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Serotherapy and Chemotherapy of Pneumococcus Pneumonia
Medical Clinics of North America January, 1941. Chicago Number
CLINIC OF DRS. ITALO F. VOLINI, ROBERT O. LEVITT AND HUGH B. O'NEIL FR.OM THE COOK COUNTY HOSPITAL AND THE DEPARTMENT OF MEDICINE, LOYOLA UNIVERSITY SCHOOL OF MEDICINE
SEROTHERAPY AND CHEMOTHERAPY OF PNEUMOCOCCUS PNEUMONIA
THE progress which has been made in the therapy of pneumococcus pneumonia is characteristically illustrated by the studies reported from the Cook County Hospital. Chronologically these observations begin with the report1 of a study of a control group of patients treated by symptomatic measures employed prior to the advent of antipneumococcic horse serum. This was followed by a publication detailing the experience with the use of concentrated and refined rabbit serum. 1 Further communications have dealt with the employment of sulfapyridine in a large group of cases. 2 , 3, 4 The most recent publication describes the results with sulfathiazole. 6 The combination therapy of the newer drugs with immune serum constitutes one phase of the many investigations. THE CONTROL STUDIES
Mortality statistics have demonstrated averages ranging from 3S to 40 per cent. The investigations, however, were totally inadequate for types of pneumococci encountered until the pUblication of a control series of 164 patients. Obviously clinical case controls can no longer be employed because observation of Table 1 demonstrates a mortality percentage of 38.4 while the results of modern therapy show results well below a 10' per cent mortality. No investigator is justified in adopting a control series employing only' symptomatic therapy. Table 1 illustrates the effect of bacteremia on mortality, which in this series attained 60 per cent. It further illustrates the importance of type influence. Thus Type I accounted for 20 5
206
1. F. VOLINI, R. O. LEVITJ.', H. B. O'NEIL
TABLE 1 CONTROL CASES
Type. No. of cases.
I II III IV
V VI
VII VIII IX X XII
49 34 18 3 6 2 17 8
.>
1
5
Deaths.
Bacteremia. Type.
No.
%
-13 -2616 11 2
5 0 6 1 1 0 2
47 61 67 83 0 35 12 33 0 40
No.
Dead.
%
No. of cases.
Deaths. No.
----~
10 6 1 0
4
0 4 2 0 0 1
4 4 1 0
.>
0 4 1 0 0 0
%
Bacteremia. No.
~cad·I~~
0 40 XIII 2 0 1 0 0 0 2 0 0 0 67 XIV 0 1 0 0 0 0 100 XVI 0 2 0 0 0 0 0 XVII 0 100 0 75 XVIII 2 2 0 0 100 40 0 XIX 5 2 1 1 0 100 XXI 1 0 0 0 0 0 100 0 0 50 XXIII 1 1 0 100 0 0 0 XXVIII 1 1 0 0 0 0 0 XXIX 1 0 -- -0 ---60 Totals 164163--38A 30 18
-
thirteen deaths, or 26 per cent in the nonbacteremic group, while four patients died of the ten with bacteremia, a 40 per cent mortality. Type Il showed a mortality of 47 per cent, rising to 67 per cent in those with positive blood culture. The study of this table shows the mortality percentage for the various types. In this series, the effect of age on the mortality is demonstrated by a death rate of 45.7 per cent in the fortyone to fifty year age group, a 56.6 per cent mortality in the fifty-one to sixty age group, 55.5 per cent in the sixty-one to seventy year age period, and 84 per cent died in those over 70 years of age. The death rate of patients over forty years of age in this control group was 54 per cent. IMMUNE SERUM THERAPY
With the introduction of immune serotherapy, the mortality figures showed a pronounced decline.! The use of the refined and concentrated rabbit serum demonstrated the remarkable efficacy of this therapeutic agent-only one-fourth of deaths when contrasted with the control group. Less than 10 per cent mortality was recorded, whereas the bacteremic death rate dropped to 26 per cent. Table 2, summarizing these studies, illustrates the effect on the individual types. Type I mortality dropped to 6 per cent in the nonbacteremic group, with 16.7 per cent in the positive blood culture group. For Type Il, the figures were 8.8 per cent and 50 per cent, respectively. Rabbit serum has many advantages, both in manufacture and practical use, over the antipneumococcus horse serum. It
THERAPY OF PNEUMOCOCCUS PNEUMONIA
207
TABLE 2 TREATMENT WITH
Type. No. of cases.
CONCENTRATED AND REFINED RABBIT SERUM-TREATED CASES
Deaths.
Bacteremia. Type.
No.
%
No.
Dead.
%
2 3 3 1 0 0 2 3 0 1
6 8.8 21 0 0 0 7.6 18 0 50
6 6 0 2 1 0 3 0 0 1
1 3 0 0 0 0 1 0 0 1
16.7 50 0 0 0 0 33 0 0 100
No. of cases,
SERUM:
Deaths.
30 34 14 11 2 1 26 16 2 2
XV XVII XVIII XIX XX XXIII XXIV XXV XXVIII XXIX XXX!
OF
Bacteremia.
No.
%
No.
1 1 3 1 1 1 1 2 1 2 1
0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0
0 0 1 0 0 1 1 0 0 1 0
153
15
--- --- -- - - - - - - - - - - - - - -- -- -I II III IV V VI VII VIII XII XIV
TYPES
Dead.
%
0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0
6
26
--0 0
- - - - - -- -- -- - - - Tot~ls
9.8
23
Corrected mortality (4 deaths under eighteen hours); 11 deaths (7.2%).
has practically superseded the use of the latter in the immune serotherapy of pneumonia. Sensitivity to rabbit serum proteins is infrequent. While the three tests for sensitiveness are employed, the greatest reliance is to be placed on the conjunctival test. The intracutaneous and intravenous injection methods in themselves add very little to the results of the conjunctival testing. They are supplemental and in no way determine the use or contraindication for serum. Indications for Rabbit Serum.-At the present time the following indications for the use of rabbit serum in the typespecific treatment of pneumococcic pneumonia can be predicated. Thus serum is to be used: 1. When the effective sulfaniIamide derivatives (sulfapyridine and sulfathiazole) are contraindicated. 2. When the effective sulfanilamide derivatives produce no measure of improvement in from twenty-four to thirty-six hours. 3. When the appearance of the various toxic effects of the sulfanilamide derivatives develop during administration of these drugs and demand their cessation.
