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A Clinical Evaluation of 25 Cases Treated with Terramycin Intramuscular*
A CLINICAL EVALUATION OF 25 OASES TREATED WITH TERRAMYCIN INTRAMUSCULAR* THEO
F.
MIDDLETON, LIEUTENANT (MC)
USNR
(From the Department of Obstetrics and Gynecology, U. S. Naval Hospital, Memphis, Tenn.)
hydrochloridet is not a new antimicrobial agent any longer. TERRAMYCIN Its broad spectrum of bactericidal action is well known and has been pre-
viously reported by many workers. 1 • 4 The oral form of this drug has been clinically tried and proved. Toxic reactions, blood levels, and limitations of use are all well known. It is not the purpose of this report to evaluate the drug Terramycin, but to help determine whether or not local administration of the crystalline hydrochloride is feasible. To be able to administer a broadspectrum antibiotic by the intramuscular route has not yet been clinically possible until the advent of Terramycin Intramuscular (T.LM.). Such a route of administration would prove a valuable one in our armamentarium of drugs for parenteral use where necessary, when oral therapy is not practical nor possible, as in gastrointestinal obstruction, lack of patient cooperation, i.e., coma, postoperative shock, nausea, and other contraindications to oral therapy. The accepted dose recommended by previous workers and adhered to in this report was 100 mg. twice a day. Higher dosage may be used but this has been found to be an optimum dose for most acute infections of mild and moderate severity. It has been recommended that 200 mg. doses every 8 to 12 hours be used for severe infections. 1t has already been shown that 100 mg. of Terramycin Intramuscular will produce a blood level equivalent to 500 mg. of the oral drug. 5 These levels are maintained for at least 9 hours, reaching a peak between 4 and 6 hours after administration. Therapeutic levels of over 1.5 mg. per milliliter are reached by 2 hours and a height of 2.5 mg. by 4 hours. These levels have been found to parallel the blood levels of a 500 mg. oral capsule. Daily intramuscular doses of above 200 mg. may be used but this report ineluded only eases treated with 100 mg. twice a day, with a total of 200 mg. in 24 hours. Administration The drug was supplied in 250 mg. vials in the form o£ hydrochloric salt with the addition of magnesium chloride to improve local tissue tolerance. Also included in the vial was 2 per cent procain hydrochloride to alleviate pain and discomfort at the site of injection.
•Presented at a meeting of the Memphis and Shelby County Medical Society, Jan. 5, 1954. tTerramycin Intramuscular contains 100 mg. oxytetracycline hydrochloride and 50 mg. procaine hydrochloride, 100 mg. of sodium glycinate, 100 mg. of polyvinyl pyrrolidone and 0.2 per cent sodium bisulfite as a preservative and is manufactured by Pfizer Laboratories.
1287
1288
1vfiDDLETOli
& G:rne(. June, 195S
Am j. Ohst.
Sterile water was used as a diluent in these 25 cases. Physiologic saline will be used in later cases. The drug was administered with care through 22 gauge needles, into the lateral aspect of the thigh muscles. Care was observed to avoid injection into fat and subcutaneous tissues where sequelae are reported to be more prominent. Each injection totaled 100 mg., utilizing 50 mg. to 1 c.c. diluent, or a 2 c.c. total injection. NO. OF MORBID TOTAL INITIALS NUMBER DAYS NUMBER AND OF AFTER OF HOSPITAL START OF INJEC· CASE CHART NO. r NUMBER I DAYS 1 DRUG 1 TIO:t~S 1
1 M.M. 2 E.T.
3 7
2 0
6
7
3
v.s.
10
0
8
4
D.B.
7
0
4
4
0
2
5 J.J.
6
E.B.
7
0
7
7 8
B.R. B.R.
5 4
1 0
4 4
9
R.
s.
7
0
14
10
v. R.
8
5
5
11
M.W.
4
1
3
12 C.P.
10
2
14
13 K.M.
5
1
6
14
8
0
5
6
0
12
M.D.
