Characteristics and clinical outcomes of culture-negative and culture-positive septic shock: a single-center retrospective cohort study

The incidence of sepsis and septic shock has been increasing worldwide over the past decade, and its morbidity and mortality are still unacceptably high [1]. Early resuscitation for maintaining adequate tissue perfusion and the choice of proper antibiotics are mainstays to improve outcomes [2]. Although current guidelines recommend obtaining cultures before prescribing empirical antibiotics, in many cases, isolation of specific organisms by culture remains challenging. Previous studies have reported the proportion of culture-negative cases was between 28 and 49% of all patients with sepsis [3‐5]; however, clinical outcomes between culture-negative and -positive patients have only been documented inconsistently and are controversial. Moreover, there is a remarkable paucity of investigations evaluating the characteristics and clinical outcomes of culture-negative patients with septic shock, especially among those visiting emergency departments.

Time-to-positivity (TPP) is defined as the duration of time from the start of incubation to the detection of bacterial growth by an automated culture system. It has been suggested as a prognostic marker of a fatal outcome. Numerous reports have revealed that a shorter TTP is associated with mortality among patients with each specific type of bacteremia [6, 7]. Septic shock is a heterogeneous syndrome, involving a variety of microorganisms and affecting numerous vital organs. However, the relationship between TTP and the entire sepsis entity is rarely reported.

We hypothesized that culture negativity was associated with worse outcomes than culture positivity because identifying the pathogens might help physicians choose the most appropriate antibiotics and determine the optimal duration of their use. Moreover, we presumed that an earlier detection time of culture could reflect the extent of bacterial loading and would be correlated with the severity of the illness. To prove this, we compared the clinical characteristics and outcomes of culture-negative septic shock (CNSS) cases versus culture-positive septic shock (CPSS) cases. We also evaluated the relationship between TTP and 90-day mortality in patients with septic shock.

During the study period, 2,499 adult septic shock patients visited the emergency department, and 781 were not included in this study due to the exclusion criteria (218 transferred from/to other hospitals, 298 had do-not-resuscitate orders, 89 refused treatment, and 176 had known viral or fungal pathogens) (Fig. 1). Of the 1,718 cases, 706 (41.1%) were in the CNSS and 1,012 (58.9%) were in the CPSS group.

Table 1 presents the baseline characteristics of the study population according to the culture results. The CPSS group tended to be older and had a higher proportion of female patients. All underlying diseases, except chronic kidney diseases (10.9 vs. 18.1%, P < 0.01; CPSS vs. CNSS, respectively), were similar between the groups. Patients who were pathogen-positive showed slightly lesser tachypnea and a higher mean body temperature than those who were pathogen-negative. In the laboratory results, initial lactate (3.2 vs. 2.5 mmol/L, P < 0.01) and total bilirubin (1.3 vs. 0.9 mg/dL, P < 0.01) were elevated more in the CPSS than in the CNSS patients. Furthermore, the initial SOFA score (8.0 vs. 7.0, P < 0.01) was higher, and source control (44.6 vs. 28.6%, P < 0.01) and the escalation of antibiotics (15.6 vs. 4.4%, P < 0.01) were more frequent in patients with CPSS.

Escherichia coli was the most common causative organism, followed by Klebsiella species (including Klebsiella pneumoniae, oxytoca, and ornithinolytica) (Table 2). Gram-positive bacteria, such as Staphylococcus and Streptococcus, were less frequent than Gram-negative bacteria. An additional table shows this in more detail [see Additional file 2].

Figure 2 shows the frequencies of infection focuses and culture types according to the culture results. Lower respiratory tract and gastrointestinal focuses were the most frequent sites in the negative culture cases; meanwhile, the urinary tract and hepatobiliary pancreas were the most common sites among the positive culture cases. Blood cultures were predominantly performed and showed the highest positive rates (47.1%) followed by the others (32.8%), including pleural effusion, ascites, open pus, and closed pus obtained by endoscopic or percutaneous drainage.

For the clinical outcomes, both groups had similar ICU admission rates, ICU length of stay, and requirements for renal replacement therapy (Table 3). The CNSS patients had higher requirements for mechanical ventilators; however, the median duration of mechanical ventilator use was not different between the groups. Moreover, multivariate logistic regression was performed for the variables that were statistically different in the univariate analysis [see Additional file 3], and the effect of culture positivity on the requirements for mechanical ventilators disappeared after adjusting for the confounders [see Additional file 4]. There was no multicollinearity among the variables, especially between the lactate level and SOFA score (variance inflation factors 1.084). The in-hospital and 90-day mortalities were similar in both groups. Subgroup analysis according to the sites of infection showed that patients with lower respiratory infections had the highest in-hospital mortality (38%) [see Additional file 5]. Figure 3 represents a comparison of 90-day survivor curves between patients with CNSS and CPSS. They showed similar 90-day survival rates (log-rank P = 0.56).

The median TPP for the culture-positive pathogens detection time was 9.5 h (aerobic 10.2 h and anaerobic 9.0 h), and most of the aerobic and anaerobic detection times were within 16 h (Fig. 4). Although the 90-day survivor and nonsurvivor groups had similar detection times (9.6 [IQR 8.1–11.9] vs. 9.4 h [IQR 8.0–12.2] for aerobe; 8.4 [IQR 6.8–10.1] vs. 8.4 h [IQR 6.8–11.0] for anaerobe), the shorter TPP of both aerobe and anaerobe was correlated with higher SOFA scores (Spearman’s rho = − 0.12, p < 0.01 for aerobe; Spearman’s rho = − 0.10, p = 0.01 for anaerobe) (Fig. 4).

