WO1985001208A1

WO1985001208A1 - Antimicrobial compositions containing 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid or metal salts thereof and silver sulfadiazine

Info

Publication number: WO1985001208A1
Application number: PCT/US1983/001376
Authority: WO
Inventors: Charles L. Fox, Jr.; Shanta M. Modak
Original assignee: Research Corporation
Priority date: 1983-09-12
Filing date: 1983-09-12
Publication date: 1985-03-28
Also published as: EP0154622A4; JPS61500067A; EP0154622A1

Abstract

Compositions which include 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid or its metal salts, e.g., silver, zinc, cobalt or cerium salts, and silver sulfadiazine are effective in the treatment of burns. Of special interest are compositions containing silver sulfadiazine and the silver salt of the above-identified quinoline carboxylic acid, wherein even though each compound is present in a concentration which would be ineffective if either compound were present alone, the resulting compositions are effective. The compositions of this invention may be applied to the affected surface of a burn victim either directly or in combination with a physiologically acceptable carrier, such as a water-dispersible, hydrophilic carrier.

Description

ANTIMICROBIAL COMPOSITIONS CONTAINING 1-ETHYL-6-FLUORO-1,4-DIHYDRO-4-OXO-7(1-PIPERAZINYL)-3-QUIN0LINE CARBOXYLIC ACID OR METAL SALTS THEREOF AND SILVER SULFADIAZINE

BACKGROUND OF THE INVENTION

Despite the development of effective topical and systemic antibiotics, invasive wound sepsis and septicemia from

Pseudomonas aeruginosa remain problems in seriously burned patients. Emergence and development of drug resistant species of bacteria have defied the control obtained through the regimen of potent antibiotics. In recent years, numerous reports of gentamicin resistant gram negative organisms (Shulman, J.A., Terry, P.M., Hough, C.E.: Colonization with a gentamicin resistant Pseudomonas aeruginosa pyocine type 5 in a burn unit. J. of Inf. Diseases 124;S18, 1971), especially Pseudomonas, have appeared in the literature. (Snelling, C.F.T., Ronald, A.R., Cates, C.Y., et al.: Resistance of gram negative bacilli to gentamicin, J. of Inf. Diseases 124:S264, 1971; Chadwick, P.: Resistance of Pseudomonas aeruginosa to gentamicin, Canadian Med. Assoc. J. 109:585, 1973; Bryan, L.E., Shahrabadi, M.S., Van Denelzen, H.M.: Gentamicin resistance in Pseudomonas aeruginosa. R-factor mediated resistance. Antimicrobial Agents and Chemotherapy 6:191, 1974). Although silver sulfadiazine (AgSD), presently the most commonly used topical agent in the treatment of burn wound infections (Fox, Jr., C.L.: A new topical therapy for Pseudomonas in burns. Arch. Surg.

96:184, 1968; Fox, Jr., CL., Rappole, B.W., Stanford, J.W.: Control of Pseudomonas infection in burns by silver sulfadiazine, Surg. Gyn. Obstr. 128:1021, 1969), appeared to surmount these problems, Pseudomonas infections resistant to silver sulfadiazine treatment have been reported recently in burned patients (Gayle, W.E., Mayhall, C.G., Lamb, A., et al.: Resistant enterobacter cloacal in a burn center. The effectiveness of silver sulfadiazine, J. of Trauma 18:327, 1978; Heggers, J.P., Robson, M.C.: The emergence of silver sulfadiazine resistant Pseudomonas aeruginosa. Burns 5:184, 1978).

Similar occurrences of AgSD-resistant Pseudomonas infections in patients have been observed in other parts of the world. Several such resistant strains have been obtained and the nature of their resistance studied in an experimental burn model. This investigation revealed an unusual phenomenon, namely, normal sensitivity of Pseudomonas to AgSD in vitro, but resistance to topical AgSD therapy in infected burn wounds in mice and rats. (Modak, S., Stanford, J.W., Bradshaw, W., Fox, Jr., C.L.: Silver sulfadiazine resistant Pseudomonas infection in experimental burn wounds. 3rd

Intrl. Congr. of Pharma. Treatment of Burns, 1980 (in press) ed. Donati,L., Burke, J., Bertelli, A., Italy,)

Comparative studies of the virulence and drug sensitivity of in vivo AgSD sensitive and nonsensitive strains were carried out to investigate the possible mechanism of in vivo resistance. Since all the resistant strains obtained from burn patients appeared to be sensitive in vitro, the evaluation of a topical agent for its effectiveness was determined in experimental burn models. Several other antibacterial agents known to be effective in vitro were also ineffective against these strains.

