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Streptomycin
Comments
on Current Literature STREPTOMYCIN
R E C E N T issue of the Journal of Laboratory and Clinical Medicine carries a report by Major Edwin J. Pulaski and Colonel Sam F. Seetey1 describing cumulative experiences with streptomycin therapy in the United States Army Hospitals, Halloran General and Brooke General. This report presents their observations in summary lorm, and is based on an analysis of 1,200 cases. Of special interest is the series of 465 patients with infections of the urinary tract, all of whom had complete bacteriologic survey of the urine before treatneut. Seventy-nine per cent of the micro-organisms isolated were gram-negative bacilli. Of the remaining 21 per cent, which were gram-positive cocci, one-third ~ were nonhemo]ytic streptococci. Extensive culture sensitivity studies revealed that streptomycin exerted a bacteriostatic effect in vitro on 87 per cent of the bacteria recovered before treatment and that 13 per cent were naturally drug-fast. I n correlating the laboratory findings with the clinical response to therapy, the authors conclude that " i f bacteria are not inhibited in vitro by a concentration of 16 ~g. per cubic centimeter, the chances of eliminating them by streptomycin therapy are not good." Since the drug is excreted in very high concentration in the urine (1,000 ~g. per cubic centimeter, or more), failure of response, according to the authors, "suggests that streptomycin acts primarily through delivery by way of the blood stream to the tissues and not through the urine." Therapy resulted in cure in 34 per cent of the patients treated, improvement in 21 per cent but without complete bacteriologic remission, and in no beneficial effect in 45 per cent. Failures were most common when the infections agent was Pseudomonas aeruginosa or Streptococcus faecalis. While many factors entered into failure of therapy, drug-fastness is believed to be a constant feature in cases where the urine was not sterilized by the prescribed course of treatment. Administration of a second course of therapy did not seem to give better results than did the first course. Local instillation of streptomycin in the genitourinary tract seem ed of little value. Ten patients with tularemia were treated with streptomycin, one oculoglandular type, one typhoida], and the others ulceroglandular. Streptomycin, administered intramuscularly in daily dose of 2 Gm. for a period of seven to fourteen days, resulted in recovery in all patients without relapse or complication. As Pulaski and Seeley state, their experiences support the conclusions of others that streptomycin is the most effective agent now available for the treatment of tularemia. In the treatment of infection involving the central nervous system, the results obtained were similar to those reported by other authors. The need for intrathecal administration combined with the intramuscular route was emphasized. Twenty-nine patients with brucellosis were treated with streptomycin; sixteen of these were considered to have 'acute cases and thirteen were considered chronic. Blood cultumes were positive for brucella in fourteen of the sixteen patients with acute brucellosis, and bacteremia was demonstrated in two of the chronic cases. All strains of brucella isolated were sensitive to streptomycin in vitro. The dosage of streptomycin varied between 1 and 2 Gm. daily, and in two patients was 6 Gm. daily, for an average period of fourteen days. None of the A
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THE JOURNAL OF PEDIATRICS
patients with chronic brucellosis derived any benefit whatsoever from streptomycin therapy. Of the patients with acute brucellosis, only two of the twelve treated with streptomycin alone had fairly prompt remission and negative blood cultures. Exacerbations occurred in five of the twelve patients. It was the clinical impression of the authors that the loci of infection in brucellosis were not penetrated by streptomycin administered parenterally. Oral sulfadiazine added to parenteral streptomycin therapy produced favorable response in two of five patients treated in this manner. In this connection it is interesting to point out that Howe and HeyF in the New England Journal of Medicine report the successful therapy of an acute case of brucellosis in a 52-year-old woman. These authors re-emphasize the concept of Meyer~ that the selective intracellular parasitism in mesenchyme cells of various organs is of greatest significance in the pathogenesis of brucella infections. Howe and Heyl suggest the administration of relatively large doses of streptomycin, since in sufficiently high blood concentration maintained for adequate periods, Streptomycin exerts bacteriostatic or bacteriocidal action on intracellular organisms. In their patient, a 52-year-old adult, Howe and I~Ieyl succeeded in obtaining blood levels of streptomycin varying between 20 and 25 t~g. per cubic centimeter of blood, by giving 6 Gm. daily, one gram every four hours over a period of ten days, In reviewing the literature, these authors gained the general impression that patients in whom the highest blood levels of drug were maintained for even relatively short periods, showed signs of better response than those in whom lower levels