Updates and Controversies in Necrotizing Soft Tissue Infections

The morbidity and mortality in patients with necrotizing soft tissue infections (NSTIs) remain high, with about one-fifth of patients experiencing amputation or death.¹ Although the mortality rate of patients with NSTIs decreased from 28.3% before 2000 to 20.6% after 2000 across data from 109 studies, the past 20 years have not seen further improvements.¹ Many of the available data on NSTIs come from observational studies and their meta-analyses. An April 2018 Cochrane Review identified only 3 randomized controlled trials evaluating medical or surgical treatments for NSTIs, with fewer than 200 patients enrolled between them.² The slow development of new evidence is partly due to the infrequency of NSTIs, whose published estimated incidence ranges from 0.2 to 6.9 per 100,000 person-years.³ Given the rarity of NSTIs and limitations of the current evidence for treatment, a recent review proposed NSTIs to be “a major neglected worldwide disease.”³ This article highlights recent updates and controversies in the field, focusing on changes in microbiology, antimicrobial resistance patterns, and adjunctive antitoxin treatments.

UPDATES IN THE MICROBIOLOGY OF NSTIS
The microbiology of NSTIs can be divided into 4 broad categories: type 1 (polymicrobial with gram positives, gram negatives, and anaerobes), type 2 (monomicrobial from group A Streptococcus [GAS] or Staphylococcus aureus), type 3 (other monomicrobial infections, eg, due to Vibrio, Aeromonas, or Clostridium species), and type 4 ( fungal pathogens, eg, Candida and Mucorales species).³ Globally, most NSTIs are polymicrobial, followed by monomicrobial due to GAS or S aureus, with a pooled prevalence of 53% and 38%, respectively. ⁴ In the United States and Canada, the predominant pathogens are S aureus (20.8%) and GAS (18.3%).⁴ From 1990 to 2020, the prevalence of monomicrobial NSTIs has increased by 1.1% annually.⁴ Monomicrobial NSTI is more common among infections of the extremities, whereas polymicrobial NSTI is associated with Fournier gangrene.⁴ Clostridial and fungal NSTIs are rare, representing 4.1% and 4.6%, respectively, of NSTIs.⁴ Although uncommon, monomicrobial Enterobacterales NSTIs have a dire prognosis, with reported mortality rates exceeding 70%.⁵ Among GAS infections, increasing resistance to clindamycin threatens further use of this first-line antitoxin agent for NSTI. Within the United States, invasive GAS clindamycin resistance has increased drastically in the last few years, from 8.9% in 2011 to 29.2% in 2020.⁶ Clindamycin resistance among GAS infections appears to be a highly local phenomenon, with results of a recent study from China finding 94.2% resistance to clindamycin among GAS isolates.⁷ Clindamycin resistance is also increasingly common in non-GAS β-hemolytic streptococci (BHS). For group B streptococci (GBS), 36.8% of isolates were resistant to clindamycin in 2011 compared with 47.1% in 2020 in the United States.⁶ Fortunately, GAS and GBS remain 100% susceptible to penicillin. ⁶ However, the rise of clindamycin resistance in GAS has led some clinicians to question whether clindamycin should remain the first-line antitoxin for GAS NSTI.

IN GAS NSTI, SHOULD CLINDAMYCIN OR LINEZOLID BE THE PREFERRED ADJUNCTIVE ANTITOXIN ANTIBIOTIC?
The 2014 Infectious Diseases Society of America guidelines for skin and soft tissue infections recommend the combination of penicillin and clindamycin for GAS NSTI.⁸ However, with the subsequent rise of clindamycin-resistant GAS, this regimen may no longer be the preferred therapy. We recently published a debate on the merits of clindamycin vs linezolid as the adjunctive antitoxin antibiotic of choice, which serves as the foundation for this discussion.⁹ The primary advantage of clindamycin is its more substantial evidence base, as data from a meta-analysis of 8 retrospective studies demonstrated an odds ratio of 0.45 (95% CI, 0.27-0.78) for reduced mortality with use of clindamycin compared with no clindamycin, albeit these studies occurred in geographic areas and time periods in which clindamycin resistance was scarce.⁹ Given that penicillin remains 100% susceptible to GAS and that clindamycin appears to retain antitoxin activity even to clindamycin-resistant GAS isolates in in vivo murine models, it is unclear what effect clindamycin resistance has when clindamycin is combined with penicillin.¹⁰ However, findings from 1 study showed that clindamycin-resistant BHS NSTI was associated with a higher risk of amputation, which is concerning.¹¹

