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Chloromycetin in the Therapy of Granuloma Inguinale*
OHLOROMYOETIN IN THE THERAPY OF GRANULOMA INGUINALE* RoBERT B. GREE::-lBLATT, M.D., VrRGEXE S. 'VAMMOCK, M.D., RoBERT B. DIENST, Pn.D., AND RoBERT M. WEsT, B.S., AuGUSTA, GA. (From the Unive-rsit:IJ of Georgia School of Medteine)
inguinale, a perplexing problem which has long plagued the G RANULOMA South is, at least in Georgia, well on its way to complete eradication. In fact, of the many patients admitted to the wards of the University Hospital in the past ten months, only one was from the city of Augusta. The rapid disappearance of this disease is due primarily to the effectiveness of various antibiotics in therapy. The use of streptomycin/ aureomycin/ and Chloromycetin 3 has rapidly reduced the number of patients available for study.
Material
•
Streptomycin was employed in the therapy of 142 patients with granuloma inguinale. A cure rate of 86.6 per cent was obtained with a single course of treatment. The average effective dose was 20 Gm. administered intramuscularly in 1 Gm. doses every six hours for five days. In the nineteen failures the initial dose was inadequate in six, being 10 Gm. or less. Fourteen who failed to obtain a cure following the first course responded successfully to a second course of treatment. There were only five patients who proved to be streptomycin resistant, a failure rate of 3.5 per cent. All of the streptomycin-resistant patients, however, proved responsive to aureomycin therapy. The advantage of streptomycin therapy is the shortness of the period necessary for treatment, i.e., five days. The disadvantage is the need for hospitalization. Aureomycin has been used in forty-six patients. Intramuscularly, in doses of 250 mg. every four hours for totals of 800 to 1,500 mg., the drug proved ineffective. Orally, this antibiotic proved most efficacious. The lesions in the five streptomycin-resistant patients were healed with oral aureomycin and the lesions in most of the other patients responded readily. Early in our experience with the use of this antibiotic as little as 5 Gm. were used in doses of 250 mg. every four to six hours. The lesions healed superficially but Donovan bodies could be demonstrated deep in the tissues after apparent healing. Breakdown occurred in each instance and the dosage was stepped up so that the average patient received 20 to 30 Gm. in doses of 500 mg. every six hours for ten to fifteen days. In this series the smallest dosage used that effected a cure was 10.8 Gm. and the largest dose required was 70 Gm. In this latter instance the patient had extensive lesions measuring some 300 sq. em. in size. The patient proved resistant to three courses of streptomycin in which a total of 158 Gm. was used. Although complete healing was obtained with 50 Gm. of aureomycin, another 20 Gm. were added as insurance against a relapse. Though 20 to 30 Gm. of the drug appear to be sufficient for the average case. it was found that patients with extensive lesions or with slowly responsive lesions required from 40 to 70 Gm. In several instances, healing was incomplete after one course of • Aided by grants from the State of Georgia Department of Public Health and the United States Public Health Service.
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therapy and a second course was given. Only two relapses have thus far been observed in patients who had healed after receiving 20 Gm. or more of the drug. In these instances successful responses were obtained on re-treatment. The patients in this series have now been under observation from one to ten months. Half of them have been followed for at least five months. Toxic reactions such as nausea, vomiting, and diarrhea have been encountered in several of the patients with 500 mg. dosage, and much more frequently when the dosage was stepped up to 1 flm. every six hours.
Fig. l ( C:<~e 1 J .-A., Before treatment with Chlorumycetin. B. After 20 Gm. of Chloromyeetin admirrillterefl in dosage of 500 mg. every six hours for ten days.