When the following conditions are present, a combination of serotherapy and chemotherapy is usually advised: 1. When the history indicates a seventy-two-hour duration of the disease.
2. 3. 4. 5_ 6.
When the patient is over fifty years of age. When multiple lobes are involved. When blood cultures are positive. In pneumonia during pregnancy or the puerperium. When there is serious concomitant complicating disease.
208
,
I. F. VOLINI, R. O. LEVITT, H. B. 0 NEIL
Serum is usually contraindicated in the patient with a positive conjunctival test. However, horse serum and rabbit serum are both available and nonreactor serum can be employed. The aged patient and the very weak individual should be given serum with considerable caution. It is perfectly obvious from the above discussion that the necessity for sputum typing and blood culture investigation can not be neglected despite the effectiveness of chemotherapy. Recourse to serum therapy is frequently necessary and this decision may be, and often is, sudden. Disaster is invited for the patient by further delay while awaiting for the reports of the type organisms producing this disease. Dosage.-The dosage of serum usually approximates 100,000 units. This is doubled or trebled by such factors as advancing age, bacteremia, increased duration of illness, multiplicity of pulmonary lobe involvement, complicating disease, and severity of symptoms. Types II and III infections demand more serum. Improvement in the symptomatology is the usual guide for efficacy and adequacy of dosage. When available, reliance is placed on the Francis test, the serum agglutination test, and the mouse protection test. Ordinarily, however, the temperature, pulse and respiration rate with the general condition of the patient determine the indication for more serum. This should be given at four- to twelve-hour intervals, until the desired result is obtained. Retyping and careful, thorough examination of the patient should be carried out when response to adequate dosage of serum is not obtained. Method of Administration.-The method of administration consists of the usual test or trial dose given intravenously followed, after one to two hours, by the remaining calculated dose. The total dosage is frequently given by the intravenous drip method, diluting the serum with normal salt solution in the drip flask. With the concentrated unitages now available, the single total dose method may be employed, injecting the entire amount undiluted directly into the blood stream. The first cubic centimeter should require two minutes, while the remainder should be injected at the rate of % to 1 minute per cc. REACTIONs.-The serious immediate reactions are best prevented by the careful preliminary testing, although the antidote epinephrine should always be ready at hand for immediate use. The onset of a reaction demands immediate cessation of the serum injection. Thermal reactions and the late serum
THERAPY OF PNEUMOCOCCUS PNEUMONIA
209
effects occur frequently. They are disturbing and annoying, but rarely dangerous, and respond promptly to appropriate treatment. Figure 9 A illustrates treatment with concentrated and re·· fined rabbit serum, all the pertinent data being given. Anti· DUE
Da,0I0he...
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Fig. 9.-Results of treatment of pneumococcus pneumonia with concentrated and refined rabbit serum. See text for details.
pneumococcus serum was given by the single total dose method. The sharp critical form of response is demonstrated in the Type I infection. Figure 9 B shows the necessary repetition of serum dosage guided by the Frands test. The injec· tions of serum were continued until a satisfactory clinical VOL. 25-14
210
I. F.
VOLINI,
R.
O. LEVITT,
H. B.
O'NEIL
response was obtained and the Francis test was changed from negative to positive. SULFAPYRIDINE THERAPY
The value of sulfapyridine as a therapeutic agent in the treatment of pneumococcic pneumonia was quickly indicated. Early experience with this drug demonstrated an even greater efficiency than immune serum. The first report2 published from the Cook County Hospital on a series of 160 patients, fifteen of whom had positive blood cultures, revealed a mortality of 3.3 per cent. A later study 4 of 200 patients treated with sulfapyridine showed a 4 per cent mortality-3 per cent in the nonbacteremic series and 7.8 per cent in thirty-eight patients with positive blood cultures. It is remarkable that in this group of 200 patients, there were forty-seven with Type I infection, none of whom died from the pneumonia. This included eight patients with bacteremia. In a report soon to appear describing the use of sulfathiazole 5 (control series treated with sulfapyridine) there were thirty-one patients with Type I infection, three with positive blood cultures; there were no deaths. There is thus demonstrated a remarkable specificity of sulfapyridine in Type I pneumococcus infection. The total group, comprising over 400 patients treated with sulfapyridine, shows results superior to those obtained by serum alone. Dosage.-The dosage has been standardized so that, initially, 4 gm., or eight tablets, are administered followed by 1 gm. every four hours until a normal temperature has been sustained for forty-eight hours. Experience has indicated that associated drug medication or using the powdered drug in various liquids has not materially changed the unpleasant effects. The nausea and vomiting so commonly encountered in the administration of this drug do not seem to be any more frequent or severe by the initial 4-gm. dosage than with the usually advised 2-gm., four-hour schedule for two doses. In those cases where the initial vomiting was severe and persistent, or in patients unable to swallow the drug, an intravenous injection of 100 cc. of 5 per cent aqueous solution of sodium sulfapyridine was administered. This was then followed by the oral dosage after four hours, using 1-gm. doses. BLOOD CONcENTRATION.-Optimum concentration levels in the blood are rapidly attained by the use of the large initial dosage. Blood levels fluctuate moderately on the usual maintenance dose. The clinical response, however, cannot be very
THERAPY OF PNEUMOCOCCUS PNEUMONIA
2I I
definitely correlated with the blood concentration. While adequate blood levels are difficult to fix, five milligrams per cent of the free sulfapyridine is usually considered as the accepted concentration. UNTOWARD REACTIONs.-The seriousness of the toxic reactions demands continuous supervision of the patient. Adequate laboratory investigation must be made prior to the onset of therapy. Toxic reactions demand cessation of sulfapyridine administration and, frequently, a change to other forms of therapy. This therefore means that the patient must be investigated just as thoroughly as the pneumonia patient was prior to the discovery of sulfapyridine. The laboratory examinations before drug therapy include as a minimum, sputum typing, blood cultures, complete blood counts and urine studies. And these must be frequently repeated in addition to the blood concentration studies. The damaging effects on the red and white hemopoietic organs and cells are not rarely encountered. Acute hemolytic anemia is common. One agranulocytic reaction with fatality was experienced. Another case of aplastic anemia with agranulocytosis, with a fatal outcome, resulted from sulfapyridine therapy. Various kidney complications are met with, such as calculi, anuria, albuminuria and casts, hematuria, and nonprotein nitrogen elevation in the blood. Drug rashes and drug fever must be kept in mind as they occur rather frequently and introduce a puzzling pattern in the clinical picture. Hepatic injury and central and peripheral nervous system effects are described, but these have not been met with in over 400 patients treated with sulfapyridine. The nausea and vomiting are often troublesome; while unquestionably these are of central origin, the intravenous use of the drug may so .improve the patient that vomiting lessens. The intravenous fluids and employment of sedatives may frequently accomplish much in reducing these effects. Persistence of administration may acclimate the patient to the drug so that vomiting, initially present, may disappear, although often the opposite result occurs. It must be kept in mind that as a general rule the toxic reactions appear from relatively long and continued use of the dr.ug, especially where large total doses are employed. The beneficial effects of sulfapyridine are produced early in its use. An evaluation, therefore, should be made after five days of use of the drug; this usually means after 20 to 25 gm. are consumed, provided of course no serious toxic effects appear.
