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Keywords:

  • Antimicrobial therapy;
  • children;
  • complication;
  • enteric infection;
  • nontyphoidal Salmonella

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References

Clin Microbiol Infect 2011; 17: 300–305

Abstract

Increasing antimicrobial resistance in nontyphoidal Salmonella (NTS) species complicates the use of antibiotics if indicated. We investigated the impact of antimicrobial resistance on clinical outcomes and discussed how to use antibiotics rationally. Hospitalized children in 2005–2006 with stool cultures positive for NTS were identified. The clinical and microbiological features were retrospectively reviewed. A total of 683 children were included [371 (54.3%) male; 89.5% <5 years of age]. Antibiotics were given to 56.5% of the patients; third-generation cephalosporin was the most commonly used drug class. Cases receiving antibiotics that were inactive in vitro did not have more complications than those receiving antibiotics active in vitro. Complications occurred in 7.9% of the patients, with bacteraemia being the most common (57.4%). Compared to the others, patients with longer febrile duration and higher C-reactive protein (CRP) levels (CRP ≥100 mg/L) were more frequently put on empirical antimicrobial therapy and had more complications. These patients usually had shorter hospitalization and duration of fever if antimicrobial agents that can reach high tissue concentrations in the intestinal mucosa were administered, such as fluoroquinolone or ceftriaxone. It is concluded that adequate antibiotics may be clinically beneficial to a subset of patients with high CRP and longer duration of fever among children with NTS enteritis. To prevent the induction of antibiotic resistance from this therapy, we suggested a short course (3–5 days) of intravenous ceftriaxone for such patients, which would lead to a faster clinical recovery.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References

Nontyphoidal Salmonella (NTS) infection is still a serious threat to global public health [1–4]. Most NTS infections result in mild-to-moderate enteritis, although systemic infections, including bacteraemia and meningitis, may occur, especially in infants and immunocompromised hosts [5,6]. Antimicrobial therapy is not recommended for routine treatment of nontyphoidal salmonellosis [7,8]; however, effective antibiotic treatment is essential if NTS infection spreads beyond the intestine or if NTS enteritis occurs in patients with low immunity (e.g. infants younger than 3 months of age and patients with immunosuppressive illnesses) [9]. Antimicrobial therapy may also be considered in severely ill immunocompetent adult patients, such as those with severe diarrhoea (more than nine or 10 stools per day), high fever, or those needing hospital admission [10].

Ampicillin, chloramphenicol and trimethoprim-sulphamethoxazole were the drugs of choice in the treatment of invasive salmonellosis before the 1980s but, during the past two decades, resistance to these agents has increased in many areas of the world [11–13]. Expanded-spectrum cephalosporins and fluoroquinolones are recommended as alternatives in such a setting because of their favourable pharmacokinetic properties and low prevalence of resistance [13–16]. However, increasing numbers of cases of ciprofloxacin- or ceftriaxone-resistant Salmonella have been reported subsequent to the 1990s [13,17].

Despite the increasing incidence of antimicrobial-resistant NTS infections, little is known about the impact of antibiotic resistance on patient outcome. In the present study, we analyzed the clinical and microbiological features of hospitalized children with nontyphoidal salmonellosis. We used the data to reassess indications for parenteral antimicrobial therapy in immunocompetent children with NTS enteric infection.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References

From January 2005 to December 2006, hospitalized patients aged younger than 18 years of age with stool culture positive for NTS were identified from the records of the clinical microbiology laboratory at Chang Gung Children’s Hospital. Demographic features, clinical manifestations, laboratory findings, microbiological results, antimicrobial susceptibility, treatment regimens and clinical outcomes were retrospectively reviewed and analyzed.

