Types of Compound

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Chapter: Pharmaceutical Microbiology : Chemical Disinfectants, Antiseptics And Preservatives

The following section presents, in alphabetical order by chemical grouping, the agents most often employed for disinfection, antisepsis and preservation.


TYPES OF COMPOUND

 

The following section presents, in alphabetical order by chemical grouping, the agents most often employed for disinfection, antisepsis and preservation. This information is summarized in Table 19.6.




A)               Acids And Esters

 

Antimicrobial activity, within a pharmaceutical context, is generally found only in the organic acids. These are weak acids and will, therefore, dissociate incompletely to give the three entities HA, H+ and A in solution. As the undissociated form, HA, is the active antimicrobial agent, the ionization constant, Ka, is important and the pKa of the acid must be considered, especially in formulation of the agent.

 

      i)   Benzoic acid

 

This is an organic acid, C6H5COOH, which is included, alone or in combination with other preservatives, in many pharmaceuticals. Although the compound is often used as the sodium salt, the non-ionized acid is the active substance. A limitation on its use is imposed by the pH of the final product as the pKa of benzoic acid is 4.2 at which pH 50% of the acid is ionized. It is advisable to limit use of the acid to preservation of pharmaceuticals with a maximum final pH of 5.0 and if possible less than 4.0. Concentrations of 0.05–0.1% are suitable for oral preparations. A disadvantage of the compound is the development of resistance by some organisms, in some cases involving metabolism of the acid resulting in complete loss of activity. Benzoic acid also has some use in combination with other agents, salicylic acid for example, in the treatment of superficial fungal infections.

 

ii)       Sorbic acid

 

This compound is a widely used preservative as the acid or its potassium salt. The pKa is 4.8 and, as with benzoic acid, activity decreases with increasing pH and ionization. It is most effective at pH 4 or below. Pharmaceutical products such as gums, mucilages and syrups are usefully preserved with this agent.

 

iii)             Sulphur  dioxide, Sulphites and Meta bisulphites

 

Sulphur dioxide has extensive use as a preservative in the food and beverage industries. In a pharmaceutical context, sodium sulphite and metabisulphite or bisulphite have a dual role, acting as preservatives and antioxidants.

 

iv)     Esters of p-hydroxybenzoic acid (parabens)

 


 

A series of alkyl esters (Figure 19.1) of p-hydroxybenzoic acid was originally prepared to overcome the marked pH dependence on activity of the acids. These parabens, the methyl, ethyl, propyl and butyl esters, are less readily ionized, having pKa values in the range 8–8.5, and exhibit good preservative activity even at pH levels of 7–8, although optimum activity is again displayed in acidic solutions. This broader pH range allows extensive and successful use of the parabens as pharmaceutical preservatives. They are active against a wide range of fungi but are less so against bacteria, especially the pseudomonads which may utilize them as a carbon source. They are frequently used as preservatives of emulsions, creams and lotions where two phases exist. Combinations of esters are most successful for this type of product in that the more water-soluble methyl ester (0.25%) protects the aqueous phase, whereas the propyl or butyl esters (0.02%) give protection to the oil phase. Such combinations are also considered to extend the range of activity. As inactivation of parabens occurs with non-ionic surfactants due care should be taken in formulation with  both materials.

 

B)    Alcohols

 

          i) Alcohols Used For Disinfection And Antisepsis

 

The aliphatic alcohols, notably ethanol and isopropanol, are used for disinfection and antisepsis. They are bactericidal against vegetative forms, including Mycobacterium species, but are not sporicidal. Overall cidal activity drops sharply below 50% concentration. Alcohols have poor penetration of organic matter and their use is, therefore, restricted to clean conditions. They possess properties such as a cleansing action and volatility, are able to achieve a rapid and large reduction in skin flora and have been widely used for skin preparation before injection or other surgical procedures. The risk of transmission of infection due to poor hand hygiene has been attributed to lack of compliance with hand-washing procedures. An alcohol hand-rub offers a rapid, easy-to-use alternative that is more acceptable to personnel and is frequently recommended for routine use. However, the contact time of an alcohol-soaked swab with the skin prior to venepuncture is so brief that it is thought to be of doubtful value.

