RESISTANCE TO GLYCOPEPTIDE ANTIBIOTICS

Glycopeptides

1. Vancomycin
- its use is increased in response to the increasing incidence of MRSA
- resistance was first reported in the enterococci in 1988.
- VRE ( Vancomycin-Resistant Enterococcus ) - account for more than
20% of all enterococcal infections.
Ent. faecium strains and Ent. Faecalis ( Resistance is greatest)
VanA resistance - most common, high level of resistance to
vancomycin
- mediated by a seven gene cluster on the transposable genetic
element Tn 1546
7 Gene Cluster:
VanS - resistance to vancomycin is via a sensor histidine kinase
VanR - response regulator
VanH
VanX- encodes a d Alad - Ala dipeptidase
Van A
P VanR
P VanH

Encodes a d - lactate dehydrogenase/ - keto acid reductase and

generates d lactate
Cell wall precursors terminating in d - Ala- d - Lac to which
vancomycin binds with very low affinity
change in affinity is mediated by one hydrogen
bond
Vancomycin and d - Ala- d - Ala => stabilized by five hydrogen
bonds
Vancomycin and d - Ala- d Lac => only four hydrogen bonds
can form
complex is unstable
 2. Tekoplanin

BOTH

Used clinically
They bind the terminal d - alanyl - d alanine side chains of
peptidoglycan and prevent cross - linking in a number of Gram -
positive organisms

Not active against Gram - negative organisms

Its use is increased in response to the increasing incidence of MRSA

Genes present in the vancomycin - producing organism Amycolatopsis

orientalis , suggesting that selective pressure has forced genes
originally present to protect antibiotic -producing organisms to jump to
other species.

VanB resistance is also acquired and the peptidoglycan precursor is

again d - Ala- d - Lac, but isolates often remain susceptible to
teicoplanin.

VanC resistance is intrinsic and chromosomally encoded in some

enterococcal species such as Ent. gallinarum

MRSA AND REDUCED GLYCOPEPTIDE SUSCEPTIBILITY

There is major concern that high - level, VanA - type resistance could
transfer to staphylococci, particularly MRSA.

1960s and 1970s - MRSA was not feared because several other
treatment options existed, including use of tetracyclines, macrolides
and aminoglycosides
 1980s- Empirical therapy of staphylococcal infections, particularly
nosocomial sepsis, was changed to the glycopeptide antibiotic
vancomycin.

Early 1990s - MRSA levels were rising and major increase in

vancomycin use.

1997- isolation of the fi rst Staph. aureus strain with reduced

susceptibility to vancomycin and teicoplanin (vancomycin MIC = 8
g/ml) which is the inevitable consequence of the selective pressure

Beginning of the 21st century- MRSA is responsible for up to 25%

of nosocomial infections in the USA and reports of community -
acquired MRSA infections are increasing.

Susceptibility and Resistance:

1. Sensitive- Strains with MIC values < 4 g/ml

2. Intermediate- Strains with MIC values 8 16 g/ml
3. Resistant Strains with MIC values > 32 g/ml

VISA - (vancomycin- intermediate Staph. aureus )

GISA- (glycopeptide - insensitive Staph. aureus )
Both used to denote strains with vancomycin or teicoplanin MICs of 8 g/ml
VRSA - (vancomyin- resistant Staph. aureus )
Reserved for strains with MIC values > 32 g/ml
Increased quantities of PBP2 and PBP2 are presumed to trap vancomycin,
Amidation of glutamine residues in cell wall muropeptides reduces the cross -
linking and consequently the number of vancomycin target molecules.

RESISTANCE TO AMINOGLYCOSIDE ANTIBIOTICS

Aminoglycoside

hydrophilic sugars
amine groups are protonated at biological pH
polycation
binds to the A site
Interferes recognition of cognate tRNA by rRNA during translation.
perturb translocation of the tRNA from the A site to the peptidyl -
tRNA site (P site)
Methylation of the rRNA
High - level resistance in aminoglycoside - producing
microorganisms
NOT the mechanism of resistance in previously susceptible strains
Structural modification by enzymes
 most common mechanism for clinical aminoglycoside resistance
3 classes of enzymes:
A. 7 aminoglycoside phosphatases (APHs)
1. APH(3)
2. APH(2)
3. APH(3)
4. APH(6)
5. APH(9)
6. APH(4)
7. APH(7)
B. 4 aminoglycosidenucleotidyltransferases (ANTs)
1. ANT(6)
2. ANT(4)
3. ANT(3)
4. ANT(2)
C. 4 aminoglycoside acetyltransferases (AACs)
1. AAC(2)
2. AAC(6)
3. AAC(1)
4. AAC(3)

*2 Bifunctional enzyme aminoglycosides:

- typically susceptible to attack by multiple enzymes

1. AAC(6)
2. AAC(2).