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The Use of Streptomycin in the Treatment of Meningitis
THE USE OF STREPTOMYCIN IN THE TREATMENT OF MENINGITIS TOM FITE PAINE, M.D.~ AND MAXWELL FINLAND,
M.D.,
F.A.C.P.t
AMONG the bacterial meningitides, those least favorably affected by the sulfonamides and penicillin are the ones which are caused by gram~negative bacilli and, of course, the cases of tuberculous meningitis. Streptomycin has proved to be the most effective agent now available in the treatnlent of these infections. 1 ,2 Streptomycin alone also appears to be at least as effective, or even more so, than the cOP1bination of sulfonamides and rabbit type specific antiserum in the treatment of Hemophilus inHuenzae Type b meningitis. 3 , 4 An acquaintance with the proper use and limitations of streptomycin in this very serious group of infections is, therefore, essential for those who may be called upon to treat such cases.
INCIDENCE OF CASES OF MENINGITIS POTENTIALLY SUITABLE FOR STREPTOMYCIN THERAPY
In a series of 3178 cases of bacterial meningitis reported by Neal, 5 the over-all incidence of cases due to gram-negative bacilli was about 5 per cent. In infants and young children, the incidence of gramnegative bacillus meningitis was higher than in adults. In patients below the age of 3 years, 9.5 per cent of 1077 cases were due to gramnegative bacilli 5 and in a series of 149 fatal cases of bacterial meningitis in patients below 3 years of age, 32 per cent were due to such organisms. 6 Most of the gram-negative bacillus infections of the meninges in infants and children are caused by Hemophilus influenzae. The coliform organisms rank next but are much less frequent. In Neal's series/' 8.5 per cent of the cases in patients under 3 years of age were due to Hemophilus influenzae and 0.56 per cent to Bacillus coli. From the Thorndike Memorial Laboratory, Second and Fourth M'edical Services ( Harvard), Boston City Hospital, and the Department of Medicine, Harvard Medical School, Boston. The studies on which this presentation is based were aided by a grant from the United States Public Health Service and were carried out with the collaboration of Doctors Roderick Murray, H. William Harris, Lawrence Kilham, and Albert O. Seeler and with the technical assistance of Miss Clare Wilcox. :\'!: Assistant in Medicine, Harvard Medical School and Research Fellow, Thorndike Memorial Laboratory. t Associate Professor of Medicine, Harvard Medical School; Chief, Fourth Medical Service and Associate Physician, Thorndike Memorial Laboratory, Boston City I-Iospital.
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Among the 149 fatal cases of bacterial meningitis in patients below 3 years of age Hemophilus inHuenzae accounted for 26 per cent and the colon bacillus for 6 per cent. 6 Other gram-negative bacilli which have been encountered less often are: Klebsiella pneumoniae (Friedlander:Js bacillus),5,7 the typhoid-dysentery group,S Pseudomonas aeruginosa (Bacillus pyocyaneus),9 the proteus. group,lO Aerobacter aerogenes,ll Pasteurella tularensis l2 and others. Tuberculosis of the central nervous system is a common condition, comprising 31 per cent of Neal's series of 3178 cases. 5 Here, again, the highest incidence of the disease is among children. It is to be borne in mind that streptomycin also exerts antibiotic action against gram-positive and gram-negative cocci, though these organisms are generally considered to be affected best by penicillin and sulfonamides. In occasional infections due to such organisms, streptomycin has proved useful when the other agents apparently failed. l3 ,14 It may, therefore, be considered as tit, substitute for, or as an adjunct to therapy with other antibacterial agents under such conditions. HEMOPHILUS INFLUENZAE MENINGITIS
This is primarily a disease of infancy and early childhood; most of the cases are caused by the smooth Type b strain. The usual history in such cases is that of a mild upper respiratory infection followed by signs of meningitis. The organisms probably reach the meninges by the blood stream after invasion through the respiratory tract. The over-all mortality in this disease has been reduced by combined sulfonamide and type-specific rabbit antiserum therapy from nearly 100 per cent to between 15 and 50 per cent. l5- 20 Streptomycin now provides the best available means for treating this disease. Furthermore, since the action of streptomycin is not type-specific, it may be used in Hemophilus influenzae infections due to strains other than those of Type b. The mortality rate in the 100 cases of Hemophilus inHuenzae meningitis treated with streptomycin under the auspices of the National Research Council l was 17 per cent. Streptomycin was given to many of these patients, however, only" after other forms of therap,y had proved unsuccessful. In the treatment of twenty-five cases with streptomycin alone or combined with other therapeutic agents, Alexander4 reported three deaths. Strains of Hemophilus influenzae resistant to streptomycin developed in two of her cases. There were two deaths in the nine cases treated by Weinstein;3 one of these deaths was due to a secondary staphylococcal infection. i' The experience at the Boston City Hospital in the treatment of Hemophilus influenzae meningitis has been equally encouraging. In fifteen cases treated to date there has been only one death; ten of these fifteen patients were under 1 year old.
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Treatment of Hemophilus Influenzae Meningitis.-Streptomycin. -The administration of streptomycin by the intramuscular or intravenous route alone cannot be depended upon to maintain adequate concentrations of the drug in the cerebrospinal fluid. 1 , 21-27 Little if any streptomycin is "detectable in the cerebrospinal fluid after injection by these routes. when there is no meningitis, and only relatively low concentrations are found in the cerebrospinal fluid under these conditions in cases of meningitis. Consequently, it is advisable to give the antibiotic by both the parenteral and intrathecal routes in the treatment of meningitis. In infants and young children the administration of 0.5 to 2 gmt intramuscularly and 50 mg. intrathecally during each twenty.. four hour period usually results in the maintenance of high concentrations in the blood and cerebrospinal fluid. Levels of 3 to 6 units per cubic centimeter of streptomycin may still be found in the cerebrospinal fluid twenty-four hours after the intrathecal injections. Most of the pathogenic strains of Hemophilus inHuenzae that have been tested are inhibited by 1 to 5 units per cubic centimeter. 2 Administration of Streptomycin.-Streptomycin is supplied commercially as a dry sterile powder, either as the hydrochloride or sulfate. Each vial contains the equivalent of 0.5 gmt or 1 gmt of pure streptomycin base, each gram being equivalent to 1,000,000 units. Sterile isotonic saline is added to the vial to make up the desired concentration. Solutions are less stable than the dry powder and should be kept in a refrigerator. Intramuscular Iniection.-The administration of 30 to 75 mg. per pound of body weight or a total of 0.25 to 2 gmt daily to infants and yqung children in divided intramuscular doses at six hour intervals is recommended. In adults 1 gmt every four or six hours is suggested. The gluteal muscles, the lateral aspects of the thigh and the triceps may be used in rotation. Each gram of streptomycin may be dissolved in as little as 4 to 5 cC. of sterile, pyrogen-free distilled water or isotonic saline, making possible the administration of a large amount of streptomycin in a relatively small volume. Procaine hydrochloride, 1 cC. of a 1 per cent solution, may be added to 4 or 5 ce. of the streptomycin solution if desired, but the discomfort of intramuscular injection is probably minimized best by keeping the volume of injected material as small as possible. Intravenous administration is rarely indicated as the drug is absorbed very rapidly from intramuscular injections with peak levels in the blood usually being reached within thirty minutes. Intravenous injections are more often followed by immediate untoward reactions. 'Subcutaneous injections may be given but they produce pain and irritation more frequently. Intramuscular therapy should be continued for fouf or :five days after the clinical and laboratory findings have indicated that the infection has subsided. Intrathecal Iniections.-Streptomycin may be applied safely in ther-
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apeutic doses to the central nervous system. The daily administration of 50 mg. (50,000 units) to infants and 50 to 100 mg. to adults is recommended. In newborn infants it . may be advisable to use 25 mg. for the initial intrathecal doses. It has been found useful to add 20 cc. of sterile isotonic saline solution to a vial containing 1 gm. of streptomycin, making a final dilution of 50 mg. per cubic centimeter, and then to use this vial exclusively for intrathecal injections throughout the illness. At the "time of the injection, 1 cc. of the streptomycin solution is withdrawn from the vial mixed with another 3 to 5 cc. of sterile isotonic saline. The solution is injected slowly into the lumbar subarachnoid space after the slow withdrawal of a larger volume of cerebrospinal fluid. Streptomycin may also be injected into the lateral cerebral ventricles through the anterior fontanelle in infants or into the basal cistern when a block is suspected. In severely ill patients the first two or three intrathecal doses may be administered at twelvehour intervals and subsequent ones every twenty-four hours. Intrathecal injections should be continued until tli~ patient has shown marked clinical improvement and the cultures and other cerebrospinal fluid findings indicate that the infection has been controlled. Continued administration of streptomycin intrathecally after the temperature has reached normal may be associated with a secondary febrile response and was noted in about half of the patients treated in this hospital. In most cases the temperature reached normal between the fourth and seventh day of streptomycin therapy and the secondary rise in temperature occurred quite promptly thereafter. In some cases there is also an increase in the number of leukocytes, largely polymorphonuclear, in the cerebrospinal fluid associated with this secondary fever. This fever usually subsides and the number of polynuclear cells in the cerebrospinal fluid drops promptly after the intrathecal injections are discontinued. Sulfadiazine.-Sulfadiazine is not indicated initially in most cases of Hemophilus inHuenzae meningitis since streptomycin alone in adequate doses will probably conb·ol the infection. However, in very young infants, in patients who are extremely ill or where treatment is begun late in th~ course of the disease, sulfadiazine should be given, preferably by hypodermoclysis. The sulfonamide is also indicated if the patient fails to respond to streptomycin or when there is evidence of a relapse of the infection during the streptomycin treatment. Four cases have been reported in which resistant strains of Hemophilus inHuenzae appeared during streptomycin therapy.4. 28.29 The institution of sulfadiazine therapy in such cases is obviously indicated and there is probably no advantage in continuing streptomycin when that occurs. The appearance of secondary infections in the ears, nasopharynx, meninges or elsewhere while the patient is receiving strep-
