Should Linezolid Replace Clindamycin for Necrotizing Soft Tissue Infections?

Necrotizing skin and soft tissue infections (SSTIs) are considered life-threatening and require prompt surgical management in addition to antimicrobial therapy.¹ SSTI guidelines from 2014 recommend therapy containing broad gram-positive, gram-negative, and anaerobic coverage for necrotizing SSTIs. Empiric regimens often consist of vancomycin or linezolid plus piperacillin-tazobactam or a carbapenem, or they will consist of a cephalosporin plus metronidazole. Penicillin plus clindamycin is still the first-line recommendation for Group A Streptococcus (GAS) necrotizing infections.² Results from a large retrospective study found improved mortality for patients who receive clindamycin vs no toxin-suppressive agent in GAS infections.³ Although GAS retains susceptibility to penicillin, it has developed resistance to clindamycin over the past few decades.^3,4 This leads clinicians to use linezolid, which demonstrates toxin suppression activity for GAS and Staphylococcus aureus.^5,6

Investigators from the University of Pittsburgh in Pennsylvania, University of Rochester in New York, and Prisma Health Midlands in Columbia, South Carolina, conducted a retrospective, single-center, quasi-experimental study to compare outcomes of patients who received clindamycin plus vancomycin vs those of patients who received linezolid for necrotizing SSTIs.⁷ They first revised their institutional necrotizing soft tissue infection guideline to recommend that linezolid be used in place of vancomycin plus clindamycin and in combination with piperacillin-tazobactam as first-line therapy for empiric necrotizing soft tissue infections.

The preintervention period included patients who received clindamycin plus vancomycin prior to the guideline revision, and the postintervention period was once the guideline was implemented. The investigators included patients admitted between June 2018 and June 2019 (preintervention) and between May 2020 and October 2021 (postintervention). Only patients with surgical interventions for necrotizing soft tissue infections were included. Patients in the preintervention and postintervention periods were matched for analysis. The primary end point was 30-day mortality, and secondary outcomes included acute kidney injury (AKI), Clostridioides difficile infection (CDI), inpatient mortality, 60-day mortality, duration of antibiotics, admission cultures with gram-positive bacteria resistant to clindamycin or linezolid, duration of vasopressor use, time to resolution of leukocytosis, intensive care unit (ICU) and hospital length of stay, discharge to home, thrombocytopenia, or serotonin syndrome. Per the pathway in the supplemental information, linezolid was considered contraindicated in patients with a platelet count of 25,000 or more than 2 serotonergic drugs in the past 2 weeks. Patients received standard gram-negative and anaerobic coverage along with the studied regimens: aztreonam, meropenem, piperacillin-tazobactam, cefepime, and metronidazole.

There were 62 patients in the vancomycin plus clindamycin group, and 102 patients received linezolid. The average age of patients was 56 years and was similar between groups. Polymicrobial infections were common in both groups, with mixed gram-positive and mixed anaerobic infections predominating. Few patients had cultures positive for GAS or S aureus. Five patients in the clindamycin group and 1 patient in the linezolid group had cultures with positive results for gram-negative or anaerobic organisms (Acinetobacter baumannii, Pseudomonas aeruginosa, Clostridium perfringens). Rates of adequate source control were comparable between groups (92%). More patients in the clindamycin group had upper extremity infections, whereas more patients in the linezolid group had genital infections. Additionally, 77% of patients in each group had an ICU stay and 38% of patients required vasopressors.

Researchers found no difference in the rate of 30-day mortality between the preintervention and postintervention groups. More patients who received vancomycin plus clindamycin developed AKI (P = .05) or had a composite of death, AKI, or CDI (P = .02). Interestingly, CDI was not more common in the group receiving clindamycin. No patients who received linezolid developed serotonin syndrome, although 20% of patients in this group were on a serotonergic agent. This is in line with other research showing that linezolid can be safely administered to patients receiving serotonergic agents.⁸ Finally, more patients in the linezolid group were able to be discharged on an enteral regimen.

This article was timely because intravenous clindamycin recently faced a shortage in the United States. Findings from this study demonstrate the effectiveness and safety of using linezolid for necrotizing skin infections in place of clindamycin and in combination with adequate source control. Although GAS is a common cause of necrotizing fasciitis, it was infrequent in this study, making the extrapolation of these data to patients with GAS necrotizing fasciitis more challenging. Guidelines recommend penicillin plus clindamycin for GAS infections, but linezolid has activity against GAS and the ability to suppress toxin production. With growing resistance to clindamycin, linezolid may become a more popular choice among clinicians. It has the added benefit of good S aureus coverage, making it a good choice for empiric use. This helps clinicians avoid vancomycin and subsequent increase of the patient’s risk for AKI. Additionally, in this group of patients, there were no episodes of serotonin syndrome, indicating more patients can safely receive linezolid.

Highlighted Study

Dorazio J, Chiappelli AL, Shields RS, et al. Clindamycin plus vancomycin versus linezolid for treatment of necrotizing soft tissue infection. Open Forum Infect Dis. 2023;10(6):ofad258. doi:10.1093/ofid/ofad258

References

1.Nawijn F, Smeeing DPJ, Houwert RM, Leenen LPH, Hietbrink F. Time is of the essence when treating necrotizing soft tissue infections: a systematic review and meta-analysis. World J Emerg Surg. 2020;15:4. doi:10.1186/s13017-019-0286-6

2.Stevens DL, Bisno AL, Chambers HF, et al. 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(2):147-159. doi:10.1093/cid/ciu296.Babiker A, Li X, Lai YL, et al. Effectiveness of adjunctive clindamycin in β-lactam antibiotic-treated patients with invasive β-haemolytic streptococcal infections in US hospitals: a retrospective multicentre cohort study. Lancet Infect Dis. 2021;21(5):697-710. doi:10.1016/S1473-3099(20)30523-5

4.ABCs Bact Facts Interactive data dashboard. CDC. March 22, 2023. Accessed July 31, 2023. https://www.cdc.gov/abcs/bact-facts-interactive-dashboard.html

5.Campbell AJ, Dotel R, Blyth CC, Davis JS, Tong SYC, Bowen AC. Adjunctive protein synthesis inhibitor antibiotics for toxin suppression in Staphylococcus aureus infections: a systematic appraisal. J Antimicrob Chemother. 2019;74(1):1-5. doi:10.1093/jac/dky387

6.Coyle EA, Cha R, Rybak MJ. Influences of linezolid, penicillin, and clindamycin, alone and in combination, on streptococcal pyrogenic exotoxin A release. Antimicrob Agents Chemother. 2003;47(5):1752-1755. doi:10.1128/aac.47.5.1752-1755.2003

7.Dorazio J, Chiappelli AL, Shields RK, et al. Clindamycin plus vancomycin versus linezolid for treatment of necrotizing soft tissue infection. Open Forum Infect Dis. 2023;10(6):ofad258. doi:10.1093/ofid/ofad258

8.Bai AD, McKenna S, Wise H, Loeb M, Gill SS. Association of linezolid with risk of serotonin syndrome in patients receiving antidepressants. JAMA Netw Open. 2022;5(12):e2247426. doi:10.1001/jamanetworkopen.2022.47426