Interventions for necrotizing soft tissue infections in adults
Necrotizing soft tissue infections (NSTIs) are severe and rapidly spreading soft tissue infections of the subcutaneous tissue, fascia, or muscle, which are mostly caused by bacteria. Associated rates of mortality and morbidity are high, with the former estimated at around 23%, and disability, sequelae, and limb loss occurring in 15% of patients. Standard management includes intravenous empiric antimicrobial therapy, early surgical debridement of necrotic tissues, intensive care support, and adjuvant therapies such as intravenous immunoglobulin (IVIG).
To assess the effects of medical and surgical treatments for necrotizing soft tissue infections (NSTIs) in adults in hospital settings.
We searched the following databases up to April 2018: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers, pharmaceutical company trial results databases, and the US Food and Drug Administration and the European Medicines Agency websites. We checked the reference lists of included studies and reviews for further references to relevant randomised controlled trials (RCTs).
RCTs conducted in hospital settings, that evaluated any medical or surgical treatment for adults with NSTI were eligible for inclusion. Eligible medical treatments included 1) comparisons between different antimicrobials or with placebo; 2) adjuvant therapies such as intravenous immunoglobulin (IGIV) therapy compared with placebo; no treatment; or other adjuvant therapies. Eligible surgical treatments included surgical debridement compared with amputation, immediate versus delayed intervention, or comparisons of number of interventions.
RCTs of hyperbaric oxygen (HBO) therapy for NSTI were ineligible because HBO is the focus of another Cochrane Review.
Data collection and analysis
We used standard methodological procedures expected by Cochrane. The primary outcome measures were 1) mortality within 30 days, and 2) proportion of participants who experience a serious adverse event. Secondary outcomes were 1) survival time, and 2) assessment of long‐term morbidity. We used GRADE to assess the quality of the evidence for each outcome.
We included three trials randomising 197 participants (62% men) who had a mean age of 55 years. One trial compared two antibiotic treatments, and two trials compared adjuvant therapies with placebo. In all trials, participants concomitantly received standard interventions, such as intravenous empiric antimicrobial therapy, surgical debridement of necrotic tissues, intensive care support, and adjuvant therapies. All trials were at risk of attrition bias and one trial was not blinded.
Moxifloxacin versus amoxicillin‐clavulanate
One trial included 54 participants who had a NSTI; it compared a third‐generation quinolone, moxifloxacin, at a dose of 400 mg given once daily, against a penicillin, amoxicillin‐clavulanate, at a dose of 3 g given three times daily for at least three days, followed by 1.5 g three times daily. Duration of treatment varied from 7 to 21 days. We are uncertain of the effects of these treatments on mortality within 30 days (risk ratio (RR) 3.00, 95% confidence interval (CI) 0.39 to 23.07) and serious adverse events at 28 days (RR 0.63, 95% CI 0.30 to 1.31) because the quality of the evidence is very low.
AB103 versus placebo
One trial of 43 randomised participants compared two doses, 0.5 mg/kg and 0.25 mg/kg, of an adjuvant drug, a CD28 antagonist receptor (AB103), with placebo. Treatment was given via infusion pump for 10 minutes before, after, or during surgery within six hours after the diagnosis of NSTI. We are uncertain of the effects of AB103 on mortality rate within 30 days (RR of 0.34, 95% CI 0.05 to 2.16) and serious adverse events measured at 28 days (RR 1.49, 95% CI 0.52 to 4.27) because the quality of the evidence is very low.
Intravenous immunoglobulin (IVIG) versus placebo
One trial of 100 randomised participants assessed IVIG as an adjuvant drug, given at a dose of 25 g/day, compared with placebo, given for three consecutive days. There may be no clear difference between IVIG and placebo in terms of mortality within 30 days (RR 1.17, 95% CI 0.42 to 3.23) (low‐certainty evidence), nor serious adverse events experienced in the intensive care unit (ICU) (RR 0.73 CI 95% 0.32 to 1.65) (low‐certainty evidence).
Serious adverse events were only described in one RCT (the IVIG versus placebo trial) and included acute kidney injury, allergic reactions, aseptic meningitis syndrome, haemolytic anaemia, thrombi, and transmissible agents.
Only one trial reported assessment of long‐term morbidity, but the outcome was not defined in the way we prespecified in our protocol. The trial used the Short Form Health Survey (SF36). Data on survival time were provided upon request for the trials comparing amoxicillin‐clavulanate versus moxifloxacin and IVIG versus placebo. However, even with data provided, it was not possible to perform survival analysis.
We found very little evidence on the effects of medical and surgical treatments for NSTI. We cannot draw conclusions regarding the relative effects of any of the interventions on 30‐day mortality or serious adverse events due to the very low quality of the evidence.