The continued search for an effective topical agent led to the discovery that 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7¬

(1-piρerazinyl)-3-quinoline carboxylic acid and metal salts thereof (referred to hereinafter as QC and its metal salts as MeQC) possess high anti-Pseudomonas activity in vitro (Ito, A., Hira, K., Inoue, M., et al.: In vitro antibacterial activity of AM-715, a new nalidixic acid analog.

Antimicrobial Agents and Chemotherapy 17:103, 1980, and French patents 879,106 and 870,576), and are effective in controlling AgSD-resistant Pseudomonas infections in burned mice. See also our co-pending U.S. application. Serial No. 193,307, filed October 2, 1980, the disclosure of which is hereby incorporated by reference into this application.

Specifically, that application discloses QC and MeQC, e.g., AgQC, as topical antimicrobials useful in burn therapy.

SUMMARY OF THE INVENTION

It has been found that compositions containing 1-ethyl-6fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-guinoline carboxylic acid (QC) and/or its metal salts (MeQC), such as its zinc salt (ZnQC), cobalt salt (CoQC), cerous salt (CeQC), silver salt (AgQC) and magnesium salt (MgQC) , together with silver sulfadiazine (AgSD), provide improved compositions useful in burn therapy and compositions generally useful for combatting topical or surface or skin infections, including microbial and/or fungal infections and the like.

Moreover, it has unexpectedly been found that compositions comprising the silver salt of 1-ethyl-6-fluoro-1,4-dihydro4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid and silver sufadiazine, in which the compounds are present in amounts which would be ineffective if only one of the compounds were present, are useful in the treatment of burns in animal and man. These compositions may be applied to the affected surface or burned surface of a burn victim, either directly, or preferably in the form of a composition which includes a physiologically acceptable carrier, such as a water-dispersible hydrophilic carrier, e.g., an oil-in-water dispersion.

DETAILED DESCRIPTION OF THE INVENTION

1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl)-3quinoline carboxylic acid (QC) has the structure:

and is known to have antibacterial activity in vitro against standard bacterial strains such as B. subtilis, S. aureus, P. aeruginosa, and E. coli strains. Ito, A. et al., Antimicrobial Agents and Chemotherapy 3/7:103, 1980, supra. The metal salts of QC, i.e., MeQC, viz.MgQC, CoQC, ZnQC, CeQC, and AgQC are also of interest and appear to be suitable topical antimicrobial agents. For example, AgQC, which would appear to have the structure wherein the

moiety of QC is changed t

Ag+, is a potent antimicrobial. Unlike certain compounds which have high in vitro antibacterial activity, but are ineffective in controlling silver sulfadiazine-resistant Pseudomonas infections in burned mice, QC and MeQC, are effective in controlling such infections when employed in amounts or concentrations greater than about 10mM. At lesser amounts or concentrations, the silver salt is ineffective.

The metal salts of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)-3-quinoline carboxylic acid, i.e., MeQC, are readily prepared. For example, AgQC may be prepared as follows. QC is obtained directly or synthesized by known techniques. The sodium salt of 1-ethyl-6-fluoro-1,4-dihydro-4oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid, i.e., NaQC, may then be prepared by adding an equimolar amount of sodium hydroxide to the QC. The silver salt, i.e., AgQC, may be prepared by reacting the NaQC in an aqueous solution with a stoichiometric quantity of a suitable silver salt such as silver nitrate, silver chloride, or the like.

Silver sulfadiazine is well known as an effective agent in burn therapy. However, the silver sulfadiazine must be employed in compositions in amounts or concentrations greater than about 1.0 percent by weight. At lesser amounts, silver sulfadiazine (AgSD) is ineffective.

