Zinc pyrithione in alcohol-based products for skin antisepsis: Persistence of antimicrobial effects
2005; Elsevier BV; Volume: 33; Issue: 1 Linguagem: Inglês
10.1016/j.ajic.2004.07.012
ISSN1527-3296
AutoresEugene Guthery, Lawton A. Seal, Edward L. Anderson,
Tópico(s)Medical Device Sterilization and Disinfection
ResumoAlcohol-based products for skin antisepsis have a long history of safety and efficacy in the United States and abroad. However, alcohol alone lacks the required antimicrobial persistence to provide for the sustained periods of skin antisepsis desired in the clinical environment. Therefore, alcohol-based products must have a preservative agent such as iodine/iodophor compounds, chlorhexidine gluconate, or zinc pyrithione, to extend its antimicrobial effects. Iodine, iodophors, and chlorhexidine gluconate are well-characterized antimicrobials and preservatives. The thrust of our effort was to examine the characteristics of the lesser-known zinc pyrithione and to evaluate its utility as a preservative in the formulation of alcohol-based products for skin antisepsis. This work includes a literature review of current zinc pyrithione applications in drugs and cosmetics, a safety and toxicity evaluation, consideration of the proposed mechanisms of antimicrobial action, in vitro and in vivo efficacy data, and a discussion of the mechanisms that confer the desired antimicrobial persistence. In addition, alcohol-based, zinc pyrithione-preserved, commercially available products of skin antisepsis are compared with other commercially available antimicrobials used for skin antisepsis and with additional alcohol-based products with different preservatives. The authors' conclusion is that zinc pyrithione is not only a safe and effective antimicrobial but that its use in certain alcohol-based formulations results in antimicrobial efficacy exceeding that of iodine and chlorhexidine gluconate. Alcohol-based products for skin antisepsis have a long history of safety and efficacy in the United States and abroad. However, alcohol alone lacks the required antimicrobial persistence to provide for the sustained periods of skin antisepsis desired in the clinical environment. Therefore, alcohol-based products must have a preservative agent such as iodine/iodophor compounds, chlorhexidine gluconate, or zinc pyrithione, to extend its antimicrobial effects. Iodine, iodophors, and chlorhexidine gluconate are well-characterized antimicrobials and preservatives. The thrust of our effort was to examine the characteristics of the lesser-known zinc pyrithione and to evaluate its utility as a preservative in the formulation of alcohol-based products for skin antisepsis. This work includes a literature review of current zinc pyrithione applications in drugs and cosmetics, a safety and toxicity evaluation, consideration of the proposed mechanisms of antimicrobial action, in vitro and in vivo efficacy data, and a discussion of the mechanisms that confer the desired antimicrobial persistence. In addition, alcohol-based, zinc pyrithione-preserved, commercially available products of skin antisepsis are compared with other commercially available antimicrobials used for skin antisepsis and with additional alcohol-based products with different preservatives. The authors' conclusion is that zinc pyrithione is not only a safe and effective antimicrobial but that its use in certain alcohol-based formulations results in antimicrobial efficacy exceeding that of iodine and chlorhexidine gluconate. Alcohol-based products for skin antisepsis have enjoyed a long history of safety and efficacy in the United States, as well as in many countries abroad. Examples of use include surgical scrubs, health care personnel handwashes, patient preoperative skin preparations, injection/catheter site preparations, preoperative antiseptic shower solutions, hand rubs/sanitizers, and tinctures such as those of iodine.1Hobson D.W. Woller W. Anderson L. Guthery E. Development and evaluation of a new alcohol-based surgical hand scrub formulation with persistent antimicrobial characteristics and brushless application.Am J Infect Control. 