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Mercresin, a new surgical germicide
MERCRESIN, A NEW SURGICAL GERMICIDE* WALTER
G. MADDOCK,
M.D., ALLEN M. ANN
BOYDEN, M.D. AND RU~ELL ARBOR,
T
HE probIem of wound infection is a constant one to a11 who are interested in the practice of surgery. The weak spot in the many procedures aimed at preventing the entrance of bacteria into a cIean operating wound is the presence of organisms in and on the skin itseIf. Other factors, such as undue traumatizing of tissues, unsteriIe catgut and breaks in the operative technique may aIso be the cause of the smalI percentage of wound infections that continue to occur in socalled cIean cases. The preparation of the operative field has properIy received considerabIe attention and a number of germicides are in use. AIthough many Iaboratory tests have been proposed, the bacterioIogica1 study and evaIuation of these germicides has been standardized by the United States, G0vernment.l The cIinica1 evaIuation of such products, however, is more difficult and obviously cannot be controhed so readily as in vitro experiments. The factors of individua1 resistance, immunity, possibIe differences in the kind and viruIence of contaminating organisms, variations in the type and extent of operations, and ski11 of the surgeon so add to the compIexity of the probIem that definite concIusions as to the reIative merits of one germicide over another are often difhcuIt. In full reaIization of these obstacIes, we have undertaken to evaluate “mercresin,” a new germicide recentIy brought to our attention. Mercresin is a unique type of germicide in that it contains an organic mercurial, ortho-hydroxyphenyImercuric chloride and a synthetic creso1 (mercarbolide), derivative1 (pentacreso1). There are exceIIent reasons for this combination. Despite the wide acceptance and use of many mercurial antiseptics today, it has been repeatedIy shown and is now recognized, that what have appeared to be highIy
L. MALCOLM,
M.D.
MICH.
germicidal properties have been due in reahty to the powerfu1 bacteriostatic action inherent in a11 organic mercuriaIs.“s This appears to be particuIarIy true of the action of the mercuriaIs on certain organisms, one of which, Staphylococcus aureus, is a standard used in the offrcia1 tests for germicida1 soIutions. AIthough orthohydroxyphenyImercuric chIoride has been shown to have greater germicida1 potency against standard organisms than other mercurials in common use,6 the faiIure of the mercuriaIs as a group to be quickIy bactericida1 against StaphyIoccocus aureus Ied to the addition in mercresin of the synthetic creso1 derivative, which has a high degree of the desired bactericida1 action.6 An important fmding was that when the synthetic creso1 was added to the ortho-hydroxyphenyImercuric chIoride, it did not merely suppIement the action of the Iatter on Staphylococcus aureus, but resuhed in a synergistic action which made the combination, mercresin, from 200 to 300 per cent more germicidal than the sum of the two components aIone.6 Mercresin tincture contains one part each of ortho-hydroxyphenylmercuric chIoride and the synthetic creso1 derivative in I000 parts of a soIution containing 30 per cent aIcoho1 and IO per cent acetone. The aIcoho1 and acetone favor penetration by dissoIving the fatty materiaIs and epitheIia1 debris always found on skin surfaces, and also shorten the time required for drying. Added to this soIution, for the purpose of defining the area of appIication, is a smaI1 amount of watersoIuble coloring materia1, orange G, which is easiIy removed from the skin and with soap and water. hospital linens Mercresin tincture has been shown to have sufficient germicida1 power to be effective in diIutions up to I to 20, a point where the aIcoho1 and acetone is non-irritating. It is compatible with both acids and alkaIis, does not react with the chIorides of body fluids, does not precipi-
t A mixture of 5 isomeric amyI cresols derived from the interaction of amy aIcoho1 and cresol, U.S.P.
* From the Department of Surgery, University of Michigan, Ann Arbor, blich. 47
48
AmericanJournal
Maddock
of Surgery
tate serum proteins, and is miscibIe with water in a11proportions. Mercresin has a toxicity of the same order as that of other we11 known organic mercuria1 germicides. This statement is based on the resuIts of extensive studies of the ora1, intramuscuIar, intravenous and intraperitonea1 toxicity of mercresin in rats compared with other organic mercuria1 germicides. The foIlowing data on the bacteriostatic and bactericida1 potency of mercresin are TABLE GERMICIDAL
POWER
OF
STAPHYLOCOCCUS
*“REVS
-
Dilution of Active Ingredients
Subculture, Min“WS
t”R.
