In Vitro Activity of Tedizolid in Comparison with Other Oral and Intravenous Agents Against a Collection of Community-Acquired Methicillin-Resistant Staphylococcus aureus (2014

Abstract

Tedizolid activity was compared with other agents with oral and intravenous formulations against community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). Tedizolid (MIC_50/90, 0.12/0.12 mg/L; 100.0% susceptible) was the most potent agent tested against CA-MRSA and subsets from adult and pediatric patients. Tedizolid minimum inhibitory concentrations (MICs) were twofold to fourfold lower than daptomycin (MIC_50/90, 0.25/0.5 mg/L; 99.9–100% susceptible) and fourfold to eightfold lower than linezolid (MIC_50/90, 1/1 mg/L; 100.0% susceptible), ceftaroline (MIC_50/90, 0.5–1/1 mg/L; 96.6–98.8% susceptible), and vancomycin (MIC_50/90, 0.5–1/1 mg/L; 100.0% susceptible) against CA-MRSA and subsets. Clindamycin resistance rates among CA-MRSA from pediatric and adult patients were 18.3–19.1% (13.4–14.2% constitutive, 4.9–6.4% inducible) and 36.2–37.6% (29.8–30.1% constitutive, 6.4–7.5% inducible), respectively. Tetracycline (90.4–96.4% susceptible) and trimethoprim–sulfamethoxazole (96.2–100.0% susceptible) were active against CA-MRSA or subsets, whereas erythromycin (83.8–89.4% nonsusceptible) and levofloxacin (50.2–70.8% nonsusceptible) had limited activities. Tedizolid had MIC_50/90 values of 0.12/0.12 mg/L against CA-MRSA showing clindamycin constitutive-resistance and recovered from adult or pediatric patients. Tedizolid had potent activities against CA-MRSA, regardless of clindamycin phenotype or patient population. Tedizolid may be considered for the treatment of ABSSSI in adults. Further studies are warranted for the clinical development in the pediatric population.

Introduction

Resistance to antibacterial agents is of great concern in adult and pediatric medicine.^1,2 Staphylococcus aureus continues to be a major cause of community-acquired (CA) and health care-associated (HA) infections, including skin and skin structure infections (SSSIs), pneumonia, bacteremia, endocarditis, osteomyelitis, prosthetic joint infections, and catheter-related infections.³ The prevalence of nosocomial infections caused by methicillin-resistant S. aureus (MRSA) has remained high in the United States in recent years.^4,5 Certainly MRSA, both CA-MRSA and HA-MRSA, complicates therapy in children and adults.^1,6,7 CA-MRSA in the United States was first identified in children in the upper Midwest region.⁸ Notably, the initial CA-MRSA strains were generally susceptible to numerous antimicrobial agents compared with traditional HA-MRSA strains, but variants of USA300 CA-MRSA having multidrug resistance (MDR) patterns have become more common.^9,10

As part of a postmarketing surveillance and risk management strategy framework, tedizolid activity and emerging resistance have been monitored against clinically relevant Gram-positive pathogens in the United States and Europe through the STAR (Surveillance of Tedizolid Activity and Resistance) Program.^11,12 Tedizolid has demonstrated great in vitro potency against Gram-positive cocci, including those exhibiting an MDR phenotype, such as MRSA and vancomycin-resistant enterococci.^13,14 In addition to the retained in vitro activity against linezolid-resistant cfr-carrying isolates, previous studies showed that tedizolid is well tolerated and has a lower propensity for neuropathies than its in-class comparator linezolid. Moreover, clinical trial data showed that tedizolid had less impact on hematologic parameters and gastrointestinal treatment–emergent adverse effects than its comparator linezolid.^14–17

Clindamycin remains a mainstay of therapy for uncomplicated CA-MRSA infections, or as an adjunct in more severe infections, in much of the United States, although some investigators have suggested that resistance to this agent may be increasing among CA-MRSA strains.^9,18–20 Given these concerns, a need exists for continued assessment of newly introduced non-β-lactam agents for treating CA-MRSA and HA-MRSA.^9,21,22 In addition, the increased in vitro potency, daily dose, oral and intravenous availability, and a more favorable adverse effect profile of tedizolid^14–17 warrant further investigations. This report aimed to evaluate the in vitro activity of tedizolid and comparators against CA-MRSA isolates collected from the adult and pediatric population during the 2014–2015 sampling period in the United States. The activity of tedizolid and comparators against a clindamycin-resistant subset of CA-MRSA displaying constitutive clindamycin resistance is also examined.

