Published online May 22, 2006
PEDIATRICS Vol. 117 No. 6 June 2006, pp. e1193-e1196 (doi:10.1542/peds.2005-2251)
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Salmonella enterica Serotype Choleraesuis Infections in Pediatric Patients

Cheng-Hsun Chiu, MD, PhDa, Chih-Hsien Chuang, MDa, Shun Chiu, MDa, Lin-Hui Su, MSb and Tzou-Yien Lin, MDa

a Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Children's Hospital and Chang Gung University, Taoyuan, Taiwan
b Department of Clinical Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan


   ABSTRACT
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OBJECTIVE. Among >2500 nontyphoid Salmonella serotypes, Salmonella enterica serotype Choleraesuis shows a high predilection to cause systemic infections in humans. The objective of this study was to delineate the clinical and microbiologic features of pediatric patients with Salmonella Choleraesuis infections.

METHODS. Between May 1999 and February 2003, a total of 33 patients who were <18 years of age had culture-confirmed S Choleraesuis infections. Clinical features, laboratory values, treatment, outcome, and antimicrobial susceptibility patterns of the bacterial isolates were analyzed.

RESULTS. There were 24 males and 9 females with a mean age of 3 years. Fever (rectal temperature ≥38°C; 94%) was the most common clinical presentation. Sixteen (52%) had fever lasting >5 days before admission. Only 18 (54%) patients had diarrhea. The most common mode of infection is occult bacteremia without focal infection. Compared with data obtained from adult patients, the gastrointestinal manifestations appeared more frequently seen in pediatric patients. However, among the 18 who presented with diarrhea, 14 had concomitant bloodstream infection. Only 1 patient, who was a case of acute leukemia, died of S Choleraesuis sepsis. Resistance to ceftriaxone, ciprofloxacin, ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol was found in 6%, 28%, 88%, 76%, and 83% of the isolates, respectively.

CONCLUSION. Children with S Choleraesuis infections usually presented with occult bacteremia with mild gastrointestinal involvement. The mortality of S Choleraesuis infections in previously healthy children is low. Ciprofloxacin resistance among S Choleraesuis isolates from pediatric patients was lower than that of isolates from adult patients. In view of the high rate of multidrug resistance, third-generation cephalosporins seem to be the drug of choice for treatment of invasive S Choleraesuis infections.

Key Words: Salmonella enterica serotype Choleraesuis • bacteremia • antimicrobial resistance

Salmonella infection can cause 3 distinct clinical syndromes, including acute gastroenteritis, enteric fever, and bacteremia with or without focal extraintestinal infection.1 The most common manifestation of nontyphoid Salmonella infection is self-limited gastroenteritis.1 Among >2500 nontyphoid Salmonella serotypes, Salmonella enterica serotype Choleraesuis is one with a narrow host range. The most common host is swine; however, when it infects humans, it tends to cause invasive infections. For example, in the United States, 63% of the Salmonella Choleraesuis isolates, in contrast to only 6% of total nontyphoid Salmonella, were derived from blood of the patients.2 In England and Wales, between 1981 and 1990, the ratio of bloodstream isolates to total isolates of S Choleraesuis was 74.1%.3

Antimicrobial therapy, therefore, is essential in the treatment of S Choleraesuis infections. The emergence of resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, and, notably, fluoroquinolone and third-generation cephalosporins in S Choleraesuis has aroused concern on the use of these agents for the treatment of systemic infections caused by this organism.4,5

To the best of our knowledge, there has been a lack of comprehensive study about the clinical manifestation, treatment, and outcome of S Choleraesuis infections in children. We, thus, conducted this study to delineate the clinical and microbiologic features of pediatric S Choleraesuis infections in Taiwan.


   METHODS
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 METHODS
RESULTS
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Patients enrolled in this study were children <18 years of age who were treated in Chang Gung Children's Hospital from May 1999 to February 2003 with positive culture for S Choleraesuis. The case definition was a patient with positive culture of S Choleraesuis isolated from blood, urine, stool, wound, or tissue during hospitalization. We identified 33 pediatric patients from whom 34 isolates were recovered. The medical charts of these 33 cases were retrospectively reviewed for demographic data, laboratory data, underlying disease, clinical manifestation, prior use of antibiotics, and antibiotic susceptibility. Mortality because of S Choleraesuis infection was defined as death occurring within 7 days of the onset of infection episode.

