Risk factors for resistant Gram-positive bacteremia in febrile neutropenic patients with cancer

doi:10.21203/rs.3.rs-2887646/v1

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Risk factors for resistant Gram-positive bacteremia in febrile neutropenic patients with cancer

https://doi.org/10.21203/rs.3.rs-2887646/v1

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published 01 Mar, 2024

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Purpose

Gram-positive bacteria are frequently resistant to empirical beta-lactams in febrile neutropenic patients with cancer. As microbiology and antibiotic susceptibility changes, we reevaluated the risk factors for resistant Gram-positive bacteremia in febrile neutropenic patients with cancer.

Methods

Episodes of bacteremic febrile neutropenia in Seoul National University Hospital from July 2019 to June 2022 were reviewed. Resistant Gram-positive bacteria were defined as a pathogen susceptible only to glycopeptide or linezolid in vitro (e.g., methicillin-resistant staphylococci, penicillin-resistant viridans streptococci, and ampicillin-resistant enterococci). Episodes were compared to identify independent risk factors for resistant Gram-positive bacteremia.

Results

Of 225 episodes, 78 (34.7%) involved resistant Gram-positive bacteremia. Multivariate analysis revealed that breakthrough bacteremia while being administered antibiotics (adjusted odds ratio [aOR], 8.006; 95% confidence interval [95% CI], 3.532–18.151; P < 0.001), catheter-related infection (aOR 4.425, 95% CI 1.469‒13.331; P = 0.008), and skin or soft tissue infection (aOR 24.421, 95% CI 2.043‒291.862; P = 0.012) were associated with resistant Gram-positive bacteremia. Chronic liver disease (aOR 0.245, 95% CI 0.063‒0.973; P = 0.046) and hypotension at bacteremia (aOR 0.462, 95% CI 0.219‒0.972; P = 0.042) were inversely associated with resistant Gram-positive bacteremia.

Conclusion

Resistant Gram-positive bacteria should be considered in breakthrough bacteremia, catheter-related infection, and skin or soft tissue infection in febrile neutropenic patients with cancer.

febrile neutropenia

bacteremia

Gram-positive bacteria

resistance

cancer

Bacteremia is an important complication of febrile neutropenia in cancer patients, leading to an increased mortality and economic burden (1, 2). Early administration of appropriate empirical antibiotics in bacteremic febrile neutropenia is critical to improve clinical outcomes (3). However, Gram-positive bacteria, such as Staphylococcus or Enterococcus species, are frequently resistant to beta-lactams, which are recommended as empirical antibiotics for febrile neutropenic patients. Moreover, the resistance rate of Gram-positive bacteria has increased, resulting in poor prognoses (4, 5).

A meta-analysis of randomized controlled trials of the empirical addition of antibiotics targeting resistant Gram-positive bacteria, such as vancomycin, teicoplanin, or linezolid, did not show a reduction in mortality of patients with febrile neutropenia (6). However, these antibiotics could be helpful in certain patients with risk factors for resistant Gram-positive bacterial infections, which include pneumonia, catheter-related infection, skin or soft tissue infection, and colonization by resistant Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus species (7, 8).

As microbiology and antibiotic susceptibility change over time, it is necessary to reevaluate indications for broad-spectrum antibiotics in certain infectious diseases (4, 9). Therefore, we explored the risk factors for resistant Gram-positive bacteremia in febrile neutropenic patients with cancer, which could guide clinicians regarding whether to administer empirical antibiotics for resistant Gram-positive bacteria in neutropenic patients with cancer.

Bacteremic episodes and patients

Among 312 reviewed episodes of bacteremic febrile neutropenia, 225 episodes were included in the analysis after excluding 41 episodes of recurrent bacteremia due to the same pathogen within 1 month, 39 contamination episodes, and seven episodes of polymicrobial bacteremia with both groups of bacteria. Of those, 78 episodes were included in the resistant Gram-positive bacteremia group and 147 were included in the other bacteremia group. Resistant Gram-positive bacteria made up 82.2% (83/101) of the Gram-positive bacteria, with the most commonly isolated bacteria being Enterococcus species (41.0%, 34/83), followed by Corynebacterium species (21.7%, 18/83) and coagulase-negative staphylococci (20.5%, 17/83) (Table 1). Gram-negative bacteria accounted for 88.5% (139/157) of the other bacteremia group, and Escherichia coli (46.8%, 65/139) and Klebsiella species (30.2%, 42/139) were common Gram-negative bacteria.