All decisions regarding antibiotic therapy were made by the attending physicians who took care of the patients. The initial antibiotic regimen was administered after blood and stool cultures had been taken. Definitive antimicrobial therapy was then given after culture results were obtained. The antibiotic regimen was considered as concordant treatment if it contained at least one drug active in vitro against the subsequent Salmonella isolate. Discordant antimicrobial therapy comprised the use of a regimen without any appropriate drug to which the causative organism was sensitive. Antibiotics that can achieve high tissue concentration, such as third-generation cephalosporins or fluoroquinolones, were considered as ‘adequate’ agents.

All isolates were identified by standard methods [18]. Salmonella serogroup was determined by the slide agglutination method using antisera specific to O antigen (Difco Laboratories, Detroit, MI, USA). (Group C1) Salmonella negative for Vi antigen and citrate-negative were defined as the serogroup Salmonella choleraesuis. Salmonella of group D1 that were Vi antigen-negative were designated serogroup D1. Salmonella typhi/paratyphi strains were excluded by detection of Vi-specific antigen. The antimicrobial susceptibilities of the isolates were investigated by a standard disc-diffusion method [19]. The antimicrobial agents examined included ampicillin, flomoxef, cefixime, ceftriaxone, imipenem, chloramphenicol, ciprofloxacin and trimethoprim/sulphamethoxazole. Susceptibility and resistance were defined according to the criteria suggested by the CLSI [19].

Data were analyzed using spss, version 11.0 (SPSS inc., Chicago, IL, USA). Student’s t-test was used to analyze numerical data. If the data were not normally distributed, the Mann–Whitney U-test was used to compare nonparametric data. A chi-square test or Fisher’s exact test was used to analyze categorical data. p <0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References

Demographics and clinical characteristics

A total of 683 children were identified during the study period. Three hundred and seventy-one (54.3%) patients were male and 611 (89.5%) were aged under 5 years, with a median age of 18 months. Thirty-four patients (5.0%) had underlying conditions [febrile seizures in ten, prematurity in five, asthma in five, thalassemia trait in three, glucose-6-phosphate dehydrogenase deficiency in three, congenital heart disease in two, and others (including cerebral palsy, gastroesophageal reflux disorder, vesicoureteral reflux, craniosynostosis and lung anomaly with cystic adenomatoid malformation) in six]; no abnormalities in the gastrointestinal tract and no life-threatening diseases or immunodeficiency conditions were recorded. The majority of the infections (416, 60.9%) occurred between June and October.

Fever and diarrhoea were the most common initial presentations. Bloody and mucoid diarrhoea was found in 39.3% (262/667 and 28.0% (187/667) of the patients, respectively.

Blood cultures were obtained in 93.4% (638/683) of the patients; 4.9% (31/638) showed NTS bacteraemia. Follow-up information for at least 6 months after cessation of antibiotic therapy was obtained from medical records. Neither focal suppurative complications, nor clinically recurrent diseases were found in these patients during the follow-up period. Complications were found during or after antimicrobial therapy in 7.9% (54/683) of the patients overall, including bacteraemia (31 cases), toxic megacolon (20 cases), bowel perforation (two cases) and acute appendicitis (one case). The patients with bowel perforation and appendicitis received surgical intervention. No fatality occurred in this cohort of patients. The only parameter among demographics and clinical manifestations associated with complications was C-reactive protein (CRP), especially a level ≥100 mg/L (OR 2.08, 95% CI 1.17–3.72, p 0.013; multivariate analysis: OR 1.85, 95% CI 1.01–3.46, p 0.047) (data of other parameters not shown).

Serogroup distribution and antimicrobial susceptibility

The distribution of serogroups and patterns of antimicrobial susceptibility of the NTS isolates are shown in Table 1. Salmonella serogroup B was the most common, accounting for 50.1% (342/683) overall, followed by serogroups D1, C2, and C1. Of these isolates, antimicrobial resistance rates to conventional antibiotics (43.9% to ampicillin, 44.8% to chloramphenicol and 27.1% to trimethoprim/sulphamethoxazole) were much higher than those to other drugs (0% to ciprofloxacin and to imipenem, 4.1% to ceftriaxone, 3.3% to flomoxef and 4.4% to cefixime). For the third-generation cephalosporins, there was resistance to ceftriaxone in 28/676 (4.1%,) of isolates and resistance to cefixime in 29/663 (4.4%) isolates. Most of these isolates belonged to serogroups B and D1. In 31 cases with Salmonella bacteraemia, serogroup B accounted for 15 (48.4%), followed by serogroups C2 (22.6%), D1 (19.4%) and C1 (9.7%).

