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Tratamiento antibiótico para la diarrea asociada al Clostridium difficile en adultos

Appendices

Appendix 1. Search strategies

MEDLINE (Ovid)

[mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

1. exp Anti‐Bacterial Agents/

2. exp Aminoglycosides/

3. exp Cephalosporins/

4. (Vancomycin or Metronidazole or Fusidic acid or Nitazoxanide or Teicoplanin or Rifampicin or Rifaximin or Bacitracin or Fidaxomicin or Amoxicillin or Azithromycin or Cephalosporin* or Cephalexin or Ciprofloxacin or Clarithromycin or Clindamycin or Doxycycline or Erythromycin or Flouroquinolone* or Levofloxacin or Macrolide* or Nitrofurantoin or Penicillin or Tetracycline or Trimethoprim or antibiotic* or anti‐bacterial* or anti bacterial* or antibacterial* or bacteriocid* or bactericid* or antimicrobial* or anti‐microbial*).mp.

5. 1 or 2 or 3 or 4

6. exp Clostridium difficile/

7. exp Clostridium Infections/

8. exp Diarrhea/dt [Drug Therapy]

9. exp Enterocolitis, Pseudomembranous/dt [Drug Therapy]

10. (Clostridium difficile or difficile or pseudomembranous enterocolitis).mp.

11. 6 or 7 or 8 or 9 or 10

12. 5 and 11

13. randomised controlled trial.pt.

14. controlled clinical trial.pt.

15. randomized.ab.

16. placebo.ab.

17. clinical trial.sh.

18. randomly.ab.

19. trial.ti.

20. 13 or 14 or 15 or 16 or 17 or 18 or 19

21. humans.sh.

22. 20 and 21

23. 12 and 22

EMBASE (Ovid)

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

1. *antiinfective agent/

2. (Vancomycin or Metronidazole or Fusidic acid or Nitazoxanide or Teicoplanin or Rifampicin or Rifaximin or Bacitracin or Fidaxomicin or Amoxicillin or Azithromycin or Cephalosporin* or Cephalexin or Ciprofloxacin or Clarithromycin or Clindamycin or Doxycycline or Erythromycin or Flouroquinolone* or Levofloxacin or Macrolide* or Nitrofurantoin or Penicillin or Tetracycline or Trimethoprim or antibiotic* or anti‐bacterial* or anti bacterial* or antibacterial* or bacteriocid* or bactericid* or antimicrobial* or anti‐microbial*).m_titl.

3. 1 or 2

4. *Clostridium difficile/

5. *Clostridium infection/

6. *diarrhoea/dt [Drug Therapy]

7. *pseudomembranous colitis/dt [Drug Therapy]

8. (Clostridium difficile or difficile or pseudomembranous enterocolitis).mp.

9. 4 or 5 or 6 or 7 or 8

10. 3 and 9

11. randomised controlled trial/

12. randomization/

13. controlled study/

14. multicenter study/

15. phase 3 clinical trial/

16. phase 4 clinical trial/

17. double blind procedure/

18. single blind procedure/

19. ((singl* or doubl* or trebl* or tripl*) adj (blind* or mask*)).ti,ab.

20. (random* or cross* over* or factorial* or placebo* or volunteer*).ti,ab.

21. 16 or 13 or 17 or 19 or 12 or 18 or 14 or 11 or 20 or 15

22. "human*".ti,ab.

23. (animal* or nonhuman*).ti,ab.

24. 23 and 22

25. 23 not 24

26. 21 not 25

27. 10 and 26

Cochrane Library (CENTRAL)

#1 MeSH descriptor Anti‐Bacterial Agents explode all trees

#2 MeSH descriptor Aminoglycosides explode all trees

#3 MeSH descriptor Cephalosporins explode all trees

#4 (Vancomycin or Metronidazole or Fusidic acid or Nitazoxanide or Teicoplanin or Rifampicin or Rifaximin or Bacitracin or Fidaxomicin or Amoxicillin or Azithromycin or Cephalosporin* or Cephalexin or Ciprofloxacin or Clarithromycin or Clindamycin or Doxycycline or Erythromycin or Flouroquinolone* or Levofloxacin or Macrolide* or Nitrofurantoin or Penicillin or Tetracycline or Trimethoprim or antibiotic* or anti‐bacterial* or anti bacterial* or antibacterial* or bacteriocid* or bactericid* or antimicrobial* or anti‐microbial*):ti,ab,kw