Table 1

Pathogens in bacteremic febrile neutropenia
Variables	Resistant gram-positive bacteria¹ (n = 83)	Other bacteria² (n = 157)
Gram-positive bacteria	83 (100.0)	18 (11.5)
Enterococcus species	34 (41.0)	5 (27.8)
Vancomycin-susceptible	15 (44.1)	5 (100.0)
Vancomycin-resistant	19 (55.9)	-
Corynebacterium species	18 (21.7)	-
Coagulase-negative staphylococci	17 (20.5)	1 (5.6)
Viridans streptococci	4 (4.8)	5 (27.8)
Staphylococcus aureus	5 (6.0)	2 (11.1)
Bacillus species	4 (4.8)	-
Others³	1 (1.2)	5 (27.8)
Gram-negative bacteria	-	139 (88.5)
Escherichia coli	-	65 (46.8)
Klebsiella species	-	42 (30.2)
Pseudomonas aeruginosa	-	5 (3.6)
Stenotrophomonas maltophilia	-	4 (2.9)
Citrobacter species		4 (2.9)
Enterobacter species	-	4 (2.9)
Acinetobacter baumannii	-	3 (2.2)
Others ⁴	-	12 (8.7)
Data are presented with numbers (%), if not otherwise specified.
¹ Pathogens were counted separately in 6 episodes of polymicrobial bacteremia.
² Pathogens were counted separately in 8 episodes of polymicrobial bacteremia.
³ Other gram-positive bacteria included Paenibacillus species, Micrococcus luteus, Clostridium tertium, and Streptococcus dysgalactiae.
⁴ Other gram-negative bacteria included Elizabethkinga meningoseptica, Acinetobacter junii, Raoultella planticola, Providencia rettgeri, Raoultella planticola, Morganella morganii, Bacteroides species, Leptotrichia species, Capnocytophaga species, and Salmonella species.

The median (interquartile range [IQR]) age was 54.5 (33–62) years in the resistant Gram-positive bacteremia group, which was younger than 60 (45–65) years for the other bacteremia group (P = 0.024, Table 2). Females accounted for 52.6% (41/78) and 51.7% (76/147) of the resistant Gram-positive bacteremia and other bacteremia, respectively. Hypertension (26.7%, 60/225) was the most common comorbidity, followed by diabetes mellitus (16.9%, 38/225) and chronic liver disease (10.2%, 23/225). Chronic liver disease was less common in the resistant Gram-positive bacteremia group than the other bacteremia group (3.8%, 3/78 vs. 13.6%, 20/147; P = 0.021). Hematological malignancies accounted for 82.2% (185/225) of all episodes, with a significantly higher frequency in the resistant Gram-positive bacteremia group (94.9%, 74/78 vs. 75.5%, 111/147; P < 0.001). Acute myeloid leukemia (49.2%, 91/185) was the most common hematological malignancy, followed by acute lymphoblastic leukemia (20.5%, 38/185) and myelodysplastic syndrome (10.8%, 20/185). Solid organ cancer accounted for 17.8% (40/225) of all episodes, and pancreatic cancer was the most common of those, making up 40.0% (16/40).

