Comparison of antipseudomonal beta-lactams

for febrile neutropenia empiric therapy.

<<Supplementary File>>

Supplementary Text 1. Search formulas.

Pubmed

#1 (((Fever[mh:noexp] OR fever*[tiab] OR febrile*[tiab]) AND

(granulocytopeni*[tiab] OR leukocytopeni*[tiab] OR neutropeni*[tiab])) OR

Febrile Neutropenia[mesh])

#2 (beta-Lactams[mh:noexp] OR beta-Lactam*[tiab])

#3 Penicillins[mh:noexp] OR penicillin*[tiab] OR piperacillin[mh:noexp] OR

piperacillin*[tiab] OR pipracil*[tiab] OR PIPC[tiab] OR piperacillin,

tazobactam drug combination [Supplementary Concept] OR zocyn*[tiab] OR

zosyn*[tiab] OR tazocin*[tiab]

#4 (Cephalosporins[mh:noexp] OR cephalosporin*[tiab] OR

Ceftazidime[mh:noexp] OR ceftazidime*[tiab] OR modacin*[tiab] OR

fortaz*[tiab] OR tazicef*[tiab] OR CAZ[tiab] OR Cefoperazone[mh:noexp] OR

cefoperazone*[tiab] OR sulperazon*[tiab] OR CPZ SBT[tiab] OR SBT

CPZ[tiab] OR C/S[tiab] OR cefepime [Supplementary Concept] OR

cefepime*[tiab] OR CFPM[tiab] OR maxipime*[tiab] OR voco*[tiab] OR

Cefpirome [Supplementary Concept] OR cefpirome*[tiab] OR CPR[tiab] OR

cefrom*[tiab] OR keiten*[tiab] OR broact*[tiab] OR cefozopran

[Supplementary Concept] OR cefozopran*[tiab] OR CZOP[tiab] OR

firstcin*[tiab])

#5 ("Carbapenems"[Mesh] OR carbapenem*[tiab] OR Imipenem[mh:noexp]

OR cilastatin, imipenem drug combination [Supplementary Concept] OR

imipenem*[tiab] OR tienam*[tiab] OR primaxin*[tiab] OR IMPM[tiab] OR

panipenem [Supplementary Concept] OR panipenem*[tiab] OR PAPM[tiab]

OR panipenem betamipron [Supplementary Concept] OR carbenin*[tiab] OR

meropenem [Supplementary Concept] OR meropenem*[tiab] OR MEPM[tiab]

OR merrem*[tiab] OR meropen*[tiab] OR biapenem [Supplementary

Concept] OR BIPM[tiab] OR omegacin*[tiab] OR biapenem*[tiab] OR

doripenem [Supplementary Concept] OR doripenem*[tiab] OR DRPM[tiab]

OR finibax*[tiab] OR doribax*[tiab] OR Ertapenem [Supplementary Concept]

OR ertapenem*[tiab] OR ERPM[tiab] OR invanz*[tiab])

#6 (#2 OR #3 OR #4 OR #5)

#7 (#1 AND #6)

#8 (randomized controlled trial [pt] OR controlled clinical trial [pt] OR

random* [tiab] OR placebo [tiab] OR "clinical trials as topic"[mesh: noexp]

OR trial [ti] OR RCT* [tiab] OR Groups [tiab])

#9 (#7 AND #8)

#10 (#9 NOT (animals [mh] NOT humans [mh]))

Cochrane CENTRAL

#1 MeSH descriptor: [Fever] this term only

#2 "fever*":ti,ab

#3 "febrile*":ti,ab

#4 #1 or #2 or #3

#5 "granulocytopeni*":ti,ab

#6 "leukocytopeni*":ti,ab

#7 "neutropeni*":ti,ab

#8 #5 or #6 or #7

#9 #4 and #8

#10 MeSH descriptor: [Febrile Neutropenia] explode all trees

#11 #9 or #10

#12 MeSH descriptor: [Penicillins] this term only

#13 MeSH descriptor: [Piperacillin] this term only

#14 "penicillin*":ti,ab

#15 "piperacillin*":ti,ab

#16 "pipracil*":ti,ab

#17 "PIPC":ti,ab

#18 ("zocyn*" or "zosyn*"):ti,ab

#19 "tazocin*":ti,ab

#20 #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19

#21 MeSH descriptor: [Cephalosporins] this term only

#22 MeSH descriptor: [Ceftazidime] this term only

#23 MeSH descriptor: [Cefoperazone] this term only

#24 "cephalosporin*":ti,ab

#25 "ceftazidime*":ti,ab

#26 "modacin*":ti,ab

#27 "fortaz*":ti,ab

#28 "tazicef*":ti,ab

#29 "CAZ":ti,ab

#30 "cefoperazone*":ti,ab

#31 "sulperazon*":ti,ab

#32 "CPZ SBT":ti,ab

#33 "SBT CPZ":ti,ab

#34 "c/s":ti,ab

#35 "cefepime*":ti,ab

#36 "CFPM":ti,ab

#37 "maxipime*":ti,ab

#38 "voco*":ti,ab

#39 "Cefpirome*":ti,ab

#40 "CPR":ti,ab

#41 "cefrom*":ti,ab

#42 "keiten*":ti,ab

#43 "broact*":ti,ab

#44 "cefozopran*":ti,ab

#45 "CZOP":ti,ab

#46 "firstcin*":ti,ab

#47 #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30

or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40

or #41 or #42 or #43 or #44 or #45 or #46

#48 MeSH descriptor: [Carbapenems] explode all trees

#49 MeSH descriptor: [Imipenem] this term only

#50 "carbapenem*":ti,ab

#51 "imipenem*":ti,ab

#52 "tienam*":ti,ab

#53 "primaxin*":ti,ab

#54 "IMPM":ti,ab

#55 "panipenem*":ti,ab

#56 "PAPM":ti,ab

#57 "carbenin*":ti,ab

#58 "meropenem*":ti,ab

#59 "MEPM":ti,ab

#60 "merrem*":ti,ab

#61 "meropen*":ti,ab

#62 "biapenem*":ti,ab

#63 "BIPM":ti,ab

#64 "omegacin*":ti,ab

#65 "doripenem*":ti,ab

#66 "DRPM":ti,ab

#67 "finibax*":ti,ab

#68 "doribax*":ti,ab

#69 "ertapenem*":ti,ab

#70 "ERPM":ti,ab

#71 "invanz*":ti,ab

#72 #48 or #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56 or #57

or #58 or #59 or #60 or #61 or #62 or #63 or #64 or #65 or #66 or #67

or #68 or #69 or #70 or #71

#73 #20 or #47 or #72

#74 #11 and #73

#75 MeSH descriptor: [Animals] explode all trees

#76 MeSH descriptor: [Humans] this term only

#77 #74 not (#75 not #76)

