Microbiological characterization of bacteremia in patients with chemotherapy-induced febrile neutropenia: systematic review and meta-analysis

Abstract

Background:

Febrile neutropenia (FN) is the most common and serious adverse event of chemotherapy for solid and hematological neoplasms, with infection as a major complication. FN occurs in 10%–50% of patients with solid tumors and over 80% with hematological malignancies, with mortality rates up to 11%.

Objective:

To characterize bloodstream pathogens in post-chemotherapy FN through a systematic review and meta-analysis of studies published from 2013 to February 13, 2024.

Design:

Systematic review and meta-analysis.

Data sources and methods:

PubMed, Web of Science, Scopus, and Embase were searched using MeSH, Emtree, and keywords. Risk of bias was assessed using the JBI checklist. Random-effects proportions meta-analysis was performed.

Results:

Twenty-two studies (n = 23,319) reported 8665 positive blood cultures: 59% Gram-negative (95% CI: 46.8–67.5), 39.7% Gram-positive (95% CI: 31.3–48.2), and 2.5% fungi (95% CI: 0.9–4.1). Random-effects meta-analysis showed high heterogeneity (I² = 98.92%, p < 0.01). Meta-regression by sample size, economic development, and risk of bias did not explain this variability.

Conclusion:

Gram-negative pathogens slightly predominate over Gram-positives in bloodstream infections among post-chemotherapy FN patients.

Trial registration:

PROSPERO (CRD42023472191).

Plain language summary

Understanding blood infections in cancer patients with low white blood cell counts: a review and analysis

The study highlights the significant prevalence of pathogens in the bloodstream of patients experiencing febrile neutropenia (FN) after chemotherapy. It identified a total of 21,485 patients from 23 studies, revealing that 46.1% of positive blood cultures were Gram-negative bacteria, while Gram-positive bacteria accounted for 45.6%. Additionally, fungi represented only 1.9% of the pathogens. The systematic review and meta-analysis showed considerable heterogeneity among the studies, indicated by an I² of 98.92%. Despite evaluating various factors such as sample size, economic development, and risk of bias, none significantly influenced this heterogeneity. In conclusion, the findings suggest that Gram-negative bacteria are slightly more prevalent than Gram-positives in cases of FN following chemotherapy, underscoring the need for targeted antimicrobial strategies in this vulnerable patient population.

Keywords

bacteremia epidemiology febrile neutropenia induced by chemotherapy fungemia sepsis

Introduction

Cancer remains a leading global cause of death, with nearly 10 million deaths and 20 million new cases in 2020.¹ Chemotherapy is central to treating both solid and hematologic malignancies.^2,3 Febrile neutropenia (FN) is one of the most common and severe adverse effects of chemotherapy. FN is defined as a single oral temperature measurement of ⩾38.3°C (101°F) or ⩾38.0°C (100.4°F) sustained for more than 1 h, in patients with an absolute neutrophil count (ANC) of <500 cells/μL or expected to decrease to <500 cells/μL within 48 h.^4,5 FN often necessitates hospitalization and broad-spectrum antibiotics,^4,5 and is associated with increased mortality, healthcare costs, and delays or modifications in cancer treatment.^4,5

FN occurs in 10%–50% of patients with solid tumors and over 80% of those with hematologic malignancies receiving chemotherapy.⁶ It significantly increases the risk of serious infections, particularly bloodstream infections (BSIs), which contribute substantially to morbidity and mortality in this population. Patients with FN have an estimated 15% higher risk of death compared to those without FN.⁷

The epidemiology of BSIs in FN patients has shifted over time.⁹ While Gram-positive organisms predominated in the late 20th century, the past two decades have seen a resurgence of Gram-negative pathogens, likely driven by evolving chemotherapy regimens, antimicrobial use, and invasive procedures such as central venous catheterization.

Despite advances in FN management and prophylactic strategies, current data on BSI pathogens in post-chemotherapy FN remain fragmented, varying across regions and time periods. No clear consensus exists on the predominant microbial etiology, complicating efforts to standardize empiric therapy and prevention protocols. Discrepancies in trends—such as the resurgence of Gram-negatives—further hinder the development of universal treatment guidelines.

This study aims to systematically review and synthesize evidence on the distribution and characteristics of the pathogens causing BSI in adult patients with post-chemotherapy FN. Understanding these trends is crucial to inform empirical treatment, guide prophylaxis, and ultimately reduce FN-related morbidity, mortality, and healthcare burden in cancer patients.

Materials and methods

This study adheres to the Preferred Statement Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA 2020)¹⁰ and was previously registered with PROSPERO (ID number: CRD42023472191).

Study design

Systematic Review and meta-analysis were conducted and reported in accordance with the PRISMA guidelines.¹⁰

Eligibility criteria

Primary studies on bacteremia in post-chemotherapy neutropenic patients, aged 18 years, published between 2013 and February 13, 2024, without language restrictions, were included. Exclusion criteria comprised studies involving COVID-19, pediatric or pregnant populations, non-chemotherapy-related febrile neutropenia, as well as review articles, letters to the editor, case reports, and conference abstracts.

Sources of information

A comprehensive search was conducted in PubMed, Web of Science, Scopus, and Embase using MeSH and Emtree terms (e.g., Neoplasms, Hematologic Neoplasms, Bloodstream Infection, and Prevalence), as well as free-text terms (e.g., cancer), combined using Boolean operators (AND, OR). The search strategy was tailored to each database (see Supplemental Material).

Eligibility assessment

Eligibility assessment was conducted independently and blinded by two reviewer pairs (FC-PG and FG-HA). Discrepancies were resolved by consensus. Article selection was finalized on February 13, 2024.

Data extraction

Data was extracted using a standardized Excel spreadsheet (Microsoft Excel, version 15.24; 2016). Two authors (FC and PG) extracted data from the included studies, and three others (FG, YYL, and HA) verified the data. Disagreements between reviewers were resolved by consensus.

Variables

The primary outcome was the prevalence of bloodstream infections. Secondary variables included tumor type, bacteria classification (Gram-positive or Gram-negative), specific pathogens, antimicrobial resistance, infection management, and the occurrence of sepsis or septic shock. Additional extracted data included study design, year of publication, country, sample size, FN diagnostic criteria, study period, number of centers, and funding source. Definitions of febrile neutropenia used by each author can be seen in Tables 1 and 2.

Table 1.

Characteristics of the studies included in the systematic review.

