Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients

Liat Vidal; Itsik Ben dor; Mical Paul; Noa Eliakim‐Raz; Ellisheva Pokroy; Karla Soares‐Weiser; Leonard Leibovici

doi:10.1002/14651858.CD003992.pub3

Tratamiento antibiótico oral versus intravenoso para la neutropenia febril en pacientes con cáncer

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor Neutropenia, this term only
#2 neutrop* or granulo* or leukop*
#3 (#1 OR #2)
#4 MeSH descriptor Fever explode all trees
#5 MeSH descriptor Bacterial Infections explode all trees
#6 MeSH descriptor Sepsis explode all trees
#7 fever* or febrile or infect* or septic or sepsis
#8 (#4 OR #5 OR #6 OR #7)
#9 Any MeSH descriptor with qualifier: DT
#10 MeSH descriptor Anti‐Infective Agents explode all trees
#11 antibiotic* or antimicrob* or anti‐microb* or antibacter* or anti‐bacter* or antiinfect* or anti‐infect*
#12 (#9 OR #10 OR #11)
#13 MeSH descriptor Drug Administration Routesexplode all trees
#14 oral* or per os or intravenous* or IV or parenteral*
#15 (#13 OR #14)
#16 MeSH descriptor Neoplasms explode all trees
#17 cancer* or tumor* or tumour* or neoplas* or malignan* or carcinoma* or lymphoma* or leukemia* or leukaemia* or myeloma*
#18 bone marrow and transplant*
#19 (#16 OR #17 OR #18)
#20 (#3 AND #8 AND #12 AND #15 AND #19)

Appendix 2. MEDLINE search strategy

1 Neutropenia/
2 (neutrop* or granulo* or leukop*).mp.
3 1 or 2
4 exp Fever/
5 exp Bacterial Infections/
6 exp Sepsis/
7 (fever* or febrile or infect* or sepsis or septic).mp.
8 4 or 5 or 6 or 7
9 drug therapy.fs.
10 exp Anti‐Infective Agents/
11 (antibiotic* or antimicrob* or anti‐microb* or antibacter* or anti‐bacter* or antiinfect* or anti‐infect*).mp.
12 9 or 10 or 11
13 exp Drug Administration Routes/
14 (oral* or per os or intravenous* or IV or parenteral*).mp.
15 13 or 14
16 exp Neoplasms/
17 Bone Marrow Transplantation/
18 (cancer* or tumor* or tumour* or neoplas* or malignan* or carcinoma* or lymphoma* or leukemia* or leukaemia* or myeloma*).mp.
19 (bone marrow and transplant*).mp.
20 16 or 17 or 18 or 19
21 3 and 8 and 12 and 15 and 20
22 randomized controlled trial.pt.
23 controlled clinical trial.pt.
24 randomized.ab.
25 placebo.ab.
26 clinical trials as topic.sh.
27 randomly.ab.
28 trial.ti.
29 22 or 23 or 24 or 25 or 26 or 27 or 28
30 21 and 29

key:
mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier
pt=publication type
ab=abstract
ti=title
sh=subject heading

Appendix 3. EMBASE search strategy

1 exp neutropenia/
2 (neutrop* or granulo* or leukop*).mp.
3 1 or 2
4 exp fever/
5 exp bacterial infection/
6 exp sepsis/
7 (fever* or febrile or infect* or septic or sepsis).mp.
8 4 or 5 or 6 or 7
9 exp antiinfective agent/
10 (antibiotic* or antimicrob* or anti‐microb* or antibacter* or anti‐bacter* or antiinfect* or anti‐infect*).mp.
11 9 or 10
12 exp drug administration route/
13 (oral* or per os or intravenous* or IV or parenteral*).mp.
14 12 or 13
15 exp neoplasm/
16 exp bone marrow transplantation/
17 (cancer* or tumor* or tumour* or neoplas* or malignan* or carcinoma* or lymphoma* or leukemia* or leukaemia* or myeloma*).mp.
18 (bone marrow and transplant*).mp.
19 15 or 16 or 17 or 18
20 3 and 8 and 11 and 14 and 19
21 crossover procedure/
22 randomized controlled trial/
23 single blind procedure/
24 random*.mp.
25 factorial*.mp.
26 (crossover* or cross over* or cross‐over).mp.
27 placebo*.mp.
28 (doubl* adj blind*).mp.
29 (singl* adj blind*).mp.
30 assign*.mp.
31 allocat*.mp.
32 volunteer*.mp.
33 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32
34 20 and 33

key:
mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword

Appendix 4. LILACS search strategy

((fever*:ME OR febrile OR infection*:ME OR infect* OR sepsis*:ME) AND (neutropenia*:ME OR neutropen* OR neutropaen* OR granolucytopen* OR granolucytopaen* OR leukopen* OR leukopaen*) AND (oral OR per‐os) AND (intravenous OR parenteral) AND ((antibiotics*:ME OR antibiot* OR antimicrob* OR anti‐microb* OR antibact* OR anti infective agents*:ME) NOT decontamination*:ME))