45197 15
C. M.C.
43252
PAIN
None With 6th shot
Infected. incomtlete abortion Adominal hystereeto:m...y1 ~ingo oophorectomy, appenaeetomy, multipie :iibroids With 7th Cesarean section, wound dehiscence, shot secondary closure None Low cesarean section, 30 hours, trial labor, ruptured men~.branes None 6 months premature delivery of stillborn infant with shock and he:nwrrhage, manual removal of retaiired placeD.tar With 5th Left taboovarian abscess subacute, shot surgieally removed None Pyelitis of pregnancy With 3rd InMmplete abortion shot None Vaginal hysterectomy (medicine neglooted to· be diseontinued) With Srd Pyelitis. Poor response to Terramycin. shot SulfaqJ~zine used None Acute salpingitis With 2nd Third-degree tear, Rectal contaminashot tion With Srd Third-degree laceration shot None Placenta previa. Vag~naJ del~very, ruptured membranes 48 hours None Pyelitis
7
0
6
None
45602 17 D.B.
9
5
6
45700 L. S.
7
With.4th shot
0
10
None
Third-degree- laceration
19 M.W.
5
0
6
None
Third·degree laceration
46739 G. B.
8
0
13
M.D.
5
2
6
16
18
20 21
J.K.
Secondary closu.-.oe of episictomy with hematoma Pyelitis. Drug changed to sulfadi~e
45764
45952
46051
With 6th ·Third-degree laceration shot None Pyelitis of pregnaney
22
'\V.
~~-
7
0
5
23
47132 B.G. 47026
6
0
4
24 E.C. 47093
6
2
7
Vlith 3rd Third-degree laceration shot With 2nd Ruptured corpus luteum with hemo· shot peritoneum, shock Postpartal sepsis. Acute endometritis None
25
4
0
8
None
G.M.
Volume 69 :-iumher 6
CLINICAL EVALUATION OF TERRAMYCIN INTRAMUSCULAR
1289
The d1·ug was administered in the 25 cases in Table I. All patients were told it was Terramycin in intramuscular form, though none were told it was a clinical study. All were asked to report any local reactions of unusual nature to delineate clearly the amount of discomfort they experienced, and to report any reactions of a systemic or general nature.
Reactions In the 25 cases, 170 intramuscular doses of 100 mg. of Terramycin were given by various registered nurses. There was no reported deep abscess formation, skin discoloration, or subcutaneous skin reaction at the site of injection. There were numerous complaints of pain which are further tabulated. In no case was a report made of generalized skin reaction, and no unusual systemic reaction was recorded. As mentioned, the most distressing difficulty encountered was the complaint of pain. In 25 cases 44 ver cent suffered pain at the site of injection. At no time was the pain severe enough to merit discontinuing the drug. There were 2 patients who received a total of 14 shots each, one a total of 13, and another a total of 10. In none of these patients was the pain unusual, though it was present after the third shot in 3 of these cases. In all cases where pain was experienced, it was found the discomfort disappeared 24 to 48 hours after the drug was discontinued. If the number of injections is greater some residual soreness may remain for a longer period of time. Discussion of Oases The 25 cases were chosen at random from the service here at U. S. Naval Hospital, Memphis, Tennessee. In each instance, infection was known to be present by clinical manifestation, or could be expected from known contamination during delivery or surgery. Morbidity was defined as a temperature of 100.4° F. for two successive days, or over 101. 0 :B'. for any one day, excluding the day medication was started. In 15 of the 25 cases, there were no morbid days after the start of the drug. Of the 10 patients who did show morbidity, only two were found to be resistant to Terramycin therapy. These two had pyelitis. Both responded to sulfadiazine. The total number of morbid days for the 25 patients in the study was 21. 'l'he total number of hospital days was 159. 'l'hough this series is yet small, it is believed the use of intramuscular Terramycin will lower morbidity appreciably in the cases usually classified as potentially infected ones, i.e., those with ruptured membranes of long duration, rectal and vaginal surgery, secondary surgical procedures, and manual invasion of the uterus. This will, in turn, reduce the number of hospital days a group of patients of this type will incur. This is a prime consideration to all oi us and to the private patient, with our present high cost of hospitalization. In these 25 cases, none were hospitalized over 10 days. The average for the group was 6.3 days. Comments From the observations made in this small series, it is believed Terramycin Intramuscular will prove a valuable addition to the parenteral antibiotics in the broad-spectrum group. The intramuscular route of administration of Terramycin is much easier than the previously developed intravenous route and is apparently most efficacious in acute infections of mild and moderate severity.