#5 (#1 OR #2 OR #3 OR #4)

#6 MeSH descriptor Clostridium difficile explode all trees

#7 MeSH descriptor Clostridium Infections explode all trees

#8 MeSH descriptor Diarrhea explode all trees with qualifier: DT

#9 MeSH descriptor Enterocolitis, Pseudomembranous explode all trees with qualifier: DT

#10 (Clostridium difficile or difficile or pseudomembranous enterocolitis):ti,ab,kw

#11 (#6 OR #7 OR #8 OR #9 OR #10)

#12 (#5 AND #11)

Study flow diagram.
Figuras y tablas -
Figure 1

Study flow diagram.

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Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

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Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
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Figure 3

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Comparison 1 Metronidazole vs Vancomycin, Outcome 1 Sustained Symptomatic Cure with all exclusions treated as failures.
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Analysis 1.1

Comparison 1 Metronidazole vs Vancomycin, Outcome 1 Sustained Symptomatic Cure with all exclusions treated as failures.

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Comparison 1 Metronidazole vs Vancomycin, Outcome 2 Bacteriologic Cure.
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Analysis 1.2

Comparison 1 Metronidazole vs Vancomycin, Outcome 2 Bacteriologic Cure.

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Comparison 1 Metronidazole vs Vancomycin, Outcome 3 Sustained Cure (Combined symptomatic and bacteriologic cure).
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Analysis 1.3

Comparison 1 Metronidazole vs Vancomycin, Outcome 3 Sustained Cure (Combined symptomatic and bacteriologic cure).

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Comparison 2 Bacitracin vs Vancomycin, Outcome 1 Symptomatic Cure.
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Analysis 2.1

Comparison 2 Bacitracin vs Vancomycin, Outcome 1 Symptomatic Cure.

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Comparison 3 Teicoplanin vs Vancomycin, Outcome 1 Symptomatic Cure.
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Analysis 3.1

Comparison 3 Teicoplanin vs Vancomycin, Outcome 1 Symptomatic Cure.

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Comparison 3 Teicoplanin vs Vancomycin, Outcome 2 Bacteriologic Cure.
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Analysis 3.2

Comparison 3 Teicoplanin vs Vancomycin, Outcome 2 Bacteriologic Cure.

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Comparison 4 Metronidazole vs Fusidic Acid, Outcome 1 Symptomiatic Cure.
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Analysis 4.1

Comparison 4 Metronidazole vs Fusidic Acid, Outcome 1 Symptomiatic Cure.

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Comparison 4 Metronidazole vs Fusidic Acid, Outcome 2 Bacteriologic Cure.
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Analysis 4.2

Comparison 4 Metronidazole vs Fusidic Acid, Outcome 2 Bacteriologic Cure.

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Comparison 5 Fidaxomicin vs Vancomycin, Outcome 1 Symptomatic Cure.
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Analysis 5.1

Comparison 5 Fidaxomicin vs Vancomycin, Outcome 1 Symptomatic Cure.

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Summary of findings for the main comparison. Metronidazole versus vancomycin for Clostridium difficile‐associated diarrhoea in adults

Metronidazole versus Vancomycin for Clostridium difficile‐associated diarrhoea in adults

Patient or population: patients with Clostridium difficile‐associated diarrhoea in adults
Settings:
Intervention: Metronidazole versus Vancomycin

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

Metronidazole versus Vancomycin

Symptomatic cure with all exclusions treated as failures
Follow‐up: mean 4 weeks

792 per 10001

713 per 1000
(665 to 768)

RR 0.9
(0.84 to 0.97)

872
(4 studies)

⊕⊕⊕⊝
moderate2

Bacteriologic cure
Follow‐up: mean 4 weeks

529 per 10001

449 per 1000
(328 to 619)

RR 0.85
(0.62 to 1.17)

163
(2 studies)

⊕⊝⊝⊝
very low2,3

Cure (combined symptomatic and bacteriologic cure) ‐ mild disease
Follow‐up: mean 4 weeks

841 per 10001

740 per 1000
(597 to 917)

RR 0.88
(0.71 to 1.09)

90
(1 study)

⊕⊝⊝⊝
very low3,4,5

Cure (combined symptomatic and bacteriologic cure) ‐ severe disease

711 per 10001

526 per 1000
(369 to 739)

RR 0.74
(0.52 to 1.04)

82
(1 study)

⊕⊝⊝⊝
very low3,4,5

*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 Control group risk comes from control arm of meta‐analysis, based on included trials.
2 High risk of bias.
3 Serious imprecision.
4 Unclear risk of bias.
5 Unclear if stratification by severity was post hoc.

