Open Journal of Pediatrics, 2011, 1, 27-29
doi:10.4236/ojped.2011.13007 Published Online September 2011 ( OJPed
Published Online September 2011 in SciR es.
Antimicrobial therapy using sulfamethoxazole trimethoprim
for Kawasaki disease patients unresponsive to intravenous
Satoru Nagata1,2, Yu ichiro Yamashiro2, Makoto Fujimori3, Yukihide Chiba3, Yoshikaz u Ohtsuka3,
Toshiaki Shimizu3
1Departments of Pediatrics and Neonatology, Shizuoka Hospital, Juntendo University School of Medicine, Shizuoka, Japan;
2Division of Laboratory for Probiotics Research, Juntendo University Postgraduate School, Tokyo, Japan;
3Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan.
Received 22 May 2011; revised 27 June 2011; accepted 23 August 2011.
Our previous study suggested that the production of
superantigens and heat-shock protein 60 by small
intestinal bacteria might play a role in Kawasaki
disease (KD). We demonstrated that they were all re-
sistant to commonly used antibiotics, except for sul-
famethoxazole trimethoprim (SMX-TMP). We used
SMX-TMP for 7 cases of KD that were unresponsive
to intravenous immunoglobulin (IVIG) and studied
the antipyretic potency of this treatment. In 6 out of
the 7 cases, we demonstrated that antipyretic potency
was observed without side effects within 2 days of the
initial administration. Antimicrobial therapy using
SMX-TMP might represent a novel strategy for cases
of KD that are unresponsive to IVIG.
Keywords: Antimicrobial Therapy; Intravenous Immu-
noglobulin Resistance; Kawasaki Disease; Sulfameth-
oxazole Trimethoprim
Immunoglobulin is helpful during the acute phase of
Kawasaki disease (KD), but there is an approximate 5%
failure rate, and close to a 30% adverse effect rate. In
addition, immun oglobu lin is exp ensive, at app roximately
$100 per gram [1]. Antibiotic treatments targeting the
causative bacteria may be a more effective and eco-
nomical treatment for KD if the detailed pathogenic
mechanism of the disease can be elucidated. In our pre-
vious study, we found some particular Gram-negative
microbes producing heat-shock protein 60 and several
Gram-positive cocci having superantigen ic properties on
the surface of the gastrointestinal tract which mig ht play
a role in the onset of Kawasaki disease (KD) [2]. We
performed antibiotic sensitivity testing on these strains,
considering them to be the cause of this disease if they
participated in the onset, and found that they were all
resistant to all of the commonly used antibiotics except
for sulfamethoxazole trimethoprim (SMX-TMP). In this
study, we used SMX-TMP for 7 cases of KD that were
unresponsive to intravenous immunoglobulin (IVIG) and
studied the antipyretic po tency of this treatment.
We identified seven patients with intractable IVIG-re-
fractory KD at Juntendo University and its two branch
hospitals between January 2008 and February 2009 who
were treated with 2 courses of IVIG at a dose of 2 g/kg
given over 24 hours and 1 course of pulsed intravenous
methylprednisolone (IVP: methylprednisolone intrave-
nously at a dose of 30 mg/kg/day given up to a maxi-
mum 1000 mg/day) therapy. This trial was approved by
the Juntendo University Review Board.
The demographic characteristics of the 7 patients de-
scribed in this report are summarized in Ta b le 1. All of
the cases had received primary IVIG therapy but ex-
perienced no decline of fever within 24 hours from the
end of the infusion, and were therefore defined as unre-
sponsive cases. Three of the cases had received addi-
tional IVIG therapy, and 4 had received IVP therapy.
However, in all of the cases, the patients did not respond
to the secondary therapy and did not experience any de-
crease in their fever within 24 hours after treatment, and
therefore, underwent tertiary therapy.
For the tertiary therapy, IVP was selected for the pa-
tients who had consecutively received IVIG therapy
twice, and IVIG was selected for the patients who had
received IVP therapy during the second round of treat-
ment. However, because all 7 cases were resistant to
S. Nagata et al. / Open Journal of Pediatrics, 2011, 1, 27-29
Table 1. Demographic characteristics of the patients with Ka-
wasaki disease.