1998; 26: 507-512Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 2Hobson D.W. Seal D.S. Antimicrobial body washes.in: Paulson D.S. Handbook of topical antimicrobials: industrial applications in consumer products and pharmaceuticals. Marcel Dekker, New York2003: 221-240Google Scholar, 3Hobson D.W. Seal L.A. Brushless surgical scrubbing and handwashing.in: Paulson D.S. Handbook of topical antimicrobials: industrial applications in consumer products and pharmaceuticals. Marcel Dekker, New York2003: 167-180Google Scholar, 4Food and Drug Administration. 21 CFR Parts 333 and 369. Tentative final monograph for health-care antiseptic drug products: proposed rule. Federal Regulation Part III. (June 17, 1994). p. 31402-52.Google Scholar, 5Seal L. Paul-Cheadle D. A systems approach to preoperative surgical patient skin preparation.Am J Infect Control. 2004; 32: 57-62Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Of the antimicrobials routinely used for skin antisepsis (alcohols, chlorhexidine gluconate [CHG], iodine/iodophors, parachlorometaxylenol [PCMX], triclosan, and quaternary ammonium compounds), alcohols are by far the fastest acting and most efficacious.6Ayliffe G.A. Surgical scrub and skin disinfection.Am J Infect Control. 1984; 5: 23-27Google Scholar, 7Larson E.L. APIC guidelines for infection control practice: guideline for use of topical antimicrobial agents.Am J Infect Control. 1988; 16: 253-266Abstract Full Text PDF PubMed Scopus (180) Google Scholar, 8Rotter M.L. Alcohols for antisepsis of hands and skin.in: Ascenzi J.M. Handbook of disinfectants and antiseptics. Marcel Dekker, New York1996: 177-233Google Scholar, 9Boyce J.M. Pittet D. Guideline for hand hygiene in the health care setting.Am J Infect Control. 2002; 30: S1-S46Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar, 10McDonnell G. Russell A.D. Antiseptics and disinfectants: activity, action, and resistance.Clin Microbiol Rev. 1999; 12: 147-179Crossref PubMed Google Scholar, 11Walker E.B. Quaternary ammonium compounds.in: Paulson D. Handbook of topical antimicrobials: industrial applications in consumer products and pharmaceuticals. Marcel Dekker, New York2003: 99-116Google Scholar Almost exclusively, the short-chain, aliphatic alcohols—ethanol, isopropanol, and, in Europe, n-propanol—are used for skin and hand antisepsis. They have excellent activity against bacteria, fungi, and enveloped (and some nonenveloped) viruses.10McDonnell G. Russell A.D. Antiseptics and disinfectants: activity, action, and resistance.Clin Microbiol Rev. 1999; 12: 147-179Crossref PubMed Google Scholar Alcohols may be used either alone or in combination with other antimicrobials to increase the efficacy and confer substantivity (persistence). The Centers for Disease Control (CDC) and Prevention in its "Guideline for Prevention of Surgical Site Infection, 1999" acknowledged the utility of alcohol-based products in preoperative hand/forearm antisepsis and preoperative skin preparation.12Mangram A.J. Horan T.C. Pearson M.L. Silver L.C. Jarvis W.R. Guideline for the prevention of surgical site infection.Infect Control Hosp Epidemiol. 1999; 20: 247-278Crossref Scopus (1754) Google Scholar In late 2002, the recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force were published.9Boyce J.M. Pittet D. Guideline for hand hygiene in the health care setting.Am J Infect Control. 2002; 30: S1-S46Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar This report recognized the speed and broad antimicrobial spectrum of alcohol, codified uses for alcohol-based products in skin antisepsis practices, and noted the lack of antimicrobial persistence associated with alcohol when used alone. The FDA also noted alcohol's lack of antimicrobial persistence; however, it allows a preservative agent to be incorporated into the vehicle (defined as the product without the active ingredient) to provide for the persistent antimicrobial effect necessary to sustain a reduction in the number of bacteria for 6 hours postapplication.4Food and Drug Administration. 