Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy

Anat Gafter‐Gvili; Abigail Fraser; Mical Paul; Marianne D van de Wetering; Leontien CM Kremer; Leonard Leibovici

doi:10.1002/14651858.CD004386.pub2

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Figure 1

Funnel plot of standard error plotted against study's effect

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Analysis 1.1

Comparison 1 All‐cause mortality, Outcome 1 drug vs. placebo/no intervention.

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Analysis 1.2

Comparison 1 All‐cause mortality, Outcome 2 quinolone vs. TMP‐SMZ.

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Analysis 1.3

Comparison 1 All‐cause mortality, Outcome 3 quinolone+other vs. quinolone.

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Analysis 1.4

Comparison 1 All‐cause mortality, Outcome 4 TMP‐SMZ vs. other.

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Analysis 1.5

Comparison 1 All‐cause mortality, Outcome 5 non‐absorbable vs. systemic.

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Analysis 1.6

Comparison 1 All‐cause mortality, Outcome 6 systemic + non‐absorbable vs systemic.

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Analysis 2.1

Comparison 2 Infection related mortality, Outcome 1 drug vs. placebo/no intervention.

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Analysis 2.2

Comparison 2 Infection related mortality, Outcome 2 quinolone vs. TMP‐SMZ.

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Analysis 2.3

Comparison 2 Infection related mortality, Outcome 3 quinolone+other vs. quinolone.

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Analysis 2.4

Comparison 2 Infection related mortality, Outcome 4 TMP‐SMZ vs. other.

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Analysis 2.5

Comparison 2 Infection related mortality, Outcome 5 non‐absorbable vs. systemic.

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Analysis 2.6

Comparison 2 Infection related mortality, Outcome 6 systemic + non‐absorbable vs systemic.

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Analysis 3.1

Comparison 3 Febrile patients and febrile episodes, Outcome 1 drug vs. placebo/ no intervention.

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Analysis 3.2

Comparison 3 Febrile patients and febrile episodes, Outcome 2 quinolone vs. TMP‐SMZ.

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Analysis 3.3

Comparison 3 Febrile patients and febrile episodes, Outcome 3 quinolone+other vs. quinolone.

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Analysis 3.4

Comparison 3 Febrile patients and febrile episodes, Outcome 4 TMP‐SMZ vs. other.

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Analysis 3.5

Comparison 3 Febrile patients and febrile episodes, Outcome 5 non‐absorbable vs. systemic.

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Analysis 3.6

Comparison 3 Febrile patients and febrile episodes, Outcome 6 systemic + non‐absorbable vs systemic.

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Analysis 4.1

Comparison 4 Clinically documented infection, Outcome 1 drug vs. placebo/ no intervention.

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Analysis 4.2

Comparison 4 Clinically documented infection, Outcome 2 quinolone vs. TMP‐SMZ.

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Analysis 4.3

Comparison 4 Clinically documented infection, Outcome 3 quinolone+other vs. quinolone.

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Analysis 4.4

Comparison 4 Clinically documented infection, Outcome 4 TMP‐SMZ vs. other.

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Analysis 4.5

Comparison 4 Clinically documented infection, Outcome 5 non‐absorbable vs. systemic.

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Analysis 4.6

Comparison 4 Clinically documented infection, Outcome 6 systemic + non‐absorbable vs systemic.

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Analysis 5.1

Comparison 5 Microbiologically documented infection, Outcome 1 drug vs. placebo/ no intervention.

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Analysis 5.2

Comparison 5 Microbiologically documented infection, Outcome 2 quinolone vs. TMP‐SMZ.

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Analysis 5.3

Comparison 5 Microbiologically documented infection, Outcome 3 quinolone+other vs. quinolone.

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Analysis 5.4

Comparison 5 Microbiologically documented infection, Outcome 4 TMP‐SMZ vs. other.

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Analysis 5.5

Comparison 5 Microbiologically documented infection, Outcome 5 non‐absorbable vs. systemic.

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Analysis 5.6

Comparison 5 Microbiologically documented infection, Outcome 6 systemic + non‐absorbable vs systemic.

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Analysis 6.1

Comparison 6 Gram‐negative infection, Outcome 1 drug vs. placebo/ no intervention.

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Analysis 6.2

Comparison 6 Gram‐negative infection, Outcome 2 quinolone vs. TMP‐SMZ.

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Analysis 6.3

Comparison 6 Gram‐negative infection, Outcome 3 quinolone+other vs. quinolone.

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Analysis 6.4

Comparison 6 Gram‐negative infection, Outcome 4 TMP‐SMZ vs. other.

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Analysis 6.5

Comparison 6 Gram‐negative infection, Outcome 5 non‐absorbable vs. systemic.

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Analysis 6.6

Comparison 6 Gram‐negative infection, Outcome 6 systemic + non‐absorbable vs systemic.

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Analysis 7.1

Comparison 7 Gram‐positive infection, Outcome 1 drug vs. placebo/ no intervention.

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Analysis 7.2

Comparison 7 Gram‐positive infection, Outcome 2 quinolone vs. TMP‐SMZ.

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Analysis 7.3

Comparison 7 Gram‐positive infection, Outcome 3 quinolone+other vs. quinolone.

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Analysis 7.4

Comparison 7 Gram‐positive infection, Outcome 4 TMP‐SMZ vs. other.

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Analysis 7.5

Comparison 7 Gram‐positive infection, Outcome 5 non‐absorbable vs. systemic.

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Analysis 7.6

Comparison 7 Gram‐positive infection, Outcome 6 systemic + non‐absorbable vs systemic.

