Alexander et al. (2018) |
Multicenter open label randomized trial |
ALs and patients undergoing HSCT |
624 patients (6 months - 21 years old)
200 (ALL)
424 (HSCT)
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Protocol:
AML: Cytarabine, daunorubicin, etoposide
cytarabine, etoposide
mitoxantrone, cytarabine, others
ALL:
Mitoxantrone, vincristine, dexamethasone, asparaginase
cytarabine, asparaginase
cyclophosphamide, etoposide, others
Autologous HSCT:
Busulfan/melphalan carboplatin based/ others
Allogeneic HSCT:
Total body irradiation based, busulfan based, others
|
Levofloxacin |
Bacteremia
ALs
Prophylaxis group: 21.9%
Control group: 43.4%
risk difference (95%CI); 21.6% (8.8% - 34.4%) p = 0.001
Patients undergoing HSCT
Prophylaxis group: 11.0%
Control group: 17.3%.
risk difference (95%CI): 6.3% (0.3% -13.0%) p = 0.06
When all patients combined, levofloxacin significantly reduced the likelihood of bacteremia: risk difference (95%CI): 11.4%;(5.1% -17.6%) p < .001
Fever and neutropenia
Prophylaxis group: 71.2%
Control group: 82.1%
risk difference (95%CI): 10.8% (4.2% -17.5%) p = 0.002
Severe infection
Prophylaxis group: 3.6%
Control group: 5.9%
risk difference (95%CI): 2.3% (-1.1 - 5.6%) p = 0.204
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The likelihood of fever and neutropenia was lower in the levofloxacin prophylaxis group than in the control group in children with AL (71.2% us. 82.1%; 95% IC, p = 0,002) as was the risk of bacteremia (21.9% us. 43.4%; 95% IC, p = 0.01). However, the study did not demonstrate this same effect in reducing the risk of bacteremia in children undergoing HSCT. |
Sulis et al. (2017) |
Prospective |
ALL |
1,024 patients (1 - 21 years old)
230 patients - (DFCI 11-001)
794 patients - (DFCI 05-001)
|
Protocol:
DFCI 11-001 (prophylaxis group)
DFCI 05-001 (control group)
|
Oral
levofloxacin or moxifloxacin
|
Bacteremia during induction P < 0.0001 DFCI 11-00110.9%
DFCI 05-001 24.4%
Infection during induction P <0.0001DFCI 11-00114.3%
DFCI 05-001 26.3%
Induction death (0.9% us. 2%) was not significantly different |
The study demonstrated that FQ use for prophylaxis is effective in reducing gram-negative and some gram-positive bacteremia. Also shown that levofloxacin did not lead to an incidence increase of multi resistant germs or infection by Clostridium difficile or fungi. |
Wolf et al. (2017) |
Single-center observational cohort study |
ALL |
344 patients |
Protocol: TOTXVI and TOTXV |
Levofloxacin (from August 2014) (n=69)
Cefepime, ciprofloxacin or vancomycin plus cefepime or ciprofloxacin (2007-July 2014) (n = 102)
|
Effectiveness of Primary Prophylaxis
FN - adjusted OR (95% CI): 0.23 (0.14-.40) p <.001
BSI - adjusted OR (95% CI): 0.30 (0.13-0.73) p = 0.008
Clostridium difficile
infection -adjusted OR (95% CI): 0.38 (0.16 -0.93) p = 0.04
Levofloxacin vs no prophylaxis
FN - adjusted OR (95% CI): 0.28 (0.15 - 0.52) p <.001 BSI - adjusted OR (95% CI): 0.42 (0.15 - 1.16) p = 0.09
Clostridium difficile
infection -adjusted OR (95% CI): 0.03 (< .01 to .24) p <.001
Levofloxacin vs other prophylaxis
FN - adjusted OR (95%CI): 1.17 (0.64 - 2.14) p = 0.60
BSI - adjusted OR (95%CI): 1.85 (.54 -6.35) p = 0.33
Clostridium difficile
infection -adjusted OR (95%CI): 0.04 (< 0.01 - 0.36) p = <. 001
(Shouldn't this be “≥”???)