21 CFR Parts 333 and 369. Tentative final monograph for health-care antiseptic drug products: proposed rule. Federal Regulation Part III. (June 17, 1994). p. 31402-52.Google Scholar The preservative supplies the required persistent antimicrobial activity for these formulations to meet or exceed the established agency efficacy. Preservative systems in some of the currently marketed alcohol-based products for skin antisepsis include iodine/iodophors compounds, CHG, and zinc pyrithione (ZPT). Although much has been written about the antimicrobial effects and the preservative potential of iodine and CHG, little has been published regarding these characteristics as attributes of ZPT. Therefore, this article includes a brief review of the published literature related to the development, safety, efficacy, and clinical utility of ZPT and evaluating its merits as a preservative for alcohol-based products of skin antisepsis. The natural antibiotic aspergillic acid contains a cyclic hydroxamic acid functional group in a pyrazine nucleus. Attempts to develop synthetic methods for introducing heterocyclic rings into the hydroxamic acid group present in aspergillic acid led in 1950 to the preparation for N-hydroxy-2-pyridinethione (HPT). The synthesis was achieved by conversion of a 2-pyridyl ether to its N-oxide, followed by dealkylation.13Lott W.A. Shaw E. Analogs of aspergillic acid. II. Various antibacterial heterocyclic hydroxamic acids.J Am Chem Soc. January 1949; 71: 70-73Crossref PubMed Scopus (39) Google Scholar Reaction of 2-bromopyridine-N-oxide with thiourea forms 2-pyridyl-N-oxide-isothiourea hydrobromide and, followed by treatment with aqueous sodium carbonate, produces N-hydroxy-2-pyridinethione (HPT).14Shaw E. Bernstein J. Losee K. Lott W.A. Analogs of aspergillic acid. IV. Substituted 2-bromopyridine-N-oxides and their conversion to cyclic thiohydroxamic acids.J Am Chem Soc. 1950; 72: 4362-4364Crossref Scopus (102) Google Scholar This compound was shown to have potent antimicrobial properties. In vitro, 1 μg HPT would inhibit Staphylococcus aureus.15United States Patent 2,734,903.Google Scholar Thus, this synthetic analog was 30 times more potent as an antimicrobial than the native aspergillic acid. Later, HPT was shown to have extremely potent activity against gram-positive and gram-negative bacterial species as well as strong activity against yeasts and fungi: eg, Aspergillus, Trichophyton species, Candida albicans, and Cryptococcus species.16Pansy F.E. Stander H. Koerber W.L. Donovick R. In vitro studies with 1-hydroxy-2 (1H) pyridinethione.Proc Soc Exp Biol Med. 1953; 82: 122-124Crossref PubMed Scopus (13) Google Scholar Cox, in the mid-1950s, reviewed the uses of pyridine-N-oxides and noted that the mercapto derivatives formed quaternary ammonium compounds or heavy metal salts, which were described as effective fungicides and antibacterial agents and suggested their uses in pharmaceutic preparations.17Cox AJ. Pyridine N-oxides and their uses. Manufacturing Chemist October 1957.Google Scholar As a zinc chelate of HPT, ZPT exists in the monomeric form as 2 pyridine rings bound to a central zinc atom by bonds between the zinc atom and the sulphur and oxygen molecules of the pyridine ring structures.18Nelson J.D. Hyde G.A. Sodium and zinc omadine as cosmetic preservatives.Cosmetics and Toiletries. 1981; 96: 87-90Google Scholar, 19Barnett B.L. Kretschmar H.C. Hartman F.A. Structural characterization of Bis (n-oxopyridine-2-thionato) zinc (II).Inorg Chem. 1977; 16: 1834-1838Crossref Scopus (101) Google Scholar ZPT is practically insoluble in water, organic solvents, or surfactants—a property that can be problematical when formulating with the compound.20Olin Chemicals product data: Zinc Omadine and Sodium Omadine antimicrobial agents; 1993.Google Scholar The structure of ZPT is presented in Fig 1. ZPT has a long history of numerous medical, scientific, and industrial applications. The compound has a master file registered with the FDA. Of some 1350 compounds screened, ZPT was one of the most active antifungal and antibacterial compounds examined.20Olin Chemicals product data: Zinc Omadine and Sodium Omadine antimicrobial agents; 1993.Google Scholar, 21Snyder F.H. Buehler E.V. Winek C.L. Safety evaluation of zinc 2-pyridinethiol 1-oxide in a shampoo formulation.Toxicol Appl Pharmacol. 1965; 7: 425-437Crossref PubMed Scopus (51) Google Scholar For example, Pityrosporum ovale is thought to play a pathogenic role in skin conditions such as seborrheic dermatitis and dandruff.22Van Cutsem J. Gerven F.V. Fransen J. Schrooten P. Janssen P.A.J. The in vitro antifungal activity of ketoconazole, zinc pyrithione, and selenium sulfide against Pityrosporum and their efficacy as a shampoo in the treatment of experimental pityrosporosis in guinea pigs.J Am Acad Dermatol. 