Salmonella was first identified by standard biochemical procedures.6 The serogroup was checked with O antisera by the slide agglutination method (Difco Laboratories, Detroit, MI). The antimicrobial susceptibility of these isolates was investigated by using a standard disk diffusion method.7 The antibiotics tested included ampicillin, ciprofloxacin, ceftriaxone, trimethoprim-sulfamethoxazole, and chloramphenicol. The interpretive standard for these antibiotics follows those recommended by the National Committee for Clinical Laboratory Standards.7 Isolates in the "intermediate" category were considered as resistant in this study.

The {chi}2 test and Fisher's exact test were used to determine the significance of differences. A difference was considered statistically significant with a P < 0.05.


   RESULTS
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 METHODS
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DISCUSSION
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There were 24 males and 9 females. Age ranged from 3 months to 16 years with a mean of 3 years. Figure 1 shows the age distribution of the patients. Twenty-four (72%) of the 33 patients were <3 years of age. The sites of isolation of S Choleraesuis are listed in Table 1. Eighty-five percent of the isolates were recovered from nonfecal specimens. We compared data obtained from pediatric patients with those from adult patients treated at Chang Gung Memorial Hospital.8 The adult data for comparison were collected over the same time period as the pediatric data reported in the present article. It seems that more adult patients with S Choleraesuis infection had extraintestinal involvement, and, in contrast, more pediatric patients presented with intestinal infections (Table 1). Nevertheless, nearly 80% of the patients in both groups had bacteremia (Table 1). Focal infections were observed in 3 pediatric patients: 1 leukemic patient had pyogenic spondylitis and splenic microabscess, 1 had subdural empyema, and 1 had a wound infection. Six pediatric cases in this series had underlying medical conditions, including 3 with malignancy, 1 with Wiskott-Aldrich syndrome, 1 with cerebral palsy with tracheostomy, and 1 with gastroesophageal reflux, according to the records in the medical charts.


Figure 1
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  		FIGURE 1 Age distribution of 33 pediatric patients with S Choleraesuis infections.

 

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  		TABLE 1 Sites of Isolation of S Choleraesuis From Pediatric Patients and Comparison With Isolates From Adult Patients

 
Detailed clinical symptoms and signs on admission are shown in Table 2. Fever (rectal temperature ≥38°C; 94%) was the most common, followed by diarrhea (54%), abdominal pain (21%), and nausea/vomiting (12%). Among the 31 patients with fever, 16 (52%) had fever lasting >5 days before admission. Compared with data from adult patients, the gastrointestinal manifestations appeared more frequently seen in pediatric patients. However, among the 18 patients who presented with diarrhea, 13 had their blood culture positive for S Choleraesuis. Only 5 patients had enterocolitis caused by S Choleraesuis without bloodstream infection. Twelve patients presented with occult bacteremia; they usually came to the hospital because of fever with or without mild gastrointestinal symptoms. None of the pediatric patients presented with mycotic aneurysm, the most feared endovascular complication of S Choleraesuis infection in humans. Among the 33 patients, 21% (7 patients) had their leukocyte count >15000/µL, and 6% (2 patients) were <5000/µL; 52% (17 patients) had serum CRP >50 mg/L.


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  		TABLE 2 Clinical Manifestations of 33 Pediatric Patients With S Choleraesuis Infections and Comparison With Those of Adult Patients

 
Ninety-four percent of the isolates were sensitive to ceftriaxone. Resistance to ciprofloxacin, ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol was found in 28%, 88%, 76%, and 83% of the isolates, respectively. In comparison, among isolates derived from adult patients during the same period, the rate of ciprofloxacin resistance was >60%.4,8 Resistance of adult isolates to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol was 85%, 81%, and 96%, respectively.8

One death among these patients occurred during the study period. This was a case of acute lymphoblastic leukemia, which was complicated with sepsis, pyogenic spondylitis, and splenic abscess caused by S Choleraesuis after chemotherapy. All of the patients received antimicrobial therapy. Two, who had unexpected, occult bacteremia, received only oral antibiotics (cefixime) for 10 days. Others were admitted and received ceftriaxone for ~7 days, followed by oral antibiotics for 3–5 days. All except 1 recovered fully without relapse.


