Multi-Resistant Gram Negative Organisms (MRGNs)


While MRSA and C-diff rates are falling, MRGNs increasing.
Limited ABX for MRGN.
Most common and troublesome RGN are ESBLs, Acinetobacter spp, Stenotrophomonas and Pseudomonas.

Risk factors for acquisition
ICU admission
Indwelling catheters
Parenteral nutrition
High APACHE 2 score


B-lactam ring is the backbone of several antibiotic families including:

  • Penicillins
  • Cephalosporins
  • Carbapenems
  • Monobactams (aztreonam)
Most common SE of B-lactams is fever of which eosinophilia and rash accompany 25% of patients.

They work by binding to penicillin binding proteins and inhibiting cell wall synthesis and are active against a broad spectrum of gram +ve and -ve bacteria.
Resistance in 2 ways:
1) Some bacteria have developed ability to produce B-lactamases which break and inactivate the B-lactam ring of penicillin related antibiotics. Produced by gram +ve and -ve bacteria.
2) Some bacteria have changed the penicillin binding proteins that B-lactams bind to. Mechanism of MRSA

Substances can be added to antibiotics to nullify B-lactamases. These B-lactamase inhibitors include calvulanic acid, tazobactam and sulbactam.

There are well over 100 types of B-lactamases which can be classified molecularly (into A, B, C and D) or functionally (into groups depending on whether they are penicillinases, cephalosporinases or broad spectrum and whether they are inhibited by clavulanic acid).

Rssistance in gram -ve bacteria

The 1st B-lactamases discovered in the 1960‘s inactivated penicillins and narrow spectrum cephalosporins. Found in many enterobacteria (gram -ve anaerobic rods found in gut, water and soil - Enterobacter, Escherichia, Klebsiella, Salmonella, Serratia, Shigella etc)
ESBLs were discovered in the 1980s. They inactivate oxyimino-beta-lactams (3rd generation cephalosporins and monobactams). They are susceptible to 2nd generation cephalosporins. There is a high associated incidence of resistance to aminoglycosides, co-trimoxazole and fluroquinolones. They are inhibited by BL inhibitors in vitro but this cannot be relied upon in vivo.

Other BLs, while not strictly ESBLs, are often grouped with them and include:
Inhibitor resistant B-lactamases
They are resistant to clavulanic acid and sulbactam but usually susceptible to tazobactam.
AmpC B-lactamases
Inactivate 2nd and 3rd generation cephalosporins and monobactams and are not inhibited by B-lactamase inhibitors.
Carbapenems are usually very stable to AmpCBLs and ESBLs. Carbapenemases are active against 2nd and 3rd generation cephalosporins as well as carbapenems.

Most commonly isolated ESBLs are Klebsiella, E coli and Enterobacter.
Incidence in the UK is currently around 10%. >25% in south eastern Europe.
Increased mortality.

Treatment of choice is the carbapenems.
Carbapenemases are usually susceptible to aztreonam but ESBLs and AmpCs are not.


Widespread in environment.
Can survive on dry surfaces for days.

Innately resistant to many classes of ABX and further resistance develops quickly mediated through active drug efflux (rather than B-lactamases).

Commonly colonises health workers.
Few virulence factors so primarily affects those with impaired host defense.
Causes CAP in immunocompromised, VAP, soft tissue infection from IV catheters or surgery.

Colonisation does not require treatment but isolate if MDR.
Remove IV catheters.
Drain abscesses.

ATS and IDSA (infectious diseases society of America) recommend:

or Piperacillin/tazobactam
in combination with

Little evidence for combination therapy if not MDR.
Aerosolised polymixin B or colistin with or without IV rifampicin if MDR.
Length 10-14 days.
Carbapenem resistance 5% in UK.


Common in wet environments - frequently colonises tracheal tubes, respiratory tract and indwelling catheters.
Ammonia like odour.
Usually colonisation rather than infection.
Isolation from BCs represents infection - often from foreign material which should be removed eg central lines.
Intrinsically resistant to most ABX via reduced membrane permeability, efflux pumps and beta-lactamases. These include carbapenems and piperacillin.
Usually sensitive to co-trimoxazole (trimethoprim and sulfamethoxazole)
Tigecycline, polymixins and ticarcillin can have a role.
Low virulence but most difficult to treat.


Grape-like odour.
Like stenotrophomonas likes water and colonises moist surfaces.
Opportunistic pathogen with 25% of healthy humans skin carriers.
Can cause infection in most body sites.
Most common cause VAP.
Has high intrinsic resistance to many ABX through drug efflux pumps, B-lactamases and low membrane permeability. Also acquires resistance by mutation and horizontal gene transfer.
Antipseudomonal drugs include piperacillin, 3rd and 4th generation cephalosporins, aztreonam, carbapenems and fluroquinolones. Gentamycin and rifampicin can be used in combination.
Multidrug resistant strains are becoming more common. Treatment includes combinations of a number of ABX. Nebulised polymixins have been used successfully.

Prevention and management

Isolate colonised and infected patients
Hand washing
Barrier care
Cleaning environmental surfaces
Limit broad spectrum ABX use - particularly the use of oxyimino-B-lactams
De-escalation (narrowing treatment)

Antibiotic cycling
Microflora surveillance
Blood cultures prior to ABX
Regular review of prescriptions
Oversight by pharmacists and microbiologists