Table 1.   Serogroup distribution and antimicrobial resistance of nontyphoidal Salmonella isolates from stool
AntibioticsSerogroupTotal (N = 676)a n (%)
Group B (= 342) n (%)Group C1 (N = 54) n (%)S. choleraesuis (N = 3) n (%)Group C2 (N = 85) n (%)Group D1 (N = 184) n (%)Group E (N = 6) n (%)Group G (N = 2) n (%)
  1. TMP/SMX, trimethoprim/sulphamethoxazole.

  2. aA total of 683 children had stool culture positive for nontyphoidal Salmonella (NTS). However, the results of serogrouping distribution were not available in 7 of them. Thus, only 676 cases are shown in Table 1.

Ampicillin237/342 (69.3)9/54 (16.7)1/3 (33.3)39/85 (45.9)9/184 (4.9)2/6 (33.3)0/2297/676 (43.9)
Chloramphenicol248/342 (72.5)8/54 (14.8)1/3 (33.3)39/85 (45.9)5/184 (2.7)1/6 (16.7)1/2 (50.0)303/676 (44.8)
TMP/SMX125/342 (36.5)16/54 (29.6)1/3 (33.3)37/85 (43.5)3/184 (1.6)1/6 (16.7)0/2183/676 (27.1)
Ciprofloxacin0/3420/540/30/850/1840/60/20
Ceftriaxone16/342 (4.7)1/54 (1.9)1/3 (33.3)3/85 (3.5)7/184 (3.8)0/60/228/676 (4.1)
Flomoxef12/342 (3.5)1/54 (1.9)1/3 (33.3)3/85 (3.5)5/184 (2.7)0/60/222/676 (3.3)
Cefixime17/334 (5.1)1/54 (1.9)1/3 (33.3)3/83 (3.6)7/181 (3.9)0/60/229/663 (4.4)
Imipenem0/3420/540/30/850/1840/60/20

Antimicrobial therapy

Fifty-seven percent (386/683) of patients received antimicrobial therapy; the most commonly used empirical regimes were third-generation cephalosporins (46.6%, 180/386) and ampicillin (39.9%, 154/386), alone or with gentamicin. The most common regimens used for definitive antimicrobial therapy were also third-generation cephalosporins (54.9%, 212/386) and ampicillin (32.6%, 126/386), alone or with gentamicin. The rates of initial and definitive concordant antibiotic usage were 75.1% (290/386) and 80.6% (311/386), respectively. In our series, the average duration of antimicrobial therapy was 4.7 ± 2.4 days (range 1–16 days).

We analyzed the clinical features of patients with or without antimicrobial therapy (Table 2). Cases with fever were more frequently put on antimicrobials than those without. The duration of fever and diarrhoea was longer in patients treated with antimicrobials than those not treated. CRP levels were significantly higher and white blood cell counts were borderline higher in patients who received antibiotics than in those who did not. More cases of bacteraemia were identified among patients who were given empirical antibiotics on admission (7.0%, 27/386 vs. 1.3%, 4/297, p <0.001).

Table 2.   Demographics, clinical manifestations, and laboratory findings of 683 paediatric cases with and without antimicrobial therapy
CharacteristicsTotal N = 683 n (%)Cases with antimicrobial therapy N = 386 n (%)Cases without antimicrobial therapy N = 297 n (%)p-value
  1. SD, standard deviation; WBC, white blood cell; CRP, C-reactive protein.

  2. aNontyphoidal Salmonella infectious complications include bacteraemia (31), toxic megacolon (20), bowel perforation (2) and acute appendicitis (1).

