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A comparison of intramuscular benzathine penicillin and oral sulfonamide in the control of rheumatic recurrences
A C O M P A R I S O N OF I N T R A M U S C U L A R B E N Z A T H I N E P E N I C I L L I N AND ORAL S U L F O N A M I D E IN T H E CONTROL OF RHEUMATIC RECURRENCES CAROLYN MOORE M C C U E ,
M.D., COUNT D.
GIBSON,
JR., M.D.,
AND
LILLIAN C. LINDEMANN, M . D . X~IOttMOND, VA.
H E crucial role of the Group A in the causation of rheumatic fever is generally admitted by most authorities. This notion has been supported by the results of antimicrobial t h e r a p y in two types of investigation : (1) reduction of rheumatic fever incidence following mass treatment of streptococcal infections; (2) reduction of rheumatic fever recurrences during continuous prophylaxis in individuals who have already suffered one or more episodes. 1 The I~ichmond Clinic of the Virginia State Rheumatic F e v e r P r o g r a m has been studying the characteristics of rheumatic fever in Virginia since 1940. A preliminary report in 19482 described the nature of our patient population and the diagnostic criteria utilized in classification. A recurrence rate of 61 per cent in a group of 225 cases followed for three years was observed. A second communication in 19522 reported the results of continuous sulfonamide prophylaxis in 190 cases followed for an average of fortyfour months. A recurrence rate of 2.9 per cent was seen during an average period of twenty-four months with sulfadiazine and 1.5 per cent during an average of eleven months with sulfisoxazole (Gantrisin).
Benzathine penicillin* (N-N'dibenzylethylenediamine penicillin) is an ester of penicillin G 4 with a differing pharmaeodynamic action depending on its route of administration. An oral dose of 200,000 to 400,000 units is taken daily for continuous prophylaxis. When 1,200,000 units of the drug is injected intramuscularly, measurable blood levels can be detected up to twenty-eight days subsequently. This remarkably prolonged repository action is presumably due to the slow release of active penicillin from the depot. Reports on the use of benzathine penicillin intramuscularly for prophylaxis against rheumatic recurrence are few at present. The available data are summarized in Table I, including our own results.
T streptococcus
PURPOSE
From the Departments of Pediatrics and Medicine, l~{edieal ColIege of Virginia, and the Richmond Clinic of Virginia State Rheumatic Fever Program.
It is now recognized that any patient who has had acute rheumatic fever should have some type of prophylactic medication for an indefinite period of time. The p r i m a r y purpose of this project was to study recurrences of rheumatie fever as influenced by two drugs. The plan was to observe over a two-year period the influence of monthly intramuscular injections of benzathine penicillin G on rheumatic recurrences. A series of patients on sulfonamides served as controls.
450
*SuDPlied by Wyeth Laboratories, Philadelphia, Pa.
451
/YiC CUE ET AL. : CONTROL OF RHEUMATIC RECURRENCES MATERIAL
F i f t y patients were selected f r o m the convalescent wards and outpatient d e p a r t m e n t of the Richmond Rheumatic F e v e r Clinic in the fall of 1952 for benzathine t h e r a p y . All of this group had recently experienced rheumatic fever and were in the age group and stage of the disease where some type of prophylaxis was d e a r l y indicated. They were of necessity in the hospital or in the area served by Richmond so that visits to the clinic every twenty-eight days for intramuscular injections were feasible. M a n y had such a background that reliable oral dosage was impossible. Seven had a leukopenia on a sulfonamide, requiring TABLE I.
INTRA1VfUSCULAI{BENZATHINE PENICILLIN I:~t{EUIcIATIC I~ECURRENCE NO. OF
I~u163 S t o l l e r m a n , G. H., a n d associates5 DieM, A. IV[., a n d assoelates6 P e r r y , C. B., a n d Gillespie, W. A.7 McCue, C. M., a n d associates Totals
significant difference. Of these, twentyfour were males and twenty-two females with thirty-one white and 15 Negro. Again four cases failed to follow through. While every a t t e m p t was made to s t a r t patients on prophylaxis as soon as possible, m a n y of the benzathinc penicillin group had previously tried other drugs. The most irresponsible of the group were shifted to this program. Other new cases were started on it promptly. The average age when prophylaxis was stm~ed was 1.0.2 years. The mean months since the onset of the last attack were 12. I n the sulfonamide controls, m a n y were started in the late 1940%. The usual procedure was to wait until the
INJECTIONS 2,631
NO. OF PATIENTS 285
AVERAGE I~ PERIOD (lV[O.) ]0
962
96
14
64
22
3
1,103
46
24
4,760
449
its cessation. The ages at onset of prophylaxis, race, sex, and cardiac diagnoses are listed in Table II. There were twenty-two males and twenty-four females, twenty of whom were white and twenty-six Negro. F o u r patients dropped out. F i f t y comparable cases were chosen and maintained on sulfonamide prophylaxis. The same criteria for diagnosis and same general care were given to both groups. As will be noted f r o m Table I I I , p a r t of this group was on sulfadiazine and p a r t on Gantrisin, but it was not felt t h a t this made any
PROPHYLAXIS OF
pATIENT iVs 2,841
RHEUMATIC REGUI~- ALLERGIC R E N C E S REACTIONS 0 7
1,344
0
2
:1
0
1,104
0
1
5,289
1
10
patient was considered inactive before sulfa was begun. Often the initial episode was a long one. The average age at onset of prophylactic t h e r a p y was 11 years with a mean of 9 months since the beginning of the last attack (see Table IV). The criteria f o r diagnosis in the benzathine group and sulfa group were as follows : Benzathine -Penge~;lli~ Cardltis a n d p o l y a r t h r l t i s Carditis alone P o l y a r t h r i t l s alone P o l y a r t h r i t l s a n d chorea Carditis a n d chorea
32 5 6 1 2
Sulfonamides 31 4 8 1 2
452
THE JOURNAL OF PEDIATRICS
TABLE I~. CASE STUDT : BENZATHINE PENICILLIN GROUP AGE PROPHY
MONTHS o
[
SINCE
BICILLIN
LAXIS STARTED
RAGE AND SEX
1
3
WM
13
:YLI.
:12
2
14
NF
24
l~.I.
28
NO.
8
C.E. C.E. Myo. M.I. M.S. C.E. No tt.D. No H.D. C.E. Myo. M.I. M.S. C.E. Failure
SHOTS NO.
3
6
4
]4
NF
24
5 6 7
12 13 4
WM W~[ NF
2 :14 3
8
]1
NM
9
9
15
WF
6
]0 I]
12 7
WM WF
50 12
:12 13 14
16 13 10
WM WF WF
5 :13 8
Myo. No. H.D. M.I.
19 20 28
15
10
NF
15
21
16 17
14 6
WM NF
48 9
18
7
NF
9
M.I. C.E. M.I. M.L M.S. C.E. A.L M.I.
19
10
WM
36
20
9
NF
3
21 22
5 5
NF WF
2 I
23
11
NM
]2
24
12
NM
36
Key : ~.I. M.S. A.I. A.S. C.E.
iq~I
ONSET LAST CARDIAG ATTACK R.F. DIAGNOSIS
~r insufficiency. ]Y[itral stenosis. Aortic insufficiency. Aortic stenosis. Cardiac enlargement.
M.I. C.E. M.S. A.I. M.I. Myo.
M.L C.E. M.I. C.E. C.E. M.I. C.E. M.I. M.S. C.E. Failure M.I.
~r H.D. S.B.E. R.F. I.A.S.D.