Case Age Sex 1st 2nd 3rd
of the 1st
PSL used
1 5 m M IVIG IVP IVIG 5 2 mg/kg/d
2 10 m M IVIG IVP IVIG 5 1 mg/kg/d
3 2 y 4 m M IVIG IVP IVIG 5 2 mg/kg/d
4 4 y 6 m M IVIG IVIG IVP 4 1 mg/kg/d
5 5 y 3 m M IVIG IVIG IVP 5 1 mg/kg/d
6 10 m F IVIG IVIG IVP 7 2 mg/kg/d
7 2 y 3 m F IVIG IVP IVIG 5 1 mg/kg/d
SMX-TMP: sulfamethoxazole trimethoprim; IVIG; intravenous immuno-
globulin; IVP: pulsed in traveno us methylpre dnisolone; PSL: pr ednisolone.
these therapies as well, and no decrease in fever was
observed for 24 hours or more, one of the authors (SN)
was consulted, and upon receiving authorization from
the families of the patients, the use of SMX-TMP was
At the time of the co nsult, 5 of the 7 cases already had
coronary artery aneurysms, and in 1 case that had been
diagnosed and treated late, giant aneurysms had formed.
In blood tests of the patients performed immediately be-
fore starting SMX-TMP administration, the C reactive
protein (CRP) values were 6.9 to 16.4 mg/dl (mean: 11.8).
In all cases, SMX-TMP was orally administered 2 times
per day at a dose of 0.04 g/kg/time, which is the general
dose for infants, for 5 consecutive days. For concomitant
treatment, aspirin was administered 3 times per day at 10
mg/kg/time, and prednisolone was administered orally at
1 - 2 mg/kg/ day as supp ort i ve therapy fo r IVP.
After SMX-TMP administration, a decline in fever
was observed w ithin 2 days (mean: 1.5 days) in 6 out of
the 7 cases (Ta bl e 2 ). In the case that had formed giant
aneurysms, a decrease in the fever was observed after 8
days. In the blood tests of the patients taken 1 week after
SMX-TMP administration, the CRP values were 4.7 to
17.2 mg/dL (mean: 8.3). At 2 weeks after SMX-TMP
administration, the coronary lesions had undergone ei-
ther minimal growth or had regressed, with the excep-
tion of the 1 case that had formed giant aneurysms. In
this case, an enlargement of the aneurysms was observed.
In all of the cases, no side effects that were believed to
have been caused by SMX-TMP were observed during
the course of treatment or follow-up.
It is often considered common knowledge that antimicr-
obial agents are ineffective for KD [3]. In 6 of the 7 ca se s
described in this study, the KD was unresponsive to
IVIG, but there was a decrease in fever within 2 days of
starting SMX-TMP administration. Because concomitant
Table 2. Clinical characteristics of the patients with Kawasaki
Duration of fever
(days) CRP value
(mg/dl) Maximum cor onary
artery z-scores*
Case Until
TMP use
TMP use
TMP use
1 week
TMP use
TMP use
TMP use
111 1 6.9 4.7 15.7 11.2
212 2 12.1 8.2 14.6 6.0
311 2 10.6 6.1 12.6 0.8
411 1 12.3 6.8 7.0 3.5
510 1 13.2 7.3 6.5 3.1
619 8 16.4 17.2 21.0 28.0
712 2 11.3 7.8 12.7 4.8
SMX-TMP: sulfamethoxazole trimethoprim; CRP: C reactive protein; *:
maximum coronary artery z score was defined as the larger of the proximal
left anterior descending coronary artery and the proximal right coronary
artery z score s adjusted by body surface area [4].
drugs were used only for supportive therapy, these re-
sults suggest that the declines in fever were induced by
the SMX-TMP. In addition to the decrease in fever, the
CRP values also decreased, and the progression of coro-
nary aneurysms also appeared to have been suppressed.
The high efficacy of SMX-TMP w as probab ly due to the
fact that several types of pathogenic bacteria that were
hypothesized to have triggered the onset of KD were
sensitive to SMX-TMP. The case that had formed giant
aneurysms required 8 days for the fever to subside after
initiating SMX-TMP treatment, so it is difficult to con-
clude whether the SMX-TMP treatment was effective for
that patient. In this case, it is possible that the pathogens
were not sensitive to SMX-TMP, or that the window for
administration had been missed.