Materials and Methods

Bacterial isolates

A total of 1,768 CA-MRSA isolates were analyzed. The organisms were consecutively collected between January 2014 and December 2015 from 28 medical centers located in the 9 U.S. census divisions. Within this collection, a total of 955 isolates were from patients with SSSIs, 387 were from patients with bacteremia, 317 were from patients hospitalized with pneumonia, 49 were from patients with intra-abdominal infections, 32 were from patients with urinary tract infections, and 28 were from patients with miscellaneous other types of infection. All organisms were isolated from documented infections and only one organism per patient infection episode was included in the survey.

CA-MRSA isolates were defined according to the Centers for Disease and Control and Prevention criteria⁹: S. aureus isolates recovered from clinical specimens collected either from an outpatient or from an inpatient <48 hours after hospitalization were selected for this study. However, the lack of further demographic information does not allow segregating CA from HA community-onset infection.

For data analysis purposes, isolates were segregated according to a patient's age group (adult [≥18 years old] and pediatric [≤17 years old]) as well as those resistant (MIC ≥4 mg/L) to clindamycin, based on the CLSI (Clinical and Laboratory Standards Institute) breakpoint for constitutive resistance.

All isolates were identified locally and forwarded to a central monitoring laboratory (JMI Laboratories, North Liberty, IA) for confirmation of species identification, if necessary (using Vitek2, matrix-assisted laser desorption ionization–time of flight mass spectrometry or manual methods).

Antimicrobial susceptibility testing

Susceptibility testing was performed by broth microdilution, following the guidelines of the CLSI,²³ and included screening for inducible resistance to clindamycin. Quality control (QC) and interpretation of minimum inhibitory concentration (MIC) results obtained against QC strains were performed according to the CLSI M100 document.²⁴ MIC results for tested agents obtained against clinical isolates were interpreted using CLSI M100 and EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoint criteria, where available.^24,25 U.S. Food and Drug Administration product package insert criteria were used as an alternative breakpoint source as necessary (e.g., tigecycline).²⁶

Results

Overall activity of tedizolid against CA-MRSA

Tedizolid activity when tested against contemporary CA-MRSA isolates is summarized in Table 1. The 1,732 isolates tested included 247 isolates from pediatric patients and 1,485 from adults: 475 isolates (27.4%) showed a constitutive resistance phenotype to clindamycin (33 pediatric and 442 adult). Overall, a 33.6–35.0% clindamycin resistance rate was observed, which consisted of 27.4–27.8% and 6.2–7.2% of constitutive and inducible resistance rates, respectively (Table 2). The total clindamycin resistance rates among CA-MRSA from pediatric and adult patients were 18.3–19.1% (13.4–14.2% constitutive and 4.9–6.4% inducible) and 36.2–37.6% (29.8–30.1% constitutive and 6.4–7.5% inducible), respectively (Table 2).

Table 1.

Activity of Tedizolid Against Contemporary Community-Acquired Methicillin-Resistant Staphylococcus aureus Isolates in the United States

CA-MRSA/phenotype population (No. tested)	MIC (mg/L)		No. (cumulative %) of isolates inhibited at MIC (mg/L) of
CA-MRSA/phenotype population (No. tested)	50%	90%	≤0.015	0.03	0.06	0.12	0.25
All (1,732)	0.12	0.12		7 (0.4)	469 (27.5)	1,195 (96.5)	61 (100.0)
Pediatric (247)	0.12	0.12		2 (0.8)	76 (31.6)	166 (98.8)	3 (100.0)
Adult (1,485)	0.12	0.12		5 (0.3)	393 (26.8)	1,029 (96.1)	58 (100.0)
Clindamycin resistant^a (475)	0.12	0.12		2 (0.4)	118 (25.3)	332 (95.2)	23 (100.0)
Pediatric (33)	0.12	0.12			13 (39.4)	19 (97.0)	1 (100.0)
Adult (442)	0.12	0.12		2 (0.5)	105 (24.2)	313 (95.0)	22 (100.0)

Represents constitutive resistance (CLSI breakpoint).