1990; 22: 993-998Abstract Full Text PDF PubMed Scopus (85) Google Scholar This led one well-known pharmaceutic company to conduct safety evaluations of ZPT in a shampoo formulation.21Snyder F.H. Buehler E.V. Winek C.L. Safety evaluation of zinc 2-pyridinethiol 1-oxide in a shampoo formulation.Toxicol Appl Pharmacol. 1965; 7: 425-437Crossref PubMed Scopus (51) Google Scholar The result was an antidandruff product, Head & Shoulders (Procter & Gamble, Cincinnati, Ohio) that is currently sold over-the-counter with 1.0% ZPT as the active ingredient. Presently, the FDA acknowledges the efficacy of ZPT in the treatment of dandruff and seborrheic dermatitis.23Food and Drug Administration. 21 CFR Parts 348 and 358. Dandruff, seborrheic dermatitis, and psoriasis drug products for over-the-counter human use: tentative final monograph. Federal Regulation (July 30, 1986).Google Scholar, 24Opdyke D.L. Burnett C.M. Brauer E.W. Anti-seborrhoeic qualities of zinc pyrithione in a cream vehicle. II. Safety evaluation.Food Cosmetic Toxicol. 1967; 5: 321-331Crossref PubMed Scopus (23) Google Scholar The ZPT-based shampoo has shown to be effective in treating tinea versicolor,25Faergemann J. Fredriksson T. An open trial of the effect of a zinc pyrithione shampoo in tinea versicolor.Dermatology. 1980; 25: 667-668Google Scholar and it is highly effective for psoriasis of the scalp.26Crutchfield C.E. Lewis E.J. Zelickson B.D. The highly effective use of topical zinc pyrithione in the treatment of psoriasis.Dermatol Online J. 1997; 3: 3-5PubMed Google Scholar Cosmetic preservation has been a frequent use of ZPT for many years.18Nelson J.D. Hyde G.A. Sodium and zinc omadine as cosmetic preservatives.Cosmetics and Toiletries. 1981; 96: 87-90Google Scholar ZPT has proven to be effective, even at low concentrations, against both gram-positive and gram-negative bacteria and fungi. It is compatible with most commonly used cosmetic ingredients; has a good toxicity profile for this type of application; and can be safely used to minimize discoloration, off-odors, and emulsion breaks because of microorganisms. ZPT helps to prevent spoilage of cosmetics because of microbial contamination during use, is found in GoJo Hand Cleaner products (GOJO Industries, Inc. Akron, Ohio), and in over-the-counter antimicrobials such as Lanacane (Combe, Inc.,White Plains, NY).27Olin Chemicals product data: Omadine antimicrobials for cosmetic preservation: combine broad spectrum antimicrobial activity and wide compatibility with cosmetic ingredients; 1993.Google Scholar Finally, ZPT has also been used in commercial laundries for inhibiting mold growth on fabrics.20Olin Chemicals product data: Zinc Omadine and Sodium Omadine antimicrobial agents; 1993.Google Scholar In addition to a 50-year product history, the safety and toxicity of ZPT has been formally evaluated in animal models and by in vitro and human in vivo studies. When ZPT was applied to intact skin of monkeys with surfactants, the absorption was only 0.20% of the amount applied.28Gibson W.B. Calvin G. Percutaneous absorption of zinc pyridinethione in monkeys.Toxicol Appl Pharmacol. 1978; 43: 425-437Crossref PubMed Scopus (14) Google Scholar Concentrations of ZPT in the blood stream following topical application are below the threshold of detection. The absorbed dose would likely be further reduced in humans by the fact that hand skin has a lower permeability than scalp skin.29Parran J.J. Deposition on the skin of particles of antimicrobial agents from detergent bases.J Invest Dermatol. 1965; 45: 86-88Crossref PubMed Scopus (9) Google Scholar, 30Wedig J.H. Maibach H.I. Percutaneous penetration of dipyrithione in man: effect of skin color (race).J Am Acad Dermatol. 1981; 5: 433-438Abstract Full Text PDF PubMed Scopus (47) Google Scholar ZPT does not induce primary skin irritation or sensitization in human skin.30Wedig J.H. Maibach H.I. Percutaneous penetration of dipyrithione in man: effect of skin color (race).J Am Acad Dermatol. 