Not only have combinations of AgSD and QC and MeQC been found to provide potent antimicrobial compositions, but, also, it has unexpectedly been found that a synergistic resuit is obtained when AgSD and AgQC are combined for use in burn treatment. Specifically, compositions useful in burn therapy have been discovered in which the amounts of AgSD and of AgQC are below the amounts required for antibacterial activity or effectiveness if only one of the compounds is present or included.

Thus, compositions useful in burn therapy may be prepared in which the amount or concentration of AgQC is less than about 10mM, such as an amount from about 1mM up to about 10mM, e.g., about 3mM; and the amount or concentration of AgSD is less than about 1.0 percent by weight, such as an amount from about 10mM up to about 1.0 percent, e.g., about 30mM.

The compositions of this invention may be applied directly to the surface of burn wounds or infections, or, preferably, may be employed in combination with a physiologically acceptable carrier. When employed in a composition with a physiologically acceptable carrier, the carrier is desirably a conventional water-dispersible, hydrophilic or oil-in-water carrier, particularly a conventional semi-soft or cream-like, water-dispersible or water-soluble, oil-in-water emulsion, which may be applied to an affected burn surface or infected surface with a minimum of discomfort. Suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment. One technique in accordance with this invention for incorporating the metal salts, e.g., the silver salt, in a hydrophilic ointment, such as an oil-in-water emulsion, involves reacting equimolar aqueous solutions of silver nitrate and NaQC to yield a white precipitate which is AgQC. The resulting precipitate, after washing and drying, is then mixed or blended with the candidate hydrophilic ointment, such as the oil-in-water emulsion, to yield a composition which includes the silver salt dispersed in the ointment. The AgSD may be incorporated into the composition either together with the AgQC or independently.

Compositions in accordance with this invention containing AgSD and MeQC dispersed in a water-dispersible, hydrophilic carrier or ointment, e.g., a hydrophilic, oil-in-water emulsion, are usually characterized by the following components and amounts by weight set forth in Table I:

TABLE I Component Amount¹ Petrolatum 0-25

Water-insoluble C₁₆-C₂₂ fatty alcohol 7-45 Emollient 0-15

Emulsifying Agents, preferably non-ionic 4-16 Humectant 7-40 AgSD 10mM-1.0

QC or MeQC 1mM-10mM Preservative 0-0.3 Deionized or Distilled Water q.s. 0-80 100

Amounts are in percent by weight unless otherwise indicated. The fatty alcohols, stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol are useful in the preparation of compositions in accordance with this invention. These preferential oil-soluble fatty alcohols act as stiffeners in the resulting compositions. As the emollient, isopropyl myristate, lanolin, lanolin derivatives, isopropyl palmitate, isopropyl stearate and the corresponding sebacates and other known emollients are suitable. As the emulsifying agent sorbitan monooleate, such as an amount in the range 0.5-4 percent by weight, and polyoxyl 40 stearate in an amount in the range 7-12 percent by weight, both non-ionic emulsifying agents, are satisfactory. A suitable humectant would be propylene glycol, sorbitol, or glycerin, or mixtures thereof, all being water-soluble compounds. A suitable preservative would be any of the useful conventional watersoluble preservatives which exhibit anti-microbial activity, such as sorbic acid, benzoic methylparaben, propylparaben, and mixtures thereof.

In the formulation of a composition having the make-up set forth in Table I hereinabove, as the amount of aqueous phase is increased, the solid content, i.e., the water-immiscible or water-insoluble components, e.g., fatty alcohol, such as stearyl alcohol, and/or petrolatum, must also be increased relatively to help stiffen the composition. The preservative, e.g., methylparaben, is employed in the formulation only as a preservative for the overall composition and, as indicated, methylparaben was found to be a satisfactory preservative. Methylparaben, as indicated, however, may also be used in combination with propylparaben.