Our results demonstrated that (1) about 41% of patients with septic shock were culture-negative; (2) patients with CNSS showed similar in-hospital and 90-day mortality as those with CPSS; and (3) a shorter detection time of both aerobes and anaerobes was correlated with a higher SOFA score but not with mortality.

This study found that negative culture results were quite common in septic shock patients, which is supported by the findings of a recent retrospective study using nationwide data covering ten years that revealed that the incidence of culture-negative status among patients with severe sepsis was increasing annually by about 28% [15]. The reasons for the continuous increment of culture negativity could be multifactorial. First, the patients could have been prescribed empirical antibiotics at local clinics before sepsis developed [16]. Second, the proportion of sepsis cases caused by atypical pathogens, including viral and fungal infections, might be increasing [17, 18]. In these cases, conventional cultures, such as blood, urine, stool, and pus swabs, were not enough to detect the pathogens, but definitive evaluations could be helpful. For example, our results showed that sputum cultures had a quite low positivity rate, and bronchial aspiration could enhance the possibility of identifying the causative pathogens [19]. Third, some of the patients with negative cultures had sepsis that was the result of noninfectious causes, such as metabolic disorders, inflammatory diseases, adverse effects of drugs, or malignancies. However, the proportion of those mimics would not be significant and not change the results because all of the data in this registry were reviewed retrospectively by experienced physicians before the final analysis.

Our study also found that CNSS behaved quite similarly to CPSS. Looking at the literature, Gupta et al. reported that severe sepsis cases with negative cultures had more comorbidities and organ failure, and it was an independent predictor of death after adjusting for confounders (OR 1.75 [95% CI 1.72–1.77]) [15]. On the other hand, two retrospective studies found that culture-negative and culture-positive severe sepsis had similar outcomes after adjusting for confounders, such as demographics, the site of infection, and appropriate antibiotics [20, 21]. These differences are likely due to differences in patient populations, proportions of the sites of infection, and resistance of the bacteria to antibiotics. For example, our study included much older patients (mean 66.0 vs. 63.0 years) with higher proportion of malignancies (45.5 vs. 7.0%) compared with the retrospective study of Phua et al. [20]. Furthermore, the sites of infection were also quite different between the studies. Because sepsis is a heterogeneous syndrome, infectious sites with specific organisms may have totally different clinical characteristics. One multicenter, prospective study in Japan supported this assumption that the clinical characteristics and outcomes of patients with severe sepsis and septic shock varied according to the sites of infection [22]. Their finding was also consistent with ours that urinary tract infections were associated with less in-hospital mortality than that of the others [see Additional file 5]. Interestingly, lower respiratory and intra-abdominal infections were predominant in our culture-negative group, which suggests the site of infection may be associated with CNSS. Previous retrospective studies found that culture-positive patients with lung and intra-abdominal infections were associated with poor outcomes [23, 24]. The authors thought that culture negativity might imply susceptibility to the initial antibiotic regimens prescribed, leading to a lesser severity of illness. On the other hand, subgroup analyses of our study showed higher mortality among CNSS with lung infections that could lead to different outcomes, suggesting that the clinical outcomes may be associated with not only the infection sources but also the management of the shock.

We also explored the correlation between time to blood culture positivity and outcomes. TPP may provide practical information because a short incubation time can reflect a higher bacterial load with greater virulence [25]. Moreover, TPP has a prognostic role in some specific disease entities, such as catheter-related bloodstream infections and infective endocarditis [26, 27]. One notable finding was that the TTPs of both the aerobic and anaerobic bottles were distributed within 16 h in the CPSS, which was significantly shorter than that of a prior study of Staphylococcus aureus bacteremia (11.0 vs. 21.8 h) [28]. Septic shock, the most severe form of infection, generally presents with a higher bacterial load. In contrast to our initial hypothesis, we found that a quick detection time of the microorganism was correlated with greater severity of the disease with a higher SOFA score, but not with mortality. These results could be interpreted to mean that although a faster TTP could imply a high bacterial load, a shorter time could give more timely information about the antibiotics susceptibility and help with the selection of the proper antimicrobial agents [29].

We noticed several limitations to our study. First, the study results were derived from a single institution retrospectively, which therefore limited its generalizability to other populations. Second, there could be unmeasured confounders, including the selection, timing, and duration of antibiotics, which might lead to different outcomes. However, we tried to include numerous well-known variables related to the outcomes of sepsis in the multivariate analysis, such as age, lactate, source control, and SOFA score. Third, some culture-negative results were because of inappropriate sampling. Nonetheless, most culture samples were obtained by experienced nurses and physicians, and this was less likely to be a significant confounder.

In conclusion, our study confirmed that about 40% of patients with septic shock are culture-negative. CNSS patients had similar clinical outcomes as those who had CPSS, which means CNSS and CPSS status did not demonstrate prognostic value in our investigation. Moreover, an early detection time to culture positivity is not associated with mortality.