#78 #77 in Trials

EMBASE

#1 'febrile neutropenia'/de AND [embase]/lim NOT [medline]/lim

#2 'fever'/de AND [embase]/lim NOT [medline]/lim

#3 fever*:ab,ti AND [embase]/lim NOT [medline]/lim

#4 febrile*:ab,ti AND [embase]/lim NOT [medline]/lim

#5 granulocytopeni*:ab,ti AND [embase]/lim NOT [medline]/lim

#6 leukocytopeni*:ab,ti AND [embase]/lim NOT [medline]/lim

#7 neutropeni*:ab,ti AND [embase]/lim NOT [medline]/lim

#8 #2 OR #3 OR #4

#9 #5 OR #6 OR #7

#10 #8 AND #9

#11 #1 OR #10

#12 'beta lactam'/de AND [embase]/lim NOT [medline]/lim

#13 'beta lactam*':ab,ti AND [embase]/lim NOT [medline]/lim

#14 #12 OR #13

#15 'penicillin derivative'/de AND [embase]/lim NOT [medline]/lim

#16 penicillin*:ab,ti AND [embase]/lim NOT [medline]/lim

#17 'piperacillin'/de AND [embase]/lim NOT [medline]/lim

#18 piperacillin*:ab,ti AND [embase]/lim NOT [medline]/lim AND lim

#19 pipracil*:ab,ti AND [embase]/lim NOT [medline]/lim

#20 pipc:ab,ti AND [embase]/lim NOT [medline]/lim

#21 'piperacillin plus tazobactam'/de AND [embase]/lim NOT [medline]/lim

#22 zocyn*:ab,ti OR zosyn*:ab,ti AND [embase]/lim NOT [medline]/lim

#23 tazocin*:ab,ti AND [embase]/lim NOT [medline]/lim

#24 #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23

#25 'cephalosporin derivative'/de AND [embase]/lim NOT [medline]/lim

#26 cephalosporin*:ab,ti AND [embase]/lim NOT [medline]/lim

#27 'ceftazidime'/de AND [embase]/lim NOT [medline]/lim

#28 ceftazidime*:ab,ti AND [embase]/lim NOT [medline]/lim

#29 modacin*:ab,ti AND [embase]/lim NOT [medline]/lim

#30 fortaz*:ab,ti AND [embase]/lim NOT [medline]/lim

#31 tazicef*:ab,ti AND [embase]/lim NOT [medline]/lim

#32 'cefoperazone'/de AND [embase]/lim NOT [medline]/lim

#33 sulperazon*:ab,ti AND [embase]/lim NOT [medline]/lim

#34 cpz:ab,ti AND sbt:ab,ti AND [embase]/lim NOT [medline]/lim

#35 cefepime*:ab,ti AND [embase]/lim NOT [medline]/lim

#36 cfpm:ab,ti AND [embase]/lim NOT [medline]/lim

#37 maxipime*:ab,ti AND [embase]/lim NOT [medline]/lim

#38 voco*:ab,ti AND [embase]/lim NOT [medline]/lim

#39 'cefpirome'/de AND [embase]/lim NOT [medline]/lim

#40 cefpirome*:ab,ti AND [embase]/lim NOT [medline]/lim

#41 cpr:ab,ti AND [embase]/lim NOT [medline]/lim

#42 cefrom*:ab,ti AND [embase]/lim NOT [medline]/lim

#43 broact*:ab,ti AND [embase]/lim NOT [medline]/lim

#44 'cefozopran'/de AND [embase]/lim NOT [medline]/lim

#45 cefozopran*:ab,ti AND [embase]/lim NOT [medline]/lim

#46 czop:ab,ti AND [embase]/lim NOT [medline]/lim

#47 firstcin*:ab,ti AND [embase]/lim NOT [medline]/lim

#48 #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 

OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42O

R #43 OR #44 OR #45 OR #46 OR #47

#49 'carbapenem derivative'/de AND [embase]/lim NOT [medline]/lim

#50 carbapenem*:ab,ti AND [embase]/lim NOT [medline]/lim

#51 'imipenem'/de AND [embase]/lim NOT [medline]/lim

#52 imipenem*:ab,ti AND [embase]/lim NOT [medline]/lim

#53 'cilastatin plus imipenem'/de AND [embase]/lim NOT [medline]/lim

#54 tienam*:ab,ti AND [embase]/lim NOT [medline]/lim

#55 primaxin*:ab,ti AND [embase]/lim NOT [medline]/lim

#56 impm:ab,ti AND [embase]/lim NOT [medline]/lim

#57 'panipenem'/de AND [embase]/lim NOT [medline]/lim

#58 panipenem*:ab,ti AND [embase]/lim NOT [medline]/lim

#59 papm:ab,ti AND [embase]/lim NOT [medline]/lim

#60 'panipenem plus betamipron'/de AND [embase]/lim NOT [medline]/lim

#61 carbenin*:ab,ti AND [embase]/lim NOT [medline]/lim

#62 'meropenem'/de AND [embase]/lim NOT [medline]/lim

#63 meropenem*:ab,ti AND [embase]/lim NOT [medline]/lim

#64 mepm:ab,ti AND [embase]/lim NOT [medline]/lim

#65 merrem*:ab,ti AND [embase]/lim NOT [medline]/lim

#66 meropen*:ab,ti AND [embase]/lim NOT [medline]/lim

#67 'biapenem'/de AND [embase]/lim NOT [medline]/lim

#68 biapenem*:ab,ti AND [embase]/lim NOT [medline]/lim

#69 omegacin*:ab,ti AND [embase]/lim NOT [medline]/lim

#70 bipm:ab,ti AND [embase]/lim NOT [medline]/lim

#71 'doripenem'/de AND [embase]/lim NOT [medline]/lim

#72 doripenem*:ab,ti AND [embase]/lim NOT [medline]/lim

#73 drpm:ab,ti AND [embase]/lim NOT [medline]/lim

#74 finibax*:ab,ti AND [embase]/lim NOT [medline]/lim

#75 doribax*:ab,ti AND [embase]/lim NOT [medline]/lim

#76 'ertapenem'/de AND [embase]/lim NOT [medline]/lim

#77 ertapenem*:ab,ti AND [embase]/lim NOT [medline]/lim

#78 erpm:ab,ti AND [embase]/lim NOT [medline]/lim

#79 invanz*:ab,ti AND [embase]/lim NOT [medline]/lim

#80 #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57 

OR #58 OR #59 OR #60 OR #61 OR #62 OR #63 OR #64 OR #65 OR #66O