Table 2

Comparison of clinical characteristics between resistant gram-positive and other bacteremic episodes in febrile neutropenic patients with cancer
Variables	Resistant gram-positive bacteremia (n = 78)	Other bacteremia (n = 147)	P value
Age, years, median (IQR)	54.5 (33‒62)	60 (45‒65)	0.024
Sex, female	41 (52.6)	76 (51.7)	0.902
Comorbidities
Hypertension	22 (28.2)	38 (25.9)	0.704
Diabetes mellitus	8 (10.3)	30 (20.4)	0.053
Chronic liver disease	3 (3.8)	20 (13.6)	0.021
Chronic kidney disease or end stage renal disease	5 (6.4)	6 (4.1)	0.520
Cerebrovascular disease	-	5 (3.4)	0.166
Underlying cancer
Hematologic malignancy	74 (94.9)	111 (75.5)	< 0.001
Acute myeloid leukemia	39 (52.7)	52 (46.8)	0.435
Acute lymphoblastic leukemia	15 (20.3)	23 (20.7)	0.941
Myelodysplastic syndrome	10 (13.5)	10 (89.0)	0.334
Multiple myeloma	6 (8.1)	7 (6.3)	0.639
B-cell lymphoma	1 (1.4)	11 (9.9)	0.029
T-cell lymphoma	3 (4.1)	4 (3.6)	> 0.999
Others¹	-	4 (2.2)	0.151
Solid organ cancer	4 (5.1)	36 (24.5)	< 0.001
Pancreatic cancer	1 (25.0)	15 (41.7)	0.638
Hepatobiliary cancer	-	8 (22.2)	0.566
Gynecologic cancer	3 (75.0)	3 (8.3)	0.008
Others²	-	10 (27.8)	0.556
Hospitalization period until bacteremia, days, median (IQR)	23 (14‒48)	14 (1‒20)	< 0.001
Neutropenia duration until bacteremia, days, median (IQR)	11 (4‒28)	4 (1‒8)	< 0.001
Fever duration until bacteremia, days, median (IQR)	2 (1‒5)	1 (1‒2)	0.003
Absolute neutrophil count at bacteremia, cells/mm³
< 100	60 (76.9)	103 (70.1)	0.273
100–499	14 (17.9)	32 (21.8)	0.499
≥ 500	4 (5.1)	12 (8.2)	0.399
Presence of central venous catheter	70 (89.7)	120 (81.6)	0.110
Severity of bacteremia
Pitt bacteremia score, median (IQR)	1 (0‒2)	1 (0‒2)	0.013
Hypotension at bacteremia	17 (21.8)	58 (39.5)	0.007
Mechanical ventilation at bacteremia	5 (6.4)	12 (8.2)	0.636
Breakthrough bacteremia during antibiotic administration	66 (84.6)	56 (38.1)	< 0.001
3rd generation cephalosporin	1 (1.5)	6 (10.7)	0.047
Piperacillin/tazobactam	20 (30.3)	19 (33.9)	0.669
Cefepime	5 (7.6)	5 (8.9)	> 0.999
Carbapenem	36 (54.5)	15 (26.8)	0.002
Fluoroquinolone	6 (9.1)	10 (17.9)	0.153
Vancomycin or teicoplanin	9 (13.6)	7 (12.5)	> 0.999
Linezolid	-	3 (5.4)	0.094
Others³	1 (1.5)	5 (8.9)	0.093
Foci of infection
Primary bacteremia	32 (41.0)	50 (34.0)	0.298
Gastrointestinal tract	13 (16.7)	41 (27.9)	0.061
Catheter	15 (19.2)	7 (4.8)	0.001
Hepatobiliary	2 (2.6)	15 (10.2)	0.039
Perianal	3 (3.8)	14 (9.5)	0.125
Urinary tract	3 (3.8)	10 (6.8)	0.550
Pharyngo-tonsillar	3 (3.8)	5 (3.4)	> 0.999
Skin or soft tissue	4 (5.1)	1 (0.7)	0.050
Lung	2 (2.6)	2 (1.4)	0.611
Others⁴	1 (1.3)	2 (1.4)	> 0.999
Treatment outcome
7 day all-cause mortality	4 (5.1)	12 (8.2)	0.399
30 day all-cause mortality	10 (12.8)	17 (11.6)	0.783
IQR; interquartile range
Data are presented with numbers (%), if not otherwise specified.
¹ Other hematologic malignancy included chronic lymphocytic leukemia, natural killer-cell lymphoma, and blastic plasmacytoid dendritic cell neoplasm
² Other solid organ cancer included gastrointestinal tract cancer, bone cancer, breast cancer, urologic cancer, and thymoma.
³ Other antibiotics being administered in breakthrough bacteremia included colistin, amoxicillin/clavulanate, metronidazole, and amikacin.
⁴ Other foci of infection included vertebral osteomyelitis, necrotizing fasciitis, and intramuscular abscess.