212
1. F. VOLINI, R. O. LEVITT, H. B. O'NEIL
The evaluation should consider the clinical and laboratory evidence at this time. Continuation of medication is decided by this appraisal. The drug is usually stopped after forty-eight hours of normal temperature, although flexibility rather than rigidity of this rule should be stressed. Evidence is available that organisms may become sulfapyridine-fast by interrupted medication. Nevertheless, few relapses occur from drug cessation after the drug is continued during forty-eight hours of normal temperature. In fact, relapses are infrequent in cases TABLE 3 A STUDY OF 200 PNEUMococcus PNEUMONIAS TREATED WITH SULFAPYRIDlNE Nonbacteremic.
Total.
Type.
No. of cases.
J?eaths. No.
%
2 1 0 0 3 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
.~. 7 5.2 0 0 13.0 10.5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Deaths.
No. of ca!;es.
Bacteremic.
No.
%
0 1 0 0 2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 5.2 0 0 11.1 11.7 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
No. of cases.
Deaths. No.
%
2 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
10 .., 0 0 0 20 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
- - - - - - - - - - - ---I- - - - - -0- ._0 0 0 0 47 8 39 0 II
III IV V VII VIII IX XII XIII XIV XV XVI XVII XVIII XIX XX XXIII XXIV XXVII XXIX XXXI Total
54 19 4 6 23 19 1 6 2 2 1 2 2 1 1 2 2 3 1 1 1
200
35 19 3 5 18 17 0 5 2 0 0 1 0 0 0 0 0 0 0 0 0
19 0 1 1 5 2 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0
- - - - - - - -- -- -8- -4 - - 162 7.8 38 5 3 3
in which the drug is suddenly stopped when a normal temperature is obtained. INDICATIONS AND CONTRAINDICATIONs.-In addition to the foregoing toxic reactions, impaired kidney function and hepatic disease should contraindicate sulfapyridine. Curiously, granulocytopenia, the result of bacterial infection, frequently shows tremendous improvement with sulfapyridine. Serious anemias, such as pernicious anemia, sickle cell anemia complicated by pneumonia have responded well as far as the infection is concerned to sulfapyridine medication. Blood transfusions have been frequently employed.
21 3
THERAPY OF PNEUMOCOCCUS PNEUMONIA
.Methods of Administration.-Sulfapyridine can be administered by parenteral injection, using the sodium salt. When given intravenously, a 5 per cent solution in distilled water is used, employing from 3.5 to 5 gm. per dose. The injection may be repeated in from twelve to twenty-four hours. If escape into the adjacent tissues occurs, a severe irritating
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Fig. lO.-Results of treatment of pneumococcus pneumonia with sulfapyridine.
and necrotic effect may be produced. Subcutaneous or intramuscular injection may also be employed and is frequently very satisfactory; 5 gm. in 1000 cc. of normal salt solution is the concentration advised. No untoward effects have been observed and a steady blood level has been obtained. Results of Treatment.-In the combined therapy, using immune serum with sulfapyridine, the results very curiously indicate superiority of sulfapyridine alone over the combina-
214
I. F. VOLINI, R. O. LEVITT, H. B. O'NEIL
tion therapy. This was not the result of selection of cases, i.e., the more seriously ill were not chosen for the combined therapy. Similar findings were. reported by the Illinois Pneumonia Control Commission. Further study must determine the adequate explanation of these results. Table 3 reveals the results obtained by the use of sulfapyridine in 200 cases of pneumococcic pneumonia. Type 11 pneumonia was responsible for 27 per cent of the cases, with a bacteremic frequency of 35 per cent. Many of the Type 11 cases had a common origin in a shelter for homeless men who were housed in a school hall. Types VII and VIII showed a higher percentage of Negroes, Type VII being particularly virulent; 58 per cent of these patients were admitted seventy-two hours or more after the onset of the disease. Malnutrition, undernutrition, alcoholism and associated acute and chronic diseases were present in a good number of these individuals admitted to the large charity hospital. Nevertheless, the results indicate the tremendous progress that the therapy of pneumococcus pneumonia has made by the introduction of sulfapyridine. SULFATHIAZOLE
There are unquestioned advantages in the chemotherapeutic management of pneumococcus pneumonia and some evidence to indicate its superiority over immune serotherapy. The modus operandi of the recovery induced by drug therapy is not considered as following the immunological pattern created in a serum-induced recovery. Chemotherapy demonstrates effectiveness against nearly all types of infection. The cost is low. The ease of administration is of comfort to both the patient and physician. But efficiency in producing recovery from pneumonia contributes most of all to the popularity of chemotherapy. Theoretically there should be an enhancement of the therapeutic value in the combination of serotherapy and chemotherapy. However, the additive use of these two methods, each of proved value, has not been strikingly more efficient, as comment has already indicated. In the use of sulfapyridine, definite disadvantages are readily apparent. The nausea and vomiting, so frequently severe, detract from the usefulness of the drug. This effect not only aggravates the illness of the patient, but interferes with the continuation of treatm.ent, whereby entrance of the drug into the blood stream is prevented. The toxicity of the drug is pronounced, as has been pointed out. Many of these results are produced by what is known as acetylation or conju-