1\'lll.J.ULJ:.i'l'V.i'l
Am. J. Ubst.
~ \..iynec. June, 19.15
The use of Terramycin in surgery and obstetrics should become general after consideration of the clinical results in these 25 cases. The only undesirable factor found in administration of this new rm:-paration is the pain experienced at the site of injection. Forty-four per cent of the patients who received the drug complained of pain of varying degrees of severity and until this pain is eliminated or reduced to a smaller percentage it may prove a retarding factor in the acceptance of the intramuscular route of administration of Terramycin.
Conclusions 1. Terramycin can be safely administered intramuscularly. 2. A dose of 100 mg. twice a day will adequately control most acute infections of mild and moderate severity. 3. Pain at the site of injection is the only apparent limitation of use of Terramycin Intramuscular. There were no syste-mic reactions r&tad in_- this series. 4. The amount of pain at the injection site, though a problem at present, does not prohibit the use of the intramuscular preparation where necessary. I wish to express my appreciation to Harry Seneca, M.D., of the Pfizer Laboratories for his assistance in the prep1uation of this report. In addition I wish to express my grati· tude to the nursing personnel of the U. S. Naval Hospital, Memphis, 1'ennessee, and to Mrs. Helen Meadows and Mrs. Alice Hulseherg for their efforts in the preparation of this manuscript.
References 1. Reed, M. Nesbit, Adcock, John, Brown, W. C., and Owen, Col'a R.: J. Urol. 65,:336, 1951. 2. Caldwell, E. R., Jr., Spies, H. W., Wolfe, C. K., Lepper, M. H., and Dowling, .H. F.: J. Lab. & Clin. Med. 36: 747, 1950.
3. Jackson, G. G., et al.: Ann. Int. Med. 35: 1175, 1951. 4. Miller. F. L .• and Walker. Rhev: New Eneland J. Med. 249.:.-479, 1953. 5. Wagner, Henry J., Jr.: Bull. Johns Hopkins Hosp. 91: 75, 1952. 1302 GOVERNMENT ST. MOBILE, ALA.
F.
MIDDLETON, LIEUTENANT (MC)
USNR
(From the Department of Obstetrics and Gynecology, U. S. Naval Hospital, Memphis, Tenn.)
hydrochloridet is not a new antimicrobial agent any longer. TERRAMYCIN Its broad spectrum of bactericidal action is well known and has been pre-
viously reported by many workers. 1 • 4 The oral form of this drug has been clinically tried and proved. Toxic reactions, blood levels, and limitations of use are all well known. It is not the purpose of this report to evaluate the drug Terramycin, but to help determine whether or not local administration of the crystalline hydrochloride is feasible. To be able to administer a broadspectrum antibiotic by the intramuscular route has not yet been clinically possible until the advent of Terramycin Intramuscular (T.LM.). Such a route of administration would prove a valuable one in our armamentarium of drugs for parenteral use where necessary, when oral therapy is not practical nor possible, as in gastrointestinal obstruction, lack of patient cooperation, i.e., coma, postoperative shock, nausea, and other contraindications to oral therapy. The accepted dose recommended by previous workers and adhered to in this report was 100 mg. twice a day. Higher dosage may be used but this has been found to be an optimum dose for most acute infections of mild and moderate severity. It has been recommended that 200 mg. doses every 8 to 12 hours be used for severe infections. 1t has already been shown that 100 mg. of Terramycin Intramuscular will produce a blood level equivalent to 500 mg. of the oral drug. 5 These levels are maintained for at least 9 hours, reaching a peak between 4 and 6 hours after administration. Therapeutic levels of over 1.5 mg. per milliliter are reached by 2 hours and a height of 2.5 mg. by 4 hours. These levels have been found to parallel the blood levels of a 500 mg. oral capsule. Daily intramuscular doses of above 200 mg. may be used but this report ineluded only eases treated with 100 mg. twice a day, with a total of 200 mg. in 24 hours. Administration The drug was supplied in 250 mg. vials in the form o£ hydrochloric salt with the addition of magnesium chloride to improve local tissue tolerance. Also included in the vial was 2 per cent procain hydrochloride to alleviate pain and discomfort at the site of injection.