Author	Year	Type of study	Country	Study period	Population	Number of centers	Definition of neutropenic fever	Financing
De Rosa¹⁵	2013	Retrospective	Italy	June 2001–December 2007	81	1	ANC ⩽ 500/mm³ and external temperature ⩾ 38°C	Turin Hospital
Bousquet¹⁶	2014	Retrospective	France	2003–2010	1413	1	ANC ⩽ 500/mm³ and external temperature ⩾ 38°C	N/R
Rosa¹⁷	2014	From Prospective Cohort	Brazil	October 2009–August 2011	307	1	ANC ⩽ 500/mm³ or with expectation of decreasing to < 500 mm³ over 48 h and external temperature ⩾ 38°C or sustained temperature of ⩾ 38.0°C over a 1-h period	APIC
Mandal³⁵	2015	Prospective	India	September 2010–October 2013	268	1	ANC ⩽ 500/mm³ and external temperature ⩾ 38°C or sustained temperature of ⩾ 38.0°C over a 1-h period	N/R
Marin³⁶	2015	Prospective Observational	Spain	January 2006–December 2013	602	1	ANC ⩽ 500/mm³ and external temperature ⩾ 38°C	N/R
Piukovics¹⁸	2015	Retrospective Observational	Hungary	2005–2008	469	1	Single oral temperature was measured higher than 38.3°C, or temperature was 38.0°C or higher for 1 h. ANC < 0.5 × 10⁹/L or less than 1.0 × 10⁹/L and rapidly declined below 0.5 × 10⁹/L	N/R
Cattaneo¹⁹	2016	Prospective Observational	Italy	December 2010–December 2014	293	9	PMN count < 0.5 × 10⁹/L; axillary temperature ⩾38.3 or ⩾ 38°C for a least 1 h	None
Rönkkö²⁰	2018	Prospective and compared with a retrospective series	Finland	December 2006–November 2012	178	1	ANC ⩽ 500/mm³ and external temperature ⩾ 38°C or sustained temperature of ⩾ 38.0°C over a 1-h period	N/R
Zhu²¹	2018	From cohort Retrospective	China	January 2005–December 2012	1139	1	ANC ⩽ 500/mm³	Shanghai Science and Technology Committee, National Natural Science Foundation of China and MSD
Garzón²²	2019	Retrospective Observational	Colombia	January 2013–December 2014	193	1	ANC ⩽ 500/mm³ and external temperature ⩾ 38°C or sustained temperature of ⩾ 38.0°C over a 1-h period	San Ignacio University Hospital
Herrera²³	2019	Retrospective Observational	Argentina	June 2015–August 2017	32	1	ANC ⩽ 500/mm³ or with expectation of decreasing to < 500 mm³ over 48 h and external temperature ⩾ 38°C or sustained temperature of ⩾ 38.0°C over a 1-h period	N/R
Kim²⁴	2019	Retrospective Observational	South Korea	June 2012–June 2018	179	1	Single oral temperature was measured higher than 38.3°C, or temperature was 38.0°C or higher for 2 h. ANC ⩽ 500/mm³ or with expectation of decreasing to < 500 mm³ over 48–72 h	N/R
Mert²⁵	2019	Retrospective	Türkiye	January 2012–December 2017	266	1	N/R	N/R
Widmer²⁶	2019	Prospective	Germany, Austria, Switzerland	2002–2010	13.525	20	ANC < 1000 × 10⁹/L; AGC < 500 × 10⁹/L; AGC of 1000 × 10⁹/L with an expected dop to < 500 × 10⁹/L	German Federal Ministry of Health
Jung²⁷	2020	Retrospective Observational	South Korea	June 2012–December 2016	133	1	ANC ⩽ 500/mm³	N/R
Martinez²⁸	2020	Prospective Observational	Spain	January 2006–January 2017	1615	2	ANC ⩽ 500/mm³ and external temperature ⩾ 38°C or sustained temperature of ⩾ 38.0°C over a 1-h period	Ministry of Health and Consumer Affairs, Carlos III Health Institute, and research grant from Merck Sharp and Dohme, Catalonia Support Agency
Finello⁹	2021	Retrospective	Argentina	April 2009–December 2016	143	2	Temperature was measured higher than 38.2°C, or temperature was 38.0°C or higher for 1 h. ANC ⩽ 500/mm³ or with expectation of decreasing to < 500 mm³ over 48 h	None
Caro²⁹	2022	Retrospective	USA	June 2012–October 2019	121	1	Temperature was measured higher than 38.3°C, or temperature was 38.0°C or higher for 1 h. ANC ⩽ 500/mm³ or 1000/mm³ with expectation of decreasing to < 500 mm³	Astellas Pharma and AbbVie
Schulz³⁰	2022	From Prospective Cohort	Australia	September 2020–July 2021	61	1	ANC ⩽ 500/mm³ or 1000/mm³ with expectation of decreasing to < 500 mm³ in the next 2 days; Temperature was measured higher than 38.3°C, or temperature was 38.0°C or higher for 1 h or measured two times within 12 h, respectively	None
Zimmer³¹	2022	Observational Cross-sectional Prospective	USA	December 2016–May 2019	343	14	Temperature was measured higher than 38.0°C. ANC ⩽ 500/mm³ or with expectation of decreasing to < 500 mm³ over 48 h	University of Nebraska Medical Center
Perez³²	2023	Pre- to post quasi-experimental	Peru	October 2015–October 2022	93	1	ANC ⩽ 500/mm³ or 1000/ mm³ with expectation of decreasing to < 500 mm³. Oral temperature was measured higher than 38.3°C, or temperature was 38.0°C or higher for 1 h or measured 2 times within 2 h.	Pfizer Peru
Schonardie³³	2023	Case-control Retrospective	Brazil	January 2012–January 2021	1865	1	ANC ⩽ 500/mm³ or 1000/mm³ with expectation of decreasing to < 500 mm³ within 48 h. Axillary temperature was measured higher than 38.3°C, or 38.0°C for 1 h	Porto Alegre Clinics Hospital Incentive Fund.

ANC, Absolute Neutrophil Count; N/R, Not Report.

Table 2.

Characteristics of included studies on febrile neutropenia treatment, infection management, and isolated pathogens.