Figuras y tablas -
Summary of findings for the main comparison. Metronidazole versus vancomycin for Clostridium difficile‐associated diarrhoea in adults
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Summary of findings 2. Teicoplanin versus vancomycin for Clostridium difficile‐associated diarrhoea in adults

Teicoplanin versus Vancomycin for Clostridium difficile‐associated diarrhoea in adults

Patient or population: patients with Clostridium difficile‐associated diarrhoea in adults
Settings:
Intervention: Teicoplanin versus Vancomycin

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

Teicoplanin versus Vancomycin

Symptomatic Cure
Follow‐up: mean 4 weeks

727 per 10001

880 per 1000
(727 to 1000)

RR 1.21
(1 to 1.46)

110
(2 studies)

⊕⊝⊝⊝
very low2,3

Bacteriologic Cure
Follow‐up: mean 4 weeks

452 per 10001

822 per 1000
(537 to 1000)

RR 1.82
(1.19 to 2.78)

59
(1 study)

⊕⊝⊝⊝
very low2,4

*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 Control group risk comes from control arm of meta‐analysis, based on included trials.
2 High risk of bias. Blinding not done in either study and other pathogens not excluded in Wenisch
3 Serious imprecision. Two very small studies
4 Serious imprecision. Just a single small study

Figuras y tablas -
Summary of findings 2. Teicoplanin versus vancomycin for Clostridium difficile‐associated diarrhoea in adults
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Summary of findings 3. Fidaxomicin compared to vancomycin for Clostridium difficile‐associated diarrhoea in adults

Fidaxomicin compared to Vancomycin for Clostridium difficile‐associated diarrhoea in adults

Patient or population: patients with Clostridium difficile‐associated diarrhoea in adults
Settings:
Intervention: Fidaxomicin
Comparison: Vancomycin

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Vancomycin

Fidaxomicin

Symptomatic Cure
Follow‐up: mean 4 weeks

610 per 10001

713 per 1000
(652 to 774)

RR 1.17
(1.07 to 1.27)

1164
(2 studies)

⊕⊕⊕⊝
moderate2

*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 Control group risk comes from control arm of meta‐analysis, based on included trials.
2 High risk of bias in both studies.

Figuras y tablas -
Summary of findings 3. Fidaxomicin compared to vancomycin for Clostridium difficile‐associated diarrhoea in adults
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Summary of findings 4. Bacitracin versus vancomycin for Clostridium difficile‐associated diarrhoea in adults

Bacitracin versus Vancomycin for Clostridium difficile‐associated diarrhoea in adults

Patient or population: patients with Clostridium difficile‐associated diarrhoea in adults
Settings:
Intervention: Bacitracin versus Vancomycin

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

Bacitracin versus Vancomycin

Symptomatic Cure
Follow‐up: mean 4 weeks

462 per 10001

268 per 1000
(157 to 457)

RR 0.58
(0.34 to 0.99)

104
(2 studies)

⊕⊝⊝⊝
very low2,3

*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 Control group risk comes from control arm of meta‐analysis, based on included trials.
2 High risk of bias. Attrition and blinding issues in one trial.
2 Very serious imprecision. Two very small studies with few events.

Figuras y tablas -
Summary of findings 4. Bacitracin versus vancomycin for Clostridium difficile‐associated diarrhoea in adults
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Table 1. Summary study

