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Appendices

Appendix 1. Details of previous searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library) (2007, Issue 1 and 2013, Issue 5), MEDLINE (1966 to February 2007 and to May 2013) and EMBASE (1980 to February 2007 and to May 2013), and handsearched the references of all identified studies.

The following search terms were run over MEDLINE and CENTRAL. The MEDLINE search was combined with the search strategy designed by The Cochrane Collaboration for identifying randomised controlled trials. See Appendix 3 for the EMBASE search strategy.

MEDLINE (Ovid)
1 exp MENINGOCOCCAL INFECTIONS/
2 exp Neisseria meningitides/
3 (neisseria adj mening$).mp.
4 meningococ$.mp
5 or/1‐4
6 exp Anti‐bacterial Agents/
7 (antibiotic$ or penicillin or cefotaxime or ampicillin$ or sulfa$ or ciprofloxacin$ or norfloxaci$ or ofloxaci$ or quinol$ or fluoroquinol$ or fluoro‐quinolon$ or ceftriaxon$ or rifampi$ or azithromyci$ or minocyclin$ or macrolid$ or cephalospori$.).mp.
8 or/6‐7
9 exp Patient Admission/
10 (preadmission or pre‐admission).mp.
11 empiric.mp.
12 or/9‐11
13 5 and 8 and 12

Embase.com
#16 #6 and #10 and #15
#15 #11 or #12 or #13 or #14
#14 (empiric in ti) or (empiric in ab)
#13 (preadmission or pre‐admission)in ab
#12 (preadmission or pre‐admission)in ti
#11 explode 'hospital‐admission' / all subheadings in DEM,DER,DRM,DRR
#10 #7 or #8 or #9
#9 (antibiotic* or penicillin or cefotaxime or ampicilli* or sulfa* or ciprofloxacin* or norfloxaci* or ofloxaci* or quinol* or fluoroquinol* or fluoro‐quinolon* or ceftriaxon* or rifampi* or azithromyci* or minocyclin* or macrolid* or cephalospori*) in ab
#8 (antibiotic* or penicillin or cefotaxime or ampicilli* or sulfa* or ciprofloxacin* or norfloxaci* or ofloxaci* or quinol* or fluoroquinol* or fluoro‐quinolon* or ceftriaxon* or rifampi* or azithromyci* or minocyclin* or macrolid* or cephalospori*) in ti
#7 'antibiotic‐agent' / all subheadings in DEM,DER,DRM,DRR
#6 #1 or #2 or #3 or #4 or #5
#5 (neisseria adj mening*) in ab
#4 (neisseria adj mening*) in ti
#3 explode 'Neisseria‐meningitidis' / all subheadings in DEM,DER,DRM,DRR
#2 (meningococcal infection* in ti) or (meningococcal infection* in ab)
#1 explode 'meningococcosis‐' / all subheadings in DEM,DER,DRM,DRR

Appendix 2. MEDLINE (Ovid) search strategy

1 exp Meningococcal Infections/
2 exp Neisseria meningitidis/
3 (neisseria adj2 mening*).tw.
4 meningococc*.tw.
5 Meningitis/
6 meningit*.tw.
7 or/1‐6
8 exp Anti‐Bacterial Agents/
9 antibiotic*.tw,nm.
10 (penicillin* or cefotaxim* or ampicillin* or sulfa* or ciprofloxacin* or norfloxacin* or ofloxacin* or quinol* or fluoroquinol* or fluoro‐quinol* or ceftriaxon* or rifampi* or azithromyci* or minocyclin* or macrolid* or cephalosporin*).tw,nm.
11 or/8‐10
12 Patient Admission/
13 (patient* adj2 (admis* or admit*)).tw.
14 ((pre or before or prior or previous) adj2 hospital*).tw.
15 ((previous or prior or before) adj2 (admit* or admiss*)).tw.
16 (preadmit* or pre admit* or pre‐admit* or preadmiss* or pre admiss* or pre‐admiss*).tw.
17 empiric.tw.
18 or/12‐17
19 7 and 11 and 18