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The article identified that prophylaxis was able to significantly prevent FN and systemic infection during induction chemotherapy by ≥ 70%. The use of levofloxacin also minimized the use of antibiotic treatment with cefepime/ceftazidime, vancomycin and aminoglycosides. |
Yeh et al. (2014) |
Single-center cohort study |
ALL and AML |
149 patients (< 18 years old)
113 with ALL
36 with AML
|
Protocol: ALL: Taiwan Pediatric Oncology Group-ALL-2002 protocol AML: Taiwan Pediatric Oncology Group-AML-97A protocol |
Oral ciprofloxacin
Oral voriconazole
|
ALL
BSI (P = 0.02)
Pre-prophylaxis: 19
Prophylaxis: 5
IFI ( p < 0.01)
Pre-prophylaxis: 10
Prophylaxis: 0
FN ( p < 0.01)
Pre-prophylaxis: 50
Prophylaxis: 19
OS
Pre-prophylaxis: 86% ±5%
Prophylaxis: 98% ± 2%
EFS
Pre-prophylaxis: 78% ±9%
Prophylaxis: 87% ± 6,5%
AML
BSI ( p < 0.01)
Pre-prophylaxis: 25
Prophylaxis: 5
IFI ( p < 0.01)
Pre-prophylaxis: 12
Prophylaxis: 0
FN ( p = 0.01)
Pre-prophylaxis: 24
Prophylaxis: 14
OS
Pre-prophylaxis: 60% ± 20%
Prophylaxis: 68% ± 16%
EFS
Pre-prophylaxis: 50% ± 11%
Prophylaxis: 55% ± 11%
|
The study demonstrated that the combined prophylaxis was able to reduce the rates of bloodstream infection, IFI, FN and length of stay (LOS) in ICU patients with ALL. It was also able to reduce rates of bloodstream infection, FN, IFI and infection-related deaths in children with AML. They did not demonstrate ciprofloxacin resistance rate increase during treatment. |
Widjajanto et al. (2013) |
Randomized doubleblind study- |
ALL |
110 patients (0 -14 years old) |
Protocol: (WK)-ALL-2000 |
Ciprofloxacin |
Fever (p = 0.07):
- Placebo:
risks = 32.7%
- Prophylaxis:
risks = 50%
Clinical sepsis
( p = 0.22):
- Placebo:
risks = 38.5%
- Prophylaxis:
risks = 50%
Death ( p = 0.05):
- Placebo:
risks = 5.8%
- Prophylaxis:
risks = 18.9%
Nadir of absolute neutrophil count (p = 0.01)
- Placebo: 270 (range: 14 - 25,480) × 1099 Alexander S, Fisher BT, Gaur AH, Dvorak CC, Villa Luna D, Dang H, et al. Effect of levofloxacin prophylaxis on bacteremia in children with acute leukemia or undergoing hematopoietic stem cell transplantation. JAMA. 2018;320(10):995-1004. Sep 11. cells/L
- Prophylaxis: 62 (range: 5 - 884) × 1099 Alexander S, Fisher BT, Gaur AH, Dvorak CC, Villa Luna D, Dang H, et al. Effect of levofloxacin prophylaxis on bacteremia in children with acute leukemia or undergoing hematopoietic stem cell transplantation. JAMA. 2018;320(10):995-1004. Sep 11. cells/L
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The study concluded that ciprofloxacin, when used during chemotherapy induction, led to a higher nadir of neutrophil count (median of 62 us. 270, p < 0.01) and increased risk of mortality (18.9% us. 5.8%, p = 0.05), when compared to placebo. |
Laoprasopwattana et al. (2013) |
Prospective doubleblind
randomized placebo-controlled trial
|
ALL and lymphoma |
95 patients (3 months -18 years old)
71 had ALL 24 had lymphoma
|
Protocol: induction or consolidation phase chemotherapy (unspecified) |
Ciprofloxacin |
Fever:
- Placebo: 17/34 (50.0)
- Prophylaxis: 27/37 (73.0)
- Absolute difference in risk: -23.0 (-45.0 to -0.9) p = 0.046
- ALL 13/24 (54.2) 24/30 (80.0) -25.8 (-50.4 to -1.3)
p = 0.042
-Lymphoma 4/10 (40.0) 3/7 (42.9) -2.9 (-50.4 to 44.7) p < 0.999
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The authors show that the cipro-floxacino was able to prevent febrile episodes in neutropenic children with ALL (P=0,046). However, this effect was only identified in the remission induction phase. And, there was an increase in the percentage of ciprofloxacin-resistant Escherichia coli and Klebsiella pneumoniae in a control rectal swab |
Feng et al. (2013) |
Prospective |
AML |
38 patients (2 -16 years old) |
Protocol: NOPHO 2004 |
Vancomycin/Cefepime or Piperacillin/Tazobactam |
Frequency of fever (events) p < 0.001
Prophylaxis group: 0.4 ± 0.1
Control group: 0.9 ± 0.1
Interval between agranulocytosis and fever (days) p = 0.07
Prophylaxis group: 6.4 ± 0.9
Control group: 3.8± 0.4
Hospitalization (days) p < 0.001
Prophylaxis group: 21.5 ± 0.7
Control group: 28.5 ± 1.7
Lung Infection p < 0.001
Prophylaxis group: 80%
Control group: 39%
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Prophylactic antibiotics during the period of chemotherapy-induced agranulocytosis in this study reduced the incidence of infectious fever and shortened the mean length of hospital stay.1010 Feng X, Ruan Y, He Y, Zhang Y, Wu X, Liu H, et al. Prophylactic first-line antibiotics reduce infectious fever and shorten hospital stay during chemotherapy-induced agranulocytosis in childhood acute myeloid leukemia. Acta Haematol. 2014;132 (1):112-7.
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