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Mechanisms and clinical relevance of bacterial heteroresistance


Antibiotic heteroresistance is a phenotype in which a bacterial isolate contains subpopulations of cells that show a substantial reduction in antibiotic susceptibility compared with the main population. Recent work indicates that heteroresistance is very common for several different bacterial species and antibiotic classes. The resistance phenotype is often unstable, and in the absence of antibiotic pressure it rapidly reverts to susceptibility. A common mechanistic explanation for the instability is the occurrence of genetically unstable tandem amplifications of genes that cause resistance. Due to their instability, low frequency and transient character, it is challenging to detect and study these subpopulations, which often leads to difficulties in unambiguously classifying bacteria as susceptible or resistant. Finally, in vitro experiments, mathematical modelling, animal infection models and clinical studies show that the resistant subpopulations can be enriched during antibiotic exposure, and increasing evidence suggests that heteroresistance can lead to treatment failure.

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Nature Reviews Microbiology thanks W. van Schaik, M. Valvano and D. S. Weiss for their contribution to the peer review of this work.


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Work in the authors’ laboratory was supported by a grant from the Swedish Research Council (to D.I.A.).

Author information

D.I.A., H.N. and K.H. researched data for the article, contributed substantially to the discussion of content, wrote the article and reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Correspondence to Dan I. Andersson.


Minimal inhibitory concentration

(MIC). The lowest concentration of an antimicrobial drug that prevents growth of a bacterial population.

Antimicrobial susceptibility test

(AST). A method used to determine the minimal inhibitory concentration or clinical resistance level of a bacterial isolate.

Clinical breakpoint

The concentration of an antibiotic that defines whether infection with a bacterial species is treatable with the antibiotic (susceptible) or untreatable (resistant) with the antibiotic.

Persister cells

Bacteria that are sensitive to an antibiotic but that can survive in the presence of the antibiotic because their growth has temporarily stopped.

Compensatory mutations

Mutations that alleviate or suppress the phenotypic effect of a previous mutation.

Small colony variant

Naturally occurring bacterial mutants with defects in electron transport that result in slow growth and resistance to certain antibiotic classes.


Mutants that carry a second mutation (see Compensatory mutations) that alleviates or reverses the phenotypic effects of an already existing mutation.

Inoculum effect

A phenomenon where the minimal inhibitory concentration of an antibiotic increases with the density of cells in the inoculum in the antimicrobial susceptibility test.

Major errors

Major errors are observed when one bacterial isolate is characterized as susceptible to an antibiotic when tested by one type of antimicrobial susceptibility test but is characterized as resistant to that antibiotic when tested by another antimicrobial susceptibility test.

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Fig. 1: Factors to consider when defining heteroresistance.
Fig. 2: Population analysis profile (PAP) test to identify heteroresistance and clinical relevance of heteroresistance.
Fig. 3: Mechanisms of heteroresistance.
Fig. 4: Gene amplifications as a cause of unstable heteroresistance.