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Sulfamylon acetate in the treatment of pseudomonas pyocyanea infection of burns
SULFAMYLON A C E T A T E IN T H E T R E A T M E N T O F P S E U D O M O N A S PYOCYANEA INFECTION OF B U R N S By I. F. K. MUIR,M.B.E., V.R.D., M.S., F.R.C.S., D. OWEN,S.R.N., B.T.A. and JILL MURPHY,S.R.N., S.C.M. Mount Vernon Centre for Plastic and Reconstructive Surgery, Northwood, Middlesex
IN burns, pseudomonas infection is common and the difficulties of preventing infection increase as the size of the burn increases. Sachs (1967) has pointed out that patients with burns involving the buttocks, perineum, groins and thighs are particularly liable to become infected with pseudomonas and describes these as "pyo-prone ". Apart from the risks associated with invasive infection the main danger of pseudomonas infection is its power to cause loss of skin grafts and this may seriously delay the healing of the burn. Treatment by silver nitrate applications has recently been reintroduced and when used prophylactically has been shown to have a marked effect in preventing infection with pseudomonas and other organisms (Mayer et al., 1965; Cason et al., 1966; Cason and Lowbury, 1968). This treatment, however, carries considerable disadvantages. The use of polymyxins in local applications has had some success in prophylaxis against pseudomonas infection but even when this treatment is applied to fresh burns a disappointingly large proportion of patients become infected (Jackson et al., 1951 ; Cason and Lowbury, 196o). Once pseudomonas infection has become established it proves very difficult to eradicate and the results of treatment by polymyxins and other local agents have been disappointing. Sulfamylon hydrochloride (mafenide), a sulphonamide, has been shown to be particularly effective against Pseudomonas pyocyanea (Lindberg et al., 1965). Lindberg and his colleagues reported a reduction in the mortality rate from 64 to 19 per cent. in patients with 4o to 5o per cent. body surface burns. There were, however, certain unpleasant side effects. Some patients complained of considerable pain following the application of the cream and some patients developed skin sensitivity. The most serious complication, however, was hyperchlormmic acidosis due to the absorption of the Sulfamylon hydrochloride. It was thought that the use of the acetate of Sulfamylon might avoid the danger of acidosis. Sulfamylon acetate became available in the Burns Ward of the Mount Vernon Centre for Plastic Surgery in April 1967 and the first part of the present report concerns I 2 patients with extensive burns who have been treated by local application of Sulfamylon acetate cream. Preparation.--Sulfamylon (4-aminomethylbenzine-sulphonamide) differs from other sulphonamides in having the amino group separated from the benzine ring by a methyl group. The base is not soluble but the hydrochloride and the acetate are. In vitro, Sulfamylon acetate is active against a wide range of organisms and is unaffected by the presence of serum (Holt et aL, 1968). In the present trial Sulfamylon acetate was made up in a cream containing i 1.2 per cent. w/w in a hydrophylic cream base. CLINICAL MATERIAL In the Burns Ward of the Mount Vernon Centre for Plastic Surgery, treatment by exposure has been, for many years, the routine treatment for extensive burns.
