Download Mechanisms of Anti-microbial Resistance

Anti-Bacterial Resistance – Mechanisms, Prevention and Implications in ICU
1/9/10
PY Mindmaps
Yung, A. et al (2004) “Infectious Disease: A Clinical Approach” Second Edition, IP
Communications Ltd
MECHANISMS
(i) Natural Resistance – they do not possess the molecular target of the drug or are
impermeable to it
(ii) Acquired resistance – occurs through mutation or the acquisition of new genetic
material carried by mobile elements (plasmids and transposons)
(1)
(2)
(3)
(4)
Decreased permeability
Inactivation of drug (via enzymes)
Target site modification
Active drug efflux
- these mechanisms often act synergistically to produce a resistant phenotype
- selective pressure may result in the ‘bundling’ together of several resistance genes in a
single package of exchangeable genetic material (ie. highly resistant Gram negative
organisms)
Decreased Permeability
- this often acts synergistically with another mechanism such as drug inactivation to produce
clinical resistance
- this is mechanism used by S. maltophilia and P. aeruginosa
- carbapenems access P. aeruginosa via porin channels -> loss of porin channels results in
resistance
Jeremy Fernando (2011)
Inactivation of Drug (via enzymes)
Beta-lactamases
- hydrolyse the beta-lactam ring -> make it ineffective
- resistance developed through chromosomal mutation and plasmids transfer
- agents that contain a betalactam ring = penicillins, cephalosporins, carbapenems,
monobactam
- resistant to pencillin BUT sensitive to cephalosporins and the rest
Extended spectrum beta-lactamases
- resistance developed through aminoacid substitution
- resistant to penciillin + third generation cephalosporins
- some of these are specific cephalosporinases and others possess resistance to betalactamase inhibitors (clavulanic acid, tazobactam and sulbactam)
Target Site Modification
- modification of antimicrobial target -> reduced affinity for the drug OR replacement of the
target with an alternative pathway
- Enterococci, Streptococci and MRSA producers a low-affinity penicillin-binding proteins
- VRE uses a new substrate for cell wall synthesis that is not affected by vancomycin
Active Drug Efflux
= energy dependent removal of drugs from organisms before the drug can act
- macrolide and tetracycline efflux systems
- MexABOprM system can export a broad range of substrates in P.aeruginosa including
pencillins, cephalosporins, fluoroquinolones, tetracyclines and chloramphenicol
- MexB protein = broadspectrum cytoplasmic pump
- OprM protein = pore that provides a portal through the outer membrane
- MexA protein = links the above two
- multi-drug efflux mechanisms have been identified in other organisms including
Enterobacteraceae
- mutation of the MAR (multiple antibiotic resistance) chromosomal locus -> produces
resistance to unrelated antimicrobials
- it producers a combination of active efflux and down regulation of OmpF porin channel
Jeremy Fernando (2011)
PREVENTION
General Approach
REMINISCE PAPA DAD Mneumonic
Restrict access to specific agents if an outbreak of antibiotic resistance takes place
Early ID consult
Multiple drug classes
Infection control procedures
Narrow spectrum antibiotics (once culture known)
Isolation of those with MDR organisms
Surveillance to ID those infected/colonized with MDR organisms
Cease antibiotics after 24-48 hours after achieving appropriate response
Embrace local guidelines
Prophylaxis discouraged unless indicated
Appropriate drug, dose, duration, timing
Preventative measures (VAP and headup)
Avoid unnecessary use of antibiotics
Descale (empiric -> narrow spectrum once cultures known)
Antiseptic techniques for all invasive procedures
Disinfection of commonly used equipment
Prevention of Occurrence
-
proper culture and sensitivity before antibiotic use
rationalised choice when results available
antibiotic policy established in the unit
regular ward rounds with ID
treat cause of infections (ie. remove lines, drains, abscesses)
control the use of broad spectrum antibiotics
stop antibiotics if no organism found
short course of prophylactic antibiotics
microbiological surveillance regularly but don’t treat colonisation
Prevention of Spread
-
strict hand washing/alcohol based gels
isolation of infected patients
gloves and gowns
adequate staffing to prevent cross infection
single patient stethoscopes
sterilisation of re-usable equipment
universal precautions mandated
IMPLICATIONS
- increased mortality
- increased length of stay
Jeremy Fernando (2011)
- increased hospital costs
- delays in treatment because organisms are not susceptible to empiric first line agents
- preventative strategies must be employed (see above)
Jeremy Fernando (2011)