Study	Year	Mortality N (%)	Febrile neutropenia treatment	Chemotherapy	Febrile neutropenia guideline	Infection management	Isolates found
De Rosa¹⁵	2013	6 (7.4)	N/R	Standard induction chemotherapy ICE followed by post-remissional therapy with repeated consolidation courses with high-dose cytarabine (HDAraC)	IDSA	Oral itraconazole, Levofloxacin	Gram-positive: • Staphylococcus epidermidis • Enterococcus faecium • S. mitis • Corynebacterium spp. • MRSA • S. hominis • Corynebacterium spp. • E. faecalis Gram-negative • E. cloacae • E. coli • Klebsiella pneumoniae • Pseudomonas aeruginosa • S. maltophilia • S. marcescens • Citrobacter
Bousquet¹⁶	2014	N/R	N/R	N/R	IDSA	Broad-spectrum, empirical, Ciprofloxacin, Piperacillin, Tazobactam	• Streptococcaceae • Staphylococcaceae • GPC • Enterobacteriaceae • Non-fermenting • GNB
Rosa¹⁷	2014	N/R	N/R	N/R	Unspecified	Vancomycin	Gram-positive • Methicillin-resistant coagulase-negative staphylococci • Methicillin-resistant S. aureus • Vancomycin-resistant E. faecalis Gram-negative • E. coli ESBL • K. pneumoniae ESBL • Enterobacter spp. • Serratia spp.
Mandal³⁴	2015	N/R	N/R	N/R	IDSA 1997 Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever 2002 Guidelines for the use of antimicrobial agents in neutropenic patients with cancer	N/R, does indicate drug-resistant isolates, however	Gram-positive • MRSA • MSSA • CONS • S. pneumoniae • MR CONS • S. viridians Gram-negative • Acinetobacter spp. • P. aeruginosa • ESBL E. coli • K. pneumoniae • Citrobacter koseri • C. freundii • Ralstonia paucula • C. neteri • Non-Fermenting Gram-negative bacilli • E. coli
Marin³⁵	2015	H: 61 (12.1) S: 33 (36.3)	N/R	N/R	IDSA	Cefepime + amikacin	Gram-positive • Coagulase-negative staphylococci • S. aureus • MRSA • Viridans group streptococci • S. pneumoniae • Enterococcus spp. • Other Gram-negative • E. coli • K. pneumoniae • P. aeruginosa • Enterobacter spp. • Other • MDR Gram-negative bacilli • ESBL-producing Enterobacteriaceae • S. maltophilia • AmpC-producing Enterobacteriaceae • MDR P. aeruginosa Polymicrobial Anaerobes
Piukovics¹⁸	2015	N/R	N/R	N/R	IDSA ESMO 2002 Guidelines for the use of antimicrobial agents in neutropenic patients with cancer CLSI	Piperacillin-tazobactam, Cefepime, imipenem, meropenem, vancomycin	Gram-positive • Coagulase-negative staphylococci • S. aureus • Enterococcus spp • P. acnes • Beta-hemolytic streptococci • S. pneumoniae • Alfa-hemolytic streptococci • Clostridium spp. • Others Gram-negative • E. coli • P. aeruginosa • Klebsiella spp. • Enterobacter spp. • Citrobacter spp. • S. maltophilia • Acinetobacter spp. • Fusobacterium spp. • Others
Cattaneo¹⁹	2016	37 (8.5) Gram-positive 6.7% Gram-negative 9.1%	N/R	N/R	IDSA 2011 Fourth European Conference on Infections in Leukemia American Society of Clinical Oncology Clinical Practice Guidelines	Cephalosporin, cefotaxime, ceftazidime, cefepime; piperacillin/tazobactam + amikacin	Gram-positive • S. aureus • CoNS • Viridans group streptococci • Enterococci • Others Gram-negative • Enterobacteria • P. aeruginosa • Other Polymicrobic Fungi • C. parapsilosis • C. guilliermondii • C. tropicalis • Fusarium solani
Rönkkö²⁰	2018	Dec 2006–Nov 2012: 4 (2.8) 1996–2006: 9 (3.4)	N/R	BEAM BEAC HD-MEL Others	IDSA ACCP/SCCM SEPSIS-3 Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective 2002 Guidelines for the use of antimicrobial agents in neutropenic patients with cancer SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference	Empiric antimicrobial, Broad-spectrum beta-lactam + aminoglycoside, ceftazidime, tobramycin, vancomycin, trimethoprim/sulfamethoxazole, ciprofloxacin	Gram-positive • S. epidermidis • E. faecium • S. mitis • S. haemolyticus • S. pneumoniae • S. viridans • S. salivarius • Gemella morbillorum • Other Gram-positive coccus Gram-negative • E. coli • P. aeruginosa • Klebsiella pneumoniae • Other
Zhu²¹	2018	N/R	N/R	N/R	IDSA ESMO Updated Guidelines of the AGIHO of the DGHO	Imipenem, Meropenem, Amikacin, Cefoperazone-sulbactam, Piperacillin-tazobactam, Cefepime, Ampicillin, Ciprofloxacin, Trimethoprim-Sulfamethoxazole, Vancomycin, Linezolid, Teicoplanin, Cefazolin, Cefuroxime, Phosphonomycin, Methicillin, Rifapicin, Levofloxacin	• P. aeruginosa • K. pneumoniae • Acinetobacter baumannii • S. maltophilia • E. faecalis • E. cloacae • E. faecium • S. haemolytic • S. aureus • S. epidermidis • Other
Garzón²²	2019	N/R	N/R	HyperCVAD, RCHOP, HIDAC, 7 × 3, IDAFLAG, PETHEMA, MEC	IDSA	Cefepime, Piperacillin/Tazobactam, Meropenem	• E. coli • K. pneumoniae • S. aureus • S. epidermidis • E. faecalis • Enterococcus Spp. • Candida spp. • P. aeruginosa • A. iwoffii • Proteus spp. • Clostridium spp. • K. oxytoca • E. faecium • Aeromonas spp. • Other Gram-negative Staphylococci coagulosa • Salmonella spp. • C. freundii • S. pneumoniae • Burkholedoria cepacian • Aspergillus spp. • S. viridans • S. maltophilia • S. haemolyticus • S. marcescens • S. agalactiae • S. mitis • K. ascorbate • Moraxella catarrhalis • Bacteroides spp. • Other/Undetermined
Herrera²³	2019	15 (45)	N/R	N/R	Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer IDSA 2011 Fourth European Conference on Infectious in Leukemia	Methicillin, Antipseudonomic penicillin, cefalosporin, carbapenem, quinolone, vancomycin, beta-lactam, carbapenem	Gram-positive cocci • Negative S. coagulase • Enterococcus spp. • Streptococcus spp. Gram-negative bacillus • K. pneumoniae • E. coli • Enterobacter spp. • Serratia spp. • Others Non-fermenting Gram-negative bacillus • Acinetobacter spp. • P. aeruginosa • S. maltophilia Toxins for C. difficile Fungi Others
Kim²⁴	2019	28-day mortality: 51 (28.5) In-hospital mortality: 46 (25.7)	N/R	N/R	IDSA Surviving Sepsis Campaign ESMO Clinical Practice Guidelines American Society of Clinical Practice Guideline Update	Piperacillin/tazobactam, cefepime, ceftazidime and cefazolin.	• E. coli • Other strains, unspecified
Mert²⁵	2019	71 (23.3)	N/R	N/R	IDSA NCCN Clinical Practice Guidelines in Oncology (2014)	Cefoperazone-sulbactam, Piperacillin-tazobactam, Meropenem, Cefoperazone-sulbactam + vancomycin, Piperacillin-tazobactam + teicoplanin, Meropenem + daptomycin, Linezolid, Colistin, Meropenem + teicoplanin	Gram-positive • E. coli • K. pneumoniae • P. aeruginosa • E. cloacae • A. baumannii • A. hydrophila/caviae • Pseudomonas spp. • S. paucimobilis • K. oxytoca • S. maltophilia • Acinetobacter lwoffi • Proteus mirabilis Gram-negative • S. haemolyticus • Corynebacterium spp. • S. epidermidis • E. faecium • S. mitis • S. hominis • S. aureus • S. warneri • Kocuriakristinae • Staphylococcus spp.
Widmer²⁶	2019	No BSI: 266 (2.0) Early-onset BSI: 62 (3.9) Late-onset BSI: 94 (10.9)	N/R	Unspecified antineoplastic chemotherapy	CDC criteria for pathogenic bacteria from a single blood culture IDSA 2011 Fourth European Conference on Infectious in Leukemia	N/R	Gram-positive • Coagulase-negative staphylococci • Enterococcus spp. • E. faecium • Streptococcus spp. • S. aureus Gram-negative • E. coli • KES group • P. aeruginosa • S. maltophilia Anaerobes Fungi • Candida spp. • C. albicans • Non-albicans Candida spp.
Jung²⁷	2020	N/R	N/R	N/R	Surviving Sepsis Campaign Sepsis-3 ACCP/SCCM Consensus Infectious Diseases Society of America (IDSA) 2014 AGIHO Updated Guidelines Evidence-based Guidelines for Empirical Therapy of Neutropenic Fever in Korea SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference	Extended-spectrum penicillin/beta-lactamase inhibitors (piperacillin-tazobactam), cephalosporin (cefepime), cefazolin/ceftazidime combination, or meropenem	Gram-positive • S. aureus • S. pneumoniae • Beta-Hemolytic streptocci • Viridans group streptococci • Enterococcus spp. • Corynebacterium spp. • Other Gram-positive bacteria Gram-negative • E. coli • Klebsiella spp. • P. aeruginosa • Enterobactar spp. • Acinetobacter spp. • Legionella pneumophila • Other Gram-negative bacteria Anaerobic bacteria • Anaerobic Gram-negative bacteria • Anaerobic Gram-positive bacteria
Martinez²⁸	2020	Total: 21% E. coli: 80 (21) Klebsiella spp: 33 (24) P. aeruginosa: 87 (35) S. maltophilia: 13 (39) CoNS: 31 (9) Enterococcus spp: 58 (28) S. aureus: 10 (13)	N/R	N/R	IDSA 2011 Fourth European Conference on Infections in Leukemia 2015 ESC Guidelines for the Management of Acute Coronary Syndromes in Patients Presenting Without Persistent ST-Segment Elevation	Amikacin, cefepime, meropenem, vancomycin, piperacillin-tazobactam, and imipenem	Gram-positive • CoNS • Enterococcus spp. ○ E. faecium ○ E. faecalis • S. aureus ○ Methicillin-resistant S. Aureus Gram-negative • E. coli ○ ESBL • P. aeruginosa ○ Multidrug-resistant • Klebsiella spp. ○ ESBL • Enterobacter spp. • S. maltophilia Anaerobes Candida spp.
Finello⁹	2021	0–7 days: 33 (23.1) 8–30 days: 27 (18.9) 31–60 days: 9 (6.3) 61–90 days: 2 (1.4) 90 days: 71 (49.7)	N/R	N/R	IDSA CDC/NHSN Surveillance Definition of Healthcare-Associated Infection and Criteria for Specific Types of Infections in the Acute Care Setting New Diagnostic Criteria and Severity Assessment of Acute Cholangitis in Revised Tokyo Guidelines 2011 Fourth European Conference on Infections in Leukemia	Penicillin, Antipseudomonics, cefalosporin, carbapenem, aminoglucosides, fluoroquinolones	S. aureus Negative S. coagulase E. coli K. pneumoniae P. aeruginosa A. baumannii
Caro²⁹	2022	Hazard ratio: 0.98 (0.56–1.71)	N/R	7 + 3 (cytarabine + daunorubicin or idarubicin)	Antibacterial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guidelines update CTCAE 5.0 2011 International Consensus Criteria on Antimicrobial Resistance	N/R	Gram-positive • S. aureus • Coagulase-negative Staphylococcus • Enterococci • Viridans group Streptococci • Other Gram-negative • E. coli • B. thetaiotomicron • P. aeruginosa • K. pneumoniae • S. maltophilia • H. parainfluenzae • A. baumanii
Schulz³⁰	2022	N/R	N/R	N/R	IDSA 2018 AGIHO and iCHOP guidelines (DGHO) on the management of sepsis in neutropenic cancer patients	N/R	Blood culture positive • A. ursingii • E. cloacae • E. faecium • G. haemolysans • P. aeruginosa • Rothia mucilaginosa • S. epidermidis • S. hominis
Zimmer³¹	2022	Seven days after FN presentation among single-organism bacteremia: 11 (3.6) 30 days after FN presentation among single-organism bacteremia: 28 (9.3) 30-day mortality general: 33 (9.6)	N/R	Unspecified non-transplant chemotherapy regimens (68%), others (32%) received allogeneic or autologous HSCT	IDSA European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance Clinical Practice Guidelines in Oncology (NCCN)	Cefepime, piperacillin-tazobactam, antipseudomonal carbapenems, meropenem, vancomycin, linezolid, daptomycin, aminoglycosides, beta-lactam	Gram-negative organisms • E. coli • Klebsiella spp. • P. aeruginosa • E. cloacae • Stenotrophomonas • Other Enterobacterales • Other Gram-negative Gram-positive organisms • Viridans group streptococci • S. aureus Oxacillin-resistant Oxacillin-susceptible • Coagulase-negative staphylococci • Enterococcus spp. Vancomycin-resistant Vancomycin-susceptible • Rothia spp • S. pneumoniae • Other Gram-positive Anaerobes
Perez³²	2023	In-hospital mortality • Before ASP Intervention: 9 (28.1) • After ASP Intervention: 5 (16.7) • After ASP Intervention Plus BCID2: 11 (35.5) 30-day all-cause hospital readmission (n = 68) • Before ASP Intervention: 12 (52.1) • After ASP Intervention: 9 (36) After ASP Intervention Plus BCID2: 7 (35)	N/R	N/R	ESMO IDSA	Drug-resistant strains identified; however, the medications were not named specifically	Gram-positive bacteria • Staphylococcus spp. • S. aureus • E. faecium • Streptococcus spp. Gram-negative bacteria • E. coli • K. pneumoniae • P. aeruginosa • Acinetobacter baumannii • C. freundii • E. cloacae • Acinetobacter lwoffii • P. putida • A. hydrophila • S. marcescens • K. oxytoca • L. richardii • S. maltophilia • Proteus spp. Candida spp. • C. albicans • C. tropicalis • Candida kefyr
Schonardie³³	2023	N/R	N/R	N/R	IDSA ESCMID guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli	Amikacin + colistin, ceftazidime, vancomycin, polymyxins, aminoglycodies, tigecycline	• Fungus • Coagulase-negative Staphylococcus • S. aureus • Streptococcus spp. • Enterococcus spp. • Other Gram-positive bacteria • E. coli • Klebsiella spp • Enterobacter spp • P. aeruginosa • Acinetobacter app • Other Gram-negative bacteremia