1981; 5: 433-438Abstract Full Text PDF PubMed Scopus (47) Google Scholar Finally, when a 2.0% suspension of ZPT was instilled into the conjunctival sacs of the eyes of 6 albino rabbits, ZPT produced only slight irritation of the conjunctival vessels, which lasted 3 days, but no corneal opacities were observed.31Black J.G. Howes D. Toxicity of pyrithiones.Clin Toxicol. 1978; 31: 1-26Crossref Scopus (14) Google Scholar Ocular toxicity is well known to be associated with other preservative systems such as CHG, and skin irritation and sensitization with iodine and CHG-based products has been documented.10McDonnell G. Russell A.D. Antiseptics and disinfectants: activity, action, and resistance.Clin Microbiol Rev. 1999; 12: 147-179Crossref PubMed Google Scholar, 32Paulson D.S. Current topical antimicrobials.in: Paulson D.S. Topical antimicrobial testing and evaluation. Marcel Dekker, New York1999: 53-59Google Scholar, 33Paulson D.S. Chlorhexidine gluconate.in: Paulson D.S. Handbook of topical antimicrobials: industrial applications in consumer products and pharmaceuticals. Marcel Dekker, New York2003: 117-122Google Scholar, 34Rosenberg A. Alatary S.D. Peterson A.F. Safety and efficacy of the antiseptic chlorhexidine gluconate.Surg Gynecol Obstet. 1976; 143: 789-792PubMed Google Scholar The available data on the mode of antimicrobial action suggest that ZPT is membrane active, as indicated by the inhibition of uptake of several unrelated substrates in both bacteria and fungi35Chandler C.J. Segel I.H. Mechanism of the antibacterial action of pyrithione: effects on membrane transport, ATP levels and protein synthesis.Antimicrob Agents Chemother. 1978; 14: 60-68Crossref PubMed Scopus (87) Google Scholar, 36Friedman S.A. Studies on the mode of antimicrobial action of metal complexing thiohydroxamic acids against Escherichia coli. University of San Diego, San Diego (CA)1981Google Scholar, 37Khattar M.M. Salt W.G. Stretton J.R. The influence of pyrithione on the growth of microorganisms.J Appl Bacteriol. 1988; 64: 265-272Crossref PubMed Scopus (23) Google Scholar, 38Khattar M.M. Salt W.G. Stretton J.R. Growth and survival of Klebsiella pneumoniae in the presence of pyrithione.J Chromatogr. 1989; 1: 224-226Google Scholar and the observed depolarization of the transmembrane potential in Neurospora crassa.39Ermolayeva E. Sanders D. Mechanism of pyrithione-induced membrane depolarization in Neurospora crassa.Appl Environ Microbiol. 1995; 61: 33-90Google Scholar The effects of an antimicrobial agent on substrate transport and related metabolism may be used as indicators of the membrane activity of the test agent.40Gilbert P. Barber J. Ford J. Interaction of biocides with model membranes and isolated membrane fragments.in: Denyer S.P. Hugo W.B. Mechanism of action of chemical biocides. Blackwell Scientific Publications, Oxford1991: 55-170Google Scholar In turn, these effects may be reflected as a reduction in intracellular ATP levels.41Harold F.M. Conservation and transformation of energy by bacterial membranes.Bacteriol Rev. 1972; 36: 172-320Crossref PubMed Google Scholar ZPT is a poor inhibitor of substrate catabolism. Subinhibitory concentrations of the biocide greatly reduce intracellular ATP levels in both Escherichia coli and Pseudomonas aeruginosa. This is thought to be due to the action of ZPT on the gram-negative bacterial membrane.42Dinning A.J. Al-Adham I.S.I. Eastwood I.M. Austin P. Collier P.J. Pyrithione biocides as inhibitors of bacterial ATP synthesis.J Appl Microbiol. 1998; 85: 141-146Crossref PubMed Scopus (63) Google Scholar Further investigation of the action at the membrane suggests that ZPT forms stable interactions with the bacterial membrane phospholipid phosphatidylethanolamine. This may result in the disaggregation of the phospholipid head structure at the outer membrane and may also indicate chelation of phosphorylethanolamine head groups from the core structure of the external lipopolysaccharide. This would further disrupt the membrane.43Dinning A.J. Al-Adham I.S.I. Austin P. Charlton M. Collier P.J. Pyrithione biocide interactions with bacterial phospholipid head groups.J Appl Microbiol. 