Antimicrobial Agents I

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Antimicrobial drugs are the greatest contribution of the present century to therapeutics. As the class they are one of the most frequently used in medicine. J. Zemmelweiss, the Hungarian obstetrician used lime for medicine stuff hands washing. An English surgeon J. Lister suggested phenol as an antiseptic to surgery. Further development of antiseptics was based on Paster’s discovery of pathogenic microorganisms and researches of R. Koch, I.I. Mechnikov and others.

Drug in this class differ from all others in that they designed to inhibit or to kill the infecting organism and to have minimal effect on the recipient. If agent primary inhibit the germ growing, it acts bacteriostatic. Direct lethal action is the feature of bacteriocidic activity. A practical distinction between these two mechanisms action is futile as these are often concentration dependent action.

Antimicrobial preparations are subdivided into the following groups:
disinfectants,
antiseptics and
chemotherapeutic agents.

Disinfectants are chemical agents that inhibit or kill microorganisms on inanimate objects (walls, floor, air, and medical tools). The process of disinfection prevents infection by reducing the number of potentially infective organisms either by killing, removing, or diluting them.

Antiseptics are agents with sufficiently low toxicity for host cells that they can be used directly on skin, mucous membranes, or wounds. Disinfectants and antiseptics can be used both for disinfecting of medical tools and human skin depending on their concentration. There is considerable overlap and many agents are used in either way.

Chemotherapeutic agents are used for germs killing inside the organism. Disinfectants and antiseptics differ from chemotherapeutic agents by their low parasite selectivity and high toxicity for systemic use.

A good desinfectant/antiseptic should be: active against all pathogens (bacteria, fungi, viruses, protozoa), active even in the presence of blood, pus and exudates. A desinfectant in addition should be not corrode instruments. An antiseptic also should be: non-irritating to tissues, produce minimum toxicity.

Spectrum activity of agent is the list of microorganisms, that sensitive to him. Spectrum activity of majority of antiseptic/disinfectants is wide, reflecting nonselectivity of action.

Evaluation of effectiveness of antiseptics, disinfectants although seemingly simple in principle, are very complex. Factors in any evaluation include the intrinsic resistance of the microorganism, the number of present microorganisms, mixed populations of microorganisms, amount of present organic material (e.g. blood, feces, tissue), concentration and stability of disinfectant or sterilant, time and temperature of exposure, pH, and hydration and binding of the agent to surfaces.

CLASSIFICATION OF DISINFECTANTS AND ANTISEPTICS

1. Halogens (chlorinated lime, chloramine B, chlorhexidine, iodinole, iodovidone)

2. Oxidizing agents (hydrogen peroxide, potassium permanganate)

3. Acids (salicylic acid, boric acid)

4. Phenol derivatives (phenol, cresol, resorcinol, vagotil)

5. Aldehydes and alcohols (formaldehyde, glutaraldehyde, ethanol, isopropanol)

6. Metallic salts (silver nitrate, zinc sulfate, and copper sulfate)

7. Dyes or tints (brilliant green, rivanol, methylene blue)

8. Detergents (roccal, aethonium, cerigelum, decamethoxinum, soaps)

9. Derivatives of different chemical groups (furacilinum)

10. Agents from plant source (novoimaninum, chlorophylliptum, and lysocim)


HALOGENS

Anti-germ activity of halogens depends on their ability to release chlorine and iodine. They form chloric and iodic acids in water solutions. The latter release atomic oxygen and haloids. These ions denature proteins of germs and act bactericidically.

Chlorine is a strong oxidizing agent and universal disinfectant that is most commonly provided as a 5.25% sodium hypochlorite solution, a typical formulation for household bleach. Chlorine is used to disinfect urban water supplies. Because chlorine is inactivated by blood serum, feces, and protein-containing materials, surfaces should be cleaned before chlorine disinfectant is applied. Solutions of chlorine are corrosive to aluminum, silver, and stainless steel.

Chlrophores (chlorinated lime, chloramine B) are compounds that slowly release hypochlorous acid (HOCl). Because of ease of handling, they are used in preference to gaseous chlorine. These agents retain chlorine longer and have a prolonged bactericidal action. Chlorinated lime (bleaching powder) is obtained by the action of chlorine on lime. It is used as disinfectant for medical tools, drinking water, swimming pools and sanitizer for privies. Chloramine B may be used for disinfecting of clothes, skin and instruments, which are not made from metal.