ACCP/SCCM, American College of Chest Physicians/Society of Critical Care Medicine; AGIHO, Infectious Diseases Working Party; ASCO, American Society of Clinical Oncology; ATS, American Thoracic Society; CDC, Centers for Disease Control; CLSI, Clinical and Laboratory Standards Institute; CONS, Coagulase-Negative Staphylococci spp.; CTCAE, Common Terminology Criteria for Adverse Events; DGHO, German Society of Hematology and Medical Oncology; ESBL, Extended-Spectrum Beta-Lactamases; ESC, European Society of Cardiology; ESCMID, European Society of Clinical Microbiology and Infectious Diseases; ESICM, European Society of Intensive Care Medicine; ESMO, European Society for Medical Oncology; GNB, Gram-negative bacilli; GPC, Gram-positive cocci; HNSN, National Healthcare Safety Network; iCHOP, Intensive Care Working Party; IDSA, Infectioius Diseases Society of America; KES Group, Klebsiella, Enterobacter, and Serratia spp.; MDR, multiple-drug resistance (was defined as nonsusceptibility to ⩾1 agent in ⩾3 antimicrobial categories); MR CONS, Methicillin-resistant Coagulase-Negative Staphylococci spp.; MRSA, Methicillin-Resistant Staphylococcus aureus; MSSA, Methicillin-susceptible Staphylococcus aureus; NCCN, National Comprehensive Cancer Network; SIS, Surgical Infection Society.

Study risk of bias assessment

The risk of bias was assessed independently by two reviewers (AF-C, PG) through the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for studies reporting prevalence data.^11–13 This tool assesses nine domains where final scores were determined based on the percentage of affirmative responses. Studies were classified as high risk of bias (score of 49% or less, leading to exclusion of the study), moderate risk (score ranging from 50% to 69%), or low risk (score above 70%). Discrepancies were resolved by consensus.

Risk of bias summaries were generated using the ROBVIS R package v.0.3.0.900.¹⁴

Data synthesis

Descriptive statistics (percentages, frequencies, and means) were used to summarize the data. A random-effects meta-analysis was performed using the Freeman-Tukey reverse transformation model. Studies with a high risk of bias were excluded. Heterogeneity was assessed using Cochran’s Q test (significance set at p < 0.05) and the I² statistic. Univariate meta-regression was performed using the covariates: risk of bias, sample size, and Country Development Status.

Sensitivity analyses included subgroup analysis assuming I² = 10%, leave-one-out meta-analysis, and standard error adjustments using the Sidik-Jonkman and truncated Knapp-Hartung methods. All analyses were performed using Stata 18 statistical software (StataCorp LLC, College Station, TX, USA).

Reporting bias assessment

To assess small-study effects, funnel plots were generated, and Egger’s test was performed for studies reporting Gram-negative, Gram-positive, and fungal infections. A p < 0.05 was considered statistically significant. Trim-and-fill analysis was performed to determine if imputed studies affected the effect size.

Assessment of certainty

It was not considered.

Ethics

Secondary evidence does not require the authorization of an Institutional Review Board; thus, ethics approval was not considered.

Results

A total of 7630 articles were identified across the databases. After removing duplicates and screening titles and abstracts, 266 articles were retained for full-text review. Of these, only 22 studies^{8,9,15–23,24–34} met the inclusion criteria and were the basis of the qualitative and quantitative analysis (Figure 1).

Figure 1.

PRISMA flow of selection and exclusion of the information.

Characteristics of studies

A total of 22 studies were included for the assessment.^{8,9,15–23,24–34} Table 1 describes the author, year of publication, type of study, country, study period, patient population, number of centers, and funding status.

Based on publication year, 14 (63.6%)^{15–23,24–26,34,35} studies were published before 2020 and 8 (36.4%)^9,27–33 2020 and 2023. Geographically, eight studies (36.4%) were from Europe,^{8,15,16,18–20,27,29} 6 (27.3%) from South America,^{9,17,22,23,32,33} 5 (22.7%) from Asia,^{21,24–25,27,34} equivalent to 22.7%; 2 (9.1%) from North America^30,32 and 1 (4.5%) from Oceania.³¹ Tables 1 and 2 describe the characteristics of patients with chemotherapy-induced FN with positive blood culture.

Regarding study design, 12 studies (54.5%) were retrospective,^{9,15,16,18,21–23,24,25,27,29,33} 8 (36.4%) were prospective,^{8,17,19,20,26,28,30,34} 1 (4.5%) was a prospective-retrospective comparison, and 1 (4.5%) was a quasi-experimental pre-post study.²⁰ Most studies (81.8%, n = 18) were single center,^{15–18,20–23,24,25,27,29,30,32–35} while 5 (22.7%) were multicenter^{9,19,26,28,31} (22.7%; Table 1).

Febrile neutropenia definitions were based on guidelines and definitions explicitly referenced by the authors. Four studies (18.2%)^16,22,35 used the Infectious Diseases Society of America (IDSA) definition alone. Sixteen studies (72.7%)^{9,18–21,23,24–28,30–34} referenced multiple sources additional to the IDSA guidelines: the 1997 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Unexplained Fever, the 2002 Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer, the European Society for Medical Oncology (ESMO), the fourth European Conference on Infections in Leukemia (2011), the American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines, and guidelines for preventing infectious complications in hematopoietic cell transplant recipients. One study (4.5%)²⁹ did not use the IDSA guidelines, and one (4.5%)¹⁷ did not specify a guideline. Definitions are detailed in Table 1.

