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. 2023 Mar 5;15(5):1611. doi: 10.3390/cancers15051611

Table 1.

Clinical characteristics of the included randomized controlled trials in our systematic review.

Articles, Published Year Published Country Study Design/Patient Age Study
Period		 Patient Characteristics,
High- or Low-Risk Febrile Neutropenia/Prophylaxis in Cases of Neutropenia		 Type of Beta-Lactam Antibiotics/Intervention Number of Patients in Each Arm/Definition of Treatment Failure Follow-Up Period
De Jonge
2022 [12]		 The Netherlands RCT, open label trial, multicenter study/median age-59 years (IQR, 52 to 65) December 2014–July 2019 hematologic malignancy or SCT, high-risk FN/yes

  • IMP/CS or MEPM

  • The antibiotics were discontinued 72 h [60–84] irrespective of the presence of fever

  • More than 9 days until being afebrile for 5 days or neutrophil recovery

 short therapy arm (n = 144),
long-therapy arm (n = 137)
Occurrence of either a microbiologically documented or clinically suspected carbapenem-sensitive infection; recurrence of fever from days 4–9 of empirical antibiotic treatment; or septic shock, respiratory insufficiency, or death due to any cause from day 4 until neutrophil recovery (≥0·5 × 109/L)		 30 days after neutrophil recovery
Ram 2021 [25] Israel RCT, open label trial, single center study/mean age (SD)-antibiotic stewardship strategy (intervention group, 61.2 (±12.5),
standard therapy (control group), 60.6 years (±8.3)		 January 2020–
March 2021		 HCT, CAR-T,
high-risk FN/yes

  • PIPC/TAZ or CAZ

  • discontinued after 48–72 h providing there was no evidence of clinical or microbiologically documented infection

  • until recovery of counts (control group)

 antibiotic stewardship strategy (n = 59), standard therapy (n = 51)/
definition of treatment success: successful response to treatment, defined as the combination of continued clinical improvement on day 5 after initiation of antibiotics, no reoccurrence of bacteremia/fever/clinical infection signs on day 5, and no need for additional therapy on days 4–5 after starting antibiotics		 Not appliable
Kumar [22] 2020 India RCT,
open label trial,
single center
study/
mean age (SD)
Arm A- 7.0 (4.0),
Arm B- 8.9 (4.7)		 January 2017–
December 2018		 all pediatric patients, aged 3–18 y with solid tumors and lymphoma leukemia/no

  • Cefoperazone/Sulbactam + Amikacin

  • Prior to randomization, patient had to be afebrile for at least 24 h with a documented negative blood culture and ANC < 500,

  • confirmation of a negative blood culture report, patients with persisting neutropenia (ANC < 500) were randomized between two arms

  • (Arm A: stoppage of antibiotics and Arm B: short AMPC/CVA+LVFX).

 Arm A (n = 38),
Arm B (n = 37)/
Reoccurrence of fever		 until resolution of neutropenia
Aguilar-Guisado
2017 [19]		 Spain RCT,
open label trial,
multicenter study/median age (IQR) short-therapy arm, 52 years (42 to 61)
long-therapy arm, 54 years (39 to 63)		 April 2012–May 2016 hematologic malignancy or
SCT, high-risk FN/yes

  • antipseudomonal beta-lactam as monotherapy or combination

  • short-until apyrexia + signs and symptoms resolution + normal vital signs

  • long-until apyrexia + signs and symptoms resolution + normal vital signs + ANC > 500/μL

 short-therapy arm (n = 78),
long-therapy arm (n = 79)/
recurrent fever		 28 days
Santolaya
2017 [27]		 Chile RCT, open label trial, multicenter study/mean age (SD) short therapy: 4.0 years (3 to 8)
long therapy: 5.0 years (3 to 9)		 July 2012–December 2015 high and low risk FN + a positive nasopharyngeal sample for a respiratory virus/yes CTRX for low-risk FN, CAZ + AMK +/− anti-Gram-positive beta-lactam or glycopeptide for high-risk FN