•Presented at a meeting of the Memphis and Shelby County Medical Society, Jan. 5, 1954. tTerramycin Intramuscular contains 100 mg. oxytetracycline hydrochloride and 50 mg. procaine hydrochloride, 100 mg. of sodium glycinate, 100 mg. of polyvinyl pyrrolidone and 0.2 per cent sodium bisulfite as a preservative and is manufactured by Pfizer Laboratories.
1287
1288
1vfiDDLETOli
& G:rne(. June, 195S
Am j. Ohst.
Sterile water was used as a diluent in these 25 cases. Physiologic saline will be used in later cases. The drug was administered with care through 22 gauge needles, into the lateral aspect of the thigh muscles. Care was observed to avoid injection into fat and subcutaneous tissues where sequelae are reported to be more prominent. Each injection totaled 100 mg., utilizing 50 mg. to 1 c.c. diluent, or a 2 c.c. total injection. NO. OF MORBID TOTAL INITIALS NUMBER DAYS NUMBER AND OF AFTER OF HOSPITAL START OF INJEC· CASE CHART NO. r NUMBER I DAYS 1 DRUG 1 TIO:t~S 1
1 M.M. 2 E.T.
3 7
2 0
6
7
3
v.s.
10
0
8
4
D.B.
7
0
4
4
0
2
5 J.J.
6
E.B.
7
0
7
7 8
B.R. B.R.
5 4
1 0
4 4
9
R.
s.
7
0
14
10
v. R.
8
5
5
11
M.W.
4
1
3
12 C.P.
10
2
14
13 K.M.
5
1
6
14
8
0
5
6
0
12
M.D.
45197 15
C. M.C.
43252
PAIN
None With 6th shot
Infected. incomtlete abortion Adominal hystereeto:m...y1 ~ingo oophorectomy, appenaeetomy, multipie :iibroids With 7th Cesarean section, wound dehiscence, shot secondary closure None Low cesarean section, 30 hours, trial labor, ruptured men~.branes None 6 months premature delivery of stillborn infant with shock and he:nwrrhage, manual removal of retaiired placeD.tar With 5th Left taboovarian abscess subacute, shot surgieally removed None Pyelitis of pregnancy With 3rd InMmplete abortion shot None Vaginal hysterectomy (medicine neglooted to· be diseontinued) With Srd Pyelitis. Poor response to Terramycin. shot SulfaqJ~zine used None Acute salpingitis With 2nd Third-degree tear, Rectal contaminashot tion With Srd Third-degree laceration shot None Placenta previa. Vag~naJ del~very, ruptured membranes 48 hours None Pyelitis
7
0
6
None
45602 17 D.B.
9
5
6
45700 L. S.
7
With.4th shot
0
10
None
Third-degree- laceration
19 M.W.
5
0
6
None
Third·degree laceration
46739 G. B.
8
0
13
M.D.
5
2
6
16
18
20 21
J.K.
Secondary closu.-.oe of episictomy with hematoma Pyelitis. Drug changed to sulfadi~e
45764
45952
46051
With 6th ·Third-degree laceration shot None Pyelitis of pregnaney
22
'\V.
~~-
7
0
5
23
47132 B.G. 47026
6
0
4
24 E.C. 47093
6
2
7
Vlith 3rd Third-degree laceration shot With 2nd Ruptured corpus luteum with hemo· shot peritoneum, shock Postpartal sepsis. Acute endometritis None
25
4
0
8
None
G.M.
Volume 69 :-iumher 6
CLINICAL EVALUATION OF TERRAMYCIN INTRAMUSCULAR
1289
The d1·ug was administered in the 25 cases in Table I. All patients were told it was Terramycin in intramuscular form, though none were told it was a clinical study. All were asked to report any local reactions of unusual nature to delineate clearly the amount of discomfort they experienced, and to report any reactions of a systemic or general nature.
