Comparative clinical characteristics and outcomes of patients with community acquired bacteremia caused by Escherichia coli , Burkholderia pseudomallei and Staphylococcus aureus : A prospective observational study (Ubon-sepsis)

Abstract

Background

Community acquired bacteremia (CAB) is a common cause of sepsis in low and middle-income countries (LMICs). However, knowledge about factors associated with outcomes of CAB in LMICs is limited.

Methodology/Principal findings

A prospective observational study (Ubon-sepsis) of adults admitted to a referral hospital with community-acquired infection in Northeastern Thailand was conducted between March 1, 2013 and February 1, 2017. In the present analysis, patients with a blood culture collected within 24 hours of admission that was positive for one of the three most common pathogens were studied. Clinical features, management, and outcomes of patients with each cause of CAB were compared. Of 3,806 patients presenting with community-acquired sepsis, 155, 131 and 37 patients had a blood culture positive for Escherichia coli, Burkholderia pseudomallei and Staphylococcus aureus, respectively. Of these 323 CAB patients, 284 (89%) were transferred from other hospitals. 28-day mortality was highest in patients with B. pseudomallei bactaeremia (66%), followed by those with S. aureus bacteraemia (43%) and E. coli (19%) bacteraemia. In the multivariable Cox proportional hazards model adjusted for age, sex, transfer from another hospital, empirical antibiotics prior to or during the transfer, and presence of organ dysfunction on admission, B. pseudomallei (aHR 3.78; 95%CI 2.31–6.21) and S. aureus (aHR 2.72; 95%CI 1.40–5.28) bacteraemias were associated with higher mortality compared to E. coli bacteraemia. Receiving empirical antibiotics recommended for CAB caused by the etiologic organism prior to or during transfer was associated with survival (aHR 0.58; 95%CI 0.38–0.88).

Conclusions/Significance

Mortality of patients with CAB caused by B. pseudomallei was higher than those caused by S. aureus and E. coli, even after adjusting for presence of organ dysfunction on admission and effectiveness of empirical antibiotics received. Improving algorithms or rapid diagnostic tests to guide early empirical antibiotic may be key to improving CAB outcomes in LMICs.

Abstract

Background

Community acquired bacteremia (CAB) is a common cause of sepsis in low and middle-income countries (LMICs). However, knowledge about factors associated with outcomes of CAB in LMICs is limited.

Methodology/Principal findings

A prospective observational study (Ubon-sepsis) of adults admitted to a referral hospital with community-acquired infection in Northeastern Thailand was conducted between March 1, 2013 and February 1, 2017. In the present analysis, patients with a blood culture collected within 24 hours of admission that was positive for one of the three most common pathogens were studied. Clinical features, management, and outcomes of patients with each cause of CAB were compared. Of 3,806 patients presenting with community-acquired sepsis, 155, 131 and 37 patients had a blood culture positive for Escherichia coli, Burkholderia pseudomallei and Staphylococcus aureus, respectively. Of these 323 CAB patients, 284 (89%) were transferred from other hospitals. 28-day mortality was highest in patients with B. pseudomallei bactaeremia (66%), followed by those with S. aureus bacteraemia (43%) and E. coli (19%) bacteraemia. In the multivariable Cox proportional hazards model adjusted for age, sex, transfer from another hospital, empirical antibiotics prior to or during the transfer, and presence of organ dysfunction on admission, B. pseudomallei (aHR 3.78; 95%CI 2.31–6.21) and S. aureus (aHR 2.72; 95%CI 1.40–5.28) bacteraemias were associated with higher mortality compared to E. coli bacteraemia. Receiving empirical antibiotics recommended for CAB caused by the etiologic organism prior to or during transfer was associated with survival (aHR 0.58; 95%CI 0.38–0.88).

Conclusions/Significance

Mortality of patients with CAB caused by B. pseudomallei was higher than those caused by S. aureus and E. coli, even after adjusting for presence of organ dysfunction on admission and effectiveness of empirical antibiotics received. Improving algorithms or rapid diagnostic tests to guide early empirical antibiotic may be key to improving CAB outcomes in LMICs.

Author summary

Bloodstream infections are very common and associated with significant numbers of death and disability around the world. Less is known about the rates, risks and impact of common bloodstream infections in low and middle-income countries. We conducted a large prospective four-year observational study in northeastern Thailand of persons admitted to a tertiary-care hospital with severe infections and analyzed those who had bloodstream infections. The three most common bacteria causing bloodstream infections were Escherichia coli, Burkholderia pseudomallei and Staphylococcus aureus. Most of the patients were transferred from other hospitals. Overall mortality was 41%. The highest mortality was among those who had B. pseudomallei infection, at 66%, and the lowest mortality was among those who had E. coli infection, at 19%. If appropriate antibiotics were given early, i.e. prior to or during the transfer, this was associated with survival. Our large study was able to identify the types, risk factors and impact of bloodstream infections in a low and middle-income country. These important results highlight the need for the development and implementation of rapid diagnostic tests and hospital algorithms for early diagnosis to improve care and outcomes of bloodstream infections in low and middle-income countries.