Clinical characteristics of resistant Gram-positive bacteremia

The median (IQR) hospitalization period (23 [14‒48] vs. 14 [1–20] days, P < 0.001), duration of neutropenia (11 [4‒28] vs. 4 [1–8] days, P < 0.001), and duration of fever (2 [1–5] vs. 1 [1–2] day, P = 0.003) were significantly longer in the resistant Gram-positive bacteremia group than the other bacteremia group. The Pitt bacteremia score (median [IQR]; 1 [0‒2] vs. 1 [0‒2], P = 0.013) and percentage of hypotensive presentation at bacteremia (21.8%, 17/78 vs. 39.5%, 58/147; P = 0.007) were lower in the resistant Gram-positive bacteremia group. The percentage of breakthrough bacteremia was 84.6% (66/78) in resistant Gram-positive bacteremia, which was significantly higher than 38.1% (56/147) in other bacteremia (P < 0.001). Among breakthrough cases, the percentage of third generation cephalosporins was lower (1.5%, 1/66 vs. 10.7%, 6/56; P = 0.047), while that of carbapenem was higher (54.5%, 36/66 vs. 26.8%, 15/56; P = 0.002) in the resistant Gram-positive bacteremia group.

The percentage of catheter-related infection was 19.2% (15/78) in resistant Gram-positive bacteremia, which was higher than 4.8% (7/147) in other bacteremia (P = 0.001). Hepatobiliary infection was more frequent in the other bacteremia group than in the resistant Gram-positive bacteremia group (10.2%, 15/147 vs. 2.6%, 2/78; P = 0.039). There were no significant differences in the 7- and 30-day all-cause mortality between the two groups.

The administered empirical antibiotics in breakthrough and non-breakthrough bacteremia are shown in the Supplementary Table 1. The percentage of appropriate empirical antibiotics was lower in the resistant Gram-positive bacteremia group than the other bacteremia group in both breakthrough (16.7%, 11/66 vs. 50.0%, 28/56; P < 0.001) and non-breakthrough (8.3%, 1/12 vs. 64.0%, 57/91; P < 0.001) bacteremia.

Risk factors for resistant Gram-positive bacteremia

Multivariate analysis showed that breakthrough bacteremia (adjusted odds ratio [aOR], 8.006; 95% confidence interval [95% CI], 3.532–18.151; P < 0.001), catheter-related infection (aOR 4.425, 95% CI 1.469‒13.331; P = 0.008), and skin or soft tissue infection (aOR 24.421, 95% CI 2.043‒291.862; P = 0.012) were independently associated with resistant Gram-positive bacteremia (Table 3). Chronic liver disease (aOR 0.245, 95% confidence interval [95% CI] 0.063‒0.973; P = 0.046) and hypotension at bacteremia (aOR 0.462, 95% CI 0.219‒0.972; P = 0.042) were inversely associated with the resistant Gram-positive bacteremia group.

Table 3

Factors associated with resistant gram-positive bacteremia in febrile neutropenic patients with cancer by multivariate logistic regression analysis
Variables	Adjusted odds ratio (95% confidence interval)	P value
Breakthrough bacteremia	8.006 (3.532‒18.151)	< 0.001
Foci of infection
Catheter	4.425 (1.469‒13.331)	0.008
Skin or soft tissue	24.421 (2.043‒291.862)	0.012
Chronic liver disease	0.245 (0.063‒0.973)	0.046
Hypotension at bacteremia	0.462 (0.219‒0.972)	0.042

Resistant Gram-positive bacteremia was significantly associated with breakthrough bacteremia, catheter-related infection, and skin or soft tissue infection in febrile neutropenic patients with cancer. Chronic liver disease as an underlying disease and hypotensive presentation favor bacteremia by pathogens other than resistant Gram-positive bacterium.