CA-MRSA, community-acquired methicillin-resistant Staphylococcus aureus; CLSI, Clinical and Laboratory Standards Institute; MIC, minimum inhibitory concentration.

Table 2.

Antimicrobial Activity of Tedizolid and Comparator Agents Against Community-Acquired Methicillin-Resistant Staphylococcus aureus Clinical Isolates Causing Infections in Pediatric and Adult Patients in the United States

Antimicrobial agent	MIC₅₀	MIC₉₀	Range	CLSI ^a			EUCAST ^a
Antimicrobial agent	MIC₅₀	MIC₉₀	Range	%S	%I	%R	%S	%I	%R
All (1,732)
Tedizolid	0.12	0.12	0.03 to 0.25	100.0	0.0	0.0	100.0		0.0
Linezolid	1	1	≤0.12 to 2	100.0		0.0	100.0		0.0
Ceftaroline	1	1	0.06 to 2	96.9	3.1	0.0	96.9	3.1	0.0
Clindamycin	≤0.25	>2	≤0.25 to >2	66.2	0.2	33.6^b	65.0	0.0	35.0^c
Daptomycin	0.25	0.5	≤0.12 to 2	99.9			99.9		0.1
Erythromycin	>8	>8	≤0.12 to >8	11.3	4.3	84.4	11.8	1.0	87.2
Levofloxacin	4	>4	≤0.12 to >4	32.2	1.4	66.4	32.2		67.8
Teicoplanin	≤2	≤2	≤2 to 8	100.0	0.0	0.0	99.9		0.1
Tetracycline	≤0.5	1	≤0.5 to >8	93.1	1.0	5.9	90.9	1.6	7.5
Tigecycline	0.06	0.12	≤0.015 to 0.5	100.0^d			100.0		0.0
Trimethoprim–sulfamethoxazole	≤0.5	≤0.5	≤0.5 to >4	96.8		3.2	96.8	0.5	2.7
Vancomycin	1	1	≤0.12 to 2	100.0	0.0	0.0	100.0		0.0
Pediatric (247)
Tedizolid	0.12	0.12	0.03 to 0.25	100.0	0.0	0.0	100.0		0.0
Linezolid	1	1	0.25 to 1	100.0		0.0	100.0		0.0
Ceftaroline	0.5	1	0.25 to 2	98.8	1.2	0.0	98.8	1.2	0.0
Clindamycin	≤0.25	>2	≤0.25 to >2	80.7	1.0	18.3^e	80.9	0.0	19.1^f
Daptomycin	0.25	0.5	≤0.12 to 1	100.0			100.0		0.0
Erythromycin	>8	>8	≤0.12 to >8	15.8	2.0	82.2	16.2	0.8	83.0
Levofloxacin	2	>4	≤0.12 to >4	49.8	1.6	48.6	49.8		50.2
Teicoplanin	≤2	≤2	≤2	100.0	0.0	0.0	100.0		0.0
Tetracycline	≤0.5	≤0.5	≤0.5 to >8	96.4	0.4	3.2	93.5	1.6	4.9
Tigecycline	0.06	0.06	0.03 to 0.25	100.0^d			100.0		0.0
Trimethoprim–sulfamethoxazole	≤0.5	≤0.5	≤0.5 to 1	100.0		0.0	100.0	0.0	0.0
Vancomycin	0.5	1	≤0.12 to 2	100.0	0.0	0.0	100.0		0.0
Adult (1,485)
Tedizolid	0.12	0.12	0.03 to 0.25	100.0	0.0	0.0	100.0		0.0
Linezolid	1	1	≤0.12 to 2	100.0		0.0	100.0		0.0
Ceftaroline	1	1	0.06 to 2	96.6	3.4	0.0	96.6	3.4	0.0
Clindamycin	≤0.25	>2	≤0.25 to >2	63.7	0.1	36.2^g	62.4	0.0	37.6^h
Daptomycin	0.25	0.5	≤0.12 to 2	99.9			99.9		0.1
Erythromycin	>8	>8	≤0.12 to >8	10.6	4.6	84.8	11.1	1.0	87.9
Levofloxacin	4	>4	≤0.12 to >4	29.2	1.3	69.4	29.2		70.8
Teicoplanin	≤2	≤2	≤2 to 8	100.0	0.0	0.0	99.9		0.1
Tetracycline	≤0.5	1	≤0.5 to >8	92.5	1.1	6.3	90.4	1.6	8.0
Tigecycline	0.06	0.12	≤0.015 to 0.5	100.0^d			100.0		0.0
Trimethoprim–sulfamethoxazole	≤0.5	≤0.5	≤0.5 to >4	96.2		3.8	96.3	0.5	3.2
Vancomycin	1	1	≤0.12 to 2	100.0	0.0	0.0	100.0		0.0