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Analysis 8.1

Comparison 8 Bacteremia, Outcome 1 drug vs. placebo/ no intervention.

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Analysis 8.2

Comparison 8 Bacteremia, Outcome 2 quinolone vs. TMP‐SMZ.

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Analysis 8.3

Comparison 8 Bacteremia, Outcome 3 quinolone+other vs. quinolone.

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Analysis 8.4

Comparison 8 Bacteremia, Outcome 4 TMP‐SMZ vs. other.

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Analysis 8.5

Comparison 8 Bacteremia, Outcome 5 non‐absorbable vs. systemic.

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Analysis 8.6

Comparison 8 Bacteremia, Outcome 6 systemic + non‐absorbable vs systemic.

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Analysis 9.1

Comparison 9 Gram‐negative bacteremia, Outcome 1 drug vs. placebo/ no intervention.

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Analysis 9.2

Comparison 9 Gram‐negative bacteremia, Outcome 2 quinolone vs. TMP‐SMZ.

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Analysis 9.3

Comparison 9 Gram‐negative bacteremia, Outcome 3 quinolone+other vs. quinolone.

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Analysis 9.4

Comparison 9 Gram‐negative bacteremia, Outcome 4 TMP‐SMZ vs. other.

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Analysis 9.5

Comparison 9 Gram‐negative bacteremia, Outcome 5 non‐absorbable vs. systemic.

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Analysis 9.6

Comparison 9 Gram‐negative bacteremia, Outcome 6 systemic + non‐absorbable vs systemic.

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Analysis 10.1

Comparison 10 Gram‐positive bacteremia, Outcome 1 drug vs. placebo/ no intervention.

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Analysis 10.2

Comparison 10 Gram‐positive bacteremia, Outcome 2 quinolone vs. TMP‐SMZ.

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Analysis 10.3

Comparison 10 Gram‐positive bacteremia, Outcome 3 quinolone+other vs. quinolone.

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Analysis 10.4

Comparison 10 Gram‐positive bacteremia, Outcome 4 TMP‐SMZ vs. other.

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Analysis 10.5

Comparison 10 Gram‐positive bacteremia, Outcome 5 non‐absorbable vs. systemic.

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Analysis 10.6

Comparison 10 Gram‐positive bacteremia, Outcome 6 systemic + non‐absorbable vs systemic.

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Analysis 11.1

Comparison 11 Side effects, Outcome 1 drug vs. placebo/ no intervention.

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Analysis 11.2

Comparison 11 Side effects, Outcome 2 quinolone vs. TMP‐SMZ.

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Analysis 11.3

Comparison 11 Side effects, Outcome 3 quinolone+other vs. quinolone.

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Analysis 11.4

Comparison 11 Side effects, Outcome 4 TMP‐SMZ vs. other.

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Analysis 11.5

Comparison 11 Side effects, Outcome 5 non‐absorbable vs. systemic.

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Analysis 11.6

Comparison 11 Side effects, Outcome 6 systemic + non‐absorbable vs systemic.

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Analysis 12.1

Comparison 12 Side effects requiring discontinuation, Outcome 1 drug vs. placebo/no intervention.

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Analysis 12.2

Comparison 12 Side effects requiring discontinuation, Outcome 2 quinolone vs. TMP‐SMZ.

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Analysis 12.3

Comparison 12 Side effects requiring discontinuation, Outcome 3 quinolone+other vs. quinolone.

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Analysis 12.4

Comparison 12 Side effects requiring discontinuation, Outcome 4 TMP‐SMZ vs. other.

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Analysis 12.5

Comparison 12 Side effects requiring discontinuation, Outcome 5 non‐absorbable vs. systemic.

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Analysis 12.6

Comparison 12 Side effects requiring discontinuation, Outcome 6 systemic + non‐absorbable vs systemic.

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Analysis 13.1

Comparison 13 Fungal infection, Outcome 1 drug vs. placebo/ no intervention.

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Analysis 13.2

Comparison 13 Fungal infection, Outcome 2 quinolone vs. TMP‐SMZ.

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Analysis 13.3

Comparison 13 Fungal infection, Outcome 3 quinolone+other vs. quinolone.

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Analysis 13.4

Comparison 13 Fungal infection, Outcome 4 TMP‐SMZ vs. other.

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Analysis 13.5

Comparison 13 Fungal infection, Outcome 5 non‐absorbable vs. systemic.

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Analysis 13.6

Comparison 13 Fungal infection, Outcome 6 systemic + non‐absorbable vs systemic.

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Analysis 14.1

Comparison 14 Infection resistant to drug taken, Outcome 1 drug vs. placebo/ no intervention.

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Analysis 14.2

Comparison 14 Infection resistant to drug taken, Outcome 2 quinolone vs. TMP‐SMZ.

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Analysis 14.3

Comparison 14 Infection resistant to drug taken, Outcome 3 ciprofloxacin vs. norfloxacin.

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Analysis 14.4

Comparison 14 Infection resistant to drug taken, Outcome 4 norfloxacin vs. pefloxacin.

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Analysis 14.5

Comparison 14 Infection resistant to drug taken, Outcome 5 quinolone+other vs. quinolone.

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Analysis 14.6

Comparison 14 Infection resistant to drug taken, Outcome 6 non‐absorbable vs. systemic.

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Analysis 14.7

Comparison 14 Infection resistant to drug taken, Outcome 7 TMP‐SMZ vs. other.

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Analysis 15.1

Comparison 15 Sensitivity Analyses by randomisation generation, Outcome 1 Mortality.