were maintained over relatively longer periods. Such intensive therapy, however, is not without hazard. Another interesting section of the PulasM and Seeley report concerns their experiences with infections of intestinal Origin. Six patients with typhoid fever were treated, and no remarkable results were achieved. However, in the case of one 5-year-old child who was given the usual adult dose, the fever dropped abruptly, which suggested response to streptomycin therapy. It is possible that in typhoid fever, intensive therapy over a short time might give results comparable to those achieved with brucellosis. Beneficial effects were noted in bacillary dysentery caused by Shigella sonnei and Shigella flexneri. The most striking results were noted in patients during the first attack of illness. Three infants with diarrheas due to salmonella responded favorably to oral streptomycin (100 rag. per kilogram daily for four to seven days). In thirteen cases of epidemic diarrhea of unknown etiology, oral streptomycin therapy in a dosage of 0.1 Gm. per pound per day was given in the milk. In addition to the routine measures employed in the therapy of infantile dlarrhea, it was the impression of the authors that streptomycin was the determining factor in saving at least four of the ten survivors. Pulaski and Seeley also summarize their experiences with streptomycin in the treatment of baeteremia, peritonitis, wound infection, and tuberculosis. One section of the report is devoted to the incidence of untoward reactions, and the ease records of 1,153 patients are reviewed and tabulated. The over-all incidence of side effects was 27.9 per cent (322 patients). Since this series was begun in 1945 when streptomycin was relatively impure, it is believed that a number of the side reactions might have been due to impurities in the streptomycin rather than to the streptomycin molecule itself. Neurological disturbances Were the most important, and two types were noted: the persistent, slowly regressing type, and the transient type. The transient reactions, which include cireumoral paIlor and tingling of the face and extremities, were observed fifty times and appeared as early as following the first intramuscular injection. Tinnitus, which also appeared early, was noted in twenty-eight patients. Vertigo may be either transient or persistent, and
COMMENTS ON ~URREbIT LITERATURE
621
its appearance should be reason for caution. Transient vertigo, which appeared between the third and the tenth days of treatment, was recorded thirty times, a probable underestimation of the incidence. Persistent vertigo, accompanied by ataxic gait and absence of vestibular response to caloric tests, was noted in fiftysix patients (5 per cent). It is important to point out that all patients with persistent vertigo received therapy for a period of from twenty-one to 120 days, the incidence of this reaction being highest in those treated for 120 days. The earliest appearance of the disturbance was recorded in a patient receiving 3 Gin. of streptomycin daily for fourteen days. Partial deafness was recorded in twelve patients (1 per cent). All were patients with tuberculosis on the 120-day program. Dermatoses which were accompanied by pruritis, usually With fever and eosinophilia, occurred in thirty-five patients. These sensitization reactions usually occurred between the fifth and tenth days of therapy. Withdrawal of the drug always resulted in subsidence, and reappearance did not always follow a second course. In some patients the reaction gradually disappeared in the face of continued streptomycin administration. Antihistamine drug therapy was used in conjunction with streptomycin. There were four instances of exfoliative dermatitis, all in patients with tuberculosis. The reaction is serious and requires prompt withdrawal of the drug. Disappearance of the dermatitis is gradual. In summarizing their experiences, Pulaski and Seeley emphasize the wide variation in streptomycin sensitivity among the bacterial species, and urge that wherever possible susceptibility of the organism be checked by the laboratory prior to therapy. Indications for streptomycin therapy include: urinary tract infections with gram-negative organisms, tularemia, bacteremia, pneumonia, and meningitis due to susceptible organisms, certain otolaryngologie conditions associated with gram-negative bacteria, and possibly bacillary dysentery and salmonella infection. Acute brucellosis with baeteremia responded favorably to streptomycin therapy, especially when given in combination with sulfadiazine. It is the opinion of Pulaski and Seeley that in spite of the incidence and the type of untoward reactions, the toxicity of presently available streptomycin is sufficiently low to justify its use in serious infection against which it has been shown to be effective. RUSSELL J. BLATTNER. REFERENCES
1. Pulaski, Edwin J., and Seeley, Sam F.: Further Experiences With Streptomycin Therapy ia United States Army Hospita]s~ J. Lab. & Clin. 1V[ed.33: 1, 1948. 2. Howe, Calderon, and Iteyl, James T.: Streptomycin Treatment in Acute J~ruce]]osis~ New England J. Med. 238: 431, 1948. 3. lV[eyer, K.F.: Observations oa Pathogenesis of Undulant Fever, In Essays in Biology in Honor of Herbert 1~[.Evans, Berkeley, 1943~ University of California Press.