Accordingly, compositions useful in the practices of this invention would include compositions comprising 0-25 percent by weight petrolatum, 7-45 percent by weight stearyl alcohol, 0-15 percent by weight isopropyl myristate, 5-20 percent by weight of an emulsifying agent, 7-40 percent by weight propylene glycol, 10mM-1.0 percent by weight AgSD and 1mM-10mM of AgQC, the remainder being water, as required, to bring the total percentage to 100 percent. Other useful compositions would include compositions consisting essentially of 3mM AgQC, 30mM AgSD, 7-8 percent by weight propylene glycol, 38-44 percent by weight water,

14-18 percent by weight petrolatum, 14-18 percent by weight stearyl alcohol, 5-8 percent by weight isopropyl myristate, 0.5-2 percent by weight sorbitan monooleate and 6-10 percent by weight polyoxyl 40 stearate. Another composition useful in the practice of this invention would include the composition consisting essentially of 0-25 percent by weight petrolatum, 7-45 percent by weight of an aliphatic fatty alcohol having a carbon atom content in the range C₁₆-C_22' 0-15 percent by weight of an emollient, 7-16 percent by weight of an emulsifying agent, 7-14 percent by weight of a humectant, 3mM AgQC, and 30mM AgSD.

Although the preceding discussion has primarily concerned the use of AgSD in combination with QC or MeQC, especially AgQC, it is likely that other metal salts of sulfadiazine may be usefully employed in the practices of this invention. For example, zinc sulfadiazine, cerous sulfadiazine, and cobaltous sulfadiazine are known to be useful as topical antimicrobial agents in the treatmentof burn victims. Thus, it may be that combinations of one or more of these compounds with QC or MeQC will provide advantages when employed in burn therapy or the treatment of surface infections.

The results of various experiments illustrating the practices of this invention are now set forth. EXPERIMENTAL DETAILS

METHODS AND MATERIALS

Bacterial Strains: Ps. Boston was the strain used in our previous investigations (Fox, Jr., C.L., Sampath, A.C, Stanford, J.W.: Virulence of pseudomonas infection in burned rats and mice. Arc. Surg. 101:508, 1970); Ps. Mangalore was isolated from a burn patient in Kasturba Medical College, Mangalore, India; Ps. 181 was obtained from Hospital de los Ninos, Lima, Peru; and AgSD resistant Ps. Boston was produced in our laboratory by repeatedly growing this organism in medium containing increasing amounts of AgSD.

In vitro assay of microbial inhibition: Inhibition indices are obtained by tube dilution tests using nutrient broth. Growth in the presence and absence of drugs was observed by turbidity measurement after incubation at 37°C for 24-48 hours (Fox, Jr., C.L., Modak, S.M., Stanford, J.W.: Cerium sulfadiazine as a topical agent for burn wound infections: A comparison with silver sulfadiazine and zinc sulfadiazine. Burns 4:233, 1978).

Animal experiments: Mice (female Swiss 18-22 grams) received scalds using methods reported previously (Fox, Jr., C.L.: A new topical therapy for pseudomonas in burns. Arch. Surg. 96:184, 1968; Fox, Jr., CL., Sampath, A.C, Stanford, J.W.: Virulence of pseudomonas infection in burned rats and mice. Arch. Surg. 101:508, 1970; Fox, Jr., CL., Modak, S.M., Stanford, J.W.: Cerium sulfadiazine as a topical agent for burn wound infections: A comparison with silver sulfadiazine and zinc sulfadiazine. Burns 4: 233, 1978). The wounds were contaminated one hour post burn with freshly prepared 18-20 hour broth culture of pseudomonas diluted to optical density 0.30. Infection was induced by immersing the tail in the culture. The first treatment was administered 4 hours post infection by rubbing the medicated creams over all burned surfaces. All drugs used were mixed in a cream base such as described hereinabove. Thereafter, all animals were observed and treated once daily. The primary criteron was survival. Animals that succumbed were autoposied and the cardiac blood cultured to verify the presence of pseudomonas.

