Interventions for necrotizing soft tissue infections in adults

Camille Hua; Romain Bosc; Emilie Sbidian; Nicolas De Prost; Carolyn Hughes; Patricia Jabre; Olivier Chosidow; Laurence Le Cleach

doi:10.1002/14651858.CD011680.pub2

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Figure 1

Flow diagram.

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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 Moxifloxacin versus amoxicillin‐clavulanate, Outcome 1 Mortality within 30 days.

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Analysis 1.2

Comparison 1 Moxifloxacin versus amoxicillin‐clavulanate, Outcome 2 Proportion of patients who experienced serious adverse events.

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Analysis 2.1

Comparison 2 AB 103 versus placebo, Outcome 1 Mortality within 30 days.

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Analysis 2.2

Comparison 2 AB 103 versus placebo, Outcome 2 Proportion of patients who experienced serious adverse events.

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Analysis 3.1

Comparison 3 IGIV versus placebo, Outcome 1 Mortality within 30 days.

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Analysis 3.2

Comparison 3 IGIV versus placebo, Outcome 2 Proportion of patients who experienced serious adverse events.

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Summary of findings for the main comparison. Moxifloxacin compared to amoxicillin‐clavulanate for NSTI

Moxifloxacin compared to amoxicillin‐clavulanate for NSTI
Patient or population: NSTI Setting: hospital Intervention: moxifloxacin Comparison: amoxicillin‐clavulanate
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Risk with Amoxicillin‐clavulanate	Risk with Moxifloxacin
Mortality follow‐up: 30 days	Study population		RR 3.00 (0.39 to 23.07)	54 (1 RCT)	⊕⊝⊝⊝ Very low^a	Data from a larger trial including several types of soft tissue infections; total number of included patients N = 804
	6 per 100	17 per 100 (2 to 100)
Serious adverse events (SAE) follow‐up: 28 days	Study population		RR 0.63 (0.30 to 1.31)	54 (1 RCT)	⊕⊝⊝⊝ Very low^a	Description of nature of serious adverse events was not available
	44 per 100	28 per 100 (13 to 58)
Survival time	—	—	—	54 (1 RCT)	⊕⊝⊝⊝ Very low^a	The median time of death after start of antibiotic treatment was shorter in the moxifloxacin group than in the amoxicillin‐clavulanate group (10.5 days versus 42 days) (not possible to calculate hazard ratio with the data provided)
Assessment of long‐term morbidity	—	—	—	—	—	Not reported
*The risk in the intervention group (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). Assumed risk for mortality was based on data of the literature (Audureau 2017; May 2009). For serious adverse effects it was based on the results of the trial. CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality/certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality/certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality/certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality/certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aDowngraded by five levels to very low certainty of evidence. We downgraded two levels because of high risk of bias regarding blinding (open label trial) and high risk for attrition bias because of a high rate of withdrawal (20%). We downgraded one level for serious imprecision because of small sample size (and CI of RR included 1, where reported). We downgraded a further two levels because no clear criteria for clinical diagnosis of necrotizing fasciitis were provided and because antibiotic used as comparator is not relevant (indirectness)

Summary of findings for the main comparison. Moxifloxacin compared to amoxicillin‐clavulanate for NSTI

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Summary of findings 2. AB103 compared to placebo for NSTI

AB103 compared to Placebo for NSTI
Patient or population: NSTI Setting: hospital Intervention: AB103 Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality/certainty of the evidence (GRADE)	Comments
	Risk with Placebo	Risk with AB103
Mortality follow‐up: 30 days	Study population		RR 0.34 (0.05 to 2.16)	43 (1 RCT)	⊕⊝⊝⊝ Very low^a	—
	23 per 100*	6 per 100 (1 to 39)
Serious adverse events (SAE) follow‐up: 28 days	Study population		RR 1.49 (0.52 to 4.27)	43 (1 RCT)	⊕⊝⊝⊝ Very low^a	There were no data about the nature of serious adverse events reported
	27 per 100	41 per 100 (14 to 100)
Survival time	—	—	—	—	—	Not reported
Assessment of long‐term morbidity	—	—	—	—	—	Not reported
*The risk in the intervention group (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). Assumed risk for mortality was based on data of the literature (Audureau 2017; May 2009). For serious adverse effects it was based on the results of the trial. CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality/certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality/certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality/certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality/certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aDowngraded by three levels: one level for high risk of attrition bias, one level for no clear clinical definition of criteria for necrotizing fasciitis diagnosis at inclusion (indirectness), and one level for serious imprecision because of small sample size and CI included no difference

