The use of Sulfamerazine in Pneumococcal Pneumonia

THE USE OF SULFAMERAZINE IN PNEUMOCOCCAL PNEUMONIA

A.

GENECIN,

M.D.'"'

AND

R. A.

NELSON,

M.D.t

THE desirability of discovering safer and more effective sulfonamide derivatives for the treatment of bacterial infections has led to the recent extensive trials of sulfamerazine by a number of investigators.l-12 A methyl derivative of sulfadiazine, this drug has been shown to be very rapidly and completely absorbed after oral ingestion and relatively slowly excreted, thus making it possible to maintain adequate blood concentrations on smaller or less frequently administered doses. Beta-hemolytic streptococcal, meningococcal and pneumococcal infections have already received extensive clinical trial with results which compare favorably with already well-tested sulfonamide drugs. The preliminary studies seem to indicate that the toxicity of sulfamerazine is approximately the same as that of sulfadiazine.

CASES INCLUDED IN THIS STUDY

Between January 1943 and June 1944, we have treated 292 cases of lobar pneumonia at the Johns Hopkins Hospital with sulfamerazine with gratifying results. We believe that the cases which have come under our observation on the public wards are relatively severe infections. For example, 20.9 per cent of the patients were found to have a blood stream infection with a typable pneumococcus at the time of entry. Likewise, the incidence of involvement of more than one lobe is 31 per cent. Many of our patients had other severe concomitant illnesses which are known to jeopardize the outcome of lobar pneumonia. Approximately 15 per cent of the series were chronic alcoholics-a group of patients in whom multiple lobe involvement, bacteriemia, leukopenia, jaundice and delirium are especially apt to occur either singly or in combination. Fifty-two patients were admitted with lobar pneumonia at the height of the influenza epidemic in December 1943. These patients were noted to have particularly virulent infections, often associated with leukopenia. A routine attempt to corroborate the clinical diagnosis with direct demonstrations of pneumococci in the sputum was made in almost all instances. It is our impression that the direct capsular "quellung" procedure is of the utmost value in confirming the diagnosis of pneuFrom the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. * Instructor in Medicine, Johns Hopkins University School of Medicine. t Associate in Medicine, Johns Hopkins University School of Medicine; Assistant Physician, Johns Hopkins Hospital. 294

295

SULFAMERAZINE IN PNEUMOCOCCAL PNEUMONIA

blococcal pneumonia at the earliest possible moment. Failure to obtain a direct typing from the sputum or from the inoculated mouse peritoneum should awaken a suspicion that the infection may not be primary lobar pneumonia and a re-evaluation of the patient's status is indicated. Thirty-four patients, many of whom had been treated with other sulfonamide drugs prior to entry, had no pneumococci in the .sputum. These are included in the present series because the history and clinical course was otherwise typical of primary lobar pneumonia. We have not included influenzal, primary atypical, staphylococcal or streptococcal infections in the study. PLAN OF TREATMENT

The plan of treatment was to give an initial dose of 4 gm. of sulfamerazine by mouth or 5 gm. of sodium sulfamerazine by vein, followed by maintenance oral doses of 3 to 6 gm. a day. In the early part of the study, thirteen of the more severe cases were given antipneu15 0~

~

(!)

:2: I

14

12

>

9

....J

8

0

7

0 0

....J

m w W a:::

........

11 10

W

...................................

13

....J

W

../ ....,./•......... _...........................

-------

6

5 (3 GM. I DAY)

4

SCHEDULES

I AND 2

lJ..

3

SCHEDULES

3 AND 4

(4 GM. I DAY)

Z

2

SCHEDULES

5 AND 6

(6 GM. I DAY)

«

15 w ~

.'.