RES ULTS

In vivo efficacy of silver salt of 1-ethyl-6-fluoro-1,

4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinoline carboxylic acid in combination with silver sulfadiazine

In vivo efficacy of the silver salt of the carboxylic acid and of silver sulfadiazine against Ps. Mangalore, Ps. 181, and AgSD-resistant Ps. Boston were tested and compared with that of a combination of both compounds in burned mice. The results are summarized in Table II. After infection with these resistant strains, the mortality with 30mM silver sulfadiazine therapy was 80 percent by the eighth day post burn. In the groups of mice receiving topical therapy with the silver salt of the carboxylic acid, the mortality was 0 percent for both Ps. Mangalore and Ps. 181 infection when the concentration of the drug in the cream was 10mM/kg. When lower amounts were used, there was 4580 percent mortality. The synergistic results obtained when both compounds are present are clearly shown.

TABLE II

Topical Therapy of Burned Mice

Infected with AgSD Resistant Pseudomonas

No. of % Mortality (Days Post Burn)

Groups Mice 2 3 4 5 6 7 8

Control 10 40 100 100 100 100 100 100

30mM AgSD 10 10 10 30 50 80 80 80

10mM Ag salt 10 0 0 0 0 0 0 0

6mM Ag salt 9 0 10 10 10 10 30 45

3mM Ag salt 5 20 40 40 40 40 80 80

3mM Ag salt

+ 30mM AgSD 5 0 0 0 0 0 0 0 In Vivo Efficacy

Mice anesthetized with ether were given a 30 percent scald by dipping the lower third of their body into a water bath at 68°C for 7 seconds. One hour post burn, mice were given 1 ml of Normosol by I.P. injection and then infected by dipping the tail in an overnight culture of pseudomonas diluted to 0.30 O.D. at 600nm.

The animals were divided at random into groups of 5, and topical therapy was initiated 4 hours post infection. Thereafter they were treated once daily. The primary criterion was survival. Animals that succumbed were autopsied and their cardiac blood was cultured to verify the presence of pseudomonas sepsis.

The results were as follows:

1

Cream used in Silvadene; see footnote 2.

²Trademaik for silver sulfadiazine with a cream carrier manufactured and sold by Marion Laboratories, Inc., Kansas City, Missouri 64137. TABLE III

Weights of Rats Showing Results of Tbpical Therapy with Various Compositions

Topical Agents Days Post Burn 1 3 5 7 9 11 13 15 17 18 21

Control #1 195163 -¹ - - - - - - - -

Control #2 193159 - - - - - - - - -

Control #3 201172 - - - - - - - - -

Ag Sulfadiazine #1 202 181 150 - - - - - - - -

Ag Sulfadiazine #2 194 178 148 - - - - - - - -

Ag Sulfediazine #3 194 166 - - - - - - - - -

Silver Salt #1 202 191 189 203 205 212 203 202 210 206 207 Silver Salt #2 194 187 190 198 200 210 212 215 217 210 216

Silver Salt #3 195 190 183 191 197 200 218 219 223 225 225

Ag Salt + AgSD #1 207 200 203 192 188 206 210 214 214 215 226

Ag Salt + AgSD #2 195 190 193 196 200 209 213 218 223 216 217 AG Salt + AgSD #3 193 193 199 207 213 220 219 219 223 218 224

¹Dash ed lines indicate rats died.

Claims

WHAT IS CLAIMED IS:

1. A composition useful in burn therapy which comprises 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piρerazinyl)-3quinoline carboxylic acid or a metal salt thereof, silver sulfadiazine, and a physiologically acceptable carrier, said carboxylic acid or metal salt thereof and said silver sulfadiazine being present in amounts which are ineffective when only one of said compounds is present, but effective when both compounds are present.

2. A composition in accordance with Claim 1 wherein said metal salt is selected from the group consisting of silver, zinc, cobaltous, and cerous.

3. A composition in accordance with Claim 1 wherein the amount of said carboxylic acid or metal salt thereof is less than about 10mM.

4. A composition in accordance with Claim 1 wherein the amount of said carboxylic acid or metal salt thereof is an amount from about ImM up to about 10mM.

5. A composition in accordance with Claim 1 wherein the amount of said carboxylic acid or metal salt thereof is about 3mM.

6. A composition in accordance with Claim 1 wherein the amount of said silver sulfadiazine is less than about 1.0 percent by weight.