202
BRITISH
JOURNAL
or
PLASTIC
SURGERY
Pseudomonas infection has been endemic in the ward ; during the period immediately preceding the present trial, for example, IO out of I2 patients with burns of 15 per cent. body surface or over became infected with pseudomonas. When Sulfamylon acetate first became available, patients were treated initially by exposure and Sulfamylon was used only if pseudomonas infection occurred. Later, a small number of patients who were considered to be " p y o - p r o n e " were treated prophylactically by application of Sulfamylon from an early stage. During the nine months April to December 1967 inclusive, 3° patients with burns were treated by local application of Sulfamylon cream. A number of patients with small burns were transferred to other wards or soon discharged, and we have selected for analysis the results in 12 patients with burns of 15 per cent. body surface or more, who remained in the ward for at least one week. Two additional patients, both elderly, died soon after burning from causes unconnected with infection and are not included in the analysis. Seven of the patients had established infection with Pseudomonas pyocyanea before commencing treatment with Sulfamylon, while five were treated prophylactically from an early stage. Mode ofApplication.--The Sulfamylon acetate cream was applied by first spreading it on large gauze squares (8-ply), which were then laid directly on the burned surface. No absorptive dressing was placed outside the layers of gauze. The gauze packs were changed every two days, except after grafting when they were left undisturbed for five to seven days. When the burn was mostly healed either spontaneously or after skin grafting, treatment by Sulfamylon was discontinued. The ease with which the dressings could be removed was noticeable and compared well with other topical applications which we have used. There was little bleeding at change of dressings and the granulations were pale compared with those produced following applications such as Eusol. This did not seem to have any detrimental effect on the take of skin grafts. Complications.--In the initial group of 3o patients, no adverse reaction to the use of Sulfamylon acetate was noted. In later trials one patient complained of severe pain immediately after application of the cream and treatment had to be abandoned. One further patient also developed a skin sensitivity and treatment by Sulfamylon was discontinued. Absorption.--There were no obvious metabolic disturbances in the patients but blood levels of three patients with burns of 35 per cent. or more were estimated and these studies have been reported separately (Holt et al., 1968 ). Two patients showed no detectable Sulfamylon in the blood, and the third showed 15 to 20 tzg./ml. Treatment of Established Pseudomonas Infection .(see Table).--When used for treatment of established pseudomonas infection, treatment over a period of seven days was usually found to be sufficient to render the dressings free from the typical odour and green staining associated with pseudomonas infection. Bacteriological cultures showed that after seven days the growth of pseudomonas was greatly reduced and within a further seven days was eliminated. However, later when healing had advanced to the point where the cream was no longer being used, reappearance of pseudomonas in the bacteriological cultures was observed in some cases. One patient (D. N.) had pseudomonas septica~mia before treatment was commenced. The septica:mia was not controlled and he died. Prophylactic Treatment (see Table).--Partial thickness burns healed well in the presence of Sulfamylon acetate and surviving epithelium enabled spontaneous healing to take place. No case treated prophylactically by the cream developed pseudomonas infection, although four of them fell into the "pyo-prone" group.
PSEUDOMONAS
PYOCYANEA
INFECTION
OF
203
BURNS
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204
BRITISH JOURNAL OF PLASTIC SURGERY ILLUSTRATIVE CASE HISTORIES
Treatment of established infection Patient J. J.--A 6-year-old girl sustained burns when her nightdress caught fire. Fifty per cent. of the body surface was burned and it was thought that most of this was of full thickness depth. The areas involved were the trunk, the neck, the arms, both hands and thighs. She was treated initially by exposure. The burn became infected with pseudomonas and treatment with Sulfamylon acetate was commenced. Eight days after the beginning of treatment the heavy growth of pseudomonas had been reduced and by 22 days the cultures were negative. Because of the small areas available for donor sites, three skin grafting operations were performed using the same donor site each time. Fifty-five days after burning grafting was completed and shortly afterwards she was discharged to convalescence.
Prophylactic use Patient N. P.mA 69-year-old woman was burned when her pyjamas caught alight on an electric fire. There were deep burns of the arms, trunk, buttocks, perineum and legs involving 35 per cent. of body surface. She was admitted to hospital on the day of the injury and treated initially by exposure, but after two days, treatment with Sulfamylon acetate was commenced. In spite of difficulties in nursing the patient, the burns remained clean and no pseudomonas was cultured during her stay in hospital. Skin grafting was performed 54 days after burning with IOO per cent. take of graft. Residual raw areas were covered by skin homografts 79 days after burning. These grafts were replaced by epithelial ingrowth as they were rejected and no further grafting was required. She was discharged home four and a half months after injury. C o n t r o l l e d T r i a l . ~ I n view of the encouraging results obtained in the preliminary survey it was decided to set up a controlled trial in order to assess more precisely the effectiveness of Sulfamylon in preventing infection with pseudomonas. During the course of one year all the patients with fresh burns of over 7 per cent. of body surface area admitted to the ward were included in the trial. Patients were allotted alternately to the Sulfamylon group, who were treated by application of Sulfamylon cream every other day as described above, or to the control group who received similar treatment except that the local application was N.C.P. cream (Neomycin Chlorhexidine Polymyxin) (Cason and Lowbury, 196o). N.C.P. cream was used because this was the application which we had previously found most effective in preventing and controlling the infection. There were 21 patients in the Sulfamylon group and 23 in the N.C.P. group. Swabs for bacteriological culture were taken once a week or more often if indicated.