REMARKS
Moved to N o r t h Carolina, 3/5~i 2 attacks prior to Bieillin
26 25
2 attacks prior to P,icillin
24 26 21 27
25
26 25
2 attacks p r i o r to Bicillin S.B.E. in 1951 N e p h r i t i s in :1952 Failure in :1952 *Failure in 1954 3 attacks prior to Bicillin
3 attacks prior to Bicillin L e g g - P e r t h e s disease in 1953 A n e m i a in 1953 Sister developed R.F. E n t e r e d Navy, 5/54 Repeated polyarthritis. No u n k n o w n in p a s t 2 attacks p r i o r to Bieillin
23 26
2 attacks p r i o r to Bicillin
25
Sister and cousin died with R.F. 2 attacks prior to Bicillin
26 25 25 20
? Attack, aged 4
28
Severe lung, first attack
23
2 attacks prior to Bicillln Nephrotic stage of glomerulonephritis in 1951-1952 1Yiyocarditis. H e a r t disease. Subacute bacterial endocarditis. l~heumatic fever. I n t e r a t r i a l septal defect.
453
1Y[C CUE ET AL. : CONTROL OF RHEUMATIC RECURRENCES
TABLE I I . - - C o N T 'D AGE
MONTttS
PROPHY-
SINCE
LAXIS
NO. 25
STARTED 10
RACE A N D SEX
WM
ONSET LAST
I
I
BICILLIN CARDIAO
ATTACK R.F. DIAGNOSIS
29
A.l.
SHOTS
NO. 27
RE3s 3 a t t a c k s prior to Bieillin F a i l u r e a n d p e r i c a r d i t i s in 1949-1951
27
2 a t t a c k s prior to Bicillin S.B.E. in 1951
A.S. M.I. M.S.
26
9
NM
16
27
6
WM
3
28 29 30
8 8 13
NF NM NF
3 29 15
C.E. M.I. M.S. C.E. M.I. C.E. A.S. M.I. N o I-I.D. M.I. M.S. A.S. C.E. Failure Fibrillation M.I. M.S. C.E. M.I. M.I. C.E. Myo. M.I. M.S.
23 25 28 27
31
14
NF
13
32 33
15 12
NM NM
40 8
34
13
WF
30
35
11
WM
18
M.I.
16
36 37
4 12
NF NM
8 10
22 21
38 39
12 11
NF NF
6 24
40 41 42
14 9 16
NM WF NM
< 1 6 60
43
11
WF
48
44
12
NF
12
45
6
WF
7
46
6
WM
5
C.E. C.E. M.I. A.I. Pericarditis Failure M.I. M.I. C.E. N o H.D. No tI.D. M.I. M.S. A.I. C.E. C.E. Myo. (Nodules) C.E. M.I. C.E. (Rash) No ]:I.D.
*Case discussed in text u n d e r "Results."
25
*See t e x t Chronic R.It.D. J u n e , 1951
active
since
4 a t t a c k s prior to Bicillin Severe social p r o b l e m s
26 26 23
26 26
W o u l d n o t take oral prophylaxis A n e m i a now Mentally retarded Chronic m a s t o i d i t i s Severe bronchitis, 3 / 5 4 3 a t t a c k s prior to Bicillin with p e r i e a r d i t i s
2 a t t a c k s prior to Bicillln
17 25 27
2 a t t a c k s prior to Bicillin Active disease over 2 y e a r s
23
Active disease 3-plus y e a r s
25 25 19
M o t h e r developed active R.F. in 1954
454
THE J O U R N A L OF PEDIATRICS
TABLE I I I .
RACE AND
lYIONTHS SINCE ONSET LAST ATTACK
SEX WM NF
R.F. 8 5
NO. 1 2
AGE PROPHYLAXIS STARTED 16 14
3
9
I~M
4
4
14
WM
13
5
17
WM
6
6
17
I~F
24
CASE STUDY: SULEONAMIDE GROUP*
CARDIAc DIAGNOSIS
MONTHS RECURDURATION RENCES 0 N THERAPY SULFA
24 40
1VLI. M.S. A.I. A.S. 0.E. 1Yf.I. C.E. Myo. M.I. M.S. O.E. A.L
16
Sulfadiazine Sulfadiazine Sister h a d R.F. in ]944 2 a t t a c k s p r i o r to sulfadiazine Sulfadiazine
46
Gantrisin and sulfadiazine
60
7 a t t a c k s p r i o r to s u l f a diazine
24
Sulfadiazine 2 a t t a c k s p r i o r to s u l f a dlazine
47
Gantrisin
69
Sulfadiazine F i r s t a t t a c k , d u r a t i o n over 2 yr.
55
Gantrisin
23 33 4
Sulfadiazine Gantrisin Sulfadiazine F a t h e r h a d R.F. Sulfadiazine Sulfadiazine
M.I. M.S.
7
19
WM
19
8
12
NF
33
9
8
WM
7
10 ll 12
]6 ]3 4
WM NF WF
5 ]3 7
A.I. C.E. Myo. i.I. A.S. M.I. M.S. C.E. M.I. ~.S. I.A.S.D. Failure M.I. M.S. C.E. Myo. Failure ]Y[.I. M.I. N o tt.D.
13 14
15 10
WF WF
6 8
M.I. N o I-I.D.
7 24
]5
8
WM
6
N o H.D.
30
16
11
NF
12
15
17 18
9 7
WM WM
8 8
A.I. M.I. M.S. C.E. N o H.D. No. tt.D.
]9
15
WF
12
A.I. M.I.
27
20
WM
3
l attack 2/54 1 attack
2/53
Pericarditis ~i.I. *For key to abbreviations, see Table ]I. 14
REMARKS
M.I. M.I.
? Attack 4/53
26 68
24
? Attack 9/53
2 a t t a c k s p r i o r to sulfadiazine Gantrisin 2 a t t a c k s prior to Gantrisin Sulfadiazlne 3 a t t a c k s p r i o r to s u l f a diazine B r o t h e r h a d R.F. 3 a t t a c k s p r i o r to sulfadiazine Chorea 2 a t t a c k s prior to sulfadiazine
MC CUE E T AL. :
CONTROL OF R H E U M A T I C R E C U R R E N C E S
TABLE I I L
455
CONT'D
MONTHS
SINCE ONSET
NO.
AGE PROPhYLAXIS STARTED
RACE AND BEX
21
16
WM
22
13
NF
23
7
24
15
LiST ATTACK I~.F.
CARDIAC DIAGNOSIS
MONTHS DURATION TSERAPY
No H.D.
36
WM
I0
NM
12
1V~.S.
3
25
10
26
8
WM
24
27
7
WF
12
28
11
NM
6
29
9
NF
1
30
12
WM
31
8
WF
32
11
WM
33
12
WM
34
13
WF
IVLI. A.S. A.I. C.E. Niyo. IV[.I. M.S. C~ M.I. M.S. C.E. Failure lV[.I. C.E. M~ M.S~ C.E. Failure M.L A.I. A.S. C.E. A.I. Myo. Failure M.I. M.S.
81
47
3 attacks prior to sulfadiazlae Third attack lasted over 1 yr. Sulfadiazine
3
50
REMARKS
Mother h a d l%.F. Chorea in 3 attacks prior to Gantrisin Chronic otitis media Gantrisin Delivered normal infant, 1953
44
18 A.I. A.S. C.E. No H.D.
NF
RECURRENCES ON SULFA
? Attack
5/51 11
3 attacks prior to Gantrisin Low WBC Discontinued 4 attacks prior to sulfadiazine F o u r t h attack, duration 1 8 9 yr. Gantrisin 5 attacks prior to sulfadiazine Sister listed below, No. 29 4 attacks prior to sulfadlazine Brother listed above, No. 28 Hepatitis, 1953 3 attacks prior to sulfadiazine 5 attacks prior to sulfadiazine Sister had Ir
20 25
83 78
C.E.