Chloromycctin is the antibiotic now under scrutiny. Between :VIareh lH, 1H49, and Sept. 16, 1949, therapy with this antibiotic was employed in twentythree women patients. The dosage at first was chosen arbitrarily at 20 Gm. One-half gram every six hours was administered over a period of ten days to four patients. The response was striking. One gram was administered every six hours over a period of five days to the four other 'Patients. The results appeared equally good. In each group there was one case with incomplete healing and a second course of therapy was necessary before complete healing ocf•nrred. Two patients were treated with 70 and 40 Gm., respectively. It appeared that that dosage was required for complete healing in patients with extensive lesions; hence the variance in dosage. Most of these patients have now been followed for four to six months. The results are most promising. Untoward effects have not been noted. Two relapses occurred and these patietits responded to a second course of Chloromycetin. Donovan bodies disappear from the lesions more rapidly than with aureomycin or streptomycin. The advantages of its use are that it may he administered on an outpatient basis and that it is not toxic. When administer·ed to hospita.lized patients the (lisadvantage is the length of time required for treatment, i.e., 10 to 20 days. The following case histories illustrate the ~'xcellent results: UASE 1.···-L. :M., a N
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although the Frei test was negative. Donovan bodies were found in smears from the lesions. She received 20 Gm. of Chloromycetin as 500 mg. four times daily for ten days. The lesions regressed rapidly and Donovan bodies disappeared within seventy-two hours. 'l'he lesions were 90 per cent IJealed upon completion of therapy. She lias been observed at monthly intervals since and the lesions have remained healed (Fig. 1 ).
i•
Fig. 2 (Case 2) .-Donovan bodies.
·-.
A.
B.
0.
Fig. 3 (Case 2).-A, Before treatment with Chloromycetin. B, After ft1·st course of 2fl Gm. of Chloromycetin over a period of ten days. showing 80 per cent improvement in lesion. 0, After a second similar course of therapy healing was completed.
CASE 2.-C. L. \Y., a 23-year-old Negro woman, who was placed on treatment Mar('h lG, 1949, presented a large granulomatous lesion on the right cheek cowring 1!0 sq. em. in area, in addition to lesions of similar size on the vulva and perineum which had been present for two years. The vulvar lesions had previously healed under antimonial therapy hut recurred. Donovan bodies were plentiful in smears from both areas (Fig. 2). 'l'hese dis· appeared within seventy-two hours after the institution of Chloromycetin therapy, 20 Gm. in ten days. The vulval lesions were entirely healed and the lesion on the right cheek was 80 per cent healed by the completion of treatment (.Fig. 3, A ami B). However, the extragenital lesion did not completely heal and Donovan bodies could again be demon· strated in smears from this lesion. Another course of 20 Gm. was administered. Healing occurred and 10 Gm. more were added for good measure. The patit>nt remains well (Fig. 3, C).
Am.). Obst. & Gynec. May, 1950
GREENBLATT ET AL.
1132
CASE 3.-E. P., a 17-year-old Negro woman, presented a lesion o£ granuloma inguinale o£ the vulva which had been present :for eight months. Therapy with Chloromycetin was begun on April 18, 1949. She received 20 Gm. in ten days and the lesions were 90 per cent healed upon completion of therapy. The patient has been seen for follow-up and the lesions l1ave remained well. CASE 4.-c·C. L., a 22-year-old Negro woman, presented lesions o£ the vulva o£ five weeks' duration in which Donovan bodies were df'monstrated. She was placed on therapy with Chloromycetin on March 25, Hl49, and received 20 Gm. in five days. Healing was only 50 per cent complete and a second course of 20 Gm. over ten days was given. She has been seen at monthly intervals and has remained well.
CASE 5.-1>. IV., a 35-year-old Negro woman, seen April 4, 1949, presented a small granulomatous lesion of the lower abdomen and several small similar lesions of the vaginal wall. Donovan bodies were found in these lesions and Chloromycetin was given as 1 Gm. four times daily for a total of 20 Gm. in :five days. Donovan bodies could not be demon· strated in seventy-two hours and the lesions were healed at the completion of therapy.
A.
B.
F'!gc. 4 (Case 6).-Granuloma inguinale of the cervix.
A, Before treatment with Chloromycetin.
B, After 40 Gm. of Chloromycetin over a period of twenty days.