 

Ethanol (CH3CH2OH) is widely used as a disinfectant and antiseptic. The presence of water is essential for activity, hence 100% ethanol is relatively ineffective. Concentrations between 60% and 95% are bactericidal and a 70% solution is usually employed for the disinfection of skin, clean instruments or surfaces. At higher concentrations, e.g. 90%, ethanol is also active against fungi and most lipid-containing viruses, including HIV, though less so against non-lipid-containing viruses. Ethanol is also a popular choice in pharmaceutical preparations and cosmetic products as a solvent and preservative, but it is not recommended for cleaning class II recirculating safety cabinets; ethanol vapours are flammable and the lower explosive limit (LEL) is easily attained. Mixtures with other disinfectants, e.g. with formaldehyde (100 g/L), are more effective than alcohol alone.

 

Isopropyl alcohol (isopropanol, CH3.CHOH.CH3) has slightly greater bactericidal activity than ethanol but is also about twice as toxic. It is less active against viruses, particularly non-enveloped viruses, and should be considered a limited-spectrum viricide. Used at concentrations of 60–70%, it is an acceptable alternative to ethanol for preoperative skin treatment and is also employed as a preservative for cosmetics.

 

ii) Alcohols as preservatives

 


 

The aralkyl alcohols and more highly substituted aliphatic alcohols (Figure 19.2) are used mostly as preservatives. These include:

       Benzyl alcohol (C6H5CH2OH). This has antibacterial and weak local anaesthetic properties and is used as an antimicrobial preservative at a concentration of 2%, although its use in cosmetics is restricted.

       Chlorbutol (chlorobutanol; trichlorobutanol; trichlorot-butanol) is typically used at a concentration of 0.5% and is employed as a preservative in injections and eye drops. It is unstable, decomposition occurring at acid pH during autoclaving, while alkaline solutions are unstable at room temperature.

       Phenylethanol (phenylethyl alcohol; 2-phenylethanol), having a typical in-use concentration of 0.25–0.5%, is reported to have greater activity against Gram-negative organisms and is usually employed in conjunction with another agent.

Phenoxyethanol (2-phenoxyethanol). Typical in-use concentration: 1%. It is more active against Ps. Aeruginosa than against other bacteria and is usually combined with other preservatives such as the hydroxybenzoates to broaden the spectrum of antimicrobial activity.

                              Bronopol (2-bromo-2-nitropropan-1,3-diol). Typical in-use concentration: 0.01–0.1%. It has a broad spectrum of antibacterial activity, including Pseudomonas species. The main limitation on the use of bronopol is that when exposed to light at alkaline pH, especially if accompanied by an increase in temperature, solutions decompose, turning yellow or brown. A number of decomposition products including formaldehyde are produced. In addition, nitrite ions may be produced and react with any secondary and tertiary amines present forming nitrosamines, which are potentially carcinogenic.


C)    Aldehydes

 

A number of aldehydes possess broad-spectrum antimicrobial properties, including sporicidal activity. These highly effective biocides can be employed in appropriate conditions as chemosterilants.

 

         i) Glutaraldehyde

 

Glutaraldehyde (CHO(CH2)3CHO) has a broad spectrum of antimicrobial activity and rapid rate of kill, most vegetative bacteria being killed within a minute of exposure, although bacterial spores may require 3 hours or more. The kill rate depends on the intrinsic resistance of spores, which may vary widely. It has the further advantage of not being affected significantly by organic matter. The glutaraldehyde molecule possesses two aldehyde groupings which are highly reactive and their presence is an important component of biocidal activity. The monomeric molecule is in equilibrium with polymeric forms, and the physical conditions of temperature and pH have a significant effect on this equilibrium. At a pH of 8, biocidal activity is greatest but stability is poor due to polymerization. In contrast, acid solutions are stable but considerably less active, although as temperature is increased, there is a breakdown in the polymeric forms which exist in acid solutions and a concomitant increase in free, active dialdehyde, resulting in better activity. In practice, glutaraldehyde is generally supplied as an acidic 2% or greater aqueous solution, which is stable on prolonged storage. This is then ‘activated’ before use by addition of a suitable alkalizing agent to bring the pH of the solution to its optimum for activity. The activated solution will have a limited shelf life, of the order of 2 weeks, although more stable formulations are available. Glutaraldehyde is employed mainly for the cold liquid chemical sterilization of medical and surgical materials that cannot be sterilized by other methods. Endoscopes, including for example arthroscopes, laparascopes, cystoscopes and bronchoscopes, may be decontaminated by glutaraldehyde treatment (see section 2.5 concerning toxicity issues). Times employed in practice for high-level disinfection are often considerably less than the many hours recommended by manufacturers to achieve sterilization. The contact time for sterilization can be as long as 10 hours. Times for general disinfection generally range from 20–90 minutes at 20 °C depending on formulation and concentration.