Minutes
_ 5 10 15
__
1-3
t--
+++
1-3
---
+++ ++-
r-5
+++ +++ +++
---
1-5 r-20
---
-----
*This represents i”p;redients.
IN
F.D.A.
STAPHYLOCOCCUS
T
BROTH
AIQD
AUREUS
AT
SERUM 37%.
Highest DiIutions Which Are Bacteriostatic
F.D.A. Broth
Serum Broth
_.._ Mercurochrome tincture. MerthioIate tincture. Metaphen tincture. HexyIresorcinoI. . Mercresin tincture.
~~~~~
r-40 r-800 I-300 I-20
I-20 1-400 r-80 x-10 (fails)
I-_3200
I-800
-
,--I
OUS).................
“SING
-
---
Mercurophen.. Mercuric chloride.. Hexylresorcinol (I-rooo aqueous). Mercresin tincture..
BROTH
ACTION
TOWARD
5 1or:
Mercurochrome (z per cent tincture). Merthiolate (I-I”“” tint ture)............... Metaphen (I-ZOO tincrure)................ Phenyl mercuric nitrata. P.M.N. (l-1250 aque-
TABLEII BACTERIOSTATIC
Product ANTISEPTICS
CdDilution of Comma&d Product
Product
TabIe n7 shows the data comparing the bacteriostatic or growth-inhibiting power of mercresin with severa other commercial products. ResuIts are expressed in diIutions of equa1 concentration (1-1000). For exampIe, mercresin 1-3200 means I voIume
I
VARIOUS
OTTOBER, 1936
et aI.-Mercresin
a I--zo.“o”
dilution
of rach
of
the
active
based on investigations by Dunn, of the Department of BacterioIogy of Massachusetts Institute of Technology6 and by the Department of BacterioIogy, Iowa State CoIIege.7 Table P shows the germicida1 power of mercresin compared with using the other commercial products, officia1 F.D.A. method at 37Oc. with StaphyIococcus aureus. The negative signs in the coIumn headed “CuIture” indicate a faiIure of growth. This might be due either to a bacteriostatic or a germicidal effect. The occurrence of growth in the subcuIture, as shown by a positive sign in that column, indicates that the faiIure of growth for the corresponding time period in the “CuIture” column was due to a bacteriostatic effect and not to the death of the organisms. OnIy hexyIresorcino1 and mercresin were IethaI at a11 time periods.
of mercresin diIuted to 3200 parts of water. The superiority of mercresin is apparent. The importance of testing germicides against a variety of bacteria rather than Iimiting the examination to the commonIy used test organisms has been emphasized repeatedly.*-11 TabIe IIP shows the diIutions of mercresin which are IethaI to a variety of organisms in five minutes. TABLE MAXIMUM WERE
DILUTIONS LETHAL
OF
III
MERCRESIN
TO VARIOUS
ORGANISMS
TINCTURE IN
WHICH
5 MINUTES
DiIutions of Mercresin Tincture 1-20 I--IO I-30 1-25
Organisms Staphylococcus aureus *Eschcrichia coIi (B. coli) Pseudomonas aeruginosa (B. pyocyaneus) Serratia pyoseptica (simiIar to B. prodigiosus) EbertheIIa typhosa (B. typhosus) I-3o Corynebacterium pseudodiphtherium (B. I-20 Hofmanni) Streptococcus hemoIyticus 1-25 1-20 Corynebacterium diphtheriae (B. diphtheriae) Tricophyton interdigitzde (ringworm) I-40 I--I20 Actinomyces I-20 Blastomyces * I0 minutes.
Since in preoperative use the interva1 of time between the application of the antiseptic and the start of the operation is brief, it is important to know the rapidity of the germicida1 action of mercresin. This
NEW
SERXES
VOL. XXXIV, No.
Maddock
,
et aI.-Mercresin
is given in TabIe IV.~ A dihrtion of I-IO kiIIed StaphyIococcus aureus in a minute, and in less time with greater concentrations. . TABLE IV THE RAPIDITY OF TKE GERMICIDAL ACTION OF MERCRESIN AGAINST STAPHYLOCOCCUSAUREUS BY A MODIFlED F.D.A.