35
NF
36
WM
50
Gantrlsin
6
i.I. A.S. M.S. C.E. M.L
38
15
M,I.
8
3 attacks prior to G a n trisin 5 attacks prior to sulfadiazine F i f t h attack, duration 1 yr. L e f t hospital 6/53 Severe failure Acute disease over 2 yr. Sensitive to Gantrisin Sulfadiazine
26 6
C.E. i.I. Failure C.E. M.L Failure No I-I.D.
36 72
Died 9 / 5 / 53 Cause not known
456
THE JOURNAL OF PEDIATRICS TABLE III.
37
11
WF
54
Myo. A.I. Fibrillation C.E. M.I.
38
8
WM
15
NLI. ~.S.
39
13
NF
18
WM
36
WF WF
11 5
NF
28
40
8
41 42
10 10
43
6
44
8
NNI
11
45
10
WF
10
46
14
WM
13
No R.H.D. Patent duc~us ~.I. M.S. C.E. A.I. Failure
CONT'D
63
Sulfadiazine First attack, duration 3 yr.
35
Gantrisin
27
Sulfadiazine Refuses surgery for ductus Pregnancy, 1954 3 attacks prior to sulfadiazine Third attack, duration 2 yr.
69
Gantrisin Sulfadiazine
44
IVLI.
No H.D. M.I. C.E. 2-1 Heart block C.E.
12 60
42
Sulfadiazine First attack lasted over 1
M.L Myo. Pericardit~s M.I. M.S. Myo.
50
3 attacks prior to Gantrisin
30
3 attacks prior to sulfadiazine (2 with modules)
Sulfadiazine
First attack at 21/2 yr. Second attack at 4 yr.
yr.
TABLE
IV.
AGE
AND ]DURATION
OF TI-IZ~APY
I BENZATmNE
Average age prophylaxis started Average months on therapy 1Kean months since onset last rheumatic fever attack
PENICILLIN
G I
10.2 24 12
SULFA
11.0 38.6 9.0
TABLE V. CAI~DIACDIAGNOSES ]
No heart disease Mitral insufficiency alone Cardiac enlargement and/or serious valve damage F ailur e METHODS
L e t t e r s were w r i t t e n to the r e f e r r i n g p h y s i c i a n s of both g r o u p s e x p l a i n i n g the p r o j e c t a n d r e q u e s t i n g t h a t a d d i t i o n a l a n t i b i o t i c s be g i v e n o n l y w h e n s p e c i f i c a l l y i n d i c a t e d a n d t h a t we be notified of t h e i r use.
T h e p a r e n t s of
each child also received letters a n d a g r e e d to cooperate w i t h t h e project. This eliminated four patients from
BENZATIIINE PENICILLIN G
7 10 29 4
I SULFA
10 8 28 8
each g r o u p of fifty, a n d f o r t y - s i x followed t h e d i r e c t i o n s r e a s o n a b l y well. E i g h t y p e r cent of the p a t i e n t s o n b e n z a t h i n e a n d 70 p e r cent of the pat i e n t s on s u l f o n a m i d e s w e r e i n the h o s p i t a l or c o n v a l e s c e n t u n i t s of the Medical College of V i r g i n i a H o s p i t a l during" the a c u t e or c o n v a l e s c e n t stages of t h e i r course a n d t h e r e f o r e c a r e f u l l y followed. I t c a n be e l e a r l y seen f r o m Table V that a very large percentage
1ViC CUE E T AL. :
CONTROL OF RHEU1ViATIC R E C U R R E N C E S
had heart disease of a serious nature. Seventy-eight per eent of the sulfonamide group had heart disease as did 85 per cent of the benzathine penicillin group. The benzathine penicillin G group was started in November, 1952, on deep intramuscular injections of 1,200,000 units every twenty-eight days. These patients had initial throat cultures and repeat cultures every three months routinely or at the sign of a respiratory infection. Close eontaet with the patients and their parents was mainrained by an excellent technical assistant so that the attendance rate was remarkably good. Most complained of the injection at first but the slight pain was no serious deterrent and many hardly noticed it. Rare febrile reactions were noted. The patients were seen in rotation, approximately twelve each Wednesday, from November, 1952, through December, 1954. A total of 1,103 injections was given, or an average of twenty-four to each patient in a twenty-six-month study period. The sulfonamide group was divided with thirty-two on sulfadiazine and fourteen on Gantrisin. These drugs were supplied by the Virginia State Rheumatic Fever Program. They were given according to the schedule previously deseribed, with careful observation of leukoeytes and urine in the early weeks. Prophylaxis in these children was often begun prior to November, 1952; hence the longer duration of months on prophylaxis. However, all continued their therapy through the years 1953 and 1954, during the same period as the penicillin group. Throat cultures were also made initially and at three-month intervals, but we were not as sueeessful in getting these more distant patients in for eul-
457
tures at regular intervals. These par tients had a total of 1,776 months on
therapy, or an average of 38.6 months. RESULTS
Benzathine Penicillin G.--Among forty-six patients on benzathine penieillin G there were, in our opinion, no true recurrences of rheumatic fever. During most of the study our laboratory methods failed to distinguish properly the Group A, beta hemolytic streptococci from other groups. We are, therefore, unable to report the influence of the two programs on pharyngem flora. One patient, Case 36, had a severe asthmatic bronchitis with aching knees but no heat or swelling, which subsided in two weeks on increased dosage of penicillin. Her sedimentation rate fell to normal in two to three weeks; no cardiac damage was present before, during, or after this episode. H er antistreptolysin liter did not rise. Two other patients with severe heart disease and failure, Cases 8 and 30, had long-standing carditis which is still smouldering. The first of these is a Negro boy of 13 years who began with rheumatic fever at 6 years of age in 1947. He was seen by us in his second attack in 1951 and was in the hospital for almost a year with subacute bacterial endocarditis, severe rheumatic earditis with mitral valve disease, and cardiac enlargement. In early ]952, he had acute glomerulonephritis and later in the year, evideuces of cardiac failure. Failure has become acute several times during the last two years and in November, 1954, he began to fibrillate, lViitral sienosis has become more pronounced and the electrocardiogram has altered from a left to a marked right strain pattern
458
THE JOURNAL OF PEDIATRICS
in the last six months. H e has been carefully studied for the possibility of a m i t r a l valvulotomy. He did respond to f u r t h e r digitalis, diuretics, and oxygen, and is now a m b u l a t o r y with a cardiothoracic ratio of 73 per cent. Repeated antistreptolysin titers have been ]ess than 50. We do not believe that he has ever been inactive since 1951. The patient in Case 30 is a 15-yearold Negro girl whose disease began in June, 1951. She was in the hospital for six months and given col~isone at t h a t time but developed severe cardiac enlargement a n d mitral valve disease. D u r i n g 1954, she had been hospitalized f o u r times briefly for pneumonia, fibrillation with failure, dental abscesses, with questionable bacterial endocarditis, and p u l m o n a r y edema. Antistreptolysin titers done on each admission were n n d e r 50. We consider that her disease also has been constantly active with severe mechanical defects since 1951. Only one patient (Case 45) had any significant reaction to the drug. She developed an urticarial skin rash with nausea in December, 1953, a f t e r one injection. This was thought b y a dermatologist to be a penicillin reaction. However, it was not severe and the next month another injection was given with oral Benadry] and no reaction occurred. Subsequent injections have caused no difficulty. This child's mother developed acute rheumatic fever early in 1954. Sulfonamides.--A clear-cut recurrence has occurred in two patients (Cases 14 and 15) on sulfadiazine. Both of these consisted of severe recurrent polyarthritis with no heart disease present either before or a f t e r the recurrence. No positive throat eul-
