Antibiotic treatment for <i>Clostridium difficile</i>‐associated diarrhoea in adults

Richard L Nelson; Katie J Suda; Charlesnika T Evans

doi:10.1002/14651858.CD004610.pub5

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Figure 1

Study flow diagram.

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Figure 2

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

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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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Analysis 1.1

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

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Analysis 1.2

Comparison 1 Metronidazole vs Vancomycin, Outcome 2 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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Analysis 2.1

Comparison 2 Bacitracin 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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Analysis 3.2

Comparison 3 Teicoplanin vs Vancomycin, Outcome 2 Bacteriologic Cure.

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Analysis 4.1

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

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Analysis 4.2

Comparison 4 Metronidazole vs Fusidic Acid, Outcome 2 Bacteriologic 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 low^2,3
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 low^3,4,5
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 low^3,4,5
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.

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 low^2,3
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 low^2,4
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

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.

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 low^2,3
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.

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

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

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]

Comparison 1. Metronidazole vs Vancomycin

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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]

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]

Comparison 3. Teicoplanin vs Vancomycin

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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]

Comparison 4. Metronidazole vs Fusidic Acid

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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]

Comparison 5. Fidaxomicin vs Vancomycin

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