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Analysis 15.2

Comparison 15 Sensitivity Analyses by randomisation generation, Outcome 2 Febrile patients.

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Analysis 15.3

Comparison 15 Sensitivity Analyses by randomisation generation, Outcome 3 Clinically documented infection.

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Analysis 15.4

Comparison 15 Sensitivity Analyses by randomisation generation, Outcome 4 Microbiologically documented infection.

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Analysis 16.1

Comparison 16 Sensitivity Analyses by allocation concealment, Outcome 1 Mortality.

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Analysis 16.2

Comparison 16 Sensitivity Analyses by allocation concealment, Outcome 2 Febrile patients.

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Analysis 16.3

Comparison 16 Sensitivity Analyses by allocation concealment, Outcome 3 Clinically documented infection.

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Analysis 16.4

Comparison 16 Sensitivity Analyses by allocation concealment, Outcome 4 Microbiologically documented infection.

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Analysis 17.1

Comparison 17 Sensitivity Analyses by blinding, Outcome 1 Mortality.

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Analysis 17.2

Comparison 17 Sensitivity Analyses by blinding, Outcome 2 Febrile patients.

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Analysis 17.3

Comparison 17 Sensitivity Analyses by blinding, Outcome 3 Clinically documented infection.

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Analysis 17.4

Comparison 17 Sensitivity Analyses by blinding, Outcome 4 Microbiologically documented infection.

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Table 1. Other studies

Study ID	Intervention 1	Intervention 2	Overall mortality	Inf‐related mortalit	febrile patients	clin.doc.inf	micro.doc.inf	gram neg. inf	gram pos. inf
D'Antonio 1994	ciprofloxacin	ofloxacin	0.77(0.18‐3.33)	0.77(0.18‐3.33)		1.41(0.60‐3.32)	0.9(0.47‐1.71)	0.68(0.12‐3.98)	0.95(0.46‐1.94)
GIMEMA 1991	ciprofloxacin	norfloxacin	0.97(0.64‐1.47)	1.11(0.72‐1.72)	0.89(0.81‐0.99)	0.92(0.62‐1.37)	0.71(0.52‐0.98)	0.46(0.24‐0.88)	0.92(0.59‐1.44)
Maschmeyer 1988	ciprofloxacin	norfloxacin	1.43(0.22‐9.44)	0.46(0.04‐4.74)	0.92(0.64‐1.32)	1.84(0.52‐6.52)	0.51(0.20‐1.30)	0.18(0.01‐3.65)	0.66(0.24‐1.78)
D'Antonio 1991	norfloxacin	ofloxacin	3.08(0.13‐73.23)	3.08(0.13‐73.23)		9.25(0.52‐165.69)	9.25(0.52‐165.69)	11.31(0.65‐197.11)	1.54(0.61‐3.88)
D'Antonio 1992	norfloxacin	pefloxacin	1.03(0.22‐4.92)	1.03(0.07‐16.13)	1.3(1‐1.69)	2.83(0.95‐8.46)	2.06(1.06‐4.00)	7.21(0.91‐57.02)	1.69(0.86‐3.30)
Bender 1979	gentamycin+vancomycin	gentamycin	3.15(0.14‐72.88)		0.95(0.62‐1.47)	0.48(0.14‐1.57)	2.06(1.06‐4.00)	4.44(1.08‐18.25)	0.44(0.1‐2.01)

Table 1. Other studies

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Table 2. Other studies ‐ continued

Study ID	Intervention 1	Intervention 2	Bacteremia	Gram neg bacteremia	Gram pos bacteremia	Side effects	S/E requiring D/C	fungal infection	Inf.res. to quinolon
D'Antonio 1994	ciprofloxacin	ofloxacin	1.03(0.35‐3.04)	0.15(0.01‐2.79)	2.05(0.53‐7.92)	1.32(0.52‐3.37)			0.96(0.50‐1.85)
GIMEMA 1991	ciprofloxacin	norfloxacin	0.77(0.53‐1.13)	0.57(0.23‐1.42)	0.84(0.52‐1.36)	1.58(0.75‐3.33)	1.7(0.75‐3.84)	1.06(0.22‐5.23)	0.37(0.16‐0.87)
Maschmeyer 1988	ciprofloxacin	norfloxacin	0.92(0.21‐4.11)		0.92(0.21‐4.11)	0.46(0.04‐4.74)	0.18(0.01‐3.65)	0.31(0.01‐7.2)
D'Antonio 1991	norfloxacin	ofloxacin	6.17(0.78‐48.68)	5.14(0.26‐103.37)	4.11(0.48‐35.02)	2.06(0.2‐21.68)		3.08(0.13‐73.23)	2.4(1.04‐5.53)
D'Antonio 1992	norfloxacin	pefloxacin	2.47(0.92‐6.64)	4.12(0.47‐35.91)	2.27(0.83‐6.17)	0.69(0.2‐2.32)		2.06(0.19‐22.18)	2.15(1.18‐3.91)
Bender 1979	gentamycin+vancomycin	gentamycin	1.11(0.48‐2.55)	1.48(0.38‐5.74)	0.56(0.05‐5.62)

Table 2. Other studies ‐ continued

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Comparison 1. All‐cause mortality

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 drug vs. placebo/no intervention Show forest plot	41	5211	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.55, 0.79]

1.1 quinolone vs. placebo/ no intervention	16	3545	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.40, 0.75]
1.2 TMP‐SMZ vs. placebo/ no intervention	14	870	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.49, 1.02]
1.3 other systemic vs. placebo/ no intervention	6	525	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.63, 1.45]
1.4 non‐absorbable vs. placebo/ no intervention	6	271	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.44, 0.94]
2 quinolone vs. TMP‐SMZ Show forest plot	10	917	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.66, 1.72]

