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linforma- for pre- Merck d p. 95 Compan- À Reports, vumiatuoa. 3243-267, pe Diseases: 7 Anti-infective Agents JOHN M. BEALE, JR The history of work on the prevention of bacterial infection cam be traced back to the 19th century when Joseph Lister tin 1867) introduced antiseptic principles for use in surgery und posttraumatic injury! He used phenol (carbolic acid) as a wash for the hands, as a spray on an incision site, and on bandages applied to wounds. Lister's principles caused a dramatic decrease in the incidence of postsurgical infections. Around 1881 and continuing to 1900, microbiologist Paul Ebrlich, a disciple of Robert Koch, began work wilh a set of untibacterial dyes and antiparasitic organic arsenicals, His goul was to develop compounds that retained antimicrobial activity at the expense of toxicity to the human host; he called the agents that he sought “magic bullets.” At the time that Ehrlich began his experiments, there were only a few compounds that could be used in treating infectious discases, and none was very useful in the treatment of severe Gram-positive and Gram-negative infections. Ehrlich dis- covered that the dyes and arsenicals could stain target cells selectively and that the antimicrobial properties of the dyes paralleled the staining activity. This discovery was the first demonstration of selective toxicity, the property of certain chemicals to kill one type of organism while not harming another. Selective toxicity is the main tenet of modern anti- microbial chemotherapy, and Ehrlich's seminal discovery paved the way for the development of the sulfonamides and pemcillins and the elucidation of the mechanisms of their selective toxicity, Prior to Ehrlich's studies, the local antimi- trobial properties of phenol and iodine were well known, butihe only useful systemic agents were the herbal remedies enchona for malaria and ipecac for amebic dysentery, Ehr- lich's discovery 0f compound 606, the effective antisyphi- lc drug Salvarsan,> * was a breakthrough in the treatment vfa serious, previously untreatable disease. NHa HCl OH PS A Salvarsan Until the 1920s, most successful anti-infective agents were based on the group HB element mercury and the group VA elements arsenic and antimony. Atoxyl (sodium arsani- le, arsphenamine) was used for sleeping sickness.* Certain ves, such as gentian violet and methylene blue, were also found to be somewhat effective, as were a few chemical congeners of the quinine molecule. Some of these agents represented significant achievements in anti-infective ther- apy, but they also possessed some important limitations. Heavy metal toxicity after treatment with mercury, arsenic, and antimony severely limited the usefulness of agents con- taining these elements. o Lo Esc o ces a HaN Arsphenamine Justprior to 1950, great strides were made in anti-infective therapy. The sulfonamides and sulfones (this chapter), more effective phenolic compounds such as hexachlorophene, synthetc antimalarial compounds (Chapter 9), and a number ofantibiotics (Chapter 10) were introduced to the therapeutic armamentarium. Anti-infective agents may be classified according to a va- riety of schemes. The chemical type of the compound, the brological property, and the therapeutic indication may be used singly or in combination to describe the agents. In this texthook, a combination of these classification schemes is used to organize the anti-infective agents, When several chemically divergent compounds are indicated for a specific disease or group of diseases, the therapeutic classification is used, and the drugs are subclassified according to chemical type. When the information is best unified and presented in a chemical or biological classification system, as for the sulfonamides or antibacterial antibiotics, then one of these classification systems is used, This chapter addresses an extremely broad base of anti- infective agents, including the local compounds (alcohols, phenols, oxidizing agents, halogen-contaming compounds, cationic surfactants, dyes, and mercurials), preservalives, antifungal agents, synihetic antibacterial drugs, antitubercu- lar and antiprotozoal agents, and anthelmintics. Other chap- ters in this textare devoted to antibacterial antibioties (Chap- ter 10), antiviral agents (Chapter 11), and antincoplastic antibioties (Chapter 12). Anti-infective agents that are used locally are called ger- micides, and within this classification there are two primary subtypes (see Table 8-1) and a number of other definitions of sanitization. Antisepties are compounds that kill (-cidal) or prevent the growth of (-static) microorganisms when ap- plied to living tissue. This caveat of use on living tissue points to the properties that the useful antiseptic must have, The ideal antiseptic must have low enough toxicity that it can be used directly on skin or wounds; it will exert a rapid and sustained lethal action against microorganisms. (the 217 218 Wilton and Gisvold's Teabook of Organic Medicinal and Pharmaceutical Chemistry TABLE 8-1 Definitions and Standards for Removing Microorganisms Antisepsts Application of um agent to living tssie for the purpose of preventing infection Destruction or marked reduction in the manibes or autivity of microorgunismas Decontamination Disintecmon Chemical or physical treatment (hat destroys most vegotanive microbes or viruses, but not apores, in or on inanimats sirtáces Reduction of microlial Load om am Anamimane surfaçe to à level considered acceptabio for public health purposes Samitizuthon Sterilizatio A process intended po kill or remove all types of microorganisms, incloding spores, and usually including viruses wrtth am acceprabty low probability of survival Pasteotrteation A process that kills momsporalutimp mberocnganisms boy fue meme cr sita mt 65-100"C spectrum may be narrow or broad depending on the use) The agent should have a low surface tension so that it will spread into the wound, dt should retain activity im the pres- ence of body fluids (including pus), be nonirritating to tis- sues, be nonallergente, lack systemic toxicity when applied toskin or mucous membranes, and not interfere with healing. No antiseptic available today meets all of these criteria. A few antibioties, such as bacitracin, polymyxin, silver sulfadi- azine, and neomyein, are poorly absorbed through the skin and mucous membranes and are used topically for the treat ment of local infections; they have been found very effective against infections such as these. In general, however, the TABLE 8-2 Common Sterilants and Their Range of Use topical use of antibiotics has been restricted by concern about the development of resistant microbial sirains and possible allergic reactions, These problems can reduce the usefulness of these antibiotics for more serious infections A disinfectant 15 an agent that prevents transmission df infection by the destruchon of pathogenic microorganisms when applied to inanimate objects. The ideal disinfectam exerts à rapidly lethal action against all potentially pathos genic