Third generation cephalosporins versus conventional antibiotics for treating acute bacterial meningitis

Kameshwar Prasad; Amit Kumar; Tarun Singhal; Praveen Kumar Gupta

doi:10.1002/14651858.CD001832.pub3

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Figure 1

Funnel plot showing symmetry of risk difference (RD) against the standard error (SE) in individual studies

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Figure 2

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 3

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

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Analysis 1.1

Comparison 1 Third generation cephalosporins versus conventional therapy, Outcome 1 Death.

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Analysis 1.2

Comparison 1 Third generation cephalosporins versus conventional therapy, Outcome 2 Deafness.

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Analysis 1.3

Comparison 1 Third generation cephalosporins versus conventional therapy, Outcome 3 Culture positive 10 to 48 hours after start of treatment.

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Analysis 1.4

Comparison 1 Third generation cephalosporins versus conventional therapy, Outcome 4 Diarrhoea.

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Analysis 1.5

Comparison 1 Third generation cephalosporins versus conventional therapy, Outcome 5 Neutropenia.

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Analysis 1.6

Comparison 1 Third generation cephalosporins versus conventional therapy, Outcome 6 Skin rash.

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Analysis 1.7

Comparison 1 Third generation cephalosporins versus conventional therapy, Outcome 7 Treatment failure (either death or deafness).

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Analysis 2.1

Comparison 2 Cephalosporins versus conventional therapy for H. influenzae meningitis, Outcome 1 Death.

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Analysis 3.1

Comparison 3 Third generation cephalosporins versus conventional antibiotics for S. pneumoniae meningitis, Outcome 1 Death.

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Analysis 4.1

Comparison 4 Third generation cephalosporins versus conventional therapy for meningococcal meningitis, Outcome 1 Death.

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Analysis 5.1

Comparison 5 Third generation cephalosporins versus conventional antibiotics (high and low/middle‐income countries), Outcome 1 Death.

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Analysis 5.2

Comparison 5 Third generation cephalosporins versus conventional antibiotics (high and low/middle‐income countries), Outcome 2 Deafness.

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Analysis 5.3

Comparison 5 Third generation cephalosporins versus conventional antibiotics (high and low/middle‐income countries), Outcome 3 Treatment failure.

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Summary of findings for the main comparison. Third generation cephalosporins versus conventional therapy for acute bacterial meningitis

Third generation cephalosporins versus conventional therapy for acute bacterial meningitis
Patient or population: patients treated for acute bacterial meningitis Settings: acute bacterial meningitis Intervention: third generation cephalosporins versus conventional 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
	Control	Third generation cephalosporins versus conventional therapy
Death	Study population		See comment	1496 (19)		Risks were calculated from pooled risk differences
	67 per 1000	65 per 1000 (37 to 87)
	Medium risk population
	47 per 1000	46 per 1000 (26 to 61)
Deafness	Study population		See comment	501 (10)		Risks were calculated from pooled risk differences
	118 per 1000	83 per 1000 (28 to 127)
	Medium risk population
	72 per 1000	50 per 1000 (17 to 78)
Culture positivity 10 to 48 hours start of treatment	Study population		See comment	442 (12)		Risks were calculated from pooled risk differences
	117 per 1000	58 per 1000 (7 to 117)
	Medium risk population
	25 per 1000	12 per 1000 (1 to 25)
Diarrhoea	Study population		See comment	750 (12)		Risks were calculated from pooled risk differences
	125 per 1000	202 per 1000 (155 to 255)
	Medium risk population
	77 per 1000	125 per 1000 (95 to 157)
Neutropenia	Study population		See comment	472 (10)		Risks were calculated from pooled risk differences
	54 per 1000	29 per 1000 (‐16 to 74)
	Medium risk population
	13 per 1000	7 per 1000 (‐4 to 18)
Skin rash	Study population		See comment	533 (8)		Risks were calculated from pooled risk differences
	16 per 1000	4 per 1000 (‐24 to 26)
	Medium risk population
	0 per 1000	0 per 1000 (0 to 0)
Treatment failure (either death or deafness)	Study population		See comment	1496 (19)		Risks were calculated from pooled risk differences
	87 per 1000	79 per 1000 (47 to 107)
	Medium risk population
	67 per 1000	61 per 1000 (36 to 82)
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