Chlorhexidine is a cationic biguanide with very low water solubility. Water-soluble chlorhexidine bigluconate is used in water-based formulations as an antiseptic. It is most effective against gram-positive cocci and less active against gram-positive and gram-negative rods. Spore germination is inhibited by chlorhexidine. It is resistant to inhibition by blood and organic materials. Chlorhexidine is used in the treatment of inflammation of the oral mucosa caused by bacterial or fungal actions, for surgeon hands washing before operation, for medical tools disinfection. Chlorhexidine has a very low skin-sensitizing or irritating capacity. Oral toxicity is low because chlorhexidine is poorly absorbed through the alimentary tract. Chlorhexidine must not be used during surgery on the middle ear because it causes sensorineural deafness. Similar neural toxicity may be encountered during neurosurgery.

Iodine is a rapidly acting, broad spectrum (bacterial, fungi, and viruses) microbicidal agent. Acts by iodinating and oxidizing germ protoplasm. Iodine in a 1:20,000 solution is bactericidal in 1 minute and kills spores in 15 minutes. It is the most active antiseptic for intact skin. It is not commonly used because of serious hypersensitivity reactions, skin, irritation that may occur and because of its staining of clothing and dressings.

Iodophors are complexes of iodine with a surface-active agent such as polyvinylpyrrolidone (iodinole, iodovidone). The amount of free iodine is low, but it is released as the diluted solution. Iodophors retain the activity of iodine. Iodophors are less irritating and less likely to produce skin hypersensitivity than tincture of iodine. They kill vegetative bacteria, mycobacterium, fungi, and lipid-containing viruses. They may be sporicidal upon prolonged exposure. Iodophors can be used as antiseptics or disinfectants, the latter containing more free iodine. Dilution may release more free iodine. An iodophor solution must be diluted according to the manufacturer's directions in order to obtain full activity.

OXIDIZING AGENT

Oxidizing agent are free atomic oxygen releasers. Atomic oxygen lead to irreversible damage of oxidizing-restoring reaction of germ. The hydrogen peroxide has high killing activity and a broad spectrum against bacteria, spores, viruses, and fungi when used in appropriate concentration. It has the advantage that its decomposition products are not toxic and does not injure the environment. Hydrogen peroxide is powerful oxidizer that is used primarily as antiseptic. Organisms with the enzymes catalase and peroxidase rapidly degrade hydrogen peroxide. The innocuous degradation products are atomic and molecule oxygen, and water. Molecule oxygen forms the foam that helps in loosing and removing slough dead tissues. Hydrogen peroxide has been proposed for wound irrigation, disinfection of respirators, acrylic resin implants, plastic eating utensils, soft contact lenses. Hydrogen peroxide has poor penetrability and a transient action.

Potassium permanganate. It liberates oxygen, which oxidizes bacterial protoplasm, and MnO2, which cause astringent and irritating effects. Solution of potassium permanganate is used for gargling, douching, and irrigating cavities, urethra and wounds. It has also been used for stomach wash in alkaloid poisoning. It promotes rusting and is not good for surgical instruments.

ACIDS

Boric acid possesses fungistatic and weak bacteriostatic properties. Drug has greater bacteriostatic activity in bases containing large amounts of water than in fatty bases. Boric acid retards the growth of fungi but is not fungicidal. Aqueous solutions of boric acid are used topically for ophthalmic irrigation to cleanse and refresh irritated eyes. It is used topically as a skin protection for relief of discomfort of chafed skin, dry skin, abrasions, or other skin irritations and has been used topically for the treatment of superficial fungal infections; however, the drug is generally considered as lacking substantial evidence of efficacy for these uses.

The risk of systemic toxicity from topical application of boric acid depends on the concentration used (more than 5%), age of the patient (children appear to be more susceptible), skin condition (increased with abraded, or macerated skin). Boric acid can produce severe and fatal poisoning, consisting of GI disturbances, erythematous skin eruptions, and signs of CNS stimulation followed by depression. Treatment of acute boric acid intoxication consists mainly of intensive symptomatic and supportive therapy.

