CA1219527A - 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 - Google Patents

Abstract

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
ABSTRACT OF THE DISCLOSURE
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 sulfa-diazine and the silver salt of the above-identified quino-line carboxylic acid, wherein even though each compound is present in a concentration which would be ineffective if either compound were present alone, the resulting composi-tions 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 ac-ceptable carrier, such as a water-dispersible, hydrophilic carrier.

Description

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

BACKGROVND OF THE INVENTION
. .

Despite the development of effective topical and systemic antibiotics, invasive wound sepsis and septicemia from Pseudomonas aeruginosa remain problems in serlously 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, numer-ous 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. JO of Inf. Diseases 124:S18, 1971), espe-cially Pseudomonas, have appeared in the literature.
(Snelling, C.F.T., Ronald, A.R., Cates, C.Y., et al.: Re-sistance of gram negative bacilli to gentamicin, J. of Inf.
Diseases 124:S264, 1971;-Chadwick, P.: Resistance of Pseudo-monas aeruginosa to gentamicin, Canadian Med. Assoc. J.
109:585, 1973; Bryan, L.E., Shahrabadi, M.S., Van Denelzen, ; 25 H.M.: Gentamicin resistance in Pseudomonas aeruginosa.
R-factor mediated resistance, Antimicrobial _ nts 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., C.L., Rappole, B.W., Stanford, J.W.:
Control of Pseudomonas infection in burns by silver sula-diazine, Surg. Gyn. Obstr. _ :1021, 1969), appeared to sur-mount 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 efectiveness o~ silver sul~adiazine, J. o Trauma 18:327, 1978; Heggers, J.P., Robson, M.C.: The emergence o 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 ohtained and the nature of their resistance studied in an experimental burn 10 model. This investigation revealed an unusual phenomenon, namely, normal sensitivity of Pseudomonas to AgSD in vltro, but resistance to topical ~gSD therapy in infected burn wounds in mice and rats. (Modak, S., Stanford, J.W., Bradshaw, W., Fox, Jr., C.L.: Silver sulfadiazine resistant 15 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 20 in vivo AgSD sensitive and nonsensitive strains were carried out to investigate the possible mechanism of in ViVO resis-tance. 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 25 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 30 the discovery that 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(l-piperazinyl)-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 antibacter-35 ial activity of AM-715, a new nalidixic acid analog.
Antimic_obial Agents and Chemothera~ 17:103, 1980, and French patents 879,106 and 870,576), and are effective in controlling AgSD-resistant Pseudomonas infections in burned 1;2~9S~

mice. See also applicant's European Patent 49593 which 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 l-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinoline car-boxyllc acid (QC) and/or its metal salts (MeQC), such as its æinc salt (ZnQC), cobalt salt (CoQC), cerous salt (CeQC), silver salt (AgQC) and magnesium salt (MgQC), together with silver sulfadiazine (AgSD), provide improved compositions use-ful 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 l-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(l-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 com-pounds were present, are useful in the treatment of burns inanimal 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 2S a water-dispersible hydrophilic carrier, e.g., an oil-in-water dispersion.

9~27 DET~ILED DESCRIPTION OF THE INVENTION
. _ . . ..

l-Ethvl-6-fluoro-l~4-dihydro-4-oxo-7-(l-piDerazinyl)-3 quinoline carboxylic acid (QC) has the structure:

~ COOH

HN~I C2H5 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 A~ents and Chemothera~y 17:103, 1980, supra.
The metal salts of QC, i.e., MeQC, viz.MgQC, CoQC, ZnQC, CeQC,and AgQC are also of interes-t and appear to be suitable topical antimicrobial agents. For example, AgQC, which would appear to have the structure wherein the "COOH moiety of QC is changed to ~ OO~ Ag+, is a potent antimicrobial.
Unlike certain compounds which have high in vitro antibac-terial activity, but are ineffective in controlliny silver sulfadiazine-resistant Pseudomonas infections in burned mice, QC and MeQC, are effective in con-trolling such infections when employed in amounts or concen-trations greater than about 10mM. At lesser amounts or con-centrations, the silver salt is ineffective.
The metal salts of l-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-tl-Piperazinyl)-3-quinoline carboxylic acid, i.e., MeQC, are readily prepared. For example, AgQC may be prepared as fol-lows. QC is obtained directly or synthesized by known tech-35 niques. The sodium salt of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-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 ~2~g~7 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 em-ployed 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 re-sult is obtained when AgSD and AgQC are combined for use inburn 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 10~1, such as an amount from about lmM up to about lOmM, 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 lOmM up to about-l.0 percent, e.g., about 30mM.

The compositions of this invention may be applied directly to the surface of burn wounds or infecti~ns, or, preferably may be employed in combination with a physiologically ac-ceptable 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.