   DISCUSSION
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S Choleraesuis is the swine-adapted serotype of Salmonella that causes swine paratyphoid but may be isolated from other animals, including humans. Although S Choleraesuis is an infrequent serotype to cause human infections in many countries, this highly invasive serotype is of particular concern in Taiwan. After S Typhimurium and S Enteritidis, it is the third most common serotype that caused nontyphoid salmonellosis in Taiwan.8,9 In this study, we found that 85% of the S Choleraesuis isolates were recovered from extraintestinal sources. There are some differences between pediatric and adult cases of S Choleraesuis infections. First, most of the pediatric patients had no preexisting underlying diseases. Only 16% of the patients in this series had underlying medical conditions. Among these diseases, there are malignancy, Wiskott-Aldrich syndrome, and gastroesophageal reflux. These underlying diseases, which impaired cellular immune mechanisms or caused rapid gastric emptying, have been regarded as predisposing factors for Salmonella infections.1 This study also demonstrated that most (72%) of the pediatric patients were <3 years old. This is consistent with earlier reports,1,10 showing that nontyphoid salmonellosis usually occurred in young children. Second, various types of extraintestinal localized infections were more common in adult patients. Of particular concern is mycotic aneurysm, the most feared complication of Salmonella bacteremia that usually occurred in adults.11–13 In contrast, more than half of the pediatric patients presented with diarrhea to our hospital before admission. Most of these patients had concomitant bacteremia. Salmonella has been reported as one of the bacterial organisms to cause occult bacteremia in young children.10,14 All of the bacteremic patients in this series had persistent fever for several days. All were well treated with antibiotics without complications. One patient did not receive any antibiotic until the blood culture came back positive for S Choleraesuis. Before the antibiotic was given, a repeat blood culture was taken and, again, grew S Choleraesuis, indicating that this was not a case of transient bacteremia. Occult bacteremia caused by Salmonella is different from that by Streptococcus pneumoniae. Although focal infection is uncommon, occult bacteremia caused by S Choleraesuis seemed to produce more fever, and antibiotic therapy is, therefore, necessary for the treatment.

Laboratory findings of patients with S Choleraesuis infection are not different from those of patients with bacteremia caused by other serotypes of Salmonella. The most important diagnostic method is blood culture, because most of the pediatric cases presented with unexpected, occult bacteremia, which would not be detected without blood cultures. The mortality of S Choleraesuis infection in children is low. In this series, although majority of the patients had bacteremia, only 1 patient, who was a case of acute leukemia, died of S Choleraesuis sepsis.

The majority of the isolates were resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole and about one fourth of the isolates was resistant to ciprofloxacin in this study. The third-generation cephalosporins remained active against this serotype. The emergence of fluoroquinolone resistance in S Choleraesuis was first reported in Taiwan in 2000.4,15 It seems that the rate of ciprofloxacin resistance among S Choleraesuis isolates from pediatric patients was lower than that of isolates from adult patients.8 Most of the S Choleraesuis isolates from humans and swine exhibited the same or similar DNA fingerprints, indicating that human infections were acquired from pigs.4 A possible explanation for the discrepancy in resistance is that, by 2004, there have been no fluoroquinolones approved for use in children under the age of 16 because of the potential damage to growing cartilage. There has been less selective pressure for ciprofloxacin resistance in the hospital setting before that time. In view of the high rate of multidrug resistance, the third-generation cephalosporins seem to be the drug of choice for treatment of invasive infections caused by this organism in both pediatric and adult patients.


   ACKNOWLEDGMENTS
 
This study was in part supported by grant NSC94-2321-B-182A-003 from National Science Council, Executive Yuen, Taiwan. This retrospective study was approved by the Committee of Medical Education, Chang Gung Memorial Hospital, Taiwan.

We are grateful to Prof Jonathan T. Ou, who unfortunately passed away on June 7, 2005, for his advice in the preparation of this article.


   FOOTNOTES
 
Accepted Dec 14, 2005.

Address correspondence to Cheng-Hsun Chiu, MD, PhD, Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Children's Hospital, 5 Fu-Hsin St, Kweishan 333, Taoyuan, Taiwan. E-mail: chchiu{at}adm.cgmh.org.tw

The authors have indicated they have no financial relationships relevant to this article to disclose.


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  7. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard. 7th ed. M2-A7. Villanova, PA: NCCLS; 2000
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics




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