Age (months)
 Median (range)18.0 (1.0–210.0)20.0 (1.0–210.0)16.0 (1.0–153.0)0.121
 <3 months21138 
 3 months to 1 year1889692 
 >1 year474277197 
 Sex (male/female)371/312210/176161/1360.959
 Fever641 (93.9)374 (96.9)267 (89.9)<0.001
Before admission (days)
 Median (range)2.0 (0.0–28.0)2.0 (0.0–28.0)2.0 (0.0–14.0)0.025
After antibiotics treatment (days)
 Median (range)2.0 (0.0–10.0)2.0 (0.0–10.0)0.0 (0.0–4.0)<0.001
Total febrile duration (days)
 Median (range)4.0 (0.0–32.0)5.0 (0.0–32.0)3.0 (0.0–20.0)<0.001
 Diarrhoea667 (97.7)377 (97.7)290 (97.6)1.000
Duration (days)
 Median (range)6.0 (0.0–35.0)7.0 (0.0–35.0)6.0 (0.0–20.0)<0.001
 Bloody/mucous (proportion)262/187125/100137/870.228
 Nausea/vomiting235 (34.4)137 (35.5)98 (33.0)0.496
WBC (/mm3)
 Mean ± SD10505.2 ± 4557.010794.0 ± 5044.810125.7 ± 3798.00.058
 Range1400–391001400–391003300–22800 
 <5000463115 
 5000–15 000535285250 
 >15 000977027 
Platelet (×103/mm3)
 Mean ± SD281.2 ± 96.7283.6 ± 95.7278.0 ± 98.00.459
 Range26.0–762.0107.0–615.026.0–762.0 
CRP (mg/L)
 Median50.370.834.7<0.001
 Range0.3–442.80.7–442.80.3–386.3 
 <10883652 
 10–4019581114 
 >40388263125 
Complicationsa
 All complications 48 (12.4)6 (2.0)<0.001
 Complications excluding bacteraemia 21 (5.4)2 (0.7)<0.001
 Bacteraemia 27 (7.0)4 (1.3)<0.001

Impact of antimicrobial resistance on clinical outcomes

To assess the impact of antimicrobial resistance on the clinical course of nontyphoidal salmonellosis, we compared outcomes between cases with and without concordant initial antimicrobial therapy in the antibiotic-treated group (Table 3). Patients receiving antibiotics inactive in vitro did not have more severe illnesses than those receiving antibiotics active in vitro, in terms of duration of fever, length of hospitalization and the occurrence of complications such as bacteraemia or toxic megacolon.

Table 3.   Comparison of disease severity and complications in 386 paediatric cases receiving antimicrobial treatment with and without concordant therapy, and selected patientsa with and without adequate antimicrobial therapy
CharacteristicsTotal N = 386Selected patients N = 142
Cases with initial concordant antimicrobial therapyb N = 290 n (%)Cases with initial discordant antimicrobial therapy N = 96 n (%)p-valueCases with initial adequate antimicrobial therapyc N = 74 n (%)Cases without initial adequate antimicrobial herapy N = 68 n (%)p-value
  1. SD, standard deviation.

  2. aSelected patients = patients who suffered from fever ≥2 days prior to admission and had an initial C-reactive protein ≥100 mg/L.

  3. b‘Concordant’ initial antimicrobial therapy = antibiotic regimen which contained at least one drug active in vitro against the Salmonella isolate; ‘discordant’ initial antimicrobial therapy = antibiotic regimen which included the use of a regimen without any appropriate drug or a drug to which the causative organism was resistant.

  4. cAdequate antimicrobial therapy = antibiotics which can achieve high tissue concentration such as third-generation cephalosporin or fluoroquinolone.

  5. dNontyphoidal Salmonella infectious complications include bacteraemia (31), toxic megacolon (20), bowel perforation (2) and acute appendicitis (1).