Appendix 3. Embase.com search strategy

#31 #22 AND #30
#30 #25 NOT #29
#29 #26 NOT #28
#28 #26 AND #27
#27 'human'/de
#26 'nonhuman'/de OR 'animal'/de OR 'animal experiment'/de
#25 #23 OR #24
#24 random*:ab,ti OR placebo*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR allocat*:ab,ti OR trial:ti OR (doubl* NEXT/1 blind*):ab,ti
#23 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp
#22 #7 AND #21
#21 #11 AND #20
#20 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19
#19 (emergenc* NEAR/3 treat*):ab,ti OR triage:ab,ti
#18 'emergency health service'/de
#17 empiric*:ab,ti
#16 preadmit*:ab,ti OR preadmis*:ab,ti OR (pre NEXT/1 (admit* OR admis*)):ab,ti
#15 ((previous OR prior OR before) NEAR/3 (admit* OR admis*)):ab,ti
#14 ((pre OR before OR prior OR previous) NEAR/5 hospital*):ab,ti
#13 ((hospital* OR patient*) NEAR/3 (admis* OR admit*)):ab,ti
#12 'hospital admission'/de
#11 #8 OR #9 OR #10
#10 penicillin*:ab,ti OR cefotaxim*:ab,ti OR ampicillin*:ab,ti OR sulfa*:ab,ti OR ciprofloxacin*:ab,ti OR norfloxacin*:ab,ti OR ofloxacin*:ab,ti OR quinol*:ab,ti OR fluoroquinol*:ab,ti OR fluoro‐quinol*:ab,ti OR ceftriaxon*:ab,ti OR rifampi*:ab,ti OR azithromyci*:ab,ti OR minocyclin*:ab,ti OR macrolid*:ab,ti OR cephalosporin*:ab,ti
#9 antibiotic*:ab,ti
#8 'antibiotic agent'/exp
#7 #1 OR #2 OR #3 OR #4 OR #5 OR #6
#6 meningococc*:ab,ti OR meningit*:ab,ti OR (neisseria NEAR/2 mening*):ab,ti OR 'n. meningitidis':ab,ti
#5 'neisseria meningitidis'/de
#4 'meningitis'/de
#3 'bacterial meningitis'/de
#2 'epidemic meningitis'/de
#1 'meningococcosis'/exp

Appendix 4. Web of Science (Thomson Reuters) search strategy

# 3

#2 AND #1

Databases=SCI‐EXPANDED, CPCI‐S, CCR‐EXPANDED, IC Timespan=1985‐2012

Lemmatization=Off  

# 2

Title=(trial) OR Topic=(random* or placebo* or ((singl* or doubl*) NEAR/1 blind*))

Databases=SCI‐EXPANDED, CPCI‐S, CCR‐EXPANDED, IC Timespan=1985‐2012

Lemmatization=Off  

Appendix 5. LILACS (BIREME) search strategy

Search > (MH:"Meningococcal Infections" OR "Infecciones Meningocócicas" OR "Infecções Meningocócicas" OR MH:C01.252.400.625.549$ OR MH:"Neisseria meningitidis" OR MH:B03.440.400.425.550.550.641$ OR MH:B03.660.075.525.520.500$ OR "Neisseria meningitidis" OR "N. meningitidis" OR meningit$ OR meningococ$ OR MH:Meningitis OR MH:"Meningitis, Bacterial" OR "Meningitis Bacteriana" OR "Meningite Bacteriana" OR "Bacterial Meningitis" OR MH:"Meningitis, Meningococcal" OR "Meningitis Meningocócica" OR "Meningite Meningocócica" OR "Meningitis Meningocóccica" OR "Meningite Meningocóccica") AND (MH:"Anti‐Bacterial Agents" OR antibacter$ OR antibiotic$ OR Antibióticos OR Antibacterianos OR MH:D27.505.954.122.085$ OR penicillin$ OR cefotaxim$ OR ampicillin$ OR sulfa$ OR ciprofloxacin$ OR norfloxacin$ OR ofloxacin$ OR quinol$ OR fluoroquinol$ OR fluoro‐quinol$ OR ceftriaxon$ OR rifampi$ OR azithromycin$ minocyclin$ OR macrolid$ OR cephalosporin$) > clinical_trials

Appendix 6. CAB Abstracts (Thomson Reuters) search strategy

# 3

#2 AND #1

Databases=CAB Abstracts Timespan=1985‐2012

Lemmatization=Off  

# 2

Title=(trial) AND Topic=((random* or placebo* or ((singl* or doubl*) NEXT/1 blind*)))

Databases=CAB Abstracts Timespan=1985‐2012

Lemmatization=Off  

# 1

Topic=((meningococcal OR "Neisseria meningitidis" OR "N. meningitidis" OR meningitis)) AND Topic=(antibiotic* OR penicillin* OR cefotaxim* OR ampicillin* OR sulfa* OR ciprofloxacin* OR norfloxacin* OR ofloxacin* OR quinol* OR fluoroquinol* OR fluoro‐quinol* OR ceftriaxon* OR rifampi* OR azithromycin* OR minocyclin* OR macrolid* OR cephalosporin*)

Databases=CAB Abstracts Timespan=1985‐2012

Lemmatization=Off  

Study flow diagram
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Figure 1

Study flow diagram

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'Risk of bias' summary: review authors' judgements about each risk of bias item for Nathan 2005.
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Figure 2

'Risk of bias' summary: review authors' judgements about each risk of bias item for Nathan 2005.