R #67 OR #68 OR #69 OR #70 OR #71 OR #72 OR #73 OR #74 OR #75 O

R #76 OR #77 OR #78 OR #79

#81 #14 OR #24 OR #48 OR #80

#82 #11 AND #81

#83 'clinical trial'/de OR 'randomized controlled trial'/de

OR 'randomization'/de OR 'single blind procedure'/de OR 'double blind

procedure'/de OR'crossover procedure'/de OR 'placebo'/de OR 'prospective

study'/de OR ('randomi?ed controlled' NEXT/1 trial*):ab,ti OR rct*:ab,ti

OR 'randomly allocated':ab,ti OR 'allocated randomly':ab,ti OR 'random

allocation':ab,ti OR (allocated NEAR/2 random):ab,ti OR

(single NEXT/1 blind*):ab,ti OR (double NEXT/1 blind*):ab,ti OR

((treble OR triple) NEAR/1 blind*):ab,ti OR placebo*:ab,ti OR groups:ab AND

[embase]/lim NOT [medline]/lim

#84 #82 AND #83

#85 #84 NOT ([animals]/lim NOT [humans]/lim)

Web of Science Core Collection

# 1 TS=((fever* OR febrile*) AND (granulocytopeni* OR leukocytopeni*

OR neutropeni*))

# 2 TS=(betaLactam*)

# 3 TS=(penicillin* OR piperacillin* OR pipracil* OR PIPC OR zocyn* OR

zosyn* OR tazocin*)

# 4 TS=(cephalosporin* OR ceftazidime* OR modacin* OR fortaz* OR

tazicef* OR CAZ OR cefoperazone* OR sulperazon* OR (CPZ SBT) OR (SBT

CPZ) OR (C/S) OR cefepime* OR CFPM OR maxipime* OR voco* OR

cefpirome* OR CPR OR cefrom* OR keiten* OR broact* OR cefozopran* OR

CZOP OR firstcin*)

# 5 TS=(carbapenem* OR imipenem* OR tienam* OR primaxin* OR IMPM

OR panipenem* OR PAPM OR carbenin* OR meropenem* OR MEPM OR

merrem* OR meropen* OR BIPM OR omegacin* OR biapenem* OR

doripenem* OR DRPM OR finibax* OR doribax* OR ertapenem* OR ERPM OR

invanz*)

# 6 #5 OR #4 OR #3 OR #2

# 7 #6 AND #1

# 8 TS= clinical trial* OR TS=research design OR TS=comparative stud*

OR TS=evaluation stud* OR TS=controlled trial* OR TS=followup stud* OR

TS=prospective stud* OR TS=random* OR TS=placebo* OR TS=(single

blind*) OR TS=(double blind*)

# 9 #8 AND #7

Supplementary Text 2. List of included studies

1. Aamir M, Abrol P, Sharma D, et al. A clinical evaluation of efficacy and safety of

cefepime monotherapy versus piperacillin-tazobactam in patients of

paediatric age group with febrile neutropenia in a tertiary care centre of

north India. Trop Doct 2016;46(3):142-8. doi: 10.1177/0049475515617571

2. Akan H, Koc H, Aydogdu I, Ilhan O, Beksac M, Gurman G, Konuk N, Uysal A. A

single center randomized study comparing the efficacy of sulbactam

/cefoperazone + amikacin vs ceftazidim + amikacin in febrile neutropenic

patients. Mikrobiyol Bult 1995; 29:131-5.

3. Aynioglu A, Mutlu B, Hacihanefioglu A. A comparison of the efficacy of

piperacillin-tazobactam and cefoperazone-sulbactam therapies in the

empirical treatment of patients with febrile neutropenia. Rev Esp Quimioter

2016;29(2):69-75.

4. Biron P, Fuhrmann C, Cure H, et al. Cefepime versus imipenem-cilastatin as

empirical monotherapy in 400 febrile patients with short duration

neutropenia. CEMIC (Study Group of Infectious Diseases in Cancer). J

Antimicrob Chemother 1998;42(4):511-8.

5. Böhme A, Shah PM, Stille W, et al. Piperacillin/tazobactam versus cefepime as

initial empirical antimicrobial therapy in febrile neutropenic patients: a

prospective randomized pilot study. Eur J Med Res 1998;3(7):324-30.

6. Bow EJ, Rotstein C, Noskin GA, et al. A randomized, open-label, multicenter

comparative study of the efficacy and safety of piperacillin-tazobactam and

cefepime for the empirical treatment of febrile neutropenic episodes in

patients with hematologic malignancies. Clin Infect Dis 2006;43(4):447-59.

doi: 10.1086/505393

7. Chandrasekar PH, Arnow PM. Cefepime versus ceftazidime as empiric therapy for

fever in neutropenic patients with cancer. Ann Pharmacother

2000;34(9):989-95.

8. Cherif H, Björkholm M, Engervall P, et al. A prospective, randomized study

comparing cefepime and imipenem-cilastatin in the empirical treatment of

febrile neutropenia in patients treated for haematological malignancies.

Scand J Infect Dis 2004;36(8):593-600. doi: 10.1080/00365540410017590

9. Chuang YY, Hung IJ, Yang CP, et al. Cefepime versus ceftazidime as empiric

monotherapy for fever and neutropenia in children with cancer. Pediatr

Infect Dis J 2002;21(3):203-9.

10. Cometta A, Zinner S, de Bock R, et al. Piperacillin-tazobactam plus amikacin

versus ceftazidime plus amikacin as empiric therapy for fever in

granulocytopenic patients with cancer. The International Antimicrobial

Therapy Cooperative Group of the European Organization for Research and

Treatment of Cancer. Antimicrob Agents Chemother 1995;39(2):445-52.