Salicylic acid has a potent keratolytic action and a slight antifungal and antiseptic action when applied topically to the skin. In low concentrations, the drug has keratoplastic activity (activation of keratinization) and in higher concentrations (i.e., 1% or higher), the drug has keratolytic activity (causes peeling of skin). At high concentrations, salicylic acid has a caustic effect. Salicylic acid is used topically for its keratolytic effect in controlling scaling dermatoses (seborrheic, psoriasis). It has also been used in the treatment of localized hyperkeratosis, such as occurs on the palms and soles. Salicylic acid is not used systemically because of its severe irritating effect on GI mucosa and other tissues.

PHENOL DERIVATIVES

Phenol itself perhaps the oldest of the surgical desinfectant/antiseptic. It is used to disinfect urine, feces, and pus, for drug conservation. Phenol no longer used as an antiseptic because of its corrosive effect on tissues, its toxicity upon absorption, and its carcinogenic effect. When swallowed (with suicidal purpose) it causes buccal, esophageal and stomach burns, excitation, convulsions, respiratory paralysis and vascular collapse.

Phenolderivatives (cresol, resorcin, and vagotil) are less toxic than phenol. Phenolic compounds disrupt cell wall and membranes, precipitate proteins, and inactivate enzymes. They are bactericidal (including mycobacteria), fungicidal, and capable of inactivating lipophilic viruses. Cresol more active than phenol. It is used for hard surface decontamination in hospitals and laboratories, e.g., floors, beds, and counters or bench tops. Resorcin is 1/3 as potent as phenol. It also has keratolytic activity, that’s why resorcin employed on seborrheic dermatitis, eczema, acne as solution or ointment. Vagotil in addition acts on trichomonas – used for topical vaginitis treatment.

Detergents are often added to formulations to clean and remove organic material that may decrease the activity of a phenolic compound. Skin absorption and skin irritation still occur with phenolderivatives, and appropriate care is necessary in their use. They are not recommended for use in nurseries and especially bassinets, where their use has been associated with hyperbilirubinemia.

ALDEHYDES AND ALCOHOLS

The two alcohols most frequently used for antisepsis and disinfection are ethanol and isopropyl alcohol (isopropanol). They are rapidly active, killing vegetative bacteria, M tuberculosis, and many fungi and inactivating lipophilic viruses. They are not sporicidal, may not be active against hydrophilic viruses, and lack residual action because it evaporates completely. Alcohols probably act by denaturation of proteins. Alcohols have been used for skin disinfecting in case of abrasion and before hypodermic injection. The rapidity of antiseptic action increases with concentration upto 70% and decreases above 90%. At 90% concentration they form a coagulum under which bacteria could grow.

Alcohols are an irritant and should not be applied to mucous coats. They are poor disinfectant for instruments – does not kill spores and promote rusting.

Aldehydes (formaldehyde and glutaraldehyde) act by alkylation of chemical groups in proteins and nucleic acids. Activated solutions are bactericidal, sporicidal, fungicidal, and virucidal for both lipophilic and hydrophilic viruses. They are not corrosive for metal, plastic, or rubber.

Formaldehyde has a characteristic pungent odor and is highly irritating to respiratory mucous membranes and eyes. Formaldehyde solutions are used for high-level disinfection of hemodialyzers, preparation of vaccines, and preservation and embalming of tissues. Formaldehyde is available as a 37% solution in water (100% formalin). The 3,7% formaldehyde (10% formalin) solutions used for fixation of tissues and embalming may not be mycobactericidal. Including formaldehyde preparation decrease foot sweating. The urinary antiseptic hexamethylentetramine (methenamine) acts by releasing formaldehyde in acidic medium. It is used for urinary tract infections.

Those who handle formalin can develop eczematoid reaction. It has declared that formaldehyde is a potential carcinogen. Glutaraldehyde is less pungent and better sterilizing agent than formalin. Solutions of 2% glutaraldehyde are most commonly used. It is used for disinfection or sterilization of instruments such as fiberoptic endoscopes, respiratory therapy equipment, hemodialyzers, and dental handpieces.

METALLIC SALTS

Metals cause antiseptic action, because they easily combine with sulfhydryl-(SH) group of thiolic enzymes, thus stopping the oxidizing process of microorganisms. When metal-ions interact with human proteins, physical properties of the protein are usually altered; the protein may be denatured and precipitation usually occurs. When the concentration of metal is low, precipitation prevents deep tissue penetration and astringent action occurs. When the concentration of metal is high, membrane and intracellular structures are damaged and caustic or escharotic action occurs.