Age (months)
 Median (range)21.0 (1.0–210.0)19.0 (1.0–125.0)0.34927.5 (2.0–137.0)26.0 (2.0–175.0)0.969
Hospitalization (days)
 Mean ± SD6.2 ± 2.76.1 ± 2.60.7095.4 ± 2.66.2 ± 2.60.051
Fever280 (96.6)94 (97.9)0.738   
 Before admission (days)
  Median (range)2.0 (0.0–28.0)3.0 (0.0–17.0)0.292   
 After antibiotics treatment (days)
  Median (range)2.0 (0.0–10.0)2.0 (0.0–8.0)0.6602.0 (0.0–9.0)2.0 (0.0–8.0)0.022
 Total febrile duration (days)
  Mean ± SD5.4 ± 3.55.7 ± 3.30.4625.5 ± 2.46.8 ± 3.20.008
Diarrhoea285 (98.3)92 (95.8)0.23573 (98.6)66 (97.1)0.607
 After antibiotic treatment (days)
  Median (range)4.0 (0.0–14.0)4.0 (0.0–14.0)0.2524.0 (0.0–14.0)5.0 (0.0–11.0)0.103
 Duration (days)
  Mean ± SD7.1 ± 3.57.8 ± 5.00.1206.8 ± 3.67.9 ± 3.30.076
NTS infectious complicationsd
 All complications36 (12.4)9 (9.4)0.4699 (12.2)9 (13.2)0.848
 Complications excluding bacteraemia15 (5.2)3 (3.1)0.5795 (6.8)4 (5.9)1.000
 Bacteraemia21 (7.2)6 (6.3)1.0004 (5.4)5 (7.4)0.740

Comparison of disease severity of selected patients with and without adequate antimicrobial therapy

Our data showed that patients with a longer duration of fever before admission and higher CRP had more severe illnesse and were put on antibiotics. To investigate whether adequate antimicrobial therapy affected the clinical course of these patients, we compared disease severity among selected patients with and without adequate antimicrobial treatment. Patients were selected for comparison if they suffered from fever for more than 2 days prior to admission and had an initial CRP ≥100 mg/L. Table 3 shows the results of this comparison. We found that total febrile duration and febrile duration after antimicrobial therapy was shorter in the cases with adequate antimicrobial therapy compared to those without. (mean: 1.8 ± 1.7 days vs. 2.6 ± 2.0 days)

Cases with adequate antimicrobial therapy had a borderline shorter duration of hospitalization compared to those without. There was no significant difference between the groups, in terms of the duration of diarrhoea and occurrence of complications.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References

Patients with invasive salmonellosis or severe enteritis require antimicrobial therapy. However, the difficulty in differentiating between severe and self-limited enteritis in clinical practice complicates the issue of antimicrobial therapy [12,20,21]. Careful identification of at-risk patients and the early initiation of effective antibiotics are crucial in the treatment of nontyphoidal salmonellosis. In the present study, patients with a longer duration of fever prior to admission and higher CRP values were frequently put on empirical antimicrobial therapy and these patients indeed had some characteristics of more severe illness, including duration of fever, diarrhoea and bacteraemia. In the univariate and multivariate analyses, higher CRP (≥100 mg/L) was also a significant risk factor for an eventful outcome. Despite having a longer total duration of fever and diarrhoea and a higher rate of complications, patients with higher CRP (especially ≥100 mg/L) and a longer febrile duration prior to admission (especially ≥2 days) may benefit from the administration of antibiotics that can reach high tissue concentrations in the intestinal mucosa, such as third-generation cephalosporins or fluoroquinolones, as shown by the shortened duration of fever or hospitalization in the present study. Thus, CRP ≥100 mg/L and febrile duration ≥2 days prior to treatment appear to be simple and objective indicators of patients with severe NTS enteritis who need antimicrobial therapy. Although a previous meta-analysis of 12 trials involving 778 healthy individuals with NTS enteritis found no significant benefit from antimicrobial therapy on the length of illness [22], most cases in these studies were not severely ill, and most received chloramphenicol or sulphamethoxazole-trimethoprim as empirical antibiotics. On the basis of the result obtained in the present study, we speculate that the use of antibiotics that achieve higher tissue concentrations, such as the fluoroquinolones and expanded-spectrum cephalosporins, may produce different conclusions.