 

ii)       Ortho-phthalaldehyde

 

Ortho-phthalaldehyde (OPA) is a relatively recent addition to the aldehyde group of high-level disinfectants. This agent has demonstrated excellent mycobactericidal activity with complete kill of M. tuberculosis within 12 minutes at room temperature. OPA has several other advantages over glutaraldehyde. It requires no activation, is considerably less irritant to the eyes or nasal passages and has excellent stability over the pH range 3–9. It can be used for disinfection of endoscopes (Table 19.5).

 

iii)    Formaldehyde

 

Formaldehyde (HCHO) can be used in either the liquid or the gaseous state for disinfection purposes. In the vapour phase it has been used for decontamination of isolators, safety cabinets and rooms. The combination of formaldehyde vapour with low-temperature steam (LTSF) has been employed for the sterilization of heatsensitive items . Formaldehyde vapour is highly toxic and potentially carcinogenic if inhaled, thus its use must be carefully controlled. It is not very active at temperatures below 20 °C and requires a relative humidity of at least 70%. The agent is not supplied as a gas but either as a solid polymer, paraformaldehyde, or a liquid, formalin, which is a 34–38% aqueous solution. The gas is liberated by heating or mixing the solid or liquid with potassium permanganate and water. Formalin, diluted 1 : 10 to give 4% formaldehyde, may be used for disinfecting surfaces. In general, however, solutions of either aqueous or alcoholic formaldehyde are too irritant for routine application to skin, while poor penetration and a tendency to polymerize on surfaces limit its use as a disinfectant for pharmaceutical purposes.

 

iv)     Formaldehyde-releasing agents

 

Various formaldehyde condensates have been developed to reduce the irritancy associated with formaldehyde while maintaining activity, and these are described as formaldehyde-releasing agents or masked-formaldehyde compounds.

 

Noxythiolin (N-hydroxy N-methylthiourea) is supplied as a dry powder and on aqueous reconstitution slowly releases formaldehyde and N-methylthiourea. The compound has extensive antibacterial and antifungal properties and has been used both topically and in accessible body cavities as an irrigation solution and in the treatment of peritonitis. Polynoxylin (poly[methylenedi(hydroxymethyl)urea]) is a similar  compound available in gel and lozenge formulations. Taurolidine     (bis-(1,1-dioxoperhydro-1,2,4-thiadiazinyl-4) methane) is a condensate of two molecules of the amino acid taurine and three molecules of formaldehyde. It is more stable than noxythiolin in solution and has similar uses.

 

D)   Biguanides

 

       i)  Chlorhexidine

 

Chlorhexidine is an antimicrobial agent first synthesized in 1954. The chlorhexidine molecule, a bisbiguanide, is symmetrical with a hexamethylene chain linking two biguanide groups, each with a para-chlorophenyl radical (Figure 19.3).

 


 