7. A composition in accordance with Claim 1 wherein the amount of said silver sulfadiazine is an amount from about 10mM up to about 1.0 percent.

8. A composition in accordance with Claim 1 wherein the amount of said silver sulfadiazine is about 30mM.

9. A composition in accordance with Claim 1 which comprises less than about lOmM silver salt of 1-ethyl-6-fluoro1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid, less than about 1.0 percent by weight silver sulfadiazine, and a physiologically acceptable carrier.

10. A composition in accordance with Claim 1 wherein said physiologically acceptable carrier is a water-soluble hydrophilic carrier.

11. A composition in accordance with Claim 1 wherein said physiologically acceptable carrier is a semi-soft or creamlike, water dispersible or water-soluble, oil-in-water emulsion carrier.

12. A composition in accordance with Claim 9 wherein said physiologically acceptable carrier is a water-dispersible hydrophilic carrier.

13. A composition in accordance with Claim 9 wherein said physiologically acceptable carrier is a semi-soft or creamlike, water-dispersible or water-soluble, oil-in-water emulsion carrier.

14. A method of treating burns in animal or man which comprises topically applying the composition of Claim 1 to the affected surface.

15. A method of treating burns in animal or man which comprises topically applying the composition of Claim 9 to the affected surface.

16. A composition useful in burn therapy which comprises about 3mM silver salt of 1-ethyl-6-fluoro-1,4-dihydro-4oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid, about

30mM silver sulfadiazine, and a physiologically acceptable carrier.

17. A method of treating burns in animal or man which comprises topically applying the composition of Claim 16 to the affected surface.

18. A composition useful in burn therapy which comprises 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3quinoline carboxylic acid or a metal salt thereof, a metal salt of sulfadiazine, and a physiologically acceptable carrier, said carboxylic acid or metal salt thereof and said metal salt of sulfadiazine being present in amounts which are ineffective when only one of said compounds is present, but effective when both compounds are present.

19. A method of treating burns in animal or man which comprises topically applying the composition of Claim 18 to the affected surface.

20. A composition useful in antimicrobial topical therapy which comprises 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7¬

(1-piperazinyl)-3-quinoline carboxylic acid or a metal salt thereof, silver sulfadiazine, and a physiologically acceptable carrier therefor.

21. A method of treating burns, surface infections, and the like which comprises applying to the affected surface the composition of Claim 20.

22. A composition in accordance with Claim 20 wherein said carboxylic acid or said metal salt is present in said composition at a concentration below about its effective minimum antimicrobial level.

23. A composition in accordance with Claim 22 wherein said concentration is less than about 10mM.

24. A composition in accordance with Claim 20 wherein said silver sulfadiazine is present in said composition at a concentration below about its effective minimum antimicrobial level.

25. A composition in accordance with Claim 24 wherein said concentration is less than about 1.0 percent by weight.

26. A composition in accordance with Claim 20 wherein said silver sulfadiazine is present in said composition at a concentration greater than its effective minimum antimicrobial level and said carboxylic acid or metal salt thereof is present in said composition at a concentration below its effective minimum antimicrobial level.

27. A composition in accordance with Claim 26 wherein said silver sulfadiazine is present at a concentration greater than about 1.0 percent by weight and said carboxylic acid or metal salt thereof is present at a concentration less than about 10mM.

28. A composition in accordance with Claim 20 wherein said silver sulfadiazine is present in said composition at a concentration less than its effective minimum antimicrobial level and said carboxylic acid or metal salt thereof is present in said composition at a concentration greater than its effective minimum antimicrobial level.

29. A composition in accordance with Claim 28 wherein said silver sulfadiazine is present at a concentration less than about 1.0 percent by weight and said carboxylic acid or metal salt thereof is present at a concentration greater than about 10mM.

30. A composition in accordance with Claim 20 wherein said metal salt is selected from the group consisting of silver, zinc, cobaltous, and cerous.

31. A composition in accordance with Claim 20 wherein said physiologically acceptable carrier is a water-soluble or water-dispersible hydrophilic carrier.