on Current Literature STREPTOMYCIN
R E C E N T issue of the Journal of Laboratory and Clinical Medicine carries a report by Major Edwin J. Pulaski and Colonel Sam F. Seetey1 describing cumulative experiences with streptomycin therapy in the United States Army Hospitals, Halloran General and Brooke General. This report presents their observations in summary lorm, and is based on an analysis of 1,200 cases. Of special interest is the series of 465 patients with infections of the urinary tract, all of whom had complete bacteriologic survey of the urine before treatneut. Seventy-nine per cent of the micro-organisms isolated were gram-negative bacilli. Of the remaining 21 per cent, which were gram-positive cocci, one-third ~ were nonhemo]ytic streptococci. Extensive culture sensitivity studies revealed that streptomycin exerted a bacteriostatic effect in vitro on 87 per cent of the bacteria recovered before treatment and that 13 per cent were naturally drug-fast. I n correlating the laboratory findings with the clinical response to therapy, the authors conclude that " i f bacteria are not inhibited in vitro by a concentration of 16 ~g. per cubic centimeter, the chances of eliminating them by streptomycin therapy are not good." Since the drug is excreted in very high concentration in the urine (1,000 ~g. per cubic centimeter, or more), failure of response, according to the authors, "suggests that streptomycin acts primarily through delivery by way of the blood stream to the tissues and not through the urine." Therapy resulted in cure in 34 per cent of the patients treated, improvement in 21 per cent but without complete bacteriologic remission, and in no beneficial effect in 45 per cent. Failures were most common when the infections agent was Pseudomonas aeruginosa or Streptococcus faecalis. While many factors entered into failure of therapy, drug-fastness is believed to be a constant feature in cases where the urine was not sterilized by the prescribed course of treatment. Administration of a second course of therapy did not seem to give better results than did the first course. Local instillation of streptomycin in the genitourinary tract seem ed of little value. Ten patients with tularemia were treated with streptomycin, one oculoglandular type, one typhoida], and the others ulceroglandular. Streptomycin, administered intramuscularly in daily dose of 2 Gm. for a period of seven to fourteen days, resulted in recovery in all patients without relapse or complication. As Pulaski and Seeley state, their experiences support the conclusions of others that streptomycin is the most effective agent now available for the treatment of tularemia. In the treatment of infection involving the central nervous system, the results obtained were similar to those reported by other authors. The need for intrathecal administration combined with the intramuscular route was emphasized. Twenty-nine patients with brucellosis were treated with streptomycin; sixteen of these were considered to have 'acute cases and thirteen were considered chronic. Blood cultumes were positive for brucella in fourteen of the sixteen patients with acute brucellosis, and bacteremia was demonstrated in two of the chronic cases. All strains of brucella isolated were sensitive to streptomycin in vitro. The dosage of streptomycin varied between 1 and 2 Gm. daily, and in two patients was 6 Gm. daily, for an average period of fourteen days. None of the A
619
620
THE JOURNAL OF PEDIATRICS
patients with chronic brucellosis derived any benefit whatsoever from streptomycin therapy. Of the patients with acute brucellosis, only two of the twelve treated with streptomycin alone had fairly prompt remission and negative blood cultures. Exacerbations occurred in five of the twelve patients. It was the clinical impression of the authors that the loci of infection in brucellosis were not penetrated by streptomycin administered parenterally. Oral sulfadiazine added to parenteral streptomycin therapy produced favorable response in two of five patients treated in this manner. In this connection it is interesting to point out that Howe and HeyF in the New England Journal of Medicine report the successful therapy of an acute case of brucellosis in a 52-year-old woman. These authors re-emphasize the concept of Meyer~ that the selective intracellular parasitism in mesenchyme cells of various organs is of greatest significance in the pathogenesis of brucella infections. Howe and Heyl suggest the administration of relatively large doses of streptomycin, since in sufficiently high blood concentration maintained for adequate periods, Streptomycin exerts bacteriostatic or bacteriocidal action on intracellular organisms. In their patient, a 52-year-old adult, Howe and I~Ieyl succeeded in obtaining blood levels of streptomycin varying between 20 and 25 t~g. per cubic centimeter of blood, by giving 6 Gm. daily, one gram every four hours over a period of ten days, In reviewing the literature, these authors gained the general impression that patients in whom the highest blood levels of drug were maintained for even relatively short periods, showed signs of better response than those in whom lower levels were maintained over relatively longer periods. Such intensive