Study

n=Total

Deaths

Harms due to

Intervention

Attrition%

Stratified by

Severity

Anonymous 1994

49

1

joint pain

<10%

Boero 1990

20

0

0

0

Cornley 2012

535

20 Fid

17 Van

none

4.9%

Yes post

randomisation

De Lalla 1992

51

2

NR

10%

Dudley 1986

62

0

NR

52%

Fekety 1989

46

0

NR

18%

Garey 2011

79

skin rash

14%

Johnson 2014

1118

23 Met

16 Van

none

1.8%

Yes post

randonisation

Lagrotteria 2006

39

2

0

Lee 2016a

209

4

5

7%

Louie 2009

49

0

4%

Louie 2011

629

16 Fid

21 Van

elevated

liver enzymes

5.2%

Yes post

randomisation

Louie 2015

82

2

7.3%

Mullane 2015

72

0

44%

Musher 2006

142

4

23%

Musher 2009

50

0

2%

Yes post

randomisation

Teasley 1983

101

2

NR

7%

Wenisch 1996

126

3

5.5%

Wullt 2004

131

0

26%

Young 1985

42

0

NR

0

Zar 2007

172

7

13%

Yes but

uncertain

when

TOTAL

140

NR: None reported
Figuras y tablas -
Table 1. Summary study
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Table 2. Published Guidelines for Antibiotic Treatment of CDAD

HPA1

ESCMID2

SHEA & IDSA3

MILD CDAD

Stop inciting antibiotic and observe, or oral metronidazole 500 mg three times daily

Alternate dosing also recommended and change to vancomycin if no better in 4 days

Stop inciting antibiotic and observe, or oral metronidazole 500 mg three times daily

Stop inciting antibiotic, or oral metronidazole 500 mg three times daily for 10 days

SEVERE CDAD

Oral vancomycin 500 mg four times daily with tapering

Oral vancomycin 125 mg four times daily for 10 days

Oral vancomycin 125 mg four times daily for 10 days

SEVERE AND CANNOT TOLERATE ORAL MEDS

Intravenous metronidazole and vancomycin via nasogastric tube or enemas four times daily

Same

Same

SURGERY

For toxic megacolon or lactate > 5

For perforation, toxic megacolon, Ileus, lactate > 5

RECURRENCE

First as Primary

2nd: oral vancomycin with taper

Same

1HPA 2008; HPA 2016

2Bauer 2009

3Cohen 2010

Figuras y tablas -
Table 2. Published Guidelines for Antibiotic Treatment of CDAD
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Comparison 1. Metronidazole vs Vancomycin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Sustained Symptomatic Cure with all exclusions treated as failures Show forest plot

4

872

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.84, 0.97]

2 Bacteriologic Cure Show forest plot

2

163

Risk Ratio (M‐H, Fixed, 95% CI)

0.85 [0.62, 1.17]

3 Sustained Cure (Combined symptomatic and bacteriologic cure) Show forest plot

1

172

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.68, 0.99]

3.1 Mild disease

1

90

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.71, 1.09]

3.2 Severe disease

1

82

Risk Ratio (M‐H, Fixed, 95% CI)

0.74 [0.52, 1.04]
Figuras y tablas -
Comparison 1. Metronidazole vs Vancomycin
Ir a la tabla de la revisión
Comparison 2. Bacitracin vs Vancomycin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Symptomatic Cure Show forest plot

2

104

Risk Ratio (M‐H, Fixed, 95% CI)

0.58 [0.34, 0.99]
Figuras y tablas -
Comparison 2. Bacitracin vs Vancomycin
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Comparison 3. Teicoplanin vs Vancomycin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Symptomatic Cure Show forest plot

2

110

Risk Ratio (M‐H, Fixed, 95% CI)

1.21 [1.00, 1.46]

2 Bacteriologic Cure Show forest plot

1

59

Risk Ratio (M‐H, Fixed, 95% CI)

1.82 [1.19, 2.78]
Figuras y tablas -
Comparison 3. Teicoplanin vs Vancomycin
Ir a la tabla de la revisión
Comparison 4. Metronidazole vs Fusidic Acid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Symptomiatic Cure Show forest plot

2

191

Risk Ratio (M‐H, Fixed, 95% CI)

1.12 [0.88, 1.41]

2 Bacteriologic Cure Show forest plot

2

191

Risk Ratio (M‐H, Fixed, 95% CI)

1.07 [0.84, 1.36]
Figuras y tablas -
Comparison 4. Metronidazole vs Fusidic Acid
Ir a la tabla de la revisión
Comparison 5. Fidaxomicin vs Vancomycin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Symptomatic Cure Show forest plot

2

1164

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [1.07, 1.27]
Figuras y tablas -
Comparison 5. Fidaxomicin vs Vancomycin
Ir a la tabla de la revisión