: Resistance to clindamycin (ClinR) and erythromycin (ErmR) is increasing in group A streptococcal (GAS) strains causing invasive disease and other protein synthesis inhibitor antibiotics are urgently needed. Tedizolid (Tzd) is a newer oxazolidinone with improved potency and safety over the first drug in this class, linezolid (Lzd). We compared Tzd and Lzd efficacy in experimental murine myonecrosis caused by ErmS/ClinS and ErmR/ClinR GAS.
Methods: Adult female Swiss Webster outbred mice (10/group) were infected intramuscularly with 109, 108 or 107 ErmS/ClinS GAS (ATCC 12384; M-type 3) or an ErmR/ClinR GAS from invasive human infection (VA15-003; emm type 1, ermB+). Treatments began 4 h post-infection and continued for 72 h. Saline, penicillin (Pen), Clin and Erm were given q 6 h. Tzd and Lzd (40, 20,10 mg/kg) were given q 12 h. Survival was followed for 14 d; mice were scored daily from 0-4 for severity of local infection or systemic illness.
Results: Both GAS strains were sensitive to Pen, Lzd and Tzd. ErmR/ClinR was confirmed for GAS 15-003. Blood levels of Lzd40 and Tzd40 were 30.9 ± 4.0 and 21.9 ± 5.3 ug/mL, respectively. ErmS/ClinS GAS Infection: Without treatment, ≥107 GAS was rapidly lethal. Clin and Erm significantly improved 14-d survival (60–100%). Pen was protective (90% survival) only at the 108 or 107 infection doses. Tzd and Lzd significantly delayed mortality, but 90-100% of Lzd-treated mice ultimately succumbed to 109 GAS whereas Tzd was protective. ErmR/ClinR GAS Infection: ≥108 GAS was 100% lethal in saline-, Clin- and Erm-treated mice by 50 h; 107 GAS was not uniformly lethal and was not studied further. Lzd significantly delayed mortality, but protection (50% survival) was afforded only to mice infected with 108 GAS who received Lzd40. Survivals of Tzd40, 20, 10-treated mice infected with 109 or 108 GAS were 30-70% and 80%, respectively, while 90% of all Pen-treated mice survived. The 14-d mean infection severity scores in Pen- vs Tzd40-treated mice infected with 108 GAS were .46 vs 1.98.
Conclusion: Tzd is markedly superior to Lzd for the treatment of experimental GAS myonecrosis, including that caused by ErmR/ClinR GAS. Penicillin’s unexpected efficacy against ErmR/ClinR GAS requires further study but may be related to strain-specific differences in exotoxin profile or penicillin-binding protein expression.