2.1 ciprofloxacin vs. TMP‐SMZ	3	431	Risk Ratio (M‐H, Fixed, 95% CI)	2.06 [0.91, 4.69]
2.2 ofloxacin vs. TMP‐SMZ	3	258	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.32, 1.77]
2.3 norfloxacin vs. TMP‐SMZ	3	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.23, 2.99]
2.4 nalidixic acid vs. TMP‐SMZ	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.15, 1.83]
3 quinolone+other vs. quinolone Show forest plot	9	1232	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.66, 2.30]

3.1 rifampin	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [0.25, 8.28]
3.2 vanco	2	183	Risk Ratio (M‐H, Fixed, 95% CI)	1.59 [0.28, 9.13]
3.3 penicillins	3	644	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.45, 2.15]
3.4 roxi	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	3.14 [0.34, 29.42]
4 TMP‐SMZ vs. other Show forest plot	2	135	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.53, 2.89]

5 non‐absorbable vs. systemic Show forest plot	8	813	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.74, 1.50]

6 systemic + non‐absorbable vs systemic Show forest plot	2	83	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.34, 2.38]

Comparison 1. All‐cause mortality

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Comparison 2. Infection related mortality

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 drug vs. placebo/no intervention Show forest plot	38	5238	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.47, 0.75]

1.1 quinolone vs. placebo/ no intervention	12	3323	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.31, 0.77]
1.2 TMP‐SMZ vs. placebo/ no intervention	15	1017	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.41, 0.87]
1.3 other systemic vs. placebo/ no intervention	7	683	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.42, 2.61]
1.4 non‐absorbable vs. placebo/ no intervention	5	215	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.40, 0.98]
2 quinolone vs. TMP‐SMZ Show forest plot	11	1019	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.54, 1.54]

2.1 ciprofloxacin vs. TMP‐SMZ	3	431	Risk Ratio (M‐H, Fixed, 95% CI)	3.32 [0.81, 13.56]
2.2 ofloxacin vs. TMP‐SMZ	4	360	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.30, 1.51]
2.3 norfloxacin vs. TMP‐SMZ	3	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.23, 2.99]
2.4 nalidixic acid vs. TMP‐SMZ	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.15, 1.83]
3 quinolone+other vs. quinolone Show forest plot	9	1232	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.63, 1.95]

3.1 rifampin	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.10, 11.58]
3.2 vanco	2	183	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.32, 2.58]
3.3 penicillins	3	644	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.55, 2.40]
3.4 roxi	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	2.09 [0.19, 22.53]
4 TMP‐SMZ vs. other Show forest plot	2	135	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.40, 2.82]

5 non‐absorbable vs. systemic Show forest plot	11	1005	Risk Ratio (M‐H, Fixed, 95% CI)	2.48 [1.65, 3.73]

6 systemic + non‐absorbable vs systemic Show forest plot	2	83	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.23, 3.24]

Comparison 2. Infection related mortality

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Comparison 3. Febrile patients and febrile episodes

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 drug vs. placebo/ no intervention Show forest plot	48	6023	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.74, 0.81]

1.1 quinolone vs. placebo/ no intervention	21	3699	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.68, 0.77]
1.2 TMP‐SMZ vs. placebo/ no intervention	16	1424	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.70, 0.84]
1.3 other systemic vs. placebo/ no intervention	8	709	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.86, 0.97]
1.4 non‐absorbable vs. placebo/ no intervention	4	191	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.68, 1.06]
2 quinolone vs. TMP‐SMZ Show forest plot	10	931	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.86, 1.04]

2.1 ciprofloxacin vs. TMP‐SMZ	3	431	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.96, 1.23]
2.2 ofloxacin vs. TMP‐SMZ	3	272	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.56, 0.85]
2.3 norfloxacin vs. TMP‐SMZ	3	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.68, 1.06]
2.4 nalidixic acid vs. TMP‐SMZ	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.99, 1.77]
3 quinolone+other vs. quinolone Show forest plot	8	1133	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.98, 1.12]

3.1 rifampin	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.84, 1.05]
3.2 penicillins	3	629	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.99, 1.21]
3.3 roxi	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.86, 1.39]
3.4 vancomycin	1	99	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.94, 1.15]
4 TMP‐SMZ vs. other Show forest plot	2	89	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.56, 1.16]

5 non‐absorbable vs. systemic Show forest plot	8	808	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [1.00, 1.13]

6 systemic + non‐absorbable vs systemic Show forest plot	2	103	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.72, 1.20]

Comparison 3. Febrile patients and febrile episodes

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Comparison 4. Clinically documented infection

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 drug vs. placebo/ no intervention Show forest plot	44	5278	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.61, 0.73]

1.1 quinolone vs. placebo/ no intervention	17	3409	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.57, 0.74]
1.2 TMP‐SMZ vs. placebo/ no intervention	17	1229	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.58, 0.76]
1.3 other systemic vs. placebo/ no intervention	5	413	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.25, 0.71]
1.4 non‐absorbable vs. placebo/ no intervention	5	227	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.74, 1.13]
2 quinolone vs. TMP‐SMZ Show forest plot	10	931	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [1.06, 1.66]