'

2

3

4

5

6

DAYS Fig. 47.-Median whole blood concentrations of free sulfamerazine observed in 165 patients on a dosage of 3 gm. a day, in 62 patients on 4 gm. a day, and 33. patients on 6 gm. a day.

mococcal rabbit serum as supplementary therapy, either because of initial grave prognosis or poor response to chemotherapy. As penicillin became more generally available later in 1943, twenty-two patients were given that drug in addition to full doses of sulfamerazine. Penicillin was given in doses of 20,000 units intravenously or intramuscularly every three hours.

296

A. GENECIN, R. A. NELSON

Treatment with sulfamerazine was continued in all cases until fortyeight hours or more after the temperature and clinical response indicated satisfactory control of the infection. It was found that the period of time and total quantity of drug necessary to effect a cure was exceedingly variable. In general, many of those admitted early in the course of the disease had a prompt artificial crisis, but despite the temptation in these cases to discontinue therapy after two or three days, it was thought wiser to continue treatment until the risk of relapse was minimized. Treatment was promptly discontinued on suspicion of toxic reaction. Whenever possible, an oral test dose of 0.5 to 1 gm. was given before hospital discharge where febrile and cutaneous sensitivity was suspected. Blood sulfamerazine determinations were done at frequent intervals by the method of Bratton and Marshall. The median blood levels of free sulfamerazine (whole oxalated blood) on schedules of 3, 4 and 6 gm. a day taken by mouth after an initial intravenous or oral dose are shown in Figure 47. As is to be expected, higher and better sustained levels are obtained with the more intensive schedules. With the passage of time, the daily median blood levels on all schedules decrease. On the 3 gm. per day schedule, the daily medians vary between approximately 5 and 10 mg. per 100 cc.; on the 4 gm. per day dosage, between 7.5 and 9.5 mg. per 100 cc.; and on the 6 gm. per day, between 10.5 and 15.5 mg. per 100 cc. TOXIC REACTIONS

The toxic reactions which were encountered were of the same character and approximate frequency observed with other suifonamide drugs in current use. In Table 1, there is presented an analysis of toxic manifestations in relation to dosage intensity. Fever and/or rash and renal irritation head the list of untoward effects. The rashes were similar to those seen with other sulfonamides; one of the patients developed an erythema multiforme-like syndrome with stomatitis, conjunctivitis and a papulovesicular eruption. Erythema nodosum was not seen. Two patients who developed urinary suppression, flank pain and hematuria were vigorously treated with forced fluids and alkalies and recovered promptly. The routine administration of alkalies in the form of sodium bicarbonate in large doses was not pursued. Although it would appear advisable to maintain a constantly alkaline urine, inconveniently large doses of sodium bicarbonate are necessary. Furthermore, many of the fatal renal reactions which are observed during sulfonamide administration are associated with a widespread toxic reaction in the tissues rather than simple mechanical obstruction by sulfonamide calculi. It is our impression that careful observation of the urinary output together with frequent urine examinations is adequate in most instances. Nausea and vomiting were exceedingly rare. Delirium was COI\l-

r.n

TABLE 1.-TOXIC REACTIONS TO SULFAMERAZINE IN 292 PATIENTS TREATED FOR LOBAR PNEUMONIA ---

-

?

--------

3 Gm. per Day

Irregular

Schedule

4 Gm. per Day

I.-j

6 Gm. per Day

;..

Total

~

t"l

:;::

No. of patients ........

32 patients

165 patients

62 patients

33 patients

:.-N

292 patients

Z

t"l

No.

Per Cent

No.

Per Cent

No.

Per Cent

No.

Per Cent

No.

No toxic reaction ......

28

87.5

148

89.7

57

91. 9

28

84.8

261

Fever and/or rash ......

2

6.2

8

4.8

1

1.6

3

9.0

14

(microscopic Renal hematuria) ..........

0

0

5

3.0

2

Renal (gross hematuria)

0

0

1

0.6

1

Leukopenia ...........

2

6.2

2

1.2

1

Gastrointestinal. .......

0

0

1

0.6

0

Percentage of patients wi th toxic reactions ..