11. Corapcioglu F, Sarper N, Zengin E. Monotherapy with piperacillin/tazobactam

versus cefepime as empirical therapy for febrile neutropenia in pediatric

cancer patients: a randomized comparison. Pediatr Hematol Oncol

2006;23(3):177-86. doi: 10.1080/08880010500506370

12. Cordonnier C, Herbrecht R, Pico JL, et al. Cefepime/amikacin versus

ceftazidime/amikacin as empirical therapy for febrile episodes in neutropenic

patients: a comparative study. The French Cefepime Study Group. Clin Infect

Dis 1997;24(1):41-51.

13. Demirkaya M, Celebi S, Sevinir B, et al. Randomized comparison of piperacillin-

tazobactam plus amikacin versus cefoperazone-sulbactam plus amikacin for

management of febrile neutropenia in children with lymphoma and solid

tumors. Pediatr Hematol Oncol 2013;30(2):141-8. doi:

10.3109/08880018.2012.756565

14. Erman M, Akova M, Akan H, et al. Comparison of cefepime and ceftazidime in

combination with amikacin in the empirical treatment of high-risk patients

with febrile neutropenia: a prospective, randomized, multicenter study.

Scand J Infect Dis 2001;33(11):827-31.

15. Feld R, DePauw B, Berman S, et al. Meropenem versus ceftazidime in the

treatment of cancer patients with febrile neutropenia: a randomized, double-

blind trial. J Clin Oncol 2000;18(21):3690-8. doi:

10.1200/jco.2000.18.21.3690

16. Ferdosian F, Ghiliyan R, Hashemi A, et al. Comparing the efficacy of ceftazidime

and meropenem in treatment of febrile neutropenia in pediatric patients with

cancer. Iran J Ped Hematol Oncol 2013;3(3):103-7.

17. Figuera A, Rivero N, Pajuelo F, et al. [Comparative study of

piperacillin/tazobactam versus imipenem/cilastatin in febrile neutropenia

(1994-1996)]. Med Clin (Barc) 2001;116(16):610-1.

18. Fleischhack G, Hartmann C, Simon A, et al. Meropenem versus ceftazidime as

empirical monotherapy in febrile neutropenia of paediatric patients with

cancer. J Antimicrob Chemother 2001;47(6):841-53.

19. Freifeld AG, Walsh T, Marshall D, et al. Monotherapy for fever and neutropenia in

cancer patients: a randomized comparison of ceftazidime versus imipenem. J

Clin Oncol 1995;13(1):165-76. doi: 10.1200/jco.1995.13.1.165

20. Ghalaut PS, Chaudhry U, Ghalaut VS, et al. Cefepime versus ceftazidime as

empirical therapy for fever in neutropenic patients with haematological

malignancies. Indian J Hematol Blood Transfus 2007;23(3-4):104-6. doi:

10.1007/s12288-008-0007-x

21. Ghalaut PS, Chaudhary U, Ghalaut VS, et al. Piperacillin-tazobactum plus

amikacin versus ceftazidime plus amikacin as empirical therapy for Fever in

neutropenic patients with hematological malignancies. Indian J Hematol

Blood Transfus 2011;27(3):131-5. doi: 10.1007/s12288-011-0076-0

22. Gómez L, Estrada C, Gómez I, et al. Low-dose beta-lactam plus amikacin in

febrile neutropenia: cefepime vs. piperacillin/tazobactam, a randomized trial.

Eur J Clin Microbiol Infect Dis 2010;29(4):417-27. doi: 10.1007/s10096-010-

0879-1

23. Harter C, Schulze B, Goldschmidt H, et al. Piperacillin/tazobactam vs ceftazidime

in the treatment of neutropenic fever in patients with acute leukemia or

following autologous peripheral blood stem cell transplantation: a

prospective randomized trial. Bone Marrow Transplant 2006;37(4):373-9. doi:

10.1038/sj.bmt.1705256

24. Ichikawa M, Suzuki D, Ohshima J, et al. Piperacillin/tazobactam versus

cefozopran for the empirical treatment of pediatric cancer patients with

febrile neutropenia. Pediatr Blood Cancer 2011;57(7):1159-62. doi:

10.1002/pbc.23106

25. Jing Y, Li J, Yuan L, et al. Piperacillin-tazobactam vs. imipenem-cilastatin as

empirical therapy in hematopoietic stem cell transplantation recipients with

febrile neutropenia. Clin Transplant 2016;30(3):263-9. doi:

10.1111/ctr.12685

26. Karaman S, Vural S, Yildirmak Y, et al. Comparison of piperacillin tazobactam

and cefoperazone sulbactam monotherapy in treatment of febrile

neutropenia. Pediatr Blood Cancer 2012;58(4):579-83. doi:

10.1002/pbc.23245

27. Kebudi R, Görgün O, Ayan I, et al. Randomized comparison of cefepime versus

ceftazidime monotherapy for fever and neutropenia in children with solid

tumors. Med Pediatr Oncol 2001;36(4):434-41. doi: 10.1002/mpo.1107

28. Kutluk T, Kurne O, Akyüz C, et al. Cefepime vs. Meropenem as empirical therapy

for neutropenic fever in children with lymphoma and solid tumours. Pediatr

Blood Cancer 2004;42(3):284-6. doi: 10.1002/pbc.10442

29. Kwon KT, Cheong HS, Rhee JY, et al. Panipenem versus cefepime as empirical

monotherapy in adult cancer patients with febrile neutropenia: a prospective

randomized trial. Jpn J Clin Oncol 2008;38(1):49-55. doi:

10.1093/jjco/hym151

30. Laszlo D, Bacci S, Bosi A, et al. Randomized trial comparing netilmicin plus

imipenem-cilastatin versus netilmicin plus ceftazidime as empiric therapy for

febrile neutropenic bone marrow transplant recipients. J Chemother

1997;9(2):95-101. doi: 10.1179/joc.1997.9.2.95

31. Liang R, Yung R, Chiu E, et al. Ceftazidime versus imipenem-cilastatin as initial

monotherapy for febrile neutropenic patients. Antimicrob Agents Chemother

1990;34(7):1336-41.