microorganisms and spores, has good penetrating properties into organic matter, shares compatibility with or ganic compounds (particularly soaps), is not inactivated by living tissue, is noncorrosive, and is esthetically pleasimg (nonstaining and odorless). Locally acting anti-infective drugs are widely used by the lay public and are prescribed by members of the medical profession (even though the eÊ fectiveness of many of the agents has not been established completely). The germicide may be harmful in certain cases (Le., ii may vetard healing). Standardized methods for evalu ating and comparing the efficacy of germicides have only recently been developed. Numerous classes of chemically divergent compounds possess local anti-infective properties. Some of these are outlined in Table 8-2 The most important means of preventing transmission of infectious agents from person to person or from regions df high microbial load, such as the mouth, nose, or gut, to po tential sites of infection is simply washing the hands. In fact one of the breakihroughs in surgical technique in the 180 was the finding that the incidence of postsurgical infection decreased dramatically if surgeons washed their hands be fore operating. Regular hand washing is properly done with out disinfection to minimize dry ing. imitaton, and sensitiaa tion of the skin. Simple soap and warm water remove bacteria efficiemly. Skin disinfectants along with soap ant Bacteria Viruses Other Gram- Gram- Amebic positive negative Acidfast Spores Lipophilic Hydrophilic Fungi Cysts Prions Alcohol de 4 4 di de + k ] + NIA NiA - Lisopropanol, etanol) Aldehydes +++ + + ++ t+ + NA (eluturaldehye, torimaldehyde) Chlorhexidime dd b + . NIA NIA Eluconate Sosliura ho 4d + ++ + (pH + + (high ee + ++ (high hypochiorite, cume.) cone) ehlorine donde Hesachiorophenc 4 E Povidone-lodine +++ +. + + (high + há SU] Phenols, quatermary +++ + dd a t NA NIA tr ATRCILEAAA Strong oxhdizing +44 + +44- agents, crésuls 220 Wilsenr ame Gisvold"s Texthook of Organic Medicinal and Pharmaceutical Chemistry asfely for preoperative sterilization of the skin.” Alcohols are flammable and must be stored in cool, well-ventilated ureas, Dehydrated Ethanol, USP. Dehvydrated etanol. or ab- solute ethanol, contains not less than 99% wlwy of CsH.0H. tis prepared commercially by azeotropic distillation of am ethanol:benzene mixture, with provistons made for efficient removal of water. Absolute ethanol has a very high affinity for water and must be stored in tighily sealed containers, This form of ethanol is used primarily as a chemical reagent or solvent but has been injected for the local relicf of pain in carcinomas and neuraleias. Absolute alcohol cannot be ingested because there is always some benzene remaining from the azeotropic distillation that cannot be removed. Isopropy! Alcohol, USP. Esopropano! (2-propano!) is a colorless, volatile liquid with à characteristic odor and a slightly bitter taste. It is considered a suitable substituto for ethanol in most cases but must not be ingested. Isopropyl alcohol is prepared commercially by the sulfurio acid=cata- Iyzed hydration of propylene HO CH HS0, P Ho” “CH; HO OH The alcohol forms a constant-boiling mixture with water that contains 91% v/v of 2-propanol. Isopropyl alcohol is used primarily us a disinfectant for the skin and for surgical instruments. The alcohol is rapidly bactericidal in the con- centration range of 50 to 95%. A 40% concentration 15 con- sidered equal in antiseptic efficacy to a 60% ethanol in water solution. Azeotropic ixopropvl alcohol, USP, is used on gauze pads for sterilization of the skin prior to hypodermic injections. Esopropvl alcohol is also used in pharmaceuticals and toiletries as à solvent and preservative. Ethylene Oxide. Ethylene oxide, CsH40, is à colorless flammable gas that liquefies at I2ºC, lt has been used to sterilize temperature-sensitive medical equipment and certain pharmaceuticals that cannot be hear sterilized in am autoclave. Ethylene oxide difluses readily through porous materials and very effectively destroys all forms of microorganisms at ambient temperatures” (6) F / CHa—CHa Ethylene Oxide Ethylene oxide forms explosive mixtures in air at concen- trations ranging from 3 to 80% by volume. The explosion hazard às eliminated when the gas is mixed with sufficient concentrations of carbon dioxide. Carboxide is a commercial sterilant containing 10% ethylene oxide and 90% carbon dioxide by volume that can be handied and released in ur without danger of explosion. Sterilization is accomplished in a sealed, autoclave-like chamber or in gas-impermeable bags The mechanism of the germicidal action of ethylene oxide probably involves the alkylation of functional groups in nu- cleic acids and proteins by nucleophilic opening of the oxide ring. Ethylene oxide is à nonselective alkylating agent and as such is extremely toxic and potentially carcinogento. Ex- posure to skin and mucous membranes should be avoided, and inhalation of the gas should be prevented by use of um appropriate respiratory mask during handiing and steriliza- ton procedures, Aldehydes Formaldehyde Solution, USP. Formalin is a coloriess aqueous solution that officially contains not less than 37% wiv of formaldehyde (HCHO), with methanol added to res tard polymerization. Formalin is miscible with water ané alcohol and has a charactenstic pungent aroma. Formaldes hyde readily undergoes oxidation and polymerization, leais ing to formic acid and paraformaldehyde, respectively, so the) preparation should be stored in tighily closed. highi-resistanto containers. Formalin must be stored at temperatures above 15º€ to prevent cloudiness, which develops at lower temper atures. ” | Formie Acid Ed E sá “H o r Ei Paraformaldehyde Õ ao ae The germicidal action of formaldehyde is slow but power ful, The mechanism of action is believed to involve dire nonspecific alkylation of pucleophilic functional groups (amino, hydroxy), and sulfhydryl) in proteins and muclas acids 10 form carbinol derivatives. The action of formalds hyde is not confined to microorganisms, The compound E irritating to mucous membranes and causes hardening of be skin. Oral ingestion of the solution leads to severe gastrois testinal distress. Contact dermatitis is common with forme lin, and pure formaldehyde is suspected to be a carcinogam HC = 0 Glutaraldehyde Disinfectant Solution, USP. Guta aldehyde (Cidex, a 5-carbon dialdehyde) is used as a diiB solution for sterilization of equipment and instruments HM cannot be autoclaved. Commercial glutaraldehyde is subs lized in alkaline solution. The preparation actually consis of two components, glutaraldehyde and buffer, which mixed together immediately before use. The activated solk tion contains 2% glutaraldehyde buffered at pH 7,5 108 Stabilized glutaraldehyde solutions reuuin over 80% of he original activity 30 days after preparation," whereas the no stabilized alkaline solutions lose about 449% of their nctini after 15 days. At higher pH (>8.5), glutaraldehyde raphh polymerizes. Nonbuffered solutions of glutaraldehyde acidic, possibly