Predictive scoring models for persistent gram-negative bacteremia that reduce the need for follow-up blood cultures: a retrospective observational cohort study

Although the positive rate of detection from follow-up blood cultures (FUBCs) in gram-negative bacteremia (GNB) is relatively low (5.8–10.9%) [1‐3], and the risk factors for persistent GNB have not been investigated extensively, FUBCs have been routinely conducted in cases of GNB in many acute care hospitals [1‐4]. Unnecessary routine blood cultures are invasive, and false positives due to contamination increase medical costs and time spent in hospitals [2, 5, 6]. The authors of a previous study identified the risk factors for persistent bacteremia, and fever was found to be the only risk factor associated with GNB [1]. Owing to the rarity of persistent GNB, the previous study had limitations, including an insufficient number of persistent GNB cases.

Recently, several studies have reported that a shorter course of antibiotics in uncomplicated GNB (hemodynamically stable patients who have received effective antibiotics and adequate source control) [7, 8] does not produce an inferior prognosis compared to a longer course. Further, a recent randomized control study showed that a 7-day course of antibiotic therapy in uncomplicated GNB was not inferior to a 14-day course. Thus, FUBCs may not be necessary for the management of uncomplicated GNB, since it can be adequately treated by a short course of antibiotics [8].

Therefore, we attempted to identify the risk factors for a positive FUBC result in GNB and developed a predictive scoring model to reduce the need for performing unnecessary FUBCs.

Overall, 1481 GNB cases were identified during the study period. Of these, FUBCs were performed in 1276 cases (86.2%), and 122 produced positive results (9.6%) (Fig. 1). There were no cases of suspected contamination, and a new bacteremia was identified in eight cases of FUBC (Supplementary Table 1). Comparisons between the FUBC group and the no-FUBC group are shown in Table 1. Variables such as hematologic malignancy, the presence of an intravascular device, and the presence of extended spectrum beta lactamase (ESBL)-producing microorganisms were significantly higher in the FUBC group. There was no significant difference in the incidence of in-hospital mortality between the two groups.

Positive and negative clinical characteristics in the FUBC groups are compared in Table 2, according to the eradicability of the infection source, and the identified independent risk factors are listed in Table 3. In cases where the source of infection was eradicable, the independent risk factors were as follows: the presence of ESBL-producing microorganisms, catheter-related bloodstream infection, unfavorable treatment responses, a qSOFA score of at least 2 points, the administration of effective antibiotics, and adequate source control. In cases where the source of infection was non-eradicable, the independent risk factors were as follows: end-stage renal disease on hemodialysis, unfavorable treatment responses, and the administration of effective antibiotics. We assigned points to the independent risk factors for positive FUBC, based on the beta-coefficients from the logistic regression analysis (Table 3). In cases of eradicable and non-eradicable sources of infection, the values of the area under the curve of the receiver operating characteristic curve (AUC-ROC) of each scoring model were 0.861 (95% confidence interval (CI) 0.806–0.916) and 0.792 (95% CI, 0.724–0.861), respectively (Table 3, Fig. 2). The sensitivities, specificities, positive predictive values (PPVs), and negative predictive values (NPVs) according to the cut-off values are listed in Table 4.

When we applied a cut-off value of 0, the specificities of the eradicable and non-eradicable sources of infection were 95.6 and 95.5%, respectively. The NPVs of the predictive scoring models in the eradicable and non-eradicable source infections were 92.6 and 95.0%, respectively.

The percentage of positive FUBCs according to the scores of eradicable and non-eradicable source of infection is shown in Fig. 3. The percentage of positive FUBCs was less than 2% in cases with − 3 or − 2 points of eradicable or non-eradicable sources of infection, but 40 and 70% had positive FUBCs in cases with 1 or 2 points of non-eradicable or eradicable sources of infection, respectively.

Our study revealed that FUBCs were performed in most of the patients with GNB, but less than 10% produced positive results. In contrast to gram-positive bacteremia, positive FUBC results were not common in GNB [1, 3].

In eradicable sources of infection, variables such as ESBL-producing organisms, catheter-related bloodstream infections (CRBSIs), unfavorable treatment responses, and qSOFA scores of at least 2 were independent risk factors, but when effective antibiotics were administered and there was adequate source control the day before performing FUBC, the probability of negative conversion of bacteremia in FUBC increased significantly. When appropriate management (e.g., administration of effective antibiotics and source control) was performed, and there was a clear clinical response (qSOFA score < 2), the score predicted by the model did not exceed the cut-off value (zero points), and the probability of negative conversion in FUBC was as high as 92.6%. In Staphylococcus aureus infections, delays in the removal of eradicable sources of infection, the initial administration of inappropriate antibiotics, and delays in the delivery of appropriate antibiotics were important risk factors for persistent bacteremia [10, 12]. Early source control (within 48 h) was also important for eradicating bacteremia in both gram-positive and gram-negative bacteremia [3]. Therefore, as with S. aureus bacteremia, in cases of GNB with eradicable sources of infection—regardless of the site of infection, underlying diseases, or causative microorganisms—if there is appropriate management and the clinical response is favorable, FUBC provides little benefit.