32. Lindblad R, Rödjer S, Adriansson M, et al. Empiric monotherapy for febrile

neutropenia--a randomized study comparing meropenem with ceftazidime.

Scand J Infect Dis 1998;30(3):237-43.

33. Marie JP, Vekhoff A, Cony-Makhoul P, et al. [Piperacilline/tazobactam

combination+amikacin versus ceftazidime+amikacin in patients with

neutropenia and fever. An open multicenter study. Groupe d'étude des

Aplasies Fébriles]. Presse Med 1995;24(8):397-401.

34. Marie JP, Marjanovic Z, Vekhoff A, et al. Piperacillin/tazobactam plus tobramycin

versus ceftazidime plus tobramycin as empiric therapy for fever in severely

neutropenic patients. Support Care Cancer 1999;7(2):89-94.

35. The Meropenem Study Group. Equivalent efficacies of meropenem and

ceftazidime as empirical monotherapy of febrile neutropenic patients. J

Antimicrob Chemother 1995;36(1):185-200.

36. Mustafa MM, Carlson L, Tkaczewski I, et al. Comparative study of cefepime

versus ceftazidime in the empiric treatment of pediatric cancer patients with

fever and neutropenia. Pediatr Infect Dis J 2001;20(3):362-9.

37. Nakagawa Y, Suzuki K, Ohta K, et al. Prospective randomized study of cefepime,

panipenem, or meropenem monotherapy for patients with hematological

disorders and febrile neutropenia. J Infect Chemother 2013;19(1):103-11.

doi: 10.1007/s10156-012-0466-8

38. Nakane T, Tamura K, Hino M, et al. Cefozopran, meropenem, or imipenem-

cilastatin compared with cefepime as empirical therapy in febrile

neutropenic adult patients: A multicenter prospective randomized trial. J

Infect Chemother 2015;21(1):16-22. doi: 10.1016/j.jiac.2014.08.026

39. Oguz A, Karadeniz C, Citak EC, et al. Experience with cefepime versus

meropenem as empiric monotherapy for neutropenia and fever in pediatric

patients with solid tumors. Pediatr Hematol Oncol 2006;23(3):245-53. doi:

10.1080/08880010500506867

40. Reich G, Cornely OA, Sandherr M, et al. Empirical antimicrobial monotherapy in

patients after high-dose chemotherapy and autologous stem cell

transplantation: a randomised, multicentre trial. Br J Haematol

2005;130(2):265-70. doi: 10.1111/j.1365-2141.2005.05608.x

41. Sano H, Kobayashi R, Suzuki D, et al. Comparison between

piperacillin/tazobactam and cefepime monotherapies as an empirical therapy

for febrile neutropenia in children with hematological and malignant

disorders: A prospective, randomized study. Pediatr Blood Cancer

2015;62(2):356-58. doi: 10.1002/pbc.25178

42. Sanz MA, López J, Lahuerta JJ, et al. Cefepime plus amikacin versus piperacillin-

tazobactam plus amikacin for initial antibiotic therapy in haematology

patients with febrile neutropenia: results of an open, randomized,

multicentre trial. J Antimicrob Chemother 2002;50(1):79-88.

43. Sarashina T, Kobayashi R, Yoshida M, et al. A randomized trial of cefozopran

versus cefepime as empirical antibiotic treatment of febrile neutropenia in

pediatric cancer patients. Pediatr Blood Cancer 2014;61(11):1992-5. doi:

10.1002/pbc.25148

44. Serefhanoglu K, Ersoy Y, Serefhanoglu S, et al. Clinical experience with three

combination regimens for the treatment of high-risk febrile neutropenia. Ann

Acad Med Singapore 2006;35(1):11-6.

45. Sezgin G, Acipayam C, Ozkan A, et al. Meropenem versus piperacillin-

tazobactam as empiric therapy for febrile neutropenia in pediatric oncology

patients. Asian Pac J Cancer Prev 2014;15(11):4549-53.

46. Shah PM, Heller A, Fuhr HG, et al. Empirical monotherapy with meropenem

versus imipenem/cilastatin for febrile episodes in neutropenic patients.

Infection 1996;24(6):480-4.

47. Uygun V, Karasu GT, Ogunc D, et al. Piperacillin/tazobactam versus cefepime for

the empirical treatment of pediatric cancer patients with neutropenia and

fever: a randomized and open-label study. Pediatr Blood Cancer

2009;53(4):610-4. doi: 10.1002/pbc.22100

48. Vandercam B, Gérain J, Humblet Y, et al. Meropenem versus ceftazidime as

empirical monotherapy for febrile neutropenic cancer patients. Ann Hematol

2000;79(3):152-7.

49. Vural S, Erdem E, Gulec SG, et al. Imipenem-cilastatin versus piperacillin-

tazobactam as monotherapy in febrile neutropenia. Pediatr Int

2010;52(2):262-7. doi: 10.1111/j.1442-200X.2009.02952.x

50. Wang FD, Liu CY, Hsu HC, et al. A comparative study of cefepime versus

ceftazidime as empiric therapy of febrile episodes in neutropenic patients.

Chemotherapy 1999;45(5):370-9. doi: 7228

Supplementary Text 3. Resistance to antibiotics.

Biron 1998: randomized episodes 344.

Baseline: microbiologically documented infection 76, isolated 98; methicillin-

resistant Staphylococci 3, enterococci resistant to Cefepime 3, P. aeruginosa

resistant to Imipenem 2.

Chuang 2002: randomized episodes 116.

Baseline: microbiologically documented infection 14, extended-spectrum

beta-lactamases producing Klebsiella oxytoca 1, methicillin-resistant

Staphylococcus aureus 1, Acinetobacter baumanii resistant to Ceftazidime

1.

After treatment: extended-spectrum beta-lactamases producing Klebsiella

pneumoniae 1.

Cometta 1995: randomized episodes 858.