Results.--Pseudomonas infection.roOf the 23 N.C.P. cases four (16 per cent.) grew pseudomonas in the cultures at one time or other, while of the 21 Sulfamylon cases three (14 per cent.) grew pseudomonas. In none of the cases was the growth reported as more than slight, and in none of the cases was clinical pyocyaneas infection manifest by the presence of blue green pus or by clinical illness. In none of the cases did the infection appear to affect the clinical progress of the patient adversely, and there was no interference with the taking of grafts. Proteus infection.--The N.C.P. group showed no cases with proteus infection, but in the Sulfamylon group 6 out of 12 (29 per cent.) developed a proteus infection. Staphylococcal infection.--In the N.C.P. group I I out of 23 (48 per cent.) grew Staphylococcus aureus. In the Sulfamylon group 2o (95 per cent.) grew Staphylococcus aureus at one time or another. In neither of the groups, however, did staphylococcal infection cause any serious trouble although the take of grafts in the presence of staphylococcal and proteus infection was slightly less good. The total number of bacteriological cultures in the N.C.P. group was lO8, and of these 36 were reported as
PSEUDOMONAS
PYOCYANEA
I N F E C T I O N OF BURNS
205
showing no growth (3o per cent.), while in the Sulfamylon group 20 out of a total of I49 (I 4 per cent.) were reported as showing no growth. DISCUSSION
As a comparison between the two applications the results of the controlled trial are clearly inconclusive, and the striking feature of the trial was the low incidence of infection in both groups, both when judged clinically and also on the results of the bacteriological cultures. The overall incidence of pseudomonas infection in the whole trial, 6 out of 44 cases, was low when compared with our previous experiences, particularly when it is recalled that the majority of these patients had large burns over 15 per cent. Even when pseudomonas was demonstrated bacteriologically it did not cause clinical illness. Both proteus and staphylococcal infection occurred more frequently in the Sulfamylon group and gave rise to some trouble clinically, although this was not serious. It should be noted that before the present trial, it was the practice to change dressings less frequently, perhaps only once in four days. In the present trial dressings were done every other day because previous reports had suggested the Sulfamylon should be changed frequently. It is therefore possible that the low overall rate of infection may be associated with the frequency of change of dressings and this point needs further study. For treatment of established pseudomonas infection Sulfamylon is the most effective substance we have used. The occasional reappearance of pseudomonas organisms in patients who were almost healed and who were no longer having Sulfamylon applications suggests that the organisms may not be completely eliminated, but are so reduced in activity that they cease to have serious effects, and do not interfere with the taking of grafts. Sulfamylon does not appear to be very effective against proteus or staphylococcal infection and in order to achieve protection against these organisms it would be necessary to combine Sulfamylon with some other antiseptic. SUMMARY
Sulfamylon acetate is a synthetic antiseptic which is particularly active against Pseudomonas pyocyanea. It is free from the disadvantages of the hydrochloride previously used. Seven patients with extensive burns infected with pseudomonas were treated. In six the infection was soon brought under control and these patients recovered. One patient already had septic~emia when treatment was commenced and he died. Five patients with extensive burns were treated prophylactically and none became infected with pseudomonas. The use of Sulfamylon acetate has reduced the incidence of pseudomonas infection in the ward as a whole. In a controlled trial comparing Sulfamylon with N.C.P. cream there was no significant difference in the incidence of pseudomonas infection. Staphylococcus aureus and Bacillus proteus were more frequent in the Sulfamylon group than in the N.C.P. group, but the incidence of significant clinical infection was very low in both groups. It is suggested that the frequency of dressings may have something to do with this result. We wish to thank the Bayer Products Company for the supply of Sulfamylon and in particular Mr. P. J. O'Donnell for assisting with the trial arrangements. The bacteriological investigations were carried out under the supervision of Dr. IV. Andrews, Consultant Pathologist, Mount Vernon Hospital, and we are grateful to him for his assistance.
