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Chlorhexidine

Chlorhexidine is a synthetic cationic bisbiguanide compound with broad-spectrum antimicrobial properties, effective against Gram-positive and , fungi such as , and certain viruses. It is included on the World Health Organization's List of Essential Medicines. Its chemical formula is C₂₂H₃₀Cl₂N₁₀, featuring two p-chlorophenyl guanide units connected by a hexamethylene bridge, and it is most commonly employed in salt forms like gluconate or digluconate for enhanced water solubility and stability at physiological pH. As a topical , chlorhexidine disrupts microbial cell membranes by binding to negatively charged groups, leading to increased permeability, leakage of intracellular contents, and eventual , with bactericidal effects at concentrations of 2% or higher. It exhibits substantivity, allowing prolonged adherence to oral tissues and sustained antibacterial action for up to 12 hours, which distinguishes it from other antiseptics like . In medical and dental applications, it is widely used for preoperative preparation to reduce surgical site infections, cleansing, and as an oral rinse (typically 0.12–0.2%) for managing . Despite its efficacy, chlorhexidine can cause side effects such as tooth staining, altered taste perception, increased supragingival formation, and dry mouth. Rare but serious allergic reactions, including , have been reported, prompting FDA warnings for immediate discontinuation and medical attention upon symptoms like , swelling, or difficulty breathing; it is contraindicated in those with known . Safety in B), , and children under 18 remains unestablished, and its environmental persistence raises concerns about aquatic toxicity.

Uses

Human Medicine

Chlorhexidine serves as a broad-spectrum in human medicine, primarily employed for preventing and treating infections across various clinical settings. It exhibits strong antimicrobial activity against Gram-positive and , certain fungi, and enveloped viruses by disrupting their cell membranes and causing precipitation of cellular components, though it is ineffective against bacterial spores. In 2023, chlorhexidine accounted for approximately 912,485 prescriptions , reflecting its widespread clinical utility. In surgical contexts, chlorhexidine is a cornerstone for pre-operative disinfection to minimize surgical site infections (SSIs). Guidelines recommend using 2% chlorhexidine gluconate in for skin preparation immediately before incision, applied via scrubbing or painting to achieve persistent effects lasting several hours. Preoperative or showering with 4% chlorhexidine solution the night before and morning of further reduces bacterial , with randomized trials demonstrating a 40% in SSIs compared to alternatives. For instance, a landmark multicenter trial involving over 1,000 patients showed chlorhexidine- preparation lowered SSI rates to 9.5% versus 16.1% with . For oral health, chlorhexidine mouthwashes and gels are standard for managing gingivitis and periodontitis by reducing plaque accumulation and gingival inflammation. Clinical trials have established that 0.12% to 0.2% chlorhexidine rinses, used twice daily for 1-2 weeks as an adjunct to mechanical plaque control, significantly decrease plaque index scores by 50-60% and gingival bleeding by up to 40% over placebo or saline. A Cochrane systematic review of 51 randomized controlled trials confirmed these anti-plaque effects, particularly in patients with mild-to-moderate gingivitis, where short-term use prevents progression to periodontitis without promoting resistance in oral biofilms. Chlorhexidine is also used to prevent alveolar osteitis (dry socket) after tooth extractions, with rinses or gels reducing incidence by up to 58% compared to placebo. Additionally, pre-procedural rinses with 0.2% chlorhexidine minimize bacterial aerosols generated during dental procedures, reducing contamination risk for patients and staff. In intensive care units, chlorhexidine-based oral care protocols, involving 0.12% gel applied every 6-8 hours to the oral mucosa, have been shown to reduce ventilator-associated pneumonia (VAP) incidence by 30-65% in mechanically ventilated patients, primarily by decreasing oral bacterial load and aspiration risk, as evidenced by meta-analyses of over 3,000 ICU cases. Chlorhexidine also plays a key role in wound care and device-related infection prevention. In wound management, with 0.05-0.2% solutions cleanses contaminated sites and inhibits , supporting healing in chronic or surgical wounds by reducing without delaying tissue repair. For urinary catheter maintenance, meatal cleaning with 0.1% chlorhexidine before insertion and during routine care lowers catheter-associated rates by up to 94%, outperforming saline in randomized studies of hospitalized patients. Neonatal umbilical cord care involves daily application of 4% chlorhexidine to the stump, which meta-analyses of trials in low-resource settings indicate reduces risk by 23-32% and all-cause mortality by 20% compared to dry cord care, particularly in high-infection environments. In , chlorhexidine (typically 0.2-2%) is used as an irrigant during procedures to disinfect the canal system. It effectively eliminates residual bacteria in infected pulp spaces, with in vitro and clinical studies showing comparable antimicrobial efficacy to against common endodontic pathogens like , while providing substantivity for up to 12 weeks post-treatment. In gynecology, chlorhexidine vaginal preparations (2-4% solutions or gels) treat and prevent postoperative infections. Vaginal cleansing with 4% chlorhexidine before cesarean sections or hysterectomies reduces surgical site infections by 50-60%, as demonstrated in prospective trials, and topical gels improve symptoms in cases more effectively than , targeting biofilms without disrupting normal excessively.