Citation: Somayaji R, Hantrakun V, Teparrukkul P, Wongsuvan G, Rudd KE, Day NPJ, et al. (2021) Comparative clinical characteristics and outcomes of patients with community acquired bacteremia caused by Escherichia coli, Burkholderia pseudomallei and Staphylococcus aureus: A prospective observational study (Ubon-sepsis). PLoS Negl Trop Dis 15(9): e0009704. https://doi.org/10.1371/journal.pntd.0009704

Editor: Farah Naz Qamar, Aga Khan University Hospital, PAKISTAN

Received: April 4, 2021; Accepted: August 4, 2021; Published: September 3, 2021

Copyright: © 2021 Somayaji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The datasets generated during and/or analyzed during the current study are available in the Figshare repository, https://doi.org/10.6084/m9.figshare.14257457.

Funding: The study was funded by the Wellcome Trust (090219/Z/09/Z) and National Heart, Lung and Blood Institute, National Institutes of Health (R01HL113382) to TEW. DL is supported by an intermediate fellowship from the Wellcome Trust (101103/Z/13/Z). All study procedures, data collection, data analyses, data interpretation, and writing of the report were performed solely by the participating authors without the sponsors’ involvement. Full access to data was granted to the corresponding author. All authors participated in the study design or analysis and approved the submission of the manuscript. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the mansuscript.

Competing interests: The authors have declared that no competing interests exist.

Background

Community-acquired bacteremia (CAB) or bloodstream infection is a common cause of sepsis, potentially leading to death, in low and middle-income countries (LMICs) [1, 2]. Sepsis is a life-threatening organ dysfunction due to dysregulated host response to infection [1]. In 2017, 11 million sepsis-related deaths were estimated to occur worldwide, with the highest burden in sub-Saharan Africa, Oceania, south Asia, east Asia and southeast Asia [3]. The importance of obtaining a blood culture especially in persons with sepsis has been highlighted in sepsis guidelines to identify the cause of infection and ensure appropriate antimicrobial therapies [2]. In high-income countries, the rate of hospitalization due to CAB is around 77 to 92 per 100,000 people per year, and the 30-day mortality is around 13 to 19% [4–8]. However, due to challenges of access to diagnostic microbiology facilities and data sources, our understanding of the epidemiology and outcomes of CAB in resource-limited settings remains rudimentary [9, 10].

In recent years, there have been greater efforts to examine the clinical characteristics and deaths of patients with bacteremia caused by specific pathogens in tropical developing countries and particularly in South-east Asia [9]. Nonetheless, the need for comprehensive studies to improve our understanding and to develop antibiotic prescribing recommendations for CAB or community-acquired sepsis cannot be understated. Observational studies in Northeast Thailand have demonstrated a rising incidence of CAB with a significant all-cause mortality [11–15]. The most commonly identified organisms causing CAB in this region are Escherichia coli, Burkholderia pseudomallei, and Staphylococcus aureus [11]. While E. coli, B. pseudomallei and S. aureus bacteremia have each been studied in isolation [9, 12–15], no studies to date have prospectively and directly compared these bacteremia which may provide discrete or overlapping risk factors and epidemiology to utilize in screening and treatment pathways. Thus, we sought to evaluate clinical characteristics, treatment and outcomes of hospitalized patients with CAB caused by E. coli, B. pseudomallei, or S. aureus in Northeast Thailand, a representative resource-limited setting.

Methods

Ethics statement

The study was approved by the ethics committees at Sunpasitthiprasong Hospital (039/2556), Mahidol University Faculty of Tropical Medicine (MUTM2012-024-01), the University of Washington IRB (42988) and the University of Oxford (OXTREC172-12). Informed consent was obtained from all study participants.

Study design and study site

This was a pre-planned analysis of the Ubon-Sepsis study, a prospective observational study completed in Sunpasitthiprasong Hospital in Ubon Ratchathani province, Northeast Thailand from March 1, 2013 through February 1, 2017 (NCT02217592); the details of the study design and variables are described elsewhere [16–18]. Ubon Ratchathani has a population of 1.8 million persons and is the largest province with an area of 16,113 km2. The study site is a public tertiary-care hospital and acts as a referral center due to its availability of intensive care unit (ICU) and microbiology facilities.

