By Jake Scott, MD
Clinical Assistant Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley
SYNOPSIS: In a retrospective, single-center cohort study of patients with severe group A streptococcal infection, there was no significant difference in clinical response in those treated with adjunctive clindamycin as compared with adjunctive linezolid.
SOURCE: Heil EL, Kaur H, Atalla A, et al. Comparison of adjuvant clindamycin versus linezolid for severe invasive group A streptococcal skin and soft tissue infections. Open Forum Infect Dis 2023; Nov 24:ofad588.
Heil and colleagues conducted a retrospective, single-center cohort study of patients with microbiologically confirmed severe invasive group A streptococcal (GAS) skin and soft tissue infections that compared the use of adjuvant clindamycin vs. linezolid.1 The study included adult patients admitted to the University of Maryland Medical Center between January 2017 and March 2023 with invasive GAS soft tissue infection or necrotizing fasciitis. All patients had GAS isolated from a normally sterile site, such as blood, other sterile fluid, or tissue; underwent surgical debridement of their infection; and received either clindamycin or linezolid for at least 48 hours as adjunctive therapy. Patients who had received both clindamycin and linezolid for more than one dose were excluded.
The primary outcome of the study was the relative change in Sequential Organ Failure Assessment (SOFA) score over the first 72 hours following hospital admission. Secondary outcomes measured included inpatient mortality, duration of vasopressor requirement, intensive care unit (ICU) length of stay, ventilator days, hospital length of stay, adverse drug events attributed to clindamycin or linezolid, and rates of clindamycin resistance. Since susceptibilities for GAS were not routinely performed, a post-hoc evaluation was performed on a limited number of isolates available in the institution’s biorepository.
Out of 221 patients with microbiologically confirmed GAS infections during the study period, a total of 55 patients were included in the analysis (26 patients treated with adjunctive clindamycin and 29 treated with adjunctive linezolid). There were no statistically significant differences between baseline characteristics. The mean age was 50 years and 69% were male (61.5% in the clindamycin group and 75.9% in the linezolid group). Seventeen out of 26 (35.4%) in the clindamycin group and 14 out of 29 (48.3%) in the linezolid group had been transferred from an outside facility. Median baseline SOFA scores were 5 in the clindamycin group (interquartile range [IQR], 2-8) vs. 2 in the linezolid group (IQR, 1-5) (P = 0.08). Median baseline Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) scores were 7 in the clindamycin group (IQR, 4-9) and 8 in the linezolid group (IQR, 5-9). A slightly higher percentage of patients in the linezolid group had diabetes, chronic kidney disease, and peripheral vascular disease at baseline. Two patients in both groups were considered to be immunocompromised. Twenty-seven out of the 55 patients (49.1%) had polymicrobial infections (12 of 26 [46.2%] in the clindamycin group and 15 of 29 [51.7%] in the linezolid group).
In addition to GAS, methicillin-resistant Staphylococcus aureus (MRSA) was isolated from clinical cultures in four of 26 (15.4%) in the clindamycin group and seven of 29 (24.1%) in the linezolid group. The median duration of adjunctive clindamycin therapy was 2.7 days (IQR, 2.3-4.3) compared to 3.5 days (IQR, 2-5-5.5) of adjunctive linezolid therapy (P = 0.4). The median time from admission to first surgery was 4.6 hours for all patients (IQR, 2.0-16.0) and was 6.0 hours for the clindamycin group (IQR, 1.7-18.0) and 4.0 hours for the linezolid group (IQR, 2.0-14.5) (P = 0.7).
After adjusting for the time to first surgery among patients with a baseline SOFA score greater than 0 (n = 23 in both groups), there was no statistically significant difference between the two groups in the relative change in SOFA score over the first 72 hours after admission. The relative change in SOFA score was similar between groups at each measured 12-hour interval. There was a 61.4% drop in SOFA score from baseline to 72 hours post-admission in the clindamycin group compared to a 48.4% drop in the linezolid group (P = 0.4). Similarly, there were no significant differences in secondary outcomes between groups. Three patients (5.5%) died during their hospital admission, two of 26 (7.7%) in the clindamycin group and one of 29 (3.4%) in the linezolid group (P = 0.6). The median amount of time requiring vasopressors was similar in both groups (42.1 hours [IQR, 22.5-66.8] in the clindamycin group and 39.1 hours [IQR, 30.0-151.2] in the linezolid group). The median ICU length of stay was 8.2 days (IQR, 3.0-13.0) in the clindamycin group and 9.5 days (IQR, 2.3-16.8) in the linezolid group (P = 0.6), and the median hospital length of stay was 14 days (IQR, 9-31) and 10 days (IQR, 8-20), respectively (P = 0.05). One patient in each group developed Clostridioides difficile infection (CDI) during their admissions. Antimicrobial susceptibilities were performed on 17 GAS isolates that were identified in the biorepository, one of which was resistant to clindamycin. There was no resistance to linezolid.