We reevaluated the risk factors for resistant Gram-positive bacteremia in febrile neutropenic patients with cancer, which require specific antibiotics other than the primarily recommended empirical antibiotics. More than 10 years have passed since the international guidelines for febrile neutropenia were published. In that time, antibiotic resistance and causative microorganisms have changed (7, 8). In addition to coagulase-negative staphylococci and viridans streptococci, which were common Gram-positive pathogens in bacteremia of patients with febrile neutropenia, Enterococcus species are gradually increasing (9, 10). Resistant Gram-positive bacteria such as methicillin-resistant S. aureus and vancomycin-resistant enterococci are also increasing and are associated with higher mortality than coagulase-negative staphylococci (5, 10–12). Moreover, in a recent study, while 87% of patients were treated according to the Infectious Diseases Society of America guidelines, inappropriate empirical antibiotics were administered in 24%, and Gram-positive bacteria accounted for 62% of those (13). In the era of increasing microbial resistance, this study presents important data on risk factors for resistant Gram-positive bacteremia, which is important for administering appropriate empirical antibiotics in patients with bacteremic febrile neutropenia.

In this study, Enterococcus species were the most common Gram-positive bacteria, which might be because of the baseline characteristics of patients in this study commonly having risk factors for enterococcal infection in cancer patients, such as prolonged hospitalization period and breakthrough bacteremia (5, 14). Indeed, the overall antibiotic resistance rates of Gram-positive bacteria in this study were higher or similar than those in other studies. Similar to a previous study [14], Enterococcus faecium (89.7%, 35/39) was more frequent than Enterococcus faecalis (7.7%, 3/39) in this study. Vancomycin-resistant enterococci accounted for 48.7% (19/39) of the Enterococcus species in our study, much higher than the 23–26.4% reported in studies conducted in Europe and Korea (5, 9). Similarly, the resistance rate to methicillin in coagulase-negative staphylococci was 94.4% (17/18), higher than the 80% in a previous European study (9). The resistance rate to methicillin in S. aureus was 71.4% (5/7) in this study, higher than the 48.4–56% in studies conducted in Korea and Europe (9, 15). Of the viridans streptococci, 44.4% (4/9) showed intermediate susceptibility to penicillin, similar to the 40% reported in the United States (16). Several factors are associated with resistant Gram-positive bacterial infections in febrile neutropenic patients with cancer. A study of febrile neutropenia in patients with hematological malignancies reported that bacteremia due to resistant Gram-positive bacteria was more common in breakthrough bacteremia than in the first bacteremia, as our results (17). Of the antibiotics administered in breakthrough bacteremia, carbapenem was associated with resistant Gram-positive bacteria in the univariate analysis in this study. Carbapenem had limited activity against Gram-positive bacteria, such as methicillin-resistant staphylococci and E. faecium, and carbapenem administration may facilitate colonization and infection in patients with febrile neutropenia by depleting the normal gut flora and selecting resistant bacteria, such as Enterococcus species. As in a previous study that reported that the use of carbapenem is a risk factor for bacteremia due to E. faecium in cancer patients, we found that E. faecium was the most commonly isolated pathogen of breakthrough bacteremia with carbapenem administration, accounting for 55.6% (20/36) (14). Resistant Gram-positive bacterial infection should be considered in the management of breakthrough bacteremia that occurs with carbapenem administration. International guidelines recommend empirical antibiotics active against Gram-positive bacteria in catheter-related and skin or soft-tissue infections; our results concord with those findings (7, 8).

Bacteremia with hypotension and underlying chronic liver disease was associated with a reduced risk of resistant Gram-positive bacterial infection in our study. Gram-negative bacterial infection has been reported to have higher mortality and higher rates of accompanying hypotension than Gram-positive bacterial infection in bacteremia episodes of febrile neutropenia (1). Enterobacterales such as E. coli and Klebsiella species were identified as the causative bacteria in 69.6% (16/23) of the patients with chronic liver disease in our study, consistent with a study that reported that Gram-negative bacteremia was more frequent than Gram-positive bacteremia in patients with chronic liver disease (18).

Although a significantly higher percentage of inappropriate empirical antibiotics was administered in resistant Gram-positive bacteremia, there were no significant differences in the 7- and 30-day mortality between resistant Gram-positive bacteremia and other bacteremia. Gram-positive bacteria, such as coagulase-negative staphylococci, are less virulent and associated with lower mortality than Gram-negative bacterial infection (1, 12). However, in previous studies resistant Gram-positive bacteria, such as methicillin-resistant S. aureus and vancomycin-resistant enterococci, were associated with high mortality in febrile neutropenic patients (5, 11, 12). Therefore, it is difficult to interpret the failure to show a difference in mortality as indicating the low clinical importance of resistant Gram-positive bacterial infection. At our hospital, matrix-assisted laser desorption ionization–time of flight mass spectrometry is available which were known to reduce the mean turnaround time of bacterial identification from positive blood culture by more than 26.5 h (19). Rapid bacterial identification and subsequent adjustment of antibiotics might have resulted in no difference in mortality despite the use of inappropriate empirical antibiotics. The difference in mortality due to inappropriate antibiotic administration may be evident in resource-poor circumstances, where rapid bacterial identification is not available.

