Section 3 : Multidrug Resistant Organisms MDR

what is a multidrug resistance bacterium (MDR)

• Multiresistant: if a bacterium gets several resistance genes = resistant to multiple classes of antibiotics 

• AKA superbugs 

• Highly pathogenic difficult to treat 

T or F: both fungi and bacteria can be MDR

T

what type of bacteria is E coli? where is found normally?

• E coli is a gram negative bacili bacteria usually found in the intestines 

what does VRE stand for ?

 vancomycin-resistant enterococci (VRE)

what does MRSA stand for

methicillin resistance staphlococcus areus

what does FQRP stand for

Fluoroquinolone-resistant pseudomanas aerginosa

E coli is increasliny becoming resistant to what drug?

• Example : cirprofloxacin-resistant E.coli  

  • E coli is a gram negative bacteria usually found in the intestines, bacillus (rod)

  • Ciprofloxacin is a second generation fluoroquinolone (nucleic acid synthesis inhibitors) 

Why russia have increase antibiotic resistances? 

In Canada 21% of E. coli isolates tested were resistant to fluoroquinolones, whereas 60% of E. coli isolates tested were resistant to fluoroquinolones in Russia.

There could be several reasons as to why E. coli in Russia is more resistance to fluoroquinolones, including:

• Antibiotics are readily available in pharmacies without medical intervention. You can access them as over-the-counter drugs, which greatly increases use

• Antibiotics are much cheaper in Russia than other medical interventions, so individuals are more likely to use them over alternative medicine

• Outside of North America, antibiotic usage may not be restricted to health professionals - the public can access antibiotics over the counter. This means that the total reported antibiotic use is much lower, but there are higher levels of resistance because actual antibiotic use is higher. Because you need a prescription for antibiotics in North America, usage is much lower.

what are the Multidrug Resistant (MDR) Bacteria you need to know for the midterm?

1. Methicilin-Resistant S.aureus (MRSA) 

2. Vancomycin-resistant enterococci (VRE) 

3. Extended-spectrum beta lactamases (ESBLs) 

4. Carbapenem-resistant organism (CROs) 

 Staphylococcus aureus is found in the normal flora where?

• Found in normal flora of 

  • Skin 

  • Upper res tract 

• Commonly colonizes the skin, nose, perineum 

Dysbiosis of S. aureus can cause?

• Soft skin infection 

• Bacteremia

• Endocarditis

• Wound infections

• Common cause of surgical site infections 

what used to be used to treat Staphylococcus aureus 

use to be with Methicillin (a narrow spectrum B-lactam antibiotic) but then resistance developed (MRSA)

what is the mechanism of methicillin

B-lactams, specifically Methicillin, are cell wall synthesis inhibitors. They target the peptidoglycan layer in the cell wall by binding to and antagonizing the transpeptidase (TP) enzyme complex and preventing the formation of cross-links between peptidoglycan chains. This ultimately destabilizes the bacterial cell wall and results in cell death.

Methicilinn-Resistant vs Methicilinn-sensitive treatment

• Sensitive = can be treated with penicillins or cephalosporins (b-lactam)  

• Resistant = can’t use other B-lactams (MRSA developed this via altering the binding sites) 

what is the Resistance Mechanism of MRSA

• The cell wall of S. aureus is made up of penicillin binding proteins (PBP) that are targeted by B-lactam antibiotics.

• MRSA has a resistance gene - called MecA - that results in a change in the PBP (to PBP-2a). This causes the penicillin binding protein to have a reduced affinity for B-lactam antibiotics, reducing their effectiveness.

what does PBP change to in MRSA? what is the gene called?

• MRSA has a resistance gene - called MecA - that results in a change in the PBP (to PBP-2a). This causes the penicillin binding protein to have a reduced affinity for B-lactam antibiotics, reducing their effectiveness.

What is MRSA usally treated with?

MRSA usually treated with intravenous formulations of vancomycin

• Increased morbidity and mortality associated with MRSA 

Majority of MRSA infections occurs in what populations?

Majority of MRSA infections occurs in people who are in hospital or close quarters bc increased risk of infections and limited therapeutic options 

how do hospitals screen for MRSA? what do they do if test is postive?

• Screen via nasal swabs or perineum 

• If colonized they are put on contact precautions 

  • Individual room 

  • enhanced hand hygiene 

  • Use of  gloves more frequent cleaning 

what are enterococci and where are they found?