Veterinary Medicine

Chlorhexidine is extensively applied topically in to manage infections, cleanse , and treat conditions in , , and such as . In and , solutions of 2% to 4% chlorhexidine gluconate are commonly used twice daily for superficial or irrigation, while flushes employ diluted concentrations of 0.05% to 0.2% to minimize risks. For , similar topical preparations aid in care and control, with application frequencies adjusted based on severity and animal size to ensure efficacy without irritation. As a disinfectant, chlorhexidine plays a critical role in veterinary surgical procedures, where 2% to 4% solutions, often combined with alcohol, are used for skin preparation to reduce microbial load prior to incision and for sterilizing instruments between uses. In dairy farming, post-milking teat dips containing 0.35% chlorhexidine with emollients prevent bovine mastitis by reducing new intramammary infections from major pathogens like Streptococcus species by 50% and minor pathogens such as coagulase-negative staphylococci by 49% to 65%. In aquaculture, chlorhexidine gluconate at 50 to 100 mg/L inhibits oomycete pathogens like Saprolegnia parasitica and S. australis, controlling saprolegniasis in cultured fish through bath treatments without observed toxicity at minimum inhibitory concentrations. Chlorhexidine exhibits broad-spectrum activity against (e.g., ) and select (e.g., , ), with bactericidal effects at 0.1% within 15 seconds, though it is less effective against most fungi, spores, and viruses. In animals, it shows moderate antifungal efficacy against species like Malassezia pachydermatis in canine and Fusarium isolates at concentrations of 8 to 32 mg/L. Dosing requires species-specific adjustments, such as lower dilutions for cats to avoid toxicity and higher volumes for larger livestock, ensuring concentrations remain below 4% for skin applications. In , chlorhexidine use carries specific risks, including post-surgical respiratory distress linked to aerosolized particles from scrubs on surgical sites or endotracheal if not thoroughly rinsed. The () guidelines restrict chlorhexidine to topical applications in food-producing animals, noting low residue levels in (<50 μg/L) and tissues, with no maximum residue limits (MRLs) required due to its inclusion in Annex II of Regulation (EEC) No 2377/90 and an (ADI) of 0.005 mg/kg body weight/day.

Pharmacology

Mechanism of Action

Chlorhexidine, a cationic bisbiguanide , exerts its antimicrobial effects primarily through electrostatic interactions with negatively charged components on microbial surfaces. Its positive charge allows rapid adsorption and binding to and groups in bacterial cell walls, facilitating into the cytoplasmic via passive . This binding disrupts the integrity, increasing membrane permeability and resulting in the leakage of essential intracellular contents, such as and ions, which compromises cellular . The activity of chlorhexidine is concentration-dependent. At low concentrations, it acts bacteriostatically by reversibly inhibiting key activities, such as those involved in cellular , without immediate ; this effect can be reversed upon removal of the agent. At higher concentrations, it becomes bactericidal through irreversible precipitation of cytoplasmic proteins and other phosphorylated compounds, including ATP and nucleic acids, leading to and ultimate . The disruption process involves initial adsorption to the surface, followed by insertion into the layer, formation of complexes with , and creation of transient pores that allow efflux of low-molecular-weight solutes; this can be conceptually illustrated as a sequential model where cationic molecules aggregate at the negatively charged outer layer, destabilize the bilayer core, and trigger cascading leakage until cellular integrity fails. Chlorhexidine demonstrates broad-spectrum activity against Gram-positive and , as well as yeasts and enveloped viruses such as and , due to its ability to interact with diverse negatively charged microbial envelopes. However, its efficacy is limited against mycobacteria, owing to their waxy cell walls that impede penetration, and it is ineffective against bacterial spores, which possess impermeable outer layers resistant to disruption. These interactions with phospholipids and proteins underpin its selective disruption of microbial cells while sparing most host tissues, which lack the same density of negatively charged sites.