2.1 ciprofloxacin vs. TMP‐SMZ	3	431	Risk Ratio (M‐H, Fixed, 95% CI)	1.39 [1.01, 1.92]
2.2 ofloxacin vs. TMP‐SMZ	3	272	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.68, 1.66]
2.3 norfloxacin vs. TMP‐SMZ	3	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.44, 1.83]
2.4 nalidixic acid vs. TMP‐SMZ	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	2.32 [1.36, 3.94]
3 quinolone+other vs. quinolone Show forest plot	7	1093	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.79, 1.30]

3.1 rifampin	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.59, 2.07]
3.2 penicillins	2	589	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.62, 1.35]
3.3 roxi	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.83, 1.71]
3.4 vancomycin	1	99	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.01, 4.31]
4 TMP‐SMZ vs. other Show forest plot	2	152	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.56, 2.07]

5 non‐absorbable vs. systemic Show forest plot	10	862	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.95, 1.31]

6 systemic + non‐absorbable vs systemic Show forest plot	1	63	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.25, 1.15]

Comparison 4. Clinically documented infection

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Comparison 5. Microbiologically documented infection

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 drug vs. placebo/ no intervention Show forest plot	48	5948	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.48, 0.58]

1.1 quinolone vs. placebo/ no intervention	20	3647	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.46, 0.58]
1.2 TMP‐SMZ vs. placebo/ no intervention	17	1400	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.38, 0.54]
1.3 other systemic vs. placebo/ no intervention	9	753	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.50, 0.86]
1.4 non‐absorbable vs. placebo/ no intervention	3	148	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.66, 1.47]
2 quinolone vs. TMP‐SMZ Show forest plot	11	1019	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.60, 0.86]

2.1 ciprofloxacin vs. TMP‐SMZ	4	519	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.52, 1.00]
2.2 ofloxacin vs. TMP‐SMZ	3	272	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.38, 0.71]
2.3 norfloxacin vs. TMP‐SMZ	3	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.57, 1.34]
2.4 nalidixic acid vs. TMP‐SMZ	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.82, 1.80]
3 quinolone+other vs. quinolone Show forest plot	9	1217	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.75, 1.07]

3.1 rifampin	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.19, 0.77]
3.2 penicillins	3	629	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.83, 1.55]
3.3 roxi	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.58, 1.38]
3.4 vancomycin	2	183	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.73, 1.12]
4 TMP‐SMZ vs. other Show forest plot	3	205	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.71, 1.96]

5 non‐absorbable vs. systemic Show forest plot	9	712	Risk Ratio (M‐H, Fixed, 95% CI)	1.59 [1.35, 1.86]

6 systemic + non‐absorbable vs systemic Show forest plot	2	103	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [1.01, 2.65]

Comparison 5. Microbiologically documented infection

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Comparison 6. Gram‐negative infection

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 drug vs. placebo/ no intervention Show forest plot	39	5120	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.32, 0.45]

1.1 quinolone vs. placebo/ no intervention	17	3416	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.23, 0.37]
1.2 TMP‐SMZ vs. placebo/ no intervention	13	1120	Risk Ratio (M‐H, Fixed, 95% CI)	0.37 [0.26, 0.51]
1.3 other systemic vs. placebo/ no intervention	5	409	Risk Ratio (M‐H, Fixed, 95% CI)	1.30 [0.65, 2.60]
1.4 non‐absorbable vs. placebo/ no intervention	4	175	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.58, 1.22]
2 quinolone vs. TMP‐SMZ Show forest plot	9	915	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.13, 0.36]

2.1 ciprofloxacin vs. TMP‐SMZ	4	519	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.03, 0.43]
2.2 ofloxacin vs. TMP‐SMZ	2	230	Risk Ratio (M‐H, Fixed, 95% CI)	0.13 [0.05, 0.35]
2.3 norfloxacin vs. TMP‐SMZ	3	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.45 [0.22, 0.93]
3 quinolone+other vs. quinolone Show forest plot	7	597	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [0.80, 2.45]

3.1 rifampin	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.29, 3.14]
3.2 penicillins	2	93	Risk Ratio (M‐H, Fixed, 95% CI)	5.11 [0.62, 42.03]
3.3 roxi	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	4.19 [0.92, 18.98]
3.4 vancomycin	1	99	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.34, 1.76]
4 TMP‐SMZ vs. other Show forest plot	3	205	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.41, 3.70]

5 non‐absorbable vs. systemic Show forest plot	11	950	Risk Ratio (M‐H, Fixed, 95% CI)	2.15 [1.54, 3.00]

6 systemic + non‐absorbable vs systemic Show forest plot	2	103	Risk Ratio (M‐H, Fixed, 95% CI)	2.90 [1.05, 8.02]

Comparison 6. Gram‐negative infection

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Comparison 7. Gram‐positive infection

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 drug vs. placebo/ no intervention Show forest plot	40	5096	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.38, 0.51]

1.1 quinolone vs. placebo/ no intervention	17	3413	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.31, 0.46]
1.2 TMP‐SMZ vs. placebo/ no intervention	12	1009	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.26, 0.52]
1.3 other systemic vs. placebo/ no intervention	6	459	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.35, 0.74]
1.4 non‐absorbable vs. placebo/ no intervention	5	215	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [1.04, 2.98]
2 quinolone vs. TMP‐SMZ Show forest plot	9	915	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.74, 1.34]

2.1 ciprofloxacin vs. TMP‐SMZ	4	519	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.65, 1.42]
2.2 ofloxacin vs. TMP‐SMZ	2	230	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.37, 1.17]
2.3 norfloxacin vs. TMP‐SMZ	3	166	Risk Ratio (M‐H, Fixed, 95% CI)	2.09 [0.94, 4.63]
3 quinolone+other vs. quinolone Show forest plot	7	597	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.37, 0.64]