therapy, however, is not without hazard. Another interesting section of the PulasM and Seeley report concerns their experiences with infections of intestinal Origin. Six patients with typhoid fever were treated, and no remarkable results were achieved. However, in the case of one 5-year-old child who was given the usual adult dose, the fever dropped abruptly, which suggested response to streptomycin therapy. It is possible that in typhoid fever, intensive therapy over a short time might give results comparable to those achieved with brucellosis. Beneficial effects were noted in bacillary dysentery caused by Shigella sonnei and Shigella flexneri. The most striking results were noted in patients during the first attack of illness. Three infants with diarrheas due to salmonella responded favorably to oral streptomycin (100 rag. per kilogram daily for four to seven days). In thirteen cases of epidemic diarrhea of unknown etiology, oral streptomycin therapy in a dosage of 0.1 Gm. per pound per day was given in the milk. In addition to the routine measures employed in the therapy of infantile dlarrhea, it was the impression of the authors that streptomycin was the determining factor in saving at least four of the ten survivors. Pulaski and Seeley also summarize their experiences with streptomycin in the treatment of baeteremia, peritonitis, wound infection, and tuberculosis. One section of the report is devoted to the incidence of untoward reactions, and the ease records of 1,153 patients are reviewed and tabulated. The over-all incidence of side effects was 27.9 per cent (322 patients). Since this series was begun in 1945 when streptomycin was relatively impure, it is believed that a number of the side reactions might have been due to impurities in the streptomycin rather than to the streptomycin molecule itself. Neurological disturbances Were the most important, and two types were noted: the persistent, slowly regressing type, and the transient type. The transient reactions, which include cireumoral paIlor and tingling of the face and extremities, were observed fifty times and appeared as early as following the first intramuscular injection. Tinnitus, which also appeared early, was noted in twenty-eight patients. Vertigo may be either transient or persistent, and
COMMENTS ON ~URREbIT LITERATURE
621
its appearance should be reason for caution. Transient vertigo, which appeared between the third and the tenth days of treatment, was recorded thirty times, a probable underestimation of the incidence. Persistent vertigo, accompanied by ataxic gait and absence of vestibular response to caloric tests, was noted in fiftysix patients (5 per cent). It is important to point out that all patients with persistent vertigo received therapy for a period of from twenty-one to 120 days, the incidence of this reaction being highest in those treated for 120 days. The earliest appearance of the disturbance was recorded in a patient receiving 3 Gin. of streptomycin daily for fourteen days. Partial deafness was recorded in twelve patients (1 per cent). All were patients with tuberculosis on the 120-day program. Dermatoses which were accompanied by pruritis, usually With fever and eosinophilia, occurred in thirty-five patients. These sensitization reactions usually occurred between the fifth and tenth days of therapy. Withdrawal of the drug always resulted in subsidence, and reappearance did not always follow a second course. In some patients the reaction gradually disappeared in the face of continued streptomycin administration. Antihistamine drug therapy was used in conjunction with streptomycin. There were four instances of exfoliative dermatitis, all in patients with tuberculosis. The reaction is serious and requires prompt withdrawal of the drug. Disappearance of the dermatitis is gradual. In summarizing their experiences, Pulaski and Seeley emphasize the wide variation in streptomycin sensitivity among the bacterial species, and urge that wherever possible susceptibility of the organism be checked by the laboratory prior to therapy. Indications for streptomycin therapy include: urinary tract infections with gram-negative organisms, tularemia, bacteremia, pneumonia, and meningitis due to susceptible organisms, certain otolaryngologie conditions associated with gram-negative bacteria, and possibly bacillary dysentery and salmonella infection. Acute brucellosis with baeteremia responded favorably to streptomycin therapy, especially when given in combination with sulfadiazine. It is the opinion of Pulaski and Seeley that in spite of the incidence and the type of untoward reactions, the toxicity of presently available streptomycin is sufficiently low to justify its use in serious infection against which it has been shown to be effective. RUSSELL J. BLATTNER. REFERENCES
1. Pulaski, Edwin J., and Seeley, Sam F.: Further Experiences With Streptomycin Therapy ia United States Army Hospita]s~ J. Lab. & Clin. 1V[ed.33: 1, 1948. 2. Howe, Calderon, and Iteyl, James T.: Streptomycin Treatment in Acute J~ruce]]osis~ New England J. Med. 238: 431, 1948. 3. lV[eyer, K.F.: Observations oa Pathogenesis of Undulant Fever, In Essays in Biology in Honor of Herbert 1~[.Evans, Berkeley, 1943~ University of California Press.