206
BRITISH JOURNAL OF PLASTIC SURGERY REFERENCES BARCLAY,T. L. and DEXTER,F. (1968). Hr. J. Surg. 52, 197. CASON,J. S., JACKSON,D. M., LOWBIYRY,E. J. L. and RICKETTS,C. R. (1966). Hr. reed. J. 2, 1288. CASON, J. S. and LOWBURY,E. J. L. (I96o). Lancet, 2, 5Ol. (1968). Lancet, 1, 651. DOMAGK,G. (1942). Medizin Chem. 4, 82. HOLTj R. J., MURPHY,R. and O'DoNNELL, P. J. (1968). Hr. J. plast. Surg. 21, lO6. JACKSON,n . M., LOWBURY,E. J. L. and TOPLEY, E. (1951). Lancet, 2, 137. LINDBERG, R. B., MONCRIEF, J. A., SWlTZER,W. E., ORDER, S. E. and MILLS, W. (1965). J. Trauma~ 5, 6Ol. MILLER, E., SPRAGUE,J. M., KlSSENGER,L. W. and MCBuRNEY, L. F. (194o). J. Am. chem. Soc. 62, 2o99. MONCRIEF,J. A., LINDBERG,R. B., SWITZER,W. E. and PRUITT,B. A. (1966). ft. Trauma, 6, 4o7. MOYER, C. A., BRElqTANO,L., GRAVENS,D. L., MARGRAF,H. W. and MONAFO,W. W. Jr. (1965). Archs Surg., Chicago, 9o, 381. SACHS, A. (1967). Unpublished work.
IN burns, pseudomonas infection is common and the difficulties of preventing infection increase as the size of the burn increases. Sachs (1967) has pointed out that patients with burns involving the buttocks, perineum, groins and thighs are particularly liable to become infected with pseudomonas and describes these as "pyo-prone ". Apart from the risks associated with invasive infection the main danger of pseudomonas infection is its power to cause loss of skin grafts and this may seriously delay the healing of the burn. Treatment by silver nitrate applications has recently been reintroduced and when used prophylactically has been shown to have a marked effect in preventing infection with pseudomonas and other organisms (Mayer et al., 1965; Cason et al., 1966; Cason and Lowbury, 1968). This treatment, however, carries considerable disadvantages. The use of polymyxins in local applications has had some success in prophylaxis against pseudomonas infection but even when this treatment is applied to fresh burns a disappointingly large proportion of patients become infected (Jackson et al., 1951 ; Cason and Lowbury, 196o). Once pseudomonas infection has become established it proves very difficult to eradicate and the results of treatment by polymyxins and other local agents have been disappointing. Sulfamylon hydrochloride (mafenide), a sulphonamide, has been shown to be particularly effective against Pseudomonas pyocyanea (Lindberg et al., 1965). Lindberg and his colleagues reported a reduction in the mortality rate from 64 to 19 per cent. in patients with 4o to 5o per cent. body surface burns. There were, however, certain unpleasant side effects. Some patients complained of considerable pain following the application of the cream and some patients developed skin sensitivity. The most serious complication, however, was hyperchlormmic acidosis due to the absorption of the Sulfamylon hydrochloride. It was thought that the use of the acetate of Sulfamylon might avoid the danger of acidosis. Sulfamylon acetate became available in the Burns Ward of the Mount Vernon Centre for Plastic Surgery in April 1967 and the first part of the present report concerns I 2 patients with extensive burns who have been treated by local application of Sulfamylon acetate cream. Preparation.--Sulfamylon (4-aminomethylbenzine-sulphonamide) differs from other sulphonamides in having the amino group separated from the benzine ring by a methyl group. The base is not soluble but the hydrochloride and the acetate are. In vitro, Sulfamylon acetate is active against a wide range of organisms and is unaffected by the presence of serum (Holt et aL, 1968). In the present trial Sulfamylon acetate was made up in a cream containing i 1.2 per cent. w/w in a hydrophylic cream base. CLINICAL MATERIAL In the Burns Ward of the Mount Vernon Centre for Plastic Surgery, treatment by exposure has been, for many years, the routine treatment for extensive burns.
