What are the mechanisms of resistance to colistin in Acinetobacter baumannii?

Mechanisms of Colistin Resistance in Acinetobacter baumannii

The primary mechanism of colistin resistance in A. baumannii involves modification of lipopolysaccharide (LPS)/lipid A through upregulation of the PmrAB two-component system, which adds phosphoethanolamine (PEtN) moieties to lipid A, reducing colistin binding. 1, 2, 3

Primary Resistance Mechanisms

1. LPS/Lipid A Modification (Most Common)

The PmrAB two-component regulatory system represents the dominant resistance pathway:

• PmrB mutations drive overexpression of PmrA, PmrB, and PmrC proteins (increases of 2.9-5.5 fold) 4
• PmrC (also called EptA) catalyzes addition of PEtN to lipid A phosphate groups 2, 5
• This modification reduces the negative charge of the outer membrane, decreasing colistin electrostatic binding 1
• Mutations in pmrA and pmrB genes are the primary mechanism in clinical isolates 5, 3
• Hyperexpression of the cryptic eptA gene through spontaneous insertion mutations upstream or through disruption of the hns gene (histone-like protein) leads to clinically significant resistance 6

2. Complete LPS Loss

• Mutations in LPS biosynthetic genes (lpxA, lpxC, lpxD, lpsO) result in complete loss of LPS 1, 2, 5
• While this eliminates colistin's target, these mutants have severe fitness costs and cannot effectively colonize the lung 6
• Less clinically relevant than modification mechanisms due to reduced pathogenicity 6

3. Heteroresistance

Heteroresistance represents an early, critical stage in developing stable colistin resistance 7:

• Defined as resistant subpopulations (18.7-100% prevalence) emerging from otherwise susceptible strains (MIC ≤2 mg/L) 7
• Previous colistin use is a major risk factor 7
• Standard microdilution methods cannot detect heteroresistance—look for colonies within disc/E-test inhibition zones 7
• Heteroresistant strains progress to stable resistance through stepwise acquisition of additional mutations, particularly eptA insertions 6

4. Secondary Mechanisms

• Efflux pump upregulation: Enhanced expression of adeIJK, adeC, emrB, mexB, and macAB systems 4, 5
• Outer membrane remodeling: Alterations in phospholipid composition, particularly reduced glycerophospholipids and fatty acids 4
• Metabolic reprogramming: Changes in purine, glycerophospholipid, starch/sucrose, and glutathione metabolism 4
• Porin alterations: Modified outer membrane permeability 2

Clinical Implications

Critical Warnings from Guidelines

The 2015 ICU Task Force guidelines 7 emphasize:

• Inappropriate colistin use creates substantial potential for rapid resistance development and therapeutic failure
• Detection of heteroresistance provides "strong warning" about resistance risk
• Clinical impact of heteroresistance remains incompletely understood, but evidence suggests it predicts treatment failure

Fitness Costs and Stability

• PmrB mutants retain pathogenic fitness and can colonize hosts even without colistin pressure 6
• Resistant variants show stability in the absence of drug initially 6
• However, prolonged passaging without colistin selects for pseudorevertants with disrupted LPS modification enzymes, causing re-sensitization 6
• This creates a dynamic equilibrium between resistance and fitness

Key Molecular Markers

When investigating colistin resistance, prioritize detection of:

1. pmrA/pmrB mutations (most common clinical mechanism) 5, 3, 8
2. pmrC/eptA overexpression 4, 3, 9
3. lpxA, lpxC, lpxD gene disruptions 5, 3
4. Insertion mutations upstream of eptA or in hns 6

Common Pitfalls

• Don't rely on standard susceptibility testing alone—it misses heteroresistance 7
• Don't assume LPS-deficient mutants are clinically significant—they have poor colonization capacity 6
• Don't overlook prior colistin exposure—it's a major risk factor for heteroresistance 7
• Recognize that resistance is multifactorial—multiple mechanisms often coexist in the same isolate 4, 2

The resistance landscape involves coordinated changes across LPS modification, membrane composition, efflux systems, and metabolism, creating a robust defense against colistin that can emerge rapidly under selection pressure 4, 2.