The quality of the evidence is limited by the very small number of trials, the small sample sizes, and the risks of bias in the included trials. It is important for future trials to clearly define their inclusion criteria, which will help with the applicability of future trial results to a real‐life population.
Management of NSTI participants (critically‐ill participants) is complex, involving multiple interventions; thus, observational studies and prospective registries might be a better foundation for future research, which should assess empiric antimicrobial therapy, as well as surgical debridement, along with the placebo‐controlled comparison of adjuvant therapy. Key outcomes to assess include mortality (in the acute phase of the condition) and long‐term functional outcomes, e.g. quality of life (in the chronic phase).
Camille Hua, Romain Bosc, Emilie Sbidian, Nicolas De Prost, Carolyn Hughes, Patricia Jabre, Olivier Chosidow, Laurence Le Cleach
Plain language summary
Treatments for necrotizing (i.e. destructive) soft tissue infections in adults
What is the aim of this Cochrane Review?
We wanted to find out which medicines and surgical treatments are effective and safe for treating necrotizing soft tissue infections (NSTI). NSTI are serious infections of the tissues underneath the skin, mostly caused by bacteria.
The available evidence from three studies is not strong enough to enable us to draw definite conclusions about the effectiveness and safety of the different treatments for NSTI assessed in this review. All studies assessed number of deaths and risk of serious side effects.
Factors affecting our confidence in the results included the following:
‐ the small number of trials and participants;- ‐ weaknesses in the trial methodologies which affect the reliability of results; and- ‐ poor definition of the participants’ condition.
We found no evidence that assessed antimicrobial therapy (which targets a wide range of disease‐causing bacteria and fungi) or surgical removal of damaged tissue.
In future studies, risk of death should be a key outcome in the short term (i.e. within 30 days) phase of the condition, and outcomes such as loss of work and quality of life should be assessed in the long‐term phase (after 30 days).
What was studied in the review?
We included people with NSTI. These types of infections are rare, but can become life‐threatening if left untreated, or result in amputation. NSTIs need emergency treatment, usually with antibiotics and surgical removal of the infected tissue.
We searched for studies that assessed treatments for diagnosed NSTI in hospitalised adults. This included:
‐ surgical treatments: surgical removal of damaged tissue compared with amputation, immediate versus delayed treatment, or comparison of a number of treatments;- ‐ antimicrobial medicines ‐ which kill bacteria and fungi ‐ compared with placebo (i.e. an identical but inactive treatment), or each other;- ‐ medicines given as add‐on therapies in addition to the primary treatment (adjuvant therapies) compared with placebo, no treatment, or other adjuvant therapies.
Our main outcomes of interest were death within 30 days, and any serious treatment side effects.
What are the main results of the review?
We found three studies, which enrolled 197 adults (117 men, average age = 55). The trials were conducted worldwide, funded by pharmaceutical companies; they assessed antimicrobial therapy or treatments that control the immune system.
One study compared two antibiotics: moxifloxacin and amoxicillin‐clavulanate, administered directly into a vein for seven to 21 days. It found no clear difference between the treatment groups in terms of number of deaths within 30 days, but we are uncertain about this result because it is based on very low‐certainty evidence.
One study compared placebo with a new type of treatment that controls immune response (called AB103) given in a single dose (of either 0.5 mg/kg or 0.25 mg/kg), administered directly into a vein. Participants also received standard treatment for NSTI based on antibiotics and surgical treatment, so AB103 was given as an adjuvant therapy. There was no clear difference between the treatment groups in terms of number of deaths within 30 days, but we are uncertain about this conclusion because it is based on very low‐certainty evidence.
One study compared injections of immunoglobulin (an antibody, part of the body’s immune system) with placebo. Both treatments were given for three consecutive days. Participants also received standard treatment for NSTI based on antibiotics and surgical treatment, thus immunoglobulin was given as an adjuvant therapy. There was no clear difference between the treatment groups in terms of the number of deaths within 30 days (low‐certainty evidence).
No study showed any clear difference between treatments in terms of serious side effects, but the evidence is not strong enough to confirm this. The immunoglobulin study listed the side effects encountered, which included kidney injury, allergic reactions, meningitis, blood clots, and infectious agents (low‐certainty evidence).
Only one trial reported assessment of long‐term illness but it was not defined as we had required in our in the protocol (the trial used another scale: the Short Form Health Survey (SF36). Survival time was reported in two trials (but not enough data were provided to analyse these results).
How up‐to‐date is this review?
We searched for studies published up to April 2018.
Camille Hua, Romain Bosc, Emilie Sbidian, Nicolas De Prost, Carolyn Hughes, Patricia Jabre, Olivier Chosidow, Laurence Le Cleach
Implications for practice
Management of necrotizing soft tissue infections (NSTI) is complex, involving multiples interventions: antimicrobial therapy, surgical debridement, management of organ failures, and eventually adjuvant therapies.
