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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
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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
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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
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10.1002/pbc.23106
25. Jing Y, Li J, Yuan L, et al. Piperacillin-tazobactam vs. imipenem-cilastatin as
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26. Karaman S, Vural S, Yildirmak Y, et al. Comparison of piperacillin tazobactam
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27. Kebudi R, Görgün O, Ayan I, et al. Randomized comparison of cefepime versus
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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
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32. Lindblad R, Rödjer S, Adriansson M, et al. Empiric monotherapy for febrile
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33. Marie JP, Vekhoff A, Cony-Makhoul P, et al. [Piperacilline/tazobactam
combination+amikacin versus ceftazidime+amikacin in patients with
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34. Marie JP, Marjanovic Z, Vekhoff A, et al. Piperacillin/tazobactam plus tobramycin
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35. The Meropenem Study Group. Equivalent efficacies of meropenem and
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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.
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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
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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
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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
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tazobactam plus amikacin for initial antibiotic therapy in haematology
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multicentre trial. J Antimicrob Chemother 2002;50(1):79-88.
43. Sarashina T, Kobayashi R, Yoshida M, et al. A randomized trial of cefozopran
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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.
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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.
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