because of an acidic proton on the cul hemiacetal form. The acidic solutions are stable but ad sporicidal activity. d HO q H á H “ A b á [0] : so A s=—> “AAA nt mm E a t- Glutaraldolyde Glutaraldehyde Homiacetal ss PHENOLS AND THEIR DERIVATIVES e já ir Phenol, USP. remains the standard to which the activity of nd most germicidal substances is compared The phenol coeffi- Iê elent is defined as the ratio of a dilution of a given test Roo duinfectant to the dilution of phenal that is required to kill k Mioihe same extent) a strain of Salmonella typhi under care- E “illy controlled time and temperature conditions. As an ex Ec ample, if the dilution of a test disinfectant is 1O-fold greater pe: am dhe dilution of phenol, the phenol coefficient às 10, Obviously, the phenol coefficient of phenol itself is 1,0. The phenol coefficient test has many druwbacks. Phenols and her germicides do not Kill microorganisms uniformly, so anations in the pheno! coefficient will oceur, Moreover, the onditions used to conduct the test are difficult to reproduce etlv, so high variability between different measurements “ud laboratórios is expected, Hence, the phenol coefficient Pay be unreliable. A number of phenols are actually more bactericidal than pino! itself, Substitution with alkyl, aryl, and halogen (es- emally in the para position) groups increases bactericidal Mivity, Straight-chain alky] groups enhance bactericidal ac- ly more than branched groups. Álkylated phenols and Rurcinols are less toxic than the parent compounds while ing bactericidal properties, Phenols denature bacterial ins at low concentrations, while lysis of bacterial cell emb occurs at higher concentrations Ner- recto mups “leie Ade: Phenol, USP. Phenol (carbolic acid) is a colorless to ud is pe pink crystalline material with a characteristic ““medici fthe Mal odor. [e is soluble to the extent of | par to 15 parts kr, very soluble in alcohol, and soluble in methano! and lo (phenyl sulicylate), A Roe bi Ed oin- zen, H Phenol exhibits germicidal activity (general protoplasmic Wh),1s caustic to skin, exerts local anesthetic effects, and Wi be diluted to avoid tissue destruction and dermatitis. Meloseph Lister introduced pheno! as a surgical antiseptic 7, amd dt às still used oceusionally as an antipruntic in plted calamine Jotion (0.1 to 1,0% concentrations). À Eioluios of phenol in glycerin has been used to cauterize il wounds. Phenol is almost obsolete as an antiseptic and h ant. fed Phenol, USP. Liquificd phenol is simply Elcontaining 10% water. The liquid form is convenient Wing phenolto a variety of pharmaceutical preparations Chapler 8 = Ant-infective Agents 221 because it can be measured and transferred easily. The water content, however. precludes its use in fixed oils or liquid petrolatum because the solution 15 not miscible with lipo- philic ointment bases. p-Chlorophenol. p-Chlorophenol is used in combina- tion with camphor in liquid petrolatum as an extemal anti- septic and amti-irmitant. The compound has a phenol coeffi- clent of about 4, p-Chlorophenol p-Chloro-m-xylenol. p-Chloro-m-xylenol (PC-MX; Metasep) is 4 nonimitating amtiseptic agent with broad-spec- trum antibacterial and antifungal properties. It is marketed in a 2% concentration as à shampoo. It has also been used topically for the treatment of tinea (rningworm) infections suchas athlete's fool! (tinca pedisj and jock iteh (linea cruris). Hy€ 2 : 79H A | p-Chloro-m-xylenol Pd CI CH Hexachlorophene, USP. Hexachlorophene, 2,2-meth- vlenebis(3 4,6-trichlorophenol); 27 -dihydroxvd,5,6,34,5", 6-hexachlorodiphenyImethane | (Gamophen, Surgicon, pHisoHex) às a white to light tan crystalline powder that is insoluble in water but is soluble in alcohol and most other organic solvents. A biphenol such as hexachlorophene will, in gencral, possess greater potency than a monophenol. In addition, as expected, the increased degree of chlorination of hexachlorophene increases its antiseptic potency further. CG] a Hexachlorophene | df A Fo E pa ci ÓH OM Hexachlorophene is easily adsorbed onto the skin and en- ters the sebaceous glands. Because of this, topical applica- ton elicits à prolonged antiseptic effect, even in low concen- trations. Hexachlorophene is used in concentrations of 2 to 3% in soaps, detergent creams, lotions, and shampoos for a variety of antiseptic uses. It is, in general, effective against Gram-positive bacteria, but many Gram-negative bacteria are resistant. The systemic toxicity of hexachlorophene in animais after oral and parenteral administration had been known for some time, but in the late 1960s and early 1970, reports of neuro- =xy1- phe- -nsa- only ESOT- cidal =xyd- Inted rties. es local sure «ntea- local tem =" Hexytresorcinol N ne Ex OXIDIZING AGENTS In general, the oxidizing agents that are of any valve as germicidal agents depend on their ability to liberate oxygen in the tissues. Many of these agents are inorganic com- pounds, including hydrogen peroxide, a number of metal peroxides, and sodium perborate. All of these react in the issues to generate oxygen and oxygen rúdicals, Other oxi- dbing agents, such as KMnO, denature proteins in microor- tanisms through a direct oxidation reaction, Osxidizing Ments are especially effective against anacrobic bacteria and em be used in cleansing contaminated wounds. The bubbles at form during the liberation of oxygen help to dislodge debris. The effectiveness of the oxidizing agents is some- what limited by their generally poor penetrability into in- fected tissues and organic matter. Additionally, the action af lhe oxidizers is typically transient, Carbamide Peroxide Topical Solution, USP. Carbam- le peroxide (Gly-Oxide) is a stable complex of urea and Indrogen peroxide. 1 has the molecular formula HsNCON- H2H:0,. The commercial preparation is a solution of 12,6% erbamide peroxide in anhydrous glycerin. When mixed ih water, hydrogen peroxide is liberated, Carbamide per- duide is used as both an antiseptic and disinfectant. The Peparation is especially effective in the treatment of oral leerations or in dental care. The oxygen bubbles that are Iberstcd remove debris. Hydrous Benzoyl Peroxide, USP. Hydrous benzoy] peroxide (Oxy-5, Oxy-10, Vanoxide) is a white granular powder, In lts pure powder form it is explosive, The com- pound is formulated with 30% water to make it safer to handle Benzoyl Peroxide “A Q 4 PK a j ho] (O) pas Compounded at 5 and 109% concentrations, benzoy! perox- We is boih keratolytic and keratogenic. It is used in the treat- mem of scne. Benzoyl peroxide induces proliferation of epi- Nell cells, leading 10 sloughing and repair." Chapter 8 2 Anti-infective Agents 223 HALOGEN-CONTAINING COMPOUNDS IODOPHORS Elemental iodine (14) às probably the oldest germicide still in use today. lt was listed in 1830 in USP-II as a tincture and a liniment. TJodine tincture (2% dodine in 50% alcohol with sodium iodide), strong todine solution (Lugol's solu- tion, 5% jodine in water with potassium iodide), and jodine solution (2% jodine in water with sodium iodide) are cur rently official preparations in the