tures were obtained in Case 14 but in Case 15 a positive culture for beta hemolytic streptococcus was reported a few weeks before the recurrence. F o u r questionable recurrences have Occurred, but none of these was observed by us. They are discussed below. P a t i e n t 26 had severe h e a r t disease at an early age and was in the hospital for over two years. Six months a f t e r discharge he had a sudden fever and chest pain lasting twenty-four hours, responding to morphine and penicillin. tits local doctor suggested a flare-up but the story better fits a pneumonic episode, we feel. W h e n seen at the clinic three weeks later, he was at his usual status and no evidence of active rheumatic fever or heart disease could be demonstrated. P a t i e n t 19 had a positive throat culture in F e b r u a r y , 1953, and in March, 1953, her local doctor suggested a possible flare-up. She had previous aortic and mitral valve disease and, at the time of the recurrence, had aching joints but no real swelling or tenderness. The sedimentation rate was not elevated; and since she was not seen in our clinic until some months later, it is not possible to be sure about the possibility of a recurrence here. P a t i e n t 16 had headaches and pain in her thighs, but a negative throat culture in March, 1953. This child again had old severe aortic and mitral valve disease but no elevation of sedimentation rate. She did not follow a n y directions for rest or medications. H e r local physician suspected a recurrence, but when seen later in the clinic none was evident. P a t i e n t 34 was a white girl who had severe rheumatic heart disease beginning at the age of 6 years. She was
MC CUE
ET
AL. :
CONTROL
seen by us at the a g e of 13 a f t e r four previous attacks, and, at the time os admission, was in failure and almost moribund. She remained in the hospital for over a year, receiving cortisone, digitalis, and the best possible care. She was discharged with a cardiothoracic ratio of 69 per cent on J u n e 20, 1953. Until ]ate August, she had done well as an a m b u l a t o r y patient. A ten-pound weight loss in a two-week period was followed by acute nausea, vomiting, and abdominal pain. Sulfadiazine was discontinued. She was admitted to a small hospital in the western p a r t of the State. I t was thought that she had an acute gastroenteritis and so was given intravenous fluids. On September 5, she suddenly died. No f u r t h e r details are known but she was not dyspneic or in obvious failure and had no arthritis. We can only surmise that it was intercurrent infection with severe nausea and vomiting superimposed on an alr e a d y severely damaged heart. This leaves a 4.3 per cent recurrence rate, or two patients in forty-six on sulfadiazine. The last four we do not feel justified in including as true recurrences. DISCUSSION
This series of forty-six cases on int r a m u s c u l a r benzathine penicillin with no recurrence in two years is of some significance when added to those previously reported b y DieM, Stollerman, and P e r r y . 6, 5, 7 The recurrence rate on sulfonamides of 4.3 per cent is close to the 2.9 p e r cent on sulfadiazine and 1.5 per cent on Gantrisin reported in Virginia. 3 Other figures of 2 to 4 per cent recurrences on sulfa are available.S, D
0]~~ R H E U M A T I C
RECURRENCES
459
This is, a marked i m p r o v e m e n t over the 61 p e r cent reeurrenee rate before 1946 in Virginia in an u n t r e a t e d group reported in 1948. 2 While oral penicillin was not studied in this project, its worth has been soundly established if regular dosage is given. 1 The advantages and disadvantages of i n t r a m u s e u l a r benzathine penicillin G given at twenty-eight-day intervals are as follows: Advantages : 1. Advantages of penicillin, ineluding its. bactericidal effect on the beta streptococcus without the emergence of resistant strains so far. 2. Cost of d r u g less t h a n sulfonamides or oral penicillin. 3. Certainty of dosage. 4. Consistent blood levels. 5. Low rate of reaction. 6. Closer general contact between patient and physician or nurse. 7. Patient and his family kept aware of the constant threat of recurrences. Disadvantages : 1. Slight transient pain of injection. 2. Monthly visit to doctor's office necessary. 3. Rare reaction to penicillin. I f clinics for i n t r a m u s c u l a r injection can be established such as have been done with streptomycin f o r tuberculosis, it is conceivable that m a n y thousands of dollars can be saved for large state programs. Rheumatic fever is a socioeconomic problem and must be so recognized. SUMMARY
]. One thousand, one hundred three intramuscular injections of 1,200,000 units of benzathine penicillin to fortysix patients with recent rheumatic fever were given for an average of t w e n t y - f o u r months without a single
460
THE JOURNAL OF PEDIATRICS
recurrence. Two patients with old failure and enlarged hearts continue to s m o u l d e r b u t a r e s t i l l l i v i n g . 2. A s i m i l a r g r o u p of f o r t y - s i x p a t i e n t s on s u l f o n a m i d e s s h o w e d a rec u r r e n c e r a t e of 4.3 p e r c e n t i n a n a v e r a g e p e r i o d o f 38.6 m o n t h s . O n e child in this group died from what we b e l i e v e to h a v e b e e n a n i n t e r c u r r e n t infection and three others had vague aches but no clear-cut recurrences. 3. W h e n a d d e d to t h e p r e v i o u s s t u d i e s , t h e e v i d e n c e is i n c r e a s i n g l y s t r o n g f o r l a r g e - s c a l e u s e of b e n z a t h i n e penicillin G intramuscularly for prev e n t i o n of r h e u m a t i c r e c u r r e n c e s . We arc grateful for the cooperation of the other physicians working with the Virginia State Rheumatic Fever Program; namely, Ors. Louise Galvin, William Spencer, Walter Bandy, Helen Morton, and Pamela Moore. Mrs. Margaret Peple, as technical assistant, has been responsible for the good attendance rate and careful records. Miss Elizabeth Sturt and her nursing staff also assisted greatly. REFERENCES ]. Stollerm~n, G. H. : The Use of Antibiotics for the Prevention of Rheumatic Fever, Am. J'. Med. 17: 757, 1954.
2. McCue, C. M , and Galvin, L. F. : A Preliminary Report on Rheumatic Fever in Virginia, J. P]~DIAT. 33: 467, 1948. 3. Bundy~ W. E., MeCue, C. M., and Porter, R . R . : The Control of Rheumatic Fever Recurrences With Sulfadiazine and Gantrisin, J. PEDIAT. 41: 320, 1952. 4. Elias, W., Price, A. H., and Merrion, tI. J. : N-N'dibenzylethylenedia~nine Penicillin: New Repository Form of Penicillin, Antibiotics & Chemother. 1: 491, ]95]. 5. Sto]lerman, G. H., Rusoff, J. I-I., and Hirschfield, I. : Prophylaxis Against Group A Streptococci in Rheumatic Fever Patients by the Use of Single Monthly Injections of N-N'Dibenzylethylenedlamine Dipenlcillin G (Bicillia), Antibiotics Annual, p. ]14, New York, 1953-1954, Medical Encyclopedia, Inc., p. 114. 6. Dieh], A. M., ttami]~on, T. E., Keeling, I. C., and May, 3-. S.: Long-acting Repository Penicillin in Prophylaxis of Recurrent Rheumatic Fever, J. A. M. A. 155: ]466, 1954. 7. Perry, C. B., and Gillespie, W. A. : Intramuscular Benzathine Penicillin in the Prophylaxis of Streptococcal Infection in Rheumatic Children, Brit. M. J. 2: 729, 1954. 8. ]:Jansen, A. E., Platen, 1%. V., and Dwan, P.F.: Prolonged Use of a Sulfonamide Compound in Prevention of Rheumatic Recrudescences in Children, Am. J. Dis. Child. 6g: 963, ]942. 9. Dodge, K. G., Baldwin, T. S., and Weber, M. W. : The Prophylactic Use of Sulfanflamide in Children With Inactive Rheumarie Fever, J. PEDIAT. 24: 483, 1944.