THERAPY OF PNEUMOCOCCUS PNEUMONIA
2I 5
gation of the drug. This readily occurs with sulfapyridine, a major percentage of the drug being conjugated. Acetylated sulfapyridine, chemotherapeutically considered, is inactive and inert. Nevertheless, it is considered responsible for the toxic manifestations and for the renal blocking and calculi formation. Advantages over Sulfapyridine.-Naturally an analogue of sulfapyridine was sought. Many compounds have been tried. The most effective and the least toxic thus far was found to be suljathiazole. The preliminary studies have indicated that sulfathiazole equals sulfapyridine in therapeutic effectiveness when comparative studies were made with various types of pneumococcus infections. On the other hand, staphylococcic infections respond more readily to sulfathiazole medication. The drug simulates in its action many of the pharmacologic activities of sulfanilamide rather than sulfapyridine. It is readily absorbed into the blood stream. High levels are quickly attained, and it is excreted into the urine at a rapid rate. The degree of conjugation, both in the blood and urine, is much less than that which is obtained with sulfapyridine. As a consequence, a larger percentage of the total drug absorbed into the blood stream is therapeutically active. The toxic effects are generally not so severe as those induced by sulfapyridine. Thus nausea and vomiting occurred in seven patients in the series of 169 treated, only one requiring discontinuance of the drug. With sulfapyridine, the experience was over 55 per cent, 15 per cent requiring withdrawal of the drug. No evidence of renal irritation was encountered, nor were effects noted on the hemopoietic systems. UNTOWARD REACTIONs.-Injury to nerve tissue may appear. Paresthesia and neuritis, though infrequent, may be severe. Drug fever, drug rashes and conjunctival irritation have been found to be serious manifestations; five instances of this were noted, two of the five ending fatally. The mortality rate in the series of 169 patients treated was 5.3 per cent. In the positive blood culture cases (twentyfour), two died, or 8.3 per cent; in the nonbacteremic series the mortality was 4.8 per cent. The results when compared to a contemporary group of 164 patients treated with sulfapyridihe were approximately the same. Dosage.-The method of dosage employed varied from that used with sulfapyridine. An initial 4-gm. dose was followed in four hours by one of 3 gm., subsequently after four hours by 2 gm., and thereafter 1 gm. every four hours. This
216
1. F. VOLINI, R. O. LEVITT, H. B. O'NEIL
method was suggested by the pronounced variation frequently encountered in the blood level, presumably due to the rapid elimination in the urine. Results of Treatment.-Figure 11 and Table 4 show all the pertinent data and illustrate the characteristic forms of temperature response to sulfathiazole. It must be remarked that the sulfathiazole treated patient presents an appearance O."ofOiMo....
!It .
.. In u
I
_R_,I:>
~
~
:;;
r:!
A •• ++++1- -1+++·+· ·+·--i·!:·+·!·····i·:··+·+·+·· . i. ·:.. i. ..;.·+··+·+·++ DATE
7
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of relative comfort when compared to the nauseated, vomiting individual under sulfapyrjdine medication. Temperature reduction is produced more rapidly by sulfapyridine therapy. The course of the fever curve shows a declination which is a characteristic combination of crisis and lysis, without the precipitous termination of the former and the absence of the prolorged course of the latter. It resembles a concave trajectory
2I 7
THERAPY OF PNEUMOCOCCUS PNEUMONIA
curve or geometric hyperbola with the normal temperature level attained in the forty-eight to sixty-hour period. Medication should be continued at least forty-eight hours after the temperature reaches normal. Selective effectiveness TABLE 4 RESULTS OF TREATMENT WITH SULFATHIAZOLE
Nonbacteremic.
Total. Type.
I II III IV V VII VIII XIV XIX XXI XXV XXVII
No. of cases.
Deaths. No.
No. of cases.
%
Bacteremic.
Deaths. No.
%
No. of cases.
Deaths. No.
%
8 13 1 0 0 1 0 1 0 0 0 0
1 0 1 0 0 0 0 0 0 0 0 0
12.2 0 100 0 0 0 0 0 0 0 0 0
24
2
8.3
---- - - --- --- - ---- - - - - ---
Total
27 75 19 8 6 15 1.1 1 1 1 2 1
169
3 3 3 0 0 0 0 0 0 0 0 0
11.1 4.0 15.8 0 0 0 0 0 0 0 0 0 - - --9 5.3
.
19 62 18 8 6 14 13 0 1 1 2 1
2 3 2 0 0 0 0 0 0 0 0 0
10.5 4.8 11.1 0 0 0 0 0 0 0 0 0 ---- ---145 7 4.8
- -- - ---
Per cent with bacteremia: 14.2.
was demonstrated by sulfathiazole. Better results were obtained by sulfathiazole in Type II and VII pneumonia. Sulfapyridine was superior in Types I and Ill. BffiLIOGRAPHY Treatment of Pneumococcic Pneumonia with Concentrated Rabbit Serum. J.A.M.A., 113 (14): 1314 (Sept.)
1. VoJini, 1. F. and Levitt, R. 0.: 1939.
2. Volini, I. F., Levitt, R. O. and Campione, N. L.: Serum and Drug Therapy
in Pneumococcus Pneumonia. Ill. Med. J., 76: 420, 1939. 3. VoJini, 1. F.: Sulfapyridine in the Therapy of Pneumococcic Pneumonia. Merck Report, Vo!. 48, No. 4, p. 10, Oct., 1939. 4. VoJini, 1. F. and Levitt, R. 0.: SuIfapyridine Treatment of Pneumonia. Ill. Med. J., 78 (4): 305 (Oct.) 1940. 5. Volini, 1. F., Levitt, R. O. and O'Neil, H.: Sulfathiazole in the Treatment of Pneumococcus Pneumonia, With a Comparative Study Utilizing Sulfapyridine Therapy. Am. J. Med. Sci., 200 (6): 778, 1940.