In our series, the resistance rates of nontyphoidal Salmonella to conventional antibiotics, such as ampicillin, chloramphenicol and sulphamethoxazole-trimethoprim, were 27–45%. These resistance rates are similar to those reported in a previous study from the same institution in 2004 [12], except that ceftriaxone resistance (4.1%), was much higher than the 1.5% reported previously [12]. Increasing resistance to expanded-spectrum cephalosporins could be caused by indiscriminate use of antibiotics in animal feed, which might have facilitated the selection and spread of expanded-spectrum cephalosporin-resistant Salmonella [20,23]. High resistance rates to fluoroquinolones for invasive Scholeraesuis strains, which have been previously reported in Taiwan, were not found in this study (0%, 0/3) [12,17,20].

One concern regarding antimicrobial therapy is that, despite its clinical efficacy, fluoroquinolone or expanded-spectrum cephalosporins may prolong the duration of Salmonella excretion after clinical recovery. This situation was found in the pre-fluoroquinolone era when other antibiotics such as chloramphenicol or sulphamethoxazole-trimethoprim were used [7,24]. Salmonella species are known to persist within the reticuloendothelial system and survive and replicate within phagocytes [25]. Possible causes for the ineffectiveness of these antibiotics to eradicate Salmonella include the failure of these antibiotics to reach an adequate concentration and/or the loss of antimicrobial activity in the phagosomes [26]. Animal studies showed that ceftriaxone is effective in the intracellular environment of macrophages [27]. In addition, these agents, including fluoroquinolones, reach high concentrations in the intestinal mucosa and gallbladder, and therefore can effectively kill Salmonella that usually reside in these environments [27,28]. Thus, antimicrobial therapy with these newer agents may be effective in preventing or suppressing the excretion of Salmonella.

Another concern is whether antimicrobial resistance may affect treatment outcomes of nontyphoidal salmonellosis. Although previous studies have identified an association between drug resistance and increased rates of illness and death [20,21], we found that patients receiving antibiotics inactive in vitro did not have more severe illnesses than those who received active antibiotics. The cause for such a discrepancy is unclear. One possible explanation is that some patients who actually did not need antimicrobial therapy were treated with antibiotics and the inclusion of such patients may have biased the data analysis in the present study. Nevertheless, in order to suppress the load of Salmonella in the intestinal tract and to simultaneously prevent the possible induction of antibiotic resistance, a short course (3–5 days) of an adequate antibiotic such as ceftriaxone is suggested in the treatment of severe NTS gastroenteritis. Antibiotics should be discontinued as soon as possible when the patient’s clinical condition improves.

The major limitation of the present study is that the benefit of adequate antimicrobial therapy for NTS infection was primarily based on clinical observations, such as the shortening of hospitalization or febrile duration. Quantitative analysis of the amount and duration of NTS faecal shedding would give us more objective information on the impact of antimicrobial therapy for NTS infection, especially on the appropriate duration of treatment.

In summary, we found that patients with a high CRP and longer duration of fever before admission may be considered as having ‘severe NTS enteritis’ and these patients appear to benefit clinically from antibiotic treatment. A short course of an effective antibiotic, such as ceftriaxone, is recommended in such a setting. A large prospective, randomized study may be needed to evaluate this issue in the future.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References

We thank the members of the Research Center for Pathogenic Bacteria of Chang Gung University, Taoyuan, Taiwan, for their suggestions and assistance in this study.

Transparency Declaration

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References

The study was in part supported by a grant (CMRPG460102) from Chang Gung Memorial Hospital, Taoyuan, Taiwan. The authors have no conflicts of interest to declare.

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  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Transparency Declaration
  9. References
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