Antibacterial Resistance

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) Decreased permeability
(2) Inactivation of drug (via enzymes)
(3) Target site modification
(4) 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

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 beta-lactam ring = penicillins, cephalosporins, carbapenems, monobactam
• resistant to penicillin BUT sensitive to cephalosporins and the rest

Extended spectrum beta-lactamases

• resistance developed through amino acid substitution
• resistant to penicillin + third generation cephalosporins
• some of these are specific cephalosporinases and others possess resistance to beta-lactamase 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

PREVENTION

General Approach (REMINISCE PAPA DAD Mnemonic)

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
• increased hospital costs
• delays in treatment because organisms are not susceptible to empiric first line agents
• preventative strategies must be employed (see above)