1998; 85: 132-140Crossref PubMed Scopus (45) Google Scholar In addition, current-voltage analysis demonstrates that the depolarization of the bacterial membrane is accompanied by a decrease in membrane electrical conductance in a manner consistent with inhibition of the primary proton pump and consistent with a mode of action of ZPT on plasma membrane ion channels. Therefore, ZPT inhibits membrane transport via a direct or indirect effect on the primary proton pump that energizes transport, and the site of action of ZPT is likely to be intracellular rather than extracellular.42Dinning A.J. Al-Adham I.S.I. Eastwood I.M. Austin P. Collier P.J. Pyrithione biocides as inhibitors of bacterial ATP synthesis.J Appl Microbiol. 1998; 85: 141-146Crossref PubMed Scopus (63) Google Scholar Other studies on the mode of action of pyridine-N-oxides has demonstrated their potent bactericidal activity to be linked to their ability to chelate: ie, to form cyclic complexes with the ions of heavy metals.44Albert A. Rees C.W. Tomlinson A.J.H. The influence of chemical constitution on anti-bacterial activity. Part VIII. 2-Mercaptopyridine-N-oxide, and some general observations on metal binding agents.Br J Exp Pathol. 1956; 37: 500-511PubMed Google Scholar Additional investigations reported by Hyde and Nelson have suggested that other mechanisms may be applicable.18Nelson J.D. Hyde G.A. Sodium and zinc omadine as cosmetic preservatives.Cosmetics and Toiletries. 1981; 96: 87-90Google Scholar The authors propose that the pyrithione is an antimetabolite of the pyridine derivative pyridoxal and suggest that the activity of ZPT may be analogous to the inhibition of microbial folate production by sulfa drugs. Finally, dipole structure of the molecule creates a pseudoquaternary ammonium group, providing yet another potential mode of antimicrobial action for ZPT. Multiple mechanisms appear to be at work, suggesting that antimicrobial resistance is unlikely to develop. Reports of the development of antimicrobial resistance are not readily available, and further detailed investigation may be appropriate. The in vitro composite data in Table 1 document the broad spectrum of antimicrobial activity of ZPT as well as quantify the inhibitory capacity of this compound when tested against numerous bacteria, yeast, and fungi (Personal communications from Ron Jones, M. D., Professor and Director, Division of Medical Microbiology, Director, Anti-Infectives Research Center and Special Microbiology Laboratories, Department of Pathology, University of Iowa College of Medicine, Iowa City, Ia, January 1993).20Olin Chemicals product data: Zinc Omadine and Sodium Omadine antimicrobial agents; 1993.Google Scholar, 22Van Cutsem J. Gerven F.V. Fransen J. Schrooten P. Janssen P.A.J. The in vitro antifungal activity of ketoconazole, zinc pyrithione, and selenium sulfide against Pityrosporum and their efficacy as a shampoo in the treatment of experimental pityrosporosis in guinea pigs.J Am Acad Dermatol. 1990; 22: 993-998Abstract Full Text PDF PubMed Scopus (85) Google Scholar, 27Olin Chemicals product data: Omadine antimicrobials for cosmetic preservation: combine broad spectrum antimicrobial activity and wide compatibility with cosmetic ingredients; 1993.Google Scholar, 42Dinning A.J. Al-Adham I.S.I. Eastwood I.M. Austin P. Collier P.J. Pyrithione biocides as inhibitors of bacterial ATP synthesis.J Appl Microbiol. 1998; 85: 141-146Crossref PubMed Scopus (63) Google Scholar The antimicrobial range of ZPT is sufficient to include many pathogenic, opportunistic, and saprophytic organisms. Inhibitory concentrations are often achieved at a level of 40 μg/mL (40 ppm) or less for numerous pathogenic species.Table 1Mean minimal inhibitory concentration of ZPT for selected bacteria, yeast, and fungi∗Expressed as composite data from various sources.20,22,27,4253Organism testedNumber of strains/strain identificationMIC 50 in ppmMIC 90 in ppmStaphylococcus aureus10 strains1010CNS†Includes S epidermidis (4 strains), S hominis (1 strain), S saprophyticus (3 strains), and S simulans (2 strains).10 strains1010Enterococcus species‡Includes E faecalis (5 strains), E faecium (2 strains), E avium (1 strain), E durans (1 strain), and E raffinosus (1 strain).10 strains2020Streptococcus faecalisATCC 194331020Bacillus cereusATCC 117781010Sarcina luteaATCC 93411020Escherichia coli10 strains1010Proteus vulgarisATCC 99201010Pseudomonas aeruginosaNCIMB 10548ND13Citrobacter species§Includes C diversus (6 strains) and C freundi (4 strains).10 