M.D., COUNT D.
GIBSON,
JR., M.D.,
AND
LILLIAN C. LINDEMANN, M . D . X~IOttMOND, VA.
H E crucial role of the Group A in the causation of rheumatic fever is generally admitted by most authorities. This notion has been supported by the results of antimicrobial t h e r a p y in two types of investigation : (1) reduction of rheumatic fever incidence following mass treatment of streptococcal infections; (2) reduction of rheumatic fever recurrences during continuous prophylaxis in individuals who have already suffered one or more episodes. 1 The I~ichmond Clinic of the Virginia State Rheumatic F e v e r P r o g r a m has been studying the characteristics of rheumatic fever in Virginia since 1940. A preliminary report in 19482 described the nature of our patient population and the diagnostic criteria utilized in classification. A recurrence rate of 61 per cent in a group of 225 cases followed for three years was observed. A second communication in 19522 reported the results of continuous sulfonamide prophylaxis in 190 cases followed for an average of fortyfour months. A recurrence rate of 2.9 per cent was seen during an average period of twenty-four months with sulfadiazine and 1.5 per cent during an average of eleven months with sulfisoxazole (Gantrisin).
Benzathine penicillin* (N-N'dibenzylethylenediamine penicillin) is an ester of penicillin G 4 with a differing pharmaeodynamic action depending on its route of administration. An oral dose of 200,000 to 400,000 units is taken daily for continuous prophylaxis. When 1,200,000 units of the drug is injected intramuscularly, measurable blood levels can be detected up to twenty-eight days subsequently. This remarkably prolonged repository action is presumably due to the slow release of active penicillin from the depot. Reports on the use of benzathine penicillin intramuscularly for prophylaxis against rheumatic recurrence are few at present. The available data are summarized in Table I, including our own results.
T streptococcus
PURPOSE
From the Departments of Pediatrics and Medicine, l~{edieal ColIege of Virginia, and the Richmond Clinic of Virginia State Rheumatic Fever Program.
It is now recognized that any patient who has had acute rheumatic fever should have some type of prophylactic medication for an indefinite period of time. The p r i m a r y purpose of this project was to study recurrences of rheumatie fever as influenced by two drugs. The plan was to observe over a two-year period the influence of monthly intramuscular injections of benzathine penicillin G on rheumatic recurrences. A series of patients on sulfonamides served as controls.
450
*SuDPlied by Wyeth Laboratories, Philadelphia, Pa.
451
/YiC CUE ET AL. : CONTROL OF RHEUMATIC RECURRENCES MATERIAL
F i f t y patients were selected f r o m the convalescent wards and outpatient d e p a r t m e n t of the Richmond Rheumatic F e v e r Clinic in the fall of 1952 for benzathine t h e r a p y . All of this group had recently experienced rheumatic fever and were in the age group and stage of the disease where some type of prophylaxis was d e a r l y indicated. They were of necessity in the hospital or in the area served by Richmond so that visits to the clinic every twenty-eight days for intramuscular injections were feasible. M a n y had such a background that reliable oral dosage was impossible. Seven had a leukopenia on a sulfonamide, requiring TABLE I.
INTRA1VfUSCULAI{BENZATHINE PENICILLIN I:~t{EUIcIATIC I~ECURRENCE NO. OF
I~u163 S t o l l e r m a n , G. H., a n d associates5 DieM, A. IV[., a n d assoelates6 P e r r y , C. B., a n d Gillespie, W. A.7 McCue, C. M., a n d associates Totals
significant difference. Of these, twentyfour were males and twenty-two females with thirty-one white and 15 Negro. Again four cases failed to follow through. While every a t t e m p t was made to s t a r t patients on prophylaxis as soon as possible, m a n y of the benzathinc penicillin group had previously tried other drugs. The most irresponsible of the group were shifted to this program. Other new cases were started on it promptly. The average age when prophylaxis was stm~ed was 1.0.2 years. The mean months since the onset of the last attack were 12. I n the sulfonamide controls, m a n y were started in the late 1940%. The usual procedure was to wait until the
INJECTIONS 2,631
NO. OF PATIENTS 285
AVERAGE I~ PERIOD (lV[O.) ]0
962
96
14
64
22
3
1,103
46
24
4,760
449
its cessation. The ages at onset of prophylaxis, race, sex, and cardiac diagnoses are listed in Table II. There were twenty-two males and twenty-four females, twenty of whom were white and twenty-six Negro. F o u r patients dropped out. F i f t y comparable cases were chosen and maintained on sulfonamide prophylaxis. The same criteria for diagnosis and same general care were given to both groups. As will be noted f r o m Table I I I , p a r t of this group was on sulfadiazine and p a r t on Gantrisin, but it was not felt t h a t this made any
PROPHYLAXIS OF
pATIENT iVs 2,841
RHEUMATIC REGUI~- ALLERGIC R E N C E S REACTIONS 0 7
1,344
0
2
:1
0
1,104
0
1
5,289
1
10
patient was considered inactive before sulfa was begun. Often the initial episode was a long one. The average age at onset of prophylactic t h e r a p y was 11 years with a mean of 9 months since the beginning of the last attack (see Table IV). The criteria f o r diagnosis in the benzathine group and sulfa group were as follows : Benzathine -Penge~;lli~ Cardltis a n d p o l y a r t h r l t i s Carditis alone P o l y a r t h r i t l s alone P o l y a r t h r i t l s a n d chorea Carditis a n d chorea
32 5 6 1 2
Sulfonamides 31 4 8 1 2
452
THE JOURNAL OF PEDIATRICS
TABLE I~. CASE STUDT : BENZATHINE PENICILLIN GROUP AGE PROPHY
MONTHS o
[
SINCE
BICILLIN
LAXIS STARTED
RAGE AND SEX
1
3
WM
13
:YLI.
:12
2
14
NF
24
l~.I.
28
NO.
8
C.E. C.E. Myo. M.I. M.S. C.E. No tt.D. No H.D. C.E. Myo. M.I. M.S. C.E. Failure
SHOTS NO.
3
6
4
]4
NF
24
5 6 7
12 13 4
WM W~[ NF
2 :14 3
8
]1
NM
9
9
15
WF
6
]0 I]
12 7
WM WF
50 12
:12 13 14
16 13 10
WM WF WF
5 :13 8
Myo. No. H.D. M.I.
19 20 28
15
10
NF
15
21
16 17
14 6
WM NF
48 9
18
7
NF
9
M.I. C.E. M.I. M.L M.S. C.E. A.L M.I.
19
10
WM
36
20
9
NF
3
21 22
5 5
NF WF
2 I
23
11
NM
]2
24
12
NM
36
Key : ~.I. M.S. A.I. A.S. C.E.
iq~I
ONSET LAST CARDIAG ATTACK R.F. DIAGNOSIS
~r insufficiency. ]Y[itral stenosis. Aortic insufficiency. Aortic stenosis. Cardiac enlargement.
M.I. C.E. M.S. A.I. M.I. Myo.
M.L C.E. M.I. C.E. C.E. M.I. C.E. M.I. M.S. C.E. Failure M.I.
~r H.D. S.B.E. R.F. I.A.S.D.