COMMENTARY
GAS, also known as Streptococcus pyogenes, causes a wide array of infections, ranging from pharyngitis and non-necrotizing skin and soft tissue infection to invasive infections, which are less common and include necrotizing soft tissue infections, bacteremia, and toxic shock syndrome (TSS). Invasive GAS infection is associated with significant morbidity and mortality rates, with case-fatality rates of approximately 12% overall and 29% for necrotizing fasciitis, 38% for TSS, and 45% for septic shock, according to one study.2 Rates of invasive GAS recently have been reported with increasing frequency in Europe.3 GAS has a number of particular virulence factors and clinical manifestations that are the result of a complex interplay between streptococcal and host factors. Severe GAS infections are mediated in part by M protein and by streptococcal superantigens, which are extracellular protein toxins that can trigger an overstimulation of the host inflammatory response and cause systemic toxicity, tissue necrosis, multi-organ failure, and shock.4
The successful management of invasive GAS infections generally requires a combination of prompt and aggressive source control with surgical exploration and debridement, supportive care, and antimicrobial therapy. Prior to confirming the diagnosis of GAS infection, an empirical broad-spectrum antimicrobial regimen typically is preferred, followed by targeted therapy consisting of a beta-lactam antimicrobial such as penicillin or ceftriaxone.5 Antimicrobial therapy also should include an adjunctive bacterial synthesis inhibitor, such as clindamycin, which has been shown to suppress exotoxin and M protein produced by GAS in in vitro studies, and which also has been associated with decreased mortality, even in patients without shock or necrotizing fasciitis.6,7 In addition, unlike beta-lactam agents, the mechanism of action of clindamycin is not dependent on the physiologic state of the organism.8 However, rates of clindamycin resistance among gram-positive organisms, including beta-hemolytic streptococci and Staphylococcus aureus, have been steadily increasing; among GAS, rates of resistance climbed to 24% in the United States as of 2018.9 Furthermore, clindamycin use is associated with a significantly increased risk of CDI; in a recent case-control study, clindamycin use was associated with the greatest overall level of risk for community-associated CDI (adjusted odds ratio, 25.39; 95% confidence interval, 24.11 to 26.72) as compared with other agents.10
Linezolid is similar to clindamycin mechanistically in that it inhibits protein synthesis by binding to the 50S ribosomal subunit, and it also has been shown to significantly suppress the release of streptococcal exotoxin.6,11 Linezolid has maintained high levels of in vitro activity against most clinically important gram-positive organisms, including S. aureus and GAS, and it is associated with a significantly lower risk of CDI than clindamycin.10,12 For these reasons, linezolid is increasingly appealing as an alternative for adjunctive treatment of severe GAS infections.
Prior to the study by Heil and colleagues, published clinical data pertaining to the use of adjunctive linezolid for GAS infections were limited to a single case report and a retrospective, single-center, quasi-experimental, cohort study of patients with necrotizing soft tissue infections not specific to GAS.13,14 In this study, Dorazio and colleagues evaluated clinical outcomes at their hospital before and after an institutional change in management guidelines that recommended linezolid in place of clindamycin and vancomycin for necrotizing soft tissue infections, in combination with standard gram-negative and anaerobic therapy, and they found no difference in the primary outcome of 30-day mortality. Patients with confirmed GAS only made up a small subgroup, however; five patients in the pre-intervention and three patients in the post-intervention group had culture-positive invasive GAS infections. Therefore, conclusions about the clinical effect of antimicrobial choice on GAS infection were limited. Although the study by Heil and colleagues is relatively small (n = 55), it is the largest study to date comparing clinical outcomes among patients treated with clindamycin and linezolid for GAS. Since it was a retrospective study with potential for residual confounding, prospective, randomized studies are needed.
In summary, in the current era of increasing clindamycin resistance and the higher risk of CDI associated with clindamycin, linezolid is a promising alternative for adjunctive therapy in patients with invasive GAS.
REFERENCES
- Heil EL, Kaur H, Atalla A, et al. Comparison of adjuvant clindamycin versus linezolid for severe invasive group A streptococcal skin and soft tissue infections. Open Forum Infect Dis 2023; Nov 24:ofad588
- Nelson GE, Pondo T, Toews KA, et al. Epidemiology of invasive group A streptococcal infections in the United States, 2005-2012. Clin Infect Dis 2016;63:478-486.
- Mohapatra RK, Kutikuppala LVS, Mishra S, et al. Rising global incidence of invasive group A streptococcus infection and scarlet fever in the COVID-19 era — our knowledge thus far. Int J Surg 2023;109:639-640.
- Walker MJ, Barnett TC, McArthur JD, et al. Disease manifestations and pathogenic mechanisms of group A Streptococcus. Clin Microbiol Rev 2014;27:264-301.
- 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:e10-e52.
- 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;47:1752-1755.
- 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;21:697-710.
- Stevens DL, Gibbons AE, Bergstrom R, Winn V. The Eagle effect revisited: Efficacy of clindamycin, erythromycin, and penicillin in the treatment of streptococcal myositis. J Infect Dis 1988;158:23-28.
- White BP, Siegrist EA. Increasing clindamycin resistance in group A streptococcus. Lancet Infect Dis 2021;21:1208-1209.
- Miller AC, Arakkal AT, Sewell DK, et al. Comparison of different antibiotics and the risk for community-associated Clostridioides difficile infection: A case-control study. Open Forum Infect Dis 2023;10:ofad413.
- Swaney SM, Aoki H, Ganoza MC, Shinabarger DL. The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria. Antimicrob Agents Chemother 1998;42:3251-3255.
- Pfaller MA, Mendes RE, Streit JM, et al. ZAAPS Program results for 2015: An activity and spectrum analysis of linezolid using clinical isolates from medical centres in 32 countries. J Antimicrob Chemother 2017;72:3093-3099.
- Rac H, Bojikian KD, Lucar J, Barber KE. Successful treatment of necrotizing fasciitis and streptococcal toxic shock syndrome with the addition of linezolid. Case Rep Infect Dis 2017;2017:5720708.
- 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:ofad258.
