What is the mechanism of action of chlorhexidine?

October 9, 2025 •

4 min read

Chlorhexidine (CHX) was first discovered in the 1950s as part of a research program for antimalarial agents but is now considered a gold-standard antiseptic in various medical and dental applications. This article explores the nuanced and concentration-dependent mechanism of action of chlorhexidine and its impact on a wide range of microorganisms.

Quick Summary

Chlorhexidine's mechanism involves a positively charged molecule binding to negatively charged microbial cell surfaces. This binding action disrupts the cell membrane's integrity, leading to leakage of internal components at low concentrations and complete cell death via cytoplasm coagulation at higher concentrations.

Key Points

Cationic Binding: Chlorhexidine's positive charge attracts it to and binds with the negatively charged bacterial cell walls, initiating its antimicrobial effect.
Dual Concentration Action: It acts as a bacteriostatic agent by causing cytoplasmic leakage at low concentrations and as a bactericidal agent by causing cytoplasm precipitation and cell death at high concentrations.
Membrane Disruption: The primary mechanism involves damaging the cell membrane, which leads to a loss of osmotic control and inhibits cellular respiration.
Prolonged Substantivity: Chlorhexidine binds effectively to body tissues like skin and oral mucosa, allowing for a gradual release over time that provides a prolonged antimicrobial effect.
Broad-Spectrum Efficacy: It is effective against a wide range of microorganisms, including Gram-positive and Gram-negative bacteria, fungi, and certain enveloped viruses.
Superiority Over Povidone-Iodine: Clinical trials have shown that chlorhexidine, particularly with alcohol, is more effective than povidone-iodine at preventing surgical site infections due to its rapid and sustained action.

Understanding the Antimicrobial Power of Chlorhexidine

Chlorhexidine (CHX) is a broad-spectrum antimicrobial agent renowned for its effectiveness against a wide array of microorganisms, including Gram-positive bacteria, Gram-negative bacteria, and some fungi and enveloped viruses. Its potent activity stems from a unique mechanism of action that targets the microbial cell membrane, though its specific effects vary significantly with concentration. The compound is a cationic bisbiguanide, and at physiological pH, its salts dissociate to release a positively charged chlorhexidine cation. This positive charge is the critical factor that drives its interaction with the negatively charged components of microbial cell walls and membranes, ultimately compromising cellular function and viability.

The Cationic Attraction: Initial Binding

Upon contact with a microorganism, the positively charged chlorhexidine molecule is electrostatically attracted to the negatively charged components on the cell's outer surface, such as the phosphate groups of phospholipid headgroups. This initial binding process, which can occur within seconds, neutralizes the local charge and begins to destabilize the cell wall. The speed and strength of this binding are influenced by the specific bacterial strain and the concentration of CHX applied.

Concentration-Dependent Effects on the Cell Membrane

The true genius of chlorhexidine lies in its dual action, which is determined by its concentration.

At lower, bacteriostatic concentrations:

Initial binding occurs, affecting the permeability of the cell membrane.
This disturbance leads to the leakage of low-molecular-weight intracellular components, most notably potassium ions and other vital components.
The loss of these substances disrupts the cell's osmotic balance and inhibits its metabolic activity, effectively halting its ability to grow and reproduce.

At higher, bactericidal concentrations:

The initial membrane damage progresses rapidly and severely.
The CHX molecules flood into the cytoplasm, causing a complete loss of membrane integrity.
Once inside, the molecules cause the coagulation and precipitation of intracellular proteins and nucleic acids, leading to the rapid and irreversible death of the cell. This mechanism is so effective that resistance is considered less likely to develop than with targeted antibiotics.

The 'Substantivity' Advantage

Another key pharmacological feature of chlorhexidine is its "substantivity," a property that allows it to bind to certain tissues, such as the skin and oral mucosa, and be released slowly over an extended period. This creates a long-lasting antimicrobial reservoir, providing sustained protection against re-infection. In dentistry, for example, this property ensures a prolonged inhibitory effect on plaque formation and bacterial count in the oral cavity for several hours after a single application. However, this effect is hampered by interactions with anionic compounds found in some common toothpastes, so waiting at least 30 minutes after brushing is often recommended.