15.5

I

10.3

I

I

8.1

! Per Cent Z i .'0 I 89.4 Z

I I

:

3.2

2

6.1

9

1.6

0

0

2

1.6

0

0

5

[

0

0

0

1

!

I

15.4

!

i

10.6

4.8 3.1 0.7 1.7 0.3

t"l

-

~

~

o

8n n

~ '0

Z

t"l ~

~ Z

o

:; N

'0

-....}

t~

\0

oc

TABLE 2.-ANALYSES OF 292 PATIENTS WITH LOBAR PNEUMONIA TREATED WITH SULFAMERAZINE

Number of Cases

I NUI?ber with

Nonbacteriemic Bacteriemic Number with Multiple Concurrent \ Lobes Disease Number Con;plica- Deaths Number COfPlica-1 Deaths IOns tlOns

I

I

~

Total Deaths

Z

trJ

n ....

Sulfamerazine alone ............

256

64

108

33

5

7

223

26

7

14 (5.4%)

Sulfamerazine plus serum .......

13

9

8

9

4

4

4

2

1

5 (38.4%)

Sulfamerazine plus penicillin .....

22

18

12

19

8

5

3

0

1

6 (27.3%)

plus serum plus pernclllm ....................

1

1

0

1

0

1

0

0

0

1 (100%)

Totals ......................

292

92

128

62

17

17

230

28

9

26 (8.9%)

Sulf~~r~ine

Cl trJ

~Z

?:I ~

z M

t"' 0

'"Z

SULFAMERAZINE IN PNEUMOCOCCAL PNEUMONIA

299

monly observed in very ill patients, particularly alcoholics, but was not thought to be related to therapy in any instance. Despite the presence of the methyl group in sulfamerazine, no case of peripheral neuritis was observed, although all investigators have looked for an example of this reaction in view of the structural analogy with sulfamethylthiazole. Leukopenia, although frequent, was never alarming and there were no instances of agranulocytosis. Since the incidence of toxic reactions may be higher with the higher dosage schedules, we recommend a dose of 3 or 4 gm. a day. RESULTS

Analyses of groups of cases treated with sulfamerazine alone, sulfamerazine plus serum and sulfamerazine plus penicillin are presented. The relatively low incidences of involvement of more than one lobe, WM66

. F. P. DAY OF

DISEASE

TEMP.

3 4

Ll~

TYPE 3

5 6

7

12 13 14 15 16 17 18 19

8 9 10

105

10 101 100 99 CULTURE

+ +

WBe

4.4

BLOOD

3.0

7.3

13.0 14.0

11.2

9.5

12.4

1.8

XIOOO

BLOOD LEVEL

6

MGM"Io 4

r--

~

2

DOSAGE If--GRAMS

~

Fig. 48.-A gravely ill patient, presenting many unfavorable clinical features, who responded well to the combination of suIfamerazine and penicillin.

concurrent illnesses and bacteriemia in the sulfamerazine group attests to the milder nature of these infections as contrasted with the selected groups of more seriously ill individuals who required supplementary treatment. The most unfavorable group prognostically was the penicillin-treated, as is shown by the bacteriemic rate of 86.3 per cent (nine-

300

A. GENECIN, R. A. NELSON

teen out of twenty-two). The case fatality rate of 27.3 per cent in this group seems to indicate that penicillin is at least as effective as serum, if not more so, as an adjunct to sulfonamide treatment. The course of treatment in a 66 year old white man with arteriosclerotic heart disease, myocardial insufficiency, bundle branch block, chronic alcoholic addiction and Laennec's cirrhosis with jaundice, who developed type III lobar pneumonia with bacteriemia is illustrated in Figure 48. In the entire series of 292 cases the case fatality rate was 8.9 per cent and the incidence of non fatal complications was 15.4 per cent. It should be mentioned that 15 of the twenty-six deaths occurred within twenty-four hours of entry. The case fatality rate, excluding deaths within twenty-four hours after institution of therapy, is 4.0 per cent. TABLE 3.-COMPLICATIONS ENCOUNTERED IN 292 LOBAR PNEUMONIA PATIENTS TREATED WITH SULFAMERAZINE

256 Cases Without Supplementary Tre'ltment L iving without complication .... D eath ......... .. . .... . . . · . Spread ........