• Enterococci are gram positive cocci (pairs or short chains) 

• Part of normal flora of human GI tract 

2 major species of enteroccoci

• Enterococcus faecium

• Enterococcus faecalis

Where Enterococcus are found to cause infection

• dysbiosis, these bacteria may be found in the urinary tract and cause infection

  • most common type of infections caused by enterococci are urinary tract infections that can lead to urosepsis (a severe infection of the urinary tract) 

Common treatment of enterococci:

Common treatment of enterococci: Enterococci are commonly treated with vancomycin (a glycopeptide antibiotic), however, resistance has developed.

• Mechanism of action of Vancomycin 

• Vancomycin binds and blocks the (D)-Ala-(D)-Ala side chain of the NAM subunit of peptidoglycan, and thus, cross-linking cannot occur between peptidoglycan.

where/with who are Vancomycin-Resistant Enterococci  infections common

• Infection common in immunocompromised patients (eg bone marrow transplant) 

• High rate of morbidity 

• Infection usually occurs in patients with many other comorbidities

VRE infections are more resistant to what 5 antibiotics

• VRE infections are more resistant to 

  • Vancomycin (glycopeptide)

  • Cephalosporins (B-lactam)

  • Ciprofloxacin (fluoroquinolone)

  • Trimethoprim/sulfamethoxazole (folate inhibitor)

  • 95% resistant to ampicillin (a B-lactam) 

Resistance Mechanism of VRE

• VRE uses altered binding sites as a mechanism of an antibiotic resistance 

• The vancomycin-resistant gene, VanA, results in the generation of cell wall molecules with a low affinity for vancomycin.

• Altered binding site:  change in affinity to vancomycin is the result of an alteration of the (D)-Ala-(D)-Ala tripeptide to D-Ala-D-Lac during cell wall synthesis.

what type of antibiotic Vancomycin

glycopeptide

T or F: there is lots of treatment for VRE infections

F: Limited treatment for VRE → screening and prevention is very important 

Screening for VRE is what?

Screening: Rectal swap 

T or F: VRE is screened more at hospitals then MRSA

F: Unlike screening for MRSA, VRE is not screened for in all hospitals as VRE is not as pathogenic 

T or F: VRE has high rate of colonization but a low rate of infection

T : VRE sterile site infections are rare

• Infection usually occurs in patients with many other comorbidities

  • Comorbidities: The simultaneous presence of two chronic diseases or conditions in a patient.

• Ex undergoing a stem cell transplant or a bone marrow transplant 

How to handle an outbreak of VRE?

• environmental cleaning (i.e. patient rooms, patient environments) rather than hand hygiene. 

• You would likely order the quarantine of patients, extensive patient room and hallway cleaning, in addition to vigilant hand washing.

what is Extended-spectrum beta lactamases (ESBLs)

• Extended-spectrum B-lactamases (ESBLs) are enzymes that allow for  resistance by inactivating most ß-lactam antibiotics (penicillins and cephalosporins).

what is the treatment for organisms harbouring ESBL genes

• sensitive to carbapenems.

  a class of broad-spectrum beta-lactam antibiotics reserved for severe, life-threatening, or multidrug-resistant (MDR) bacterial infections

T or F: you can use cephalosporins to treat Extended-spectrum beta lactamases (ESBLs) 

F: Treatment : Organisms harbouring ESBL genes are resistant to 1st, 2nd, and 3rd generation cephalosporins, but are sensitive to carbapenems.

examples of bacteria that have ESBL genes

• E. coli, Klebsiella pneumoniae* , and Proteus mirabilis*.

A Gram-negative enterobacterium that can cause severe pneumonia, enteritis (inflammation of the intestine), urinary tract infections, and more. has ESBLs

Klebsiella pneumoniae

 A Gram-negative, rod-shaped bacteria that can cause urinary tract infections. has ESBLs

Proteus mirabilis

Resistance Mechanism of ESBLs

• ESBL enzyme breaks apart B-lactam ring to inactivate the antibiotic 

• This mechanism neutralizes the penicillins, as well as 1st, 2nd, and 3rd generation cephalosporins.

what are 4 Risk factors for ESBL 

• Prior use of antibiotics

• Travel

• Hospitalization or any communal facility

• Carriage of ESBL organisms in your GI tract

2 ways of developing resistance via ESBL 

1. AmpC Genes

2. Class A ESBL Genes 

what is the AmpC genes? how is it spread? what does encode?