3.1 rifampin	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	0.13 [0.05, 0.35]
3.2 penicillins	2	93	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.21, 0.89]
3.3 roxi	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.28, 0.99]
3.4 vancomycin	1	99	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.69, 1.27]
4 TMP‐SMZ vs. other Show forest plot	3	205	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.53, 2.03]

5 non‐absorbable vs. systemic Show forest plot	10	800	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [1.33, 2.08]

6 systemic + non‐absorbable vs systemic Show forest plot	2	103	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.49, 2.25]

Comparison 7. Gram‐positive infection

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Comparison 8. Bacteremia

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 drug vs. placebo/ no intervention Show forest plot	48	5947	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.47, 0.59]

1.1 quinolone vs. placebo/ no intervention	18	3518	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.50, 0.68]
1.2 TMP‐SMZ vs. placebo/ no intervention	18	1511	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.34, 0.52]
1.3 other systemic vs. placebo/ no intervention	8	703	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.38, 0.72]
1.4 non‐absorbable vs. placebo/ no intervention	5	215	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.43, 0.96]
2 quinolone vs. TMP‐SMZ Show forest plot	10	931	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.63, 1.06]

2.1 ciprofloxacin vs. TMP‐SMZ	3	431	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.67, 1.94]
2.2 ofloxacin vs. TMP‐SMZ	3	272	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.27, 0.62]
2.3 norfloxacin vs. TMP‐SMZ	3	166	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.82, 2.45]
2.4 Nalidixic acid vs. TMP‐SMZ	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.61, 3.07]
3 quinolone+other vs. quinolone Show forest plot	8	681	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.57, 0.92]

3.1 rifampin	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.15, 0.66]
3.2 penicillins	2	93	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.33, 1.94]
3.3 roxi	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.64, 1.91]
3.4 vancomycin	2	183	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.61, 1.07]
4 TMP‐SMZ vs. other Show forest plot	3	205	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.80, 2.69]

5 non‐absorbable vs. systemic Show forest plot	10	716	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [1.18, 1.91]

6 systemic + non‐absorbable vs systemic Show forest plot	2	106	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.38, 5.24]

Comparison 8. Bacteremia

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Comparison 9. Gram‐negative bacteremia

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 drug vs. placebo/ no intervention Show forest plot	36	4920	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.35, 0.54]

1.1 quinolone vs. placebo/ no intervention	12	2949	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.25, 0.49]
1.2 TMP‐SMZ vs. placebo/ no intervention	15	1161	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.33, 0.65]
1.3 other systemic vs. placebo/ no intervention	7	662	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.38, 1.43]
1.4 non‐absorbable vs. placebo/ no intervention	3	148	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.28, 1.29]
2 quinolone vs. TMP‐SMZ Show forest plot	10	931	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.21, 0.59]

2.1 ciprofloxacin vs. TMP‐SMZ	3	431	Risk Ratio (M‐H, Fixed, 95% CI)	0.14 [0.03, 0.76]
2.2 ofloxacin vs. TMP‐SMZ	3	272	Risk Ratio (M‐H, Fixed, 95% CI)	0.13 [0.04, 0.39]
2.3 norfloxacin vs. TMP‐SMZ	3	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.26, 1.32]
2.4 Nalidixic acid vs. TMP‐SMZ	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	10.86 [0.61, 193.50]
3 quinolone+other vs. quinolone Show forest plot	8	681	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.79, 2.38]

3.1 rifampin	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.29, 3.14]
3.2 penicillins	2	93	Risk Ratio (M‐H, Fixed, 95% CI)	5.11 [0.62, 42.03]
3.3 roxi	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	8.38 [1.08, 65.08]
3.4 vancomycin	2	183	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.33, 1.58]
4 TMP‐SMZ vs. other Show forest plot	3	205	Risk Ratio (M‐H, Fixed, 95% CI)	3.80 [0.66, 21.74]

5 non‐absorbable vs. systemic Show forest plot	10	842	Risk Ratio (M‐H, Fixed, 95% CI)	2.70 [1.63, 4.49]

6 systemic + non‐absorbable vs systemic Show forest plot	2	106	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.14, 5.83]

Comparison 9. Gram‐negative bacteremia

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Comparison 10. Gram‐positive bacteremia

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 drug vs. placebo/ no intervention Show forest plot	35	4857	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.55, 0.78]

1.1 quinolone vs. placebo/ no intervention	12	2949	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.63, 0.96]
1.2 TMP‐SMZ vs. placebo/ no intervention	14	1098	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.24, 0.60]
1.3 other systemic vs. placebo/ no intervention	7	662	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.38, 0.89]
1.4 non‐absorbable vs. placebo/ no intervention	3	148	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.33, 3.79]
2 quinolone vs. TMP‐SMZ Show forest plot	10	931	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.86, 1.60]

2.1 ciprofloxacin vs. TMP‐SMZ	3	431	Risk Ratio (M‐H, Fixed, 95% CI)	1.66 [0.94, 2.93]
2.2 ofloxacin vs. TMP‐SMZ	3	272	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.39, 0.99]
2.3 norfloxacin vs. TMP‐SMZ	3	166	Risk Ratio (M‐H, Fixed, 95% CI)	4.19 [1.47, 11.95]
2.4 Nalidixic acid vs. TMP‐SMZ	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.28, 2.06]
3 quinolone+other vs. quinolone Show forest plot	8	681	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.45, 0.83]

3.1 rifampin	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.11, 0.72]
3.2 penicillins	2	93	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.31, 1.67]
3.3 roxi	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.31, 1.24]
3.4 vancomycin	2	183	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.51, 1.11]
4 TMP‐SMZ vs. other Show forest plot	3	205	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.57, 2.24]