USP. The jodide salt às adimixed to increase the solubility of the todine and to reduce its volatility. lodine is one of the most effective and useful of the germicides. lt probably acts to inactivate proteins by iodination of aromatic residues (phenylalanvi and tyrosvl) and oxidation (sulfhydryl groups) Mixing with a number of nonionic and cationic surfactunts can solubilize todine Complexes form that retain the germicidal properties of the iodine while reducing its volatility and removing its irmitant properties." In some of the more active, nonionie surfactant complexes, it is estimated that approximately 809% of the dissolved iodine remains available in bacteriologically ac- tive form. These active complexes, both bactericidal and fungicidal, called iodophors, are Povidone-lodine USP. Povidone-iodine (Betadine, Is odine, PVP-jodine) às 4 charge-transfer complex of todine with the nonionic surfactant polymer polyvinylpyrrolidone (PVP). The complex is extremely water soluble and releases iodine very slowly, Hence, the preparation provides a non toxic, nonvolatile, and nonstaining form of iodine that is not irritating to the skin or to wounds. Approximately 10% of the iodine in the complex is bioavailable. Povidone-iodine is used us an aqueous solution for presurgical disinfecton of the incision site, can also be used to treat infected wounds and damage to the skin. and it 1s effective for local bacterial and fungal infections. A number of other forms ol PVP-odine are available, including acrosols, foums, oini- ments, surgical serubs, antiseptic guuze pads, sponges, mouthwashes, and a preparaton that disinfects whiripoo! baths and hot tubs | |] 4 du Cha sa CHLORINE-CONTAINING COMPOUNDS Chlorine and chlorine-releasing compounds have been used in the disinfection of water supplies for more than a century The discovery that hypochlorous acid (HCIO) 15 the active germicidal species that is formed when chlorine is dissolved in water led to the development and use of the first inorganic hypochlorite salts such as NaOCI and Ca(OC]. Later, or- ganic N-chloro compounds were developed as disinfectants These compounds release hypochlorous acid when dissólved in water, especially in the presence of acid. Two equally plausible mechanisms have been proposed for the germicidal action of hypochlorous acid: the chlorination of amide nitro » ci Povidone-lodine 224 gen atoms and the oxidation of sulfhydry] groups in proteins. Organic compounds that form stable N-chloro derivatives include amides, imides, and amidines. N-Chloro compounds slowly release HOCI in water. The antiseptic effect of these agents is optimal at around pH 7. Halazone, USP. p-DichlorosulfamoylIbenzoic acid is à white, crystalline, photosensitive compound with a faim chlorine odor. Haluzone is only slightly soluble in water at pH 7 but becomes very soluble in alkaline solutions. The sodium salt of halazone is used to disinfect drinking water HO, / ES li É Halazone prm== S—N Ó vm u dg Chloroazodin. NN-Dichlorodicarbonamidine . (Azo- chloramid) is a bright yellow crystalline solid wilh a faimt odor of chlorine. It is mostly insoluble in water and organic solvents and is unstable to light or heat, Chloroazodin will explode if heated above 155ºC. The compound is soluble enough in water to be used in very dilute solution to disinfect wounds, as packing for dental caries, and for lavage and imigation. A glyceryltriacetate solution is used as a wound dressing. The antiseptc action of chloroazodin is long last- ing because of its extremely slow reaction with water Chiloroazodin Oxychlorosene Sodium. Oxvehlorosene (Clorpactin) is à complex of the sodium salt of dodecylbenzenesulfonic acid and hypochlorous acid. The complex slowly releases hypochlorous acid in solution. Oxvehlorosene occurs as an amorphous white powder that has a faint odor of chlorine. lt combines the germicidal prop- erties of HOC] with the emulsifying. wetting, and keratolytic actions of an anionic detergent. The agent has a marked and rapid -cidal action against most microorganisms, including both Gram-positive and Gram-negative bacteria, molds, veasts, viruses, and spores. Oxychlorosene is used to treat SÃO Sea Rs a aà a CHs N OH 0 Ci E Wilson and Gisvold's Texthook of Organic Medicinal and Pharmacentical! Chemistry localized infecuons (especially when resistant organisms are present), to remove necrotic tissue from massive infections or radiation necrosis, to counteract odorous discharges, to act as am irritant, and to disinfect cysts and fistulas. Oxys chlorosene is marketed as a powder for reconstitution into a solution. A typical application uses a 0.1] to 01.5% concen- tration in water. Dilutions 0F 0.) to 0.2% are used in urology and ophthalmology. CATIONIC SURFACTANTS AML of the cationic surfactants are qualemary ammonium compounds (Table 8-3), As such, they are always jonized in water and exhibit surface-active properties, The compounds, with a polar head group and nonpolar hydrocarbon chain, form micelles by concentrating at the interface of immiscible solvents. The surface activity of these compounds, exempli- fied by lauryl tmethylammonium sulfato, results from two structural mojeties: (a) a cationic head group, which has a high affinity for water, and (b) a long hydrocarbon tail, which has an affinity for lipids and nonpolar solvents. Cos cr CHy(CHo)n—N>—CoHs Cos At the night concentration (the critical micelle concentra tion), lhe molecules concentrate at the interface between im miscible solvents, such as water and lipid, and water-in-oll or oil-in-water emulsions may be formed with the ammo mium head group in the water laver and the nonpolar hydro carbon chain associated with the oil phase. The syntheste and antimicrobial actions of the members of this class df compounds were first reported in 1908, but it was not until the pioneering work of Gerhard Domagk in 1935" that attene ton was directed to their usefulness as antiseptics, disinfe tants, and preservatives, The cationie surfactants exert a bactericidal action again a broad spectrum of Gram-positive and Gram-negative has teria. They are also active against several pathogenic specis vf fungi and protozoa. All spores resist Ihese agents, The mechanism of action probably involves dissolution of fé surfactant into the microbial cell membrane, destabilizatios and subsequent lysis, The surfactants may also interfere will enzymes associated with the cell membrane. The cationic surfactamis possess several other properties In addition to their broad-spectrum antimicrobial activity Oxychiorosene Sds rms cz do md mia a — 22-02» 226 HC Ni Paio q EN CH, CHs HC——EH, CHy tá so DE a e a We Ve Ha& | CHa Hy€ CHy 1 CH Benzethonium Chioride, USP. Benzyldimethyl[2-[2- [p-(1,1,3,3-tetramethyIbuty Dphenoxy jethoxy Jethyl Jammon- ium chloride (Phemerol chlornde) is a coloriess crystalline powder that is soluble in water, alcohol, and most organic solvents. The actions and uses of this agent are similar to those of benzalkonium chloride, lis used ata 1:750 concen- tration for skin antisepsis. For the irrigation of múcous mem- branes, à 1:5,000 