The main strength of this study was that it provides updated data on risk factors for resistant Gram-positive bacteremia in febrile neutropenic patients with cancer in the context of recent high antibiotic resistance. In this study, breakthrough bacteremia was an independent risk factor for resistant Gram-positive bacteremia, in addition to well-known risk factors, such as catheter-related infection and skin or soft tissue infection (7, 8). This study, which was conducted at a tertiary hospital with high rate of antibiotic resistance and inappropriate antibiotics administration, would reflect the situation that other medical institutions encounter as antibiotic resistance increases in clinical settings. The study results will aid clinical decisions regarding the administration of antibiotics targeting resistant Gram-positive bacteria in febrile neutropenic patients with cancer. In addition, when evaluating the effect of the empirical administration of antibiotics targeting resistant Gram-positive bacteria in patients with febrile neutropenia, the risk factors identified here can be considered when selecting subgroups that would benefit from empirical antibiotics.

This study had several limitations. First, it was a retrospective study performed at a single center. Our results have limited generalizability, as the distribution of causative microorganisms and epidemiology of microbial resistance vary greatly by center or region. Although a small number of episodes was analyzed, only data from the most recent 3 years were included to reflect the up-to-date status of microbiology and microbial resistance. Second, resistant Gram-positive bacteria formed a heterogeneous group of bacteria, including bacteria that acquired antibiotic resistance and bacteria with intrinsic antibiotic resistance. The aim of this study was to evaluate the factors requiring the administration of antibiotics targeting resistant Gram-positive bacteria, such as glycopeptide or linezolid, so the groups were subdivided according to in vitro antibiotic susceptibility.

Antibiotics targeting resistant Gram-positive bacteria, such as glycopeptide or linezolid, should be considered in breakthrough bacteremia, as well as catheter-related infection, skin or soft tissue infection, in bacteremia of febrile neutropenic patients with cancer.

Patients and study design

Episodes of bacteremic febrile neutropenia in patients with cancer at Seoul National University Hospital from July 2019 to June 2022 were reviewed using the electronic medical records. We screened all episodes of bacteremic febrile neutropenia in hospitalized patients older than 15 years (Fig. 1). If the same pathogen caused multiple episodes of bacteremia within 1 month, only the first episode was included in the study. Common skin commensals, such as coagulase-negative staphylococci and Cutibacterium acnes, were considered contaminants unless these organisms had been identified in more than two separate blood cultures (20).

For each bacteremia, we collected demographic variables, underlying cancers and other comorbidities, foci of infection, pathogens and their antibiotic susceptibility, antibiotics that had been administered before the bacteremia, and empirical regimens. The length of hospitalization, duration of neutropenia and fever, absolute neutrophil count at bacteremia, presence of a central venous catheter, and Pitt bacteremia score were also recorded (21).

Episodes were subdivided into the resistant Gram-positive bacteremia group and others, depending on the identified pathogen. Resistant Gram-positive bacteria were defined as pathogens susceptible only to glycopeptide or linezolid in vitro, such as methicillin-resistant Staphylococcus aureus or methicillin-resistant coagulase-negative staphylococci, penicillin-resistant viridans streptococci, ampicillin-resistant enterococci, and Corynebacterium, Bacillus, and Paenibacillus species (22, 23). Episodes with polymicrobial bacteremia with both groups of bacteria were excluded from the analyses. The clinical characteristics of and risk factors for resistant Gram-positive bacteremia were analyzed by comparing the two groups.

This study was approved by the Institutional Review Board at Seoul National University Hospital (No. 2208-106-1350). The need for informed consent was waived by institutional review board of Seoul National University Hospital because of the retrospective nature and minimal risk of the study. Personal identifiers were removed before data processing, and the study complied with the tenets of the Declaration of Helsinki.