Study participants

The study prospectively enrolled consenting patients ≥18 years old who were admitted to the general medical wards or the medical ICUs with a primary diagnosis of community-acquired infection made by the attending physician, were within 24 hours of admission to the study hospital, and had at least three Surviving Sepsis Campaign criteria for sepsis documented in the medical record (S1 Table from primary study publication) [16]. Patients with a previous hospitalization within the past 30 days, those who were transferred from other hospitals with a total duration of hospitalization >72 hours and those who were diagnosed with hospital-acquired infections were excluded. In this study, patients with blood culture collected within 24 hours of admission culture positive for the most common three pathogens were included for analysis.

Study team point-of-care assessments

Following enrollment, patients were evaluated by the study nurses using four point-of-care assessments; including a whole blood glucose rapid diagnostic test (RDT) (ACCU-CHECK Performa, Roche Diagnostic, Germany), a whole blood lactate RDT (Lactate Pro 2, Arkray Global Business Inc., Australia), pulse oximetry (Nellcor N-65, Covidien plc., Ireland) and the Glasgow Coma Scale (GCS). Blood samples (4±10 mL) were also collected for culture using BD BACTEC automated blood culture system (Becton-Dickinson, Sparks, MD, USA) [16]. During the study period, antimicrobial susceptibility was determined using the disc diffusion method according to Clinical and Laboratory Standards Institute (CLSI) [19]. The results were reported to the attending physicians. The study did not involve any clinical interventions and all medical treatment was provided by the attending physicians and respective medical teams.

Data collection

Demographic and clinical data was collected onto a validated case report form (CRF) for the study period. Mortality in hospital and at 28 days was collected through chart review and telephone contact as applicable.

Definitions

Blood culture results from blood samples collected within 24 hours of admission were evaluated. Patients with more than one blood stream pathogen were excluded from analysis. Presenting clinical syndromes were classified based on the primary diagnoses of attending physicians. The clinical syndromes were grouped into acute febrile illness, lower respiratory infection, diarrheal illness, sepsis, septic shock and others [16]. Infection with organ dysfunction (sepsis) was determined in accordance with recent sepsis guidelines; a modified sequential organ failure assessment (SOFA) score (continuous and categorized as ≥2 and <2) within 24 hours of admission was used to define organ dysfunction and is detailed elsewhere [16, 20, 21]. Laboratory values of hemoglobin, hematocrit, platelets, white blood cells (WBC), blood urea nitrogen (BUN), creatinine, albumin, aspartate transaminase (AST), bilirubin, and international normalized ratio (INR) within 24 hours of admission were used for analysis. Recommended antibiotics for treatment of E. coli bacteraemia were aminoglycosides, third-generation cephalosporins, fluoroquinolones, penicillin plus beta-lactamase inhibitors and carbapenems [22, 23]. Recommended antibiotics for treatment of B. pseudomallei bacteraemia were ceftazidime, carbapenems and amoxicillin/clavulanic acid [24, 25]. Recommended antibiotics for treatment of S. aureus bacteraemia were oxacillin, cefazolin, clindamycin, daptomycin and vancomycin [22, 26].

Statistical analysis

Continuous and categorical variables were compared with Kruskal-Wallis tests and Chi-square tests, respectively. Fisher’s exact test was used when appropriate. The primary outcome was 28-day mortality. We performed survival analyses using Kaplan-Meier methods and Cox proportional hazard models. The multivariable models were developed using purposeful selection [27]. The modified SOFA score was included as a continuous variable in the models. Because of collinearity between empirical antibiotic prior to or during transfer and empirical antibiotic effective within the first day of hospital admission, we conducted a separate analysis including empirical antibiotic within the first day of hospitalization in the multilevel Cox proportional hazard model. To explore the effect of antimicrobial resistance, a sensitivity analysis was also conducted by categorizing receipt of antibiotics into: (a) did not receive any empirical antibiotics recommended for the causative organism, (b) received recommended empirical antibiotic, to which the causative organism was susceptible and (c) received recommended empirical antibiotics, to which the causative organism was resistant. All analyses were performed with STATA 14.2 (StataCorp, College Station, TX, USA). The final data dictionary and database are accessible online (https://doi.org/10.6084/m9.figshare.14257457).

Results

The Ubon-sepsis study prospectively evaluated 3,806 patients presenting with community-acquired sepsis from March 2013-January 2017. A total of 522 (14%) patients had blood collected within 24 hours of admission to the study hospital culture positive for a pathogenic organism. The most common pathogens were E. coli (n = 155), B. pseudomallei (n = 131) and S. aureus (n = 37), and those 323 patients were included for analysis (Fig 1).