Pharmacokinetics

Chlorhexidine exhibits minimal systemic absorption when applied topically or orally, with bioavailability typically less than 1% due to its poor penetration through intact skin and gastrointestinal tract. In oral rinses, approximately 30% of the dose is retained in the mouth, but systemic levels remain low, with peak plasma concentrations around 0.206 µg/g occurring 30 minutes after a 300 mg dose. This retention contributes to its substantivity on oral mucosa, where chlorhexidine persists at microgram per milliliter levels for up to 12 hours post-rinsing, providing prolonged local effects. Distribution of chlorhexidine is primarily limited to and mucous membranes, where it binds strongly to proteins such as in and , as well as to and mucosal surfaces. It does not penetrate deeply into intact layers, restricting its spread to superficial tissues and preventing significant entry into deeper systemic circulation. This protein binding aligns with its , facilitating adhesion to negatively charged bacterial membranes and host tissues. Chlorhexidine undergoes no significant in the body and is excreted primarily unchanged. Following oral ingestion, over 90% is eliminated via , with less than 1% appearing in ; any absorbed fraction follows similar routes through biliary and renal . Chlorhexidine exhibits substantivity in oral applications lasting approximately 8-12 hours, due to its gradual release from bound sites. can be influenced by formulation, such as the gluconate salt, which enhances and retention in aqueous environments, and by , with optimal binding and release occurring between 5.5 and 7.0. Repeated use of chlorhexidine may lead to accumulation in tissues like and due to its strong binding affinity, resulting in prolonged local antimicrobial effects beyond single applications.

Side Effects and Safety

Adverse Effects

Chlorhexidine can cause various local adverse effects upon topical application, including irritation, dryness, and, less commonly, . irritation and dryness are frequently reported with prolonged use of chlorhexidine solutions or gels, often manifesting as mild or xerosis that resolves upon discontinuation. , a reaction, occurs rarely, with a prevalence of 0.47–1% in patch-tested populations, and is characterized by eczematous rashes at the site of application. Immediate-type (IgE-mediated) reactions, such as urticaria, are even less common but can precede more severe systemic responses. In oral applications, such as mouthwashes, chlorhexidine commonly leads to tooth staining, altered taste perception, dry mouth, and mucosal desquamation, particularly with prolonged use. Extrinsic staining of teeth and restorations is the most frequent side effect, due to its substantivity allowing prolonged adherence to oral surfaces; clinical testing shows a measurable increase in facial anterior stain in 56% of users after six months of 0.12% rinses, compared to 35% in controls. Altered taste (dysgeusia or hypogeusia) is a common effect, often resolving after treatment cessation. Dry mouth (xerostomia) may also occur. Mucosal desquamation or superficial peeling of the oral epithelium is reported with extended use, presenting as white, sloughing patches that may cause discomfort. Systemic adverse effects are uncommon but can arise from accidental ingestion, aspiration, or high-dose exposure, including nausea, vomiting, respiratory distress, and . of small amounts typically causes transient gastrointestinal upset like nausea and vomiting, while risks include leading to respiratory distress. , a severe IgE-mediated , has been documented in 52 cases worldwide from 1969 to 2015, with symptoms such as , wheezing, and occurring within minutes of skin or mucosal contact; 26 of these were life-threatening, including two fatalities, and additional cases have been reported since 2015 indicating a rising trend. The incidence of is estimated at 0.78 per 100,000 exposures, often linked to use. Ototoxicity is a serious concern when chlorhexidine contacts the during surgical procedures, potentially causing . Animal studies demonstrate cochlear hair cell damage and vestibular dysfunction with concentrations as low as 0.05%, particularly when combined with alcohol, leading to high-frequency hearing thresholds shifts. In humans, two case reports and limited clinical data indicate permanent following inadvertent middle ear exposure during or , with toxicity dependent on concentration and contact time with the membrane. Such reactions underscore the need for caution in ear surgery, where safer antiseptics are preferred. Long-term use of chlorhexidine in dental applications may promote increased supragingival formation and exacerbate oral imbalances. Calculus deposition rises due to reduced plaque disruption over time. Prolonged exposure also shifts the oral toward higher levels of lactate-producing , potentially contributing to periodontal progression, though clinical impact varies.