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Forest plot of comparison: 1 Ceftriaxone versus long‐acting (oily) chloramphenicol, outcome: 1.1 Death
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Figure 3

Forest plot of comparison: 1 Ceftriaxone versus long‐acting (oily) chloramphenicol, outcome: 1.1 Death

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Forest plot of comparison: 1 Ceftriaxone versus long‐acting (oily) chloramphenicol, outcome: 1.2 Clinical failure
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Figure 4

Forest plot of comparison: 1 Ceftriaxone versus long‐acting (oily) chloramphenicol, outcome: 1.2 Clinical failure

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Forest plot of comparison: 1 Ceftriaxone versus long‐acting (oily) chloramphenicol, outcome: 1.3 Neurological sequelae
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Figure 5

Forest plot of comparison: 1 Ceftriaxone versus long‐acting (oily) chloramphenicol, outcome: 1.3 Neurological sequelae

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Comparison 1 Ceftriaxone versus long‐acting (oily) chloramphenicol, Outcome 1 Death.
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Analysis 1.1

Comparison 1 Ceftriaxone versus long‐acting (oily) chloramphenicol, Outcome 1 Death.

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Comparison 1 Ceftriaxone versus long‐acting (oily) chloramphenicol, Outcome 2 Clinical failure.
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Analysis 1.2

Comparison 1 Ceftriaxone versus long‐acting (oily) chloramphenicol, Outcome 2 Clinical failure.

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Comparison 1 Ceftriaxone versus long‐acting (oily) chloramphenicol, Outcome 3 Neurological sequelae.
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Analysis 1.3

Comparison 1 Ceftriaxone versus long‐acting (oily) chloramphenicol, Outcome 3 Neurological sequelae.

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Summary of findings for the main comparison. Ceftriaxone versus long‐acting (oily) chloramphenicol in people suspected to have meningococcal disease

Ceftriaxone versus long‐acting (oily) chloramphenicol in people suspected to have meningococcal disease

Patient or population: people suspected to have meningococcal disease (adults and children)
Settings: primary care centres in a low‐income country in Africa during an epidemic
Intervention: intramuscular ceftriaxone (100 mg/kg; max 4 g) single dose
Comparison: long‐acting (oily) chloramphenicol (100 mg/kg; max 3 g) single dose

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Long‐acting (oily) chloramphenicol

Intramuscular ceftriaxone

Death ‐ in all participants ‐ short term
Follow‐up: 72 hours

47 per 10001

57 per 1000
(27 to 120)

RR 1.21
(0.57 to 2.56)2

503
(1 study)8

⊕⊕⊕⊝
moderate3,4,5,6,7

All outcomes in this table are from 1 trial that randomised 510 participants to either intervention (Nathan 2005)

Death ‐ in confirmed cases of meningococcal meningitis (subgroup)
Follow‐up: 72 hours

34 per 10001

38 per 1000
(12 to 121)

RR 1.11
(0.35 to 3.56)2

308
(1 study)8

⊕⊕⊕⊝
moderate3,4,6,7

Clinical failure ‐ in all participants ‐ short term
Composite clinical criteria10
Follow‐up: 24 to 48 hours

41 per 10001

34 per 1000
(13 to 84)

OR 0.83
(0.32 to 2.15)2

477
(1 study)8

⊕⊕⊕⊝
moderate3,4,6,7,9

Clinical failure ‐ in confirmed cases of meningococcal meningitis (subgroup)
Composite clinical criteria10
Follow‐up: 24 to 48 hours

14 per 10001

19 per 1000
(3 to 107)

OR 1.39
(0.23 to 8.47)2

308
(1 study)8

⊕⊕⊕⊝
moderate3,4,6,7,9

Neurological sequelae ‐ in all participants‐ short term
Clinical assessment11
Follow‐up: 72 hours

53 per 10001

68 per 1000
(33 to 139)

RR 1.29
(0.63 to 2.62)2

477
(1 study)8

⊕⊕⊝⊝
low3,4,7,9,12,13

Neurological sequelae ‐ in confirmed cases of meningococcal meningitis (subgroup)
Clinical assesment11
Follow‐up: 72 hours

63 per 10001

91 per 1000
(41 to 203)

RR 1.44
(0.65 to 3.23)

297
(1 study)8

⊕⊝⊝⊝
very low3,4,5,7,9,12

Adverse events ‐ short term
Follow‐up: 72 hours

See comment

See comment

Not estimable

0
(1 study)8

See comment

No adverse events were detected with either intervention

*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; OR: odds ratio; 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.