CLINIC OF DRS. ITALO F. VOLINI, ROBERT O. LEVITT AND HUGH B. O'NEIL FR.OM THE COOK COUNTY HOSPITAL AND THE DEPARTMENT OF MEDICINE, LOYOLA UNIVERSITY SCHOOL OF MEDICINE
SEROTHERAPY AND CHEMOTHERAPY OF PNEUMOCOCCUS PNEUMONIA
THE progress which has been made in the therapy of pneumococcus pneumonia is characteristically illustrated by the studies reported from the Cook County Hospital. Chronologically these observations begin with the report1 of a study of a control group of patients treated by symptomatic measures employed prior to the advent of antipneumococcic horse serum. This was followed by a publication detailing the experience with the use of concentrated and refined rabbit serum. 1 Further communications have dealt with the employment of sulfapyridine in a large group of cases. 2 , 3, 4 The most recent publication describes the results with sulfathiazole. 6 The combination therapy of the newer drugs with immune serum constitutes one phase of the many investigations. THE CONTROL STUDIES
Mortality statistics have demonstrated averages ranging from 3S to 40 per cent. The investigations, however, were totally inadequate for types of pneumococci encountered until the pUblication of a control series of 164 patients. Obviously clinical case controls can no longer be employed because observation of Table 1 demonstrates a mortality percentage of 38.4 while the results of modern therapy show results well below a 10' per cent mortality. No investigator is justified in adopting a control series employing only' symptomatic therapy. Table 1 illustrates the effect of bacteremia on mortality, which in this series attained 60 per cent. It further illustrates the importance of type influence. Thus Type I accounted for 20 5
206
1. F. VOLINI, R. O. LEVITJ.', H. B. O'NEIL
TABLE 1 CONTROL CASES
Type. No. of cases.
I II III IV
V VI
VII VIII IX X XII
49 34 18 3 6 2 17 8
.>
1
5
Deaths.
Bacteremia. Type.
No.
%
-13 -2616 11 2
5 0 6 1 1 0 2
47 61 67 83 0 35 12 33 0 40
No.
Dead.
%
No. of cases.
Deaths. No.
----~
10 6 1 0
4
0 4 2 0 0 1
4 4 1 0
.>
0 4 1 0 0 0
%
Bacteremia. No.
~cad·I~~
0 40 XIII 2 0 1 0 0 0 2 0 0 0 67 XIV 0 1 0 0 0 0 100 XVI 0 2 0 0 0 0 0 XVII 0 100 0 75 XVIII 2 2 0 0 100 40 0 XIX 5 2 1 1 0 100 XXI 1 0 0 0 0 0 100 0 0 50 XXIII 1 1 0 100 0 0 0 XXVIII 1 1 0 0 0 0 0 XXIX 1 0 -- -0 ---60 Totals 164163--38A 30 18
-
thirteen deaths, or 26 per cent in the nonbacteremic group, while four patients died of the ten with bacteremia, a 40 per cent mortality. Type Il showed a mortality of 47 per cent, rising to 67 per cent in those with positive blood culture. The study of this table shows the mortality percentage for the various types. In this series, the effect of age on the mortality is demonstrated by a death rate of 45.7 per cent in the fortyone to fifty year age group, a 56.6 per cent mortality in the fifty-one to sixty age group, 55.5 per cent in the sixty-one to seventy year age period, and 84 per cent died in those over 70 years of age. The death rate of patients over forty years of age in this control group was 54 per cent. IMMUNE SERUM THERAPY
With the introduction of immune serotherapy, the mortality figures showed a pronounced decline.! The use of the refined and concentrated rabbit serum demonstrated the remarkable efficacy of this therapeutic agent-only one-fourth of deaths when contrasted with the control group. Less than 10 per cent mortality was recorded, whereas the bacteremic death rate dropped to 26 per cent. Table 2, summarizing these studies, illustrates the effect on the individual types. Type I mortality dropped to 6 per cent in the nonbacteremic group, with 16.7 per cent in the positive blood culture group. For Type Il, the figures were 8.8 per cent and 50 per cent, respectively. Rabbit serum has many advantages, both in manufacture and practical use, over the antipneumococcus horse serum. It
THERAPY OF PNEUMOCOCCUS PNEUMONIA
207
TABLE 2 TREATMENT WITH
Type. No. of cases.
CONCENTRATED AND REFINED RABBIT SERUM-TREATED CASES
Deaths.
Bacteremia. Type.
No.
%
No.
Dead.
%
2 3 3 1 0 0 2 3 0 1
6 8.8 21 0 0 0 7.6 18 0 50
6 6 0 2 1 0 3 0 0 1
1 3 0 0 0 0 1 0 0 1
16.7 50 0 0 0 0 33 0 0 100
No. of cases,
SERUM:
Deaths.
30 34 14 11 2 1 26 16 2 2
XV XVII XVIII XIX XX XXIII XXIV XXV XXVIII XXIX XXX!
OF
Bacteremia.
No.
%
No.
1 1 3 1 1 1 1 2 1 2 1
0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0
0 0 1 0 0 1 1 0 0 1 0
153
15
--- --- -- - - - - - - - - - - - - - -- -- -I II III IV V VI VII VIII XII XIV
TYPES
Dead.
%
0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0
6
26
--0 0
- - - - - -- -- -- - - - Tot~ls
9.8
23
Corrected mortality (4 deaths under eighteen hours); 11 deaths (7.2%).
has practically superseded the use of the latter in the immune serotherapy of pneumonia. Sensitivity to rabbit serum proteins is infrequent. While the three tests for sensitiveness are employed, the greatest reliance is to be placed on the conjunctival test. The intracutaneous and intravenous injection methods in themselves add very little to the results of the conjunctival testing. They are supplemental and in no way determine the use or contraindication for serum. Indications for Rabbit Serum.-At the present time the following indications for the use of rabbit serum in the typespecific treatment of pneumococcic pneumonia can be predicated. Thus serum is to be used: 1. When the effective sulfaniIamide derivatives (sulfapyridine and sulfathiazole) are contraindicated. 2. When the effective sulfanilamide derivatives produce no measure of improvement in from twenty-four to thirty-six hours. 3. When the appearance of the various toxic effects of the sulfanilamide derivatives develop during administration of these drugs and demand their cessation.
When the following conditions are present, a combination of serotherapy and chemotherapy is usually advised: 1. When the history indicates a seventy-two-hour duration of the disease.
2. 3. 4. 5_ 6.
When the patient is over fifty years of age. When multiple lobes are involved. When blood cultures are positive. In pneumonia during pregnancy or the puerperium. When there is serious concomitant complicating disease.