Contraindications and Interactions

Chlorhexidine is contraindicated in patients with a known to chlorhexidine or other biguanides, as this can lead to severe allergic reactions including . It must also be avoided in direct contact with the eyes, ears, or , where it poses risks of serious and permanent injury, such as corneal damage, , or . Relative contraindications include use during and , classified as FDA B based on animal studies showing no fetal harm but with limited human data; it should be employed only if the potential benefits justify the risks. In neonates, particularly premature infants or those under 2 months, chlorhexidine requires caution due to potential or chemical burns, though it is applied with care for care to prevent infections. Chlorhexidine's antimicrobial activity is inactivated by anionic agents, such as those found in soaps, toothpastes, and natural detergents, which form insoluble salts and reduce its efficacy. Its effectiveness is also diminished in high environments, where or altered can occur, limiting its use in alkaline formulations. In combined therapies, potential interactions with other antiseptics or antibiotics may alter outcomes; for instance, concurrent use with iodine-based products like requires evaluation for compatibility, as they are often alternatives rather than synergists in preventing infections. For patients with renal impairment, no specific is typically required, given that excretion occurs primarily via feces with minimal urinary involvement (less than 1%).

Chemistry

Properties

Chlorhexidine is a symmetric cationic bisbiguanide compound with the chemical formula \ce{C22H30Cl2N10} and a molar mass of 505.45 g/mol. Its structure consists of two 4-chlorophenyl rings linked by a hexamethylene bridge to two biguanide groups, forming a linear molecule approximately 1.5 nm in length. The base form of chlorhexidine appears as a white to off-white crystalline powder. It is sparingly soluble in water, with a solubility of about 0.08 g/100 mL at 20°C, but its salts such as gluconate and acetate exhibit significantly higher solubility, enabling aqueous formulations. The biguanide groups confer basic properties, with pKa values of approximately 10.8 and 11.3, indicating protonation at physiological pH. Chlorhexidine is stable in neutral pH conditions (around 5–8) but decomposes in alkaline environments above pH 8, where the free base may precipitate from solution. Spectrally, it exhibits UV absorption with a maximum at 254 nm, useful for analytical detection. In practice, it is most commonly employed as chlorhexidine digluconate, supplied as a 20% w/v aqueous solution for formulation purposes.

Synthesis

Chlorhexidine was originally synthesized in the 1940s by chemists at (ICI) in the as part of research into bisbiguanide compounds for potential antimalarial applications. The compound, known initially as a derivative in the Hibitane series, was patented by ICI in 1954 (filed 1951) and first marketed in 1954 under the trade name Hibitane for use. The seminal description of its synthesis appeared in a 1956 publication by F. L. Rose and G. Swain, detailing the formation of the symmetric bisbiguanide structure. The original synthesis proceeds via a two-step to build the moieties. In the first step, reacts with two equivalents of sodium dicyanamide (cyanoguanidine) in at elevated temperature (around 100–110°C) to form 1,6-hexamethylenebis(dicyandiamide) as the key , typically in yields exceeding 80%. This then undergoes with two equivalents of hydrochloride in a high-boiling solvent such as β-ethoxyethanol (cellosolve), heated under at 130–140°C for 2–4 hours. The involves the displacement and cyclization to form the diguanide units, yielding chlorhexidine dihydrochloride after cooling, , and recrystallization from aqueous acetic acid ( 258–260°C). Chlorination is inherent in the use of the p-chloroaniline precursor, with no separate coupling step required due to the symmetric design. Modern industrial production largely follows this route but optimizes for scalability and purity, often using continuous flow reactors for the intermediate formation and employing solvents like n-butanol or -ethanol mixtures to enhance efficiency. The bis-dicyandiamide intermediate is generated via SN2-type displacements of dicyanamide ions on protonated , achieving overall yields of 70–90% on a multi-ton scale. Post-synthesis, the chlorhexidine base is liberated and purified by acidification, then converted to the water-soluble gluconate salt by neutralization with in aqueous medium, facilitating for applications. This salt formation improves from <0.01% () to over 20% in , with minimal impurities due to rigorous steps.