CASE 6.-L. S., a 29-year-old Negro woman, seen April li'i, 1949, presented granulomatous involvement of most of the cervix together with roentgen evidence of granuloma inguinale of the sacrum as represented by cystic areas. Bacitracin in suppository form was tried without success. Chloromycetin was then given and Donovan bodies could not be demon· strated after seventy-two hours. 'l'he cervix was entirely healed upon completion o£ 40 Gm. in twenty days. The tenderness and swelling over the sacrum decreased rapidly and the cystic areas had healed within one week. She has been observed at monthly intervals and has remained well (Fig. 4, A and B).
Other antibiotics have been tried. Penicillin proved ineffective, tyrothricin used locally and bacitracin used in the form of suppositories proved valueless. Iu this connection, it may be stated that streptomycin suppositories were used in seven cases and proved effective in four.
Conclusions l. Twenty-three women patients with granuloma inguinale were effeetively treated with Chloromycetin. Six case histories are detailed in the text.
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2. The total dosages necessary for cure were 20 Gm. in six cases, 40 Gm. in two, 50 Gm. in one, and 70 Gm. in another. From our experience it appears that the ideal dosage is 500 mg. every six hours for ten to twenty days. If healing is incomplete or the lesions are extensive it is advisable to continue Chloromycetin until 50 to 70 Gm. are given. 3. Donovan bodies, in most instances, disappeared from the lesions in two to four days after therapy was begun. 4. Untoward effects were not observed. 5. One hundred forty-two patients with granuloma inguinale were treated with streptomycin with excellent results. Five patients proved to be streptomycin resistant. Twenty grams intramuscularly in dosages of 1 Gm. every six hours over a period of five days seemed adequate in most instances. 6. Aureomycin was used in forty-six patients. The effective dose range varied from 10.8 to 70 Gm. On the average the dosage used was 20 to 30 Gm. Untoward results were nausea, vomiting, and occasionally diarrhea. Aureomycin given intramuscularly was not effective in the dosage employed. 7. The antibiotics Chloromycetin, aureomycin, and streptomycin have proved most effective agents in reducing the incidence of granuloma inguinale in Georgia.
References 1. (a) Greenblatt, R. B., Kupperman, H. S., and Dienst, R. B.: Proc. Soc. Exper. Bioi. & Med. 64: 389, 1947. (b) Barton, R. L., Craig, R. M., Schwemlein, G. X., and Bauer, T. J.: Arch. Dermat. & Syph. 56: 1, 1947. (e) Greenblatt, R. B., Dienst, R. B., Kupperman, H. S., and Reinstein, C. R.: J. Ven. Dis. Inform. 28: 183, 1947. (d) Kupperman, H. S., Greenblatt, R. B., and Dienst, R. B.: J. A. M. A. 136: 84, 1948. (e) Hirsh, H. L., and Taggart, S. R.: Am. J. Syph., Gonorr. & Ven. Dis. 32: 159, 1948. (f) Marshak, L. C., and Rodriguez, J.: J. A.M. A. 137: 12[!3, 1948. (g) Chen, C. H., Greenblatt, R. B., and Dienst, R. B.: J. M. A. Georgia 37: 3i3, 1948. (h) Jacoby, A., Rosenthal, T., and Sobel, N.: Am. J. Syph., Gonorr. & Yen. Dis. 33: i6, Hl411. 2. (a) Wright, L. 'r., Sanders, l£., Logan, 1\f. A., Prigot, A., and Hill, I--~. :n.L: .._4.nn. New York Aead. Sc. 51: 318, 1948. (b) Greenblatt, R. B., Dienst, R. B., Chen, C., and West, R.: South. M. J. 41: 1121, Hl48. (c) Wammor.k, Y. 8., Greenblatt, R. B., Dienst, R. B., Chen, C. H., and West, R. M.: .T. Invest. Dermat. In press. 3. (a) Greenblatt, R. B., Wammock, V. S., Dienst, R. B., and West, R. M.: J. M.A. Georgia 38: 206, 1949. (b) Greenblatt, R. B., Dienst, R. B., Wammock, V. S., Chen, C. H., and '\Vest, R. ::\£.: R~·mposium on Current Progress in the Study of Venereal Diem•es, F. H. Pubiic Health Service, l!l49, p. 131. (c) Greenblatt, R. B., Wammock, Y. 8., Chen, C. H., Dienst, R. H., nrul West, R. l\f.: .J. Ven. nil'. Inform. 31: 45, 19!30.
