Dear Editor,

Linezolid is a treatment option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia; however, its use is restricted due to toxic effects and resistance induction [1^-4]. Delpazolid (LCB01-0371) is a novel, second-generation oxazolidinone analog developed by LegoChem Biosciences Inc. (Daejeon, Korea). It has shown excellent in-vitro and in-vivo antibacterial activity against S. aureus and enterococci and has high water solubility and favorable absorption, distribution, metabolism, excretion, toxicity, and pharmacokinetic profiles [5^-7]. No studies have compared the in-vitro anti-MRSA activity of delpazolid with that of other anti-MRSA agents against MRSA bloodstream isolates. We assessed the efficacy of delpazolid and three comparators (vancomycin, daptomycin, and linezolid) against a panel of nosocomial MRSA bloodstream isolates using the broth microdilution method.

In February 2022, 100 MRSA isolates were evaluated in Seongnam, Korea. Twenty bloodstream isolates were selected yearly during 2017-2021 from a tertiary hospital in Korea. The sample size was determined using a single population proportion formula: n=(z²×P(1-P)/d²). It was assumed that 95% of MRSA isolates were susceptible to anti-MRSA agents (P=0.95), and a 95% confidence interval (z=1.96) and 5% marginal error (d=0.05) were applied. The calculated sample size was 73, but the final sample size was flexibly set to 100. All isolates were resistant to oxacillin and tested positive for the mecA gene by PCR. They were stored at –80°C in Microbank vials (Pro-Lab Diagnostics Inc., Richmond Hill, Canada). The Institutional Review Board of Seoul National University Bundang Hospital exempted the research from review as anonymous bacterial isolates were used and also waived informed consent.

The minimum inhibitory concentrations (MICs) of delpazolid and the comparators were measured by two-fold serial broth microdilution in accordance with CLSI standards [8]. Briefly, a bacterial suspension of 0.5 McFarland standard in cation-adjusted Mueller–Hinton broth was prepared and transferred into a 96-well microtiter plate at a final bacterial load of 10⁵ colony-forming units/mL. For daptomycin testing, 50 µg/mL of calcium chloride was added. All drugs were tested at concentrations ranging from 0.015 μg/mL to 32 μg/mL. The plates were incubated at 37°C for 24 hours. MICs were determined in duplicate. S. aureus ATCC 29213 was tested for QC on the test day, and the results for vancomycin, daptomycin, and linezolid fell within the CLSI-approved ranges. Correlations between MICs of each isolate for two different antimicrobial agents were evaluated using the Spearman rank-order correlation coefficient computed with R (version 4.2.1; R Foundation for Statistical Computing, Vienna, Austria).

For all isolates, the duplicate MIC measurements were identical. The MIC values showed that all isolates were susceptible to vancomycin, daptomycin, and linezolid, except for five isolates resistant to daptomycin (MIC=2 µg/mL). For delpazolid, as for linezolid, the MIC50 value was 1 µg/mL, and the MIC90 value was 2 µg/mL. Vancomycin and daptomycin were more effective than linezolid and delpazolid, with lower MIC90 values (1 µg/mL) and a higher cumulative percentage of MICs up to 1 µg/mL (≥95%). Delpazolid had a greater cumulative percentage of MICs up to 1 µg/mL than linezolid (74% vs. 52%; Table 1).

Table 1 . In-vitro activity of delpazolid and comparator antimicrobial agents against methicillin-resistant Staphylococcus aureus bloodstream isolates

Antimicrobial agent	N (cumulative %) of isolates inhibited at MIC (μg/mL) of					MIC50	MIC90	% Susceptible
	≤0.25	0.5	1	2	>2
Vancomycin	0 (0)	15 (15)	83 (98)	2 (100)	0 (100)	1	1	100
Daptomycin	0 (0)	2 (2)	93 (95)	5 (100)	0 (100)	1	1	95
Linezolid	0 (0)	0 (0)	52 (52)	48 (100)	0 (100)	1	2	100
Delpazolid	0 (0)	2 (2)	72 (74)	26 (100)	0 (100)	1	2	N/A

Abbreviations: MIC, minimum inhibitory concentration; N/A, not available.

There was a significant correlation between the MICs of vancomycin, daptomycin, and linezolid for MRSA bloodstream isolates and their potency differences with delpazolid (Fig. 1). As shown in Fig. 1A, delpazolid and vancomycin had the same potency in 60% of MRSA isolates, whereas delpazolid exhibited half the potency of vancomycin in 34% of MRSA isolates. The correlation between delpazolid potency differences and vancomycin MICs was moderately positive (r=0.59, P<0.001). In comparison to daptomycin, delpazolid was equally effective against 70% of MRSA isolates and half as effective against 24% of MRSA isolates (Fig. 1B). The correlation between delpazolid potency differences and daptomycin MICs was weak (r=0.41, P<0.001). In contrast, delpazolid demonstrated twice the activity of linezolid against 37% of MRSA isolates and the same activity against 47% of MRSA isolates (Fig. 1C). The correlation between delpazolid potency differences and linezolid MICs was the strongest among all comparators (r=0.77, P<0.001). There were no significant correlations between delpazolid MICs and comparator MICs (data not shown).

Figure 1. Pairwise comparisons of antimicrobial activities for all MRSA isolates. Delpazolid potency differences with (A) vancomycin, (B) daptomycin, and (C) linezolid.
Abbreviations: MRSA, methicillin-resistant Staphylococcus aureus; MIC, minimum inhibitory concentration.

Our study is the first to compare delpazolid with other MRSA-active antimicrobial agents against MRSA bloodstream isolates in vitro. In vitro, delpazolid was more effective against MRSA bloodstream isolates than linezolid. This finding warrants further clinical research on the use of delpazolid for MRSA infections.

None.

Kim HB conceived the presented idea. Choi YJ and Kwon K collected and identified clinical isolates and performed antimicrobial susceptibility testing. Park JS analyzed the data and wrote and edited the manuscript. Choi SJ, Moon SM, Song KH, and Kim ES verified the data and reviewed the manuscript. Park KU supervised the study. All authors discussed the results and contributed to and approved the final manuscript.

None declared.

This work was supported by LegoChem Biosciences (grant No. 06-2022-0028).