Antimicrobial Resistance: Examples in Clinical Care:
Enterococci:

• 3rd most common cause of _ infections in adults

• Cause of _, _, and _

• Naturally resistant to (many / few) antibiotics

• Only susceptible to _ and _

• _ resistance increasingly common

• Emergence and spread of _ resistance

nosocomial

intraabdominal infections, urinary tract infections and bacteremia

many

ampicillin & vancomycin

Ampicillin

vancomycin

21

Antimicrobial Resistance: Examples in Clinical Care:
Staphylococcus aureus:

• #1 _ pathogen in U.S.

• Frequent cause of _, _, _, and _

• Rates of _ increased from 8% to > 50% for some hospitals

• _ strains are resistant to multiple antibiotics but is often susceptible to _

• _ is the remaining therapeutic agent most often used

nosocomial

skin, wound infection, bacteremia & hospital acquired pneumonia

hospital acquired methicillin-resistance (HA-MRSA)

Community acquired methicillin-resistant (CA-MRSA)
TMP/SMZ

Vancomycin

22

Antimicrobial Resistance: Examples in Clinical Care:
MRSA in Healthy Children:

• Initial report of CA-MRSA between 1997 & 1999 in the absence of _ or _

• Increasing reports of CA-MRSA in previously (well / ill) children
– >60% incidence of methicillin-resistance in community S. aureus in children in Houston
– Increasing rate now recognized in Pittsburgh
– National & international _

• Unique _ compared to HA-MRSA
– _ and _
– (Broader / Narrower) choice of effective antibiotics

risk factors
exposure history

well

epidemic

genetics

SCCMec IV and Panton-Valentine Leukocidin

Broader

23

Antimicrobial Resistance: Examples in Clinical Care:
Glycopeptide Resistance in S. aureus:

-First report of S. aureus with reduced susceptibility to _ in 1996

-Cases described from Japan, Michigan and New Jersey

-All isolates were _ with prolonged exposure to _

-Mechanism of _-resistance not fully worked out
– Both up regulated and down regulated _
– Recent evidence of _ in isolates from PA

vancomycin

MRSA
vancomycin

vancomycin

genes

VRE-transposon

24

Antimicrobial Resistance: Examples in Clinical Care:
Classes of Glycopeptide in S. aureus: (3)

• Vancomycin-intermediate S. aureus (VISA)

• Heterogenous vancomycin-intermediate S. aureus (hVISA)

• High-level vancomycin-resistant S. aureus (VRSA)

25

Antimicrobial Resistance: Examples in Clinical Care:
Classes of Glycopeptide in S. aureus: (3)

• Vancomycin-intermediate S. aureus (VISA)

– Mechanism is synthesis of _ containing _ capable of binding vancomycin which reduces availability of drug to reach intracellular target molecules

• Heterogenous vancomycin-intermediate S. aureus (hVISA)

– subpopulations display (uniform / variable) rather than (uniform / variable) susceptibility to vancomycin

– hVISA populations withstand vancomycin by means of an _

• High-level vancomycin-resistant S. aureus (VRSA)

– Mechanism due to transfer of _-mediated transfer of _ gene cluster on _

unusually thickened cell wall
dipeptides (D- Ala-D-Ala)

variable
uniform

unusually thickened cell wall

plasmid
VanA
transposon

26

Antimicrobial Resistance: Examples in Clinical Care:
Streptococcus pneumoniae:

- Disease among _, _, and _

- Frequent cause of _ & community-acquired _

- Accounts for 30-50% of _ and _

- _ Resistance in S. pneumoniae

• Problem emerged in US and rapidly escalating in last few years

• Major _ differences in prevalence of resistance

• Presence of “_” & “_” resistance

• Mechanism of resistance = altered _

• Presence of “_” strains

• Risk Factors include:_, _, and _

infants, young children & adults

bacteremia
pneumonia

acute otitis media
bacterial sinusitis

Penicillin

geographic

intermediate
high-level

PBP

multiply-resistant

age

27

Antimicrobial Resistance: Examples in Clinical Care:
Group A streptococci:

- Common cause of _ and _ in children

- _ disease uncommon but may be seen in association with certain serotypes

- Mechanism of Macrolide Resistance in GAS

• _ - Target Modification
– MLSi & MLSc
– _ and _ are the genes responsible for these phenotypes

• _ - Removal of Antibiotic
– _ is gene responsible for this genotype

• Mutations at _ - Target Modification
– mutations at _ and _ mutation sites have been reported

pharyngitis
skin infection

Invasive

Ribosomal methylation
erm(A) & erm(B)

Macrolide efflux pump
mef(A)

ribosomal sites
L4 and L22

28

Emerging Resistance:

There are several important examples of new and emerging types of antibiotic resistance that will have important clinical consequences.

One of the most important of these is the development and dissemination of _ enzymes in Acinetobacter.

The presence of this resistance enzyme severely limits treatment of infections by this pathogen.

A second important emerging pattern of resistance is the development of _ resistance in Klebsiella associated with loss of _.

More recently, the _ gene was described in 2008 in isolates of K. pneumoniae recovered from India with intrinsic ability to destroy most known _ (including carbapenems).

This novel _ gene is located on a large resistance containing genetic element and codes for multiple classes of resistance.

Of concern, the NDM-gene has now been shown to be transferable to multiple _ species and has spread to isolates that have been recovered from around the world.

carbapenemase

quinolone-carbapenem
porin

NDM-1 carbapenemase
beta-lactams

metallo-beta-lactamase

GNR

29

Emerging Resistance:

These kinds of changes lead to potential for increasing emergence of new “_” strains.

Despite the fact that the crisis of antibiotic resistance has been recognized as a major public health problem for nearly 20 years, there have been only limited responses to this crisis.

This is perhaps best illustrated by the fact that only one new class of therapy against GNR is has been developed and released in the last decade, this being the _, which are a derivative of _.

Because they are a derivative of an existing antimicrobial class, the bacteria have a head start in _, limiting the utility of this “new” class of therapy.

panresistant

glycylcyclines
tetracycline

developing resistance against these pathogens