Clinical effects of bacteremia in sepsis patients with community-acquired pneumonia

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and involves a time-dependent pathological process requiring timely measures [1]. Among the community-acquired sepsis, pneumonia is a significant infection burden, with a short-term mortality rate of up to 50% in intensive care unit (ICU) patients [2‐4]. To emphasize the emergent nature of sepsis management, the Surviving Sepsis Campaign published the Hour-1 bundle comprising lactate measurement, blood cultures, appropriate antimicrobials, resuscitation with volume, and use of vasopressors to initiate resuscitation within 1 h [5]. However, there are concerns that use of the Hour-1 bundle will lead to substantial overtreatment [6, 7].

In the recent American Thoracic Society (ATS)/Infectious Disease Society of America (IDSA) practice guideline for the management of CAP [8], blood cultures are only recommended in patients with severe CAP or those with risk factors for methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, with very low quality of evidence. Blood cultures are often performed for sepsis patients with severe CAP to identify the causative organisms and optimize antimicrobial therapy. However, the clinical benefit of this practice is uncertain and disputed, as there is a lack of high-quality studies supporting it [9‐11]. Moreover, the impact of bacteremia on the outcomes of these patients is poorly understood.

In this study, we investigated the clinical characteristics and outcomes of severe CAP patients with bacteremia compared with subjects without bacteremia. In addition, we evaluated clinical factors that clinicians could use to target patients in whom blood cultures are most likely to yield a pathogen associated with bacteremia at the time of sepsis awareness.

During the study period, a total of 5,718 patients with community acquired sepsis were registered in the Korean Sepsis Alliance registry. Among them, 1,997 patients without blood cultures and 566 patients with suspected multiple sites or unclear site of infection were excluded. Of the 3,155 patients with community acquired sepsis and blood cultures, 1,510 (47.9%) sepsis patients caused by CAP were finally enrolled in this study. Out of 1,510 patients, 107 (7.1%) patients had blood cultures drawn after starting antibiotics. Pulmonary infection was most common suspected infection site, followed by abdominal and urinary tract infection (Fig. 1).

In the present study, we investigated the clinical characteristics and effects of bacteremia on severe CAP. We found that severe CAP patients with bacteremia had increased mortality compared with subjects without bacteremia. The bacteremia incidence was 14.0%, and hematologic malignancies and septic shock were associated with bacteremia occurrence.

Previously, the bacteremia incidence was suggested to vary based on infection site. In previous bacteremia studies, intra-abdominal infection was the most common cause of bacteremia, followed by urinary tract infection with increased bacteremia up to 24–26% [23, 24]. In the present study, the incidence of bacteremia was 42.5% in intra-abdominal infection and 50.3% in urinary tract infection in sepsis patients.

Positive blood cultures were found in approximately 5%–14% of CAP patients [25, 26], similar to the 14.0% identified in this study. Due to low bacteremia incidence in CAP, many clinicians question the need to perform blood cultures for all pneumonia patients. For select CAP patients requiring blood culture, some studies evaluated risk factors for bacteremia [9, 27]. Metersky et al. found that prior antibiotics, underlying liver disease, decreased systolic blood pressure, decreased or increased body temperature, increased pulse rate, increased blood urea nitrogen, decreased serum sodium, and leukocytosis or leukopenia were associated with bacteremia in patients with CAP [9]. Lee et al. reported that low blood pressure, increased pulse rate, decreased or increased body temperature, leukocytosis or leukopenia, thrombocytopenia, decreased serum albumin, and increased serum C-reactive protein were associated with bacteremia in patients with CAP at the EDs [27]. Previous studies included laboratory test results that could be delayed by hours before results were available, making these clinical factors impractical in the real world, especially sepsis patients.

One of the components of the Hour-1 bundle is obtaining blood culture. Although blood culture is considered the most sensitive method for detection of bacteremia in critically ill patients, routine blood cultures in a crowded ED is not an efficient use of resources [28, 29].