[Figure omitted. See PDF.]

Fig 1. Study flow diagram.

https://doi.org/10.1371/journal.pntd.0009704.g001

Baseline characteristics

The baseline characteristics of 323 patients included in the analysis are described in Table 1. The proportion that were male was higher among patients with B. pseudomallei and S. aureus bacteraemias (66% and 73%, respectively) compared to those with E. coli bacteraemia (42%) (p<0.001). The median age was highest among patients with E. coli bacteraemia (65 years, IQR 57–75 years) and lowest among those with B. pseudomallei bacteraemia (56 years, IQR 46–66 years) (p<0.001). A known history of diabetes mellitus was more common in patients with B. pseudomallei bacteraemia (48%) (p = 0.01) and known history of chronic kidney disease was more common in patients with S. aureus bacteraemia (32%) (p = 0.05). The proportion of patients transferred from other hospitals was highest in patients with B. pseudomallei bacteraemia (94%), followed by those with S. aureus (86%) and E. coli (83%) bacteraemias (p = 0.02). The proportion of patients presenting with lower respiratory infection was highest in patients with B. pseudomallei bacteraemia (40%), followed by those with S. aureus (35%) and E. coli (21%) bactereamia (p = 0.003).

[Figure omitted. See PDF.]

Table 1. Baseline clinical characteristics of patients with community-acquired E. coli, B. pseudomallei and S. aureus bacteraemias.

https://doi.org/10.1371/journal.pntd.0009704.t001

On enrollment, there was borderline evidence of higher blood lactate level in patients with B. pseudomallei bacteraemia (median 3.3 mmol/L [IQR 1.9–6.6 mmol/L]) than in those with E. coli (median 2.6 mmol/L [IQR 1.6–4.8 mmol/L]) and S. aureus (median 2.8 mmol/L [IQR 1.7–4.0 mmol/L]) bacteraemias (p = 0.08). The median modified SOFA score was higher in patients with B. pseudomallei bacteraemia (7 [IQR 5–10]) than in those with E. coli (6 [IQR 4–8]) and S. aureus (6 mmol/L [IQR 4–7]) bacteraemias (p = 0.05).

Empirical antibiotic treatment

Of 284 patients transferred from other hospitals, 225 (79%) received at least one antibiotic prior to or during transfer. Ceftriaxone was the most commonly administered antibiotic (N = 178, 55%), followed by ceftazidime (N = 52, 16%), clindamycin (N = 22, 7%), doxycycline (N = 18, 6%), metronidazole (N = 11, 3%), macrolide drugs (N = 8, 2%), cloxacillin (N = 4, 2%), carbapenem drugs (N = 4, 1%), ciprofloxacin (N = 3, 1%), cefazolin (N = 2, 1%) and aminoglycosides (N = 1, 0.3%). Of 129, 123 and 32 patients with E. coli, B. pseudomallei and S. aureus bacteria transferred from other hospitals, 97 (75%), 31 (25%) and 8 (25%), respectively, received recommended empirical antibiotics for the relevant bacteremia prior to or during transfer (P<0.001).

Of all 323 patients, 315 (98%) received at least one antibiotic within the first day of hospitalization at the study hospital. Of all 155, 131 and 37 patients with E. coli, B. pseudomallei and S. aureus bacteria, 149 (96%), 98 (75%) and 18 (49%), respectively, received recommended antibiotics for the relevant bacteremia given empirically within the first day of hospitalization (p<0.001).

Clinical outcomes

A total of 132 deaths occurred in the study period resulting in an overall 28-day mortality of 41% (Table 2). Patients with B. pseudomallei bacteraemia had a 28-day mortality of 66% (87/131) compared with 43% (16/37) for S. aureus and 19% for E. coli (29/155) bacteraemias (p<0.001). Among those who died, the median time to death was shortest in the S. aureus group (2 days (1–8)) but the difference was not statistically significant between groups (p = 0.76) (Table 2). Among those who survived, the median length of stay at the study hospital was greatest in the B. pseudomallei group (13 days (7–22), p<0.001). Survival curves demonstrated that the majority of deaths occurred within a week of admission (Fig 2).

[Figure omitted. See PDF.]

Fig 2. Probability of survival comparing patients with community-acquired E. coli, B. pseudomallei and S. aureus bacteraemias.

https://doi.org/10.1371/journal.pntd.0009704.g002

[Figure omitted. See PDF.]