Baseline: microbiologically documented infection 205, coagulase-negative

Staphylococci resistant to Piperacillin/Tazobactam 18, coagulase-negative

Staphylococci resistant to Ceftazidime 26, Enterococcus sp. resistant to

Piperacillin/Tazobactam 1, Enterococcus sp. resistant to Ceftazidime 4,

viridans group Streptococcus resistant to Ceftazidime 2, Corynebacterium

jeikeium resistant to Piperacillin/Tazobactam 1, Corynebacterium jeikeium

resistant to Ceftazidime 3, Staphylococcus aureus resistant to

Piperacillin/Tazobactam 1, Staphylococcus aureus resistant to Ceftazidime

1, Clostridium sp. resistant to Piperacillin/Tazobactam 1, Clostridium sp.

resistant to Ceftazidime 1, Bacillus sp. resistant to Ceftazidime 1,

Micrococcus sp. resistant to Ceftazidime 1, Corynebacterium non-jeikeium

resistant to Ceftazidime 1.

Cordonnier 1997: randomized episodes 319.

Baseline: microbiologically documented infection 99, Gram-positive

organisms resistant to Cefepime 27, Gram-positive organisms resistant to

Ceftazidime 34, Gram-negative organisms resistant to Cefepime 2.

Jing 2016: randomized episodes 133.

Baseline: documented bacteremia 18, extended-spectrum beta-lactamases

producing Escherichia coli resistant to Piperacillin/Tazobactam 2,

Alteromonas resistant to IMP 1, Klebsiella sp. resistant to

Piperacillin/Tazobactam 1.

Karaman 2012: randomized episodes 102.

Baseline: microbiologically documented infection 33, methicillin-resistant

Staphylococcus aureus 4, vancomycin resistant Enterococci 1.

Kebudi 2001: randomized episodes 63.

Baseline: isolated organisms 27, methicillin-resistant coagulase-negative

Staphylococci 5.

Kwon 2008: randomized episodes 116.

Baseline: isolated organisms 18, methicillin-resistant Staphylococcus aureus

1, methicillin-resistant coagulase-negative Staphylococci 2.

Liang 1990: randomized episodes 100.

Baseline: microbiologically documented infection 36,

Baseline and after treatment: isolate organisms 100, Gram-positive

organisms resistant to Ceftazidime 68, Gram-positive organisms resistant to

Imipenem 20, Gram-negative organisms resistant to Ceftazidime 11, Gram-

negative organisms resistant to Imipenem 17.

Marie 1995: randomized episodes 188.

Baseline: isolated organisms in blood culture 58, Escherichia coli resistant to

Piperacillin 6, methicillin-resistant Staphylococcus aureus 15, methicillin-

susceptible Staphylococcus aureus resistant to Piperacillin 14, methicillin-

susceptible Staphylococcus aureus resistant to Ceftazidime 9, Streptococcus

resistant to Ceftazidime 4.

Marie 1999: randomized episodes 147.

Baseline: isolated organisms in blood 68, methicillin-resistant coagulase-

negative staphylococci 21, Klebsiella sp. resistant to penicillin 1,

Acinetobacter sp. resistant to penicillin 1.

After treatment: following multi resistant strains were found.

Piperacillin/Tazobactam arm: Pseudomonas 2, Acinetobacter 1,

Xanthomonas 1. Ceftazidime arm: Pseudomonas 2, Xanthomonas 1,

Enterobacter 2.

MEPM study group 1995: randomized episodes 221

Baseline: Ceftazidime arm, isolated organisms in blood 103. Followings were

resistant to Ceftazidime: coagulase-negative staphylococci 14,

Corynebacterium jeikeium 2, Streptococcus sanguis 1, Entero coccusfaecalis

1, Corynebacterium sp. 1, Achromobacter sp 1, Flavobacterium sp. 1,

Micrococcus sp. 1. Localized organisms resistant to Ceftazidime, coagulase-

negative staphylococci 2. Meropenem arm, isolate organisms in blood 97.

Followings were resistant to Meropenem: coagulase-negative staphylococci

10, Stomatococcus mucilaginosus 1, viridans streptococcus 1,

Stenotrophomonas maltophilia 1, Aerococcus viridans 1, Enterococcus

faecalis 1. Localized organisms resistant to Meropenem, Staphylococcus

epidermidis 1, S. maltophilia 1.

Mustafa 2001: randomized episodes 104.

Baseline: microbiologically documented infection 12, methicillin-resistant

coagulase-negative staphylococci 1.

Nakagawa 2013: randomized episodes 255.

Baseline: isolated organisms in blood 47, methicillin-resistant

Staphylococcus aureus 1.

Nakane 2015: randomized episodes 428.

Baseline: isolated organisms in blood 79, methicillin-resistant

Staphylococcus aureus 5.

Reich 2005: randomized episodes 232.

Baseline: isolated organisms 67, methicillin-resistant Staphylococcus aureus

1.

Serefhanoglu 2006: randomized episodes 89.

Baseline: isolated organisms 24, methicillin-resistant Staphylococcus aureus

1.

Sezgin 2014: randomized episodes 284.

Baseline: microbiologically documented infection 54, extended-spectrum

beta-lactamases producing Escherichia coli 2, extended-spectrum beta-

lactamases producing Klebsiella sp. 1.

Uygun 2009: randomized episodes 127.

Baseline: microbiologically documented infection 40.

After treatment: Authors stated “there was neither any change in resistance

patterns noted during the time of the study.”

Supplementary Table 1. Risk of bias summary.

Selection

bias

(generation)

Selection

bias

(concealment

)