Summary of findings 2. AB103 compared to placebo for NSTI

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Summary of findings 3. Intravenous immunoglobulin compared to placebo for NSTI

Intravenous immunoglobulin compared to placebo for NSTI
Patient or population: NSTI Setting: intensive care unit Intervention: intravenous immunoglobulin Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality/Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with Intravenous immunoglobulin
Mortality follow‐up: 30 days	Study population		RR 1.17 (0.42 to 3.23)	100 (1 RCT)	⊕⊕⊝⊝ Low^a	—
	0 per 100	0 per 100 (0 to 0)
	Moderate
	23 per* 100	21 per 100 (8 to 58)
Serious adverse events (SAE) follow‐up: unclear	Study population		RR 0.73 (0.32 to 1.65)	100 (1 RCT)	⊕⊕⊝⊝ Low^a	Serious adverse reactions included acute kidney injury, allergic reactions, aseptic meningitis syndrome, haemolytic anaemia, thrombi, and transmissible agents
	22 per 100	16 per 100 (7 to 36)
Survival time	—	—	—	100 (1 RCT)	⊕⊕⊝⊝ Low^a	The median time of death was shorter in the IVIG group than in the placebo group (25 days versus 49 days) (not possible to calculate hazard ratio with the data provided)
Assessment of long‐term morbidity	—	—	—	—	—	Not reported
*The risk in the intervention group (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). Assumed risk for mortality was based on data of the literature (Audureau 2017; May 2009). For serious adverse effects it was based on the results of the trial. CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality/certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality/certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality/certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality/certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aDowngraded by two levels: one level for high risk of attrition bias (38% lost of follow‐up); other bias: imbalance at baseline for one dose 25 IVIG received before randomisation (40% in placebo group vs 16% IVIG group). One level for indirectness as a minority of patients have an infection linked to bacteria producing toxins

Summary of findings 3. Intravenous immunoglobulin compared to placebo for NSTI

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Table 1. Glossary of terms used

Term used	Explanation
Adjuvant treatment	Treatment that is given in addition to the primary or initial therapy to improve its effectiveness
Empiric antimicrobial therapy	Antimicrobial therapy given before the specific bacteria causing an infection is known
Aseptic meningitis	Serious inflammation of the linings of the brain not caused by pyogenic bacteria
Empiric antibiotic therapy	Antibiotics that acts against a wide range of bacteria
Bullae	Blisters on the skin usually more than 5 mm in diameters
Cirrhosis	Advanced liver disease
Crepitus	Clinical signs characterised by a peculiar sound under the skin
Debridement	Surgery excision of necrotic tissues (medical removal of dead, damaged, or infected tissue)
Endotoxin	A toxin contained in bacteria that is released only when the bacteria are broken down
Exotoxin	A toxin that is secreted by bacteria into the surrounding medium
Fascia	A fibrous connective tissue that surrounds muscle and other soft tissue. Fasciae are classified according to their distinct layers and their anatomical location: superficial fascia and deep (muscle) fascia
Fulminant inflammatory response	Systemic inflammatory response
Gram‐negative bacteria	Class of bacteria gram‐negative staining
Haemolytic anaemia	Decrease in the total amount of red blood cells due to the abnormal breakdown of red blood cells
Hyperbaric oxygen therapy	Medical use of oxygen at a level higher than atmospheric pressure. This helps fight bacteria and infection
Hypoxia	Insufficient levels of oxygen in blood or tissue
Intravenous immunoglobulin (IVIG)	Administration of antibodies through the veins
Motricity	Strength in upper and lower extremities after disease
Morbidity	Disability or degree that the health condition affects the patient
Mortality	Death rate
MRSA	Methicillin‐resistant Staphylococcus aureus
Myonecrosis	The destruction or death of muscle tissue
Necrosis	Death of body tissue
Obliterating endarteritis	Severe proliferating endarteritis (inflammation of the inner lining of an artery) that results in an occlusion of the lumen (the space inside a tubular structure) of the smaller vessels
Person‐years	Unit of measurement used to estimate rate of a disease during a defined period of observation
Polymicrobial	Polymicrobial infection is caused by several species of micro‐organisms
Subcutaneous tissue	Layer of tissue below the epidermis and the dermis of the skin. It is also called the hypodermis
Synergistic combination	Additive effects of bacterial agents
Synergistic gangrenes	Necrotizing soft tissue infection caused by a mix of bacteria (usually a mix of anaerobic and aerobic micro‐organisms)
Systemic	Affecting the entire body
Third‐generation quinolones	The quinolones are a family of synthetic broad‐spectrum antibiotic drugs
Thrombi	A blood clot inside a blood vessel
Transmissible agents	Infectious pathogens that can be transmitted
Vasopressors	Any medication that induces vasoconstriction of blood vessels to raise reduced blood pressure
Vimentin	A protein, the expression of which is increased after skeletal muscle injury