REMARKS
Moved to N o r t h Carolina, 3/5~i 2 attacks prior to Bieillin
26 25
2 attacks prior to P,icillin
24 26 21 27
25
26 25
2 attacks p r i o r to Bicillin S.B.E. in 1951 N e p h r i t i s in :1952 Failure in :1952 *Failure in 1954 3 attacks prior to Bicillin
3 attacks prior to Bicillin L e g g - P e r t h e s disease in 1953 A n e m i a in 1953 Sister developed R.F. E n t e r e d Navy, 5/54 Repeated polyarthritis. No u n k n o w n in p a s t 2 attacks p r i o r to Bieillin
23 26
2 attacks p r i o r to Bicillin
25
Sister and cousin died with R.F. 2 attacks prior to Bicillin
26 25 25 20
? Attack, aged 4
28
Severe lung, first attack
23
2 attacks prior to Bicillln Nephrotic stage of glomerulonephritis in 1951-1952 1Yiyocarditis. H e a r t disease. Subacute bacterial endocarditis. l~heumatic fever. I n t e r a t r i a l septal defect.
453
1Y[C CUE ET AL. : CONTROL OF RHEUMATIC RECURRENCES
TABLE I I . - - C o N T 'D AGE
MONTttS
PROPHY-
SINCE
LAXIS
NO. 25
STARTED 10
RACE A N D SEX
WM
ONSET LAST
I
I
BICILLIN CARDIAO
ATTACK R.F. DIAGNOSIS
29
A.l.
SHOTS
NO. 27
RE3s 3 a t t a c k s prior to Bieillin F a i l u r e a n d p e r i c a r d i t i s in 1949-1951
27
2 a t t a c k s prior to Bicillin S.B.E. in 1951
A.S. M.I. M.S.
26
9
NM
16
27
6
WM
3
28 29 30
8 8 13
NF NM NF
3 29 15
C.E. M.I. M.S. C.E. M.I. C.E. A.S. M.I. N o I-I.D. M.I. M.S. A.S. C.E. Failure Fibrillation M.I. M.S. C.E. M.I. M.I. C.E. Myo. M.I. M.S.
23 25 28 27
31
14
NF
13
32 33
15 12
NM NM
40 8
34
13
WF
30
35
11
WM
18
M.I.
16
36 37
4 12
NF NM
8 10
22 21
38 39
12 11
NF NF
6 24
40 41 42
14 9 16
NM WF NM
< 1 6 60
43
11
WF
48
44
12
NF
12
45
6
WF
7
46
6
WM
5
C.E. C.E. M.I. A.I. Pericarditis Failure M.I. M.I. C.E. N o H.D. No tI.D. M.I. M.S. A.I. C.E. C.E. Myo. (Nodules) C.E. M.I. C.E. (Rash) No ]:I.D.
*Case discussed in text u n d e r "Results."
25
*See t e x t Chronic R.It.D. J u n e , 1951
active
since
4 a t t a c k s prior to Bicillin Severe social p r o b l e m s
26 26 23
26 26
W o u l d n o t take oral prophylaxis A n e m i a now Mentally retarded Chronic m a s t o i d i t i s Severe bronchitis, 3 / 5 4 3 a t t a c k s prior to Bicillin with p e r i e a r d i t i s
2 a t t a c k s prior to Bicillln
17 25 27
2 a t t a c k s prior to Bicillin Active disease over 2 y e a r s
23
Active disease 3-plus y e a r s
25 25 19
M o t h e r developed active R.F. in 1954
454
THE J O U R N A L OF PEDIATRICS
TABLE I I I .
RACE AND
lYIONTHS SINCE ONSET LAST ATTACK
SEX WM NF
R.F. 8 5
NO. 1 2
AGE PROPHYLAXIS STARTED 16 14
3
9
I~M
4
4
14
WM
13
5
17
WM
6
6
17
I~F
24
CASE STUDY: SULEONAMIDE GROUP*
CARDIAc DIAGNOSIS
MONTHS RECURDURATION RENCES 0 N THERAPY SULFA
24 40
1VLI. M.S. A.I. A.S. 0.E. 1Yf.I. C.E. Myo. M.I. M.S. O.E. A.L
16
Sulfadiazine Sulfadiazine Sister h a d R.F. in ]944 2 a t t a c k s p r i o r to sulfadiazine Sulfadiazine
46
Gantrisin and sulfadiazine
60
7 a t t a c k s p r i o r to s u l f a diazine
24
Sulfadiazine 2 a t t a c k s p r i o r to s u l f a dlazine
47
Gantrisin
69
Sulfadiazine F i r s t a t t a c k , d u r a t i o n over 2 yr.
55
Gantrisin
23 33 4
Sulfadiazine Gantrisin Sulfadiazine F a t h e r h a d R.F. Sulfadiazine Sulfadiazine
M.I. M.S.
7
19
WM
19
8
12
NF
33
9
8
WM
7
10 ll 12
]6 ]3 4
WM NF WF
5 ]3 7
A.I. C.E. Myo. i.I. A.S. M.I. M.S. C.E. M.I. ~.S. I.A.S.D. Failure M.I. M.S. C.E. Myo. Failure ]Y[.I. M.I. N o tt.D.
13 14
15 10
WF WF
6 8
M.I. N o I-I.D.
7 24
]5
8
WM
6
N o H.D.
30
16
11
NF
12
15
17 18
9 7
WM WM
8 8
A.I. M.I. M.S. C.E. N o H.D. No. tt.D.
]9
15
WF
12
A.I. M.I.
27
20
WM
3
l attack 2/54 1 attack
2/53
Pericarditis ~i.I. *For key to abbreviations, see Table ]I. 14
REMARKS
M.I. M.I.
? Attack 4/53
26 68
24
? Attack 9/53
2 a t t a c k s p r i o r to sulfadiazine Gantrisin 2 a t t a c k s prior to Gantrisin Sulfadiazlne 3 a t t a c k s p r i o r to s u l f a diazine B r o t h e r h a d R.F. 3 a t t a c k s p r i o r to sulfadiazine Chorea 2 a t t a c k s prior to sulfadiazine
MC CUE E T AL. :
CONTROL OF R H E U M A T I C R E C U R R E N C E S
TABLE I I L
455
CONT'D
MONTHS
SINCE ONSET
NO.
AGE PROPhYLAXIS STARTED
RACE AND BEX
21
16
WM
22
13
NF
23
7
24
15
LiST ATTACK I~.F.
CARDIAC DIAGNOSIS
MONTHS DURATION TSERAPY
No H.D.
36
WM
I0
NM
12
1V~.S.
3
25
10
26
8
WM
24
27
7
WF
12
28
11
NM
6
29
9
NF
1
30
12
WM
31
8
WF
32
11
WM
33
12
WM
34
13
WF
IVLI. A.S. A.I. C.E. Niyo. IV[.I. M.S. C~ M.I. M.S. C.E. Failure lV[.I. C.E. M~ M.S~ C.E. Failure M.L A.I. A.S. C.E. A.I. Myo. Failure M.I. M.S.
81
47
3 attacks prior to sulfadiazlae Third attack lasted over 1 yr. Sulfadiazine
3
50
REMARKS
Mother h a d l%.F. Chorea in 3 attacks prior to Gantrisin Chronic otitis media Gantrisin Delivered normal infant, 1953
44
18 A.I. A.S. C.E. No H.D.
NF
RECURRENCES ON SULFA
? Attack
5/51 11
3 attacks prior to Gantrisin Low WBC Discontinued 4 attacks prior to sulfadiazine F o u r t h attack, duration 1 8 9 yr. Gantrisin 5 attacks prior to sulfadiazine Sister listed below, No. 29 4 attacks prior to sulfadlazine Brother listed above, No. 28 Hepatitis, 1953 3 attacks prior to sulfadiazine 5 attacks prior to sulfadiazine Sister had Ir
20 25
83 78
C.E.