A recent multicenter observational study of sepsis in the ED also reported that only 58% of sepsis patients obtained blood cultures within 1 h after ED visit [30]. In this study, we found several clinical factors that can be easily assessed at recognition of sepsis including several co-morbidities and shock status. We also found that underlying clinical condition are closely associated with increased bacteremia risk in severe CAP. Therefore, blood cultures should be performed in patients at risk for bacteremia, concomitant with sputum culture in patients with severe CAP. Previous studies did not find the impact of comorbidities on the risk of bacteremia [12, 19]. However, in this study, we identified hematologic malignancy as important risk factors for bacteremia. A potential explanation for the lack of significant differences in comorbidities in previous studies may be related to differences in the study population and the comparison groups. Jeon K et al. [12] compared sepsis and septic shock patients regardless of infection site. Margret M et al. [19]compared patients according to the presence of bacteremia among those with nosocomial pneumonia. However, in our study, we compared patients according to the presence of bacteremia among those with severe CAP. Some comorbidities may predispose patients to specific types of pathogens that are more likely to cause bacteremia. For instance, diabetes mellitus has been shown to increase the risk of Staphylococcus aureus bacteremia [31, 32]. Therefore, further studies are needed to elucidate the role of comorbidities in the pathogenesis and outcome of bacteremia in patients with severe CAP.

The most common pathogen in CAP is Streptococcus pneumoniae, which accounts for two-thirds of bacterial pneumonia [33], followed by Mycoplasma pneumoniae and Haemophilus influenzae. Lanks et al. demonstrated a relationship between bacterial pathogens and CAP severity. In their study, S. aureus, Legionella, and H. influenzae were associated with increased disease severity [34]. However, our study showed different results, with K. pneumoniae being the most common pathogen regardless of bacteremia, followed by E. coli and S. aureus in the bacteremia group and S. aureus and P. aeruginosa in the non-bacteremia group. This is likely due to differences in geographic and hospital-specific characteristics [35], and reaffirms that empiric antibiotic administration in consideration of geographic differences.

The study was conducted during the coronavirus disease (COVID)-19 pandemic, which may have changed the epidemiology of bacterial pneumonia due to infection control practices. This could introduce a selection bias in our results. A recent study of COVID-19 pneumonia patients by Rouze A, et al. reported that most of the early identification of bacterial coinfection was related to gram-positive cocci, predominantly S. aureus, and was associated with increased for 28-day mortality [36]. They suggested that the lack of estimates for the prevalence of bacterial infections and the inability to exclude bacterial involvement definitively have led to the widespread prescription of empirical antimicrobial therapy. Moreover, another study also found a high rate of early bacterial infection during severe COVID-19 pneumonia, and a high rate of S. aureus [37]. In our study, S. aureus also showed the highest frequency among gram-positive cocci, indicating that community-acquired infections are influenced not only by geographical factors but also by environmental factors such as prevalence of bacterial pathogen.

The definition and exclusion of bacterial contamination in bacteremia cases with non-pulmonary sources are inconsistent. As previously stated, coagulase-negative staphylococci, Corynebacterium spp., Clostridium spp., Bacillus spp., Micrococcus spp., and Propionibacterium spp. are considered contaminants in blood cultures of CAP patients. In contrast, they are often the actual pathogens in non-pulmonary sources. This discrepancy may result in a higher rate of bacteremia for non-pulmonary infections than for pulmonary infections. Thus, our data are not readily comparable with the reported incidence of bacteremia in non-pulmonary infections.

Bacteremia is a significant cause of morbidity and mortality in critically ill patients [38]. Although only a few studies exist on bacteremia and CAP, our study, like previous studies on nosocomial blood stream infections, found that in-hospital mortality was significantly higher in the bacteremia group than in the non-bacteremia group. This finding should be validated in future studies of CAP, depending on disease severity.

The incidence of bacteremia in severe CAP was low at 14.0%, but the occurrence of bacteremia was associated with increased hospital mortality. Bacteremia in severe CAP was associated with hematologic malignancy and septic shock. These easily assessable clinical factors have important implications for the initial assessment and management severe CAP patients at ED.