Definitions

Febrile neutropenia was defined as absolute neutrophil count < 500 cells/mL or < 1000 cells/mL with a decline greater than 500 cells/mL within the next 48 h, with a single oral temperature ≥ 38.3°C or a temperature above 38.0°C for at least 1 h (7). Breakthrough bacteremia was defined as bacteremia that occurred while administering prophylactic or therapeutic antibiotics within 2 days before the bacteremia. Primary bacteremia was defined as bacteremia of unknown source in a patient who had only a fever with no other symptoms or signs. Catheter-related bacteremia was defined as bacteremia in the presence of an intravascular device with more than one positive blood culture from a peripheral vein, and either a positive catheter tip culture or a blood culture obtained through a catheter positive at least 2 h earlier than the blood culture drawn peripherally at the same time (24).

The appropriateness of antibiotics was evaluated according to the in vitro susceptibility of the identified pathogen. An inappropriate antibiotic regimen was defined as a lack of antibiotics active against the isolated pathogen in vitro. In the case of polymicrobial infections, the antibiotic regimen was regarded as appropriate when all isolated bacteria were susceptible to the administered antibiotics. Empirical antibiotics were defined as antibiotics administered before a report of the Gram stain or bacterial identification. Combination therapy refers to the administration of two or more antibiotics of different classes among beta-lactams, fluoroquinolones, glycopeptides, oxazolidinones, aminoglycosides, or polymyxins. In episodes of polymicrobial bacteremia, the pathogens were counted separately. Hypotension at bacteremia was defined as a drop in systolic blood pressure > 30 mmHg and diastolic blood pressure > 2 0 mmHg, a requirement for vasopressor agents, or systolic blood pressure < 90 mmHg, within 48 h before or on the day of bacteremia (21).

Statistical analysis

Continuous data were compared using the Mann–Whitney U-test and categorical variables were compared with Pearson’s chi-square or Fisher’s exact test. P < 0.05 was considered statistically significant. Variables with P < 0.10 in univariate analyses or those of clinical importance, except for multi-collinear variables, were included in backward stepwise multivariate analyses with 0.1 as a cut-off value for elimination, to reveal independent risk factors for resistant Gram-positive bacteremia. The statistical analyses were performed using SPSS, ver. 25.0 (IBM, Armonk, NY, USA).

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by M Lee, CM Lee, J Byun, DY Shin, Y Koh, J Hong, PG Choe, WB Park, NJ Kim, SS Yoon, MD Oh, CK Kang, I Kim. The first draft of the manuscript was written by M Lee and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data availability statement