202
BRITISH
JOURNAL
or
PLASTIC
SURGERY
Pseudomonas infection has been endemic in the ward ; during the period immediately preceding the present trial, for example, IO out of I2 patients with burns of 15 per cent. body surface or over became infected with pseudomonas. When Sulfamylon acetate first became available, patients were treated initially by exposure and Sulfamylon was used only if pseudomonas infection occurred. Later, a small number of patients who were considered to be " p y o - p r o n e " were treated prophylactically by application of Sulfamylon from an early stage. During the nine months April to December 1967 inclusive, 3° patients with burns were treated by local application of Sulfamylon cream. A number of patients with small burns were transferred to other wards or soon discharged, and we have selected for analysis the results in 12 patients with burns of 15 per cent. body surface or more, who remained in the ward for at least one week. Two additional patients, both elderly, died soon after burning from causes unconnected with infection and are not included in the analysis. Seven of the patients had established infection with Pseudomonas pyocyanea before commencing treatment with Sulfamylon, while five were treated prophylactically from an early stage. Mode ofApplication.--The Sulfamylon acetate cream was applied by first spreading it on large gauze squares (8-ply), which were then laid directly on the burned surface. No absorptive dressing was placed outside the layers of gauze. The gauze packs were changed every two days, except after grafting when they were left undisturbed for five to seven days. When the burn was mostly healed either spontaneously or after skin grafting, treatment by Sulfamylon was discontinued. The ease with which the dressings could be removed was noticeable and compared well with other topical applications which we have used. There was little bleeding at change of dressings and the granulations were pale compared with those produced following applications such as Eusol. This did not seem to have any detrimental effect on the take of skin grafts. Complications.--In the initial group of 3o patients, no adverse reaction to the use of Sulfamylon acetate was noted. In later trials one patient complained of severe pain immediately after application of the cream and treatment had to be abandoned. One further patient also developed a skin sensitivity and treatment by Sulfamylon was discontinued. Absorption.--There were no obvious metabolic disturbances in the patients but blood levels of three patients with burns of 35 per cent. or more were estimated and these studies have been reported separately (Holt et al., 1968 ). Two patients showed no detectable Sulfamylon in the blood, and the third showed 15 to 20 tzg./ml. Treatment of Established Pseudomonas Infection .(see Table).--When used for treatment of established pseudomonas infection, treatment over a period of seven days was usually found to be sufficient to render the dressings free from the typical odour and green staining associated with pseudomonas infection. Bacteriological cultures showed that after seven days the growth of pseudomonas was greatly reduced and within a further seven days was eliminated. However, later when healing had advanced to the point where the cream was no longer being used, reappearance of pseudomonas in the bacteriological cultures was observed in some cases. One patient (D. N.) had pseudomonas septica~mia before treatment was commenced. The septica:mia was not controlled and he died. Prophylactic Treatment (see Table).--Partial thickness burns healed well in the presence of Sulfamylon acetate and surviving epithelium enabled spontaneous healing to take place. No case treated prophylactically by the cream developed pseudomonas infection, although four of them fell into the "pyo-prone" group.