35
NF
36
WM
50
Gantrlsin
6
i.I. A.S. M.S. C.E. M.L
38
15
M,I.
8
3 attacks prior to G a n trisin 5 attacks prior to sulfadiazine F i f t h attack, duration 1 yr. L e f t hospital 6/53 Severe failure Acute disease over 2 yr. Sensitive to Gantrisin Sulfadiazine
26 6
C.E. i.I. Failure C.E. M.L Failure No I-I.D.
36 72
Died 9 / 5 / 53 Cause not known
456
THE JOURNAL OF PEDIATRICS TABLE III.
37
11
WF
54
Myo. A.I. Fibrillation C.E. M.I.
38
8
WM
15
NLI. ~.S.
39
13
NF
18
WM
36
WF WF
11 5
NF
28
40
8
41 42
10 10
43
6
44
8
NNI
11
45
10
WF
10
46
14
WM
13
No R.H.D. Patent duc~us ~.I. M.S. C.E. A.I. Failure
CONT'D
63
Sulfadiazine First attack, duration 3 yr.
35
Gantrisin
27
Sulfadiazine Refuses surgery for ductus Pregnancy, 1954 3 attacks prior to sulfadiazine Third attack, duration 2 yr.
69
Gantrisin Sulfadiazine
44
IVLI.
No H.D. M.I. C.E. 2-1 Heart block C.E.
12 60
42
Sulfadiazine First attack lasted over 1
M.L Myo. Pericardit~s M.I. M.S. Myo.
50
3 attacks prior to Gantrisin
30
3 attacks prior to sulfadiazine (2 with modules)
Sulfadiazine
First attack at 21/2 yr. Second attack at 4 yr.
yr.
TABLE
IV.
AGE
AND ]DURATION
OF TI-IZ~APY
I BENZATmNE
Average age prophylaxis started Average months on therapy 1Kean months since onset last rheumatic fever attack
PENICILLIN
G I
10.2 24 12
SULFA
11.0 38.6 9.0
TABLE V. CAI~DIACDIAGNOSES ]
No heart disease Mitral insufficiency alone Cardiac enlargement and/or serious valve damage F ailur e METHODS
L e t t e r s were w r i t t e n to the r e f e r r i n g p h y s i c i a n s of both g r o u p s e x p l a i n i n g the p r o j e c t a n d r e q u e s t i n g t h a t a d d i t i o n a l a n t i b i o t i c s be g i v e n o n l y w h e n s p e c i f i c a l l y i n d i c a t e d a n d t h a t we be notified of t h e i r use.
T h e p a r e n t s of
each child also received letters a n d a g r e e d to cooperate w i t h t h e project. This eliminated four patients from
BENZATIIINE PENICILLIN G
7 10 29 4
I SULFA
10 8 28 8
each g r o u p of fifty, a n d f o r t y - s i x followed t h e d i r e c t i o n s r e a s o n a b l y well. E i g h t y p e r cent of the p a t i e n t s o n b e n z a t h i n e a n d 70 p e r cent of the pat i e n t s on s u l f o n a m i d e s w e r e i n the h o s p i t a l or c o n v a l e s c e n t u n i t s of the Medical College of V i r g i n i a H o s p i t a l during" the a c u t e or c o n v a l e s c e n t stages of t h e i r course a n d t h e r e f o r e c a r e f u l l y followed. I t c a n be e l e a r l y seen f r o m Table V that a very large percentage
1ViC CUE E T AL. :
CONTROL OF RHEU1ViATIC R E C U R R E N C E S
had heart disease of a serious nature. Seventy-eight per eent of the sulfonamide group had heart disease as did 85 per cent of the benzathine penicillin group. The benzathine penicillin G group was started in November, 1952, on deep intramuscular injections of 1,200,000 units every twenty-eight days. These patients had initial throat cultures and repeat cultures every three months routinely or at the sign of a respiratory infection. Close eontaet with the patients and their parents was mainrained by an excellent technical assistant so that the attendance rate was remarkably good. Most complained of the injection at first but the slight pain was no serious deterrent and many hardly noticed it. Rare febrile reactions were noted. The patients were seen in rotation, approximately twelve each Wednesday, from November, 1952, through December, 1954. A total of 1,103 injections was given, or an average of twenty-four to each patient in a twenty-six-month study period. The sulfonamide group was divided with thirty-two on sulfadiazine and fourteen on Gantrisin. These drugs were supplied by the Virginia State Rheumatic Fever Program. They were given according to the schedule previously deseribed, with careful observation of leukoeytes and urine in the early weeks. Prophylaxis in these children was often begun prior to November, 1952; hence the longer duration of months on prophylaxis. However, all continued their therapy through the years 1953 and 1954, during the same period as the penicillin group. Throat cultures were also made initially and at three-month intervals, but we were not as sueeessful in getting these more distant patients in for eul-
457
tures at regular intervals. These par tients had a total of 1,776 months on
therapy, or an average of 38.6 months. RESULTS
Benzathine Penicillin G.--Among forty-six patients on benzathine penieillin G there were, in our opinion, no true recurrences of rheumatic fever. During most of the study our laboratory methods failed to distinguish properly the Group A, beta hemolytic streptococci from other groups. We are, therefore, unable to report the influence of the two programs on pharyngem flora. One patient, Case 36, had a severe asthmatic bronchitis with aching knees but no heat or swelling, which subsided in two weeks on increased dosage of penicillin. Her sedimentation rate fell to normal in two to three weeks; no cardiac damage was present before, during, or after this episode. H er antistreptolysin liter did not rise. Two other patients with severe heart disease and failure, Cases 8 and 30, had long-standing carditis which is still smouldering. The first of these is a Negro boy of 13 years who began with rheumatic fever at 6 years of age in 1947. He was seen by us in his second attack in 1951 and was in the hospital for almost a year with subacute bacterial endocarditis, severe rheumatic earditis with mitral valve disease, and cardiac enlargement. In early ]952, he had acute glomerulonephritis and later in the year, evideuces of cardiac failure. Failure has become acute several times during the last two years and in November, 1954, he began to fibrillate, lViitral sienosis has become more pronounced and the electrocardiogram has altered from a left to a marked right strain pattern
458
THE JOURNAL OF PEDIATRICS
in the last six months. H e has been carefully studied for the possibility of a m i t r a l valvulotomy. He did respond to f u r t h e r digitalis, diuretics, and oxygen, and is now a m b u l a t o r y with a cardiothoracic ratio of 73 per cent. Repeated antistreptolysin titers have been ]ess than 50. We do not believe that he has ever been inactive since 1951. The patient in Case 30 is a 15-yearold Negro girl whose disease began in June, 1951. She was in the hospital for six months and given col~isone at t h a t time but developed severe cardiac enlargement a n d mitral valve disease. D u r i n g 1954, she had been hospitalized f o u r times briefly for pneumonia, fibrillation with failure, dental abscesses, with questionable bacterial endocarditis, and p u l m o n a r y edema. Antistreptolysin titers done on each admission were n n d e r 50. We consider that her disease also has been constantly active with severe mechanical defects since 1951. Only one patient (Case 45) had any significant reaction to the drug. She developed an urticarial skin rash with nausea in December, 1953, a f t e r one injection. This was thought b y a dermatologist to be a penicillin reaction. However, it was not severe and the next month another injection was given with oral Benadry] and no reaction occurred. Subsequent injections have caused no difficulty. This child's mother developed acute rheumatic fever early in 1954. Sulfonamides.--A clear-cut recurrence has occurred in two patients (Cases 14 and 15) on sulfadiazine. Both of these consisted of severe recurrent polyarthritis with no heart disease present either before or a f t e r the recurrence. No positive throat eul-