In cases in which the source of infection was non-eradicable, hemodialysis and an unfavorable treatment response were independent risk factors. However, if effective antibiotics were administered to the patient, bacteremia was usually eliminated. If effective antibiotics were administered—regardless of the underlying disease, microorganism type, or treatment response—the score did not exceed the cut off-value (zero points), and the probability of negative conversion of bacteremia was 95.0%.

If FUBC was performed only in cases with more than zero points of both eradicable and non-eradicable source of infection, more than 90% of FUBCs could have been avoided in our study population (Fig. 3). Even if the cutoff value was more strictly set as − 1 to increase the NPV, more than 70% of FUBCs could have been saved. Therefore, performing FUBC to evaluate the response to treatment can be avoided in most uncomplicated cases of GNB. In GNB cases, FUBC could be applied selectively to patients with a high risk of positive FUBCs, unlike in S. aureus bacteremia or candidemia.

The contamination rate of peripheral blood cultures in our hospital is as low as 0.5%, and among the 1276 cases of FUBC in our study, there were no suspected cases of contamination. However, contamination rates in blood cultures have been reported ranging from 0.9–7.9% [5]. In other studies related to FUBCs, contaminants were identified in 2.0–3.9% of FUBCs [13, 14]. Therefore, universal FUBCs of all gram-negative bacteremia may produce contamination, which could lead to increased medical costs and prolonged hospital stays [5].

Recently, one study revealed that FUBC was a useful diagnostic tool for differentiating septic thrombophlebitis in gram-negative bacteremia of patients admitted to the intensive care unit (ICU) for polytrauma [15]. If the patient had a high-risk of persistent GNB and risk factors for deep vein thrombosis, such as the presence of a central catheter, multiple traumas or admission to the ICU [16, 17], further diagnostic evaluation, such as CT angiography and duplex sonography as well as FUBCs to differentiate septic thrombophlebitis, could be considered.

Recent studies revealed that when FUBCs were performed in cases of gram-negative bloodstream infection, they were associated with improved clinical outcomes [13, 14]. However, the proportion of FUBCs performed was relatively low (17.6–68%) compared to our present study (86.2%). In addition, the rates of positive FUBC (20–38.5%) and all-cause mortality (10–13.7%) were higher than in our study population (9.7% positive-FUBC rate and 6.8% in-hospital mortality in the FUBC group). This means that FUBCs were selectively performed in severe GNB cases in these previous studies. It cannot be concluded that FUBC improves the prognosis in all GNB, especially in uncomplicated bacteremia. The FUBC group in these studies had a trend of longer treatment duration and hospital stays than the no-FUBC group, and contaminants were identified in 2.0–3.9% of FUBCs. If FUBC is conducted routinely in uncomplicated GNB, it may increase medical costs and cause various side effects due to prolonged antibiotic treatment. Therefore, the decision of conducting an FUBC should be made carefully, and our predictive scoring model will help with that decision. Appropriately conducted FUBCs, according to the results of our predictive scoring model, may improve clinical outcomes and reduce side effects and medical costs.

Our study has some limitations. First, there may have been bias towards the FUBC group, because the study was conducted retrospectively. However, variables such as hematologic malignancy, presence of an intravascular device, and ESBL-producing microorganisms—which were significantly more prevalent in the FUBC group than in the no-FUBC group— were also significant risk factors for positive FUBCs (Table 1). This means that there was a higher probability of persistent bacteremia in the FUBC group than in the no-FUBC group. The NPVs of predictive scoring models in real-world cases of GNB would be higher than those indicated in the present study. Therefore, this selection bias did not alter our conclusion. Second, we did not determine how FUBC affects patient outcomes such as mortality, morbidity, length of stay in hospital, or total cost of medical care. Therefore, our findings alone will not be sufficient to change routine practice. As discussed above, recent studies have shown that FUBC was associated with improved outcome of GNB [13, 14], but these results couldn’t be applied to the uncomplicated GNB. Further investigations such as a prospective randomized control study should be conducted to reveal the exact clinical impact of FUBC in GNB.

In this study, although FUBC was commonly used in cases of GNB, there were few positive results (< 10% of cases). We expect that the application of our simple predictive scoring model will reduce the need for performing unnecessary FUBC in uncomplicated cases of GNB.