Society and Culture

Brand Names

Chlorhexidine is marketed under various brand names globally, depending on the formulation and intended use, with many products available as topical antiseptics, oral rinses, or surgical scrubs. , prominent brands include Hibiclens, a 4% chlorhexidine gluconate skin cleanser used for preoperative skin preparation and general antisepsis, and Peridex or PerioGard, which are 0.12% oral rinses prescribed for treatment. Bactoshield is another U.S. brand offered as a surgical scrub solution containing 4% chlorhexidine gluconate for hand and skin disinfection in healthcare settings. In the , Corsodyl is a widely used brand for chlorhexidine at 0.2% concentration, available for managing oral infections and plaque, while is marketed as an lotion combining chlorhexidine with other agents for care and skin disinfection, commonly found in households. In , follows a similar formulation and availability as in the UK. Internationally, variations include Septodin in , a dental formulation of chlorhexidine for periodontal applications. Other global brands encompass Curasept for oral care in the and Elugel for topical use in . Common formulations of chlorhexidine products include 0.12% oral rinses for dental use, 2-4% topical solutions or gels for application, and 20% concentrates intended for dilution prior to use in surgical or cleansing protocols. These concentrations are standardized across many brands to ensure efficacy against while minimizing irritation. Chlorhexidine has been available in generic forms since the expiration of key patents in the , leading to widespread production by multiple manufacturers and reduced costs. In the U.S., generic chlorhexidine gluconate oral rinse, for instance, became available following the approval of Peridex's generic equivalents in the , contributing to its status as the 270th most prescribed medication in 2023 with over 900,000 prescriptions. Market leaders vary by region; in , companies like (Peridex) and Mölnlycke (Hibiclens) dominate topical and oral segments, while in and the , GlaxoSmithKline (Corsodyl) holds significant share in mouthwashes. In , including , local producers like contribute to the generic market for dental gels and solutions. Availability as over-the-counter (OTC) or prescription varies by country and formulation. In the , oral rinses like Peridex require a prescription due to potential side effects such as tooth with prolonged use, while topical solutions like Hibiclens are OTC for consumer purchase. In the UK and , both oral mouthwashes (e.g., Corsodyl) and topical lotions (e.g., ) are generally available OTC. In , topical antiseptics at 2-4% concentrations are non-prescription, but higher-strength or oral products may need professional oversight. In , dental gels like Septodin are typically OTC for routine oral care.

Regulatory Status

Chlorhexidine has been included on the World Health Organization's Model List of Essential Medicines since 1979, recognized as an essential antiseptic for various applications, including neonatal care and surgical preparation. It is classified under the Anatomical Therapeutic Chemical (ATC) system with codes A01AB03 for stomatological preparations (dental use) and D08AC02 for antiseptics and disinfectants used topically. In the United States, the Food and Drug Administration (FDA) addressed chlorhexidine in its over-the-counter (OTC) topical antimicrobial drug products review, with the 1994 Tentative Final Monograph establishing conditions for its use in surgical hand scrubs and healthcare personnel handwashes, classifying it as generally recognized as safe and effective for these indications when meeting specified formulation and labeling requirements. Subsequent FDA actions, including the 2017 final rule on healthcare antiseptics, deferred certain efficacy claims for chlorhexidine products pending additional data but maintained monograph status for approved uses. The () evaluates chlorhexidine for veterinary use, recommending no maximum residue limits (MRLs) for topical applications in food-producing animals due to negligible residue levels in edible tissues and products like , as supported by pharmacokinetic studies showing concentrations below detection limits post-application. Regulatory guidelines have imposed restrictions on chlorhexidine use in neonates, with agencies like the FDA and CDC advising against routine full-body bathing in preterm or low-birth-weight infants under 2 months due to potential risks of skin irritation and limited safety data from post-2010 studies, though it remains approved for targeted applications such as care. Globally, chlorhexidine is promoted for accessible use in low-resource settings, included in supply kits as a 7.1% digluconate (equivalent to 4% chlorhexidine) for care to prevent infections in newborns. As of 2025, ongoing international monitoring by organizations like the WHO and CDC tracks emerging to chlorhexidine, with recent studies highlighting low-level resistance in clinical isolates but emphasizing the need for surveillance to guide antiseptic stewardship.00046-1/fulltext)

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