strains2040Acinetobacter species¶Includes A anitratus (8 strains and A lwoffi (2 strains).10 strains40150Serratia marcescens10 strains2040Salmonella/Shigella#Includes S enteritidis (6 strains) and S sonnei (4 strains).10 strains2020Xanthomonas maltophilia10 strains150300Morganella morganii5 strains40150Enterobacter speciesIncludes E cloacae (7 strains) and E aerogenes (3 strains).10 strains2020Klebsiella speciesIncludes K oxytoca (2 strains) and K pneumoniae (8 strains).10 strains2020DermatophytesIncludes 1 strain each of M canis, M gypseum, T mentagrophytes, T rubrum, and Trichophyton spp.5 strains1010Aspergillus speciesIncludes A flavus (2 strains), A fumigatus (2 strains), and A terreus (1 strain).5 strains1010Candida speciesIncludes C glabrata (1 strain), C krusei (1 strain), C lusitaniae (1 strain), C parapsilosis (1 strain), and C tropicalis (1 strain).5 strains1010MIC, Mean minimal inhibitory concentration; ND, not done; ppm, parts per million.∗ Expressed as composite data from various sources.20Olin Chemicals product data: Zinc Omadine and Sodium Omadine antimicrobial agents; 1993.Google Scholar, 22Van Cutsem J. Gerven F.V. Fransen J. Schrooten P. Janssen P.A.J. The in vitro antifungal activity of ketoconazole, zinc pyrithione, and selenium sulfide against Pityrosporum and their efficacy as a shampoo in the treatment of experimental pityrosporosis in guinea pigs.J Am Acad Dermatol. 1990; 22: 993-998Abstract Full Text PDF PubMed Scopus (85) Google Scholar, 27Olin Chemicals product data: Omadine antimicrobials for cosmetic preservation: combine broad spectrum antimicrobial activity and wide compatibility with cosmetic ingredients; 1993.Google Scholar, 42Dinning A.J. Al-Adham I.S.I. Eastwood I.M. Austin P. Collier P.J. Pyrithione biocides as inhibitors of bacterial ATP synthesis.J Appl Microbiol. 1998; 85: 141-146Crossref PubMed Scopus (63) Google Scholar53† Includes S epidermidis (4 strains), S hominis (1 strain), S saprophyticus (3 strains), and S simulans (2 strains).‡ Includes E faecalis (5 strains), E faecium (2 strains), E avium (1 strain), E durans (1 strain), and E raffinosus (1 strain).§ Includes C diversus (6 strains) and C freundi (4 strains).¶ Includes A anitratus (8 strains and A lwoffi (2 strains).# Includes S enteritidis (6 strains) and S sonnei (4 strains).∗∗ Includes E cloacae (7 strains) and E aerogenes (3 strains).†† Includes K oxytoca (2 strains) and K pneumoniae (8 strains).‡‡ Includes 1 strain each of M canis, M gypseum, T mentagrophytes, T rubrum, and Trichophyton spp.§§ Includes A flavus (2 strains), A fumigatus (2 strains), and A terreus (1 strain).¶¶ Includes C glabrata (1 strain), C krusei (1 strain), C lusitaniae (1 strain), C parapsilosis (1 strain), and C tropicalis (1 strain). Open table in a new tab MIC, Mean minimal inhibitory concentration; ND, not done; ppm, parts per million. In 1979, Leyden et al45Leyden J.J. Stewart R. Kligman A.M. Updated in vivo methods for evaluating topical antimicrobial agents on human skin.J Invest Dermatol. 1979; 72: 165-170Crossref PubMed Scopus (51) Google Scholar developed a novel in vivo assay now known as the persistence (substantivity) test. This significant development was used to demonstrate the in vivo efficacy of ZPT in topical antisepsis applications. The assay determines the ability of the test agent to establish a reservoir in the stratum corneum. Substantive agents that diffuse into the stratum corneum or bind chemically to it will not be readily removed either by loss from the surface or by absorption. The antibacterial effect will therefore last several days. For this assay, 0.5 mL of the test agent is applied with a pipette twice daily for 4 consecutive days to the entire volar forearm. Twenty-four hours after the last application, occlusive dressings are applied. If an antimicrobial effect is demonstrable, the test is repeated, and the posttreatment interval is extended to 72 hours. The geometric means for bacterial counts per square centimeter are determined. For this study, 1.0% ZPT was compared with an equal concentration of CHG. The results of this 8-subject study demonstrated antimicrobial parity at 24 hours; however, at the 72-hour time point, ZPT provided a greater persistent effect
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