solution às used, A 1:500 tincture is also available. Cetylpyridinium Chloride, USP. |-Hexadecylpyridin- ium chloride is a white powder that is very soluble in water and alcohol. In this compound, lhe quatermary nitrogen atom is a member of an aromatic pyridine ring. JT alia MS a / N N “ TN / = Nº ho! ( q No j N / HaC e, Ve str = ) NH DE ai = NH el rs, q oa ma A =. na NH NH Wilson and Ginvold's Texthook of Organic Medicinal and Pharmacentica! Chemistry ci Pra N CHs pe e a AAA “o u f ai Ê |. CHa The cetyl derivative is the most active of a series of alkyl- pyndinium compounds, ht is used as a gencral antisepio in concentrations of [100 to [1,000 for intact skin, |U for minor lacerations, and 1:2,/000 to 1:10,000 for the miga tion 0! mucous membranes. Cervlpyridinium chloride is ala available in the form of throat lozenges and a mouthywad ata 1:20,000 ditution. Chlorhexidine Gluconate, USP. 1,6-Di(4"-chloronhe nyldiguanidojhexane gluconate (Hibiclens) is the most db fective of a series of antibacterial biguanides originally de veloped in Great Britain. The antimicrobial properties of the biguanides were de covered as a result of earlier testing of these compounh us possible antúmalarial agents (Chaprer 9). Although de biguanides are technically not bisquaternary ammonim compounds and, therefore, should probably be classifim separately, they share many physical, chemical, and anti crobial properties with the cationic surfactants. The biguu nides are strongly basic, and they existas dications af plyse logical pH. In chlorhexidine, the positive charges E counterbalanced by gluconate anions (not shown). Like tionic surfactants, these undergo inactivation when mia pi bu h di im DY Om age bio inte vio] The dit teris Fest to th Gen as hu viole pow is so) in no vagin his; Fingw used . Worm alkyd- mc im 000 trriga- is also Ivash with amionic detergents and complex anions such as phos- phate, carbonate, and silicate, Chlorhexidine has broad-spectrum antibacterial activity but is notactive against acid-fast bacteria, spores, OF viruses. lthas been used for such topical uses as preoperative skin disinfection, wound irrigation, mouthwashes, and general anitization. Chlorhexidine is not absorbed through skin or mucous membranes and does not cause systemic toxicity DYES Organic dyes were used very extensively as anti-infective dgents before the discovery of the sulfonamides and the anti- Botics. A few cationic dyes still find limited use as anti- mlectives. These include the tripheny Imethane dyes gentian Hiolet and basic fuchsin and the thiazine dye meihylene blue The dyes form colorless leucobase forms under alkaline con- ditons, Cationic dyes are active against Gram-positive bac- dera and many fungi; Gram-negative bacteria are generally fesstant, The difference in susceptibility is probably related mw ihe cellular characteristics that underlie the Gram stain, Gentian Violet, USP. Gentian violet is variously known & hexamethyl-p-rosaniline chloride, crystal violet, methyl Mole, and methylrosaniline chloride. It occurs as à green powder or green flakes with a metallic sheen. The compound Esoluble in water (1:35) and alcohol (1:10) but insoluble innonpolar organic solvents, Gentian violet is available in aginal suppositories for the treatment of yeast infections. dis also used as a | to 3% solution for the treatment of igworm and yeast infections. Gentian violet has also been Hed orally as an anthelmintic for strongyloidiasis (thread- om) and oxyuriasis. Basic Fuchsin, USP. Basic fuchsin is a mixture of the Ilúrides of rosaniline and p-rosaniline. N exists as a green Chapter 8 = Anti-infective Agents 227 e dl Rm “So NHS im PN 7º EE s” | o Ns ó = [o) HaN CHs crystaltine powder with a metallic appearance. The com- pound is soluble in water and in alcohol but insoluble in ether. Basic fuchsin is a component of carbol-fuchsin solu- ton (Castellani's paint), which is used topically in the treat- ment of fungal infections, notably ningworm and athlete”s foot. Methylene Blue, USP. Methylene blue is 3,7-bis(di- methylamino)-phenazathionium chloride (Urised) The compound oceurs as a dark green crystalline powder with a metalhc appearance that is soluble in water (1:25) and alco- hol (1:65). ide T 7" NA ida = ci ne bit | | CHs HC dd | HO me a a a , | Na0oH lia -— ri a L | | Hei | Ss É + CÍ AN No HG CH; HC” CH; Hexamethyl-p-Rosaniline Leucobase Cloride Is- In re = ve 5. he LR bit ui ix- net is ivo nd re- ity hoy pyl ble or or ble mar oruanic solvents. Methylparaben às used us a sufeguard dgaiast mold growth. Ho” Propylparaben, NF. Propyl p-hydroxybenzoale, or pro pylparaben, occurs as a white crystalline powder that is alightly soluble in water butsoluble in most organic solvents. fis used as a preservative, primarily to retard yeast growth Propyiparaben sodium is a water-soluble sodium salt of the +phenol group. The pH of solutions of propylparaben so- dum 15 basic (pH — 10) Butyiparaben, NF. n-Butyl p-hvdroxybenzoate (butyl- pariben) occurs as a white crystalline powder that is spar- inelv soluble in water but very soluble in alcohols and in monpolar organic solvents. ad na | HO. Ha HO! “CH; “CH Ehylparaben, NF. Ethyl p-hydroxybenzoate (ethy Ipar- aben) is a white crystalline powder that is slightly soluble water but soluble in alcohol and most organic solvents Chlorobutanol, NF. ano! is 4 white crystalline solid with a camphor-like aroma. occurs in am anhydrous form and a hemibydrate form, of which sublime at room temperature and pressure. borobutano) às slightly soluble in water and soluble in koho! and in organic solvents. Ei A-Trichloro-2-methyI-2-pro- Chlorobutanol is used us à bacteriostatic agent in pharma- picals for injection, ophthalmie use, and intranasa! admin- on. Mis unstable when hented in aqueous solution, 229 Chapter 8 & Anti-infective Agents especially at pH =>7, Under these conditions, chlorobutano! undergoes elimination. Solutions of pH —S5 are reasonably stable at 25º€. Chlorobutanol is stable in oils and orgame solvents Ci dh, >] ci Hg Benzyl Alcohol, NF. Benzyl alcohol (phenylcarbinol, phenyImethano!) occurs naturally as the unesterificd form in oil of jasmine and in esters of acetic, cinnamic, and ben- goic acids in gum benzoim, storax resin, Peru balsam, tolu balsam, and some volatile oils. Tt is soluble in water and alcohol and às à clear liquid with an aromatic odor Benzyl alcohol is commonly used as à preservativo in vials of injectable drugs in concentrations of [to 4% in water or saline solution. Benzy] alcohol has the added advantage of having a local anesthetic action. His commonty used in oiniments and lotions as am antiseptic in the tresiment of various pruritic skin conditions Phenylethyl Alcohol, USP. Phenylethyl alcohol (2- phenylethanol, orange oil, rose oil, C,HsCH;CH>0H) is a clear liquid that is sparingly soluble in water (29%), Kt 00- curs naturally in rose oil and pine needle oil. dt is used pri- marily in perfumery Benzoic Acid, USP. Benzoic acid and its esters vccur naturally in gum benzoin and in Peru and tolu balsams. Tt is found as à white crystalline solid that slowly sublimes