Patients with septic shock were reported in three studies (13.6%).^8,20,28 Of these, one study (4.5%)²⁰ used the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) definition. The remaining two studies (9.1%)^8,28 did not cite a specific sepsis guideline; one article⁸ offered a self-defined criterion, and the other²⁸ provided no definition. Table 2 describes Characteristics of Included Studies on Febrile Neutropenia Treatment, Infection Management, and Table 3 reports the classification of pathogens isolated from positive blood cultures.

Table 3.

Characteristics of patients with chemotherapy-induced FN with positive blood cultures.

Author	Year	Population (n)	AgeMean/Median (DS or IQR)	Female gendern (%)	Comorbiditiesn (%)	Scales(DS) (IQR)	Type of cancer		Neutropenia			Septic shockn (%)	Admission to ICUn (%)
Author	Year	Population (n)	AgeMean/Median (DS or IQR)	Female gendern (%)	Comorbiditiesn (%)	Scales(DS) (IQR)	Solidn (%)	Hematologicaln (%)	Moderate*n (%)	Serious**n (%)	Prolonged***n (%)	Septic shockn (%)	Admission to ICUn (%)
De Rosa¹⁵	2013	81	49.7 (11.4)	35 (43.2)	N/R	N/R	N/R	81 (100)	NR	81 (100)	N/R	N/R	N/R
Bousquet¹⁶	2014	1413	N/R	N/R	N/R	N/R	N/R	N/R	829 (58.6)	737 (52.1)	N/R	N/R	N/R
Rosa¹⁷	2014	307	MDR 46.21 (13.0) Others 39.97 (14.2)	149 (48.5)	N/R	N/R	N/R	307 (100)	N/R	307 (100)	N/R	N/R	N/R
Mandal³⁴	2015	268	N/R	N/R	N/R	N/R	N/R	268 (100)	N/R	N/R	N/R	N/R	N/R
Marin³⁵	2015	510	57 (19–89)	196 (38.4)	Comorbidities: 138 (27.1)	MASCC < 21 152 (31.9%)	N/R	510 (100)	N/R	510 (100)	117 (23.9)	52 (10)	54 (10.6)
Piukovics¹⁸	2015	469	Medium 60	230 (49)	N/R	N/R	N/R	469 (100)	N/R	N/R	N/R	N/R	N/R
Cattaneo¹⁹	2016	293	N/R	N/R	N/R	N/R	N/R	293 (100)	N/R	N/R	N/R	N/R	N/R
Rönkkö²⁰	2018	178	59 (22–72)	67 (38)	N/R	N/R	N/R	178 (100)	N/R	NR	N/R	15 (11)	6 (4.2)
Zhu²¹	2018	1,065	N/R	N/R	N/R	N/R	N/R	1065 (100)	N/R	322 (30.2)	N/R	N/R	N/R
Garzón²²	2019	345	50 (33–60)	177 (51.3)	Diabetes mellitus 29 (8.4) Chronic kidney Disease 20 (5.8) Autoimmune diseases 4 (1.2) HIV 10 (2.9)	N/R	N/R	345 (100)	N/R	354 (100)	N/R	N/R	N/R
Herrera²³	2019	32	53 (18–75)	18 (56)	N/R	N/R	5 (16)	27 (84)	N/R	88 (100)	N/R	N/R	N/R
Kim²⁴	2019	179	63.5 (9.8)	79 (44.1)	Liver Cirrhosis 10 (5.6) Diabetes mellitus 51 (11.7) Chronic kidney disease 8 (4.5) Arterial hypertension 51 (28.5)	APACHE 22 (17–29) SOFA 8 (6–11) ECOG 0–1 101 (56.4%) ECOG 2–4 78 (43.6%)	136 (76)	43 (24)	N/R	85 (47.5)	N/R	N/R	N/R
Mert²⁵	2019	266	45 (16.5)	111 (41.7)	N/R	N/R	N/R	266 (100)	N/R	N/R	N/R	N/R	N/R
Widmer²⁶	2019	13,525	55 (45–63)	5475 (40.5)	N/R	N/R	N/R	13,525 (100)	N/R	N/R	N/R	N/R	539 (4)
Jung²⁷	2020	133	Unknown cause 60.6 Documented infection 64.3 Documented microbiology 63.6	60 (45.1)	N/R	Unknown cause: APACHE II 18.3 Charlson 6 MASCC 12.1 Documented infection: APACHE II 21.1 Charlson 7.9 MASCC 14.6 Documented Microbiology APACHE II 25.8 Charlson 7.2 MASCC 14.8	108 (81)	25 (19)	N/R	133 (100)	N/R	N/R	N/R
Martinez²⁸	2020	1615	58 (45–66)	638 (39)	Diabetes mellitus 158 (10) COPD 104 (6) Liver disease 44 (3) Chronic kidney disease 45 (3)	N/R	179 (11)	1436 (89)	N/R	1615 (100)	N/R	271 (17)	N/R
Finello⁹	2021	143	50 (17.8)	54 (37.8)	Ischemic heart disease 7 (4.9) Diabetes mellitus 11 (7.7) COPD 15 (10.5) Chronic kidney Disease 26 (18.2) Heart failure 9 (6.3) Smoking 42 (29.4)	MASCC 14.5 (±5.5)	28 (20)	115 (80)	N/R	143 (100)	74 (51.7)	N/R	N/R
Caro²⁹	2022	121	No prophylaxis 62 (52–70) Prophylaxis 64 (52–71)	59 (48.8)	N/R	No prophylaxis: ECOG 0 11 (32.4%) ECOG 1 16 (47.1%) ECOG 2 4 (11.8) Prophylaxis ECOG 0 27 (31%) ECOG 1 31 (35.6%) ECOG 2 12 (13.8%)	N/R	121 (100)	N/R	N/R	N/R	N/R	N/R
Schulz³⁰	2022	61	60 (30–77)	27 (44)	N/R	N/R	N/R	61 (100)	N/R	N/R	N/R	N/R	N/R
Zimmer³¹	2022	343	57 (20–89)	145 (42)	N/R	MASCC 19 (5–26) PITT ⩾2 50 (15%)	N/R	343 (100)	N/R	343 (100)	N/R	N/R	N/R
Perez³²	2023	93	Before PAA 46.7 (38–57.5) After PAA 45.3 (37–56) After PAA 2nd HP 50 (40–62)	50 (53.8)	Diabetes mellitus 4 (4.3) Arterial Hypertension 7 (7.5) HIV 1 (1.1) PeS Heart Failure 1 (1.1) Chronic Kidney Failure 5D 4 (4.3)	MASCC < 21 76 (81.7%)	N/R	93 (100)	N/R	N/R	N/R	N/R	7 (7.5)
Schonardie³³	2023	35	45.3 (13.6)	17 (48.6)	Cardiovascular 12 (3403) Diabetes Mellitus 3 (8.6) Lung Disease: 3 (8.6) HIV 2 (5.7) Chronic Kidney Failure 2 (5.7)	Charlson 2 (2–3)	N/R	35 (100)	N/R	35 (100)	N/R	N/R	19 (54.3)

APACHE, Acute Physiology and Chronic Health Evaluation; CCI, Charlson Comorbidity Index; ECOG, Eastern Cooperative Oncology Group; HIV, human immunodeficiency virus; HP, positive blood culture; ICU, Intensive Care Unit; IQR, Interquartile Range; MASCC, Risk identification index in neoplastic patients with febrile neutropenia; MDR, Multidrug Resistant; N/R, Not reported; PAA, Antimicrobial stewardship program; PITT, Bacteremia score; SD, Standard Deviation; SOFA, Sepsis-related organ failure assessment.

Risk of bias

In the risk of bias assessment, two studies (9.1%) presented moderate risk, and twenty studies (90.9%) were classified as low risk (see Supplemental Materials).

Characteristics of patients with post-chemotherapy febrile neutropenia with microorganism identification in blood cultures

A total of 23,319 patients with chemotherapy-induced FN were included, with 8,665 positive blood cultures. The mean age was 48.5 years ± 7.4 years, and the proportion of female patients ranged from 37.8% to 56% across studies.