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tomycin treatment is·, also indication for sulfadiazine or penicillin, depending on the type of secondary infecting organism. 3 Penicillin.-There is little evidence that penicillin, as ordinarily used, is of therapeutic value in the treatment of Hemophilus inHuenzae meningitis although occasional cases have been reported in which the organism proved to be sensitive to penicillin and a good response followed treatment with this antibiotic and sulfonamides. 30- 32 Penicillin is certainly indicated in the treatment of complicating secondary infections with susceptible organisms during or after streptomycin therapy. Antiserum.-The use of specific Hemophilus influenzae Type b rabbit antise~um is not recommended for the routine initial therapy of most cases of Hemophilus inHuenzae meningitis. As already stated, it may be given to very young infants, to those who are extremely ill or if treatment is begun late in the disease. It is indicated if the patient fails to respond or if there is evidence of a relapse of the influenzal infection during streptomycin treatment. Tests for sensitivity' to rabbit serum·should be done and the antiserum'should be given essentially according to the recommendations of Alexander. 16 A dose of specific antiserum equivalent to 100 mg. of antibody nitrogen is given in saline solution by intravenous infusion over a period of two hours.' The volume of fluid suggested is 10 cc. per kilogram of body weight and this may be added to the infusion containing sodium sulfadiazine solution. Additional antibody, 25 mg. per day, may be given intramuscularly if the progress is not satisfactory or if the serum of the patient, diluted 1: 10, fails to produce capsular swelling with the infecting strain. Examination of Cerebrospinal Fluid.-The progress of the disease and the effect of therapy on the course of the infection can be intelligently followed only with the aid of frequent examinations of the cerebrospinal fluid. This should be done daily until the infection is controlled and at longer intervals thereafter until the fluid returns essentially to normal. Examination of the cerebrospinal fluid should include: 1. Stained smears. The presence of gram-negative bacilli in the stained smears is sufficient indication for the institution of streptomycin therapy. Gram-stained smears of the cerebrospinal fluid during therapy are of help in determining the presence or absence of Hemophilus influenzae or other secondary invaders. 2. Culture. A culture should be made of the cerebrospinal fluid obtained at the tinle of the first lumbar puncture which should be done before any antibacterial therapy is given. One should not wait for the result of this culture before starting streptomycin therapy, but the antibiotic should be given if gram-negative bacilli are found in the stained smear. Cultures should be made of all specimens of
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;:,cerebrospinal fluid obtained during therapy in order to demonstrate ,:,the persistence or recurrence of Hemophilus inHuenzae or the appearance of secondary invaders. ,3. Cell count. A total leukocyte count should be performed on each specimen of cerebrospinal fluid and a differential cell count included. (The c:J1amber differential count is adequate.) This provides a simple indication of the progress of the disease and may even be used as a guide for therapy. If the infection is subsiding, the total cell count diminishes and the percentage of mononuclear cells increases. 4. Sugar and protein. Determinations of the sugar and protein content of the cerebrospinal fluid are also helpful in following the course of the infection. The sugar rapidly increases to a normal level when the infection is subsiding or decreases in the presence of a relapse or complicating secondary infection of the meninges. The protein content decreases to a normal level somewhat less rapidly than the return of the sugar to normal when the infection is under control. Correspondingly, a relapse or secondary meningeal infection would be attended by an increase in protein content. In interpreting the sugar content the effect of recent infusions of glucose must be considered. Response to Streptomycin Therapy.-Cultures of the cerebrospinal fluid in all of the cases of Hemophilus influenzae meningitis treated at this hospital have been negative following the :6r~t intrathecal injection of streptomycin. This was associated with an increase in the sugar and a decrease in the protein content of the fluid. There was a rapid decrease in the total. number of leukocytes in the cerebrospinal fluid, with a change from a polymorphonuclear to a mononuclear predominance. The clinical response usually lags slightly behind the laboratory evidence of subsidence of the meningitis. Clinical improvement is usually striking during the first two to four days. During this time there is a return to a normal state of' consciousness, subsidence of convulsions or irritability, and the infants begin to feed well. The. temperature gradually falls to normal over a period of four to seven days. A typical response to streptomycin treatment in a case of Hemophilus influenzae meningitis is shown in Figure 182. Neurologic Sequelae.-Evidence of" neurologic damage has been uncommon in patients with influenzal meningitis who recovered fol-lowing streptomycin therapy. In the group of fifteen patients treated at this hospital, only one showed evidence of permanent neurologic damage. Treatnlent in this infant was begun on about the sixth day of the disease and following recovery the infant was apparently deaf and blind.
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Interpretation of Persistent or Recurrent Fever.-The occurrence of a secondary rise in temperature or the persistence of fever during or after apparent recovery from Hemophilus inHuenzae meningitis on streptomycin therapy is particularly disturbing to the physician. Some of the principal causes for this fever may be considered \ . briefly. 1. Relapse of the Original Infection.-This eventuality was not UDcommon in the days of combined sulfonamide-antiserum treatment of influenzal meningitis. It is much less frequent in patients adequately .L...,FEMALE
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Fig. 182.-Therapy, clinical response and relevant findings in the cerebra.. spinal fluid in a case of Hemophilus inHuenzae Type b meningitis in which treatment with streptomycin was begun early in the disease. The secondary rise in fever is probably attributable to streptomycin.
treated with intrathecal and intramuscular streptomycin. Such a relapse is heralded by an exacerbation of the clinical evidence of meningitis and the reappearance of organisms in smears and cultures of the cerebrospinal fluid. There is also an increase in the number of cells, the percentage of polymorphonuclear forms and the protein content, with a decrease in the level of sugar in the fluid. The strain of organisms that reappears during streptomycin therapy is likely to be extremely resistant to the action of streptomycin. Specific anti, serum and sulfadiazine are then indicated. It is emphasized, however,
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that in cases which are adequately treated with streptomycin by both the intrathecal and parenteral routes this phenomenon is rare. 2. Secondary Infection.-Complicating infections by organisms relatively insensitive to streptomycin may occur in the ears, nasopharynx, the meninges or elsewhere during or after streptomycin treatment of inHuenzal meningitis. The physician must watch for such a development and institute additional therapy in the form of sulfadiazine or penicillin, or both, as indicated. . 8. Streptomycin Fever.-As already noted, the appearance of a secondary febrile episode in patients recovering from influenzal meningitis and apparently related to the streptomycin is not uncommon. The course in these patients is characterized by clinical and laboratory evidence of improvement, a gradual drop in the temperature to nor.. mal followed by a fairly abrupt exacerbation of fever. This fever usually subsides promptly when the intrathecal injections of streptomycin are stopped. In some patients a slight increase in cells in tpecerebrospinal fluid, particularly polymorphonuclear leukocytes, is noted coincident with ,the fever, and this, too, subsides when the intrathecal injections are stopped. Clinically the patients continue to appear well during this febrile episode. The fever may also be related to the intramuscular injections of the streptomycin and, in that event, it subsides when these injections are discontinued. In order to minimize the occurrence of drug fever, it is recommended that'the intrathecal injections be stopped one or two days after the temperature first reaches normal, provided, of course, that other examinations indicate that the infection is completely controlled and that the parenteral therapy is carried out for two or three days longer. 4. Sulfadiazine Fever.-Drug fever associated with the administration of sulfadiazine is a relatively frequent occurrence in patients receiving this drug for more than one week. It may be associated with a rash. Stopping the sulfadiazine results in rapid subsidence of the fever, if the two are related, and the rash, if present, also clears rapidly. 5. Serum Sickness.-The incidence of serum sickness following administration of antiserum varies considerably. It usually appears seven to fourteen days after administration of the serum and is often associated with fever, urticaria, arthralgia and lymphadenopathy. MENINGITIS DUE TO OTHER GRAM·NEGATIVE BACILLI