Table 2. Day 28 mortality and duration of hospitalization in patients with community acquired bacteremia by pathogen.

https://doi.org/10.1371/journal.pntd.0009704.t002

In a multivariable Cox proportional hazard model adjusted for age, sex, transfer status, empirical antibiotics prior to or during transfer, comorbidities and modified SOFA on admission, B. pseudomallei (adjusted hazard ratio [aHR] 3.78; 95%CI 2.31–6.21) and S. aureus (aHR 2.72; 95%CI 1.40–5.28) bacteraemias were associated with higher mortality compared to those with E. coli bacteraemia (p<0.001). Empiric administration of recommended antibiotics for the relevant bacteraemia prior to or during transfer was associated with survival (aHR 0.58; 95%CI 0.38–0.88, p = 0.01) (Table 3). Because of collinearity with empiric administration of recommended antibiotics prior to or during transfer, empiric administration of recommended antibiotics within the first day of hospital admission was not included in the final model. We included empiric administration of recommended antibiotics within the first day of hospital admission in a separate multivariable model and found that this variable was not independently associated with mortality following infection (p = 0.97) (S1 Table).

[Figure omitted. See PDF.]

Table 3. Factors associated with 28-day mortality among patients with community acquired bacteraemia using Cox proportional hazards models.

https://doi.org/10.1371/journal.pntd.0009704.t003

To evaluate the potential effect of antibiotic resistance on the association of empirical antibiotics with outcome, we conducted a sensitivity analysis by categorizing empirical antibiotics based on antimicrobial susceptibility test results of the isolated organisms (S2 and S3 Tables). Of the 155 isolates of E. coli, 53 (34%) were resistant to 3rd generation cephalosporins and 2 (1%) were resistant to 3rd generation cephalosporins and carbapenem drugs. All of the B. pseudomallei isolates were susceptible to ceftazidime, amoxicillin/clavulanic acid and carbapenem drugs. Of the 37 isolates of S. aureus, 4 (11%) were methicillin-resistant S. aureus (MRSA). In a multivariable model, there was no difference in mortality comparing patients with CAB caused by an organism sensitive to the empirical antibiotic administered prior to or during transfer to patients with CAB caused by an organism resistant to the empirical antibiotic administered prior to or during transfer (aHR 0.60 vs. 0.43, p = 0.52, S2 Table). We also did not observe a difference in mortality when repeating this analysis for empirical antibiotics given within the first day of hospitalization (aHR 0.99 vs. 0.91, p = 0.24, S3 Table). Mortality of patients with CAB caused by B. pseudomallei was higher than morality in those patients with CAB caused by S. aureus and E. coli in all models (S1, S2 and S3 Tables).

Discussion

In our comparative prospective observational study of hospitalized patients with community-acquired infections in Northeastern Thailand, we demonstrated that CAB with the most prevalent pathogens of E. coli, B. pseudomallei, and S. aureus was associated with a significant 28-day mortality of 41%. Mortality of patients with CAB caused by B. pseudomallei was higher than those caused by S. aureus and E. coli, even after adjusting for transfer status, effectiveness of empirical antibiotics received prior to or during the transfer and presence of organ dysfunction on admission. Most of patients in our setting at a public tertiary-care hospital were transferred from other hospital. We found that transfer from other hospitals was associated with higher mortality [16]. The distance from the referring hospital to the study hospital could be up to 200 kilometers and the travel duration could be up to two to three hours by ambulance. However, receipt of effective empirical antibiotic against the causative pathogen prior to or during transfer was associated with survival. Antimicrobial resistance was not uncommon. The prevalence of 3rd generation cephalosporin resistance among community-acquired E. coli bacteremia was 35%. Nonetheless, in our setting, we did not observe that patients who had CAB caused by 3rd generation cephalosporin-resistant E. coli (3GCREC) and received empirical treatment with 3rd generation cephalosporins had higher mortality. We found no evidence to support the use of antibiotics recommended against 3GCREC (such as carbapenem drugs) as the first-line empirical treatment of community-acquired sepsis. Our findings suggest that improving algorithms or rapid diagnostic tests to guide the administration of empirical antibiotic, if possible prior to or during transfer, could improve the outcomes of CAB in LMICs.

As the epidemiology of CAB pathogens varies between regions, it is critical to understand local epidemiology for implementation of optimal therapeutic initiatives. Both E. coli and S. aureus are similarly observed as frequent pathogens in CAB cases in both high and low-income settings [4–6, 9, 28–31]. In our study, B. pseudomallei, the cause of melioidosis, was the second most frequently isolated bloodstream pathogen (16%). Given the environmental predilection of B. pseudomallei to tropical climates, it is a common CAB pathogen in studies of South/East Asia as well as Northern Australia [32–34]. However, the presence and prevalence of B. pseudomallei as a pathogen may still be underestimated in many tropical developing countries due to limitations in microbiology laboratory facilities, resources, and expertise [35].