at room temperature and is steam distillable. ht is slightly solu- ble in water (0.35) bu more soluble in alcohol and in other polar organic solvents. It has a pK, 0f 4.2. Benzoie acid às used externally as am antiseptic in lotions, ointments, and mouthwashes. [tis more effective as u preservative in foods and pharmaceutical products at low pH (less than the pk). When used as a preservative in emulsions, its cffectiveness depends on both pH and distribution into the two phases. Sodium Benzoate, NF. Sodium benzoate às q white crystalline solid that is soluble in water and alcohol. It is used as a preservative in acidic liquid preparations in which benzoic acid is released. Sodium Propionate, USP. Sodium propionate pecurs as transparent colorless crystals that are soluble in wuter and alcohol. H is an elfechve antifungal agent thal is used as a preservative. Sodium propionate is most effective at low pH 230 Wilson and Gisvold's Texthook of Organic Medicinal and Pharmaceutical Chemistry Sorbic Acid, NF. 2.4-Hexadienoic acid is an effective antifungal preservative. It is sparingly soluble in water and has a pK, of 4.8. Sorbic acid is used to preserve syrups, elixirs, ointments, and lotions containing components such as sugars that support mold growth. jo) Hal SS oH Potassium Sorbate, NF. Potassium sorbate occurs as a white crystalline material that is soluble in water and alcohol. lt is used in the same way as sorbic acid when greater water solubility is required. Phenylmercuric Nitrate, NF. PhenyImercuric nitrate às a mixture of phenyImercuric nitrate and phenvimercuric hy- droxide. lt occurs as a white crystalline material that is spar- ingly soluble in water and slightly soluble in alcohol. It is used in concentrations of 1:10,000 to 1:50,000 to preserve injectable drugs against bacterial contamination. A disad- vantage to organomercurials is that their bacteriostatic effi- cacy is reduced in the presence of serum, o Pd + Phenylmercuric Acetate, NF. AcetoxyphenyImercury occurs as white prisms that are soluble in alcohol but only slightly soluble in water. It is used as a preservative. ANTIFUNGAL AGENTS General Introduction to Fungi: Medical Niycology The discovery thal some infectious diseases could be attrib- uted to fungi actually preceded the pionecring work of Pas- teur and Koch with pathogenic bacteria by several years. Two microbiologists, Schônlein and Gruby, studied the fun- gus Trichophyion schoenleimii im 1839. In that same year, Langenbeck reported the yeast-like microorganism responsi- ble for thrush (Candida albicans). Gruby isolated the fungus responsible for favus on potato slices, rubbed it on the head of a child, and produced the disease. Hence, he fulfilled Koch's postulates 40 years before they were formulated." In spite of its carlier beginnings, medical mycology was quickly overshadowed by bacteriology, and it has only re- cently begun to receive the serious attention that it deserves. This is perhaps attributable to the relatively bemign nature of the common mycoses, lhe rarity of the most serious ones, and the need for a morphological basis for differential identi- fication of these structurally complex forms. Cursory examination shows that fungal infections fall into two well-defined groups: the superficial and the deep-sested mycoses. IE The superficial mycoses are by far the most com- mon and are caused for the most part by a relatively homoge- neous group of fungi, the dermatophytes. These include the various forms of tinea, or ringworm, which are infections of the hair or hair follicles, the superficial infections of the intertriginous or flat areas of hairless skin, and infections of the nails. As a rule, these lesions are mild, superficial, and restricted, The causative microbes are specialized supros phytes with the unusual ability to digest keratin, They have their ultimate reservoir in the soil. Unlike the deep-sested) mycoses, however, they are frequently transmitted from ones host to another (e.g.. athlete”s foot). A species of yeast, Can dida, also produces à dermatophyte-like disease. Systemic Mycoses The deep-seated, systemic mycoses have a sporadic distribus tion,"” being common in some parts of the world and um known in other geographical areas. These diseases have d heterogencous etiology, Diseuses caused by the systemic om ganisms include histoplasmosis, sporotrichosis, blastomyéms sis, coccidioidomycosis, cryptococeosis, and paracoccikliok domycosis. The causative agents for these diseases are sodh inhabiting saprophytes with the ability to adapt to the inter nal environment of their host. These organisms share a com mon route of infecúon. Fungal spores are inhaled into the lung, and à mild, cold-like condition may result. This may be the only symptom. In the majonity of cases, disease! inapparent. In asymptomatic disease, diagnosis is often made serendipitously. Sensitization, which reflects present or pre vious experience with the organism, may be detected by skin test or other immunological procedure. The immunê system deals with these infections by walling them off mm by producing the giant cells that aré common in type IM hypersensitivities. X-ray examination or autopsy frequento reveals these lesions. As stated above, lhe causative org isms of the systemic infections are not typically trunsminal from one host to another, but infection by the organism pm an endemic area may be very common. Few infections de velop into the severe, deep, spreading, and often-fatal de case seen in some persons, If the infection is symptoms the clinical signs may be those of a mild, self-limited disc or the infection may become progressive, with severe symp toms, tissue and organ damage, and, frequently, death, Re covery from a deep-seated infection of this type is accompr mnied by an uncertain anamnestic immune response. Opportunistic Fungal Infections””- ” In recent years, because of overzealous use of antibaciem antibiotics, lhe use of immunosuppressive agents, cvioimE ins, irradiation, and steroids, a new category of sy mycoses has become prominent. These are the opportunisia fungal infections. There has been a precipitous rise im incidence of these diseases. The patient, as a result of di 232 Wilson and Gisvold's Texibook of Organic Medicinal and Pharmaceutical Chemistry TABLE 8-5 Clinical Types of Fungal Infection E a cases tialo thron coagi | cause num case | myco Type Disease State Causative Organism Superficial infections Tinea versicolor Pirvrosporum orbiculare Piedra Trichosporon cutanewni (velhite) Picdraia hórtae (black) Cutancous infeçions Ringworm of sealp, HAIRLESS skin, mails Dermatophytes, Microsporim, Trichopliyeon,; Epidermophayton Candidosis of skin, mucous membranes, Candida albicans and related forms nails; sometimes gençralized | Subcutaneous infections Chromomycosis Fonsecaca pedrosot and related forms | Top Mycotic mycetoma Allescheria boydit, Madurella mycetomi, cual | Colle Entemophithorompeosis Basidiobolus haptosporus worm Comieltobolus coronanas ment Histoplasmosis Histoplasmea capsulatum isa topic: the bz salicy functi Systemic infections