Meningitis due to gram-negative bacilli other than Hemophilus influenzae may occur in any age group. No one of these organisms predominates in such cases in adults, but colon bacillus infections are more common in infancy. Most of the cases follow direct implantation of the organisms into the meninges by trauma or by contaminated lumbar puncture or they occur by extension from an adjacent focus
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TOM FITE PAINE, MAXWELL FINLAND
of infection in the nasal sinuses, ears, mastoid or meningocele. Occasionally they occur in association with septicemia resulting from distant foci of infection in the gastrointestinal or genitourinary tract or elsewhere. Mortality rates in this type of infection depend upon many factors but they are generally quite high (from 50 to 100 per cent). The sulfonamides have been helpful but their use has not reduced the mortality to any marked extent. s, 9, 12, 33-35 Cases of meningitis due to a wide variety of gram-negative bacilli have been treated with streptomycin by many workers 1 , 26, 36--42 and the results, though variable, were quite gratifying. The effects observed at this hospital have been encouraging. A group of six such cases have been treated; the causative organism was Pseudomonas aeruginosa (Bacillus pyocyaneus) in three cases and Bacillus proteus, Aerobacter aerogenes and Hemophilus para-influenzae, each in one case. Five of these patients have recovered. The fatal case was one due to Pseudomonas aeruginosa in which the organism became totally resistant to streptomycin after seventeen days of treatment with the antibiotic and ren1ained so. Sonle of these cases are reported elsewhere. 42 Treatment.-Streptomycin.-Streptomycin should be administered essentially as already described for Hemophilus inHuenzae meningitis and the dosage, both intramuscular and intrathecal, is the same and depends on the age of the patient. Secondary fevers related to the streptomycin have been noted with equal frequency in this type of case. The period of streptomycin therapy depends on the clinical and laboratory evidence of subsidence of the infection. In certain cases of meningitis due to Pseudomonas aeruginosa, an organism which is often naturally quite resistant to streptomycin, cerebrospinal fluid cultures may not become negative for several days after the therapy is begun. In one such case 42 streptomycin therapy was given over a period of one month before organisms disappeared completely. The possibility of the development of extremely resistant strains of organisms exists during streptomycin therapy, as already noted. This can readily be determined by growing the organism in Inedia containing varying concentrations of streptomycin. If the organism is found to be resistant, further streptomycin therapy will probably be of no avail and its administration may be discontinued. Penicillin.-Most of the gram-negative bacilli encountered in meningitis are quite resistant to penicillin. 'lndeed many such strains produce a penicillin inhibitor known as penicillinase. There is, therefore, no indication for the use of this agent initially. Should secondary infections due to penicillin-sensitive organisms arise, penicillin would be indicated and should be given in generous doses. Sulfonamides.-Most of the cases of gram-negative bacillus meningitis will probably respond to streptomycin' alone. However, if the
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organism is fairly resistant to strepton1ycin, it is probably wise to administer a sulfonamide along with the streptomycin. Again, in the event of secondary complicating infections by sulfonamide-sensitive organisms, a sulfonamide should be given. Sulfadiazine is the drug of choice and should be given in full doses orally whenever possible. If oral therapy is not feasible, the sodium salt may be given in solution. In adults, 3 gm. are given in about 250 cc. of physiological saline by hypodermoclysis every twelve hours. Corresponding doses are · given to infants and children. Surgery.-Chemotherapeutic and antibiotic agents are no substitute when surgery is indicated. If foci of infection are suspected that may require surgical drainage, the surgeon should be consulted and necessary surgery carried out. Fora discussion of the diagnostic features of- meningitis and of the focal complications that may be encountered, the reader is referred to the paper by Keefer. 43 TUBERCULOSIS MENINGITIS
Meningitis due to the tubercle bacillus often occurs in association with a spread of the disease, or miliary dissemination, from a focus of infection in the lungs or elsewhere. The 'original focus, however, is not always demonstrable. It is usually a disease of insidious onset, being marked by listlessness, lethargy, irritability, fever and headache over a period of weeks. The more dramatic signs of meningeal irritation or increased intracranial pressure come somewhat later and are usually responsible for the admission of the patient to a hospital. Heretofore it has been a uniformly fatal disease. 44 , 45 In a number of reported cases treated with streptomycin, the disease appears to have been arrested. 41 , 46-48 The follow-up in these cases was relatively short and a final evaluation of the therapy is not yet possible. The incidence of serious and permanent neurologic damage in these survivors was high. Three cases of tuberculous meningitis have been treated at this hospital. In one patient the disease appears to have been arrested after a treatment period of four months and there has been no evidence of relapse during the ensuing three months. Diagnosis.-Examination of the cerebrospinal fluid during the first few days of the disease usually shows an increase in leukocytes, pre.. dominately polymorphonuclears. By the time the patient is seen by the physician, however, the cells usually are almost all lymphocytes. This continues throughout the course of the disease except when foreign substances are injected into the thecal space or secondary bacterial infection supervenes. The sugar content of the cerebrospinal fluid may be only slightly decreased initially but drops progressively as the disease advances. The protein is elevated and a pellicle often
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TOM FITE PAINE, MAXWELL FINLAND
forms in the fluid on standing. The chloride content of the cerebrospinal fluid may be decreased. The diagnosis depends on demonstrating the acid-fast tubercle bacilli by: (1) Ziehl-Nielsen (acid-fast) stain of the pellicle or of the centrifuged sediment of the cerebrospinal fluid, or (2) appropriate culture or guinea pig inoculation of the fluid. Cultural methods now allow the demonstration of tubercle bacilli in a matter of several days rather than in the four to six week period required by older methods. Streptomycin Treatment.-In cases of tuberculous meningitis streptomycin should be administered by both the parenteral and intrathecal routes and should be carried out for a perio~ of at least four months. 48 Since the outcome of such cases may well depend on the early institution of therapy, it would seem wise to treat suspected cases as soon as possible and to continue the therapy at least until the results of culture or guinea pig inoculation are known. It is particularly important to obtain cerebrospinal fluid for culture or guinea pjg inoculation or both before streptomycin is begun since these procedures may yield negative results after the treatment is begun and the diagnosis may then remain in doubt. It should be emphasized that therapy should not be withheld pending the results of the pretreatment cultures or of guinea pig inoculations. TOXIC EFFECTS OF STREPTOMYCIN
Reactions are not unusual following streptomycin therapy and may be manifested locally and constitutionally. Local Reactions.-From Intramuscular' Iniection.-Pain, tenderness and induration are commonly noted at the site of intramuscular injections. This local reaction is minimized by keeping the volume of injected material at a minimum. From Intrathecal Iniections.-Fever and pleocytosis in the cerebrospinal fluid may follow such injections. These reactions are related to the amount of streptomycin injected and to the duration of intrathecal therapy. Injection of no more than 50 to 100 mg. of streptomycin per dose and termination of the intrathecal therapy soon after the infection is controlled will minimize these reactions. Constiiutional Reactions.-Histamine-like Effect.-Flushing of the skin, nausea, vomiting, headache, fall in blood pressure or convulsions may follow immediately after the parenteral administration of streptomycin. These reactions are encountered almost exclusively during intravenous injections, particularly when such injections are given too rapidly. Present lots of streptomycin are practically free ,of the histamine-like material which produces this immediate reaction. Benadryl has been used successfully to avoid the histamine-like reaction. 49 Sensitization Reactions.-Fever and skin rashes of varying types may follow the parenteral use of streptomycin. These usually appear be-