Chlorhexidine base is not readily soluble in water; therefore its freely soluble salts, acetate, gluconate and hydrochloride, are used in formulation. Chlorhexidine exhibits the greatest antibacterial activity at pH 7–8 where it exists exclusively as a dication. The cationic nature of the compound results in activity being reduced by anionic compounds, including soap, due to the formation of insoluble salts. Anions to be wary of include bicarbonate, borate, carbonate, chloride, citrate and phosphate, with avoidance of hard water if possible. Deionized or distilled water should preferably be used for dilution purposes. Reduction in activity will also occur in the presence of blood, pus and other organic matter. Chlorhexidine has widespread use, in particular as an antiseptic. It has significant antibacterial activity, although Gram-negative bacteria are less sensitive than Gram-positive organisms. A concentration of 0.0005% prevents growth of, for example, Staph. aureus, whereas 0.002% prevents growth of Ps. aeruginosa. Reports of pseudomonad contamination of aqueous chlorhexidine solutions have prompted the inclusion of small amounts of ethanol or isopropanol. Chlorhexidine is ineffective at ambient temperatures against bacterial spores and M. tuberculosis. Limited antifungal activity has been demonstrated, which unfortunately restricts its use as a general preservative. Skin sensitivity has occasionally been reported although, in general, chlorhexidine is well tolerated and non-toxic when applied to skin or mucous membranes and is an important preoperative antiseptic.

 

ii) Polyhexamethylene Biguanides

 

The antimicrobial activity of the bisbiguanide chlorhexidine exceeds that of monomeric biguanides. This stimulated the development of polymeric biguanides containing repeating biguanide groups linked by hexamethylene chains. One such compound is a commercially available heterodisperse mixture of polyhexamethylene biguanides (PHMB, polyhexanide) having the general formula shown in Figure 19.4.



 

Within the structure, n varies with a mean value of 5.5. The compound has a broad spectrum of activity against Gram-positive and Gram-negative bacteria and has low toxicity. PHMB is employed as an antimicrobial agent in various ophthalmic products.

 

E)    Halogens

 

Chlorine and iodine have been used extensively since their introduction as disinfecting agents in the early 19th century. Preparations containing these halogens, such as Dakin’s solution and tincture of iodine, were early inclusions in many pharmacopoeias and national formularies. More recent formulations of these elements have improved activity, stability and ease of use.

 

       i)  Chlorine

 

A large number of antimicrobially active chlorine compounds are commercially available, one of the most important being liquid chlorine. This is supplied as an amber liquid made by compressing and cooling gaseous chlorine. The terms liquid and gaseous chlorine refer to elemental chlorine, whereas the word ‘chlorine’ itself is normally used to signify a mixture of OCl, Cl2, HOCl and other active chlorine compounds in aqueous solution. The potency of chlorine disinfectants is usually expressed in terms of parts per million (ppm) or percentage of available chlorine (avCl).

 

ii)                Hypochlorites

 

Hypochlorites (bleach) are the oldest and remain the most useful of the chlorine disinfectants, being readily available, inexpensive and compatible with most anionic and cationic surface-active agents. They exhibit a rapid kill against a wide spectrum of microorganisms, including fungi and viruses. High levels of available chlorine will enable eradication of mycobacteria and bacterial spores. Their disadvantages are that they are corrosive, suffer inactivation by organic matter and can become unstable. Hypochlorites are available as powders or liquids, most frequently as the sodium or potassium salts of hypochlorous acid (HOCl). Sodium hypochlorite exists in solution as follows:

 

NaOCl + H2O = HOCl + NaOH                                  (1)

 

 

Undissociated hypochlorous acid is a strong oxidizing agent and its potent antimicrobial activity is dependent on pH as shown:

 

HOCl = H+ + OCl                                                    (2)

 

At low pH the existence of HOCl is favoured over OCl (hypochlorite ion). The relative microbicidal effectiveness of these forms is of the order of 100 : 1. By lowering the pH of hypochlorite solutions the antimicrobial activity increases to an optimum at about pH 5. However this is concurrent with a decrease in stability of the solutions. This problem may be alleviated by addition of NaOH (see equation 1) in order to maintain a high pH during storage for stability. The absence of buffer allows the pH to be lowered sufficiently for activity on dilution to use-strength. It is preferable to prepare use-dilutions of hypochlorite on a daily basis.

 

Undiluted bleach stored at room temperature in a closed container has a shelf life of about 6 months. Storage of stock or working solutions of bleach in open containers causes release of chlorine gas, especially at elevated temperatures, and this considerably weakens the antimicrobial activity of the solution. Working solutions should be prepared on a daily basis.

 

iii)  Organic chlorine Compounds

 

A number of organic chlorine, or chloramine, compounds are now available for disinfection and antisepsis. These are the N-chloro (=N-Cl) derivatives of, for example, sulphonamides giving compounds such as chloramine-T and dichloramine-T, and halazone (Figure 19.5), which may be used for the disinfection of contaminated drinking-water.



