-J.A.M.A., Jan. 14, 1956

114

PREVENTION OF RHEUMATIC FEVER BY TREATMENT OFPREVIOUS STREPTOCOCCIC INFECTIONSEFFECT OF SULFADIAZINE

For many years the sulfonamides were the only anti­
bacterial drugs available for the therapy of acute strep­
tococcic pharyngitis. Although such therapy was effec­
tive in reducing the duration of the illness and the inci­
dence of the suppurative complications,'there is little
information indicating whether or not it prevented thenonsuppurative complications, rheumatic fever andacute glomerulonephritis. In recent years, it bas been
demonstrated that the treatment of streptococcic infec­
tions with penicillin and other antibiotics will prevent thesubsequent development of rheumatic fever.2 Sincemany physicians continue to employ the su廿onarnides inthe treatment of streptococcic infections, it is importantto establish whether such therapy will similarly prevent
rheumatic fever. Therefore, in the present study, thetreatment of acute streptococcic pharyngitis with sulfa­
diazine was evaluated with particular reference to theeffect of such therapy on the attack rate of rheumaticfever.
METHODS

The clinical and laboratory methods employed havebeen described elsewhere. 3 The present study was partof a larger investigation 4 and included those airmen who
were hospitalized with exudative pharyngitis or tonsillitis
between April, 1953, and February, 1954. Excluded
were all patients who gave a personal or family historyof rheumatic fever, who had had a previous untoward
reaction to penicillin or to sulfonamides, or who ex­hibited a suppurative complication at the time of theinitial examination.
A total of 291 patients received 2 gm. of sulfadiazine
initially, followed by 1 gm. every six hours for five days.
Treatment was initiated on an average of 36 hours after
the onset of symptoms, and for 92 % of the patients
therapy was started within 60 hours. A standard his­
tory and physical examination were recorded on admis­
sion and again 9, 13, 21, and 35 days after the onset ofillness. Patients with manifestations suggestive of rheuFrom the Streptococcal Disease Laboratory, Francis E. Warren AtrForce Base, Wyo., and the Department of Preventive Medicine, WesternReserve University.
This investigation was conducted under the sponsorship of the Com­mission on Acute Respiratory Diseases and the Commission on Strepto­
coccal Diseases, Armed Forces Epidemiological Board, and was supportedby the offices of the surgeons general, Departments of the Army and Air
Force, Washington, D. C.
1. Freis, E. D.: The Treatment of Tonsillitis with Small Doses ofSulfonamides, J. A. M. A. 126: 93-94 (Sept. 9) 1944.
2. Houser, H. B., and Eokhardt, G. C.: Recent Developments in thePrevention of Rheumatic Fever, Ann. Int. Med. 37: 1035-1043 (Nov.)
1952.
3. Wannamaker, .L. W., and others: Prophylaxis of Acute Rheumatic
Fever by Treatment of the Preceding Streptococcal Infection with Various
Amounts of Depot Penicillin, Am. J. Med. 10: 673-695 (June) 1951.
4. Catanzaro, F. J., and others: Symposium on Rheumatic Fever andRheumatic Heart Disease: The Role of the Streptococcus in the Patho­
genesis of Rheumatic Fever, Am. J. Med. 17: 749-756 (Dec.) 1954.

• Patients receiving sulfadiazine for acute strepto­
coccic pharyngitis were compared with patients
receiving other therapy f�7t�e same condition. The
sulfadiazine reduced the mc,dence of complications
during the acute phase. After the first week, how­ever, the incidence of suppurative complications
was about the same in both groups. The strepto­
cocci were not eradicated. The subsequent inci­
dence of recurrent pharyngitis in the sulfadiazine
group was three times that in the contratest group,and the sulfadiazine did not prevent rheumatic
fever.