Breakpoint criteria for tedizolid and comparator agents were those from CLSI²⁴ or EUCAST.²⁵

Represents 27.4% and 6.2% of constitutive and inducible resistance, respectively.

Represents 27.8% and 7.2% of constitutive and inducible resistance, respectively.

Interpretation for tigecycline MIC results utilized breakpoints approved by the U.S. Food and Drug Administration.

Represents 13.4% and 6.4% of constitutive and inducible resistance, respectively.

Represents 14.2% and 4.9% of constitutive and inducible resistance, respectively.

Represents 29.8% and 6.4% of constitutive and inducible resistance, respectively.

Represents 30.1% and 7.5% of constitutive and inducible resistance, respectively.

EUCAST, European Committee on Antimicrobial Susceptibility Testing.

Overall, tedizolid (MIC_50/90, 0.12/0.12 mg/L) inhibited all CA-MRSA isolates at ≤0.25 mg/L, below the breakpoint for susceptibility (i.e., ≤0.5 mg/L; Tables 1 and 2). Furthermore, tedizolid showed similar MIC distribution profiles (MIC_50/90, 0.12/0.12 mg/L) against CA-MRSA, regardless of age group or clindamycin phenotype (Table 1).

Activities of tedizolid and comparators against CA-MRSA

Tedizolid (MIC_50/90, 0.12/0.12 mg/L) MIC results were twofold to eightfold lower than those obtained for intravenous options, such as daptomycin (MIC_50/90, 0.25/0.5 mg/L), and eightfold lower than linezolid (MIC_50/90, 1/1 mg/L), ceftaroline (MIC_50/90, 0.5–1/1 mg/L), and vancomycin (MIC_50/90, 0.5–1/1 mg/L) against CA-MRSA and population subsets (Table 2). Other oral agents available for treating MRSA, such as linezolid (100.0% susceptible), tetracycline (90.4–96.4% susceptible), and trimethoprim–sulfamethoxazole (TMP-SMX; 96.2–100.0% susceptible) were active against CA-MRSA subsets from adult and pediatric patients, while clindamycin (62.4–80.9% susceptible) had suboptimal antimicrobial coverage (Table 2).

Erythromycin (10.6–16.2% susceptible) and levofloxacin (29.2–49.8% susceptible) were not active against the CA-MRSA subsets; hence, they are not recommended for empiric coverage of such pathogens. Linezolid (100.0% susceptible), ceftaroline (90.0–90.8% susceptible), daptomycin (99.8–100.0% susceptible), tigecycline (100.0% susceptible), TMP-SMX (96.6–100.0% susceptible), and vancomycin (100.0% susceptible) had consistent activities against CA-MRSA and displayed a constitutive clindamycin resistance phenotype recovered from pediatric and adult patients (Table 3). Tetracycline (78.8–87.9% susceptible) retained marginal activity, whereas levofloxacin (78.8–91.6% resistant) was not active against isolates with a constitutive clindamycin resistance (Table 3).

Table 3.