 

A second group of compounds, formed by N-chloro derivatization of heterocyclic compounds containing a nitrogen in the ring, includes the sodium and potassium salts of dichloroisocyanuric acid (e.g. NaDCC). These are available in granule or tablet form and, in contrast to hypochlorite, are very stable on storage if protected from moisture. In water they will give a known chlorine coccentration. The antimicrobial activity of the compounds is similar to that of the hypochlorites when acidic conditions of use are maintained. It is, however, important to note that where inadequate ventilation exists, care must be taken not to apply the compound to acidic fluids or large spills of urine in view of the toxic effects of chlorine production. The HSE has set the occupational exposure standard (OES) short-term exposure limit at 1 ppm.

 

iv)     Chloroform

 

Chloroform (trichloromethane, CHCl3) has a narrow spectrum of activity. It has been used extensively as a preservative of pharmaceuticals since the 19th century, although more recently it has had limitations placed on its use. Marked reductions in concentration may occur through volatilization from products, resulting in the possibility of microbial growth.

 

v)  Iodine

 

Iodine has a wide spectrum of antimicrobial activity. Gram-negative and Gram-positive organisms, bacterial spores (on extended exposure), mycobacteria, fungi and viruses are all susceptible. The active agent is the elemental iodine molecule, I2. As elemental iodine is only slightly soluble in water, iodide ions are required for aqueous solutions such as Aqueous Iodine Solution, BP 1988 (Lugol’s Solution) containing 5% iodine in 10% potassium iodide solution. Iodine (2.5%) may also be dissolved in ethanol (90%) and potassium iodide (2.5%) solution to give Weak Iodine Solution, BP 1988 (Iodine Tincture).

 

The antimicrobial activity of iodine is less dependent than chlorine on temperature and pH, although alkaline pH should be avoided. Iodine is also less susceptible to inactivation by organic matter. Disadvantages in the use of iodine in skin antisepsis are staining of skin and fabrics coupled with possible sensitizing of skin and mucous membranes.

 

vi)               Iodophors

 

In the 1950s iodophors (iodo meaning iodine and phor meaning carrier) were developed, to eliminate the disadvantages of iodine while retaining its antimicrobial activity. These allowed slow release of iodine on demand from the complex formed. Essentially, four generic compounds may be used as the carrier molecule or complexing agent. These give polyoxymer iodophors (i.e. with propylene or ethyene oxide polymers), cationic (quaternary ammonium) surfactant iodophors, non-ionic (ethoxylated) surfactant iodophors and polyvinylpyrrolidone iodophors (PVP-I or povidone-iodine). The non-ionic or cationic surface-active agents act as solubilizers and carriers, combining detergency with antimicrobial activity. The former type of surfactant, especially, produces a stable, efficient formulation, the activity of which is further enhanced by the addition of phosphoric or citric acid to give a pH below 5 on use-dilution. The iodine is present in the form of micellar aggregates which disperse on dilution, especially below the critical micelle concentration (cmc) of the surfactant, to liberate free iodine.

 

When iodine and povidone are combined, a chemical reaction takes place forming a complex between the two. Some of the iodine becomes organically linked to povidone, although the major portion of the complexed iodine is in the form of tri-iodide. Dilution of this iodophor results in a weakening of the iodine linkage to the carrier polymer with concomitant increases in elemental iodine in solution and antimicrobial activity.

 

The amount of free iodine the solution can generate is termed the ‘available iodine’. This acts as a reservoir for active iodine, releasing it when required and therefore largely avoiding the harmful side effects of high iodine concentration. Consequently, when used for antisepsis, iodophors should be allowed to remain on the skin for 2 minutes to obtain full advantage of the sustained-release iodine.

 

Cadexamer-I2  is  an  iodophor  similar  to  povidoneiodine. It is a 2-hydroxymethylene cross-linked (1–4) α D-glucan  carboxymethyl  ether  containing  iodine.  The compound  is  used  especially  for  its  absorbent  and antiseptic properties in the management of  leg ulcers and pressure sores where it is applied in the form of microbeads containing 0.9% iodine.

