Clindamycin Improves Outcomes in Necrotizing Fasciitis Due to Group A Streptococcus
By Richard R. Watkins, MD, MS, FACP, FIDSA
Associate Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH
Dr. Watkins reports that he has received research support from Allergan.
SYNOPSIS: Using a murine model of necrotizing fasciitis, investigators determined that clindamycin inhibits key virulence factors of Group A Streptococcus, and should be given as soon as possible and at high doses to reach levels above MIC in affected tissues.
SOURCE: Andreoni F, Zurcher C, Tarnutzer A, et al. Clindamycin affects Group A Streptococcus virulence factors and improves clinical outcome. J Infect Dis 2017;215:269-277.
Despite aggressive surgical and medical therapy (i.e., debridement and potent intravenous antibiotics), necrotizing fasciitis (NF) remains a devastating infection with a mortality rate of 15- 36%. Recent Infectious Diseases Society of America (IDSA) guidelines recommend using clindamycin in the treatment of NF, although strong scientific evidence is lacking.1 Therefore, Andreoni and colleagues aimed to determine whether clindamycin improves outcomes in NF by modulating virulence factors of clindamycin-susceptible and clindamycin-resistant strains of invasive Group A Streptococcus (GAS) in vitro and using a mouse model.
The investigators injected either a clindamycin-susceptible or a clindamycin-resistant GAS clinical isolate into the flanks of mice, and then treated them with either low-dose clindamycin, high-dose clindamycin, or saline. The mice were sacrificed on day 3 post-inoculation, and the size of the resulting skin lesions and their bacterial counts were measured. Also, biopsy material from a patient with NF of the arm who underwent multiple debridements (on days 0, 2, and 4) was prepared in the same fashion as the mouse tissue. This patient was treated with intravenous ceftriaxone 2 g daily and clindamycin 900 mg qid.
Treatment with clindamycin in the mice that were infected with clindamycin-susceptible strains significantly reduced skin lesion sizes, but the bacterial burden was the same compared to the untreated animals. Interestingly, the animals infected with clindamycin-resistant strains who received clindamycin also had smaller skin lesions but reduced bacterial counts. When mice were injected with a clindamycin dose lower than the MIC of the infecting strain, the severity of the clinical manifestations was similar or slightly less compared to the untreated ones. In both the clindamycin-susceptible and clindamycin-resistant groups, GAS virulence factors DNase and SLO were inhibited by clindamycin. However, the in vitro model showed sub-inhibitory clindamycin concentrations caused upregulation of GAS virulence factors in both the clindamycin-susceptible and clindamycin-resistant GAS isolates. In the debrided tissue from the patient with NF, clindamycin concentration in the necrotic tissue was 10 times higher than the MIC of the infecting GAS strain. The bacterial load in the necrotic tissue was 106 CFU/g compared to 103 in the apparently adjacent healthy tissue. DNase activity was greater in the tissue with the higher bacterial counts and, by the second debridement (day 2), was undetectable.
COMMENTARY
The use of clindamycin in the treatment of NF was endorsed by many experts long before the publication of the IDSA guidelines in 2014. Yet, data to support this practice have been sparse. The paper by Andreoni and colleagues now provides a scientific basis for the role of clindamycin in NF. The finding that clindamycin was beneficial even for infections caused by clindamycin-resistant strains is surprising. Most likely it was due to the virulence factor-inhibiting properties of clindamycin rather than a directly lethal effect on the GAS. However, further experiments to confirm this observation are warranted. The finding that sub-inhibitory concentrations of clindamycin led to increased virulence factor activity is more challenging to explain. The investigators hypothesized that one particular virulence factor, streptococcal pyrogenic exotoxin B (SpeB), is downregulated by sub-inhibitory clindamycin concentrations, leading to reduced SpeB-mediated cleavage of other virulence factors, thus increasing their activity. This is another topic that needs further investigation.
The main limitation to the study is that it was conducted mainly using a mouse model, although the investigators reported results from one patient. Also, the dose of clindamycin was higher (900 mg qid) than the recommended dose in the guidelines (600-900 mg IV q8h).1 Given the finding that sub-inhibitory concentrations may lead to an increase in certain virulence factors, further studies on clindamycin dosing in NF are needed.
This study lends support to the current recommendation for NF that clindamycin be used in combination with a β-lactam agent and prompt debridement to achieve the best clinical outcome. Furthermore, we now have evidence that high-dose clindamycin still should be given, even when the GAS is resistant to it.
REFERENCE
- Stevens DL, Bisno AL, Chambers HF, et al; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis 2014;59:e10-52.
Using a murine model of necrotizing fasciitis, investigators determined that clindamycin inhibits key virulence factors of Group A Streptococcus, and should be given as soon as possible and at high doses to reach levels above MIC in affected tissues.
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