1Basis of the assumed risk: control group risk.
2Effect estimate: consistent with non‐inferiority of ceftriaxone versus chloramphenicol.
3No serious study limitations: block randomised using off‐site computer‐generated codes in blocks of 20; allocation concealed in numbered, sealed, opaque envelopes; recruitment was by personnel not involved in generating random sequence; baseline variables matched in intervention arms; open‐label trial but outcome was objective; outcomes completely and adequately reported; no other biases.
4No serious inconsistency: results for all participants and in subgroups were consistent.
5Serious imprecision: sample size was estimated to demonstrate non‐inferiority for the primary outcome and not for neurological sequelae (secondary outcome). A sample size of 175 individuals with confirmed meningococcal meningitis per group (350 total) was needed for the primary outcome with a one‐sided 5% significance level, 80% power, and assuming 10% dropouts. Only 308 participants were confirmed to have meningococcal meningitis, thus trial may be underpowered to detect non‐inferiority for neurological outcomes. Downgraded by one.
6No serious imprecision: trial was adequately powered to demonstrate non‐inferiority. Not downgraded.
7Publication bias unlikely: search for trials was comprehensive. Not downgraded.
8Parallel‐group, open‐label, non‐inferiority trial.
9Serious indirectness: trial excluded infants, pregnant women, and those with serious illness (in non‐reactive coma or with convulsions). Downgraded by one.
10Clinical failure: composite of: a) state of consciousness remaining severely altered (Glasgow Coma Scale < 11 at 24 hours or < 13 at 48 hours); b) no improvement in the state of consciousness since 0 hour; c) appearance of or worsened neurological symptoms since 0 hour; d) repeated or persistent convulsions; and e) axillary temperature above 38.5° C in the absence of other evident infectious pathological changes.
11Neurological sequelae: judged on gross clinical abnormality.
12Serious indirectness: follow‐up was too short to detect neurological sequelae adequately. Downgraded by one.
13No serious imprecision: sample size of 350 required to demonstrate non‐inferiority for primary outcome, but sample size adequately powered to demonstrate non‐inferiority for this secondary outcome as well. Not downgraded.

Figuras y tablas -
Summary of findings for the main comparison. Ceftriaxone versus long‐acting (oily) chloramphenicol in people suspected to have meningococcal disease
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Comparison 1. Ceftriaxone versus long‐acting (oily) chloramphenicol

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

1

Risk Ratio (IV, Fixed, 95% CI)

Subtotals only

1.1 In all participants ‐ short‐term

1

503

Risk Ratio (IV, Fixed, 95% CI)

1.21 [0.57, 2.56]

1.2 In confirmed cases of meningococcal meningitis ‐ short‐term

1

308

Risk Ratio (IV, Fixed, 95% CI)

1.11 [0.35, 3.56]

1.3 In cases due to other causes ‐ short‐term

1

195

Risk Ratio (IV, Fixed, 95% CI)

1.42 [0.54, 3.76]

2 Clinical failure Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 In all participants ‐ short‐term

1

477

Odds Ratio (M‐H, Fixed, 95% CI)

0.83 [0.32, 2.15]

2.2 In confirmed cases of meningococcal meningitis ‐ short‐term

1

308

Odds Ratio (M‐H, Fixed, 95% CI)

1.39 [0.23, 8.47]

2.3 In cases due to other causes ‐ short‐term

1

169

Odds Ratio (M‐H, Fixed, 95% CI)

0.81 [0.25, 2.58]

3 Neurological sequelae Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 In all participants ‐ short‐term

1

477

Risk Ratio (M‐H, Fixed, 95% CI)

1.29 [0.63, 2.62]

3.2 In confirmed cases of meningococcal meningitis ‐ short‐term

1

297

Risk Ratio (M‐H, Fixed, 95% CI)

1.44 [0.65, 3.23]

3.3 In cases due to other causes ‐ short‐term

1

180

Risk Ratio (M‐H, Fixed, 95% CI)

0.64 [0.12, 3.40]
Figuras y tablas -
Comparison 1. Ceftriaxone versus long‐acting (oily) chloramphenicol
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