In 17 studies,^{15,17–22,25–26,29–35} all patients (n = 17,960) had only hematologic malignancies. The remaining six studies reported a mixed population, with hematologic malignancy prevalence ranging from 19% to 89% and solid tumors (n = 456) ranging from 11% to 81%. Severe neutropenia (SNP) was reported in 100% of the patients in 10 studies (n = 3609).^{9,15,17,22,23,27,28,31,33,35} Three studies^16,21,24 reported SNP in 30.2%–52.1% of cases, and one study¹⁶ reported moderate neutropenia in 58.6% of patients.

Neutropenia lasted a median of 2 days (IQR 2–4), up to a maximum of 14 days (IQR 13–19). Notably, Caro et al.²⁹ reported a median duration of 23 days (IQR 15–38) with fluoroquinolone prophylaxis versus 30 days (IQR 21–51) without.

ICU admission was required in 4.2% to 54.3% of patients.^{20,26,32,33,35} Septic shock occurred in 10.2% to 17%,^20,28,35 and vasopressor use ranged from 9.6% to 28.6% in two studies.^23,35 Central venous catheter use was reported in seven studies^{9,23,24,27,31,33,35} with a prevalence of 22.9% to 77.9%. Mechanical ventilation was required in 3% to 36.1% across four studies.^20,24,31,33 Reported mortality ranged from 2% to 70%²¹ (Table 4).

Table 4.

Classification by groups of pathogens isolated in positive blood cultures.

Author	Positive blood cultures (n)	GN (n)	GN % (95% CI)	GP (n)	GP % (95% CI)	Anaerobes(n)	Anaerobes % (95% CI)	RB (n)	RB % (95% CI)	HP (n)	HP %(95% CI)	Fungi (n)	Fungi % (95% CI)
De Rosa¹⁵	79	46	58 (47.1–68.8)	33	42 (31.1–52.8)	N/R	0	3	4 (0.32–8.32)	N/R	0	N/R	0
Bousquet¹⁶	647	512	79 (75.8–82 1)	135	21 (17.8–24.1)	N/R	0	NR	0	N/R	0	N/R	0
Rosa¹⁷	39	12	31 (16.4–45.5)	27	69 (54.4–83.5)	N/R	0	37	95 (88.1–100)	N/R	0	N/R	0
Mandal³⁴	78	48	62 (51.2–72 7)	27	35 (24.4–45.9)	N/R	0	17	22 (12.8–31.1)	N/R	0	3	3 (0.79–6.79)
Marin³⁵	542	273	50 (45.7–54.2)	219	40 (35.8–44.1)	N/R	0	28	5 (3.1–6.8)	50	9 (6.5–11.4)	N/R	0
Piukovics¹⁸	796	280	35 (31.6 –38.3)	516	65 (61.6–68.3)	N/R	0	N/R	0	N/R	0	N/R	0
Cattaneo¹⁹	433	166	38 (33.4–42.5)	194	45 (40.3–49.6)	N/R	0	48	11 (8–13.9)	68	15 (11.6–18.3)	5	11 (8–13.9)
Rönkkö²⁰	91	26	29 (19.6–38.3)	65	71 (61.6–80.3)	N/R	0	NR	0	N/R	0	N/R	0
Zhu²¹	91	63	69 (59.5–7.5)	28	31 (21.5–40.5)	N/R	0	11	12 (5.3–18.6)	N/R	0	N/R	0
Garzón²²	403	175	43 (38.1–47.8)	84	21 (17–24.9)	N/R	0	21	5 (2.8–7.1)	142	35 (30.3–39.6)	2	0.4 (0.2–1.0)
Herrera²³	33	22	67 (50.9–83)	11	33 (16.9–49)	N/R	0	10	30(14.3–45.6)	N/R	0	N/R	0
Kim²⁴	23	23	100	NR	0	N/R	0	23	100	N/R	0	N/R	0
Mert²⁵	304	232	76 (71.2–80.8)	72	24 (19.2–28.8)	N/R	0	N/R	0	N/R	0	N/R	0
Widmer²⁶	2548	759	30 (28.2–31.7)	1647	65 (63.1–66.8)	30	1.1 (0.7–1.5)	N/R	0	N/R	0	112	4.3 (3.5–5)
Jung²⁷	109	82	75 (66.8–83.1)	22	20 (12.4–27.5)	5	4.5 (0.6–8.3)	32	29 (20.4–37.5)	N/R	0	N/R	0
Martinez²⁸	1736	862	50 (47.6–52.3)	611	35(32.7–-37.2)	41	2.3 (1.5–3)	202	12 (10.4–13.5)	177	10 (8.5–11.4)	45	2.5 (1.7–3.2)
Finello⁹	104	87	84 (76.9–91)	17	16 (8.9–23)	N/R	0	42	40 (30.5–49.4)	N/R	0	N/R	0
Caro²⁹	31	12	39 (21.8–56.1)	19	61 (43.8–78.1)	N/R	0	6	19 (5.1–32.8)	N/R	0	N/R	0
Schulz³⁰	30	6	20 (5.6–34.3)	9	30 (13.6–46.4)	N/R	0	N/R	0	15	50 (32.1–67.8)	N/R	0
Zimmer³¹	390	183	47 (42–51.9)	190	49 (44–53.9)	17	4.3 (2.2–6.3)	28	7 (4.4–9.5)	N/R	0	N/R	0
Perez³²	123	93	76 (68.4–83.5)	27	22 (14.6–29.3)	N/R	0	26	21 (13.8–28.2)	N/R	0	3	2.4 (0.3–5.1)
Schonardie³³	35	35	100	NR	0	N/R	0	35	100	N/R	0	N/R	0

GN, Gram-negative; GP, Gram-positive; HP, polymicrobial blood cultures; IC, confidence interval; n, number; NR, not reported; RB, bacterial resistance.

ICU admission was required in 4.2% to 54.3% of patients.^{20,26,32,33,35} Septic shock occurred in 10.2% to mortality ranged from 2% to 70%²¹ (Table 4).

Microorganisms identified in blood cultures in a patient with chemotherapy-induced febrile neutropenia

Table 4 summarizes the classification of microorganisms from 8,665 positive blood cultures, Gram-negative bacteria were the most prevalent (46.1%, 95% CI: 45.1–47.2), followed by Gram-positive (42.4%, 95% CI: 41.4–43.5), resistant bacteria (13.4%, 95% CI: 12.4–14.5), and fungi (3.2%, 95% CI: 2.8–3.7).

Among Gram-negatives, the most common were E. coli (46.2%, 95% CI: 44.6–47.8), P. aeruginosa (18.7%, 95% CI: 17.5–20.0), and K. pneumoniae (18.5%, 95% CI: 17.3–19.8) (See Supplemental Material). For Gram-positives, coagulase-negative Staphylococcus with (52.3%, 95% CI: 50.7–53.9), S. epidermidis (31.8%, 95% CI: 27.1–37.0), Enterococcus spp. (14.7%, 95% CI: 13.4–16.0), and S. aureus (9.2%, 95% CI: 8.3–10.1) (see Supplemental Material).

Bacterial resistance was reported in 572 cultures (13.4%), ranging from 3.8% to 100%. Of these, 74.1% (95% CI: 70.1–77.7) were Gram-negative bacteria, while 37.0% (95% CI: 32.5–41.7) were Gram-positive bacteria. The most prominent bacteria were: ESBL-producing E. coli (40.4%, 95% CI: 35.7–45.2), ESBL-producing Klebsiella spp. (15.2%, 95% CI: 11.9–19.3), MDR P. aeruginosa (22.2%, 95% CI: 18.3–26.7), methicillin-resistant coagulase-negative Staphylococcus (47.9%, 95% CI: 39.9–56.0), and MRSA (16.1%, 95% CI: 12.9–20.0) (See Supplemental Material).

Fungal isolations were found in six studies with a prevalence of 3.2% (95% CI: 2.8–3.7). The most frequent were Candida spp. (63.8%, 95% CI: 56.1–70.8), Candida Non-albicans (36.7%, 95% CI: 28.6–45.6) and C. Albicans (14.4%, 95% CI: 9.2–21.9) (see Supplemental Material). In a subgroup analysis, Gram-negative bacteria accounted for 59% (95% CI: 48–70) of bloodstream infections in developed countries (see Supplemental Material). Figures 2 and 3 present the analysis of the prevalence of Gram-positive and Gram-negative bacteria, including subgroup analyses stratified by risk of bias.