PROCEDURE
DiIutions of Mercresin Tincture r-6 I-8 I-10
KiIIed Staphylococcus Aureus in I I seconds 30 seconds I minute 4 minutes 3 minutes
1-12 I-20
TabIe v6 shows the resuIts obtained with the serum cup-plate test using Staphylococcus aureus at 37’~. This represents the TABLE v PENETRABILITY OF VARIOUS GERMICIDES WITH SERUM CUP-PLATE TEST USING STAPHOLOCOCCUSAUREUS AT 37%. Product Tincture of iodine. HexyIresorcinoI MerthioIate. Metaphen. Mercresin tincture
Concentration of Active Ingredients
I
I-16 1-1000
I-1000 I-200 I-1000
Average Diameter in Mm. of Zone of No-growth
I
18.0 6.0 11.5 II.0 23.0
usua1 Iaboratory method of demonstrating the penetrabihty of germicida1 soIutions. The zone of no growth was wider for mercresin than for any of the other germicides tested. With such concIusive evidence in favor of this new preparation, it seemed worth whiIe to permit a tria1 of tincture mercresin as a preoperative skin antiseptic in the University HospitaI. The results proved so gratifying in 1200 cases that it has been adopted as the routine antiseptic for a11 genera1 surgica1 cases. The percentage of wound infections has remained consistentIy Iow. The stain foIIowing its appIication disappears spontaneousIy within three to four days or can be readiIy removed by washing the skin with aIcoho1 or water. The non-irritating properties of the antiseptic have been apparent. In only one instance has there been any reaction in the skin foIIowing its use, this taking the form of a fine vesicuIar eruption superimposed upon a diffuse erythema. This dermatitis disappeared within four days, leaving no residua1 changes in the skin.
American
Journal
of Surgery
49
An evaIuation of further uses of mercresin is being continued and wiI1 be reported Iater. DiIutions of mercresin of 1-15 are being found effective in various urologica treatments. SUMMARY
The characteristics of mercresin tincture which make this soIution a powerfu1 antiseptic have been presented. Its advantages are as fohows: I. High germicidal and bacteriostatic properties. 2. Rapid action. 3. Satisfactory penetrabiIity. 4. Sufficient coIor to define the extent of the fieId prepared as we11 as the abiIity to Iose this coIor rapidly. 5. The abiIity to dissoIve fat and degenerative ceIIuIar debris from the skin surface. Furthermore, its use in a large series of surgica1 cases has proved it to be nonirritating and has demonstrated its efficacy as a preoperative skin disinfectant. REFERENCES I. RUEWLE and BREWER. United States Food and Drug Administration Methods of Testing Antiseptics and Disinfectants. LJ. S. Department of AgricuIture, Washington, D. C. Circular #IQ~, 1931. 2. LEONARD, G. F. Limitations of pheno1 coefficient tests in determining germicida1 activities. .Z. Infect. Dis., 48: 358-365 (April) 1931. 3. LEONARD, G. F. and HISCOCK, E. A method of determining the germicida1 power of products which have a high bacteriostatic activity. Am. J. Pbarm., 105: 241-243 (May) 1933. 4. WHITE, E. C. and HILL, J. H. Inefficiency of metaphen as a skin disinfectant. J. A. M. A., ~5: 27-28 (JuIy 5) 1930. 5. LEONARD, V. PitfaIls in interpretation of experiments on skin disinfection. J. A. M. A., 94: 1524 (May IO) 1930. 6. DUNN. C. G. GermicidaI orooerties of some ohenoIic compounds. In press. 7. Unpublished report from Department of BacterioIogy, Iowa State CoIIege. 8. ALLEN, A. W. and WRIGHT, I. S. Determination of the value of antiseptics. J. A. M. A., 96: 92~~925 (March 21) 1931. Q. TINKER, M. B. and SUTTON,H. B. Inefficiency of most of the common.Iy used skin antiseptics. J. A.M. A., 87: 1347-1351, @ct. 23) 1926. IO. REDDISH, G. F. Examination of disinfectants. Am. J. Public He&b, 17: 320-32~ (ApriI) 1927. I I. REDDISH, G. F. Determining the germicidal efhciency of disinfectants. Am. J. Public He&b, 16: 283-286 (March) 1926. A
G. MADDOCK,
M.D., ALLEN M. ANN
BOYDEN, M.D. AND RU~ELL ARBOR,
T