5 non‐absorbable vs. systemic Show forest plot	9	692	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.92, 1.52]

6 systemic + non‐absorbable vs systemic Show forest plot	2	106	Risk Ratio (M‐H, Fixed, 95% CI)	2.57 [0.36, 18.46]

Comparison 10. Gram‐positive bacteremia

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Comparison 11. Side effects

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 drug vs. placebo/ no intervention Show forest plot	34	5063	Risk Ratio (M‐H, Fixed, 95% CI)	1.59 [1.37, 1.85]

1.1 quinolone vs. placebo/ no intervention	15	3284	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [1.24, 1.90]
1.2 TMP‐SMZ vs. placebo/ no intervention	13	1240	Risk Ratio (M‐H, Fixed, 95% CI)	1.82 [1.39, 2.37]
1.3 other systemic vs. placebo/ no intervention	4	440	Risk Ratio (M‐H, Fixed, 95% CI)	1.88 [1.00, 3.52]
1.4 non‐absorbable vs. placebo/ no intervention	2	99	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.79, 1.11]
2 quinolone vs. TMP‐SMZ Show forest plot	10	1027	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.63, 0.87]

2.1 ciprofloxacin vs. TMP‐SMZ	4	537	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.72, 1.01]
2.2 ofloxacin vs. TMP‐SMZ	2	262	Risk Ratio (M‐H, Fixed, 95% CI)	0.40 [0.24, 0.67]
2.3 norfloxacin vs. TMP‐SMZ	3	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.26, 1.43]
2.4 Nalidixic acid vs. TMP‐SMZ	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.15, 4.51]
3 quinolone+other vs. quinolone Show forest plot	6	516	Risk Ratio (M‐H, Fixed, 95% CI)	1.94 [1.28, 2.94]

3.1 rifampin	3	243	Risk Ratio (M‐H, Fixed, 95% CI)	1.91 [1.22, 2.99]
3.2 penicillins	1	58	Risk Ratio (M‐H, Fixed, 95% CI)	1.4 [0.25, 7.77]
3.3 roxi	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	9.42 [0.52, 171.44]
3.4 vancomycin	1	84	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.14, 6.46]
4 TMP‐SMZ vs. other Show forest plot	2	128	Risk Ratio (M‐H, Fixed, 95% CI)	3.06 [0.68, 13.79]

5 non‐absorbable vs. systemic Show forest plot	10	934	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [1.01, 1.50]

6 systemic + non‐absorbable vs systemic Show forest plot	3	146	Risk Ratio (M‐H, Fixed, 95% CI)	1.75 [1.02, 3.00]

Comparison 11. Side effects

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Comparison 12. Side effects requiring discontinuation

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 drug vs. placebo/no intervention Show forest plot	16	1973	Risk Ratio (M‐H, Fixed, 95% CI)	2.32 [1.39, 3.88]

1.1 quinolone vs. placebo/ no intervention	7	1356	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [0.79, 2.92]
1.2 TMP‐SMZ vs. placebo/ no intervention	5	305	Risk Ratio (M‐H, Fixed, 95% CI)	3.63 [1.32, 9.98]
1.3 other systemic vs. placebo/ no intervention	2	213	Risk Ratio (M‐H, Fixed, 95% CI)	6.76 [0.84, 54.20]
1.4 non‐absorbable vs. placebo/ no intervention	2	99	Risk Ratio (M‐H, Fixed, 95% CI)	3.18 [0.14, 72.75]
2 quinolone vs. TMP‐SMZ Show forest plot	7	850	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.30, 0.63]

2.1 ciprofloxacin vs. TMP‐SMZ	3	481	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.36, 0.86]
2.2 ofloxacin vs. TMP‐SMZ	2	262	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.09, 0.50]
2.3 norfloxacin vs. TMP‐SMZ	2	107	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.11, 2.69]
3 quinolone+other vs. quinolone Show forest plot	5	432	Risk Ratio (M‐H, Fixed, 95% CI)	4.92 [1.61, 15.01]

3.1 rifampin	3	243	Risk Ratio (M‐H, Fixed, 95% CI)	10.0 [1.32, 75.73]
3.2 penicillins	1	58	Risk Ratio (M‐H, Fixed, 95% CI)	1.4 [0.25, 7.77]
3.3 roxi	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	9.42 [0.52, 171.44]
4 TMP‐SMZ vs. other Show forest plot	1	53	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

5 non‐absorbable vs. systemic Show forest plot	2	132	Risk Ratio (M‐H, Fixed, 95% CI)	0.04 [0.00, 0.69]

6 systemic + non‐absorbable vs systemic Show forest plot	1	63	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.56, 2.80]

Comparison 12. Side effects requiring discontinuation

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Comparison 13. Fungal infection

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 drug vs. placebo/ no intervention Show forest plot	38	2682	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.83, 1.37]

1.1 quinolone vs. placebo/ no intervention	14	1071	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.56, 1.22]
1.2 TMP‐SMZ vs. placebo/ no intervention	15	1007	Risk Ratio (M‐H, Fixed, 95% CI)	1.49 [0.98, 2.27]
1.3 other systemic vs. placebo/ no intervention	5	422	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [0.55, 4.17]
1.4 non‐absorbable vs. placebo/ no intervention	4	182	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.38, 1.40]
2 quinolone vs. TMP‐SMZ Show forest plot	10	789	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.36, 1.16]