Summary of findings for the main comparison. Third generation cephalosporins versus conventional therapy for acute bacterial meningitis

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Summary of findings 2. Cephalosporins versus conventional therapy for H. influenzae meningitis

*Cephalosporins versus conventional therapy for H. influenzae* meningitis**
Patient or population: patients treated for H. influenzae meningitis Settings: acute bacterial meningitis Intervention: cephalosporins versus conventional therapy for H. influenzae meningitis
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	*Cephalosporins versus conventional therapy for H. influenzae* meningitis**
Death	Study population		See comment	318 (10)		Risks were calculated from pooled risk differences
	62 per 1000	69 per 1000 (12 to 122)
	Medium risk population
	26 per 1000	29 per 1000 (5 to 51)
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

Summary of findings 2. Cephalosporins versus conventional therapy for H. influenzae meningitis

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Summary of findings 3. Third generation cephalosporins versus conventional antibiotics for S. pneumoniae meningitis

*Third generation cephalosporins versus conventional antibiotics for S. pneumoniae* meningitis**
Patient or population: patients treated for S. pneumoniae meningitis Settings: acute bacterial meningitis Intervention: third generation cephalosporins versus conventional antibiotics for S. pneumoniae meningitis
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	*Third generation cephalosporins versus conventional antibiotics for S. pneumoniae* meningitis**
Death	Study population		See comment	129 (11)		Risks were calculated from pooled risk differences
	255 per 1000	232 per 1000 (74 to 395)
	Medium risk population
	250 per 1000	228 per 1000 (72 to 387)
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

Summary of findings 3. Third generation cephalosporins versus conventional antibiotics for S. pneumoniae meningitis

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Summary of findings 4. Third generation cephalosporins versus conventional therapy for meningococcal meningitis

Third generation cephalosporins versus conventional therapy for meningococcal meningitis
Patient or population: patients treated for meningococcal meningitis Settings: acute bacterial meningitis Intervention: third generation cephalosporins versus conventional therapy for meningococcal meningitis
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Third generation cephalosporins versus conventional therapy for meningococcal meningitis
Death	Study population		See comment	477 (13)		Risks were calculated from pooled risk differences
	39 per 1000	35 per 1000 (‐11 to 80)
	Medium risk population
	0 per 1000	0 per 1000 (0 to 0)
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

Summary of findings 4. Third generation cephalosporins versus conventional therapy for meningococcal meningitis

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Summary of findings 5. Third generation cephalosporins versus conventional antibiotics (high and low/middle‐income countries) for acute bacterial meningitis

Third generation cephalosporins versus conventional antibiotics (high and low/middle‐income countries) for acute bacterial meningitis
Patient or population: patients treated for acute bacterial meningitis Settings: acute bacterial meningitis Intervention: third generation cephalosporins versus conventional antibiotics (high and low/middle‐income countries)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Third generation cephalosporins versus conventional antibiotics (high and low/middle‐income countries)
Death	Study population		See comment	1301 (19)		Risks were calculated from pooled risk differences
	67 per 1000	62 per 1000 (37 to 87)
	Medium risk population
	44 per 1000	40 per 1000 (24 to 57)
Death: high‐income countries	Study population		See comment	510 (9)		Risks were calculated from pooled risk differences
	27 per 1000	28 per 1000 (‐3 to 66)
	Medium risk population
	0 per 1000	0 per 1000 (0 to 0)
Death: Low/middle‐income countries	Study population		See comment	791 (10)		Risks were calculated from pooled risk differences
	94 per 1000	85 per 1000 (44 to 124)
	Medium risk population
	80 per 1000	72 per 1000 (38 to 106)
Deafness	Study population		See comment	501 (10)		Risks were calculated from pooled risk differences
	114 per 1000	76 per 1000 (24 to 124)
	Medium risk population
	54 per 1000	36 per 1000 (11 to 59)
Deafness: high‐income countries	Study population		See comment	380 (6)		Risks were calculated from pooled risk differences
	138 per 1000	90 per 1000 (28 to 148)
	Medium risk population
	72 per 1000	47 per 1000 (14 to 77)
Deafness: low‐income countries	Study population		See comment	121 (4)		Risks were calculated from pooled risk differences
	45 per 1000	39 per 1000 (‐44 to 124)
	Medium risk population
	0 per 1000	0 per 1000 (0 to 0)
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