208
,
I. F. VOLINI, R. O. LEVITT, H. B. 0 NEIL
Serum is usually contraindicated in the patient with a positive conjunctival test. However, horse serum and rabbit serum are both available and nonreactor serum can be employed. The aged patient and the very weak individual should be given serum with considerable caution. It is perfectly obvious from the above discussion that the necessity for sputum typing and blood culture investigation can not be neglected despite the effectiveness of chemotherapy. Recourse to serum therapy is frequently necessary and this decision may be, and often is, sudden. Disaster is invited for the patient by further delay while awaiting for the reports of the type organisms producing this disease. Dosage.-The dosage of serum usually approximates 100,000 units. This is doubled or trebled by such factors as advancing age, bacteremia, increased duration of illness, multiplicity of pulmonary lobe involvement, complicating disease, and severity of symptoms. Types II and III infections demand more serum. Improvement in the symptomatology is the usual guide for efficacy and adequacy of dosage. When available, reliance is placed on the Francis test, the serum agglutination test, and the mouse protection test. Ordinarily, however, the temperature, pulse and respiration rate with the general condition of the patient determine the indication for more serum. This should be given at four- to twelve-hour intervals, until the desired result is obtained. Retyping and careful, thorough examination of the patient should be carried out when response to adequate dosage of serum is not obtained. Method of Administration.-The method of administration consists of the usual test or trial dose given intravenously followed, after one to two hours, by the remaining calculated dose. The total dosage is frequently given by the intravenous drip method, diluting the serum with normal salt solution in the drip flask. With the concentrated unitages now available, the single total dose method may be employed, injecting the entire amount undiluted directly into the blood stream. The first cubic centimeter should require two minutes, while the remainder should be injected at the rate of % to 1 minute per cc. REACTIONs.-The serious immediate reactions are best prevented by the careful preliminary testing, although the antidote epinephrine should always be ready at hand for immediate use. The onset of a reaction demands immediate cessation of the serum injection. Thermal reactions and the late serum
THERAPY OF PNEUMOCOCCUS PNEUMONIA
209
effects occur frequently. They are disturbing and annoying, but rarely dangerous, and respond promptly to appropriate treatment. Figure 9 A illustrates treatment with concentrated and re·· fined rabbit serum, all the pertinent data being given. Anti· DUE
Da,0I0he...
;;.:;-;~;~ I B t
. . . 00 A.
:·I·~+·~LJ....L. __.Lt..L..LL. 106
_.!...
1'0.'".'0 It
_1,..3.).
".".'" -----;-
l..}
1 i ! 1..3. ..
".'7.'.
19.'0.<0
····:····I····I····~····L.
"'!'+"l"+"+-' . +---:-..+...1-"-
or
8
_:""~.;,, -i-~"J.l. J..uil::::,:I~:rIl+·+-!"·!-+···i+J-J"!" ·)·+,,!,,·H.
Fig. 9.-Results of treatment of pneumococcus pneumonia with concentrated and refined rabbit serum. See text for details.
pneumococcus serum was given by the single total dose method. The sharp critical form of response is demonstrated in the Type I infection. Figure 9 B shows the necessary repetition of serum dosage guided by the Frands test. The injec· tions of serum were continued until a satisfactory clinical VOL. 25-14
210
I. F.
VOLINI,
R.
O. LEVITT,
H. B.
O'NEIL
response was obtained and the Francis test was changed from negative to positive. SULFAPYRIDINE THERAPY
The value of sulfapyridine as a therapeutic agent in the treatment of pneumococcic pneumonia was quickly indicated. Early experience with this drug demonstrated an even greater efficiency than immune serum. The first report2 published from the Cook County Hospital on a series of 160 patients, fifteen of whom had positive blood cultures, revealed a mortality of 3.3 per cent. A later study 4 of 200 patients treated with sulfapyridine showed a 4 per cent mortality-3 per cent in the nonbacteremic series and 7.8 per cent in thirty-eight patients with positive blood cultures. It is remarkable that in this group of 200 patients, there were forty-seven with Type I infection, none of whom died from the pneumonia. This included eight patients with bacteremia. In a report soon to appear describing the use of sulfathiazole 5 (control series treated with sulfapyridine) there were thirty-one patients with Type I infection, three with positive blood cultures; there were no deaths. There is thus demonstrated a remarkable specificity of sulfapyridine in Type I pneumococcus infection. The total group, comprising over 400 patients treated with sulfapyridine, shows results superior to those obtained by serum alone. Dosage.-The dosage has been standardized so that, initially, 4 gm., or eight tablets, are administered followed by 1 gm. every four hours until a normal temperature has been sustained for forty-eight hours. Experience has indicated that associated drug medication or using the powdered drug in various liquids has not materially changed the unpleasant effects. The nausea and vomiting so commonly encountered in the administration of this drug do not seem to be any more frequent or severe by the initial 4-gm. dosage than with the usually advised 2-gm., four-hour schedule for two doses. In those cases where the initial vomiting was severe and persistent, or in patients unable to swallow the drug, an intravenous injection of 100 cc. of 5 per cent aqueous solution of sodium sulfapyridine was administered. This was then followed by the oral dosage after four hours, using 1-gm. doses. BLOOD CONcENTRATION.-Optimum concentration levels in the blood are rapidly attained by the use of the large initial dosage. Blood levels fluctuate moderately on the usual maintenance dose. The clinical response, however, cannot be very
THERAPY OF PNEUMOCOCCUS PNEUMONIA
2I I
definitely correlated with the blood concentration. While adequate blood levels are difficult to fix, five milligrams per cent of the free sulfapyridine is usually considered as the accepted concentration. UNTOWARD REACTIONs.-The seriousness of the toxic reactions demands continuous supervision of the patient. Adequate laboratory investigation must be made prior to the onset of therapy. Toxic reactions demand cessation of sulfapyridine administration and, frequently, a change to other forms of therapy. This therefore means that the patient must be investigated just as thoroughly as the pneumonia patient was prior to the discovery of sulfapyridine. The laboratory examinations before drug therapy include as a minimum, sputum typing, blood cultures, complete blood counts and urine studies. And these must be frequently repeated in addition to the blood concentration studies. The damaging effects on the red and white hemopoietic organs and cells are not rarely encountered. Acute hemolytic anemia is common. One agranulocytic reaction with fatality was experienced. Another case of aplastic anemia with agranulocytosis, with a fatal outcome, resulted from sulfapyridine therapy. Various kidney complications are met with, such as calculi, anuria, albuminuria and casts, hematuria, and nonprotein nitrogen elevation in the blood. Drug rashes and drug fever must be kept in mind as they occur rather frequently and introduce a puzzling pattern in the clinical picture. Hepatic injury and central and peripheral nervous system effects are described, but these have not been met with in over 400 patients treated with sulfapyridine. The nausea and vomiting are often troublesome; while unquestionably these are of central origin, the intravenous use of the drug may so .improve the patient that vomiting lessens. The intravenous fluids and employment of sedatives may frequently accomplish much in reducing these effects. Persistence of administration may acclimate the patient to the drug so that vomiting, initially present, may disappear, although often the opposite result occurs. It must be kept in mind that as a general rule the toxic reactions appear from relatively long and continued use of the dr.ug, especially where large total doses are employed. The beneficial effects of sulfapyridine are produced early in its use. An evaluation, therefore, should be made after five days of use of the drug; this usually means after 20 to 25 gm. are consumed, provided of course no serious toxic effects appear.