Figure 2.

Forest plot of the prevalence of Gram-negative bacteria and subgroup analysis by risk of bias.

Figure 3.

Forest plot of the prevalence of Gram-positive bacteria and subgroup analysis by risk of bias.

In developed countries, fungal pathogens accounted for 2% (95% CI: 1–4) of bloodstream infections (see Figure 4). Risk of bias stratification was not conducted, as all included studies were assessed as low risk.

Figure 4.

Forest plot of fungal infection prevalence by World Bank Country Development status.

Source of heterogeneity assessment

In the univariate meta-regression, no significant results were obtained with the covariates: number of participants, risk of bias, and country development status.

Reporting bias

Reporting bias was assessed in studies reporting Gram-negative, Gram-positive, and fungal infections. Egger’s test showed p-values of 0.17, 0.80, and 0.94, respectively. Although funnel plots showed asymmetry (see Supplemental Materials), the Trim-and-Fill analysis did not impute any missing studies.

Discussion

Cancer patients—especially those with chemotherapy-induced acute leukemia—commonly experience profound and prolonged neutropenia, placing them at high risk for bacteremia and associated mortality. This is the first systematic review summarizing the distribution and characteristics of BSIs in FN patients post-chemotherapy. The primary finding is the high prevalence of both Gram-negative and Gram-positive bacteria and low prevalence of fungal infections.³³

Since 2000, infections by Gram-negative bacilli have increased, consistent with our finding that they account for 59% of BSIs. Contributing factors may include long-term catheter use, chemotherapy-induced mucositis, and widespread fluoroquinolone prophylaxis.³⁶ E. coli, K. pneumoniae, and other Enterobacteriaceae were the most common Gram-negative bacteria.

Gram-positive bacteria were the second most prevalent group. Literature attributes their infections largely to catheters and skin entry points.³⁷ Our results align with previous studies,^36,38–40 identifying coagulase-negative Staphylococcus (52.3%), S. epidermidis (31.8%), and Enterococcus spp. (14.7%), and S. aureus (9.2%).

Gram-negative infections were more frequent in underdeveloped countries than in developed nations.^37,41 This is consistent with findings reported in Latin America, where a BSI prevalence of 38.7% was documented during the 2019–2020 period, with Gram-negative bacteria accounting for 86% of cases. The most frequently identified bacteria were K. pneumoniae, E. coli, and P. aeruginosa.³⁹ Similarly, a hospital in China reported 62.5% Gram-negative and 33.1% Gram-positive infections from 2012 to 2019.³⁸ This trend continued in Latin America and Korea from 2020 to 2024, although Gram-positive prevalence is rising globally.

Fungal infections were less common (2%), potentially due to early empirical antifungal treatment in high-risk patients.⁴¹ Diagnostic challenges may also delay detection.^23,44

Pathogen distribution varies widely across regions,⁴⁰ emphasizing the importance of local epidemiology in guiding empirical antibiotic therapy.⁴¹ While bacterial infections remain the primary concern, ongoing surveillance and improved diagnostics are essential for timely management in FN patients.

In infections produced by Gram-positive and Gram-negative organisms, universal quinolone prophylaxis is not recommended for low-risk patients and should be evaluated on a case-by-case basis in high-risk patients. Active monitoring is crucial to detect resistance emergence of resistance.⁴³

Several limitations of our study should be considered. First, most included studies were conducted in a single center, which introduces the possibility of selection and observation biases. Second, not all the studies included report bacterial resistance of the pathogens, which prevents a more complete representation of BSIs caused by resistant microorganisms in this group of patients. Third, patients with and without a central venous catheter as a risk factor for the development of BSI were not compared. Finally, information on predictors and mortality associated with BSI is limited. Despite this, our study provides relevant information on the distribution and characteristics of bloodstream infections in chemotherapy-induced febrile neutropenic patients. Also, there is an absence of studies in regions such as Africa and the Middle East.

Conclusion

Cancer patients with post-chemotherapy febrile neutropenia are at high risk for severe infections and mortality. Our analysis revealed a high predominance of Gram-negative (57%) and Gram-positive (39%) bacteria, where E. Coli and coagulase-negative Staphylococcus as the most common pathogens. Bacterial resistance was observed in 31% of cases, while fungal infections were rare (0.2%).

These findings highlight the importance of ongoing epidemiological surveillance and individualized clinical management to improve outcomes in this high-risk population.

Supplemental Material

sj-docx-2-tai-10.1177_20499361251376123 – Supplemental material for Microbiological characterization of bacteremia in patients with chemotherapy-induced febrile neutropenia: systematic review and meta-analysis

Supplemental material, sj-docx-2-tai-10.1177_20499361251376123 for Microbiological characterization of bacteremia in patients with chemotherapy-induced febrile neutropenia: systematic review and meta-analysis by Alvarez Franklin Correa, Paola Guasti, Luis Fuenmayor-González, Harold Alexander-León, Yunqi Yu Liu, Johana Elizabeth Salgado-Apunte, Jorge González Grijalva, Hernan Sánchez, Nayely García-Méndez and María Fernanda García-Aguilera in Therapeutic Advances in Infectious Disease

Supplemental Material

sj-pdf-1-tai-10.1177_20499361251376123 – Supplemental material for Microbiological characterization of bacteremia in patients with chemotherapy-induced febrile neutropenia: systematic review and meta-analysis

Supplemental material, sj-pdf-1-tai-10.1177_20499361251376123 for Microbiological characterization of bacteremia in patients with chemotherapy-induced febrile neutropenia: systematic review and meta-analysis by Alvarez Franklin Correa, Paola Guasti, Luis Fuenmayor-González, Harold Alexander-León, Yunqi Yu Liu, Johana Elizabeth Salgado-Apunte, Jorge González Grijalva, Hernan Sánchez, Nayely García-Méndez and María Fernanda García-Aguilera in Therapeutic Advances in Infectious Disease

Footnotes

Appendix

Acknowledgements

We would like to express our profound gratitude to the Department of Research SOLCA, NUCLEO of Quito, for their invaluable support in conducting this study. In addition, we would like to express our profound gratitude to Dr. Fabricio Picoita, whose expert guidance throughout the research process was instrumental in the study’s success. In addition, we wish to acknowledge the assistance of Universidad Central del Ecuador and the Consejo de Postgrado Rodrigo Yépez for providing the essential resources and facilities that made this study possible.

Declarations

ORCID iDs

Alvarez Franklin Correa

Luis Fuenmayor-González

Harold Alexander-León

Yunqi Yu Liu

Johana Elizabeth Salgado-Apunte

Jorge González Grijalva

Hernan Sánchez

Nayely García-Méndez

María Fernanda García-Aguilera

Supplemental material

Supplemental material for this article is available online.

References

Zaimy

Saffarzadeh

Mohammadi

, et al. New methods in the diagnosis of cancer and gene therapy of cancer based on nanoparticles. Cancer Gene Ther 2017; 24(6): 233–243.

Hausman

DM.

What is cancer?

Perspect Biol Med 2019; 62(4): 778–784.

Lalami

Klastersky

Impact of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) on cancer treatment outcomes: an overview about well-established and recently emerging clinical data. Crit Rev Oncol Hematol 2017; 120: 163–179.

Ishikawa

Masaki

Kawai

, et al. Systematic review of the short-term versus long-term duration of antibiotic management for neutropenic fever in patients with cancer. Cancers (Basel) 2023; 15(5): 1611.

Aguado

Cruz

Virizuela

, et al. Manejo de la infección y la neutropenia febril en el paciente con cáncer sólido. Enferm Infecc Microbiol Clin 2017; 35(7): 451–460.

Lutwick

Bearman

. Infecciones del torrente sanguíneo. In: International Society for Infectious Diseases. Guía para el control de infecciones asociadas a la atención en salud [Internet]. 6^a ed. Boston: ISID, https://isid.org/guia/ (2019, accessed 15 September 2024).

Weisser

Theilacker

Tschudin Sutter

, et al. Secular trends of bloodstream infections during neutropenia in 15 181 haematopoietic stem cell transplants: 13-year results from a European multicentre surveillance study (ONKO-KISS). Clin Microbiol Infect 2017; 23(11): 854–859.