tures were obtained in Case 14 but in Case 15 a positive culture for beta hemolytic streptococcus was reported a few weeks before the recurrence. F o u r questionable recurrences have Occurred, but none of these was observed by us. They are discussed below. P a t i e n t 26 had severe h e a r t disease at an early age and was in the hospital for over two years. Six months a f t e r discharge he had a sudden fever and chest pain lasting twenty-four hours, responding to morphine and penicillin. tits local doctor suggested a flare-up but the story better fits a pneumonic episode, we feel. W h e n seen at the clinic three weeks later, he was at his usual status and no evidence of active rheumatic fever or heart disease could be demonstrated. P a t i e n t 19 had a positive throat culture in F e b r u a r y , 1953, and in March, 1953, her local doctor suggested a possible flare-up. She had previous aortic and mitral valve disease and, at the time of the recurrence, had aching joints but no real swelling or tenderness. The sedimentation rate was not elevated; and since she was not seen in our clinic until some months later, it is not possible to be sure about the possibility of a recurrence here. P a t i e n t 16 had headaches and pain in her thighs, but a negative throat culture in March, 1953. This child again had old severe aortic and mitral valve disease but no elevation of sedimentation rate. She did not follow a n y directions for rest or medications. H e r local physician suspected a recurrence, but when seen later in the clinic none was evident. P a t i e n t 34 was a white girl who had severe rheumatic heart disease beginning at the age of 6 years. She was
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seen by us at the a g e of 13 a f t e r four previous attacks, and, at the time os admission, was in failure and almost moribund. She remained in the hospital for over a year, receiving cortisone, digitalis, and the best possible care. She was discharged with a cardiothoracic ratio of 69 per cent on J u n e 20, 1953. Until ]ate August, she had done well as an a m b u l a t o r y patient. A ten-pound weight loss in a two-week period was followed by acute nausea, vomiting, and abdominal pain. Sulfadiazine was discontinued. She was admitted to a small hospital in the western p a r t of the State. I t was thought that she had an acute gastroenteritis and so was given intravenous fluids. On September 5, she suddenly died. No f u r t h e r details are known but she was not dyspneic or in obvious failure and had no arthritis. We can only surmise that it was intercurrent infection with severe nausea and vomiting superimposed on an alr e a d y severely damaged heart. This leaves a 4.3 per cent recurrence rate, or two patients in forty-six on sulfadiazine. The last four we do not feel justified in including as true recurrences. DISCUSSION
This series of forty-six cases on int r a m u s c u l a r benzathine penicillin with no recurrence in two years is of some significance when added to those previously reported b y DieM, Stollerman, and P e r r y . 6, 5, 7 The recurrence rate on sulfonamides of 4.3 per cent is close to the 2.9 p e r cent on sulfadiazine and 1.5 per cent on Gantrisin reported in Virginia. 3 Other figures of 2 to 4 per cent recurrences on sulfa are available.S, D
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This is, a marked i m p r o v e m e n t over the 61 p e r cent reeurrenee rate before 1946 in Virginia in an u n t r e a t e d group reported in 1948. 2 While oral penicillin was not studied in this project, its worth has been soundly established if regular dosage is given. 1 The advantages and disadvantages of i n t r a m u s e u l a r benzathine penicillin G given at twenty-eight-day intervals are as follows: Advantages : 1. Advantages of penicillin, ineluding its. bactericidal effect on the beta streptococcus without the emergence of resistant strains so far. 2. Cost of d r u g less t h a n sulfonamides or oral penicillin. 3. Certainty of dosage. 4. Consistent blood levels. 5. Low rate of reaction. 6. Closer general contact between patient and physician or nurse. 7. Patient and his family kept aware of the constant threat of recurrences. Disadvantages : 1. Slight transient pain of injection. 2. Monthly visit to doctor's office necessary. 3. Rare reaction to penicillin. I f clinics for i n t r a m u s c u l a r injection can be established such as have been done with streptomycin f o r tuberculosis, it is conceivable that m a n y thousands of dollars can be saved for large state programs. Rheumatic fever is a socioeconomic problem and must be so recognized. SUMMARY
]. One thousand, one hundred three intramuscular injections of 1,200,000 units of benzathine penicillin to fortysix patients with recent rheumatic fever were given for an average of t w e n t y - f o u r months without a single
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recurrence. Two patients with old failure and enlarged hearts continue to s m o u l d e r b u t a r e s t i l l l i v i n g . 2. A s i m i l a r g r o u p of f o r t y - s i x p a t i e n t s on s u l f o n a m i d e s s h o w e d a rec u r r e n c e r a t e of 4.3 p e r c e n t i n a n a v e r a g e p e r i o d o f 38.6 m o n t h s . O n e child in this group died from what we b e l i e v e to h a v e b e e n a n i n t e r c u r r e n t infection and three others had vague aches but no clear-cut recurrences. 3. W h e n a d d e d to t h e p r e v i o u s s t u d i e s , t h e e v i d e n c e is i n c r e a s i n g l y s t r o n g f o r l a r g e - s c a l e u s e of b e n z a t h i n e penicillin G intramuscularly for prev e n t i o n of r h e u m a t i c r e c u r r e n c e s . We arc grateful for the cooperation of the other physicians working with the Virginia State Rheumatic Fever Program; namely, Ors. Louise Galvin, William Spencer, Walter Bandy, Helen Morton, and Pamela Moore. Mrs. Margaret Peple, as technical assistant, has been responsible for the good attendance rate and careful records. Miss Elizabeth Sturt and her nursing staff also assisted greatly. REFERENCES ]. Stollerm~n, G. H. : The Use of Antibiotics for the Prevention of Rheumatic Fever, Am. J'. Med. 17: 757, 1954.
2. McCue, C. M , and Galvin, L. F. : A Preliminary Report on Rheumatic Fever in Virginia, J. P]~DIAT. 33: 467, 1948. 3. Bundy~ W. E., MeCue, C. M., and Porter, R . R . : The Control of Rheumatic Fever Recurrences With Sulfadiazine and Gantrisin, J. PEDIAT. 41: 320, 1952. 4. Elias, W., Price, A. H., and Merrion, tI. J. : N-N'dibenzylethylenedia~nine Penicillin: New Repository Form of Penicillin, Antibiotics & Chemother. 1: 491, ]95]. 5. Sto]lerman, G. H., Rusoff, J. I-I., and Hirschfield, I. : Prophylaxis Against Group A Streptococci in Rheumatic Fever Patients by the Use of Single Monthly Injections of N-N'Dibenzylethylenedlamine Dipenlcillin G (Bicillia), Antibiotics Annual, p. ]14, New York, 1953-1954, Medical Encyclopedia, Inc., p. 114. 6. Dieh], A. M., ttami]~on, T. E., Keeling, I. C., and May, 3-. S.: Long-acting Repository Penicillin in Prophylaxis of Recurrent Rheumatic Fever, J. A. M. A. 155: ]466, 1954. 7. Perry, C. B., and Gillespie, W. A. : Intramuscular Benzathine Penicillin in the Prophylaxis of Streptococcal Infection in Rheumatic Children, Brit. M. J. 2: 729, 1954. 8. ]:Jansen, A. E., Platen, 1%. V., and Dwan, P.F.: Prolonged Use of a Sulfonamide Compound in Prevention of Rheumatic Recrudescences in Children, Am. J. Dis. Child. 6g: 963, ]942. 9. Dodge, K. G., Baldwin, T. S., and Weber, M. W. : The Prophylactic Use of Sulfanflamide in Children With Inactive Rheumarie Fever, J. PEDIAT. 24: 483, 1944.