STREPTOMYCIN IN TREATMENT OF MENINGITIS
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tween the third and tenth day of therapy. Fever, as noted above, may
follow either the intramuscular or intrathecal injection of streptomy-
cin but is more frequent following the latter. Neurologic Disturbance.-Disturbance of function of the eighth cranial nerve, particularly the vestibular portion, may appear following parenteral streptomycin therapy.5o Such a reaction is apparently not related to the intrathecal injection of the drug. The disturbance is commonly manifested by an ataxia or, rarely, by deafness. This reaction seems much more common in adults than in children. Compensation for the absence .of vestibular reflexes by other postural mechanisms usually occurs in a period of weeks resulting in a considerable or total alleviation of the disability. Effects on Other Ofgans.-Hyaline and granular casts have been noted in the urine of some patients receiving streptomycin but there has peen no evidence of lasting renal impairment. REFERENCES 1. Committee on Chemotherapeutics and Other Agents, National Research Council: Streptomycin in the Treatment of Infections. A Report of One Thousand Cases. J.A.M.A., 132:4-11 (Sept. 7) and 70-76 (Sept. 14) 1946. 2. Murray, R., Paine, T. F. and Finland, M.: Streptomycin. 1. Bacteriological and Pharmacological Aspects. New England J.. Med., 236:701-712 (May 8) 1947. Paine, T. F., Murray, R. and Finland, M.: Streptomycin. II. Clinical Uses. Ibid., 236:748-760 (May 15) 1947. 3. Weinstein, L.: The Treatment of Meningitis Due to Haemophilu8 influenzae with Streptomycin. A Report of Nine Cases. New England J. Med., 235: 101-111 (July 25) 1946. 4. Alexander, H. E., Leidy, G., Rake, G. and Donovick, R.: Hemophilus influenzae Meningitis Treated with Streptomycin. J.A.M.A., 132:434-440 (Oct. 26) 1946. 5. Neal, J. B.: Diagnosis and Treatment of Meningitis. M. CLIN. NORTH AMERICA, 19:751-769 (Nov.) 1935. 6. Hertzog, A. J.: A Study of 377 Cases of Fatal Meningitis with Special Reference to Bacteriologic Diagnosis. Am. J. Clin. Path., 15:571-574 (Dec.) 1945. 7. Jaffe, S. A.: Extrapulmonary Klebsiella pneumoniae Infections. An Analysis of the Literature: Report of Two Unusual Cases with Recovery. J.A.M.A., 122:2~2-296 (May 29) 1943. 8. Wood, W. H., Mayfield, F. H. and Frisch, A. W.: Meningitis Due to Salmonella panama. ].A.M.A., 128:868-870 (July 21) 1945. 9. Stanley, M. M.: Bacillus pyocyaneus infections. A Review, Report of Cases and Discussion of Newer Therapy Including Streptomycin. Am. J. Med., 2:253277 (March) and 347-367 (April) 1947. 10. McKee, T. L.: Bacillus proteus Infections: Review of the Literahtre and Report of Case of Septicemia of Otitic Origin Treated with Sulfapyridine with • Recovery. Arch. Otolaryng., 39:398-402 (May) 1944. 11. Barrett, G. S., Rammelkamp, C. H. and Worcester, J.: Meningitis due to Escherichia coli. Report of Two Cases with Recovery Following Cheillotherapy, Review of the Literature and Report of Experimental Studies. Am. J. Dis. Child., 63:41-59 (Jan.) 1942. 12. Stuart, B. M. and Pullen, R. L.: Tularemic Meningitis. Review of the Literature
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and Report of a Case with Postmortem Observations. Arch. Int. Moo., 76:163-166 (Sept.) 1945. 13. Pulaski, E. J.: Streptolnycin Therapy of Penicillin-Resistant and SulfonamideResistant Specific and Nonspecific Urethritis. J. Ven. Dis. Inform., 28:1-6 (Jan.) 1947. 14. Priest, W. S. and McGee, C. J.: Streptomycin in the Treatment of Subacute Bacterial Endocarditis. Report of Three Cases. J.A.M.A., 132:124-126 (Sept. 21) 1946. 15. Aleman, R.: Influenzal Meningitis; Review of Recent Literature with Case Reports. New Orleans M. & S. J., 93:25-33 (July) 1940. 16. Alexander, H. E., Ellis, C. and Leidy, G.: Treatment of Type-Specific Hemophilus influenzae Infections in Infancy and Childhood. J. Pediat., 20:673698 (June) 1942. 17. Sako, W., Stewart, C. A., and Fleet, J.: Treatment of Influenzal Meningitis with Sulfadiazine; Further Report. J. Pediat., 25:114-126 (Aug.) 1944. 18. Comly, H. H. and McKee, A. P.: Meningitis and Other Infections Caused by Hemophilus influenzae (Pfeiffer's Bacillus). J. Iowa M. Soc., 35:127-132 (April) 1945. 19. Turner, E. K.: A Further Report on the Treatment at the Children's Hospital, Melbourne, of Influenzal Meningitis with Sulphonamides and Type-Specific Serum, M. J. Australia, 1:219-221 (March 3) 1945. 20. Smith, M. H. D., Wilson, P. E. and Hodes, H. L.: The Treatment of Influenza] Meningitis. J.A.M.A., 130:331-335 (Feb. 9) 1946. 21. Zintel, H. A., Flippin, H. F., Nichols, A. C., Wiley, M. M. and Rhoads, J. E.: Studies on Streptomycin in Man. I. Absorption, Distribution, Excretion and Toxicity. Am. J. M. Sc., 210:421-430 (Oct.) 1945. 22. Anderson, D. G. and Jewell, M.: The Absorption, Excretion and Toxicity of Streptomycin in Man. New England J. Med., 233:485-491 (Oct. 25) 1945. 23. Heilman, D. H., Heilman, F. R., Hinshaw, H. C., Nichols, D. R. and Herrell, W. E.: Streptomycin: Absorption, Diffusion, Excretion, and Toxicity. Am. J. M. Sc., 210:576-584 (Nov.) 1945. 24. Buggs, C. W., Pilling, M. A., Bronstein, B. and Hirshfeld, J. W.: The Absorption, Distribution and Excretion of Streptomycin in Man. J. Clin. Investigation, 25:94-102 (Jan.) 1946. 25. Adcock, J. D. and Hettig, R. A.: Absorption, Distribution and Excretion of Streptomycin. Arch. Int. Med., 77:179-195 (Feb.) 1946. 26. Zantiny, W. C. and Carlson, H. J.: Experiences with Streptomycin: Effectiveness in Infections of Infants and Children. Clinics, 5:635-645 (Oct.) 1946. 27. Hoyne, A. L., Brown, R. H. and Drucker, A. P.: Influenzal Meningitis Treated with Streptomycin. Report of 3 Cases with Recoveries. Arch. Pediat., 63: 559-566 (Nov.) 1946. . 28. Birmingham, J. R., Kaye, R. and Smith, M. H. D.: Streptomycin in the Treatment of Influenzal Meningitis. J. Pediat." 29:1-13 (July) 1946. 29. Morgan, H. J. and Hunt, J. S.: Stteptomycin in Clinical Practice; A Review and Case Reports. Amer. Pract., 1:73-86 (Oct.) 1946. 30. Forgacs, P., Hutchinson, R. I. and Rewell, R. E.: Penicillin Sensitivity of H aemophilus influenzae; Two Sensitive Pathogenic Strains. Lancet. 1:785786 (June 23) 1945. 31. McIntosh, D. G. and Drysdale, C. F.: Meningitis Due to Penicillin and Sulphonamide-Sensitive Pittman b Strain of H. influenzae: Recovery. Brit. M. J., 2:796-797 (Dec. 8) 1945. 32. Hewitt, W. L. and Pittman, M.: Antibacterial Action of Penicillin, Penicillin X and Streptomycin on Hemophilus influenzae. Pub. Health Rep., 61:768-778 (May 31) 1946.
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BS. Burman, H. J., Rosenbluth, M. and Burman, D.: Otorhinogenic Meningitis. A Report of Fifty-Eight Cases. Arch. Otolaryng., 35:687-719 (May) 1942. 84. Neter, E. R.: Salmonella cholerae suis Meningitis. Report of a Case and Re~iew of the Literature on Salmonella Meningitis. Arch. Int. !vled., 73:425-429 (May) 1944. S5. Strong, P. S. and Edwards, J. E.: Escherichia coli Meningitis Treated with Sulfadiazine. J.A.M.A., 129:210-211 (Sept. 15) 1945. S6. Alexander, A. J.: Meningitis Due to Escherichia coli Treated with Streptomycin. J.A.M.A., 131:663-665 (June 22) 1946. 87. Cairns, M., Duthie, E. S. and Smith, H. V.: Intratracheal Strepton1ycin in Meningitis. Clinical Trial in Tuberculous, Coliform and Other Infections. Lancet, 2:153-155 (Aug. 3) 1946. 38. Barnes, M.: Salmonella Meningitis. Report of a Case Treated with Streptomycin. Bull. Charlotte Memorial Hosp., 2:44-47 (Sept.) 1946. 39. Shields, W. P.: Meningitis Due to Escherichia coli. Streptomycin Therapy. J.A.¥.A., 132:514-515 (Nov. 2) 1946. 40. Tartakoff, S., Grynbaum, B. and LeCompte, P. M.: FriedHinder-Bacillus Meningitis Treated with Streptomycin. New England J. Med., 235:681-683 (Nov. 7) 1946. 41. DeBakey, M. E. and Pulaski, E. J.: An Analysis of the Experience with Streptomycin in United States Army Hospitals.. Preliminary Report. Surgery, 20: 749-760 (Dec.) 1946. 42. Paine, T. F., Murray, R., Harris, H. W. and Finland, M.: Streptomycin in the Treatment of Certain Gram-Negative Bacillus Infections of the Central Nervous System. Am. J. M. Sc., 213:676-685 (June) 1947. 43. Keefer, C. S.: The Treabnent of Bacterial Meningitis. M. CLIN. NORTH AMERICA, 25:1287-1315 (Sept.) 1941. 44. Lindsay, J. W., Rice, E. C. and Selinger, M. A.: Meningitis in Children. A Review of 331 Cases. M. Ann. District of Columbia, 4:231-243 (Sept.) 1935. 45. Tripoli, C. J.: Bacterial Meningitis. A Comparative Study of Various Therapeutic Measures. J.A.M.A., 106:171-175 (Jan. 18) 1936. 46. Cooke, R. E., Dunphy, D. L. and Blake, F G.: Streptomycin in Tuberculous Meningitis; A Report of Its Use in a One-Year-Old Infant. Yale J. BioI. & Med., 18:221-226 (Jan.) 1946. -47. Krafchik, L. L.: 'Tuberculous Meningitis Treated with Streptomycin. J.A.M.A., 132:375-376 (Oct. 19) 1946. 48. Hinshaw, H. C., Feldman, W. H. and Pfuetze, K. H.: Treatment of Tuberculosis with Streptomycin. J.A.M.A., 132:778-782 (Nov. 30) 1946. 49. Hewitt, W. L. and Curry, J. J.: Pharmacodynamic Effect in Man of Streptomycin Containing a Histamin-like Factor J. Lab. & Clin. Med., 32:42-46 (Jan.) 1947. 50. Fowler, E. P. and Seligman, E.: Otic Complications of Streptomycin Therapy: A Prelitninary Report. J.A.M.A., 183:87-91 (Jan. 11) 1947.
M.D.,
F.A.C.P.t
AMONG the bacterial meningitides, those least favorably affected by the sulfonamides and penicillin are the ones which are caused by gram~negative bacilli and, of course, the cases of tuberculous meningitis. Streptomycin has proved to be the most effective agent now available in the treatnlent of these infections. 1 ,2 Streptomycin alone also appears to be at least as effective, or even more so, than the cOP1bination of sulfonamides and rabbit type specific antiserum in the treatment of Hemophilus inHuenzae Type b meningitis. 3 , 4 An acquaintance with the proper use and limitations of streptomycin in this very serious group of infections is, therefore, essential for those who may be called upon to treat such cases.
