Heteroresistance is a type of antimicrobial resistance where a small number of cells within a larger microbial population exhibit a higher level of resistance to an antimicrobial agent, while the majority remains susceptible. This subpopulation can proliferate when exposed to an antimicrobial, potentially leading to treatment challenges.
Understanding Heteroresistance
Heteroresistance describes a scenario where a microbial population, despite appearing susceptible to an antibiotic, harbors a minority of cells with elevated resistance. This differs from traditional, homogeneous resistance where all cells display a similar level of resistance to a drug. The resistant subpopulation, though small, can grow and become more prevalent under the selective pressure of antibiotic exposure.
This phenomenon can occur through various mechanisms, including increased copy numbers of an antibiotic resistance gene within the resistant subpopulation. This gene amplification results in a higher minimum inhibitory concentration (MIC) for these cells compared to the majority with a single gene copy. Gene amplification is a dynamic process, allowing rapid changes in gene copy number and varying levels of resistance within the population.
Implications of Heteroresistance
Heteroresistance is a concern in managing infections because it can lead to unexpected treatment failures and relapses. Even when standard laboratory tests indicate an infection should respond to an antibiotic, the resistant subpopulation allows the infection to persist. These resistant cells are not killed and can multiply, eventually becoming the dominant population.
The presence of heteroresistance can necessitate higher drug dosages or changes in treatment regimens, complicating patient care. For instance, infections with heteroresistant isolates have led to treatment failure in human patients, as seen in complicated urinary tract infections treated with beta-lactam antibiotics. This hidden resistance can make seemingly appropriate antibiotic therapy ineffective.
Identifying Heteroresistance
Detecting heteroresistance is challenging because standard laboratory tests, which assume a homogeneous bacterial response, often miss the small resistant subpopulation. These conventional tests are not sensitive enough to identify the low frequency of resistant cells, which can be as low as one per million. Therefore, isolates with heteroresistance are frequently misclassified as susceptible.
Specialized techniques identify heteroresistance, with population analysis profiling (PAP) considered a reliable method. PAP involves plating bacterial cultures on agar plates containing increasing antibiotic concentrations to quantitatively determine the frequency of surviving bacteria. Other methods, such as Etest and disk diffusion assays, can indicate heteroresistance by showing growth within zones of inhibition, but they are less quantitative and may only detect higher frequencies of resistant subpopulations.
Addressing Heteroresistance
Addressing heteroresistance involves several strategies to overcome this form of antibiotic resistance. One approach is combination antibiotic therapy. When an isolate exhibits heteroresistance to multiple drugs, combining antibiotics can be effective. One drug may target the susceptible majority while another targets the resistant subpopulation, aiming to eradicate different resistant subpopulations simultaneously.
Further research focuses on developing novel antimicrobial agents that can specifically target these resistant subpopulations or overcome the mechanisms driving heteroresistance, such as gene amplification. Advancements in detection methods, including artificial intelligence integration with microscopy, are being explored to improve the efficiency and sensitivity of identifying heteroresistant strains. A multifaceted approach, encompassing improved diagnostics and tailored treatment regimens, will be necessary to manage infections caused by heteroresistant microbes.