Antimicrobial Activity of Tedizolid and Comparator Agents Against Community-Acquired Methicillin-Resistant Staphylococcus aureus Displaying Constitutive Clindamycin Resistance (CLSI Breakpoint) Responsible for Infections in Pediatric and Adult Patients in the United States

Antimicrobial agent	MIC₅₀	MIC₉₀	Range	CLSI ^a			EUCAST ^a
Antimicrobial agent	MIC₅₀	MIC₉₀	Range	%S	%I	%R	%S	%I	%R
All (475)
Tedizolid	0.12	0.12	0.03 to 0.25	100.0	0.0	0.0	100.0		0.0
Linezolid	1	1	0.25 to 2	100.0		0.0	100.0		0.0
Ceftaroline	1	1	0.25 to 2	90.1	9.9	0.0	90.1	9.9	0.0^b
Daptomycin	0.25	0.5	≤0.12 to 2	99.8			99.8		0.2
Levofloxacin	>4	>4	≤0.12 to >4	9.3	0.2	90.5	9.3		90.7
Teicoplanin	≤2	≤2	≤2 to 4	100.0	0.0	0.0	99.8		0.2
Tetracycline	≤0.5	>8	≤0.5 to >8	86.5	2.5	11.0	80.8	5.3	13.9
Tigecycline	0.06	0.12	≤0.015 to 0.5	100.0^b			100.0		0.0
Trimethoprim–sulfamethoxazole	≤0.5	≤0.5	≤0.5 to >4	96.8		3.2	96.8	0.8	2.4
Vancomycin	1	1	≤0.12 to 2	100.0	0.0	0.0	100.0		0.0
Pediatric (33)
Tedizolid	0.12	0.12	0.06 to 0.25	100.0	0.0	0.0	100.0		0.0
Linezolid	0.5	1	0.5 to 1	100.0		0.0	100.0		0.0
Ceftaroline	1	1	0.5 to 2	90.9	9.1	0.0	90.9	9.1	0.0^b
Daptomycin	0.25	0.5	≤0.12 to 0.5	100.0			100.0		0.0
Levofloxacin	>4	>4	≤0.12 to >4	21.2	0.0	78.8	21.2		78.8
Teicoplanin	≤2	≤2	≤2	100.0	0.0	0.0	100.0		0.0
Tetracycline	≤0.5	8	≤0.5 to >8	87.9	3.0	9.1	78.8	9.1	12.1
Tigecycline	0.06	0.12	0.03 to 0.25	100.0^b			100.0		0.0
Trimethoprim–sulfamethoxazole	≤0.5	≤0.5	≤0.5	100.0		0.0	100.0	0.0	0.0
Vancomycin	0.5	1	≤0.12 to 1	100.0	0.0	0.0	100.0		0.0
Adult (442)
Tedizolid	0.12	0.12	0.03 to 0.25	100.0	0.0	0.0	100.0		0.0
Linezolid	1	1	0.25 to 2	100.0		0.0	100.0		0.0
Ceftaroline	1	1	0.25 to 2	90.0	10.0	0.0	90.0	10.0	0.0^b
Daptomycin	0.25	0.5	≤0.12 to 2	99.8			99.8		0.2
Levofloxacin	>4	>4	≤0.12 to >4	8.4	0.2	91.4	8.4		91.6
Teicoplanin	≤2	≤2	≤2 to 4	100.0	0.0	0.0	99.8		0.2
Tetracycline	≤0.5	>8	≤0.5 to >8	86.4	2.5	11.1	81.0	5.0	14.0
Tigecycline	0.06	0.12	≤0.015 to 0.5	100.0^b			100.0		0.0
Trimethoprim–sulfamethoxazole	≤0.5	≤0.5	≤0.5 to >4	96.6		3.4	96.6	0.9	2.5
Vancomycin	1	1	0.25 to 2	100.0	0.0	0.0	100.0		0.0

Breakpoint criteria for tedizolid and comparator agents were those from CLSI²⁴ and EUCAST.²⁵

Interpretation for tigecycline MIC results utilized breakpoints approved by the U.S. Food and Drug Administration.