PSEUDOMONAS
PYOCYANEA
INFECTION
OF
203
BURNS
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204
BRITISH JOURNAL OF PLASTIC SURGERY ILLUSTRATIVE CASE HISTORIES
Treatment of established infection Patient J. J.--A 6-year-old girl sustained burns when her nightdress caught fire. Fifty per cent. of the body surface was burned and it was thought that most of this was of full thickness depth. The areas involved were the trunk, the neck, the arms, both hands and thighs. She was treated initially by exposure. The burn became infected with pseudomonas and treatment with Sulfamylon acetate was commenced. Eight days after the beginning of treatment the heavy growth of pseudomonas had been reduced and by 22 days the cultures were negative. Because of the small areas available for donor sites, three skin grafting operations were performed using the same donor site each time. Fifty-five days after burning grafting was completed and shortly afterwards she was discharged to convalescence.
Prophylactic use Patient N. P.mA 69-year-old woman was burned when her pyjamas caught alight on an electric fire. There were deep burns of the arms, trunk, buttocks, perineum and legs involving 35 per cent. of body surface. She was admitted to hospital on the day of the injury and treated initially by exposure, but after two days, treatment with Sulfamylon acetate was commenced. In spite of difficulties in nursing the patient, the burns remained clean and no pseudomonas was cultured during her stay in hospital. Skin grafting was performed 54 days after burning with IOO per cent. take of graft. Residual raw areas were covered by skin homografts 79 days after burning. These grafts were replaced by epithelial ingrowth as they were rejected and no further grafting was required. She was discharged home four and a half months after injury. C o n t r o l l e d T r i a l . ~ I n view of the encouraging results obtained in the preliminary survey it was decided to set up a controlled trial in order to assess more precisely the effectiveness of Sulfamylon in preventing infection with pseudomonas. During the course of one year all the patients with fresh burns of over 7 per cent. of body surface area admitted to the ward were included in the trial. Patients were allotted alternately to the Sulfamylon group, who were treated by application of Sulfamylon cream every other day as described above, or to the control group who received similar treatment except that the local application was N.C.P. cream (Neomycin Chlorhexidine Polymyxin) (Cason and Lowbury, 196o). N.C.P. cream was used because this was the application which we had previously found most effective in preventing and controlling the infection. There were 21 patients in the Sulfamylon group and 23 in the N.C.P. group. Swabs for bacteriological culture were taken once a week or more often if indicated.
Results.--Pseudomonas infection.roOf the 23 N.C.P. cases four (16 per cent.) grew pseudomonas in the cultures at one time or other, while of the 21 Sulfamylon cases three (14 per cent.) grew pseudomonas. In none of the cases was the growth reported as more than slight, and in none of the cases was clinical pyocyaneas infection manifest by the presence of blue green pus or by clinical illness. In none of the cases did the infection appear to affect the clinical progress of the patient adversely, and there was no interference with the taking of grafts. Proteus infection.--The N.C.P. group showed no cases with proteus infection, but in the Sulfamylon group 6 out of 12 (29 per cent.) developed a proteus infection. Staphylococcal infection.--In the N.C.P. group I I out of 23 (48 per cent.) grew Staphylococcus aureus. In the Sulfamylon group 2o (95 per cent.) grew Staphylococcus aureus at one time or another. In neither of the groups, however, did staphylococcal infection cause any serious trouble although the take of grafts in the presence of staphylococcal and proteus infection was slightly less good. The total number of bacteriological cultures in the N.C.P. group was lO8, and of these 36 were reported as
PSEUDOMONAS
PYOCYANEA
I N F E C T I O N OF BURNS
205
showing no growth (3o per cent.), while in the Sulfamylon group 20 out of a total of I49 (I 4 per cent.) were reported as showing no growth. DISCUSSION