matic fever were readmitted to the hospital for furtherobservation. A culture specimen from the tonsils or oro­pharynx was obtained at the time of each examination.
The analysis was limited to 261 patients from whomgroup A streptococci were isolated at the time of admis­
sion to the hospital. Eighty-seven per cent of these pa­
tients harbored streptococci of types 3, 14, 19, or 30.
Ninety-seven per cent of the patients were examined
between 21 and 35 days after the onset of illness for evi­
dence of rheumatic fever.
For purposes of comparison, a control group of 264
patients with exudative pharyngitis due to group A strep­
tococci is included. These patients were selected andobserved in the same manner as the patients treatedwith sulfadiazine, but they received only nonspecifictherapy. Ninety-four per cent of the control patientswere examined during convalescence. The two groupsof patients appear to be comparable in that the historicaland laboratory data obtained on admission were similar
and the predominant serologic types of streptococci
were the same. The control patients, however, were ob­served during the three-month period prior to the startof the present study.
RESULTSIn the dosages employed in this study, sulfadiazine
did not eradicate the Streptococcus from the throat ofpatients with streptococcic exudative tonsillitis or phar­yngitis (table 1). Nine days after the onset of symptoms,
the infecting type of Streptococcus was isolated from
more of the control patients than from those treatedwith sulfadiazine, which probably indicates continued
suppression of the organism as a result of therapy. The
carrier rates for the infecting type were equal in thetwo groups at 13, 21, and 35 days. Of those patientswith bacteriological data available from all four examina­
tions, the infecting type of Streptococcus was isolated
at some time during the convalescent period from 8 8 %•←'�- し，Capt. Alton J. Morris, Capt. Robert Chamovitz, (MC), V. S. A. F.
Capt. Frank]. Catanzaro (MC), Army of the United StatesandCharles H. Rammelkamp Jr., M.D., ClevelandSTREPTOCOCCIC INFEcT10NS̲MORRIS ET AL.

Vol. 160, No. 2of the group treated with sulfadiazine and ftom 93% of
the con-trol group. The acquisition rate for new types of
streptococciwaislghtly leis in the patients treated withsulfadiazine.

A recurrence of exudative pharyngitis or tonsillitis
was observed in 21 of the treated patients (table 2)'
With one exception, the original infecting type of Strep-tococcus was igain isolated at the time of recurrenceof symptoms. th. clinical relapse became manifest
within Lne week after the completion of therapy inmost instances. Therapy with one of the antibiotics wasinstituted in eight patients; four patients received notreatment during the relapse; and nine patients weregiven a second course of sulfadiazine. One of the latterfever' In
iatients subsequently developed rheumatic groupdecontrast, only ieven patients in the control
theinfectingveloped a ,.iupse, alf of whom harbored
type of Streptoioccus at the time of the recurrence' Oneoi tt.t. paiients developed rheumatic fever following
the second episo,Ce of exudatn'e phall'n-litis'
Suppurative complications, first recognized after at
least-i4 hours of therapy, were observed in 1 1 patients(4.2%) treated with sulfadiazine (table 2)' In eightpatients the complication developed after the comple-115

of the drug in the elimination of the causative organism.
As a general rule, with eradication of the organism thedisease process will be terminated and complications
rviil be prevented. Streptococcic infections differ fromother inlectious illnesses in that they are responsible
for trvo nonsuppurative complications in which the infecting organiim has not been directly reiated to thepathologicai lesions. These two diseases are rheumatic
ierer and acute glomerulonephritis. Recently, however,it has been shorvn that rheumatic fever develops after
a streptococcic infection only if the organism persists-in
the oiopharynx.a Therefore, it would appoar that theeffect of therapy on the morbidity and complicationsof streptococcic infections can also be related to its
effect on the infecting organism.*
The results of this study would indicate that the administration of sulfonamides during the acute phase of
streptococcic pharyngitis will reduce the incidence of

suppuratire compiications. That such a reduction isreiaied to the effect of the drug on the infecting orranism
is shorvn by the fact that the complications u'ere pre-vented only during the period of therapy, when thegrowth of ihe Streptococcus was suppressed' Following
Ihe cessation of therapy and with the regrowth of theT:str l.-Efject of Trealment on lhe Persistence ol Grc'Lrp A Streptococctts,qtre! tococcus Llarriers, t;

I DaysType oi StreptocOCCus lsolated atConTalesceDee aS COnlpared下ith Adl101ssion Culture

Same type.......