2'7 Suitable compositions may be prepared by merely incorpora-ting or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment. One tech-nique 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 react-ing 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 in-cludes 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 emul-sion, are usually characterized by the following components and amounts by weight set forth in Table I:

TABLE I
25 Component Amount Petrolatum 0-25 Water-insoluble C16-C22 fatty alcohol 7-45 Emollient 0-15 Emulsifying Agents, preferably non-ionic 4-16 30 Humectant ` 7-40 AgSD 10mM-1.0 QC or MeQC lmM-lOmM
Preservative 0-0.3 Deionized or Distilled Water q.s. 0-80 Amounts are in percent by weight unless otherwise indicated.

~,195~7 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 ~he emollient, isopropyl myristate, lanolin, lanolin derivatives, isopropyl palmi-tate, isopropyl stearate and the corresponding sebacatesand 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 pre-servative would be any of the useful conventional water-soluble 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 I'able 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 preserva-tive, 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 per-cent by weight petrolatum, 7-45 percent by weight stearyl ~i2~ '7 alcohol, 0-15 percent by weight isopropyl myristate, 5-20 percent by weight of an emulsifying agent, 7-~0 percent by weight propylene glycol, 10mM-1.0 percent by weight AgSD
and lmM-lOmM of AgQC, the remainder being water, as re-quired, to bring the total percentage to 100 percent.
Other useful compositions would include compositions con-sisting essentially of 3mM AgQC, 30~ 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 composi-tion consisting essentially of 0-25 percent by weight petro-latum, 7-45 percent by weight of an aliphatic fatty alcohol having a carbon atom content in the range C16-C22, 0-15 per-cent 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.

3LZ195~2'7 - 1 o EXPERIMENTAL DETAILS
.
METHODS AND ~IATERIALS
.. . ...

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 ~ y of rnicrobial inhibition: Inhibition in-. ~ . .
dices 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 37C
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 (~emale Swiss 18-22 grams) re-.
ceived scalds using methods reported previously (Fox, Jr., C.L.: A new topical therapy for pseudomonas in burns.
Arch. Surg. 96:184, 1968; Fox, Jr., C.L., Sampath, A.C., _ Stanford, J.W.: Virulence of pseudomonas infection in burned rats and mice. Arch. Surg. 101:508, 1970; 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). The wounds were contaminated one hour post burn with ~reshly 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 in-fection 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.

2t7 RESULTS

In vivo efficacy of silver salt of l-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7-(l-pipera2inyl)-3-quinoline carboxylie 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 miee.
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 topieal therapy with the silver salt of the earboxylie aeid, the mortality was 0 pereent for both Ps. Mangalore and Ps. 181 infeetion when the eoncentration of the drug in the eream was lOmM/kg. ~hen lower amounts were used, there was 45-80 pereent mortality. The synergistic results obtained when both eompounds are present are elearly shown.

TABLE II
Topieal Therapy of Burned Mice Infeeted with AgSD Resistant Pseudomonas No. of % Mortality (Days Post Burn) Groups Miee 2 3 4 5 6 7 8 Control 10 40lOa100 100 100 100100 30mM AgSD 10 10 10 30 50 80 80 80 lOmM Ag salt 10 0 0 0 0 0 0 0 6mM Ag salt 9 0 10 10 10 10 30 45 31~M Ag salt 5 20 40 40 40 40 80 80 3mM Ag salt + 30m~ AgSD 5 0 0 5;2~7 In Vivo_Efflcac~

Mice anesthetized with ether were given a 30 percent scald by dipping the lower third of their body into a water bath at 68C 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 cri-terion was survival. Animals that succumbed were autopsiedand their cardiac blood was cultured to verify the presence of pseudomonas sepsis.