 

F)     Heavy Metals

 

Mercury and silver have antibacterial properties and preparations of these metals were among the earliest used antiseptics; however, they have been largely replaced by less toxic compounds. Silver has enjoyed a renaissance recently as an antimicrobial frequently incorporated in urethral catheters for the prevention of device-related infection. Various forms of silver are employed such as nanoparticulate silver, silver halides, silver oxide and combinations such as silver–palladium. A hard surface disinfectant formulation based on silver dihydrogen citrate is shown to be effective against a wide range of bacteria, fungi and viruses using as little as 30 ppm silver.

 

             i)  Mercurials

 

The organomercurial derivatives thiomersal and phenylmercuric nitrate or acetate (PMN or PMA) (Figure 19.6) have been primarily employed as preservatives. Use of both compounds has declined considerably as a result of concerns about mercury toxicity and risk of hypersensitivity or local irritation. They are absorbed from solution by rubber closures and plastic containers to a significant extent.

 


 

G)  Hydrogen Peroxide And Peroxygen Compounds

 

Hydrogen peroxide and peracetic acid are high-level disinfectants because of their production of the highly reactive hydroxyl radical. They have the added advantage that their decomposition products are non-toxic and biodegradable. The germicidal properties of hydrogen peroxide (H2O2) have been known for more than a century, but use of low concentrations of unstable solutions did little for its reputation. However, stabilized solutions are now available and because of its unusual properties and antimicrobial activity, hydrogen peroxide has a valuable role for specific applications. Its activity against the protozoan Acanthamoeba, which can cause keratitis in contact lens wearers, has made it popular for disinfection of soft contact lenses. Concentrations of 3–6% are effective for general disinfection purposes. At high concentrations (up to 35%) and increased temperature, hydrogen peroxide is sporicidal. Use has been made of this in vapour-phase hydrogen peroxide decontamination of equipment and enclosed spaces.

 

Peracetic acid (CH3COOOH) is the peroxide of acetic acid and is a more potent biocide than hydrogen peroxide, with excellent rapid biocidal activity against bacteria, including mycobacteria, fungi, viruses and spores. It can be used in both the liquid and vapour phases and is active in the presence of organic matter. It is finding increasing use at concentrations of 0.2–0.35% as a chemosterilant of medical equipment such as flexible endoscopes. Its disadvantages are that it is corrosive to some metals. It is also highly irritant and must be used in an enclosed system. The combination of hydrogen peroxide and peracetic acid is synergistic and is marketed as a cold sterilant for dialysis machines.

 

H)               Phenols

 

 

Phenols (Figure 19.7) are widely used as disinfectants and preservatives. They have good antimicrobial activity and are rapidly bactericidal but generally are not sporicidal. Their activity is markedly diminished by dilution and is also reduced by organic matter. They are more active at acid pH. Major disadvantages include their caustic effect on skin and tissues and their systemic toxicity. The more highly substituted phenols are less toxic and can be used as preservatives and antiseptics; however, they are also less active than the simple phenolics, especially against Gram-negative organisms. To improve their poor aqueous solubility, phenolic disinfectants are often formulated with soaps, synthetic detergents, and/or solvents.

 

      i)  Phenol (carbolic acid)

 

Phenol (Figure 19.7A) no longer plays any significant role as an antibacterial agent. It is largely of historical interest, as it was used by Lister in the 1860s as a surgical antiseptic and has been a standard for comparison with other disinfectants in tests such as the Rideal–Walker test.

 

 ii)    Clear  Soluble Fluids, black Fluids and white Fluids

 

Phenols obtained by distillation of coal or petroleum can be separated by fractional distillation according to their boiling point range into phenols, cresols, xylenols and high boiling point tar acids. As the boiling point increases bactericidal activity increases and tissue toxicity decreases, but there is increased inactivation by organic matter and decreased water solubility.

 

Clear soluble fluids are produced from cresols or xylenols. The preparation known as Lysol (Cresol and Soap Solution BP 1968) is a soap-solubilized formulation of cresol (Figure 19.7B) that has been widely used as a general-purpose disinfectant but has largely been superseded by less irritant phenolics. A higher boiling point fraction consisting of xylenols and ethylphenols (Figure 19.7C and D) produces a more active, less corrosive product that retains activity in the presence of organic matter. A variety of proprietary products for general disinfection purposes are available.