Summary of findings 5. Third generation cephalosporins versus conventional antibiotics (high and low/middle‐income countries) for acute bacterial meningitis

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Table 1. Income‐based classification of countries where studies were conducted

High‐income	Upper middle‐income	Lower middle‐income	Low‐income
Arnoff 1984	Haffejee 1988	Bryan 1985	Nathan 2005
Barson 1985	Odio 1986	Filali 1993	Sharma 1996
Congeni 1984	Tuncer 1988	Girgis 1987
Del Rio 1983		Rodriguz 1985
Jacobs 1985		Girgis 1988
Narciso 1983
Peltola 1989
Steele 1983
Wells 1984

Table 1. Income‐based classification of countries where studies were conducted

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Comparison 1. Third generation cephalosporins versus conventional therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	19	1496	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.03, 0.02]

2 Deafness Show forest plot	10	501	Risk Difference (M‐H, Fixed, 95% CI)	‐0.04 [‐0.09, 0.01]

3 Culture positive 10 to 48 hours after start of treatment Show forest plot	12	442	Risk Difference (M‐H, Fixed, 95% CI)	‐0.06 [‐0.11, ‐0.00]

4 Diarrhoea Show forest plot	12	750	Risk Difference (M‐H, Fixed, 95% CI)	0.08 [0.03, 0.13]

5 Neutropenia Show forest plot	10	472	Risk Difference (M‐H, Fixed, 95% CI)	‐0.02 [‐0.07, 0.02]

6 Skin rash Show forest plot	8	533	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.04, 0.01]

7 Treatment failure (either death or deafness) Show forest plot	19	1496	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.04, 0.02]

Comparison 1. Third generation cephalosporins versus conventional therapy

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Comparison 2. Cephalosporins versus conventional therapy for H. influenzae meningitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	10	318	Risk Difference (M‐H, Fixed, 95% CI)	0.01 [‐0.05, 0.06]

Comparison 2. Cephalosporins versus conventional therapy for H. influenzae meningitis

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Comparison 3. Third generation cephalosporins versus conventional antibiotics for S. pneumoniae meningitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	11	129	Risk Difference (M‐H, Fixed, 95% CI)	‐0.02 [‐0.18, 0.14]

Comparison 3. Third generation cephalosporins versus conventional antibiotics for S. pneumoniae meningitis

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Comparison 4. Third generation cephalosporins versus conventional therapy for meningococcal meningitis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	13	477	Risk Difference (M‐H, Fixed, 95% CI)	‐0.00 [‐0.05, 0.04]

Comparison 4. Third generation cephalosporins versus conventional therapy for meningococcal meningitis

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Comparison 5. Third generation cephalosporins versus conventional antibiotics (high and low/middle‐income countries)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death Show forest plot	19	1301	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.03, 0.02]

1.1 High income countries	9	510	Risk Difference (M‐H, Fixed, 95% CI)	0.00 [‐0.03, 0.04]
1.2 Low/middle income countries	10	791	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.05, 0.03]
2 Deafness Show forest plot	10	501	Risk Difference (M‐H, Fixed, 95% CI)	‐0.04 [‐0.09, 0.01]

2.1 Developed countries	6	380	Risk Difference (M‐H, Fixed, 95% CI)	‐0.05 [‐0.11, 0.01]
2.2 Developing countries	4	121	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.09, 0.08]
3 Treatment failure Show forest plot	19	1301	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.04, 0.02]

3.1 Developed countries	9	510	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.06, 0.03]
3.2 Developing countries	10	791	Risk Difference (M‐H, Fixed, 95% CI)	‐0.01 [‐0.05, 0.03]

Comparison 5. Third generation cephalosporins versus conventional antibiotics (high and low/middle‐income countries)

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