inguinale, a perplexing problem which has long plagued the G RANULOMA South is, at least in Georgia, well on its way to complete eradication. In fact, of the many patients admitted to the wards of the University Hospital in the past ten months, only one was from the city of Augusta. The rapid disappearance of this disease is due primarily to the effectiveness of various antibiotics in therapy. The use of streptomycin/ aureomycin/ and Chloromycetin 3 has rapidly reduced the number of patients available for study.
Material
•
Streptomycin was employed in the therapy of 142 patients with granuloma inguinale. A cure rate of 86.6 per cent was obtained with a single course of treatment. The average effective dose was 20 Gm. administered intramuscularly in 1 Gm. doses every six hours for five days. In the nineteen failures the initial dose was inadequate in six, being 10 Gm. or less. Fourteen who failed to obtain a cure following the first course responded successfully to a second course of treatment. There were only five patients who proved to be streptomycin resistant, a failure rate of 3.5 per cent. All of the streptomycin-resistant patients, however, proved responsive to aureomycin therapy. The advantage of streptomycin therapy is the shortness of the period necessary for treatment, i.e., five days. The disadvantage is the need for hospitalization. Aureomycin has been used in forty-six patients. Intramuscularly, in doses of 250 mg. every four hours for totals of 800 to 1,500 mg., the drug proved ineffective. Orally, this antibiotic proved most efficacious. The lesions in the five streptomycin-resistant patients were healed with oral aureomycin and the lesions in most of the other patients responded readily. Early in our experience with the use of this antibiotic as little as 5 Gm. were used in doses of 250 mg. every four to six hours. The lesions healed superficially but Donovan bodies could be demonstrated deep in the tissues after apparent healing. Breakdown occurred in each instance and the dosage was stepped up so that the average patient received 20 to 30 Gm. in doses of 500 mg. every six hours for ten to fifteen days. In this series the smallest dosage used that effected a cure was 10.8 Gm. and the largest dose required was 70 Gm. In this latter instance the patient had extensive lesions measuring some 300 sq. em. in size. The patient proved resistant to three courses of streptomycin in which a total of 158 Gm. was used. Although complete healing was obtained with 50 Gm. of aureomycin, another 20 Gm. were added as insurance against a relapse. Though 20 to 30 Gm. of the drug appear to be sufficient for the average case. it was found that patients with extensive lesions or with slowly responsive lesions required from 40 to 70 Gm. In several instances, healing was incomplete after one course of • Aided by grants from the State of Georgia Department of Public Health and the United States Public Health Service.
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therapy and a second course was given. Only two relapses have thus far been observed in patients who had healed after receiving 20 Gm. or more of the drug. In these instances successful responses were obtained on re-treatment. The patients in this series have now been under observation from one to ten months. Half of them have been followed for at least five months. Toxic reactions such as nausea, vomiting, and diarrhea have been encountered in several of the patients with 500 mg. dosage, and much more frequently when the dosage was stepped up to 1 flm. every six hours.
Fig. l ( C:<~e 1 J .-A., Before treatment with Chlorumycetin. B. After 20 Gm. of Chloromyeetin admirrillterefl in dosage of 500 mg. every six hours for ten days.