'"

Pleurisy .......

... .

.

... . .. . · . ---..... . . · .

E·mpyema ........ .. . . ... .. .

36 Cases With Supplementary Treatment

Total

211 (82.5%)

10 (27.8%)

221 (756%)

14 ( 5.4%)

12 (33.0%)

26 ( 8.9%)

9 ( 3.5%)

4(11.1%)

Ll ( 4.5%)

9 ( 3.5%)

4(11.1%)

Ll ( 4.5%)

1 ( 28%)

3 ( 1.0%)

~--------

----------.-------2 ( 08%)

------------ -------

T hrombophlebitis ......... ....

-- - - - - - -

-- ------.-

--~-----

5 ( 20%)

2 ( 56%)

7 ( 2.4%)

)

2 ( 5.6%)

2 ( 0.7%)

)

1 ( 2.8%)

1 ( 0 3%)

M eningitis ...................

o( 0 o( 0 o( 0

)

1 ( 2.8%)

1 ( 0.3%)

U nresolved pneumonia .........

6 ( 2.3%)

2 ( 5.6%)

8 ( 2.7%)

other. .......................

3 ( 1.2%)

3 ( 8.3%)

6 ( 2.1%)

45 (17.6%)

26 (72.4%)

71 (24.3%)

L ung abscess .............. ... p ericarditis ................ ...

p atients with death or compli-

cations .....................

--------

Table 3 is a presentation of the distribution of complications encountered. Approximately three quarters of all cases had a completely satisfactory outcome. The more seriously ill patients, who required supplementary therapy, suffered a combined case fatality and complication rate of 72.4 per cent, whereas this figure for the sulfamerazine group is only 17.6 per cent: Spread of the infection and the pleurisy

SULFAMERAZINE IN PNEUMOCOCCAL PNEUMONIA

301

were observed as the most common complications. More serious complications were rare. SUMMARY

1. An analysis of 292 cases of lobar pneumonia treated with sulfamerazine, either alone or in combination with anti pneumococcal serum or penicillin, is presented. 2. It is concluded that sulfamerazine is both a safe and effective chemotherapeutic agent in the treatment of lobar pneumonia. BIBLIOGRAPHY

1. Welch, A. D., Mattis, P. A., Latven, A. R., Benson, W. M. and Shiels, E. H.: J. Pharm. Exp. Ther., 77:357, 1943. 2. Clark, J. K., Flippin, H. F. and Murphy, F. D.: Am. J. Med. Se., 205:717,1943. 3. Ibid., p. 846. 4. Gefter, W. l., Rose, S. B., Domm, A. H. and Flippin, H. F.: Am. J. Med. Se., 206:211, 1943. 5. Ibid., p. 216. 6. Hageman, P. 0., Harford, C. G., Sobin, S. S. and Ahrens, R. E.: J.A.M.A., 123 (6) :325, 1943. 7. Hall, W. H. and Spink, W. W.: J.A.M.A., 123(3):125, 1943. 8. Lepper, M. H., Sweet, L. K. and Dowling, H. F.: J.A.M.A., 123(3):134, 1943. 9. Lepper, M. H. and Stanley, E. D.: Med. Ann. District Columbia, 13:54, 1944. 10. Annotation: Lancet, 2(25):773 (Dec. 18), 1943. 11. Anderson, O. G., OEver, C. S. and Keefer, C. S.: New Eng. J. Med., 230:369, 1944. 12. Dowling, H. F.: Med. Ann. District Columbia, 12:468, 1943.