Figure 1

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Funnel plot of comparison: 1 Oral versus intravenous antibiotic therapy, outcome: 1.1 Mortality.

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Figure 4

Funnel plot of comparison: 1 Oral versus intravenous antibiotic therapy, outcome: 1.3 Treatment failure ‐ per protocol analysis.

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Analysis 1.1

Comparison 1 Oral versus intravenous antibiotic therapy, Outcome 1 Mortality.

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Analysis 1.2

Comparison 1 Oral versus intravenous antibiotic therapy, Outcome 2 Treatment failure.

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Analysis 1.3

Comparison 1 Oral versus intravenous antibiotic therapy, Outcome 3 Treatment failure ‐ per protocol analysis.

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Analysis 1.4

Comparison 1 Oral versus intravenous antibiotic therapy, Outcome 4 Adverse events requiring discontinuation of antibiotics.

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Analysis 1.5

Comparison 1 Oral versus intravenous antibiotic therapy, Outcome 5 Gastrointestinal adverse events ('post‐protocol' analysis).

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Analysis 1.6

Comparison 1 Oral versus intravenous antibiotic therapy, Outcome 6 Lost to follow‐up.

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Analysis 1.7

Comparison 1 Oral versus intravenous antibiotic therapy, Outcome 7 Treatment failure not dt modification in update.

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Analysis 2.1

Comparison 2 Oral versus intravenous antibiotic therapy ‐ subgroup analysis, Outcome 1 Treatment failure ‐ age.

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Analysis 2.2

Comparison 2 Oral versus intravenous antibiotic therapy ‐ subgroup analysis, Outcome 2 Treatment failure ‐ source of infection.

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Analysis 2.3

Comparison 2 Oral versus intravenous antibiotic therapy ‐ subgroup analysis, Outcome 3 Treatment failure ‐ severity of neutropenia.

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Analysis 2.4

Comparison 2 Oral versus intravenous antibiotic therapy ‐ subgroup analysis, Outcome 4 Treatment failure ‐ type of malignancy.

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Analysis 3.1

Comparison 3 Methodological quality of studies, Outcome 1 Allocation concealment.

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Analysis 4.1

Comparison 4 Post hoc subgroup analyses, Outcome 1 Setting.

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Analysis 4.2

Comparison 4 Post hoc subgroup analyses, Outcome 2 Type of oral antibiotics.

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Summary of findings for the main comparison. Oral compared to intravenous antibiotic therapy for febrile neutropenia in cancer patients

Oral compared to intravenous antibiotic therapy for febrile neutropenia in cancer patients
Patient or population: patients with febrile neutropenia in cancer patients Settings: Intervention: oral Comparison: intravenous antibiotic therapy
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	intravenous antibiotic therapy	Oral
Mortality	Study population		RR 0.95 (0.54 to 1.68)	1392 (9 studies)	⊕⊕⊕⊝ moderate²
	32 per 1000	30 per 1000 (17 to 54)
	Low risk
	0 per 1000	0 per 1000 (0 to 0)
Treatment failure	Study population		RR 0.96 (0.86 to 1.06)	3142 (22 studies)	⊕⊕⊕⊝ moderate¹
	284 per 1000	272 per 1000 (244 to 301)
	Moderate
	211 per 1000	203 per 1000 (181 to 224)
Treatment failure ‐ per protocol analysis	Study population		RR 0.98 (0.86 to 1.11)	2912 (22 studies)	⊕⊕⊕⊝ moderate¹
	225 per 1000	221 per 1000 (194 to 250)
	Moderate
	184 per 1000	180 per 1000 (158 to 204)
Adverse events requiring discontinuation of antibiotics	Study population		RR 1.45 (0.61 to 3.46)	1823 (15)	⊕⊕⊝⊝ low^{1, 2}
	21 per 1000	31 per 1000 (13 to 73)
	Moderate
	0 per 1000	0 per 1000 (0 to 0)
Treatment failure not dt modification in update	Study population		RR 0.95 (0.85 to 1.06)	3041 (21)	⊕⊕⊕⊝ moderate¹
	267 per 1000	254 per 1000 (227 to 283)
	Moderate
	180 per 1000	171 per 1000 (153 to 191)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ High risk of detection bias in most of the trials ² A wide CI