We found only three trials that compared the following interventions:
- moxifloxacin versus amoxicillin‐clavulanate;
- a CD28 antagonist receptor (AB103) versus placebo;
- intravenous immunoglobulin versus placebo.
We cannot make conclusions about the use of AB103, moxifloxacin, or amoxicillin‐clavulanate because results for their use were based on very low‐certainty evidence.
With regard to intravenous immunoglobulin (IVIG) compared to placebo, there may be no clear difference between the treatment groups in terms of rate of mortality at 30 days or serious adverse events.
One trial assessed long‐term morbidity but not in the way we stated that we prespecified in the protocol. Survival time was reported in two trials (but not enough data were provided to analyse these results).
We found no trials assessing other interventions, notably surgical treatment or recommended empiric intravenous antibiotic treatment.
Implications for research
This review highlights the lack of evidence for the treatment of NSTI.
Several reasons can account for the lack of comparative effectiveness research in this field.
- Management of NSTI is complex, involving multiple interventions, including antimicrobial therapy, surgical debridement, management of organ failures, and adjuvant therapies.
- After a clinical hypothesis of necrotizing fasciitis, patients underwent a urgent surgical debridement. Definite diagnosis can only be obtained during the surgical debridement phase. This mandatory and very urgent surgery may hamper the inclusion of patients in clinical trials aimed at assessing therapeutic interventions for NSTI.
- Placebo‐controlled trials in this life‐threatening disease are only feasible, from an ethical point of view, for assessing the effect of adjuvant therapies, since, in spite of the lack of evidence, neither surgical debridement nor antibiotic treatment could ethically be compared to placebo.
- NSTIs are rare and greater co‐operation between centres to obtain sufficient power for meaningful studies is needed.
We list below methodological key points following a PICO (participants, interventions, comparator and outcomes) framework that could be considered in future trials.
NSTI needs to be clearly defined in the inclusion criteria. As diagnosis of NSTI is only confirmed during surgery, it is mandatory to state how to handle included patients eventually not diagnosed as having NSTI. All patients without restriction of age or gender need to be included in order to be more representative of the affected population. Patient comorbidities, involved site and micro‐organisms are mandatory information that have to be reported
Types of study
Because designing randomised controlled trials in NSTI is challenging, observational studies and prospective registries might be valuable alternatives to evaluate the effectiveness and safety of treatments. However, their methodology should be rigorous, as they potentially rely on propensity scores analyses (Anglemyer 2014). This type of research could allow us to evaluate long‐term outcomes, such as assessment of long‐term morbidity, and deduce applicability to a large proportion of the patient population undergoing procedures in real‐world settings across the world. The three trials in this review were at risk of attrition bias; future studies should ensure they take the necessary actions to reduce dropout and loss to follow‐up.
A separate assessment of interventions involved in the management of NSTI (i.e. antimicrobial therapy, surgical treatment, and adjuvant treatment) would certainly not reflect the effect of combined interventions in a "therapeutic bundle". Thus, the use of integrated complex interventions to optimise the treatment of NSTI is needed (Delaney 2008). Examples of such complex interventions include management in referral centres with a multidisciplinary approach and an early goal‐directed therapy for surgical referral.
There was no empiric antimicrobial therapy validated by a trial. Several issues concerning antimicrobial therapy in NSTI should be considered: the duration of treatment after surgery, the antimicrobial management strategies in patients with or without comorbidities and in patients with risk factors for infections with MRSA, (methicillin‐resistant Staphylococcus aureus) and the adjustment of the treatment after microbiological results to reduce the risk of resistance. A future trial in NSTI could examine the non‐inferiority of new antimicrobials agents, compared against standard accepted treatment.
Several issues should be considered: the extent of surgical debridement, and the number of surgical debridements required (including the "second look" surgery strategy). Study interventions and treatments tested would have to be clearly defined with a standardised protocol of care. As required in trials assessing surgical procedures, a detailed description of the different components of surgical treatment, anaesthesia management, as well as peri‐operative and postoperative care should be provided (Blencowe 2015; Boutron 2008).
Other adjuvant therapies using immunomodulator treatments (e.g. AB103) should be assessed in placebo‐controlled trials. The control group should receive current practice management based on guidelines and observational studies (Delaney 2008).
In the absence of consensual core outcome measures:
- in the acute phase, mortality at a disease time point seems to be the most appropriate outcome criteria for this critical care disease (Delaney 2008); and
- in the chronic phase, outcomes such as evaluation of loss of work, duration of unemployment, and level of distress needs to be evaluated. Development of validated functional assessment tools is required to assess long‐term functional outcomes, reintegration into society, and quality of life in survivors of NSTI.