INCIDENCE OF CASES OF MENINGITIS POTENTIALLY SUITABLE FOR STREPTOMYCIN THERAPY
In a series of 3178 cases of bacterial meningitis reported by Neal, 5 the over-all incidence of cases due to gram-negative bacilli was about 5 per cent. In infants and young children, the incidence of gramnegative bacillus meningitis was higher than in adults. In patients below the age of 3 years, 9.5 per cent of 1077 cases were due to gramnegative bacilli 5 and in a series of 149 fatal cases of bacterial meningitis in patients below 3 years of age, 32 per cent were due to such organisms. 6 Most of the gram-negative bacillus infections of the meninges in infants and children are caused by Hemophilus influenzae. The coliform organisms rank next but are much less frequent. In Neal's series/' 8.5 per cent of the cases in patients under 3 years of age were due to Hemophilus influenzae and 0.56 per cent to Bacillus coli. From the Thorndike Memorial Laboratory, Second and Fourth M'edical Services ( Harvard), Boston City Hospital, and the Department of Medicine, Harvard Medical School, Boston. The studies on which this presentation is based were aided by a grant from the United States Public Health Service and were carried out with the collaboration of Doctors Roderick Murray, H. William Harris, Lawrence Kilham, and Albert O. Seeler and with the technical assistance of Miss Clare Wilcox. :\'!: Assistant in Medicine, Harvard Medical School and Research Fellow, Thorndike Memorial Laboratory. t Associate Professor of Medicine, Harvard Medical School; Chief, Fourth Medical Service and Associate Physician, Thorndike Memorial Laboratory, Boston City I-Iospital.
1092
STREPTOMYCIN IN TREATMENT OF MENINGITIS
1093
Among the 149 fatal cases of bacterial meningitis in patients below 3 years of age Hemophilus inHuenzae accounted for 26 per cent and the colon bacillus for 6 per cent. 6 Other gram-negative bacilli which have been encountered less often are: Klebsiella pneumoniae (Friedlander:Js bacillus),5,7 the typhoid-dysentery group,S Pseudomonas aeruginosa (Bacillus pyocyaneus),9 the proteus. group,lO Aerobacter aerogenes,ll Pasteurella tularensis l2 and others. Tuberculosis of the central nervous system is a common condition, comprising 31 per cent of Neal's series of 3178 cases. 5 Here, again, the highest incidence of the disease is among children. It is to be borne in mind that streptomycin also exerts antibiotic action against gram-positive and gram-negative cocci, though these organisms are generally considered to be affected best by penicillin and sulfonamides. In occasional infections due to such organisms, streptomycin has proved useful when the other agents apparently failed. l3 ,14 It may, therefore, be considered as tit, substitute for, or as an adjunct to therapy with other antibacterial agents under such conditions. HEMOPHILUS INFLUENZAE MENINGITIS
This is primarily a disease of infancy and early childhood; most of the cases are caused by the smooth Type b strain. The usual history in such cases is that of a mild upper respiratory infection followed by signs of meningitis. The organisms probably reach the meninges by the blood stream after invasion through the respiratory tract. The over-all mortality in this disease has been reduced by combined sulfonamide and type-specific rabbit antiserum therapy from nearly 100 per cent to between 15 and 50 per cent. l5- 20 Streptomycin now provides the best available means for treating this disease. Furthermore, since the action of streptomycin is not type-specific, it may be used in Hemophilus influenzae infections due to strains other than those of Type b. The mortality rate in the 100 cases of Hemophilus inHuenzae meningitis treated with streptomycin under the auspices of the National Research Council l was 17 per cent. Streptomycin was given to many of these patients, however, only" after other forms of therap,y had proved unsuccessful. In the treatment of twenty-five cases with streptomycin alone or combined with other therapeutic agents, Alexander4 reported three deaths. Strains of Hemophilus influenzae resistant to streptomycin developed in two of her cases. There were two deaths in the nine cases treated by Weinstein;3 one of these deaths was due to a secondary staphylococcal infection. i' The experience at the Boston City Hospital in the treatment of Hemophilus influenzae meningitis has been equally encouraging. In fifteen cases treated to date there has been only one death; ten of these fifteen patients were under 1 year old.
1094
TOM FITE PAINE, MAXWELL FINLAND
Treatment of Hemophilus Influenzae Meningitis.-Streptomycin. -The administration of streptomycin by the intramuscular or intravenous route alone cannot be depended upon to maintain adequate concentrations of the drug in the cerebrospinal fluid. 1 , 21-27 Little if any streptomycin is "detectable in the cerebrospinal fluid after injection by these routes. when there is no meningitis, and only relatively low concentrations are found in the cerebrospinal fluid under these conditions in cases of meningitis. Consequently, it is advisable to give the antibiotic by both the parenteral and intrathecal routes in the treatment of meningitis. In infants and young children the administration of 0.5 to 2 gmt intramuscularly and 50 mg. intrathecally during each twenty.. four hour period usually results in the maintenance of high concentrations in the blood and cerebrospinal fluid. Levels of 3 to 6 units per cubic centimeter of streptomycin may still be found in the cerebrospinal fluid twenty-four hours after the intrathecal injections. Most of the pathogenic strains of Hemophilus inHuenzae that have been tested are inhibited by 1 to 5 units per cubic centimeter. 2 Administration of Streptomycin.-Streptomycin is supplied commercially as a dry sterile powder, either as the hydrochloride or sulfate. Each vial contains the equivalent of 0.5 gmt or 1 gmt of pure streptomycin base, each gram being equivalent to 1,000,000 units. Sterile isotonic saline is added to the vial to make up the desired concentration. Solutions are less stable than the dry powder and should be kept in a refrigerator. Intramuscular Iniection.-The administration of 30 to 75 mg. per pound of body weight or a total of 0.25 to 2 gmt daily to infants and yqung children in divided intramuscular doses at six hour intervals is recommended. In adults 1 gmt every four or six hours is suggested. The gluteal muscles, the lateral aspects of the thigh and the triceps may be used in rotation. Each gram of streptomycin may be dissolved in as little as 4 to 5 cC. of sterile, pyrogen-free distilled water or isotonic saline, making possible the administration of a large amount of streptomycin in a relatively small volume. Procaine hydrochloride, 1 cC. of a 1 per cent solution, may be added to 4 or 5 ce. of the streptomycin solution if desired, but the discomfort of intramuscular injection is probably minimized best by keeping the volume of injected material as small as possible. Intravenous administration is rarely indicated as the drug is absorbed very rapidly from intramuscular injections with peak levels in the blood usually being reached within thirty minutes. Intravenous injections are more often followed by immediate untoward reactions. 'Subcutaneous injections may be given but they produce pain and irritation more frequently. Intramuscular therapy should be continued for fouf or :five days after the clinical and laboratory findings have indicated that the infection has subsided. Intrathecal Iniections.-Streptomycin may be applied safely in ther-
STREPTOMYCIN IN TREATMENT OF MENINGITIS
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apeutic doses to the central nervous system. The daily administration of 50 mg. (50,000 units) to infants and 50 to 100 mg. to adults is recommended. In newborn infants it . may be advisable to use 25 mg. for the initial intrathecal doses. It has been found useful to add 20 cc. of sterile isotonic saline solution to a vial containing 1 gm. of streptomycin, making a final dilution of 50 mg. per cubic centimeter, and then to use this vial exclusively for intrathecal injections throughout the illness. At the "time of the injection, 1 cc. of the streptomycin solution is withdrawn from the vial mixed with another 3 to 5 cc. of sterile isotonic saline. The solution is injected slowly into the lumbar subarachnoid space after the slow withdrawal of a larger volume of cerebrospinal fluid. Streptomycin may also be injected into the lateral cerebral ventricles through the anterior fontanelle in infants or into the basal cistern when a block is suspected. In severely ill patients the first two or three intrathecal doses may be administered at twelvehour intervals and subsequent ones every twenty-four hours. Intrathecal injections should be continued until tli~ patient has shown marked clinical improvement and the cultures and other cerebrospinal fluid findings indicate that the infection has been controlled. Continued administration of streptomycin intrathecally after the temperature has reached normal may be associated with a secondary febrile response and was noted in about half of the patients treated in this hospital. In most cases the temperature reached normal between the fourth and seventh day of streptomycin therapy and the secondary rise in temperature occurred quite promptly thereafter. In some cases there is also an increase in the number of leukocytes, largely polymorphonuclear, in the cerebrospinal fluid associated with this secondary fever. This fever usually subsides and the number of polynuclear cells in the cerebrospinal fluid drops promptly after the intrathecal injections are discontinued. Sulfadiazine.-Sulfadiazine is not indicated initially in most cases of Hemophilus inHuenzae meningitis since streptomycin alone in adequate doses will probably conb·ol the infection. However, in very young infants, in patients who are extremely ill or where treatment is begun late in th~ course of the disease, sulfadiazine should be given, preferably by hypodermoclysis. The sulfonamide is also indicated if the patient fails to respond to streptomycin or when there is evidence of a relapse of the infection during the streptomycin treatment. Four cases have been reported in which resistant strains of Hemophilus inHuenzae appeared during streptomycin therapy.4. 28.29 The institution of sulfadiazine therapy in such cases is obviously indicated and there is probably no advantage in continuing streptomycin when that occurs. The appearance of secondary infections in the ears, nasopharynx, meninges or elsewhere while the patient is receiving strep-
