Antimicrobial therapy using sulfamethoxazole trimethoprim for Kawasaki disease patients unresponsive to intravenous immunoglobulin

doi:10.4236/ojped.2011.13007

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Open Journal of Pediatrics, 2011, 1, 27-29

doi:10.4236/ojped.2011.13007 Published Online September 2011 (http://www.SciRP.org/journal/ojped/ OJPed

Published Online September 2011 in SciR es. http://www.scirp.org/journal/OJPed

Antimicrobial therapy using sulfamethoxazole trimethoprim

for Kawasaki disease patients unresponsive to intravenous

immunoglobulin

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.

Email: [email protected]

Received 22 May 2011; revised 27 June 2011; accepted 23 August 2011.

ABSTRACT

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

1. INTRODUCTION

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.

2. CASE SERIES

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.

Treatment

Case Age Sex 1st 2nd 3rd

Hospital

day

of the 1st

treatment

PSL used

concomitantly

with

SMX-TMP

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

attempted.

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.

3. DISCUSSION

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

disease.

Duration of fever

(days) CRP value

(mg/dl) Maximum cor onary

artery z-scores*

Case Until

SMX-

TMP use

After

SMX-

TMP use

Before

SMX-

TMP use

1 week

after

SMX-

TMP use

Before

SMX-

TMP use

1month

after

SMX-

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.

S. Nagata et al. / Open Journal of Pediatrics, 2011, 1, 27-29

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.

OJPed

4. ACKNOWLEDGEMENTS

We would like to express our sincere appreciation to Dr. Shun Saito

and Dr. Riek o Nagaoka for their valuable cooperation in the trial.

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