 

Black fluids and white fluids are prepared by solubilizing the high boiling point tar acids. Black fluids are homogeneous solutions that form an emulsion on dilution with water, whereas white fluids are finely dispersed stable emulsions. Both types of fluid have good bactericidal activity. Preparations are very irritant and corrosive to skin; however, they are relatively inexpensive and are useful for household and general disinfection purposes.

 

 iii)     Synthetic phenols

 

Many derivatives of phenol are now made by a synthetic process. A combination of alkyl or aryl substitution and halogenation of phenolic compounds has produced useful derivatives. Two of the best known chlorinated derivatives are p-chloro-m-cresol (chlorocresol, Figure 19.7E) which was frequently employed as a preservative at a concentration of 0.1%, and p-chloro-m-xylenol (chloroxylenol, Figure 19.7F) which is sometimes used for skin disinfection. Chloroxylenol is sparingly soluble in water and must be solubilized, for example, in a suitable soap solution in conjunction with terpineol or pine oil. Its antimicrobial capacity is weak and is reduced by the presence of organic matter. Other phenol derivatives of note are: 2-benzyl-4-chlorophenol (Figure 19.7G), 2-phenylphenol (Figure 19.7H) and p-tert-amylphenol (Figure 19.7I).

 


 

iv)               Bisphenols

 

Bisphenols are composed of two phenolic groups connected by various linkages. Triclosan (Figure 19.7J) is the most widely used. It has been incorporated into medicated soaps, lotions and solutions and is also included in household products such as plastics and fabrics. There is some concern about bacterial resistance developing to triclosan.

 
I)    Surface-Active Agents

 

Surface-active agents or surfactants are classified as anionic, cationic, non-ionic or ampholytic according to the ionization of the hydrophilic group in the molecule. A hydrophobic, water-repellent group is also present. Within the various classes a range of detergent and disinfectant activity is found. The anionic and non-ionic surface-active agents, for example, have strong detergent properties but exhibit little or no antimicrobial activity. They can, however, render certain bacterial species more sensitive to some antimicrobial agents, possibly by altering the permeability of the outer envelope. Ampholytic or amphoteric agents can ionize to give anionic, cationic and zwitterionic (positively and negatively charged ions in the same molecule) activity. Consequently, they display both the detergent properties of the anionic surfaceactive agents and the antimicrobial activity of the cationic agents. They are used quite extensively in Europe for presurgical hand-scrubbing, medical instrument disinfection and floor disinfection in hospitals.

 

Of the four classes of surface-active agents the cationic compounds play the most important role in an antimicrobial context.

 

          i)  Cationic Surface -active agents

 

The cationic agents used for their antimicrobial activity all fall within the group known as the quaternary ammonium compounds (QACs, quats or onium ions). These are organically substituted ammonium compounds (Figure 19.8A) where the R substituents are alkyl or heterocyclic radicals to give compounds such as benzalkonium chloride (Figure19.8B), cetyltrimethylammonium bromide (cetrimide) (Figure 19.8C) and cetyl-pyridinium chloride (Figure 19.8D). Inspection of the structures of these compounds (Figure 19.8B and C) indicates that a chain length in the range C8–C18 in at least one of the R substituents is a requirement for good antimicrobial activity. In the pyridinium compounds (Figure 19.8D), three of the four covalent links may be satisfied by the nitrogen in a pyridine ring. Several ‘generational’ changes have arisen in the development of QACs. Compounds such as alkyldimethylbenzyl ammonium chloride, alkyl-dimethyl-ethyl-benzyl ammonium chloride and dodecyl-dimethyl-ammonium chloride have roles in disinfection where HIV and HBV are present. Polymeric quaternary ammonium salts such as polyquaternium 1 are finding increasing use as preservatives.

 


 

The QACs are most effective against microorganisms at neutral or slightly alkaline pH and become virtually inactive below pH 3.5. Not surprisingly, anionic agents greatly reduce the activity of these compounds. Incompatibilities have also been recorded with non-ionic agents, possibly due to the formation of micelles. The presence of organic matter such as serum, faeces and milk will also seriously affect activity.