1. gives the organisms ESBL (resistant to B lactams)

2. AmpC genes encode class C b-lactamases 

3. Bc it is chromosomally can not be HGT to spread

4. Organisms with the AmpC gene (SPICE)

   1. Serratia 

   2. Pseudomonas 

   3. Indole positive-proteus 

   4. Citrobacter 

   5. Enterobacter 

Organisms with the AmpC gene (5)

Organisms with the AmpC gene (SPICE)

1. Serratia 

2. Pseudomonas 

3. Indole positive-proteus 

4. Citrobacter 

5. Enterobacter 

what is the Class A ESBL Genes? where is it encoded? what bacteria type?

1. Class A organisms have ESBL genes encoded on a plasmid 

2. Can be ANY gram negative organism 

3. If infected with gram negative = must be tested for ESBL genes so right treatment is given 

how does ESBL in Gram + vs Gram - differ

• Gram positive (B lactamase is inducible large amounts made only when presence of drug) 

  • Releases enzyme extracellularly hydrolyzes the b lactam before entering 

• Gram negative (consistently present without drug)  

  • Keeps it in the periplasmic space = more efficient mechanism then gram + 

Only one antibiotic available to treat MDR organisms. what is it

Carbapenems

what does CRO stand for?

Carbapenem-resistant organism (CROs) 

last line of defence for the treatment of gram negative organisms (B-lactams class of antibiotics)

Carbapenems

are Carbapenems broad or narrow

• broad spectrum of use 

what class is Carbapenems

B lactam

T or F: Carbapenem antibiotics are relatively stable against hydrolysis by B-lactamase enzymes (such as penicillinases and cephalosporinases).

T

Ertapenem, Meropenem, Imipenem, and Doripenem are examples of what antibiotic

carbapenem

T or F : carbapenem are effective against very serious infections with a highly resistant organism.

T

The ultimate Superbug is resistant to what

The ultimate Superbugs: Carbapenems resistant organisms 

T or F: CRO’s are any gram - bacteria that live in your GI and are resistant to a Carbapenem 

T

The risk factors for CROs 

• Prior use of antibiotics

• Travel

• Hospitalization or any communal facility

• Carriage of CROs in your GI tract

CROs are more prevalent in certain countries. what are they

• exposure to medical services in those countries (i.e. India, Israel, Greece, US) poses a higher risk for acquisition.

To be considered a CRO they must use these 2 mechanisms 

1. Enzymatic Degradation 

2. Inhibition of Drug uptake (2 features ) 

Carbapenemase Producing Organisms (CPOs). how are they CRO what is the mechanism

• Enzymatic Degradation 

• possesses a CPO gene (carbapenemase) in plasmid 

  1. Plasmid = HGT 

  2. which enables it to produce an enzyme that can hydrolyze carbapenems - called a carbapenemase. 

  3. carbapenemase is released into the periplasmic space, where it inactives carbapenem antibiotics

  4. These organisms are called Carbapenemase Producing Organisms (CPOs).

what is the mechanism of Inhibition of Drug uptake of CRO’s

1. A porin mutation that changes a component of the cell wall to inhibit carbapenems from entering the cell

2. An ESBL gene that produces an enzyme that degrades B-lactams

3. These genes are found in the chromosome = not a mobile gene elements = not passed via HGT 

T or F: There are numerous genes that encode for the carbapenemase enzyme.

T: There are numerous genes that encode for the carbapenemase enzyme.

• common CPO carbapenemase genes are KPC, NDM-1, and OXA-48.

  • KPC : asia, north america, europe, some african 

  • NDM-1 : Europe, US, India  

  • OXA-48: Klebsiella pneumoniae in turkey, the middle east, north africa, europe 

T or F: Canada has no CRO’s

F:

• Increase in number of CRO 

• Either the NDM or KPC genes 

• NDM in ontario since 2008 

 Infection with a CRO is associated with significant morbidity and mortality rates. why?

• There is a high risk of CROs being transmitted in a healthcare facility. Infection with a CRO is associated with significant morbidity and mortality rates due to the limited choices of antibiotics against the organism.

wound infections in the lower part of the body would be attributable to what type of bacteria?

• The most common causes of wound infections in the lower part of the body would be attributable to Gram-negative bacilli (GNB) and Gram-positive cocci (GPC). 

When considering wound infections - the most common causes of wound infections include?

• When considering wound infections - the most common causes of wound infections include Staphylococcus aureus and Streptococcus pyogenes.