Chloromycctin is the antibiotic now under scrutiny. Between :VIareh lH, 1H49, and Sept. 16, 1949, therapy with this antibiotic was employed in twentythree women patients. The dosage at first was chosen arbitrarily at 20 Gm. One-half gram every six hours was administered over a period of ten days to four patients. The response was striking. One gram was administered every six hours over a period of five days to the four other 'Patients. The results appeared equally good. In each group there was one case with incomplete healing and a second course of therapy was necessary before complete healing ocf•nrred. Two patients were treated with 70 and 40 Gm., respectively. It appeared that that dosage was required for complete healing in patients with extensive lesions; hence the variance in dosage. Most of these patients have now been followed for four to six months. The results are most promising. Untoward effects have not been noted. Two relapses occurred and these patietits responded to a second course of Chloromycetin. Donovan bodies disappear from the lesions more rapidly than with aureomycin or streptomycin. The advantages of its use are that it may he administered on an outpatient basis and that it is not toxic. When administer·ed to hospita.lized patients the (lisadvantage is the length of time required for treatment, i.e., 10 to 20 days. The following case histories illustrate the ~'xcellent results: UASE 1.···-L. :M., a N
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although the Frei test was negative. Donovan bodies were found in smears from the lesions. She received 20 Gm. of Chloromycetin as 500 mg. four times daily for ten days. The lesions regressed rapidly and Donovan bodies disappeared within seventy-two hours. 'l'he lesions were 90 per cent IJealed upon completion of therapy. She lias been observed at monthly intervals since and the lesions have remained healed (Fig. 1 ).
i•
Fig. 2 (Case 2) .-Donovan bodies.
·-.
A.
B.
0.
Fig. 3 (Case 2).-A, Before treatment with Chloromycetin. B, After ft1·st course of 2fl Gm. of Chloromycetin over a period of ten days. showing 80 per cent improvement in lesion. 0, After a second similar course of therapy healing was completed.
CASE 2.-C. L. \Y., a 23-year-old Negro woman, who was placed on treatment Mar('h lG, 1949, presented a large granulomatous lesion on the right cheek cowring 1!0 sq. em. in area, in addition to lesions of similar size on the vulva and perineum which had been present for two years. The vulvar lesions had previously healed under antimonial therapy hut recurred. Donovan bodies were plentiful in smears from both areas (Fig. 2). 'l'hese dis· appeared within seventy-two hours after the institution of Chloromycetin therapy, 20 Gm. in ten days. The vulval lesions were entirely healed and the lesion on the right cheek was 80 per cent healed by the completion of treatment (.Fig. 3, A ami B). However, the extragenital lesion did not completely heal and Donovan bodies could again be demon· strated in smears from this lesion. Another course of 20 Gm. was administered. Healing occurred and 10 Gm. more were added for good measure. The patit>nt remains well (Fig. 3, C).
Am.). Obst. & Gynec. May, 1950
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CASE 3.-E. P., a 17-year-old Negro woman, presented a lesion o£ granuloma inguinale o£ the vulva which had been present :for eight months. Therapy with Chloromycetin was begun on April 18, 1949. She received 20 Gm. in ten days and the lesions were 90 per cent healed upon completion of therapy. The patient has been seen for follow-up and the lesions l1ave remained well. CASE 4.-c·C. L., a 22-year-old Negro woman, presented lesions o£ the vulva o£ five weeks' duration in which Donovan bodies were df'monstrated. She was placed on therapy with Chloromycetin on March 25, Hl49, and received 20 Gm. in five days. Healing was only 50 per cent complete and a second course of 20 Gm. over ten days was given. She has been seen at monthly intervals and has remained well.
CASE 5.-1>. IV., a 35-year-old Negro woman, seen April 4, 1949, presented a small granulomatous lesion of the lower abdomen and several small similar lesions of the vaginal wall. Donovan bodies were found in these lesions and Chloromycetin was given as 1 Gm. four times daily for a total of 20 Gm. in :five days. Donovan bodies could not be demon· strated in seventy-two hours and the lesions were healed at the completion of therapy.
A.
B.
F'!gc. 4 (Case 6).-Granuloma inguinale of the cervix.
A, Before treatment with Chloromycetin.
B, After 40 Gm. of Chloromycetin over a period of twenty days.
CASE 6.-L. S., a 29-year-old Negro woman, seen April li'i, 1949, presented granulomatous involvement of most of the cervix together with roentgen evidence of granuloma inguinale of the sacrum as represented by cystic areas. Bacitracin in suppository form was tried without success. Chloromycetin was then given and Donovan bodies could not be demon· strated after seventy-two hours. 'l'he cervix was entirely healed upon completion o£ 40 Gm. in twenty days. The tenderness and swelling over the sacrum decreased rapidly and the cystic areas had healed within one week. She has been observed at monthly intervals and has remained well (Fig. 4, A and B).