Selecting empiric antimicrobial therapy to cover pathogens commonly associated with CAB remains challenging. We identified that 75% of patients with CAB caused by E. coli had empiric antibiotics considered effective against E. coli prior to or during transfer. However, 25% of patients with CAB caused by B. pseudomallei and S. aureus had empiric antibiotics considered effective against B. pseudomallei and S. aureus prior to or during transfer. The percentage of having empiric antibiotics considered effective against B. pseudomallei and S. aureus was similarly low even within the first day of hospitalization at the study hospital. The low antimicrobial coverage of B. pseudomallei prior to or during transfer may have been due to lack of ceftazidime at district hospitals; however, this issue should not apply to S. aureus as cloxacillin and clindamycin are fully available in all district hospitals in Thailand suggesting a possibility of under-recognition or limitation of guidelines for antibiotics [36, 37]. The coverage of empirical antibiotics for patients with CAB caused by S. aureus within the first day of hospitalization in this study was low compared to early effective antibiotic therapy for patients with S. aureus infection in a previous study [14] (46% vs. 87%) and may have been due to different study designs. In this study, we enrolled only sepsis patients presenting to the hospital within 24 hours of hospital admission, while the previous study included all patients with a culture positive for S. aureus from any sterile sites and included both community-acquired and hospital-acquired S. aureus infections [14]. Further studies are required to evaluate and study how to improve the selection of empiric antimicrobial therapy for community-acquired sepsis in different settings in LMICs.

Our study has a number of strengths including the prospective study design, detailed data on organ dysfunction, a large geographic catchment area, extremely high rates of follow-up and minimal missingness of assessment data. Additionally, it is unique in its approach to a comparative assessment of the outcomes following CAB by pathogen group. However, we must consider a number of limitations. Given the resource-limited setting, although clinical assessments were captured, equipment-based testing (beyond point-of-care) was not always completed. Blood cultures were generally taken at a single time-point thus limiting our ability to delineate between transient, intermittent, and continuous bacteremia cases. This may have led to an underestimate of both the incidence and severity of cases. However, given our illness burden and mortality, it is unlikely that patients were misclassified as true infections in this cohort. It is possible that a small proportion of bacteremia cases in our study cohort were hospital acquired but this was unlikely based on our study design, timepoint cutoffs, participants presenting with sepsis, and our restriction to three pathogens that are causes of community-acquired infections. As our mortality assessment was all-cause mortality within 28 days of enrollment, the mortality might reflect other causes of death such as exacerbation of underlying diseases [38]. It is possible that we were still underpowered to account for all potential confounders including baseline socio-demographic and clinical parameters. Also, our sample size was too small to evaluate the specific association between 3rd generation cephalosporin and mortality among patients with methicillin-sensitive S. aureus bacteremia. Despite the limitations, this is one of the first prospective studies to examine the characteristics and outcomes of CAB by pathogen group in a LMIC setting.

Conclusion

In our large comparative prospective evaluation of CAB in Northeastern Thailand, we identified that CAB is associated with a significant burden of mortality. CAB caused by B. pseudomallei and S. aureus are associated with higher mortality than CAB caused by E. coli even after adjusting for presence of organ dysfunction on admission and effectiveness of empirical antibiotics received. In our setting, a tertiary-care hospital in a LMIC, most patients with CAB are transferred from other hospitals and administration of recommended empirical antibiotics prior to or during transfer is associated with survival.

Supporting information

S1 Table. Factors associated with 28-day mortality among patients with community acquired bacteraemia.

https://doi.org/10.1371/journal.pntd.0009704.s001

(DOCX)

S2 Table. Factors associated with 28-day mortality among patients with community acquired bacteraemia.

https://doi.org/10.1371/journal.pntd.0009704.s002

(DOCX)

S3 Table. Factors associated with 28-day mortality among patients with community acquired bacteraemia.

https://doi.org/10.1371/journal.pntd.0009704.s003

(DOCX)

Acknowledgments

We thank all patients, their relatives, and staff of the Sunpasitthiprasong hospital who participated in the study. We thank Mayura Malasit, Praweennuch Watanachaiprasert, Chayamon Krainoonsing, Passaraporn Kesaphun, Nannicha Jirapornuwat, Areeya Faosap, Yaowaret Dokket, Sukhumal Pewlaorng, Jintana Suwannapruek, Prapass Wannapinij and Diane Tomita for their clinical, laboratory and administrative support.