1096
TOM FITE PAINE, MAXWELL FINLAND
tomycin treatment is·, also indication for sulfadiazine or penicillin, depending on the type of secondary infecting organism. 3 Penicillin.-There is little evidence that penicillin, as ordinarily used, is of therapeutic value in the treatment of Hemophilus inHuenzae meningitis although occasional cases have been reported in which the organism proved to be sensitive to penicillin and a good response followed treatment with this antibiotic and sulfonamides. 30- 32 Penicillin is certainly indicated in the treatment of complicating secondary infections with susceptible organisms during or after streptomycin therapy. Antiserum.-The use of specific Hemophilus influenzae Type b rabbit antise~um is not recommended for the routine initial therapy of most cases of Hemophilus inHuenzae meningitis. As already stated, it may be given to very young infants, to those who are extremely ill or if treatment is begun late in the disease. It is indicated if the patient fails to respond or if there is evidence of a relapse of the influenzal infection during streptomycin treatment. Tests for sensitivity' to rabbit serum·should be done and the antiserum'should be given essentially according to the recommendations of Alexander. 16 A dose of specific antiserum equivalent to 100 mg. of antibody nitrogen is given in saline solution by intravenous infusion over a period of two hours.' The volume of fluid suggested is 10 cc. per kilogram of body weight and this may be added to the infusion containing sodium sulfadiazine solution. Additional antibody, 25 mg. per day, may be given intramuscularly if the progress is not satisfactory or if the serum of the patient, diluted 1: 10, fails to produce capsular swelling with the infecting strain. Examination of Cerebrospinal Fluid.-The progress of the disease and the effect of therapy on the course of the infection can be intelligently followed only with the aid of frequent examinations of the cerebrospinal fluid. This should be done daily until the infection is controlled and at longer intervals thereafter until the fluid returns essentially to normal. Examination of the cerebrospinal fluid should include: 1. Stained smears. The presence of gram-negative bacilli in the stained smears is sufficient indication for the institution of streptomycin therapy. Gram-stained smears of the cerebrospinal fluid during therapy are of help in determining the presence or absence of Hemophilus influenzae or other secondary invaders. 2. Culture. A culture should be made of the cerebrospinal fluid obtained at the tinle of the first lumbar puncture which should be done before any antibacterial therapy is given. One should not wait for the result of this culture before starting streptomycin therapy, but the antibiotic should be given if gram-negative bacilli are found in the stained smear. Cultures should be made of all specimens of
STREPTOMYCIN IN TREATMENT OF MENINGITIS
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;:,cerebrospinal fluid obtained during therapy in order to demonstrate ,:,the persistence or recurrence of Hemophilus inHuenzae or the appearance of secondary invaders. ,3. Cell count. A total leukocyte count should be performed on each specimen of cerebrospinal fluid and a differential cell count included. (The c:J1amber differential count is adequate.) This provides a simple indication of the progress of the disease and may even be used as a guide for therapy. If the infection is subsiding, the total cell count diminishes and the percentage of mononuclear cells increases. 4. Sugar and protein. Determinations of the sugar and protein content of the cerebrospinal fluid are also helpful in following the course of the infection. The sugar rapidly increases to a normal level when the infection is subsiding or decreases in the presence of a relapse or complicating secondary infection of the meninges. The protein content decreases to a normal level somewhat less rapidly than the return of the sugar to normal when the infection is under control. Correspondingly, a relapse or secondary meningeal infection would be attended by an increase in protein content. In interpreting the sugar content the effect of recent infusions of glucose must be considered. Response to Streptomycin Therapy.-Cultures of the cerebrospinal fluid in all of the cases of Hemophilus influenzae meningitis treated at this hospital have been negative following the :6r~t intrathecal injection of streptomycin. This was associated with an increase in the sugar and a decrease in the protein content of the fluid. There was a rapid decrease in the total. number of leukocytes in the cerebrospinal fluid, with a change from a polymorphonuclear to a mononuclear predominance. The clinical response usually lags slightly behind the laboratory evidence of subsidence of the meningitis. Clinical improvement is usually striking during the first two to four days. During this time there is a return to a normal state of' consciousness, subsidence of convulsions or irritability, and the infants begin to feed well. The. temperature gradually falls to normal over a period of four to seven days. A typical response to streptomycin treatment in a case of Hemophilus influenzae meningitis is shown in Figure 182. Neurologic Sequelae.-Evidence of" neurologic damage has been uncommon in patients with influenzal meningitis who recovered fol-lowing streptomycin therapy. In the group of fifteen patients treated at this hospital, only one showed evidence of permanent neurologic damage. Treatnlent in this infant was begun on about the sixth day of the disease and following recovery the infant was apparently deaf and blind.
1098
TOM FITE PAINE, MAXWELL FINLAND
Interpretation of Persistent or Recurrent Fever.-The occurrence of a secondary rise in temperature or the persistence of fever during or after apparent recovery from Hemophilus inHuenzae meningitis on streptomycin therapy is particularly disturbing to the physician. Some of the principal causes for this fever may be considered \ . briefly. 1. Relapse of the Original Infection.-This eventuality was not UDcommon in the days of combined sulfonamide-antiserum treatment of influenzal meningitis. It is much less frequent in patients adequately .L...,FEMALE
Bt MENINGITIS
K~FLUENZAEtTYPE I
DAY OF DISEASE
TEMPERATURE
104 103102 101 100
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2
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4
S
6
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7
a YEARS 8
9
10
0
0
0
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99 98
..... TOXICITY + 0 0 0 29 13 8 6 W.B.C. I 1000 7700 510 490 150 0 W.B.C.I CU. MM. 95 89 80 95 " POLYMORPHS. I&. 308 167 59 PROTEIN, M'./IOO ML. 68 25 117 SUGAR, MG./IOO ML. CULTURE + 0 0 0 0 0 3 SENSITIVITY: UNITS IML. Z SPINAL UNITS/ML 6 3 6 ~ FLUID HR.AF'PER I.T. DOSE n R R
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DOSE GRAMS
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10e
I
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i
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SULFADIAZINE. GRAMS I DAY 1.3- I.
Fig. 182.-Therapy, clinical response and relevant findings in the cerebra.. spinal fluid in a case of Hemophilus inHuenzae Type b meningitis in which treatment with streptomycin was begun early in the disease. The secondary rise in fever is probably attributable to streptomycin.
treated with intrathecal and intramuscular streptomycin. Such a relapse is heralded by an exacerbation of the clinical evidence of meningitis and the reappearance of organisms in smears and cultures of the cerebrospinal fluid. There is also an increase in the number of cells, the percentage of polymorphonuclear forms and the protein content, with a decrease in the level of sugar in the fluid. The strain of organisms that reappears during streptomycin therapy is likely to be extremely resistant to the action of streptomycin. Specific anti, serum and sulfadiazine are then indicated. It is emphasized, however,
STREPTOMYCIN IN TREATMENT OF MENINGITIS
1099