Summary of findings for the main comparison. Oral compared to intravenous antibiotic therapy for febrile neutropenia in cancer patients

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Table 1. Criteria for low risk patients (as defined in most included studies)

Common criteria

Haemodynamic stablity

No organ failure

Ability to take oral medications

No pneumonia

No infection of a central line

No severe soft‐tissue infection

No acute leukaemia as the background malignancy

No known drug allergy

Not pregnant or lactating women

Table 1. Criteria for low risk patients (as defined in most included studies)

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Table 2. Exclusion criteria of included trials (2004)

Study ID	Evident infection	Previous AB	Prolonged neutropeni	Performance status	Active malignancy	BMT/PSCT	Other
Kern 1999	Infected catheter or CNS infection, known bacterial /viral/fungal infection	yes	yes	no	no	yes	Need of IV supportive therapy, expected to die within 48 hours, HIV, fever unrelated to infection and protocol violation
Mullen 1999	A source of infection that required hospitalisation as: tunnelitis, pneumonia, perirectal cellulitis, typhlitis, resistant microorganism to one of the study's drugs	no	no	no	yes	yes	>10% dehydration, bleeding requiring platelet transfusion, need for IV access, no access to telephone, >1hour away from hospital unreliable caretaker
Paganini 2000	Infected catheter, perineal/ facial cellulitis, uncontrolled local infection, positive blood cultures at 72 hours	no	no	no	yes	yes	Persistance of fever >48 hours, incorrectable bleeding; refractory hypoglycemia or hypocalcemia
Rubenstein 1993	Known resistant microorganism	no	no	no	no	no	Na<128, uncontrolled hypercalcemia, more than 30 miles away
Samonis 1997	Pneumonia, deep organ infection	yes	yes	no	yes	no*	Prior hospitalisation
Shenep 2001	Pneumonia, clinical or radiographic evidence of focal bacterial infection, severe mucositis, positive blood cultures at 48 hours	no	no	no	no	no	MRSA or P.Aeroginosa in any culture obtained in preceding 12weeks
Velasco1995	Meningitis, pyelonephritis	yes	no	yes	no	no*	Long term central vein catheter
Petrilli 1999	no	no	no	no	no	no*
Flaherty 1989	no	yes	no	no	no	no
Freifeld 1999	Intravascular infection, tunnelitis, pneumonia, neurologic symtoms,	no	yes	no	no	yes	Treatment with Ca‐Mg or probenecid or alluporinol or theophylline, HIV
Giamarelou 2000	Suspected anaerobes	no	no	yes	no	no	Moribund and high probability of dying within 48 hours
Hidalgo 1999	Pneumonia, extensive cellulitis, meningitis, pyelonephritis	no	no	yes	yes	no	Clotting abnormalities, acidosis, hypercalcaemia, uncontrolled bleeding, live >2h apart from hospital; Hx of tumour fever, other severe extra hematologic chemotherapy induced toxicity, no 24 hours home companion
Innes 2003	Tunnelitis, cellulitis, abcess, clinically documented infection likely to require prolonged antibiotic therapy	yes	yes	no	no	yes	Need for the use of G/GM‐CSF and cytokines; no responsible adult living with them (carer);
Malik 1992	no	yes	no	no	no	no	Recurrent FUO
Cornely 2003	not excluded	excluded (except cotrimoxazole prophylaxis)	yes	yes	excluded	excluded	potential compromised absorption; inability to take oral medication; tenopathy, epilepsy; aplastic anaemia, acute leukaemia; septic shock or signs of sever infection; HIV carrier; serious concomitant disease, liver transaminase> x5 of norm.
Niho 2004	not excluded	excluded	no	not excluded	no	yes	Recurrent FUO; renal insufficiency; hepatic insufficiency; hypotension or peripheral circulatory failure; uncontrolled hypercalcaemia; altered sensorium; respiratory rate >30 breaths/min; serum sodium <128 mg/dl; inability to take oral medications; intestinal malabsorption
Paganini 2003	Fascial, perineal, or catheter‐associated cellulites; uncontrolled local infection; positive blood cultures within the first 48 hours; infection with microorganisms known as resistant to ceftriaxone or ciprofloxacin	included	yes	not excluded	not excluded	excluded	severe comorbidity factors; respiratory failure