Performanc

e bias

Detectio

n bias

Attrition

bias

Reportin

g bias

Aamir (2015) Unclear Unclear High High High Unclear

Akan (1995) Unclear Unclear High High Low Unclear

Aynioglu (2016) Low Low High High Low Unclear

Biron (1998) Unclear Low High High Low Unclear

Boehme (1998) Unclear Unclear High High Low Unclear

Bow (2006) Unclear Low High High Low Unclear

Chandrasekar

(2000)Unclear Unclear Low Low Low Unclear

Cherif (2004) Unclear Unclear High High Low Unclear

Chuang (2002) Unclear Unclear High High Low Unclear

Cometta (1995) Low Low High High Low Unclear

Corapcioglu (2006) Unclear Unclear High High Low Unclear

Cordonnier (1997) Low Low High High Low Unclear

Demirkaya (2012) Unclear Unclear High High Low Unclear

Erman (2001) Low Low High High Low Unclear

Feld (2000) Low Low Low Low Low Unclear

Ferdosian (2013) Unclear Unclear Low Low Low Unclear

Figuera (2001) Unclear Unclear High High Low Unclear

Fleischhack (2001) Low Low High High Low Unclear

Freifeld (1995) Unclear Unclear High High High Unclear

Ghalaut (2007) Unclear Unclear High High Low Unclear

Ghalaut (2011) Unclear Unclear High High Low Unclear

Gomez (2010) Low Low High High Low Unclear

Harter (2006) Low Low High High High Unclear

Ichikawa (2011) Unclear Unclear High High Low Unclear

Jing (2016) Unclear Unclear High High Low Low

Karaman (2012) Unclear Unclear High High Low Unclear

Kebudi (2001) Unclear Unclear High High Low Unclear

Kutluk (2004) Unclear Unclear High High Low Unclear

Kwon (2008) Unclear Low High High Low Unclear

Laszlo (1997) Unclear Unclear High High Low Unclear

Liang (1990) Unclear Unclear High High Low Unclear

Lindblad (1998) Low Low High High Low Unclear

Marie (1995) Unclear Unclear High High Low Unclear

Marie (1999) Low Low High High Low Unclear

MEPM study group

(1995)Low Low High High Low Unclear

Mustafa (2001) Unclear Unclear High High Low Unclear

Nakagawa (2013) Unclear Low High High Low Unclear

Nakane (2015) Unclear Low High High Low Unclear

Oguz (2006) Unclear Unclear High High Low Unclear

Reich (2005) Unclear Unclear High High Low Unclear

Sano (2015) Unclear Unclear High High Low Unclear

Sanz (2002) Unclear Low High High Low Unclear

Sarashina (2014) Unclear Unclear High High Low Unclear

Serefhanoglu

(2006)Unclear Unclear High High Low Unclear

Sezgin (2014) Unclear Unclear High High Low Unclear

Shah (1996) Unclear Unclear High High Low Unclear

Uygun (2009) Unclear Unclear High High Low Unclear

Vandercam (2000) Unclear Unclear High High Low Unclear

Vural (2010) Unclear Unclear High High Low Unclear

Wang (1999) Unclear Unclear High High Low Unclear

Supplementary Table 2. Definition of the febrile neutropenia.

Study Absolute

neutrophilic count

cutoff

Single measured

temperature

Multiple measured

temperatures

Aamir (2015) 500 or (1000>>500) ≥38.3C ≥38.0C

Akan (1995) 1000 39 38.5

Aynioglu (2016) 500 or >>500 ≥38.3C ≥38.0C

Biron (1998) 1000>>500 ≥38.5C ≥38.0C

Boehme (1998) 500 or (1000>>500) ≥38.3C ≥38.0C

Bow (2006) 500 or (1000>>500) ≥38.3C ≥38.0C

Chandrasekar (2000) 500 or (1000>>500) >38.5C >38.0C

Cherif (2004) 500 or (1000>>500) ≥38.5C ≥38.0C

Chuang (2002) 500 ≥38.5C ≥38.0C

Cometta (1995) 1000>>500 ≥38.5C ≥38.0C

Corapcioglu (2006) 500 or (1000>>500) ≥38.5C ≥38.0C

Cordonnier (1997) 500 or (>>500) ≥38.5C ≥38.0C

Demirkaya (2012) 500 or (1000>>500) >38.5C >38.0C

Erman (2001) 500 or (1000>>500) >38.5C >38.0C

Feld (2000) 500 or (1000>>500) ≥38.3C ≥38.0C

Ferdosian (2013) 500 or (1000>>500) ≥39.0C ≥38.5C

Figuera (2001) 500 >38.0C NA

Fleischhack (2001) 500 or (1000>>500) ≥39.0C ≥38.5C

Freifeld (1995) 500 or (1000>>500) ≥38.5C >38.0C

Ghalaut (2007) 1000 >38.3 NA

Ghalaut (2011) 500 or (1000>>500) ≥38.3C ≥38.0C

Gomez (2010) 500 or (1000>>500) NA >37.8

Harter (2006) 500 >38.5 >38.0

Ichikawa (2011) 500 ≥38.0C ≥37.5

Jing (2016) 500 or (1000>>500) ≥38.3C >38.0

Karaman (2012) 500 or (1000>>500) ≥38.3C ≥38.0C

Kebudi (2001) 500 or (1000>>500) ≥38.3C ≥38.0C

Kutluk (2004) 500 ≥38.3C ≥38.0C

Kwon (2008) 500 or (1000>>500) ≥38.3C ≥38.0C

Laszlo (1997) 500 >38.0 NA

Liang (1990) 500 >38.5C >38.0C

Lindblad (1998) 500 or (1000>>500) ≥38.5C ≥38.0C

Marie (1995) 500 NA ≥38.0C

Marie (1999) 1000 or (>>1000) >38.5 >38.0

MEPM study group

(1995)

>>500 ≥38.5C NA

Mustafa (2001) 1000 >38.5 >38.0

Nakagawa (2013) 1000 ≥38.0C ≥37.5C

Nakane (2015) 1000 ≥38.0C ≥37.5C

Oguz (2006) 500 or (1000>>500) ≥38.5C ≥38.0C

Reich (2005) 500 >38.4 >37.9

Sano (2015) 500 >38.0C ≥37.5C

Sanz (2002) 500 or (1000>>500) ≥38.5C ≥38.0C

Sarashina (2014) 500 or (1000>>500) >38.0C ≥37.5C

Serefhanoglu (2006) 500 ≥38.3C ≥38.0C

Sezgin (2014) 500 or (1000>>500) ≥38.3C ≥38.0C

Shah (1996) 500 ≥38.5C NA

Uygun (2009) 1000>>500 >38.3 ≥38.0C

Vandercam (2000) >>500 ≥38.5C ≥38.0C

Vural (2010) 500 or (>>500) >38.5 ≥38.0C

Wang (1999) 500 ≥38.5C ≥38.0C

1000>>500, being below 1000 and deemed to decrease below 500.

>>500, deemed to decrease below 500.

d: day. m: month. NA: not available. Tx: treatment.

Supplementary Table 3. Definition of outcomes.

Treatment success without modification Death

Study Timing of

evaluation

Assessment Observation duration

Aamir (2015) Day 7 Defervescence that occurred within 2 days after starting the initial

therapy and being completely maintained with significant improvement

of infection-related sign, symptoms and abnormal laboratory values.