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Klastersky J, Ameye L, Maertens J, Georgala A, Muanza F, Aoun M, et al. Bacteraemia in febrile neutropenic cancer patients. Int J Antimicrob Agents. 2007;30 Suppl 1:S51-9.
Tai E, Guy GP, Dunbar A, Richardson LC. Cost of Cancer-Related Neutropenia or Fever Hospitalizations, United States, 2012. J Oncol Pract. 2017;13(6):e552-e61.
Kang CI, Kim SH, Park WB, Lee KD, Kim HB, Kim EC, et al. Bloodstream infections caused by antibiotic-resistant gram-negative bacilli: risk factors for mortality and impact of inappropriate initial antimicrobial therapy on outcome. Antimicrob Agents Chemother. 2005;49(2):760-6.
Montassier E, Batard E, Gastinne T, Potel G, de La Cochetiere MF. Recent changes in bacteremia in patients with cancer: a systematic review of epidemiology and antibiotic resistance. Eur J Clin Microbiol Infect Dis. 2013;32(7):841-50.
Cho SY, Lee DG, Choi SM, Kwon JC, Kim SH, Choi JK, et al. Impact of vancomycin resistance on mortality in neutropenic patients with enterococcal bloodstream infection: a retrospective study. BMC Infect Dis. 2013;13:504.
Beyar-Katz O, Dickstein Y, Borok S, Vidal L, Leibovici L, Paul M. Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer. Cochrane Database Syst Rev. 2017;6(6):CD003914.
Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011;52(4):e56-93.
Averbuch D, Orasch C, Cordonnier C, Livermore DM, Mikulska M, Viscoli C, et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica. 2013;98(12):1826-35.
Mikulska M, Viscoli C, Orasch C, Livermore DM, Averbuch D, Cordonnier C, et al. Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients. J Infect. 2014;68(4):321-31.
Gudiol C, Bodro M, Simonetti A, Tubau F, Gonzalez-Barca E, Cisnal M, et al. Changing aetiology, clinical features, antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer patients. Clin Microbiol Infect. 2013;19(5):474-9.
Li Z, Zhuang H, Wang G, Wang H, Dong Y. Prevalence, predictors, and mortality of bloodstream infections due to methicillin-resistant Staphylococcus aureus in patients with malignancy: systemic review and meta-analysis. BMC Infect Dis. 2021;21(1):74.
Rosa RG, Dos Santos RP, Goldani LZ. Mortality related to coagulase-negative staphylococcal bacteremia in febrile neutropenia: A cohort study. Can J Infect Dis Med Microbiol. 2014;25(1):e14-7.
Martinez-Nadal G, Puerta-Alcalde P, Gudiol C, Cardozo C, Albasanz-Puig A, Marco F, et al. Inappropriate Empirical Antibiotic Treatment in High-risk Neutropenic Patients With Bacteremia in the Era of Multidrug Resistance. Clin Infect Dis. 2020;70(6):1068-74.
Gudiol C, Ayats J, Camoez M, Dominguez MA, Garcia-Vidal C, Bodro M, et al. Increase in bloodstream infection due to vancomycin-susceptible Enterococcus faecium in cancer patients: risk factors, molecular epidemiology and outcomes. PLoS One. 2013;8(9):e74734.
Kang CI, Song JH, Chung DR, Peck KR, Yeom JS, Son JS, et al. Bloodstream infections in adult patients with cancer: clinical features and pathogenic significance of Staphylococcus aureus bacteremia. Support Care Cancer. 2012;20(10):2371-8.
Marron A, Carratala J, Alcaide F, Fernandez-Sevilla A, Gudiol F. High rates of resistance to cephalosporins among viridans-group streptococci causing bacteraemia in neutropenic cancer patients. J Antimicrob Chemother. 2001;47(1):87-91.
Nam EY, Song KH, Kim NH, Kim M, Kim CJ, Lee JO, et al. Differences in characteristics between first and breakthrough neutropenic fever after chemotherapy in patients with hematologic disease. Int J Infect Dis. 2016;44:4-7.
Xie Y, Tu B, Xu Z, Zhang X, Bi J, Zhao M, et al. Bacterial distributions and prognosis of bloodstream infections in patients with liver cirrhosis. Sci Rep. 2017;7(1):11482.
Lagace-Wiens PR, Adam HJ, Karlowsky JA, Nichol KA, Pang PF, Guenther J, et al. Identification of blood culture isolates directly from positive blood cultures by use of matrix-assisted laser desorption ionization-time of flight mass spectrometry and a commercial extraction system: analysis of performance, cost, and turnaround time. J Clin Microbiol. 2012;50(10):3324-8.
Hall KK, Lyman JA. Updated review of blood culture contamination. Clin Microbiol Rev. 2006;19(4):788-802.
Paterson DL, Ko WC, Von Gottberg A, Mohapatra S, Casellas JM, Goossens H, et al. International prospective study of Klebsiella pneumoniae bacteremia: implications of extended-spectrum beta-lactamase production in nosocomial Infections. Ann Intern Med. 2004;140(1):26-32.
Karaman R, Jubeh B, Breijyeh Z. Resistance of Gram-Positive Bacteria to Current Antibacterial Agents and Overcoming Approaches. Molecules. 2020;25(12).
Alp S, Akova M. Management of febrile neutropenia in the era of bacterial resistance. Ther Adv Infect Dis. 2013;1(1):37-43.
Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O'Grady NP, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1-45.

No competing interests reported.

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Risk factors for resistant Gram-positive bacteremia in febrile neutropenic patients with cancer

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Bacteremic episodes and patients

Clinical characteristics of resistant Gram-positive bacteremia

Risk factors for resistant Gram-positive bacteremia

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