How Chlorhexidine Compares to Other Antiseptics

Chlorhexidine's mechanism sets it apart from other common antiseptics, such as povidone-iodine (PVI). While both are broad-spectrum, their pharmacological properties lead to different clinical performance outcomes.


Feature	Chlorhexidine (with Alcohol)	Povidone-Iodine
Mechanism	Cationic molecules bind to and disrupt microbial cell membranes.	Releases free iodine to disrupt microbial proteins and nucleic acids.
Onset of Action	Rapid, especially with alcohol.	Slower, requiring longer contact time for efficacy.
Residual Effect	High substantivity; remains active on the skin for hours.	Minimal; effectiveness diminishes quickly once dry.
Efficacy	Clinically proven superior to PVI for preventing surgical site infections.	Can be reduced by organic matter like blood or serum.
Resistance Risk	Some reports of reduced susceptibility over time with frequent use.	Lower risk of microbial resistance due to broad, non-specific action.

Clinical Applications and Considerations

Due to its robust antimicrobial properties and prolonged effect, chlorhexidine is widely used in various clinical settings. Common applications include:

Preoperative skin preparation: For surgical procedures, often combined with alcohol for enhanced speed and efficacy.
Central venous catheter care: Reduces infection risk associated with catheters.
Hand hygiene: Used in surgical scrubs and germicidal hand rinses.
Dental care: Prescribed as a mouth rinse to treat gingivitis and reduce plaque buildup.

Despite its benefits, clinicians and patients must be aware of potential adverse effects, including skin irritation, staining of teeth and oral tissues (in dental use), and rare but serious allergic reactions like anaphylaxis. Care must also be taken to avoid contact with sensitive areas, such as the eyes and ears, due to toxicity risks. For example, studies have confirmed that chlorhexidine can be ototoxic if it enters the middle ear, potentially leading to deafness. The effectiveness of chlorhexidine can also be inhibited by certain bodily fluids and other chemical agents, impacting its use in specific contexts.

Conclusion

The mechanism of action of chlorhexidine is a remarkable pharmacological story of electrostatic attraction and concentration-dependent cytotoxicity. Its positively charged molecule binds to the negatively charged components of microbial cells, causing membrane damage and subsequent cell death or growth inhibition. This dual-action, combined with its unique substantivity, makes it a highly effective and long-lasting antiseptic widely used in both medical and dental practices. While concerns about microbial resistance and adverse effects like allergic reactions and staining exist, particularly with prolonged use, its proven efficacy, often surpassing alternatives like povidone-iodine in clinical trials, ensures its continued importance. Understanding this mechanism is key to appreciating why chlorhexidine remains an indispensable tool in the fight against infection, though responsible use is paramount to maximize benefits and minimize risks. For further reading, an authoritative overview of chlorhexidine's properties and clinical applications is provided in this article from PubMed Central.

Frequently Asked Questions

The difference depends on its concentration. At lower, bacteriostatic concentrations, it causes a controlled leakage of small intracellular components, inhibiting cell growth. At higher, bactericidal concentrations, it causes extensive cell membrane disruption and coagulation of the cytoplasm, leading to rapid cell death.

Gram-positive bacteria lack an outer membrane, which allows the cationic chlorhexidine molecules easier access to the negatively charged cell wall and membrane, making them more susceptible to disruption.

Thanks to its substantivity, chlorhexidine can bind to the skin and remain active for several hours, providing a prolonged antimicrobial effect, in some cases documented up to 48 hours.

While the broad, non-specific nature of its action makes widespread resistance less likely compared to antibiotics, some studies have noted a reduced susceptibility in certain bacterial strains over time, often linked to efflux pump activity.

Chlorhexidine's effectiveness can be reduced when it interacts with anionic compounds, such as sodium lauryl sulfate found in many toothpastes. It's recommended to wait at least 30 minutes after brushing before using a chlorhexidine mouthwash.

Common side effects include taste alteration (often described as bitter), temporary staining of the teeth and tongue, and an increase in tartar buildup. Serious allergic reactions are rare but possible.

Chlorhexidine is effective against some enveloped viruses, like herpes simplex and HIV, but generally has little to no effect on non-enveloped viruses, such as rotaviruses.