Table 2. Exclusion criteria of included trials (2004)

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Comparison 1. Oral versus intravenous antibiotic therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	9	1392	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.54, 1.68]

1.1 Initially oral	6	961	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.43, 1.62]
1.2 Sequential	3	431	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [0.45, 4.22]
2 Treatment failure Show forest plot	22	3142	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.86, 1.06]

2.1 Initially oral treatment	16	2196	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.79, 1.03]
2.2 Sequential IV to oral treatment	6	946	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.90, 1.27]
3 Treatment failure ‐ per protocol analysis Show forest plot	22	2912	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.86, 1.11]

3.1 Initially oral treatment	16	1991	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.78, 1.10]
3.2 Sequential IV to oral treatment	6	921	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.88, 1.29]
4 Adverse events requiring discontinuation of antibiotics Show forest plot	15	1823	Risk Ratio (M‐H, Random, 95% CI)	1.45 [0.61, 3.46]

4.1 Initially oral treatment	10	1064	Risk Ratio (M‐H, Random, 95% CI)	2.78 [1.14, 6.75]
4.2 Sequential IV to oral treatment	5	759	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.26, 1.25]
5 Gastrointestinal adverse events ('post‐protocol' analysis) Show forest plot	15		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Initially oral treatment	11	1400	Risk Ratio (M‐H, Fixed, 95% CI)	4.49 [2.87, 7.04]
5.2 Sequential IV to oral treatment	4	784	Risk Ratio (M‐H, Fixed, 95% CI)	2.81 [1.03, 7.66]
6 Lost to follow‐up Show forest plot	19	2810	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.61, 1.10]

7 Treatment failure not dt modification in update Show forest plot	21	3041	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.85, 1.06]

7.1 Initially oral treatment	15	2095	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.79, 1.04]
7.2 Sequential IV to oral treatment	6	946	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.88, 1.25]

Comparison 1. Oral versus intravenous antibiotic therapy

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Comparison 2. Oral versus intravenous antibiotic therapy ‐ subgroup analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure ‐ age Show forest plot	20		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Children	8	1013	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.82, 1.28]
1.2 Adults	12	1652	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.85, 1.12]
2 Treatment failure ‐ source of infection Show forest plot	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Unexplained fever	10	924	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.79, 1.33]
2.2 Documented infection	10	641	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.84, 1.19]
3 Treatment failure ‐ severity of neutropenia Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Absolute neutrophil count >=10^9/L	3	328	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.45, 0.98]
3.2 Absolute neutrophil count <10^9/L	3	370	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.76, 1.49]
4 Treatment failure ‐ type of malignancy Show forest plot	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Solid tumour	7	990	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.70, 1.12]
4.2 Haemetologic malignancy	4	412	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.84, 1.28]

Comparison 2. Oral versus intravenous antibiotic therapy ‐ subgroup analysis

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Comparison 3. Methodological quality of studies

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Allocation concealment Show forest plot	22		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Adequate (A)	12	1651	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.81, 1.09]
1.2 Unclear (B)	10	1477	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.84, 1.14]

Comparison 3. Methodological quality of studies

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Comparison 4. Post hoc subgroup analyses

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Setting Show forest plot	18		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Oral‐outpatient, IV‐inpatients	3	430	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.63, 1.43]
1.2 Inpatients	6	1128	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.81, 1.07]
1.3 Outpatients	7	816	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.85, 1.50]
1.4 Only first dose in	2	161	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.41, 1.34]
2 Type of oral antibiotics Show forest plot	22		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Quinolones only	7	967	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.88, 1.20]
2.2 Quinolones in combination with augmentin, ampicillin‐sulbactam, penicillin V or clindamycin	11	1679	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.76, 1.04]
2.3 Cefixime	2	354	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.64, 1.56]
2.4 New quinolones	2	128	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.50, 1.86]

Comparison 4. Post hoc subgroup analyses

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Tratamiento antibiótico oral versus intravenoso para la neutropenia febril en pacientes con cáncer

Appendices

Appendix 1. CENTRAL search strategy

Appendix 2. MEDLINE search strategy

Appendix 3. EMBASE search strategy

Appendix 4. LILACS search strategy

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Appendices

Appendix 1. CENTRAL search strategy

Appendix 2. MEDLINE search strategy

Appendix 3. EMBASE search strategy

Appendix 4. LILACS search strategy

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