Difierent type.............
Group A Streptococcus Dot isolated.

tients subsequently developed rheumatic fever, an attack

rate of 4.2%. The interval to the onset of rheumatic
fever rvas betrveen I and 3'7 days, and the infecting typeof Streptococcus was isolated from nine patients after
the onset of rheumatic fever.
CONIMENT

To evaluate an antibacterial agent in the treatmentof an infectious disease, one criterion is the effectivenesssulra̲

Sulia‐

diazineControl

66888285757148465297568247141う15126193730

diazine Colltrol

diazine Control

diazine Control

organism. suppurative complications occurred at thesame rate as in the control group of patients'
The therapy of acute streptococcic pharyngitis withsulfadiazine was attended by an incidence of recurrent
pharyngitis that was three times the rate observed in'f *rs Z.-Re c urr e nt P hary n gi ti s an d S up p ur ativ e C o m p lic ati o ns
Developing Alter at Least Twenty-Four Hotts of Therapy
InterYal toLonrDllcrt)on
2‑7

S‐ 14Total

15‑21

22‑23Days Davs Days Days
Sulfadi azine
R,ecurrent PharYngitis... ' 'o

18

2

421

̲人

No. %―

21

8.0

Suppuratire conPlications

コ∝tion of therapy, whereas three patients manifested thecomplication between the third and fifth days of treat,.ri. In the control group, 17 patients (6.5% ) dereloped suppurative complications. During the first rreeko? ittn"tt, 12 control patients and 4 treated patients developed suppurative Complications, indicating that suchr"qoilu" were reduced by sulfadiazine du^ring this period. After the first week the incidence of suppurativecomplications was essentially equal in the two groups'
Adiagnosis of rheumatic fever was established in 14of 267 patients who rvere treated with sulfadiazine, anattack rate of 5.4% (table 3). fhe interval from theonset of symptoms of pharyngitis to the onset of rheumatic fever was between 1 and 35 days in all instances,and the infecting type of Streptococcus was again isoiated from all 14 patients after the onset of the rheumatic
episode. In addition, there were six patients who deviloped manifestations that are frequentlv associatedu'ith rheumatic fever, but the symptoms were mild andsubsided spontaneously. In the controi group, 1 1 pa-sulia‐

Sulfa‐

3; Days:1 Days

13 Days

Peritonsillar cellulitis.'Otitis media..........

.

SiDusitis

Control
Recurrent pharYngitis.....
Suppuratil'e colllplications
Peritonsillrrr cellulitis..

107

2.7

301216Otitis media............

103

1.1SiDusitis

100.8* Interval is IroD oDset oi acute illness to onset of complication'

nontreated patients. The relapse was apparently due tothe original infecting type and in most instances required
additional therapy. The most iikely er^planation is that

sulfadiazine temporarily inhibited the growth of theStreptococcus and induced a remission in the manifesta-

116

sTREPTOCOCCIC INFECT10NS―

卜10RRIS ET AL。

tions of the disease. The reduction in the number of or-J,_{.}I..{,, Jan. 1{. 1956

apy should not be expected to affect the artack rate ofrheumatic fever.
Rheumatic fever can be prevented by the use of antibacterial agents for prophylaxis against infection bygroup A streptococci or for therapy of the acute streptococcic i1lness., The daily administration of sulfonamides
or penicillin rvill prevent infection by group A streptococci,r but the application of this prophylactic measurehas been limited to special groups such as rheumaticsubjects and military or institutional populations. Therefore, the on11' practical method available for the prevention of rheumatic fever in the general population isby therapv of the streptococcic infection itself. At thepresent time. it would appe4r that a single injection ofbenzathine penicillin G is the most effective means ofganisms presumably diminished the stimulation of antibody formation' so that the patient did not develop immunity to the infecting Streptococcus. After therapy rvas

completed, the organism again proliferated and a clinical relapse occurred.
Although acute pharyngitis or tonsillitis due to group
A streptococci can be a prolonged and serious disease,particularly when suppurative complications supervene,
the acute condition is seldom life-endangering or permanently disabling. For this reason. the primary concern
in the treatment of such infections is the prevention of
the nonsuppurative complications. rheumatic fever andacute glomerulonephritis. In the preseni studr'. the attack
rate of rheumatic fever in the patrents treated *ith sulfadiazine rvas slishtlv greater than in the control patients and rvas almost trvice the usual incidence ol 3Vo

preventine rheumatic fever in the patient with acutestreptococcic pharyngitis.6 Other forms of penicillin,

Trsre 3.-Nottsuppuralive Complicatiorts Occttrring in 261 Patients with Streptococcic Pharyngitis ll/ho Were Treatedu,ith Sulfadiazine:● ￨.=● ●:Abdonl・ｌ●．
ａＩｉ Ｐ００＋０＋０００＋０００００００００００＋ 十 十 ０ 十 ０＋ ０ ＋ ＋ 十 ０