212
1. F. VOLINI, R. O. LEVITT, H. B. O'NEIL
The evaluation should consider the clinical and laboratory evidence at this time. Continuation of medication is decided by this appraisal. The drug is usually stopped after forty-eight hours of normal temperature, although flexibility rather than rigidity of this rule should be stressed. Evidence is available that organisms may become sulfapyridine-fast by interrupted medication. Nevertheless, few relapses occur from drug cessation after the drug is continued during forty-eight hours of normal temperature. In fact, relapses are infrequent in cases TABLE 3 A STUDY OF 200 PNEUMococcus PNEUMONIAS TREATED WITH SULFAPYRIDlNE Nonbacteremic.
Total.
Type.
No. of cases.
J?eaths. No.
%
2 1 0 0 3 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
.~. 7 5.2 0 0 13.0 10.5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Deaths.
No. of ca!;es.
Bacteremic.
No.
%
0 1 0 0 2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 5.2 0 0 11.1 11.7 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
No. of cases.
Deaths. No.
%
2 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
10 .., 0 0 0 20 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
- - - - - - - - - - - ---I- - - - - -0- ._0 0 0 0 47 8 39 0 II
III IV V VII VIII IX XII XIII XIV XV XVI XVII XVIII XIX XX XXIII XXIV XXVII XXIX XXXI Total
54 19 4 6 23 19 1 6 2 2 1 2 2 1 1 2 2 3 1 1 1
200
35 19 3 5 18 17 0 5 2 0 0 1 0 0 0 0 0 0 0 0 0
19 0 1 1 5 2 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0
- - - - - - - -- -- -8- -4 - - 162 7.8 38 5 3 3
in which the drug is suddenly stopped when a normal temperature is obtained. INDICATIONS AND CONTRAINDICATIONs.-In addition to the foregoing toxic reactions, impaired kidney function and hepatic disease should contraindicate sulfapyridine. Curiously, granulocytopenia, the result of bacterial infection, frequently shows tremendous improvement with sulfapyridine. Serious anemias, such as pernicious anemia, sickle cell anemia complicated by pneumonia have responded well as far as the infection is concerned to sulfapyridine medication. Blood transfusions have been frequently employed.
21 3
THERAPY OF PNEUMOCOCCUS PNEUMONIA
.Methods of Administration.-Sulfapyridine can be administered by parenteral injection, using the sodium salt. When given intravenously, a 5 per cent solution in distilled water is used, employing from 3.5 to 5 gm. per dose. The injection may be repeated in from twelve to twenty-four hours. If escape into the adjacent tissues occurs, a severe irritating
.
•
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~mIL! t
1$
'"m
:!· .~ .~:f,.:·.~.-·.:i-;:.:.VN.:.~.·:....t+rr=i.L~H~#+·j-i~.i: .,e 1:::1:::~Q~'!l~~'*•. j1~ ¥t·, ~ i·
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.M.
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i
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.
.
i:::
i .. i
·:·i . !!. ·:··i . ~?t· 1 i
l:'
!:
~
..
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i ! '- :
i
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=
;:
f
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:
i
. ~····i····;···· ··..~:···i····~····~····i···· ··t··'!"·'!'-l'·· ...
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i.
i .L.L.L...
P.".
** .iB :f~~~_d+ · . ,r: i :::;:m+-
Fig. lO.-Results of treatment of pneumococcus pneumonia with sulfapyridine.
and necrotic effect may be produced. Subcutaneous or intramuscular injection may also be employed and is frequently very satisfactory; 5 gm. in 1000 cc. of normal salt solution is the concentration advised. No untoward effects have been observed and a steady blood level has been obtained. Results of Treatment.-In the combined therapy, using immune serum with sulfapyridine, the results very curiously indicate superiority of sulfapyridine alone over the combina-
214
I. F. VOLINI, R. O. LEVITT, H. B. O'NEIL
tion therapy. This was not the result of selection of cases, i.e., the more seriously ill were not chosen for the combined therapy. Similar findings were. reported by the Illinois Pneumonia Control Commission. Further study must determine the adequate explanation of these results. Table 3 reveals the results obtained by the use of sulfapyridine in 200 cases of pneumococcic pneumonia. Type 11 pneumonia was responsible for 27 per cent of the cases, with a bacteremic frequency of 35 per cent. Many of the Type 11 cases had a common origin in a shelter for homeless men who were housed in a school hall. Types VII and VIII showed a higher percentage of Negroes, Type VII being particularly virulent; 58 per cent of these patients were admitted seventy-two hours or more after the onset of the disease. Malnutrition, undernutrition, alcoholism and associated acute and chronic diseases were present in a good number of these individuals admitted to the large charity hospital. Nevertheless, the results indicate the tremendous progress that the therapy of pneumococcus pneumonia has made by the introduction of sulfapyridine. SULFATHIAZOLE
There are unquestioned advantages in the chemotherapeutic management of pneumococcus pneumonia and some evidence to indicate its superiority over immune serotherapy. The modus operandi of the recovery induced by drug therapy is not considered as following the immunological pattern created in a serum-induced recovery. Chemotherapy demonstrates effectiveness against nearly all types of infection. The cost is low. The ease of administration is of comfort to both the patient and physician. But efficiency in producing recovery from pneumonia contributes most of all to the popularity of chemotherapy. Theoretically there should be an enhancement of the therapeutic value in the combination of serotherapy and chemotherapy. However, the additive use of these two methods, each of proved value, has not been strikingly more efficient, as comment has already indicated. In the use of sulfapyridine, definite disadvantages are readily apparent. The nausea and vomiting, so frequently severe, detract from the usefulness of the drug. This effect not only aggravates the illness of the patient, but interferes with the continuation of treatm.ent, whereby entrance of the drug into the blood stream is prevented. The toxicity of the drug is pronounced, as has been pointed out. Many of these results are produced by what is known as acetylation or conju-