HE probIem of wound infection is a constant one to a11 who are interested in the practice of surgery. The weak spot in the many procedures aimed at preventing the entrance of bacteria into a cIean operating wound is the presence of organisms in and on the skin itseIf. Other factors, such as undue traumatizing of tissues, unsteriIe catgut and breaks in the operative technique may aIso be the cause of the smalI percentage of wound infections that continue to occur in socalled cIean cases. The preparation of the operative field has properIy received considerabIe attention and a number of germicides are in use. AIthough many Iaboratory tests have been proposed, the bacterioIogica1 study and evaIuation of these germicides has been standardized by the United States, G0vernment.l The cIinica1 evaIuation of such products, however, is more difficult and obviously cannot be controhed so readily as in vitro experiments. The factors of individua1 resistance, immunity, possibIe differences in the kind and viruIence of contaminating organisms, variations in the type and extent of operations, and ski11 of the surgeon so add to the compIexity of the probIem that definite concIusions as to the reIative merits of one germicide over another are often difhcuIt. In full reaIization of these obstacIes, we have undertaken to evaluate “mercresin,” a new germicide recentIy brought to our attention. Mercresin is a unique type of germicide in that it contains an organic mercurial, ortho-hydroxyphenyImercuric chloride and a synthetic creso1 (mercarbolide), derivative1 (pentacreso1). There are exceIIent reasons for this combination. Despite the wide acceptance and use of many mercurial antiseptics today, it has been repeatedIy shown and is now recognized, that what have appeared to be highIy
L. MALCOLM,
M.D.
MICH.
germicidal properties have been due in reahty to the powerfu1 bacteriostatic action inherent in a11 organic mercuriaIs.“s This appears to be particuIarIy true of the action of the mercuriaIs on certain organisms, one of which, Staphylococcus aureus, is a standard used in the offrcia1 tests for germicida1 soIutions. AIthough orthohydroxyphenyImercuric chIoride has been shown to have greater germicida1 potency against standard organisms than other mercurials in common use,6 the faiIure of the mercuriaIs as a group to be quickIy bactericida1 against StaphyIoccocus aureus Ied to the addition in mercresin of the synthetic creso1 derivative, which has a high degree of the desired bactericida1 action.6 An important fmding was that when the synthetic creso1 was added to the ortho-hydroxyphenyImercuric chIoride, it did not merely suppIement the action of the Iatter on Staphylococcus aureus, but resuhed in a synergistic action which made the combination, mercresin, from 200 to 300 per cent more germicidal than the sum of the two components aIone.6 Mercresin tincture contains one part each of ortho-hydroxyphenylmercuric chIoride and the synthetic creso1 derivative in I000 parts of a soIution containing 30 per cent aIcoho1 and IO per cent acetone. The aIcoho1 and acetone favor penetration by dissoIving the fatty materiaIs and epitheIia1 debris always found on skin surfaces, and also shorten the time required for drying. Added to this soIution, for the purpose of defining the area of appIication, is a smaI1 amount of watersoIuble coloring materia1, orange G, which is easiIy removed from the skin and with soap and water. hospital linens Mercresin tincture has been shown to have sufficient germicida1 power to be effective in diIutions up to I to 20, a point where the aIcoho1 and acetone is non-irritating. It is compatible with both acids and alkaIis, does not react with the chIorides of body fluids, does not precipi-
t A mixture of 5 isomeric amyI cresols derived from the interaction of amy aIcoho1 and cresol, U.S.P.
* From the Department of Surgery, University of Michigan, Ann Arbor, blich. 47
48
AmericanJournal
Maddock
of Surgery
tate serum proteins, and is miscibIe with water in a11proportions. Mercresin has a toxicity of the same order as that of other we11 known organic mercuria1 germicides. This statement is based on the resuIts of extensive studies of the ora1, intramuscuIar, intravenous and intraperitonea1 toxicity of mercresin in rats compared with other organic mercuria1 germicides. The foIlowing data on the bacteriostatic and bactericida1 potency of mercresin are TABLE GERMICIDAL
POWER
OF
STAPHYLOCOCCUS
*“REVS
-
Dilution of Active Ingredients
Subculture, Min“WS
t”R.