 

QACs exhibit greatest activity against Gram-positive bacteria, with a lethal effect observed using concentrations as low as 0.0005%. Gram-negative bacteria are more resistant, requiring a level of 0.0033%, or higher still if Ps. aeruginosa is present. A limited antifungal activity is exhibited and they have no useful sporicidal activity. This relatively narrow spectrum of activity limits the usefulness of the compounds, but as they are generally well tolerated and non-toxic when applied to skin and mucous membranes they have considerable use in treatment of wounds and abrasions. Benzalkonium chloride and cetrimide are employed extensively in surgery, urology and gynaecology as aqueous and alcoholic solutions and as creams. In many instances they are used in conjunction with a biguanide disinfectant such as chlorhexidine. The detergent properties of the QACs also provide a useful activity, especially in hospitals, for general environmental cleaning.

 

J)   Other Antimicrobials

 

The full range of chemicals that can be shown to have antimicrobial properties is beyond the scope of this chapter. The agents included in this section have limited use or are of historic interest.

 

     i)  Diamidines

 

The activity of diamidines is reduced by acid pH and in the presence of blood and serum. Propamidine and dibromopropamidine, as the isethionate salts, have been employed as antimicrobial agents in eye drops (0.1%) for amoebic infection and for topical treatment of minor infections.

 

ii)          Dyes

 

Crystal violet (Gentian violet), brilliant green and malachite green are triphenylmethane dyes used to stain bacteria for microscopic examination. They have a static activity but are no longer applied topically for the treatment of infections because of carcinogenicity.

The acridine dyes acriflavine and aminacrine have been employed for skin disinfection and treatment of infected wounds or burns but are slow acting and mainly bacteriostatic.

 

iii)  Quinoline derivatives

 

The quinoline derivatives of pharmaceutical interest are little used now. The compound most frequently used is dequalinium chloride, a bisquaternary ammonium derivative of 4-aminoquinaldinium which was formulated as a lozenge for the treatment of oropharyngeal infections.

 

K)                       Antimicrobial Combinations And Systems

 

There is no ideal disinfectant, antiseptic or preservative. All chemical agents have their limitations in terms of either their antimicrobial activity, resistance to organic matter, stability, incompatibility, irritancy, toxicity or corrosivity. To overcome the limitations of an individual agent, formulations consisting of combinations of agents are available. For example, ethanol and isopropanol have been combined with chlorhexidine, QACs, sodium hypochlorite and iodine to produce more active preparations. The combination of chlorhexidine and cetrimide is also considered to improve activity. QACs and phenols have been combined with glutaraldehyde and formaldehyde so that the same effect can be achieved with lower, less irritant concentrations of the aldehydes. Some combinations are considered to be synergistic, e.g. hydrogen peroxide and peroxygen compounds. Care must be taken in deciding on disinfectant combinations, as the concentration exponents associated with each component of a disinfectant combination will have a considerable effect on the degree of activity

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Research into the resistance of microbial biofilms provides potential for improving elimination of this problematical microbial mode of growth. Bacteria often use a communication system, quorum sensing (QS), to regulate virulence factor production and the formation of biofilms. Increased understanding of how chemicals can block QS could help provide effective prevention and elimination of biofilm-related infection. The incorporation of antimicrobial agents into materials that form working and contact surfaces or those of medical devices and implants has been positive but much further developmental research is required. Such ‘bioactive’ surfaces can be formed, for example, by incorporation of silver salts and alloys, biguanides and triclosan, and have the ability to reduce infection arising from microbial adherence and biofilm formation.

 

Other means are available to potentiate the activity of disinfectants. Ultrasonic energy in combination with suitable disinfectants such as aldehydes and biguanides has been demonstrated to be useful in practice and ultraviolet radiation increases the activity of hydrogen peroxide. Super-oxidized water provides an extremely active disinfectant with a mixture of oxidizing species produced from the electrolysis of saline. The main products are hypochlorous acid (144 mg/L) and free chlorine radicals. The antimicrobial activity is rapid against a wide range of microorganisms in the absence of organic matter.

 

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