Bloodstream infections and mortality-related factors in febrile neutropenic cancer patients

Background

Chemotherapy-induced neutropenia is a major adverse effect of cancer treatment. Bacteremia (BSI) was documented in blood cultures (BC) in 11–30% of the febrile neutropenia (FN) episodes [1–5]. The mortality from FN may be as high as 10%, depending on the population studied, and FN is still responsible for the majority of chemotherapy-associated deaths [6–8]. It includes a spectrum of clinical syndromes ranging from non-infectious fever to severe life-threatening infections. Patients with FN and bacteremia form a small subgroup within this spectrum, including severely infected patients. The epidemiology of bacteremic febrile neutropenia constitutes the basis for selection of empiric antibiotic therapy for febrile neutropenia [9]. There has been a shift from the predominance of gram-negative bacteria to predominance of gram-positive bacteria in many centers over the past 2 decades [10–13]; however, in recent years there has been a reverse of this trend in several centers. In fact, these centers reported the re-emergence of gram-negative bacteria in febrile neutropenic patients [14,15]. The significant variability between locations requires investigation of local trends to guide more appropriate antibiotic treatment.

Therefore, we performed a prospective cohort study to evaluate the causative bacteria and to identify risk factors for mortality in febrile neutropenic patients with BSI.

Material and Methods

STATISTICAL ANALYSIS:

The SPSS 11.5 (Chicago, IL) package program was used for statistical analysis. Univariate statistical analysis including Student’s t test was used for continuous data. Chi-square and Fisher’s exact test were used for categorical data. P values of <0.05 were considered significant. Multivariate logistic regression analysis was performed to determine risk factors independently associated with mortality.

Results

Throughout the study period, the patients developed 420 febrile neutropenic episodes. Out of 420 episodes, only 90 (21.4%) were found to have BSI. The mean age of the patients was 45.6±18.4 years and 55.6% of the patients were male. The median time to development of BSI was 9.4±10.7 days (range 1–63). A total of 98 isolates were recovered from the cases of BSI. Polymicrobial bacteremia was detected in 6 episodes (6.7%). Forty-nine patients (54.4%) were in the low-risk group, 78 (86.7%) had hematogenous malignity, and 12 patients (13.3%) had solid malignancies. Thirty patients died. Of total bloodstream infections, 59.1% were nosocomial, and the most frequent underlying type of malignancy was AML (n=41). Table 1 shows the distribution of the patients by their diagnoses.

Gram-positive bacteria were more frequently isolated than gram-negative bacteria throughout the study period. Table 2 shows the distribution of causative bacteria. Coagulase-negative Staphylococcus (CoNS) spp. was the most common bloodstream isolate overall (33.7%), followed by E. coli (21.4%). Gram-negative bacteria were found in 30.7% of the isolates in 2004 and 2005, 42.8% of the isolates in 2006 and 2007, and 62.8% of the isolates in 2008 and 2009. The distribution of BSI episodes (n=90) according to study years were 26 episodes (28.9%) in 2004–5; 21 (23.3%) episodes in 2006–7 and 43 (47.8%) episodes in 2008–9. Percent of gram-positive bacteremia (n=42) according to study years were 18 (42.9%) episodes in 2004–5; 10 (23.8%) episodes in 2006–7, and 14 (33.3%) episodes in 2008–9. Occurrence of gram-negative bacteremia (n=44) according to study years was 8 (18.2%) episodes in 2004–5, 9 (20.5%) episodes in 2006–7, and 27 (61.4%) episodes in 2008–9 (Figure 1). There was a significant increase in the rate of gram-negative bacteria throughout the study period (p=0.028); in fact, there was a striking increase, especially in the rate of acinetobacteria (p=0.029). Acinetobacteria were not found (0%) in the first 2 years of the study, comprised 4.7% of the isolates in the second 2 years of the study, and 18.6% of the isolates in the third 2 years of the study (Figure 2). Thirty-five microorganisms isolated (35.7%) were MDR.

Univariate analyses (Table 3) showed a significant relation between mortality and MASSC scores (p=0.000) and several characteristics of causative agents. The relation between mortality and gram-negative bacteria, acinetobacteria, nonfermentative bacteria, stay in intensive care unit (ICU) wards and coagulase-negative staphylococci (CoNS) was significant (p=0.002, 0.005, 0.009,0.002,0.0001, 0.0001, respectively).

Multivariate analyses showed that MASSC scores (p=0.0001, OR=15.1, CI%95 4.5–50.7), stay in ICU wards (p=0.0002, OR= 8.6, Cl%95 1.101–68,157) and CoNS were independent risk factors associated with mortality (p=0.004, OR=12.12, CI%95 2.3–64.7) (Table 3). BSI due to CoNS was associated with lower mortality; however, MASCC high risk score and ICU stay were associated with higher mortality.