０＋ ＋ ０ ＋ ０ ＋ ＋ ＋ ０ ＋ ＋ 十 十 十０

却Elerationoi -ESR, S０ ０ ０ ０ ＋ 十＋ЮFerer i＋ ＋ ０ ＋ ＋ ＋ ＋ ０ ＋ ＋ ＋ ＋ 十 ＋

０６＋ ＋ ＋ ＋ 十 十１Carditis i０ ０ ０ ０ ０ ＋

０５ ５３ ３０璃 鑢＋ ＋ ＋ ＋ ０ ００９１ 聾０ ＋ 十 ■ ０ ０ ０ ０ ＋ ０ ＋ ＋ ＋ ＋０９１＋ 十 十 ＋ ０ ００７１＋ 十 ＋ ＋ ＋ ＋ ０ ＋ 十 ０＋ 十 ＋ ＋０

■０ ０ ０ ０ ０ ０ ０ ０ ｏ ０ ０ ＋ 十 ００３ｌ＋ ＋ 十 ＋ 十 ０ ＋ ０ ＋ ０ ＋ ＋ ＋ ＋０

Ｈ

1{ . . . . . . . . . . . . . . . .

Possible Rheumatic Fe\-er

００１

13 . . . . . . . . . . . . . . . .

０

７

11 . . . . , . . . . . . . . . . .

＋ ＋ ＋ ＋ ＋ ＋ 十 十 十 ０ 十 十 ＋ ＋

１

9................

10........ ........

-PRTgUDlt.Uis.

＋ 十 ＋ ＋ ０ ＋ ＋ ＋ ０ ＋ ＋ ０ ０ ０Joiot llar::.s:tr:: ::!
‐ ●￨='P. L,iio: R. redoess: T, tenderness; S, sryelling: IIulr., nultjple; fIig., migratory.
' r'H l:iir|ul ot 0.ll
second or-greater, partial or complete auriculol'entricularblock, signiflcantchange in heart murnur, or pelicardjal Iriction rub.
: T--.pp::Lrure ol ,]00.1 I r3;3 Cl or greater.
S Er5tbroci'te sediDeDtatioo rate 15 tn-tn. or tnore in an hour by the lvintrobe ntethod.

seen in untreated patients.s The obvious inability of suchtherapy to prevent rheumatic fever is apparently due toits ineffectiveness in the eradication of the Streptococcus.
Recent investigations have indicated that persistence of
the Streptococcus is essential for the development ofrheumatic fever t and that therapy which prevents rheumatic fever also results in the elimination of the organism.6 Since treatment with sulfadiazine does not significantly reduce the convalescent carrier rate, such ther5. Rammelkamp, C. H., Jr.; Denny, F. W.. and Wannamaker, L. W.,
in Rheumatic Fever. a Symposium Held at the University of lvlinnesotaon Nov.29-Dec.1,1951, Under the Sponsorship of the Minnesota Heart
Association, Thomas, L., editor, Minneapolis. University of Minnesora
Press, 1952, pp. 12-89.
6. Catanzaro, F. J.; Chamoyitz, R.; Morris. A. J., and Rammelkamp,
C. H., Jr.: Unpublished data.
7. Denny, F. W., in Streptococcal Infections, Mccarty, M., editor,
New York, Columbia University Press, 1954, pp. 1i6-196.
8. Chamovitz, R.; Catanzaro, F. J.; Stetson, C. A., and Rammetkamp,
C. H., Jr.: Prevention of Rheumatic Fever by Treatment of previous
Stxeptococcal Infections: L Evaluation of Benzathine penicillin G. New
England J. Med. 251:466-471 (Sept. 16) 1954.

chlortetracycline, tetracycline, erythromycin, or oxytetracycline, administered for at least 10 days. are also
effective. Sulfonamides should not be emploved in thetreatmert of streptococcic infections.
SUMMARY

Two hundred sixty-one patients with exudative pharyngitis due to group A streptococci were treated withsulfadiazine for five days. Sulfadiazine did not eradicate
the Streptococcus from the respiratory tract and did notprevent rheumatic fever. Sulfonamides, therefore. shouldnot be employed in the treatment of acute streprococcic
pharyngitis. It should be emphasized that sulfonamides
employed in prophylaxis against infection with group A
streptococci have proved to be of great value in the prevention of such streptococcic infections and that the drug

should continue to be utilized as a prophylactic measure.
3395 Scranton Rd. (9) (Dr. Rammelkamp).