Citation: Somayaji R, Hantrakun V, Teparrukkul P, Wongsuvan G, Rudd KE, Day NPJ, et al. (2021) Comparative clinical characteristics and outcomes of patients with community acquired bacteremia caused by Escherichia coli, Burkholderia pseudomallei and Staphylococcus aureus: A prospective observational study (Ubon-sepsis). PLoS Negl Trop Dis 15(9): e0009704. https://doi.org/10.1371/journal.pntd.0009704

References

1. Rhee C, Zhang Z, Kadri SS, Murphy DJ, Martin GS, Overton E, et al. Sepsis Surveillance Using Adult Sepsis Events Simplified eSOFA Criteria Versus Sepsis-3 Sequential Organ Failure Assessment Criteria. Crit Care Med. 2019;47(3):307–14. Epub 2019/02/16. pmid:30768498; PubMed Central PMCID: PMC6383796.

2. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 Update. Crit Care Med. 2018;46(6):997–1000. Epub 2018/05/17. pmid:29767636.

3. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200–11. Epub 2020/01/20. pmid:31954465; PubMed Central PMCID: PMC6970225.

4. Laupland K, Gregson DB, Flemons WW, et al. Burden of community-onset bloodstream infection: a population-based assessment. Epidemiol Infect. 2007;135:1037–42. pmid:17156500

5. Laupland K, Kibsey PC, Gregson DB, Galbraith JC. Population-based laboratory assessment of the burden of community-onset bloodstream infection in Victoria, Canada. Epidemiol Infect. 2012:1–7. pmid:22417845

6. Sogaard M, Norgaard M, Dethlefsen C, Schonheyder HC. Temporal changes in the incidence and 30-day mortality associated with bacteremia in hospitalized patients from 1992 through 2006: a population-based cohort study. Clin Infect Dis. 2011;52:61–9. pmid:21148521

7. Uslan D, Crane SJ, Steckelberg JM, et al. Age- and sex-associated trends in bloodstream infection: a populationbased study in Olmsted County, Minnesota. Archives Int Med. 2007;167:834–9.

8. Pedersen G, Schonheyder HC, Sorensen HT. Source of infection and other factors associated with case fatality in community-acquired bacteremia–a Danish population-based cohort study from 1992 to 1997. Clin Microbiol Infect. 2003;9:793–802. pmid:14616699

9. Deen J, van Seidlein L, Andersen F, Elle N, White NJ, Lubell Y. Community-acquired bacterial bloodstream infections in developing countries in south and southeast Asia: a systematic review. Lancet Infect Dis. 2012;12:480–87. pmid:22632186

10. Reddy E, Shaw AV, Crump JA. Community-acquired bloodstream infections in Africa: a systematic review and meta-analysi. Lancet Infect Dis. 2007;10:417–32.

11. Kanoksil M, Jatapai A, Peacock SJ, Limmathurotsakul D. Epidemiology, microbiology and mortality associated with community-acquired bacteremia in northeast Thailand: a multicenter surveillance study. PLoS One. 2013;8(1):e54714. Epub 2013/01/26. pmid:23349954; PubMed Central PMCID: PMC3548794.

12. Limmathurotsakul D, Wongratanacheewin S, Teerawattanasook N, et al. Increasing incidence of human melioidosis in Northeast Thailand. Am J Trop Med Hyg. 2010;82:1113–7. pmid:20519609

13. Bhengsri S, Baggett HC, Jorakate P et al. Incidence of bacterial meliodosis in eastern and northeastern Thailand. Am J Trop Med Hyg. 2011;85:117–20. pmid:21734135

14. Nickerson E, Hongsuwan M, Limmathurotsakul D et al. Staphylococcus aureus bacteremia in a tropical setting: patient outcome and impact of antibiotic resistance. PLoS One. 2009;4(e4308.).

15. Sawatwong P, Sapchookul P, Whistler T, Gregory CJ, Sangwichian O, Makprasert S, et al. High Burden of Extended-Spectrum beta-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae Bacteremia in Older Adults: A Seven-Year Study in Two Rural Thai Provinces. Am J Trop Med Hyg. 2019;100(4):943–51. Epub 2019/02/23. pmid:30793684; PubMed Central PMCID: PMC6447101.

16. Hantrakun V, Somayaji R, Teparraukkul P, et al Clinical epidemiology and outcomes of community acquired infection and sepsis among hospitalized patients in a resource limited setting in Northeast Thailand: a prospective observational study (Ubon-sepsis). PlOS One. 2018;13(9):e0204509. pmid:30256845

17. Rudd KE, Hantrakun V, Somayaji R, Booraphun S, Boonsri C, Fitzpatrick AL, et al. Early management of sepsis in medical patients in rural Thailand: a single-center prospective observational study. J Intensive Care. 2019;7:55. Epub 2019/12/13. pmid:31827803; PubMed Central PMCID: PMC6886203.