Discussion

Our study found that 21.4% of the febrile neutropenic patients with cancer had BSI. This is consistent with other reports showing that up to 30% of the episodes of FN are associated with confirmed bacteremia [5,6–18]. The most commonly isolated bacteria in the present series were CoNS, which accounted for 33 of 98 (33.7%) blood culture isolates, similar to other studies [5,19].

Overall, gram-positive organisms accounted for nearly 50% (n=47, 47.9%) of all blood culture isolates. These data support the documented high rates of gram-positive infections in cancer patients with FN [6–19]. In fact, prior studies revealed that 50%–71% of the etiological agents found in microbiological analyses in FN patients with BSI were gram-positive bacteria [5,21,22,23]; however, the rate of gram-negative infections is on the rise in some centers [24,25,26]. Recently, non-fermentative gram-negative rods such as Acinetobacter species have appeared as pathogens in FN patients [20,21].

Although the most frequent causative agents were gram-positive bacteria throughout the study period, there was a significant increase in gram-negative bacteria, especially acinetobacteria, in the last 2 years of the study; 30.7% and 62.8% of the isolates had gram-negative bacteria in the first and the last 2 years of the study, respectively. Recently, Chen et al reported that gram-negative bacteria were the predominant pathogens (60%) and that fungi were relatively uncommon (6%) in bloodstream infections in patients with neutropenia. In addition, the number of Acinetobacter and Stenotrophomonas infections increased from 2002 to 2006, and were the third (7%) and fourth (6%) most frequent after E. coli and Klebsiella[27].

A. baumannii and S. maltophilia were found in 1–3% of the bloodstream isolates from neutropenic patients in the USA and Europe [22,28]. However, in some areas the frequency of A. baumannii complex in neutropenic patients is reportedly higher, at 6–9% [21,24,29]. According to data from the infection control committee of our hospital, there has been an increase in acinetobacteria resistant to multiple antibiotics in the past few years. This increased rate of acinetobacteria in FN patients can be attributed to nosocomial transmission.

Our multivariate analysis revealed that isolation of a CoNs strain and MASSC index-score are independent predictors of mortality in patients with FN and BSI. Uys et al showed that the MASCC risk-index score correctly identifies low- and high-risk patients at presentation with febrile neutropenia [30]. This study showed that the MASCC risk-index score had a positive predictive value of 98.3% and a negative predictive value of 86.4%, with both a sensitivity and specificity of 95%.

We found that mortality was 10.2% in the low-risk patients with the MASSC score of 21 and above and 60.8% in the high-risk patients (p=0.000). Consistent with the results of the present study, Klastersky et al. [22] reported a relatively low rate of overall complications (18%) and death (3%) in low-risk patients with bacteremia and MASCC scores of >21, but that when the MASCC score was <21, the corresponding figures were 49% and 19% (P<0.001). When the score was <15, overall complications (79%) and mortality (36%) were even higher. In fact, when the score was 15–20, the rates of complications and mortality were 40% and 14%, respectively. In our study, 13 patients had a MASCC score index <15. Mortality rate was higher (76.9%) in this group. This results was statistically significant (p=0.0001) and similar to the results of Klastersky’s study. Based on MASSC scores, low-risk and high-risk patients with BSI can be identified easily, and, accordingly, an appropriate therapy can be given to the high-risk patients in order to decrease the very high overall complication and mortality rates seen in these patients [22]. We also found that CoNS bacteremia was a predictor of a very low mortality (6.9%). Klastersky et al. found a mortality of 6% in patients with CoNS and a higher mortality of 18% in patients with gram-negative bacteria (p<0.001). In the present study, the mortality was 16% in patients with gram-positive bacteremia, but 47% in patients with gram-negative bacteremia.

Prior studies have revealed that gram-negative bacteremia is usually associated with higher case fatality rates than gram-positive infections, and that the risk is further increased due to antimicrobial resistance if effective treatment is delayed [23,31–34].

In the present study, 43.2% of gram-negative bacteria were multi-drug resistant, and 20.5% of these bacteria were highly resistant bacteria such as acinetobacteria. This might have contributed to the increase in the mortality due to gram-negative bacteria. In addition, gram-positive bacteria are isolated easily and quickly; therefore, they are easily identified, which allows treatment. This may explain the low mortality from gram-positive bacteria.

Conclusions

There has been an increase in the rate of bloodstream infections due to antimicrobial-resistant gram-negative bacteria in FN patients. Bacterial epidemiology and antimicrobial resistance in these patients should be regularly monitored, which will provide guidance for local policies for the use of antimicrobial agents and the assist in the choice of agents for empirical antibiotic therapy and prophylaxis in FN patients. The MASCC risk-index score and emerging of CoNS in positive blood cultures are valuable tools in the management of patients with febrile neutropenia, and can be used to accurately predict mortality in patients with BSI.