THERAPY OF PNEUMOCOCCUS PNEUMONIA
2I 5
gation of the drug. This readily occurs with sulfapyridine, a major percentage of the drug being conjugated. Acetylated sulfapyridine, chemotherapeutically considered, is inactive and inert. Nevertheless, it is considered responsible for the toxic manifestations and for the renal blocking and calculi formation. Advantages over Sulfapyridine.-Naturally an analogue of sulfapyridine was sought. Many compounds have been tried. The most effective and the least toxic thus far was found to be suljathiazole. The preliminary studies have indicated that sulfathiazole equals sulfapyridine in therapeutic effectiveness when comparative studies were made with various types of pneumococcus infections. On the other hand, staphylococcic infections respond more readily to sulfathiazole medication. The drug simulates in its action many of the pharmacologic activities of sulfanilamide rather than sulfapyridine. It is readily absorbed into the blood stream. High levels are quickly attained, and it is excreted into the urine at a rapid rate. The degree of conjugation, both in the blood and urine, is much less than that which is obtained with sulfapyridine. As a consequence, a larger percentage of the total drug absorbed into the blood stream is therapeutically active. The toxic effects are generally not so severe as those induced by sulfapyridine. Thus nausea and vomiting occurred in seven patients in the series of 169 treated, only one requiring discontinuance of the drug. With sulfapyridine, the experience was over 55 per cent, 15 per cent requiring withdrawal of the drug. No evidence of renal irritation was encountered, nor were effects noted on the hemopoietic systems. UNTOWARD REACTIONs.-Injury to nerve tissue may appear. Paresthesia and neuritis, though infrequent, may be severe. Drug fever, drug rashes and conjunctival irritation have been found to be serious manifestations; five instances of this were noted, two of the five ending fatally. The mortality rate in the series of 169 patients treated was 5.3 per cent. In the positive blood culture cases (twentyfour), two died, or 8.3 per cent; in the nonbacteremic series the mortality was 4.8 per cent. The results when compared to a contemporary group of 164 patients treated with sulfapyridihe were approximately the same. Dosage.-The method of dosage employed varied from that used with sulfapyridine. An initial 4-gm. dose was followed in four hours by one of 3 gm., subsequently after four hours by 2 gm., and thereafter 1 gm. every four hours. This
216
1. F. VOLINI, R. O. LEVITT, H. B. O'NEIL
method was suggested by the pronounced variation frequently encountered in the blood level, presumably due to the rapid elimination in the urine. Results of Treatment.-Figure 11 and Table 4 show all the pertinent data and illustrate the characteristic forms of temperature response to sulfathiazole. It must be remarked that the sulfathiazole treated patient presents an appearance O."ofOiMo....
!It .
.. In u
I
_R_,I:>
~
~
:;;
r:!
A •• ++++1- -1+++·+· ·+·--i·!:·+·!·····i·:··+·+·+·· . i. ·:.. i. ..;.·+··+·+·++ DATE
7
_R_~2 .
._L.! ... j .. L~q.~~.
'"
1M.+·j.i··+. ++··j··.j·· .H·. !. .:. .:- '+'+':'+'1"'
Fig. H.-Results of treatment of pneumococcus pneumonia with suIfathiazole.
of relative comfort when compared to the nauseated, vomiting individual under sulfapyrjdine medication. Temperature reduction is produced more rapidly by sulfapyridine therapy. The course of the fever curve shows a declination which is a characteristic combination of crisis and lysis, without the precipitous termination of the former and the absence of the prolorged course of the latter. It resembles a concave trajectory
2I 7
THERAPY OF PNEUMOCOCCUS PNEUMONIA
curve or geometric hyperbola with the normal temperature level attained in the forty-eight to sixty-hour period. Medication should be continued at least forty-eight hours after the temperature reaches normal. Selective effectiveness TABLE 4 RESULTS OF TREATMENT WITH SULFATHIAZOLE
Nonbacteremic.
Total. Type.
I II III IV V VII VIII XIV XIX XXI XXV XXVII
No. of cases.
Deaths. No.
No. of cases.
%
Bacteremic.
Deaths. No.
%
No. of cases.
Deaths. No.
%
8 13 1 0 0 1 0 1 0 0 0 0
1 0 1 0 0 0 0 0 0 0 0 0
12.2 0 100 0 0 0 0 0 0 0 0 0
24
2
8.3
---- - - --- --- - ---- - - - - ---
Total
27 75 19 8 6 15 1.1 1 1 1 2 1
169
3 3 3 0 0 0 0 0 0 0 0 0
11.1 4.0 15.8 0 0 0 0 0 0 0 0 0 - - --9 5.3
.
19 62 18 8 6 14 13 0 1 1 2 1
2 3 2 0 0 0 0 0 0 0 0 0
10.5 4.8 11.1 0 0 0 0 0 0 0 0 0 ---- ---145 7 4.8
- -- - ---
Per cent with bacteremia: 14.2.
was demonstrated by sulfathiazole. Better results were obtained by sulfathiazole in Type II and VII pneumonia. Sulfapyridine was superior in Types I and Ill. BffiLIOGRAPHY Treatment of Pneumococcic Pneumonia with Concentrated Rabbit Serum. J.A.M.A., 113 (14): 1314 (Sept.)
1. VoJini, 1. F. and Levitt, R. 0.: 1939.
2. Volini, I. F., Levitt, R. O. and Campione, N. L.: Serum and Drug Therapy
in Pneumococcus Pneumonia. Ill. Med. J., 76: 420, 1939. 3. VoJini, 1. F.: Sulfapyridine in the Therapy of Pneumococcic Pneumonia. Merck Report, Vo!. 48, No. 4, p. 10, Oct., 1939. 4. VoJini, 1. F. and Levitt, R. 0.: SuIfapyridine Treatment of Pneumonia. Ill. Med. J., 78 (4): 305 (Oct.) 1940. 5. Volini, 1. F., Levitt, R. O. and O'Neil, H.: Sulfathiazole in the Treatment of Pneumococcus Pneumonia, With a Comparative Study Utilizing Sulfapyridine Therapy. Am. J. Med. Sci., 200 (6): 778, 1940.