18. Booraphun S, Hantrakun V, Siriboon S, Boonsri C, Poomthong P, Singkaew BO, et al. Effectiveness of a sepsis programme in a resource-limited setting: a retrospective analysis of data of a prospective observational study (Ubon-sepsis). BMJ Open. 2021;11(2):e041022. Epub 2021/02/20. pmid:33602702.

19. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-First Informational Supplement. CLSI M100-S24.2014.

20. Seymour C, Liu V, Iwashyna TJ, et al. Assessment of clinical criteria for sepsis for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA: the journal of the American Medical Association. 2016;315(8):762–74.

21. Singer M, Deutschman CS, Seymour CW et al The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA: the journal of the American Medical Association. 2016;315(8):801–10. pmid:26903338

22. Lim C, Takahashi E, Hongsuwan M, et al. Epidemiology and burden of multidrug-resistant bacterial infection in a developing country. eLife. 2016;5(e18082). pmid:27599374

23. Rodriguez-Bano J, Gutierrez-Gutierrez B, Machuca I, Pascual A. Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae. Clin Microbiol Rev. 2018;31(2). Epub 2018/02/16. PubMed Central PMCID: PMC5967687. pmid:29444952

24. Wiersinga W, Virk HS, Torres AG, et al. Meliodosis. Nature Rev Dis Primers. 2018;4(17017). https://doi.org/10.1038/nrdp.2017.107.

25. Thibault F, Hernandez E, Vidal DR, et al. Antibiotic susceptibility of 65 isolates of Burkholderia pseudomallei and Burkholderia mallei to 35 antimicrobial agents. J Antimicrob Chemother. 2004;54(6). pmid:15509614

26. Corey GR. Staphylococcus aureus bloodstream infections: definitions and treatment. Clin Infect Dis. 2009;48 Suppl 4:S254–9. Epub 2009/04/25. pmid:19374581.

27. Hosmer DW, Lemeshow S, May S. Applied Survival Analysis: Regression Modeling of Time to Event Data. 2nd ed2008.

28. Lark R, Saint S, Chenoweth C, Zemencuk JK, Lipsky BA, Plorde JJ. Four-year prospective evaluation of community-acquired bacteremia: epidemiology, microbiology, and patient outcome. Diag Microbiol Infect Dis. 2001;41:15–22.

29. Goncalves J, Pova PR, Lobo C, Carneiro AH. Bloodstream infections as a marker of community-acquired sepsis severity. Results from the Portugese community-acquired sepsis study (SACiUCI study). Clin Microbiol Infect. 2013;19:242–8. pmid:22360358

30. Kollef M, Zilberberg MD, Shorr AF et al. Epidemiology, microbiology and outcomes of healthcare-associated and community-acquired bacteremia: a multicenter cohort study. J Infect. 2010;62:130–5. pmid:21195110

31. Ortega M, Almela M, Martinez JA, et al. Epidemiology and outcome of primary community-acquired bacteremia in adult patients. European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical Microbiology. 2007;26:453–7.

32. Douglas M, Lum G, Roy J, et al Epidemiology of community-acquired and nosocomial bloodstream infections in tropical Australia: a 12-month prospective study. Trop Med Int Health. 2004;9:795–804. pmid:15228489

33. Phetsouvanh R, Phongmany S, Soukaloun D, et al Causes of community-acquired bacteremia and patterns of antimicrobial resistance in Vientiane, Laos. Am J Trop Med Hyg. 2006;75:978–85. pmid:17124000

34. Kanoksil M, Jatapai A, Peacock SJ, Limmathurotsakul D. Epidemiology, microbiology and mortality associated with community-acquired bacteremia in northeast Thailand: a multicenter surveillance study. PloS One. 2013;8(1):e54714. pmid:23349954

35. Limmathurotsakul D, Peacock SJMelioidosis: a clinical overview. British Med Bulletin. 2011;99:125–39. pmid:21558159

36. Klompas M, Calandra T, Singer M. Antibiotics for Sepsis-Finding the Equilibrium. JAMA. 2018;320(14):1433–4. Epub 2018/09/23. pmid:30242350.

37. Minderhoud TC, Spruyt C, Huisman S, Oskam E, Schuit SCE, Levin MD. Microbiological outcomes and antibiotic overuse in Emergency Department patients with suspected sepsis. Neth J Med. 2017;75(5):196–203. Epub 2017/06/28. pmid:28653945.

38. Limmathurotsakul D, Dunachie S, Fukuda K, Feasey NA, Okeke IN, Holmes AH, et al. Improving the estimation of the global burden of antimicrobial resistant infections. Lancet Infect Dis. 2019. Epub 2019/08/21. pmid:31427174.