The results were as follows:
Ps. Boston infection: _ ~ ~rn 7-9 ... . ... ._ . _ Drug Cage No. Dead(%) Dead(%) Dead(%) Dead(%) Dead(%) Control _ 1 5 0 t0) 5_(100) 5 (100) 5 (100) 5 (100?
AgSD
(30mM) 2 5 0 _(0) 9 (0) 0 (0) 2 (40) 4 (80) silver carboxylic acid 3 5 2 (40) 4 (80) 5 (100) 5 (100) 5 (100) 30 3smaMl/ktegOrf carboxylic acid plus AgSD (30mM) 4 5 0 (0) 0 (0) 0 () (? () * Trade Mark 5æ7 Ps. Boston and Ps.
Manc~alore Infection:
Davs Post Burn ' . -- -- T . __ _ ___ _ _ . __ _ _ _ -L _ _ _ Drug Cage No. Dead(%) Dead(%) Dead(%) Dead(%) Dead(%) Dead(%) , . _ _ . . _ ..
Ps. Boston Control A 5 5 (lO0) 5 (lO0) 5 (lO0) 5 (lO0) 5 (lO0) 5 (lO0) _. _ ,_ _ ----- I _ _ _ Ibpical AgSD B 5 2 (40) 3 (60) 3(60) 3 (60) 3 (60) 4 (80) .. ___ _ . . .__ ... . . ._ _ . . _ _ . . _ _ Ps. Ma galore Control C 4 4 (lO0) 4 (lO0) 4 (lO0) 4 (lO0) 4 (lO0) 4 (lO0) . . _ . _ _ _ ~ . . _ .
~bpical AgSD D 4 1 (25) 1 (25) 2 (50) 3 (75) 3 (75) 3 (75) ._ . .. ._ _ .. ~. . __ 5% Sulfamylon in Marion Basel E 4 4 (100) 4 (lO0) 4 (lO0) 4 (lO0) 4 (lO0) 4 (lO0) __ .. _ _ _ ___ _ . _ .
1% Sulfamylon in Silvadene F 4 1 (25) l (25) 2 (50) 2 (50) 2 (50) 2 (50) _ __ __ _ _ .. _ _ . . _ . _ .. . .
301rM/kg carkoxylic acid G 5 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) _ _ _ .._ . ... _ .
30}rM/kg silv~
salt of car-boxylic acid H 5 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) _. _ _ .... . _ . . _ .. _ 6rr~Vkg silver salt of car-bo~ylic acid I 4 O (0) O (0) O (0) O (0) 1 (25) 2 (50) .___ _ . . .. __ Cream used in Silvadene; see footnote 2.
I~ademark for silver sulfadiazine with a cream carrier manufactured and sold by Marion Laboratories, Inc., Kansas City~ Missouri 64137.

~L2~9~

TABLE III

Welghts of Rats Showing Results of ~bpical I~erapy with Various Compositions Ibpical Agents Days Post Burn Cbntrol #1 195 163 _1 _ _ _ _ _ _ _ Control #2 193 159 - - - - - - - - -aontrol #3 201 172 - - - - - - - - -A~ Sulfadiazine #1 202 181 150 - - - - - - - -Ag Sulfadiazine #2 194 178 148 - - - - - - - -Ag Sulfadiazine #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 ~ hed lines indicate rats died.

'7 -16~

TABLE_IV

Topical Therapy of Burned Mice Infected with Ps. 181 % Mortality Topical A~ents Concentration (Days P.B.) None --- 80 100 ________________________________________________________ Silver Salt 3mM 100 100 Silver Salt 6mM 20 100 ~ _ _ _ _ Silver Sulfadiazine 1.0%
and Silver Salt 3n~1 0 0 __ _ Silver Sulfadiazine 1.0%
and Silver Salt 6~ 0 0 SILVADENE 1.0% 40 100 -- - - --

Claims (26)

WHAT IS CLAIMED IS:

1. A composition useful in burn 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, 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 1mM 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 amountofsaid 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 com-prises less than about 10mM silver salt of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid, less than about 1.0 percent by weight silver sulfa-diazine, and a physiologically acceptable carrier.

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

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

14. A composition useful in burn therapy which comprises about 3mM silver salt of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)-3-quinoline carboxylic acid, about 30mM silver sulfadiazine, and a physiologically acceptable carrier.

15. A composition useful in burn therapy which comprises 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid or a metal salt thereof, a metal salt of sulfadiazine, and a physiologically acceptable car-rier, 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.

16. 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 accept-able carrier therefor.

17 . A composition in accordance with Claim 16 wherein said carboxylic acid or said metal salt is present in said composition at a concentration below about its effective minimum antimicrobial level.

18. A composition in accordance with Claim 17 wherein said corcentration is less than about 10mM.

19. A composition in accordance with Claim 16 wherein said silver sulfadiazine is present in said composition at a con-centration below about its effective minimum antimicrobial level.

20. A composition in accordance with Claim 19 wherein said concentration is less than about 1.0 percent by weight.

21. A composition in accordance with Claim 16 wherein said silver sulfadiazine is present in said composition at a concentration greater than its effective minimum antimicro-bial level and said carboxylic acid or metal salt thereof is present in said composition at a concentration below its effective minimum antimicrobial level.

22. A composition in accordance with Claim 21 wherein said silver sulfadiazine is present at a concentration greater than about 1.0 percent by weight and said carbo-xylic acid or metal salt thereof is present at a concen-tration less than about 10mM.

23. A composition in accordance with Claim 16 wherein said silver sulfadiazine is present in said composition at a concentration less than its effective minimum anti-microbial level and said carboxylic acid or metal salt thereof is present in said composition at a concentration greater than its effective minimum antimicrobial level.

24. A composition in accordance with Claim 23 wherein said silver sulfadiazine is present at a concentration less than about 1.0 percent by weight and said carbo-xylic acid or metal salt thereof is present at a concentra-tion greater than about 10mM.

A composition in accordance with Claim 16 wherein said metal salt is selected from the group consisting of silver, zinc, cobaltous, and cerous.

26. A composition in accordance with Claim 16 wherein said physiologically acceptable carrier is a water-soluble or water-dispersible hydrophilic carrier.