Other antibiotics have been tried. Penicillin proved ineffective, tyrothricin used locally and bacitracin used in the form of suppositories proved valueless. Iu this connection, it may be stated that streptomycin suppositories were used in seven cases and proved effective in four.
Conclusions l. Twenty-three women patients with granuloma inguinale were effeetively treated with Chloromycetin. Six case histories are detailed in the text.
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2. The total dosages necessary for cure were 20 Gm. in six cases, 40 Gm. in two, 50 Gm. in one, and 70 Gm. in another. From our experience it appears that the ideal dosage is 500 mg. every six hours for ten to twenty days. If healing is incomplete or the lesions are extensive it is advisable to continue Chloromycetin until 50 to 70 Gm. are given. 3. Donovan bodies, in most instances, disappeared from the lesions in two to four days after therapy was begun. 4. Untoward effects were not observed. 5. One hundred forty-two patients with granuloma inguinale were treated with streptomycin with excellent results. Five patients proved to be streptomycin resistant. Twenty grams intramuscularly in dosages of 1 Gm. every six hours over a period of five days seemed adequate in most instances. 6. Aureomycin was used in forty-six patients. The effective dose range varied from 10.8 to 70 Gm. On the average the dosage used was 20 to 30 Gm. Untoward results were nausea, vomiting, and occasionally diarrhea. Aureomycin given intramuscularly was not effective in the dosage employed. 7. The antibiotics Chloromycetin, aureomycin, and streptomycin have proved most effective agents in reducing the incidence of granuloma inguinale in Georgia.
References 1. (a) Greenblatt, R. B., Kupperman, H. S., and Dienst, R. B.: Proc. Soc. Exper. Bioi. & Med. 64: 389, 1947. (b) Barton, R. L., Craig, R. M., Schwemlein, G. X., and Bauer, T. J.: Arch. Dermat. & Syph. 56: 1, 1947. (e) Greenblatt, R. B., Dienst, R. B., Kupperman, H. S., and Reinstein, C. R.: J. Ven. Dis. Inform. 28: 183, 1947. (d) Kupperman, H. S., Greenblatt, R. B., and Dienst, R. B.: J. A. M. A. 136: 84, 1948. (e) Hirsh, H. L., and Taggart, S. R.: Am. J. Syph., Gonorr. & Ven. Dis. 32: 159, 1948. (f) Marshak, L. C., and Rodriguez, J.: J. A.M. A. 137: 12[!3, 1948. (g) Chen, C. H., Greenblatt, R. B., and Dienst, R. B.: J. M. A. Georgia 37: 3i3, 1948. (h) Jacoby, A., Rosenthal, T., and Sobel, N.: Am. J. Syph., Gonorr. & Yen. Dis. 33: i6, Hl411. 2. (a) Wright, L. 'r., Sanders, l£., Logan, 1\f. A., Prigot, A., and Hill, I--~. :n.L: .._4.nn. New York Aead. Sc. 51: 318, 1948. (b) Greenblatt, R. B., Dienst, R. B., Chen, C., and West, R.: South. M. J. 41: 1121, Hl48. (c) Wammor.k, Y. 8., Greenblatt, R. B., Dienst, R. B., Chen, C. H., and West, R. M.: .T. Invest. Dermat. In press. 3. (a) Greenblatt, R. B., Wammock, V. S., Dienst, R. B., and West, R. M.: J. M.A. Georgia 38: 206, 1949. (b) Greenblatt, R. B., Dienst, R. B., Wammock, V. S., Chen, C. H., and '\Vest, R. ::\£.: R~·mposium on Current Progress in the Study of Venereal Diem•es, F. H. Pubiic Health Service, l!l49, p. 131. (c) Greenblatt, R. B., Wammock, Y. 8., Chen, C. H., Dienst, R. H., nrul West, R. l\f.: .J. Ven. nil'. Inform. 31: 45, 19!30.