Metal-ions in the high concetration interact with sulfhydryl groups, inhibiting enzymes and altering cell membranes of human tissues, that’s lead to poisoning. The most distinct example is the case of mercury poisoning. Acute inhalation of elemental mercury vapors may cause chemical pneumonitis and noncardiogenic pulmonary edema. Acute gingivostomatitis may occur, and neurologic sequelae (tremor, memory loss, fatigue, insomnia, and anorexia) may also ensue. Acute ingestion of inorganic mercury salts, such as mercuric chloride, can result in a corrosive, potentially life-threatening hemorrhagic gastroenteritis followed within days by acute tubular necrosis and oliguric renal failure. In addition to intensive supportive care, acute chelation with dimercaprol (unithiol) or edetate calcium disodium (calcium EDTA) may be of value in diminishing nephrotoxicity after acute exposure to inorganic mercury salts. The sulfhydryl groups of dimercaprol form heterocyclic ring complexes with heavy metals (particularly arsenic, mercury, and gold), and these complexes prevent or reverse the binding of metallic cations to body ligands such as essential sulfhydryl-dependent enzymes. The calcium in calcium EDTA can be displaced by divalent and trivalent metals to form stable soluble complexes which can then be excreted in urine.

Silver nitrate exhibits antiseptic, germicidal, astringent, and caustic or escharotic activity. Inorganic silver salts are strongly bactericidal. Silver nitrate, 1:100, has been most commonly used, particularly as a preventive for gonococcal ophthalmitis in newborns. Silver nitrate touch is used for hypertrophied tonsillitis and aphthous ulcers.

Silver salts stain tissue black because of deposition of reduced silver. Contact of 1% silver nitrate solution with skin or other surfaces should be avoided since staining of the skin may occur. Silver nitrate is caustic and irritating to skin and mucous membranes. Cauterization of the cornea and blindness may result from repeated application of silver nitrate ophthalmic solution. Mistaken or accidental single-dose administration of 5-50% silver nitrate solutions has reportedly caused severe ocular injury including permanent corneal opacification and cataracts.

Silver sulfadiazine slowly releases silver and is used to suppress bacterial growth in burn wounds. Collargole (colloidal silver) and protargole (protein silver) also slowly release silver ions, are not irritating. They are used in cases of conjuctivitis, ulcers.

Zinc sulfate exhibits astringent and mild antiseptic activity. These effects may result from precipitation of protein by the zinc ion. Zinc sulfate is used in ophthalmic solutions as an astringent for the temporary relief of discomfort from minor eye irritation. It has also been used in the treatment of angular conjunctivitis. Zinc oxide being mildly antiseptic, it is popular dermal protective and adsorbentive agent. Zinc is necessary for the proper functioning of over 200 metalloenzymes. Physiological functions that are zinc dependent include cell growth and division, sexual maturation and reproduction, night vision, wound healing, host immunity, taste acuity.

Copper sulfate as astringent and antiseptic has been used for conjuctivitis, uretritis and vaginitis treatment. Copper is necessary for the proper functioning of many metalloenzymes. Physiological functions that are copper dependent include oxidation of iron, erythro- and leukopoiesis, bone mineralization, elastin and collagen cross-linking, myelin formation, and antioxidant protection of the cell. Such polyvitamines as “Quadevitum”, “ Complivitum” are include copper sulfate (“Complivitum” also contain zinc).

Mercury is now rarely used as disinfectant/antiseptic. Mercurials are poor antiseptics with low therapeutic index. But some are still used. For example hydrargeri amidochloride (ammoniated mercury) used for skin disease treatment.

Aluminum and lead preparations are used for antiseptic rinsing and applying. Aluminum hydroxide being an antacid is indicated for relief of symptoms associated with hyperacidity (heartburn, acid indigestion, and sour stomach).

DYES (TINTS)

Brilliant green active against fungi, staphylococci, and other Gram positive bacteria. Aqueous or alcohol solution is used on furunculosis, skin abrasion, cutting, infected eczema. Staining is a disadvantage with all dyes. Brilliant green is inactivated by blood serum, feces, and protein-containing materials.