Day 7

Akan (1995) NA NA NA

Aynioglu (2016) 7-10 d after Tx A complete improvement in all infectious signs and symptoms. NA

Biron (1998) 7 d after Tx Referred Immunocompromised Host Society consensus conference and

European Society of Clinical Microbiology and Infectious Disease

guidelines.

7 d after Tx

Boehme (1998) End of Tx Stable defervescence and complete regression of infectious foci.

Bow (2006) 7 d after Tx Resolution of all signs and symptoms of infection. During Tx

Chandrasekar (2000) 4-7 d after Tx The patient’s fever and clinical signs of infection resolved; the infecting NA

microorganism was eradicated; and resolution of the infection was

maintained.

Cherif (2004) 2 d after Tx Complete clinical and microbiological recovery.

Chuang (2002) 7 d after Tx Disappearance of fever, overall clinical improvement and eradication of

any infecting organism.

NA

Cometta (1995) 4 d after Tx Fever and clinical signs of infection resolved and infecting

microorganisms were eradicated.

At least 45 d

Corapcioglu (2006) 7 d after Tx Disappearance of fever, clinical improvement, eradication of the any

infecting organism, and maintenance of response.

Cordonnier (1997) 4 d after Tx Patient was afebrile during treatment and remained. 1 m after Tx

Demirkaya (2012) End of Tx No fever for 5 days, absolute neutrophil count > 500/mm3, negative

culture, and no clinical sign for infection.

During study

Erman (2001) 5-7 d after Tx Referred criteria of the Infectious Disease Society of America and the

Food and Drug Administration.

1 m after Tx

Feld (2000) End of Tx Either eradication or presumed eradication. 7 d after Tx

Ferdosian (2013) NA NA

Figuera (2001) NA NA NA

Fleischhack (2001) NA NA

Freifeld (1995) End of Tx The NA

Ghalaut (2007) NA NA NA

Ghalaut (2011) NA NA NA

Gomez (2010) 4 d after Tx The resolution of signs and symptoms of infection plus the eradication of

a pathogen.

Day 28

Harter (2006) NA NA NA

Ichikawa (2011) After end of Tx. Fever and clinical signs of infection had resolved within 120 hr following

initiation of antibiotic therapy and no recurrence of infection or fever.

NA

Jing (2016) End of Tx Resolution of all signs and symptoms of infection. During Tx

Karaman (2012) End of Tx The resolution of fever and clinical signs of infection. NA

Kebudi (2001) End of Tx The patient recovered from fever and neutropenia. NA

Kutluk (2004) End of Tx The patient’s fever and clinical signs of infection resolved. The infecting

organism was eradicated.

NA

Kwon (2008) 7-14 d after Tx Clinical symptoms and signs of infection improved or vanished. 7-14 d after Tx

Laszlo (1997) NA NA

Liang (1990) 7 d after Tx Complete disappearance of all clinical and laboratory evidence of

infection, including fever.

NA

Lindblad (1998) End of Tx Alive at the end of treatment with unmodified treatment. 4 died < 72hr

Marie (1995) NA NA

Marie (1999) 3 d after Tx Persistent apyrexia until polymorphonuclear neutrophils.

MEPM study group

(1995)

NA NA NA

Mustafa (2001) 7 d after Tx Resolution of the patient’s fever and clinical signs of infection.

Nakagawa (2013) NA NA

Nakane (2015) Day 3-5 Fever dropped to below 37.0C for more than one day by days 3-5

accompanied by improvement in clinical infectious signs and laboratory

data.

Day 30

Oguz (2006) 7 d after Tx Disappearance of fever, overall clinical improvement, eradication of any

infecting organism.

Reich (2005) NA NA 7 d after Tx

Sano (2015) End of Tx Referring five previous studies.

Sanz (2002) 1 w after Tx Afebrile for 4 consecutive days, clearance of signs and symptoms of

infection, infecting microorganism eradicated and no recurrence of the

primary infection.

Sarashina (2014) After Tx Solution of fever and clinical signs of infection within 120 hrs. No

recurrence of infection/fever after the end of treatment.

Serefhanoglu (2006) 5 d after Tx Fever and clinical signs and symptoms resolved and the infecting

microorganism was eradicated without recurrence of the signs and

symptoms of the primary infection.

Sezgin (2014) End of Tx Fever and clinical signs of infection resolved.

Shah (1996) NA NA. NA

Uygun (2009) End of Tx Patient recovered from fever with disappearance of signs of infection.

Vandercam (2000) 7 d after Tx All signs and symptoms of infection resolved and infecting micro-

organisms were eradicated.

During Tx

Vural (2010) End of Tx Fever and clinical signs of infection resolved and microorganism was

eradicated from blood or infection sites.

During neutropenia

Wang (1999) 0-2 wk after Tx The patient survived the neutropenic episode and became free of fever

and of the signs and symptoms of infection.

d: day. m: month. NA: not available. Tx: treatment.

Supplementary Table 4. Between-designs Q statistic after

detaching of single designs

ComparisonQ

statisticsP value

2.I/C: 3.P/T 2.61 0.956

2.I/C: 4.MEPM 5.46 0.708

2.I/C: 5.CFPM 2.27 0.972

2.I/C: 6.CZOP 5.32 0.723

2.I/C: 7.CAZ 5.21 0.735

3.P/T: 4.MEPM 5.41 0.714

3.P/T: 5.CFPM 5.34 0.721

3.P/T: 6.CZOP 5.46 0.708

3.P/T: 7.CAZ 5.37 0.718

4.MEPM: 5.CFPM 5.37 0.717

4.MEPM: 6.CZOP 5.26 0.729

4.MEPM: 7.CAZ 5.45 0.709

5.CFPM: 6.CZOP 4.92 0.766

5.CFPM: 7.CAZ 4.86 0.772

C/S: Cefoperazone/Sulbactam. CAZ: Ceftazidime. CFPM: Cefepime. CZOP:

Cefozopran. I/C: Imipenem/Cilastatin. MEPM: Meropenem P/B:

Panipenem/betamipron. P/T: Piperacillin-Tazobactam

Supplementary Figure 1. The Preferred Reporting Items in

Systematic Reviews and Meta-Analyses flow diagram for

study search.

Supplementary Figure 2. Forest plot for sensitivity/subgroup

analysis for treatment success without modification.