that in cases which are adequately treated with streptomycin by both the intrathecal and parenteral routes this phenomenon is rare. 2. Secondary Infection.-Complicating infections by organisms relatively insensitive to streptomycin may occur in the ears, nasopharynx, the meninges or elsewhere during or after streptomycin treatment of inHuenzal meningitis. The physician must watch for such a development and institute additional therapy in the form of sulfadiazine or penicillin, or both, as indicated. . 8. Streptomycin Fever.-As already noted, the appearance of a secondary febrile episode in patients recovering from influenzal meningitis and apparently related to the streptomycin is not uncommon. The course in these patients is characterized by clinical and laboratory evidence of improvement, a gradual drop in the temperature to nor.. mal followed by a fairly abrupt exacerbation of fever. This fever usually subsides promptly when the intrathecal injections of streptomycin are stopped. In some patients a slight increase in cells in tpecerebrospinal fluid, particularly polymorphonuclear leukocytes, is noted coincident with ,the fever, and this, too, subsides when the intrathecal injections are stopped. Clinically the patients continue to appear well during this febrile episode. The fever may also be related to the intramuscular injections of the streptomycin and, in that event, it subsides when these injections are discontinued. In order to minimize the occurrence of drug fever, it is recommended that'the intrathecal injections be stopped one or two days after the temperature first reaches normal, provided, of course, that other examinations indicate that the infection is completely controlled and that the parenteral therapy is carried out for two or three days longer. 4. Sulfadiazine Fever.-Drug fever associated with the administration of sulfadiazine is a relatively frequent occurrence in patients receiving this drug for more than one week. It may be associated with a rash. Stopping the sulfadiazine results in rapid subsidence of the fever, if the two are related, and the rash, if present, also clears rapidly. 5. Serum Sickness.-The incidence of serum sickness following administration of antiserum varies considerably. It usually appears seven to fourteen days after administration of the serum and is often associated with fever, urticaria, arthralgia and lymphadenopathy. MENINGITIS DUE TO OTHER GRAM·NEGATIVE BACILLI
Meningitis due to gram-negative bacilli other than Hemophilus influenzae may occur in any age group. No one of these organisms predominates in such cases in adults, but colon bacillus infections are more common in infancy. Most of the cases follow direct implantation of the organisms into the meninges by trauma or by contaminated lumbar puncture or they occur by extension from an adjacent focus
1100
TOM FITE PAINE, MAXWELL FINLAND
of infection in the nasal sinuses, ears, mastoid or meningocele. Occasionally they occur in association with septicemia resulting from distant foci of infection in the gastrointestinal or genitourinary tract or elsewhere. Mortality rates in this type of infection depend upon many factors but they are generally quite high (from 50 to 100 per cent). The sulfonamides have been helpful but their use has not reduced the mortality to any marked extent. s, 9, 12, 33-35 Cases of meningitis due to a wide variety of gram-negative bacilli have been treated with streptomycin by many workers 1 , 26, 36--42 and the results, though variable, were quite gratifying. The effects observed at this hospital have been encouraging. A group of six such cases have been treated; the causative organism was Pseudomonas aeruginosa (Bacillus pyocyaneus) in three cases and Bacillus proteus, Aerobacter aerogenes and Hemophilus para-influenzae, each in one case. Five of these patients have recovered. The fatal case was one due to Pseudomonas aeruginosa in which the organism became totally resistant to streptomycin after seventeen days of treatment with the antibiotic and ren1ained so. Sonle of these cases are reported elsewhere. 42 Treatment.-Streptomycin.-Streptomycin should be administered essentially as already described for Hemophilus inHuenzae meningitis and the dosage, both intramuscular and intrathecal, is the same and depends on the age of the patient. Secondary fevers related to the streptomycin have been noted with equal frequency in this type of case. The period of streptomycin therapy depends on the clinical and laboratory evidence of subsidence of the infection. In certain cases of meningitis due to Pseudomonas aeruginosa, an organism which is often naturally quite resistant to streptomycin, cerebrospinal fluid cultures may not become negative for several days after the therapy is begun. In one such case 42 streptomycin therapy was given over a period of one month before organisms disappeared completely. The possibility of the development of extremely resistant strains of organisms exists during streptomycin therapy, as already noted. This can readily be determined by growing the organism in Inedia containing varying concentrations of streptomycin. If the organism is found to be resistant, further streptomycin therapy will probably be of no avail and its administration may be discontinued. Penicillin.-Most of the gram-negative bacilli encountered in meningitis are quite resistant to penicillin. 'lndeed many such strains produce a penicillin inhibitor known as penicillinase. There is, therefore, no indication for the use of this agent initially. Should secondary infections due to penicillin-sensitive organisms arise, penicillin would be indicated and should be given in generous doses. Sulfonamides.-Most of the cases of gram-negative bacillus meningitis will probably respond to streptomycin' alone. However, if the
STREPTOMYCIN IN TREATMENT OF MENINGITIS
1101
organism is fairly resistant to strepton1ycin, it is probably wise to administer a sulfonamide along with the streptomycin. Again, in the event of secondary complicating infections by sulfonamide-sensitive organisms, a sulfonamide should be given. Sulfadiazine is the drug of choice and should be given in full doses orally whenever possible. If oral therapy is not feasible, the sodium salt may be given in solution. In adults, 3 gm. are given in about 250 cc. of physiological saline by hypodermoclysis every twelve hours. Corresponding doses are · given to infants and children. Surgery.-Chemotherapeutic and antibiotic agents are no substitute when surgery is indicated. If foci of infection are suspected that may require surgical drainage, the surgeon should be consulted and necessary surgery carried out. Fora discussion of the diagnostic features of- meningitis and of the focal complications that may be encountered, the reader is referred to the paper by Keefer. 43 TUBERCULOSIS MENINGITIS
Meningitis due to the tubercle bacillus often occurs in association with a spread of the disease, or miliary dissemination, from a focus of infection in the lungs or elsewhere. The 'original focus, however, is not always demonstrable. It is usually a disease of insidious onset, being marked by listlessness, lethargy, irritability, fever and headache over a period of weeks. The more dramatic signs of meningeal irritation or increased intracranial pressure come somewhat later and are usually responsible for the admission of the patient to a hospital. Heretofore it has been a uniformly fatal disease. 44 , 45 In a number of reported cases treated with streptomycin, the disease appears to have been arrested. 41 , 46-48 The follow-up in these cases was relatively short and a final evaluation of the therapy is not yet possible. The incidence of serious and permanent neurologic damage in these survivors was high. Three cases of tuberculous meningitis have been treated at this hospital. In one patient the disease appears to have been arrested after a treatment period of four months and there has been no evidence of relapse during the ensuing three months. Diagnosis.-Examination of the cerebrospinal fluid during the first few days of the disease usually shows an increase in leukocytes, pre.. dominately polymorphonuclears. By the time the patient is seen by the physician, however, the cells usually are almost all lymphocytes. This continues throughout the course of the disease except when foreign substances are injected into the thecal space or secondary bacterial infection supervenes. The sugar content of the cerebrospinal fluid may be only slightly decreased initially but drops progressively as the disease advances. The protein is elevated and a pellicle often
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TOM FITE PAINE, MAXWELL FINLAND
forms in the fluid on standing. The chloride content of the cerebrospinal fluid may be decreased. The diagnosis depends on demonstrating the acid-fast tubercle bacilli by: (1) Ziehl-Nielsen (acid-fast) stain of the pellicle or of the centrifuged sediment of the cerebrospinal fluid, or (2) appropriate culture or guinea pig inoculation of the fluid. Cultural methods now allow the demonstration of tubercle bacilli in a matter of several days rather than in the four to six week period required by older methods. Streptomycin Treatment.-In cases of tuberculous meningitis streptomycin should be administered by both the parenteral and intrathecal routes and should be carried out for a perio~ of at least four months. 48 Since the outcome of such cases may well depend on the early institution of therapy, it would seem wise to treat suspected cases as soon as possible and to continue the therapy at least until the results of culture or guinea pig inoculation are known. It is particularly important to obtain cerebrospinal fluid for culture or guinea pjg inoculation or both before streptomycin is begun since these procedures may yield negative results after the treatment is begun and the diagnosis may then remain in doubt. It should be emphasized that therapy should not be withheld pending the results of the pretreatment cultures or of guinea pig inoculations. TOXIC EFFECTS OF STREPTOMYCIN
Reactions are not unusual following streptomycin therapy and may be manifested locally and constitutionally. Local Reactions.-From Intramuscular' Iniection.-Pain, tenderness and induration are commonly noted at the site of intramuscular injections. This local reaction is minimized by keeping the volume of injected material at a minimum. From Intrathecal Iniections.-Fever and pleocytosis in the cerebrospinal fluid may follow such injections. These reactions are related to the amount of streptomycin injected and to the duration of intrathecal therapy. Injection of no more than 50 to 100 mg. of streptomycin per dose and termination of the intrathecal therapy soon after the infection is controlled will minimize these reactions. Constiiutional Reactions.-Histamine-like Effect.-Flushing of the skin, nausea, vomiting, headache, fall in blood pressure or convulsions may follow immediately after the parenteral administration of streptomycin. These reactions are encountered almost exclusively during intravenous injections, particularly when such injections are given too rapidly. Present lots of streptomycin are practically free ,of the histamine-like material which produces this immediate reaction. Benadryl has been used successfully to avoid the histamine-like reaction. 49 Sensitization Reactions.-Fever and skin rashes of varying types may follow the parenteral use of streptomycin. These usually appear be-