Aethacridine lactate (rivanol) influence mostly Gram positive germs. It’s water solution, ointment, paste are used for wounds and cavities washing and in dermatology.

Methylene blue has mild antiseptic activity that may inhibit bacterial proliferation. Methylene blue has been used as a urinary tract antibacterial agent (irrigation), however, more effective agents have replaced this medication. It is used as a bacteriological stain, as a dye in diagnostic procedures, such as fistula detection, and for the selective staining of certain body tissues during surgery. Methylene blue is indicated in the treatment of acquired and idiopathic methemoglobinemia. In low concentrations, it acts as a cofactor to accelerate the conversion of methemoglobin to hemoglobin in erythrocytes.

DETERGENTS

Detergents or surface-active compounds decrease surface tension of cell membrane act, thus alter it permeability. There are two kinds of detergents. They are cationic detergents (quaternary ammonium compounds) and anionic detergents (soaps).

The quaternary ammonium compounds ("quats") are bacteriostatic, fungistatic, and sporistatic. They highly effective against gram-positive bacteria and moderately active against gram-negative bacteria. Strains of Mycobacterium tuberculosis and Pseudomonas aeruginosa are often resistant and they are not effective against spore-forming organisms.

Quaternary compounds possess detergent, keratolytic, and emulsifying action. They are used for sanitation of noncritical surfaces (floors, bench tops, etc).

Quaternary compounds bind to the surface of colloidal protein in blood, serum, to fibers present in cotton, mops, cloths, and paper towels used to apply them, which can cause inactivation of the agent by removing it from solution. They are inactivated by anionic detergents (soaps). That’s why before applying quaternary ammonium compounds to the skin for preoperative disinfection, all traces of soap should be removed with water and with 70% alcohol.

The representatives of quaternary ammonium are Roccal (benzalkonium chloride), Aethonium, Cerigelum, Decamethoxinum.

Properly diluted, roccal is used for the preoperative disinfection of unbroken skin and prophylactic disinfection of the intact skin, in the treatment of superficial injuries and infected wounds. It is also used to preserve the sterility of surgical instruments and rubber articles during storage, and to preserve the sterility of ophthalmic solutions. Aethonium and decamethoxinum are used for the treatment of trophic ulcers, stomatitis, keratitis. Finally cerigel is used for hands washing of medicine staff before surgical treatment.

Soaps are anionic detergents. They are weak antiseptic and affect only Gram positive bacteria. Their usefulness primarily resides in their cleansing action. Other antiseptics can medicate soaps.

Furacilinum (nitrofurazone) is a synthetic antibacterial nitrofuran derivative. Furacilinum acts by transforming it nitrogroup into the aminogroup that lead to inhibiting bacterial enzymes involved in carbohydrate metabolism. Organic matter (e.g., blood, pus, serum) inhibits the antibacterial action of furacilinum. Furacilinum has a wide spectrum of activity against a variety of gram-positive and gram-negative organisms, however, particularly it does not inhibit fungi or viruses. Furacilinum may be active against organisms that have developed resistance to antibiotics and sulfanilamides. It is used topically in patients with burns, for prophylaxis and treatment of infections of the skin and mucous membranes, middle and external ear caused by susceptible bacteria. Furacilinum solutions have been used as a bladder irrigant in catheterized patients.

Allergic contact dermatitis is the most frequently reported adverse effect of topical furacilinum and has occurred in approximately 1% of patients treated.

Novoimaninum is antigerm agent, obtaining from the plant Hyperici perforatum. It acts primary on Gram positive microorganisms, including penicillin-resistance staphylococci. Novoimaninum has used topically as solution for abscess and infective wound treatment.

Chlorophylliptum is a mixture of chlorophyls getting form Eucalyptus leaves and Myrtace seeds. It can be used for the treatment of burns, trophic ulcers.

Lysocim is the protein structure enzyme. It is produced from hen egg protein. Lysocim breaks polycarbohydrates of cell membrane, acts mostly on Gram positive germs. In addition it stimulate host non-specific resistance, cause anti-inflammation and mucolytic action. Lysocim is used for chronic septic state, burns, conjunctivitis. It applies topically and injects intramusculary. It has not irritant action.