Minutes
_ 5 10 15
__
1-3
t--
+++
1-3
---
+++ ++-
r-5
+++ +++ +++
---
1-5 r-20
---
-----
*This represents i”p;redients.
IN
F.D.A.
STAPHYLOCOCCUS
T
BROTH
AIQD
AUREUS
AT
SERUM 37%.
Highest DiIutions Which Are Bacteriostatic
F.D.A. Broth
Serum Broth
_.._ Mercurochrome tincture. MerthioIate tincture. Metaphen tincture. HexyIresorcinoI. . Mercresin tincture.
~~~~~
r-40 r-800 I-300 I-20
I-20 1-400 r-80 x-10 (fails)
I-_3200
I-800
-
,--I
OUS).................
“SING
-
---
Mercurophen.. Mercuric chloride.. Hexylresorcinol (I-rooo aqueous). Mercresin tincture..
BROTH
ACTION
TOWARD
5 1or:
Mercurochrome (z per cent tincture). Merthiolate (I-I”“” tint ture)............... Metaphen (I-ZOO tincrure)................ Phenyl mercuric nitrata. P.M.N. (l-1250 aque-
TABLEII BACTERIOSTATIC
Product ANTISEPTICS
CdDilution of Comma&d Product
Product
TabIe n7 shows the data comparing the bacteriostatic or growth-inhibiting power of mercresin with severa other commercial products. ResuIts are expressed in diIutions of equa1 concentration (1-1000). For exampIe, mercresin 1-3200 means I voIume
I
VARIOUS
OTTOBER, 1936
et aI.-Mercresin
a I--zo.“o”
dilution
of rach
of
the
active
based on investigations by Dunn, of the Department of BacterioIogy of Massachusetts Institute of Technology6 and by the Department of BacterioIogy, Iowa State CoIIege.7 Table P shows the germicida1 power of mercresin compared with using the other commercial products, officia1 F.D.A. method at 37Oc. with StaphyIococcus aureus. The negative signs in the coIumn headed “CuIture” indicate a faiIure of growth. This might be due either to a bacteriostatic or a germicidal effect. The occurrence of growth in the subcuIture, as shown by a positive sign in that column, indicates that the faiIure of growth for the corresponding time period in the “CuIture” column was due to a bacteriostatic effect and not to the death of the organisms. OnIy hexyIresorcino1 and mercresin were IethaI at a11 time periods.
of mercresin diIuted to 3200 parts of water. The superiority of mercresin is apparent. The importance of testing germicides against a variety of bacteria rather than Iimiting the examination to the commonIy used test organisms has been emphasized repeatedly.*-11 TabIe IIP shows the diIutions of mercresin which are IethaI to a variety of organisms in five minutes. TABLE MAXIMUM WERE
DILUTIONS LETHAL
OF
III
MERCRESIN
TO VARIOUS
ORGANISMS
TINCTURE IN
WHICH
5 MINUTES
DiIutions of Mercresin Tincture 1-20 I--IO I-30 1-25
Organisms Staphylococcus aureus *Eschcrichia coIi (B. coli) Pseudomonas aeruginosa (B. pyocyaneus) Serratia pyoseptica (simiIar to B. prodigiosus) EbertheIIa typhosa (B. typhosus) I-3o Corynebacterium pseudodiphtherium (B. I-20 Hofmanni) Streptococcus hemoIyticus 1-25 1-20 Corynebacterium diphtheriae (B. diphtheriae) Tricophyton interdigitzde (ringworm) I-40 I--I20 Actinomyces I-20 Blastomyces * I0 minutes.
Since in preoperative use the interva1 of time between the application of the antiseptic and the start of the operation is brief, it is important to know the rapidity of the germicida1 action of mercresin. This
NEW
SERXES
VOL. XXXIV, No.
Maddock
,
et aI.-Mercresin
is given in TabIe IV.~ A dihrtion of I-IO kiIIed StaphyIococcus aureus in a minute, and in less time with greater concentrations. . TABLE IV THE RAPIDITY OF TKE GERMICIDAL ACTION OF MERCRESIN AGAINST STAPHYLOCOCCUSAUREUS BY A MODIFlED F.D.A.