2.1 ciprofloxacin vs. TMP‐SMZ	3	289	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.39, 3.92]
2.2 ofloxacin vs. TMP‐SMZ	3	272	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.25, 1.37]
2.3 norfloxacin vs. TMP‐SMZ	3	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.45 [0.12, 1.68]
2.4 Nalidixic acid vs. TMP‐SMZ	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.01, 4.83]
3 quinolone+other vs. quinolone Show forest plot	6	588	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.45, 1.95]

3.1 rifampin	3	274	Risk Ratio (M‐H, Fixed, 95% CI)	6.42 [0.27, 153.69]
3.2 roxi	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.12, 4.04]
3.3 vancomycin	2	183	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.35, 1.99]
4 TMP‐SMZ vs. other Show forest plot	2	152	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [0.20, 10.81]

5 non‐absorbable vs. systemic Show forest plot	10	800	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.77, 1.81]

6 systemic + non‐absorbable vs systemic Show forest plot	2	103	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.22, 3.02]

Comparison 13. Fungal infection

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Comparison 14. Infection resistant to drug taken

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 drug vs. placebo/ no intervention Show forest plot	19	3629	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [1.08, 2.01]

1.1 quinolone vs. placebo/ no intervention	8	2712	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.81, 1.70]
1.2 TMP‐SMZ vs. placebo/ no intervention	11	917	Risk Ratio (M‐H, Fixed, 95% CI)	2.42 [1.35, 4.36]
2 quinolone vs. TMP‐SMZ Show forest plot	6	366	Risk Ratio (M‐H, Fixed, 95% CI)	0.45 [0.27, 0.74]

2.1 ciprofloxacin vs. TMP‐SMZ	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 2.64]
2.2 ofloxacin vs. TMP‐SMZ	2	144	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.07, 0.76]
2.3 norfloxacin vs. TMP‐SMZ	3	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.35, 1.06]
3 ciprofloxacin vs. norfloxacin Show forest plot	1	619	Risk Ratio (M‐H, Fixed, 95% CI)	0.37 [0.16, 0.87]

4 norfloxacin vs. pefloxacin Show forest plot	1	136	Risk Ratio (M‐H, Fixed, 95% CI)	2.15 [1.18, 3.91]

5 quinolone+other vs. quinolone Show forest plot	3	221	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.01, 1.94]

5.1 rifampin	2	163	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.01, 1.94]
5.2 penicillin	1	58	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 non‐absorbable vs. systemic Show forest plot	4	343	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.63, 1.12]

7 TMP‐SMZ vs. other Show forest plot	2	152	Risk Ratio (M‐H, Fixed, 95% CI)	4.74 [1.27, 17.65]

Comparison 14. Infection resistant to drug taken

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Comparison 15. Sensitivity Analyses by randomisation generation

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	41	5125	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.55, 0.79]

1.1 randomisation A	13	3236	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.48, 0.90]
1.2 randomisation B	26	1723	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.49, 0.78]
1.3 randomisation C	2	166	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.59, 2.55]
2 Febrile patients Show forest plot	45	5787	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.74, 0.81]

2.1 randomisation A	13	3350	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.71, 0.82]
2.2 randomisation B	30	2274	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.75, 0.83]
2.3 randomisation C	2	163	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.61, 0.95]
3 Clinically documented infection Show forest plot	43	5228	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.61, 0.73]

3.1 randomisation A	11	2955	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.58, 0.81]
3.2 randomisation B	30	2110	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.58, 0.71]
3.3 randomisation C	2	163	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.70, 1.41]
4 Microbiologically documented infection Show forest plot	47	5812	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.48, 0.58]

4.1 randomisation A	14	3394	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.50, 0.64]
4.2 randomisation B	31	2255	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.43, 0.56]
4.3 randomisation C	2	163	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.38, 0.74]

Comparison 15. Sensitivity Analyses by randomisation generation

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Comparison 16. Sensitivity Analyses by allocation concealment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	41	5125	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.55, 0.79]

1.1 allocation A	14	3424	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.53, 0.98]
1.2 allocation B	27	1701	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.49, 0.78]
2 Febrile patients Show forest plot	46	5837	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.74, 0.80]

2.1 allocation A	15	3687	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.74, 0.84]
2.2 allocation B	31	2150	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.71, 0.79]
3 Clinically documented infection Show forest plot	43	5228	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.61, 0.73]

3.1 allocation A	12	3251	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.56, 0.76]
3.2 allocation B	31	1977	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.61, 0.75]
4 Microbiologically documented infection Show forest plot	47	5812	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.48, 0.58]

4.1 allocation A	14	3570	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.48, 0.62]
4.2 allocation B	33	2242	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.45, 0.58]

Comparison 16. Sensitivity Analyses by allocation concealment

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Comparison 17. Sensitivity Analyses by blinding

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	41	5125	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.55, 0.79]

1.1 Double Blind	17	3484	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.48, 0.93]
1.2 Unblinded	24	1641	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.52, 0.81]
2 Febrile patients Show forest plot	46	5837	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.74, 0.80]

2.1 Double Blind	20	4028	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.74, 0.84]
2.2 Unblinded	26	1809	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.70, 0.79]
3 Clinically documented infection Show forest plot	43	5228	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.61, 0.73]

3.1 Double Blind	18	3511	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.59, 0.77]
3.2 Unblinded	25	1717	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.59, 0.74]
4 Microbiologically documented infection Show forest plot	47	5856	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.48, 0.58]

4.1 Double Blind	19	3877	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.49, 0.62]
4.2 Unblinded	29	1979	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.45, 0.58]

Comparison 17. Sensitivity Analyses by blinding

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