  • short therapy 3 days, stopped at randomization

  • long therapy continuation of the same regimen until 7 days if afebrile for 24 h and CRP < 40 mg/L

 short-therapy (n = 84),
long-therapy (n = 92)/
development of sepsis, admission to PICU		 until fever and ANC resolution
Klaassen
2000 [21]		 Canada RCT, double blind placebo-controlled trial, single center study/short therapy arm, 4.3 years
long therapy arm, 4.9 years		 August 1996–April 1998 low-risk FN/no

  • PIPC + GM 48 to 120 h after admission

  • short term: placebo-48 to 120 h followed by placebo until 14 days or ANC > 500/μL

  • long term: oral cloxacillin + oral cefixime

 short therapy arm (n = 36),
long therapy arm (n = 37)/
readmission with recurrent neutropenia		 until ANC recovery
Santolaya
1997 [28]		 Chile RCT, double bind placebo- controlled trial, single center study/mean age (SD) short therapy: 6.8 years (4.3)
long-therapy: 5.6 years (3.8) 		January 1994–
January 1996		 unknown origin of FN/
regimen/no

  • anti-staphylococcal penicillin and a third generation cephalosporin or an AG for 3 days

  • short therapy: no antibiotics

  • long therapy: continuation of the same until episode of fever and neutropenia resolved

 short-therapy (n = 36),
long-therapy (n = 39)/documented bacterial infection
+ probable bacterial infection		 until fever and ANC resolution
Pizzo
1982 [23]		 USA median age (range) short therapy arm: 15 years (2 to 22)
long therapy arm: 16 years (2 to 25)
antibacterial + amphotericin B arm: 18 years (8 to 30) 		November 1975–
December 1979		 children with neutropenia and fever of unknown origin/no

  • unknown origin of FN with resolving fever after 7 days of antibiotic treatment: cefalotin + GM + carindacillin

  • short therapy: no antibiotics

  • long therapy: antibacterial arm: continuation of the same regimen until afebrile for ≥24 h and ANC > 500, antibacterial + amphotericin B arm: continuation of the same regimen + amphotericin B (0.5 mg/kg/d, IV)

 short therapy arm (n = 16)
long therapy arm (n = 16)
antibacterial + amphotericin B arm (n = 18)/any infectious complication		 until fever and ANC resolution
Pizzo
1979 [24]		 USA RCT,
open label,
single center study/median age (range) short therapy arm: 14 years (2 to 33)
long therapy arm: 15 years (1 to 30)		 November 1975–
February 1978 		unknown origin of FN with resolving fever after 7 days of antibiotic treatment/no

  • cefalotin + GM + carindacillin

  • short-therapy arm: no antibiotics

  • Long-therapy arm: continuation of the same regimen

  • Day start (day of randomization): day 7 from admission

  • until afebrile for ≥24 h and ANC > 500

 short therapy arm (n = 17)
long therapy arm (n = 16)/
recurrence of fever		 30 days after fever and ANC resolution
Bjornsson
1977 [20]		 USA RCT,
open label,
single center study/mean age (SD) short therapy arm: 42.5 years (±11.8)
long therapy arm: 43.45 years (±16.5)		 June 1975–
May 1976 		unknown origin of unresolving FN/no

  • after 3 days of antibiotic treatment/

  • carbenicillin + cephalothin + gentamicin

  • short: no antibiotics

  • long: carbenicillin + cephalothin + gentamicin + CLDM or CL

 short therapy arm (n = 6)
long therapy arm (n = 11)/		 4 weeks
Rodriguez
1973 [26]		 USA RCT, open label,
single center study/median 33 (range, 15–80) years		 July 1970–
December 1971 		unknown origin of FN/no cefalotin + carindacillin short therapy: 4 days long therapy: 10 days of additional therapy (total 14 days) or 5 days after becoming afebrile, whichever was longer short therapy non-resolving fever (n = 11), resolving fever (n = 30),
long therapy: non resolving fever (n = 14) resolving fever (n = 26)/
infection is cause of fever		 Not applicable

Abbreviations: CTRX, ceftriaxone; CAZ, ceftazidime; MEPM, meropenem; PIPC, piperacillin; PIPC/TAZ, piperacillin/tazobactam; CLDM, clindamycin; CL, Chloramphenicol; GM, gentamycin; AG, aminoglycoside; AMK, amikacin; FN, febrile neutropenia; RCT, randomized control trials; N/A, not available; ANC, absolute neutrophil count; IQR, interquale range; SD, standard deviation.