Linezolid offers several potential advantages to clindamycin for GAS NSTI. First, 100% of GAS isolates remain susceptible to linezolid.¹² Second, linezolid and clindamycin have similar antitoxin effects in vitro.¹³ Third, linezolid is advantageous for stewardship reasons. Clindamycin is associated with high rates of Clostridioides difficile, whereas linezolid is not.^14,15 Linezolid also dispenses with the need for vancomycin as a third empiric agent in NSTI because it has reliable anti-methicillin-resistant S aureus (MRSA) activity, which is no longer true of clindamycin across much of the United States. Avoiding empiric vancomycin is theoretically advantageous because of the risks of acute kidney injury (AKI) with vancomycin, particularly in patients who are experiencing severe sepsis and shock and thus already at high risk for renal injury. Indeed, evidence from 1 study of NSTI showed that empiric linezolid-based regimens had a lower risk of AKI than vancomycin-based regimens.¹⁶ The major downside of linezolid is the much smaller body of clinical evidence supporting its use in GAS NSTI vs clindamycin.

In order to improve the management of GAS NSTIs, close monitoring of local clindamycin resistance among GAS isolates and prudent antimicrobial stewardship measures should be undertaken. Where clindamycin remains effective, efforts to rapidly discontinue empiric clindamycin and vancomycin when GAS and MRSA are not isolated should be pursued to minimize excess harm from these agents. Further studies should be conducted to elucidate whether clindamycin or linezolid is the best adjunctive antimicrobial, particularly in clindamycin-resistant GAS.

IS AN ADJUNCTIVE ANTITOXIN ANTIBIOTIC NECESSARY IN NON-GAS BHS NSTI?
Although the benefit of the antitoxin effect appears to be reasonably clear for GAS, less research has been performed for non-GAS BHS NSTIs. The incidence of invasive non-GAS BHS seems to be increasing, and mortality rates appear similar to those of invasive GAS infections.¹⁷ For some time, uncertainty existed about whether clindamycin would benefit these cases. Although non-GAS BHS can cause serious infections, they are less associated with NSTI and toxic shock syndromes, partly due to differences in their virulence factors compared with GAS.^17,18 Fortunately, several retrospective studies have now been performed to address whether adjunctive clindamycin is beneficial.

Data from the largest and most recent of these studies come from Japan, and showed no significant difference in mortality between patients with invasive non-GAS BHS infections who received clindamycin and those who did not (9.7% vs 10.3%; P = .86).¹⁹ Data from a Canadian study demonstrated that early administration of clindamycin in invasive GAS infections was associated with a mortality benefit, but the same benefit was not found in invasive group B, C, or G streptococcal infections.¹⁷ Finally, findings from a US-based multicenter retrospective study also showed improved in-hospital mortality rates in patients with invasive GAS infections treated with clindamycin, and for those with invasive non-GAS BHS infections, receipt of clindamycin was associated with similar and possibly increased in-hospital mortality (9.8% vs 4.6%; P = .094).¹⁸ Thus, for non-GAS BHS NSTIs, the literature suggests a lack of benefit with adjunctive clindamycin. This may be due to a lack of toxins for clindamycin to target or the high rates of clindamycin resistance within these isolates. Regardless, clindamycin appears unhelpful in these situations.

CONCLUSIONS
The epidemiology and microbiology of NSTIs continues to change with increasing monomicrobial infections led by S aureus and GAS. The rapid increase in clindamycin-resistant GAS, which may prohibit further use of clindamycin as the first-line antitoxin antibiotic, is concerning. Linezolid is an attractive replacement for clindamycin in GAS NSTI, as it has antitoxin properties; resistance to linezolid among patients with GAS remains rare, and linezolid has associated antimicrobial stewardship benefits such as reduced C difficile risk and decreased vancomycin utilization. However, the data from GAS should not be extrapolated to non-GAS BHS infections, as data from several studies demonstrate no benefit with clindamycin. Although much debate about adjunctive antimicrobial therapies persists, a clear cornerstone of NSTI treatment continues to be prompt surgical management, which is associated with a nearly 50% reduction in mortality rate when surgery is performed within 6 hours compared with later.¹ Ultimately, NSTI remains an under-studied yet severe infection, and further studies are warranted to understand these nuances better.

References

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