PROCEDURE
DiIutions of Mercresin Tincture r-6 I-8 I-10
KiIIed Staphylococcus Aureus in I I seconds 30 seconds I minute 4 minutes 3 minutes
1-12 I-20
TabIe v6 shows the resuIts obtained with the serum cup-plate test using Staphylococcus aureus at 37’~. This represents the TABLE v PENETRABILITY OF VARIOUS GERMICIDES WITH SERUM CUP-PLATE TEST USING STAPHOLOCOCCUSAUREUS AT 37%. Product Tincture of iodine. HexyIresorcinoI MerthioIate. Metaphen. Mercresin tincture
Concentration of Active Ingredients
I
I-16 1-1000
I-1000 I-200 I-1000
Average Diameter in Mm. of Zone of No-growth
I
18.0 6.0 11.5 II.0 23.0
usua1 Iaboratory method of demonstrating the penetrabihty of germicida1 soIutions. The zone of no growth was wider for mercresin than for any of the other germicides tested. With such concIusive evidence in favor of this new preparation, it seemed worth whiIe to permit a tria1 of tincture mercresin as a preoperative skin antiseptic in the University HospitaI. The results proved so gratifying in 1200 cases that it has been adopted as the routine antiseptic for a11 genera1 surgica1 cases. The percentage of wound infections has remained consistentIy Iow. The stain foIIowing its appIication disappears spontaneousIy within three to four days or can be readiIy removed by washing the skin with aIcoho1 or water. The non-irritating properties of the antiseptic have been apparent. In only one instance has there been any reaction in the skin foIIowing its use, this taking the form of a fine vesicuIar eruption superimposed upon a diffuse erythema. This dermatitis disappeared within four days, leaving no residua1 changes in the skin.
American
Journal
of Surgery
49
An evaIuation of further uses of mercresin is being continued and wiI1 be reported Iater. DiIutions of mercresin of 1-15 are being found effective in various urologica treatments. SUMMARY
The characteristics of mercresin tincture which make this soIution a powerfu1 antiseptic have been presented. Its advantages are as fohows: I. High germicidal and bacteriostatic properties. 2. Rapid action. 3. Satisfactory penetrabiIity. 4. Sufficient coIor to define the extent of the fieId prepared as we11 as the abiIity to Iose this coIor rapidly. 5. The abiIity to dissoIve fat and degenerative ceIIuIar debris from the skin surface. Furthermore, its use in a large series of surgica1 cases has proved it to be nonirritating and has demonstrated its efficacy as a preoperative skin disinfectant. REFERENCES I. RUEWLE and BREWER. United States Food and Drug Administration Methods of Testing Antiseptics and Disinfectants. LJ. S. Department of AgricuIture, Washington, D. C. Circular #IQ~, 1931. 2. LEONARD, G. F. Limitations of pheno1 coefficient tests in determining germicida1 activities. .Z. Infect. Dis., 48: 358-365 (April) 1931. 3. LEONARD, G. F. and HISCOCK, E. A method of determining the germicida1 power of products which have a high bacteriostatic activity. Am. J. Pbarm., 105: 241-243 (May) 1933. 4. WHITE, E. C. and HILL, J. H. Inefficiency of metaphen as a skin disinfectant. J. A. M. A., ~5: 27-28 (JuIy 5) 1930. 5. LEONARD, V. PitfaIls in interpretation of experiments on skin disinfection. J. A. M. A., 94: 1524 (May IO) 1930. 6. DUNN. C. G. GermicidaI orooerties of some ohenoIic compounds. In press. 7. Unpublished report from Department of BacterioIogy, Iowa State CoIIege. 8. ALLEN, A. W. and WRIGHT, I. S. Determination of the value of antiseptics. J. A. M. A., 96: 92~~925 (March 21) 1931. Q. TINKER, M. B. and SUTTON,H. B. Inefficiency of most of the common.Iy used skin antiseptics. J. A.M. A., 87: 1347-1351, @ct. 23) 1926. IO. REDDISH, G. F. Examination of disinfectants. Am. J. Public He&b, 17: 320-32~ (ApriI) 1927. I I. REDDISH, G. F. Determining the germicidal efhciency of disinfectants. Am. J. Public He&b, 16: 283-286 (March) 1926. A