STREPTOMYCIN IN TREATMENT OF MENINGITIS
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tween the third and tenth day of therapy. Fever, as noted above, may
follow either the intramuscular or intrathecal injection of streptomy-
cin but is more frequent following the latter. Neurologic Disturbance.-Disturbance of function of the eighth cranial nerve, particularly the vestibular portion, may appear following parenteral streptomycin therapy.5o Such a reaction is apparently not related to the intrathecal injection of the drug. The disturbance is commonly manifested by an ataxia or, rarely, by deafness. This reaction seems much more common in adults than in children. Compensation for the absence .of vestibular reflexes by other postural mechanisms usually occurs in a period of weeks resulting in a considerable or total alleviation of the disability. Effects on Other Ofgans.-Hyaline and granular casts have been noted in the urine of some patients receiving streptomycin but there has peen no evidence of lasting renal impairment. REFERENCES 1. Committee on Chemotherapeutics and Other Agents, National Research Council: Streptomycin in the Treatment of Infections. A Report of One Thousand Cases. J.A.M.A., 132:4-11 (Sept. 7) and 70-76 (Sept. 14) 1946. 2. Murray, R., Paine, T. F. and Finland, M.: Streptomycin. 1. Bacteriological and Pharmacological Aspects. New England J.. Med., 236:701-712 (May 8) 1947. Paine, T. F., Murray, R. and Finland, M.: Streptomycin. II. Clinical Uses. Ibid., 236:748-760 (May 15) 1947. 3. Weinstein, L.: The Treatment of Meningitis Due to Haemophilu8 influenzae with Streptomycin. A Report of Nine Cases. New England J. Med., 235: 101-111 (July 25) 1946. 4. Alexander, H. E., Leidy, G., Rake, G. and Donovick, R.: Hemophilus influenzae Meningitis Treated with Streptomycin. J.A.M.A., 132:434-440 (Oct. 26) 1946. 5. Neal, J. B.: Diagnosis and Treatment of Meningitis. M. CLIN. NORTH AMERICA, 19:751-769 (Nov.) 1935. 6. Hertzog, A. J.: A Study of 377 Cases of Fatal Meningitis with Special Reference to Bacteriologic Diagnosis. Am. J. Clin. Path., 15:571-574 (Dec.) 1945. 7. Jaffe, S. A.: Extrapulmonary Klebsiella pneumoniae Infections. An Analysis of the Literature: Report of Two Unusual Cases with Recovery. J.A.M.A., 122:2~2-296 (May 29) 1943. 8. Wood, W. H., Mayfield, F. H. and Frisch, A. W.: Meningitis Due to Salmonella panama. ].A.M.A., 128:868-870 (July 21) 1945. 9. Stanley, M. M.: Bacillus pyocyaneus infections. A Review, Report of Cases and Discussion of Newer Therapy Including Streptomycin. Am. J. Med., 2:253277 (March) and 347-367 (April) 1947. 10. McKee, T. L.: Bacillus proteus Infections: Review of the Literahtre and Report of Case of Septicemia of Otitic Origin Treated with Sulfapyridine with • Recovery. Arch. Otolaryng., 39:398-402 (May) 1944. 11. Barrett, G. S., Rammelkamp, C. H. and Worcester, J.: Meningitis due to Escherichia coli. Report of Two Cases with Recovery Following Cheillotherapy, Review of the Literature and Report of Experimental Studies. Am. J. Dis. Child., 63:41-59 (Jan.) 1942. 12. Stuart, B. M. and Pullen, R. L.: Tularemic Meningitis. Review of the Literature
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and Report of a Case with Postmortem Observations. Arch. Int. Moo., 76:163-166 (Sept.) 1945. 13. Pulaski, E. J.: Streptolnycin Therapy of Penicillin-Resistant and SulfonamideResistant Specific and Nonspecific Urethritis. J. Ven. Dis. Inform., 28:1-6 (Jan.) 1947. 14. Priest, W. S. and McGee, C. J.: Streptomycin in the Treatment of Subacute Bacterial Endocarditis. Report of Three Cases. J.A.M.A., 132:124-126 (Sept. 21) 1946. 15. Aleman, R.: Influenzal Meningitis; Review of Recent Literature with Case Reports. New Orleans M. & S. J., 93:25-33 (July) 1940. 16. Alexander, H. E., Ellis, C. and Leidy, G.: Treatment of Type-Specific Hemophilus influenzae Infections in Infancy and Childhood. J. Pediat., 20:673698 (June) 1942. 17. Sako, W., Stewart, C. A., and Fleet, J.: Treatment of Influenzal Meningitis with Sulfadiazine; Further Report. J. Pediat., 25:114-126 (Aug.) 1944. 18. Comly, H. H. and McKee, A. P.: Meningitis and Other Infections Caused by Hemophilus influenzae (Pfeiffer's Bacillus). J. Iowa M. Soc., 35:127-132 (April) 1945. 19. Turner, E. K.: A Further Report on the Treatment at the Children's Hospital, Melbourne, of Influenzal Meningitis with Sulphonamides and Type-Specific Serum, M. J. Australia, 1:219-221 (March 3) 1945. 20. Smith, M. H. D., Wilson, P. E. and Hodes, H. L.: The Treatment of Influenza] Meningitis. J.A.M.A., 130:331-335 (Feb. 9) 1946. 21. Zintel, H. A., Flippin, H. F., Nichols, A. C., Wiley, M. M. and Rhoads, J. E.: Studies on Streptomycin in Man. I. Absorption, Distribution, Excretion and Toxicity. Am. J. M. Sc., 210:421-430 (Oct.) 1945. 22. Anderson, D. G. and Jewell, M.: The Absorption, Excretion and Toxicity of Streptomycin in Man. New England J. Med., 233:485-491 (Oct. 25) 1945. 23. Heilman, D. H., Heilman, F. R., Hinshaw, H. C., Nichols, D. R. and Herrell, W. E.: Streptomycin: Absorption, Diffusion, Excretion, and Toxicity. Am. J. M. Sc., 210:576-584 (Nov.) 1945. 24. Buggs, C. W., Pilling, M. A., Bronstein, B. and Hirshfeld, J. W.: The Absorption, Distribution and Excretion of Streptomycin in Man. J. Clin. Investigation, 25:94-102 (Jan.) 1946. 25. Adcock, J. D. and Hettig, R. A.: Absorption, Distribution and Excretion of Streptomycin. Arch. Int. Med., 77:179-195 (Feb.) 1946. 26. Zantiny, W. C. and Carlson, H. J.: Experiences with Streptomycin: Effectiveness in Infections of Infants and Children. Clinics, 5:635-645 (Oct.) 1946. 27. Hoyne, A. L., Brown, R. H. and Drucker, A. P.: Influenzal Meningitis Treated with Streptomycin. Report of 3 Cases with Recoveries. Arch. Pediat., 63: 559-566 (Nov.) 1946. . 28. Birmingham, J. R., Kaye, R. and Smith, M. H. D.: Streptomycin in the Treatment of Influenzal Meningitis. J. Pediat." 29:1-13 (July) 1946. 29. Morgan, H. J. and Hunt, J. S.: Stteptomycin in Clinical Practice; A Review and Case Reports. Amer. Pract., 1:73-86 (Oct.) 1946. 30. Forgacs, P., Hutchinson, R. I. and Rewell, R. E.: Penicillin Sensitivity of H aemophilus influenzae; Two Sensitive Pathogenic Strains. Lancet. 1:785786 (June 23) 1945. 31. McIntosh, D. G. and Drysdale, C. F.: Meningitis Due to Penicillin and Sulphonamide-Sensitive Pittman b Strain of H. influenzae: Recovery. Brit. M. J., 2:796-797 (Dec. 8) 1945. 32. Hewitt, W. L. and Pittman, M.: Antibacterial Action of Penicillin, Penicillin X and Streptomycin on Hemophilus influenzae. Pub. Health Rep., 61:768-778 (May 31) 1946.
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BS. Burman, H. J., Rosenbluth, M. and Burman, D.: Otorhinogenic Meningitis. A Report of Fifty-Eight Cases. Arch. Otolaryng., 35:687-719 (May) 1942. 84. Neter, E. R.: Salmonella cholerae suis Meningitis. Report of a Case and Re~iew of the Literature on Salmonella Meningitis. Arch. Int. !vled., 73:425-429 (May) 1944. S5. Strong, P. S. and Edwards, J. E.: Escherichia coli Meningitis Treated with Sulfadiazine. J.A.M.A., 129:210-211 (Sept. 15) 1945. S6. Alexander, A. J.: Meningitis Due to Escherichia coli Treated with Streptomycin. J.A.M.A., 131:663-665 (June 22) 1946. 87. Cairns, M., Duthie, E. S. and Smith, H. V.: Intratracheal Strepton1ycin in Meningitis. Clinical Trial in Tuberculous, Coliform and Other Infections. Lancet, 2:153-155 (Aug. 3) 1946. 38. Barnes, M.: Salmonella Meningitis. Report of a Case Treated with Streptomycin. Bull. Charlotte Memorial Hosp., 2:44-47 (Sept.) 1946. 39. Shields, W. P.: Meningitis Due to Escherichia coli. Streptomycin Therapy. J.A.¥.A., 132:514-515 (Nov. 2) 1946. 40. Tartakoff, S., Grynbaum, B. and LeCompte, P. M.: FriedHinder-Bacillus Meningitis Treated with Streptomycin. New England J. Med., 235:681-683 (Nov. 7) 1946. 41. DeBakey, M. E. and Pulaski, E. J.: An Analysis of the Experience with Streptomycin in United States Army Hospitals.. Preliminary Report. Surgery, 20: 749-760 (Dec.) 1946. 42. Paine, T. F., Murray, R., Harris, H. W. and Finland, M.: Streptomycin in the Treatment of Certain Gram-Negative Bacillus Infections of the Central Nervous System. Am. J. M. Sc., 213:676-685 (June) 1947. 43. Keefer, C. S.: The Treabnent of Bacterial Meningitis. M. CLIN. NORTH AMERICA, 25:1287-1315 (Sept.) 1941. 44. Lindsay, J. W., Rice, E. C. and Selinger, M. A.: Meningitis in Children. A Review of 331 Cases. M. Ann. District of Columbia, 4:231-243 (Sept.) 1935. 45. Tripoli, C. J.: Bacterial Meningitis. A Comparative Study of Various Therapeutic Measures. J.A.M.A., 106:171-175 (Jan. 18) 1936. 46. Cooke, R. E., Dunphy, D. L. and Blake, F G.: Streptomycin in Tuberculous Meningitis; A Report of Its Use in a One-Year-Old Infant. Yale J. BioI. & Med., 18:221-226 (Jan.) 1946. -47. Krafchik, L. L.: 'Tuberculous Meningitis Treated with Streptomycin. J.A.M.A., 132:375-376 (Oct. 19) 1946. 48. Hinshaw, H. C., Feldman, W. H. and Pfuetze, K. H.: Treatment of Tuberculosis with Streptomycin. J.A.M.A., 132:778-782 (Nov. 30) 1946. 49. Hewitt, W. L. and Curry, J. J.: Pharmacodynamic Effect in Man of Streptomycin Containing a Histamin-like Factor J. Lab. & Clin. Med., 32:42-46 (Jan.) 1947. 50. Fowler, E. P. and Seligman, E.: Otic Complications of Streptomycin Therapy: A Prelitninary Report. J.A.M.A., 183:87-91 (Jan. 11) 1947.