Marin

Gudiol

Ardanuy

, et al. Bloodstream infections in neutropenic patients with cancer: differences between patients with haematological malignancies and solid tumours. J Infect 2014; 69: 417–423.

Finello

Suasnabar

García

, et al. Clinical and microbiological characteristics of bloodstream infections in adult neutropenic patients. Rev Argent Microbiol 2021; 53(3): 183–193.

10.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. Epub ahead of print March 2021. DOI: 10.1136/bmj.n71.

11.

Munn

Moola

Lisy

, et al. Chapter 5: Systematic reviews of prevalence and incidence. In: Aromataris

Munn

(eds.) JBI manual for evidence synthesis [Internet]. Adelaide: JBI, https://jbi-global-wiki.refined.site/space/MANUAL (2020, accessed 15 September 2025).

12.

Migliavaca

Stein

Colpani

, et al. Quality assessment of prevalence studies: a systematic review. J Clin Epidemiol 2020; 127: 59–68.

13.

Munn

Moola

Lisy

, et al. Methodological guidance for systematic reviews of observational epidemiological studies reporting prevalence and cumulative incidence data. Int J Evid Based Healthcare 2015; 13(3): 147–153.

14.

Statistics Kingdom. Proportion confidence interval calculator - normal approximation (Wilson interval), Clopper–Pearson, Wilson score interval [Internet], https://www.statskingdom.com/proportion-confidence-interval-calculator.html (2024, accessed 15 August 2024).

15.

De Rosa

Motta

Audisio

, et al. Epidemiology of bloodstream infections in patients with acute myeloid leukemia undergoing levofloxacin prophylaxis. BMC Infect Dis 2013; 13: 563.

16.

Bousquet

Malfuson

Sanmartin

, et al. An 8-year survey of strains identified in blood cultures in a clinical haematology unit. Clin Microbiol Infect 2014; 20(1): O7–O12.

17.

Rosa

Goldani

Dos Santos

RP.

Risk factors for multidrug-resistant bacteremia in hospitalized cancer patients with febrile neutropenia: a cohort study. Am J Infect Control 2014; 42(1): 74–76.

18.

Piukovics

Terhes

Lázár

, et al. Evaluation of Bloodstream Infections during chemotherapy-induced febrile neutropenia in patients with malignant hematological diseases: single center experience. Eur J Microbiol Immunol (Bp) 2015; 5(3): 199–204.

19.

Cattaneo

Zappasodi

Mancini

, et al. Emerging resistant bacteria strains in bloodstream infections of acute leukaemia patients: results of a prospective study by the Rete Ematologica Lombarda (Rel). Ann Hematol 2016; 95(12): 1955–1963.

20.

Rönkkö

Juutilainen

Koivula

, et al. Changes in the microbiological epidemiology of febrile neutropenia in autologous stem cell transplant recipients. Infect Dis 2018; 50(6): 436–442.

21.

Zhu

Zhou

Jiang

, et al. Bacterial pathogens differed between neutropenic and non-neutropenic patients in the same hematological ward: an 8-year survey. Clin Infect Dis 2018; 67: S174–S178.

22.

Garzón

Isaza

Posada

, et al. Características clínicas y microbiológicas de pacientes con neutropenia febril en un hospital Universitario. Infect. [Internet]. 2019; 23(4): 347–351.

23.

Herrera

Córdova

Badía

, et al. La era de los microorganismos multirresistentes: impacto en pacientes neutropénicos febriles. Actualizaciones en Sida e Infectología. Epub ahead of print August 2019. DOI: 10.52226/revista.v27i100.13.

24.

Kim

Jung

Kang

, et al. Risk factors for extended-spectrum beta-lactamase-producing Enterobacteriaceae infection causing septic shock in cancer patients with chemotherapy-induced febrile neutropenia. Intern Emerg Med 2019; 14(3): 433–440.

25.

Mert

Ceken

Iskender

, et al. Epidemiology and mortality in bacterial bloodstream infections in patients with hematologic malignancies. J Infect Dev Ctries 2019; 13(8): 727–735.

26.

Widmer

Kern

Roth

, et al. Early versus late onset bloodstream infection during neutropenia after high-dose chemotherapy for hematologic malignancy. Infection 2019; 47(5): 837–845.

27.

Jung

Kim

Ryoo

, et al. Cancer patients with neutropenic septic shock: etiology and antimicrobial resistance. Korean J Int Med 2020; 35(4): 979–987.

28.

Martinez-Nadal

Puerta-Alcalde

Gudiol

, 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): 1068–1074.

29.

Caro

Madero-Marroquin

Zubizarreta

, et al. Impact of fluoroquinolone prophylaxis on neutropenic fever, infections, and antimicrobial resistance in newly diagnosed AML patients. Clin Lymphoma Myeloma Leuk 2022; 22(12): 903–911.

30.

Schulz

Grumaz

Hatzl

, et al. Pathogen detection by metagenomic next-generation sequencing during neutropenic fever in patients with hematological malignancies. Open Forum Infect Dis 2022; 9(8): ofac393.

31.

Zimmer

Stohs

Meza

, et al. Bloodstream infections in hematologic malignancy patients with fever and neutropenia: are empirical antibiotic therapies in the United States still effective? Open Forum Infect Dis 2022; 9(7): ofac240.

32.

Pérez-Lazo

del Valle-Mendoza

Sandoval-Ahumada

, et al. Impact of adding a rapid PCR-based blood culture identification panel to the antimicrobial stewardship program of patients with febrile neutropenia in a Peruvian Referral Hospital. Antibiotics 2023; 12(4): 648.

33.

Schonardie

Beck

Rigatto

MH.

Prevalence of bloodstream infection pathogens in hemato-oncological patients and predictors of carbapenem-resistant gram-negative bacterial infections during febrile neutropenia. Brazilian J Infect Dis 2023; 27(2): 102758.

34.

Mandal

Maji

Dolai

, et al. Micro-organisms associated with febrile neutropenia in patients with haematological malignancies in a Tertiary Care Hospital in Eastern India. Indian J Hematol Blood Transfusion 2015; 31(1): 46–50.

35.

Marín

Gudiol

Ardanuy

, et al. Factors influencing mortality in neutropenic patients with haematologic malignancies or solid tumours with bloodstream infection. Clin Microbiol Infect 2015; 21(6): 583–590.

36.

Wisplinghoff

Seifert

Wenzel

, et al. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis 2003; 36(9): 1103–1110.

37.

Siddiqui

Azmat

Tikmani

, et al. Frequency of bloodstream infection in febrile neutropenic patients, experience from a developing country. Ann Med Surg (Lond) 2018; 34: 71–74.

38.

, et al. Epidemiology, resistant pathogens, and causes of early death in cases of bloodstream infection in patients with hematological malignancies from 2012-2019. Infect Med 2022; 1(1): 23–30.

39.

Feld

Bloodstream infections in cancer patients with febrile neutropenia. Int J Antimicrob Agents 2008; 32: S30–S33.

40.

Garcia-Vidal

Cardozo-Espinola

Puerta-Alcalde

, et al. Risk factors for mortality in patients with acute leukemia and bloodstream infections in the era of multiresistance. PLoS One 2018; 13(6): e0199531.

41.

Soldi

Coelho

YNB

Paranhos

, et al. The impact of antifungal prophylaxis in patients diagnosed with acute leukemias undergoing induction chemotherapy: a systematic review and meta-analysis. Clin Exp Med 2023; 23(7): 3231–3249.

42.

Gudiol

Aguilar-Guisado

Azanza

, et al. Executive summary of the consensus document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Network for Research in Infectious Diseases (REIPI) and the Spanish Society of Haematology and Haemotherapy (SEHH) on the management of febrile neutropenia in patients with hematological malignancies. Enferm Infecc Microbiol Clin 2020; 38(4): 174–181.

43.

Rabagliati

Salazar

Pérez-Lazo

, et al. An emergent change in epidemiologic and microbiological characteristics of bloodstream infections in adults with febrile neutropenia resulting from chemotherapy for acute leukemia and lymphoma at reference centers in Chile, Ecuador, and Peru. Open Forum Infect Dis 2024; 11(3): ofae052.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

7.71 MB

0.62 MB