Blastomyoosis Blastomvyoes dermuarttidis | Paracpecidioidomyeasis Paracoecidiotdes bresiliensis Coceidioidomyeosis Coccidioides inuníris | Cryptococensis Cryplococeus neoformeans | Sporotrichosis Sporothrix schenckil Aspergillosis Aspergillus fumigatias FATTN Adult called part o | used f | sebum | the se! cated. fact ha The lage of fungici tion. Mucormyeusis Mucor spp. Absidia spp. Rhizopus spp. Histoplasmosis dubonsit Histoplasme copsulatem var. duboisit Propia I | thatisr HO—P==0 q H HH HH HH HH HH H | ent in forms 4 also fu HH HH HH HA HH HH with a « t The sal odorles Figure 8-1 = Cholesterol embedded in a lipid bilayer Zinc Pr drous fr but only moistur propion, tape. Sodium caprylic oils. The soluble | Figure 8-2 = Ergesterol embedded in a lipidb layer toa vanety of chronic disease outcomes. Granuloma with eseution and fibrocaseous pulmonary granuloma are poten- fal quitomes of infection with Histoplasma capsulatum, and trombotic arteritis, a thrombosis characterized by a purulent poapulative necrosis and invasion of blood vessels, may be Eme during aspergillosis and mucormycosis, The large numbers of fungal species of many morphotypes, their dis- ese etiology, and the diversity of outcomes make medical mycology a complex ficld. Topical Agents for Dermatophytoses Collectively, the dermatophytoses are called tinea, or ring- “worm, Since these infections tend to be topical, their treat- “ment has been directed to surface areas of the skin. The skin “sa formidable barrier to drug penetration, and many of the mopical agents work best if an adjuvant is added that opens “e barrier function of the skin. Keratolytic agents such as mlicylic acid or other a-hydroxy compounds perform this function reasonably well, FATTY ACIDS ' Adults have an acidic, fatty substance in and on the skin “ealled sebum. Sebum functions as a natural antifungal agent, “pan of the innate immune system, Fatty acids have been sed for years with the idea that if a substance similar (6 debum could be applied to the infected arca, the effect of lhe sebum would be augmented and fungi could be eradi- auted. The application of farty acids or their salis does in H het have an antifungal effect, albeit a feeble one The higher-molecular-weight fatty acids have the advan- ge of having lower volatility, Salts of fatty acids are also apicidal and provide nonvolatile forms for topical applica- ton E Propionic Acid. Propionic acid is an antifungal agent utis nonirritating and nontoxie. After application, it is pres- et in perspiration in low concentration (0.01%). Salt XH ams with sodium, potassium, calcium, and ammonium are H fungicidal. Propionic acid às a clear, corrosive liguid eia characteristic odor. It is soluble in water and alcohol. salts are usually used because they are nonvolatile and ploriess Propionate. Zine propionale occurs as an anhy- s form and as a monohydrate. Itis very soluble in water only sparingly soluble in alcohol. The salt 15 unstable to moisture, forming zinc hydroxide and propionic acid. Zinc “a is used as a fungicide, particularly on adhesive Sodium Caprylate. Sodium caprylate is prepared from lic acid, which is à component of coconut and palm The salt precipitates as cream-colored granules that are le in water and sparingly soluble in alcohol. Na a [o] A E A Naa CH 233 Chapter 8 = Anti-infecrive Agents Sodium caprylate is used topically to treat superficial der- matomycoses caused by É. albicans and Trichophvyron, Mi- crosporum, and Epidermophyton spp. The sodium salt can be purchased in solution, powder, and ointment forms. Zinc Caprylate. Zinc caprylate às a fine white powder that is insoluble in water or alcohol. The compound is used as à topical fungicide. The saltis highly unstable to moisture. Undecylenic Acid, USP. 10-Undecenoic acid (De- senex, Cruex) has the following molecular formula: o a Sa = e The acid is obtained from the destructive distillation of castor oil, Undecylenic acid às a viscous yellow liquid, It is almost completely insoluble in water butis soluble in alcohol and most organic solvents Undecylenic acid is one of the better fatty acids for use as a fungicide, although cure rates are low. IH can be used in concentrations up to 109% im solutions, oiniments, pow- ders, and emulsions for topical administration. The prepara- tion should never be applied to mucous membranes because itis q severe iritant, Undecylenic acid has been one of the agents traditionally used for athlete's foot (tinea pedis). Cure rates are low, however. Triacetin, USP. Glyceryl triacetate (Enzactin, Funga- cetin) is a colorless, oily liquid with a slight odor and a bitter taste. The compound is soluble in water and miscible with alcohol and most orgame solvents CH, [a] Pas É dd o) The activity of triacetin is due to the acetic acid released by hydrolysis of the compound by esterases present in the skin. Acid release 1s a sel-limiting process because the ester- uses are inhibited below pH 4. Salicylic Acid and Resorcinol. Salicylic acid is a strong aromatic acid (pk, 2.5) with both antiseptic and keratolytic properties, It occurs as white, needle-like crystals or a fuffy crystalline powder, depending on how the compound was brought out of solution. Salicylic acid is onhy slightly soluble in water but is soluble in most organic solvents. The greater acidity of salicylic acid and its lower solubility in water compared with p-hydroxybenzoic acid are the consequence of intramolecular hydrogen bonding. 27 al for ta Es. mg 1% of the waier-soluble cihanolamine salt, Ciclopirox à believed to act on cell membranes of susceptible fungi at low concentrations to block the transport of amino acids into the cells. At higher concentrations, membrane integrity is tos, and cellular constituents leak out. Nucleoside Antifungais Flucytosine, USP.?º 5-Fluorocytosine, 5-FC, d-amino- Sluoro-2 | H-pyrimidinone, 2-hydroxy-d-amino-5-fluoro- pyrimidine (Ancobon). 5-Fluorocytosine is an orally active anifungal agent with a very narrow spectrum of activity, Tt indicated only for the treatment of serious systemic infec- tons caused by susceptible strains of Candida and Cryp- RNCOCCUS SPP. The mechanism of action of 5-Auorocytosine has been Mulied in detail and is presented in Figure 8-3, The drug enter the fungal cell by active transport on ATPases that Wemally transport pyrimidines. Once inside the cell, 5-fuor- ensine is deaminated in a reaction catalyzed by cytosine dkaminase to yield 5-Muorouracil (5-FU). 