Reactions In the 25 cases, 170 intramuscular doses of 100 mg. of Terramycin were given by various registered nurses. There was no reported deep abscess formation, skin discoloration, or subcutaneous skin reaction at the site of injection. There were numerous complaints of pain which are further tabulated. In no case was a report made of generalized skin reaction, and no unusual systemic reaction was recorded. As mentioned, the most distressing difficulty encountered was the complaint of pain. In 25 cases 44 ver cent suffered pain at the site of injection. At no time was the pain severe enough to merit discontinuing the drug. There were 2 patients who received a total of 14 shots each, one a total of 13, and another a total of 10. In none of these patients was the pain unusual, though it was present after the third shot in 3 of these cases. In all cases where pain was experienced, it was found the discomfort disappeared 24 to 48 hours after the drug was discontinued. If the number of injections is greater some residual soreness may remain for a longer period of time. Discussion of Oases The 25 cases were chosen at random from the service here at U. S. Naval Hospital, Memphis, Tennessee. In each instance, infection was known to be present by clinical manifestation, or could be expected from known contamination during delivery or surgery. Morbidity was defined as a temperature of 100.4° F. for two successive days, or over 101. 0 :B'. for any one day, excluding the day medication was started. In 15 of the 25 cases, there were no morbid days after the start of the drug. Of the 10 patients who did show morbidity, only two were found to be resistant to Terramycin therapy. These two had pyelitis. Both responded to sulfadiazine. The total number of morbid days for the 25 patients in the study was 21. 'l'he total number of hospital days was 159. 'l'hough this series is yet small, it is believed the use of intramuscular Terramycin will lower morbidity appreciably in the cases usually classified as potentially infected ones, i.e., those with ruptured membranes of long duration, rectal and vaginal surgery, secondary surgical procedures, and manual invasion of the uterus. This will, in turn, reduce the number of hospital days a group of patients of this type will incur. This is a prime consideration to all oi us and to the private patient, with our present high cost of hospitalization. In these 25 cases, none were hospitalized over 10 days. The average for the group was 6.3 days. Comments From the observations made in this small series, it is believed Terramycin Intramuscular will prove a valuable addition to the parenteral antibiotics in the broad-spectrum group. The intramuscular route of administration of Terramycin is much easier than the previously developed intravenous route and is apparently most efficacious in acute infections of mild and moderate severity.
1\'lll.J.ULJ:.i'l'V.i'l
Am. J. Ubst.
~ \..iynec. June, 19.15
The use of Terramycin in surgery and obstetrics should become general after consideration of the clinical results in these 25 cases. The only undesirable factor found in administration of this new rm:-paration is the pain experienced at the site of injection. Forty-four per cent of the patients who received the drug complained of pain of varying degrees of severity and until this pain is eliminated or reduced to a smaller percentage it may prove a retarding factor in the acceptance of the intramuscular route of administration of Terramycin.
Conclusions 1. Terramycin can be safely administered intramuscularly. 2. A dose of 100 mg. twice a day will adequately control most acute infections of mild and moderate severity. 3. Pain at the site of injection is the only apparent limitation of use of Terramycin Intramuscular. There were no syste-mic reactions r&tad in_- this series. 4. The amount of pain at the injection site, though a problem at present, does not prohibit the use of the intramuscular preparation where necessary. I wish to express my appreciation to Harry Seneca, M.D., of the Pfizer Laboratories for his assistance in the prep1uation of this report. In addition I wish to express my grati· tude to the nursing personnel of the U. S. Naval Hospital, Memphis, 1'ennessee, and to Mrs. Helen Meadows and Mrs. Alice Hulseherg for their efforts in the preparation of this manuscript.
References 1. Reed, M. Nesbit, Adcock, John, Brown, W. C., and Owen, Col'a R.: J. Urol. 65,:336, 1951. 2. Caldwell, E. R., Jr., Spies, H. W., Wolfe, C. K., Lepper, M. H., and Dowling, .H. F.: J. Lab. & Clin. Med. 36: 747, 1950.
3. Jackson, G. G., et al.: Ann. Int. Med. 35: 1175, 1951. 4. Miller. F. L .• and Walker. Rhev: New Eneland J. Med. 249.:.-479, 1953. 5. Wagner, Henry J., Jr.: Bull. Johns Hopkins Hosp. 91: 75, 1952. 1302 GOVERNMENT ST. MOBILE, ALA.