Table 1. Glossary of terms used

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Table 2. Incidence of necrotizing fasciitis

Incidence of necrotizing fasciitis
Authors	Period of study	Country	Pathology	Incidence
Kaul R et al (Kaul 1997)	1991	Canada	GAS NF	0.085 per 100,000 p‐y
Kaul R et al (Kaul 1997)	1995	Canada	GAS NF	0.4 per 100,000 p‐y
Ellis Simonsen et al (Ellis Simonsen 2006)	January 1997 to December 2002	United States	NF	0.04 per 1000 p‐y
O'Grady et al (O'Grady 2007)	March 2002 to August 2004	Australia	IGAS	2.7 per 100,000 p‐y (10.9% of NF)
Lamagni et al (Lamagni 2008)	January 2003 to December 2004	Europe	IGAS	2.37 per 100,000 p‐y (8% of NF)
Lepoutre et al (Lepoutre 2011)	November 2006 to November 2007	France	IGAS	3.1 per 100,000 p‐y (18% of NF)
GAS NF:group A streptococcal necrotizing fasciitis; IGAS: invasive group A streptococcal disease; NF: necrotizing fasciitis; p‐y: person‐years

Table 2. Incidence of necrotizing fasciitis

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Table 3. Details of contacting authors

Study	Contact	Requested information	Contacted	Reply (last check 23 April 2017)
Darenberg 2003 (awaiting classification study)	Dr Norrby‐Teglund	Outcomes in the specific subgroup of patients with NSTI: ‐Mortality at day 30, ‐Proportion of patients with serious adverse events ‐Survival time ‐Patients with alteration of 25% of Functional Impairment Scale (%)	July 28, 2015 September 07, 2015	No response
Tally 1986 (awaiting classification study)	Dr Kellum	Outcomes in the specific subgroup of patients with NSTI: ‐Mortality at day 30, ‐Proportion of patients with serious adverse events ‐Survival time ‐Patients with alteration of 25% of Functional Impairment Scale (%)	July 24, 2015 September 07, 2015	No response
Vick‐Fragoso 2009 (included study)	Dr Bogner, Dr Petri	Outcomes in the specific subgroup of patients with NSTI: ‐Mortality at day 30, ‐Proportion of patients with serious adverse events ‐Survival time ‐Patients with alteration of 25% of Functional Impairment Scale (%)	September 07, 2015	Additional data to the publication provided for mortality, proportion of patients with serious adverse events and survival time. Outcome data for assessment of long term morbidity not provide
Bulger 2014 (included study)	Dr Bulger	Outcomes: ‐Survival time ‐Patients with alteration of 25% of Functional Impairment Scale (%)	September 07, 2015 September 09, 2015	Outcome data not provided

Table 3. Details of contacting authors

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Comparison 1. Moxifloxacin versus amoxicillin‐clavulanate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality within 30 days Show forest plot	1	54	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.39, 23.07]

2 Proportion of patients who experienced serious adverse events Show forest plot	1	54	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.30, 1.31]

Comparison 1. Moxifloxacin versus amoxicillin‐clavulanate

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Comparison 2. AB 103 versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality within 30 days Show forest plot	1	43	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.05, 2.16]

2 Proportion of patients who experienced serious adverse events Show forest plot	1	43	Risk Ratio (M‐H, Random, 95% CI)	1.49 [0.52, 4.27]

Comparison 2. AB 103 versus placebo

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Comparison 3. IGIV versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality within 30 days Show forest plot	1	100	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.42, 3.23]

2 Proportion of patients who experienced serious adverse events Show forest plot	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.32, 1.65]

Comparison 3. IGIV versus placebo

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