SMX-TMP is used throughout the world, particularly
for the purpose of preventing infections in hypoimmune
infants undergoing chemotherapy [5-6]. In the 7 cases
described in this study, no side effects were observed,
although adverse effects associated with SMX-TMP on
the hematopoietic system, etc. are not rare, and the
safety of the agen t for young infants has not been estab-
lished [7]. Therefore, there remain a number of problems
to be resolved in terms of safety in o rder for SMX-TMP
to be frequently used for treating KD, which often in-
volves infant patients. Moreover, if SMX-TMP is used
frequently, th is raises the problem of the development of
resistance by the pathogenic bacteria. Therefore, as a
method for treating cases that are unresponsive to IVIG,
SMX-TMP may only provide a temporary solution. How-
ever, it is an undeniable fact that there are cases of KD
that are resistant to IVIG and IVP [8-10], and the dis-
covery of an effective antimicrobial therapy is believed
to be a significant step toward reducing the number of
cases of myocardial infarction caused by KD.
opyright © 2011 SciRes. OJPed
S. Nagata et al. / Open Journal of Pediatrics, 2011, 1, 27-29
Copyright © 2011 SciRes.
Although our results are promising, this study does
not go beyond the realm of case reports, and in order to
determine which antimicrobial agents are effective for
cases of KD that are unresponsive to IVIG, further evi-
dence from randomized control trials will be needed.
We would like to express our sincere appreciation to Dr. Shun Saito
and Dr. Riek o Nagaoka for their valuable cooperation in the trial.
[1] Klassen, P., Rowe P.C. and Gafni, A. (1993) Economic
evaluation of intravenous immune globulin therapy for
Kawasaki disease. Journal of Pediatrics, 122, 532-542.
[2] Nagata, S., Yamashiro, Y., Ohtsuka, Y., Shimizu, T., Sa-
kurai, Y., Misawa, S. and Ito, T. (2009) Heat shock pro-
teins and superantigenic properties of bacteria from the
gastrointestinal tract of patients with Kawasaki disease.
Immunology, 128, 511-520.
[3] Kato, H., Koike, S. and Yokoyama, T. (1979) Kawasaki
disease: Effect of treatment on coronary artery involve-
ment. Pediatrics, 63, 175-179.
[4] McCrindle, B.W., Li, J. S., Minich, L.L., Cola n, S.D., Atz,
A.M., Takahashi, M., Vetter, V.L., Gersony, W.M., Mit-
chell, P.D. and Newburger, J.W. (2007) Coronary artery
involvement in children with Kawasaki disease: Risk fac-
tors from analysis of serial normalized measurements.
Circulation, 116, 174-179.
[5] Rungoe, C., Malchau, E.L., Larsen, L.N. and Schroeder,
H. (2010) Infections during induction therapy for chil-
dren with acute lymphoblastic leukemia. The role of sul-
famethoxazole -trimethopri m (SMX-TMP) prophy laxis. Pe-
diatric Blood & Cancer, 55, 304-308.
[6] Lindemulder, S. and Albano, E. (2007) Successful inter-
mittent prophylaxis with trimethoprim/sulfamethoxazole
2 days per week for Pneumocystis carinii (jiroveci)
pneumonia in pediatric oncology patients. Pediatrics,
120, e47-e51. doi:10.1542/peds.2006-1360
[7] Asmar, B.I., Maqbool, S. and Dajani, A.S. (1981) Hema-
tologic abnormalities after oral trimethoprim-sulfameth-
oxazole therapy in children. American Journal of Dis-
eases of Children, 135, 1100-1103.
[8] Sleeper, L.A., Minich, L.L., McCrindle, B.M., Li, J.S.,
Mason, W., Colan, S.D., Atz, A.M., Printz, B.F., Baker,
A., Vetter, V.L. and Newburger, J.W. (2011) Evaluation of
Kawasaki disease risk-scoring systems for intravenous
immunoglobulin resistance. Journal of Pediatrics, 158,
831-835. doi:10.1016/j.jpeds.2010.10.031
[9] Shah, I. and Prabhu, S.S. (2009) Response of refractory
Kawasaki disease to intravenous methylprednisolone. An-
nals of Tropical Paediatrics, 29, 51-53.
[10] Rowley, A.H. and Shulman, S.T. (2010) Pathogenesis
and management of Kawasaki disease. Expert Review of
Anti-Infective Therapy, 8, 197-203.