5-Fluorouracil is lhe active metabolite of the drug. 5-Fluorouracil enters into ways of both ribonucleotide and deoxyribonucleotide authesis. The fluororibonucleotide triphosphates are incor- puted into RNA, causing faulty RNA synthesis. This path- Win causes cell death. In the deoxyribonucleotide series, 5- Iuorodeoxyuridine monophosphate (F-dUMP) binds to S-methylenetetrahydrofolic acid, interrupting the one- eos pool substrate that feeds thymidylate synthesis. Hence, DNA synthesis is blocked. Resistance to 5-FC is very common, and il occurs al à Chapter 8 & Anti-infective Agents 235 number of levels. À main one is at the step in which the drug is transported into the fungal cell. The transport system simply becomes impermeable to 5-FC. The cytosine deami- nase step is another point at which resistance occurs, and the UMP pyrophosphorylase reaction is a third point at which fungal cells can become resistant. Regardless of which of these mechanisms operates, fungal resistance de- velops rapidly and completely when 5-FC is administered. Alter a few dosing intervals the drug is essentially useless, One strategy used to decrease resistance and to prolong the effect of 5-FC is to administer it with the polyene antibiotic amphotericin B. The antibiotic creates holes in the fungal cell membrane, bypassing the transport step and allowing 5-FC to enter. Additionally, a lower dose of 5-FC can be used, preventing resistance by other mechanisms for a longer period Antifungal Antibiotics”: 2º The antifungal antibiotics make up an important group of amifungal agents, AI of the antibiotics are marked by their complexity. There are two classes: the polyenes, which con- tain a large number of agents with only a few being useful. and griscofulvin (one member of the class). POLYENES A number of structurally complex antifungal antibiotics have been isolated from soil bacteria of the genus Strepromvces The compounds are similar, in that they contain a system of conjugated double bonds in macrocyclic lactone rings. They differ from the erythromycin-type structures (macrolides; see Chapter 10), in that they are larger and contain the conju- gated -ene system of double bonds. Hence, they are called the polvene antibiotics. The clinically useful polyenes fall into two groupings on the basis of the size of the macrolide ring. The 26-membered-ring polyenes, such as natamycin tpimaricin), form one group, while the 38-membered ma- crocyeles, such as amphotericin B and nystatin, form the other group, Also common to the polyenes are (a) à series 8-3 » Mechanism of action of rocytosine 5,10-Methylene-THF SFUMP — SFUDP —= 5-FUTP - RNA h A = SFU SFOUMP —» S.FdUDP — 5-FdUTP Inhibitory Complex E | > qse ) — Si 7,8-DHF of hydroxyl groups on the acid-derived portion of the ring and (b) a glycosidically linked deoxvaminohexose called mycosaminte.The number of double bonds in the macrocychie ring differs also. Natamycin, the smallest macrocycle, is à pentaene; nystatin is à hexaene; and amphotericin B is a heptaene. The polyenes have no activity against bacteria, nickensia, or viruses, but they are highly potent, broad-spectrum anti- fungal agents. They do have activity against certain pro- tozoa, such as Leishmania spp. They are effective against pathogenic yeasts, molds, and dermatophytes. Low concen- trations of the polyenes in vitro will inhibit Candida spp., Coccidioides immitis, Cryproceceus neoformans, Histo- plasma capsulatum, Blastomyces dermatitidis, Mucor mucedo, Aspergillus fumigarus, Cephalosporium spp. and Fusarium spp. The use of the polyenes for the treatment of systemic infections às limited by the toxicities of the drugs, their low water solubilíties, and their poor chemical stabilities. Am- photencin B, the only polyene useful for the treatment of serious systemic infections, must be solubilized with a deter- gent. The other polyenes are indicated only as topical agents for superficial fungal infections. The mechanism of action of the polyenes has been studied in some detail. Because of their three-dimensional shape, a barrel-like nonpolar structure capped by a polar group (the sugar), lhey penetrate the fungal cell membrane, acting as “false membrane components," and bind closely with er- gosterol, causing membrane disruption, cessation of mem- brane enzyme activity, and loss of cellular constituents, espe- cially potassium ions. In fact, the first observable in vitro reaction upon treating a fungal culture with amphotericin B is lhe loss of potassium tons. The drug is fungistatic at low concentrations and fungicidal at high concentrations. This sugpests thal at low concentrations the polyenes bind to a membrane-bound enzyme component, such as an ATPase. Amphotericin B, USP. The isolation of amphotericin B (Fungizone) was reported in 1956 by Gold et al?” The compound was purified from the fermentation beer of a soil culture of the actinomycete Strepromyces nodosus, which was isolated in Venezuela. The first isolate from the strepto- mycete was a separable mixture of two compounds, desig- nated amphotericins A and B. In test cultures, compound B proved to be more active, and this is the one used clinically *º The structure and absolute stersochemistry are as shown. 236 Wilson and Gisvold's Texthook of Organic Medicinal and Pharmaceutical Chemistry Amphotericin B is believed to interact with membrane sterols (ergosterol in fungi) to produce an aggregate that forms a transmembrane channel, Intermolecular hydrogen bonding imteractions among hydroxyl, carboxyl, and amino groups stabilize the channel in its open form. destroying symport activity and allowing the cytoplasmic contents to leak out. The effect is similar with cholesterol. This explaims the toxicity in human patients, As the name implies, ampho- tenicin B is an amphoteric substance, with a primary amino group attached to the mycosamine ring and a carboxyl group on the macrocycle. The compound forms deep yellow crys tals that are sparingly soluble in organic solvents but insolw- ble in water. Although amphotericin B forms salts with both acids and bases, the salts are only slightly soluble in water (0.1 mg/ml) and, hence, cannot be used systemically. To create à parenteral dosage form, amphotencin B is stabilized as à buffered colloidal dispersion in micelles with soditm deoxycholate.* The barrel-like structure of the antibiotic develops interactive forces with the micellar components, creating a soluble dispersion. The preparation is light, heat salt, and detergent sensitive. Parenteral amphotencin B is indicated for the treatment of severe, potentially life-threatening fungal infections, He cluding disseminated forms of coccidioidomyeosis and hi toplasmosis, sporotrichosis, North American blastomycosis) cryptococcosis, mucormycosis, and aspergillosis. The usefulness of amphotericin B is limited by a high) prevalence of adverse reactions. Neurly 80% of patente treated wilh amphotericin B develop nephrotoxicity. Fever headache, anorexia, gastrointestinal distress, malaise, an muscle and joint pain are common. Pain at the site of injes ton and thrombophlebitis are frequent complications dl intravenous administration. The drug must never be ab ministered intramuscularly. The hemolytic activity of am photericin B may be à consequence of its ability to leu cholesterol from erythrocyte cell membranes. For fungal infections of the central nervous system é (e.g. Cryptocoecosis), amphotericin B is mixed with brospinal Aluid (CSF) that is obtained from a spinal tap. solution of amphotericin B is then reinjected through fe tap. For severe infections, this procedure may need to repeated many times. Amphotericin B for injection is supplied as a sterile | ilized cake or powder containing 50 mg of antibiotic 