As a comparison between the two applications the results of the controlled trial are clearly inconclusive, and the striking feature of the trial was the low incidence of infection in both groups, both when judged clinically and also on the results of the bacteriological cultures. The overall incidence of pseudomonas infection in the whole trial, 6 out of 44 cases, was low when compared with our previous experiences, particularly when it is recalled that the majority of these patients had large burns over 15 per cent. Even when pseudomonas was demonstrated bacteriologically it did not cause clinical illness. Both proteus and staphylococcal infection occurred more frequently in the Sulfamylon group and gave rise to some trouble clinically, although this was not serious. It should be noted that before the present trial, it was the practice to change dressings less frequently, perhaps only once in four days. In the present trial dressings were done every other day because previous reports had suggested the Sulfamylon should be changed frequently. It is therefore possible that the low overall rate of infection may be associated with the frequency of change of dressings and this point needs further study. For treatment of established pseudomonas infection Sulfamylon is the most effective substance we have used. The occasional reappearance of pseudomonas organisms in patients who were almost healed and who were no longer having Sulfamylon applications suggests that the organisms may not be completely eliminated, but are so reduced in activity that they cease to have serious effects, and do not interfere with the taking of grafts. Sulfamylon does not appear to be very effective against proteus or staphylococcal infection and in order to achieve protection against these organisms it would be necessary to combine Sulfamylon with some other antiseptic. SUMMARY
Sulfamylon acetate is a synthetic antiseptic which is particularly active against Pseudomonas pyocyanea. It is free from the disadvantages of the hydrochloride previously used. Seven patients with extensive burns infected with pseudomonas were treated. In six the infection was soon brought under control and these patients recovered. One patient already had septic~emia when treatment was commenced and he died. Five patients with extensive burns were treated prophylactically and none became infected with pseudomonas. The use of Sulfamylon acetate has reduced the incidence of pseudomonas infection in the ward as a whole. In a controlled trial comparing Sulfamylon with N.C.P. cream there was no significant difference in the incidence of pseudomonas infection. Staphylococcus aureus and Bacillus proteus were more frequent in the Sulfamylon group than in the N.C.P. group, but the incidence of significant clinical infection was very low in both groups. It is suggested that the frequency of dressings may have something to do with this result. We wish to thank the Bayer Products Company for the supply of Sulfamylon and in particular Mr. P. J. O'Donnell for assisting with the trial arrangements. The bacteriological investigations were carried out under the supervision of Dr. IV. Andrews, Consultant Pathologist, Mount Vernon Hospital, and we are grateful to him for his assistance.
206
BRITISH JOURNAL OF PLASTIC SURGERY REFERENCES BARCLAY,T. L. and DEXTER,F. (1968). Hr. J. Surg. 52, 197. CASON,J. S., JACKSON,D. M., LOWBIYRY,E. J. L. and RICKETTS,C. R. (1966). Hr. reed. J. 2, 1288. CASON, J. S. and LOWBURY,E. J. L. (I96o). Lancet, 2, 5Ol. (1968). Lancet, 1, 651. DOMAGK,G. (1942). Medizin Chem. 4, 82. HOLTj R. J., MURPHY,R. and O'DoNNELL, P. J. (1968). Hr. J. plast. Surg. 21, lO6. JACKSON,n . M., LOWBURY,E. J. L. and TOPLEY, E. (1951). Lancet, 2, 137. LINDBERG, R. B., MONCRIEF, J. A., SWlTZER,W. E., ORDER, S. E. and MILLS, W. (1965). J. Trauma~ 5, 6Ol. MILLER, E., SPRAGUE,J. M., KlSSENGER,L. W. and MCBuRNEY, L. F. (194o). J. Am. chem. Soc. 62, 2o99. MONCRIEF,J. A., LINDBERG,R. B., SWITZER,W. E. and PRUITT,B. A. (1966). ft. Trauma, 6, 4o7. MOYER, C. A., BRElqTANO,L., GRAVENS,D. L., MARGRAF,H. W. and MONAFO,W. W. Jr. (1965). Archs Surg., Chicago, 9o, 381. SACHS, A. (1967). Unpublished work.