Discussion

The results of this survey demonstrate the potent activity of tedizolid against CA-MRSA from the United States. All isolates from pediatric and adult patients were susceptible to tedizolid (susceptible breakpoint, ≤0.5 mg/L) and linezolid (susceptible breakpoint, 4 mg/L) at their respective clinical breakpoints, irrespective of the clindamycin phenotype. High resistance rates were observed for clindamycin (33.6–35.0%; 27.4–27.8% constitutive and 6.2–7.2% inducible resistance), erythromycin (84.4–87.2%), and levofloxacin (66.4–67.8%), whereas newer agents, such as tedizolid, linezolid, ceftaroline, daptomycin, and tigecycline, were active against these isolates. TMP-SMX remains active against CA-MRSA with a constitutive clindamycin resistance phenotype; however, the activity of tetracycline was somewhat reduced against this resistant subset.

In summary, tedizolid displayed in vitro coverage of CA-MRSA, including the important clindamycin-resistant subset. Considering the overall clindamycin resistance rates of 18.3–19.1% and 36.2–37.6% among isolates from the pediatric and adult populations, respectively, using this agent for empirical treatment of potential CA-MRSA infections may be questionable in all but the least-complicated infections. A recent study (2012–2014) demonstrated constitutive and inducible resistance rates to clindamycin against CA-MRSA from the United States of 23.2% and 10.6% (combined rate of 33.8%), respectively, with an overall resistance rate similar to that reported in this study (33.6–35.0%).²⁷

Although these results are the first for tedizolid against pediatric CA-MRSA isolates, they are consistent with previous in vitro surveillance studies and are cited in several recent reviews.^{3,9,11–14,21,22} Tedizolid MIC results for the years 2014–2015 against U.S. pediatric CA-MRSA isolates were consistent with contemporaneous results from adult populations and do not indicate any shift in the MIC distributions or emerging resistances among MRSA. These results indicate that tedizolid may be considered for the empiric treatment of severe ABSSSIs in adults where the incidence of CA-MRSA and clindamycin resistance rates are elevated.²⁸ Further studies to determine the dosage, efficacy, and safety for tedizolid in the pediatric population are needed to ensure the most favorable antimicrobial efficacy while minimizing adverse events in children with staphylococcal infections, including CA-MRSA.

Footnotes

Acknowledgments

The authors wish to thank the following staff members at JMI Laboratories: L. Deshpande, L. Flanigan, and J. Oberholser for assistance with article preparation.

Transparency Declaration

JMI Laboratories contracted to perform services in 2017 for Achaogen, Allecra Therapeutics, Allergan, Amplyx Pharmaceuticals, Antabio, API, Astellas Pharma, AstraZeneca, Athelas, Basilea Pharmaceutica, Bayer AG, Becton Dickinson and Co., Boston, CEM-102 Pharma, Cempra, Cidara Therapeutics, Inc., CorMedix, CSA Biotech, Cutanea Life Sciences, Inc., Entasis Therapeutics, Inc., Geom Therapeutics, Inc., GSK, Iterum Pharma, Medpace, Melinta Therapeutics, Inc., Merck & Co., Inc., MicuRx Pharmaceuticals, Inc., N8 Medical, Inc., Nabriva Therapeutics, Inc., NAEJA-RGM, Novartis, Paratek Pharmaceuticals, Inc., Pfizer, Polyphor, Ra Pharma, Rempex, Riptide Bioscience, Inc., Roche, Scynexis, Shionogi, SinSa Labs, Inc., Skyline Antiinfectives, Sonoran Biosciences, Spero Therapeutics, Symbiotica, Synlogic, Synthes Biomaterials, TenNor Therapeutics, Tetraphase, The Medicines Company, Theravance Biopharma, VenatoRx Pharmaceuticals, Inc., Wockhardt, Yukon Pharma, Zai Laboratory, Zavante Therapeutics, Inc. There are no speakers' bureaus or stock options to declare.

Disclosure Statement

This study was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Kenilworth, NJ), which included funding for services related to preparing this article.

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In Vitro Activity of Tedizolid in Comparison with Other Oral and Intravenous Agents Against a Collection of Community-Acquired Methicillin-Resistant Staphylococcus aureus (2014–2015) in the United States

Abstract

Introduction

Materials and Methods

Bacterial isolates

Antimicrobial susceptibility testing

Results

Overall activity of tedizolid against CA-MRSA

Activities of tedizolid and comparators against CA-MRSA

Discussion

Footnotes

Acknowledgments

Transparency Declaration

Disclosure Statement

References