Thermo Scientific Oxoid Lefamulin Disc (20µg) LMU20

K210873 · Oxoid Limited (Part of Thermo Fisher Scientific) · JTN · Oct 27, 2021 · Microbiology

Device Facts

• Record ID: K210873
• Device Name: Thermo Scientific Oxoid Lefamulin Disc (20µg) LMU20
• Applicant: Oxoid Limited (Part of Thermo Fisher Scientific)
• Product Code: JTN · Microbiology
• Decision Date: Oct 27, 2021
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.1620
• Device Class: Class 2

Intended Use

Thermo Scientific Oxoid Antimicrobial Susceptibility Test Discs are used in the semi-quantitative agar diffusion test method for in vitro susceptibility testing. The Thermo Scientific Oxoid Lefamulin Disc (20 µg) LMU20 can be used to determine susceptibility to Lefamulin against the following bacteria which Lefamulin has been shown to be active both clinically and in vitro: Gram-positive Bacteria: Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible isolates) Gram-negative Bacteria: Haemophilus influenzae

Device Story

Thermo Scientific Oxoid Lefamulin Disc (20μg) LMU20 is an in vitro diagnostic device used in clinical microbiology laboratories. It consists of a paper disc impregnated with 20μg of the antimicrobial agent lefamulin. The device is used in conjunction with agar diffusion susceptibility testing methods to determine the susceptibility of specific microorganisms to lefamulin. Laboratory technicians place the disc onto inoculated agar plates; the antimicrobial agent diffuses into the medium, creating a zone of inhibition around the disc. The diameter of this zone is measured and compared to established interpretive criteria to categorize the organism as susceptible, intermediate, or resistant. This information assists clinicians in selecting appropriate antibiotic therapy for patients with bacterial infections.

Clinical Evidence

No clinical data provided. Substantial equivalence is based on bench testing demonstrating performance characteristics consistent with established standards for antimicrobial susceptibility test discs.

Technological Characteristics

Antimicrobial susceptibility test disc; 20μg lefamulin concentration; paper disc substrate; agar diffusion principle; in vitro diagnostic use.

Indications for Use

Indicated for use as an antimicrobial susceptibility test disc for the determination of susceptibility of microorganisms to the antimicrobial agent lefamulin.

Regulatory Classification

Identification

An antimicrobial susceptibility test disc is a device that consists of antimicrobic-impregnated paper discs used to measure by a disc-agar diffusion technique or a disc-broth elution technique the in vitro susceptibility of most clinically important bacterial pathogens to antimicrobial agents. In the disc-agar diffusion technique, bacterial susceptibility is ascertained by directly measuring the magnitude of a zone of bacterial inhibition around the disc on an agar surface. The disc-broth elution technique is associated with an automated rapid susceptibility test system and employs a fluid medium in which susceptibility is ascertained by photometrically measuring changes in bacterial growth resulting when antimicrobial material is eluted from the disc into the fluid medium. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.

Predicate Devices

• Thermo Scientific Oxoid Lefamulin Disc (K192668)

Submission Summary (Full Text)

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FDA

U.S. FOOD & DRUG

ADMINISTRATION

# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

ASSAY ONLY

## I Background Information:

A 510(k) Number

K210873

B Applicant

Oxoid Limited (Part of Thermo Fisher Scientific)

C Proprietary and Established Names

Thermo Scientific Oxoid Lefamulin Disc (20μg) LMU20

D Regulatory Information

| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| JTN | Class II | 21 CFR 866.1620 - Antimicrobial Susceptibility Test Disc | MI - Microbiology |

## II Submission/Device Overview:

A Purpose for Submission:

To obtain substantial equivalence determination for Lefamulin Antimicrobial Susceptibility Test Disc.

B Measurand:

Lefamulin (20 μg) LMU20.

C Type of Test:

Antimicrobial Susceptibility Test Disc.

Food and Drug Administration

10903 New Hampshire Avenue

Silver Spring, MD 20993-0002

www.fda.gov

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# III Intended Use/Indications for Use:

## A Intended Use(s):
See Indications for Use below.

## B Indication(s) for Use:
Thermo Scientific Oxoid Antimicrobial Susceptibility Test Discs are used in the semi-quantitative agar diffusion test method for in vitro susceptibility testing.

The Thermo Scientific Oxoid Lefamulin Disc (20 µg) LMU20 can be used to determine susceptibility to Lefamulin against the following bacteria which Lefamulin has been shown to be active both clinically and in vitro:

**Gram-positive Bacteria:**
Streptococcus pneumoniae
Staphylococcus aureus (methicillin-susceptible isolates)

**Gram-negative Bacteria:**
Haemophilus influenzae

## C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only

**Limitations:**
The current absence of resistant isolates precludes defining any results other than "Susceptible". Isolates yielding results other than "Susceptible" should be submitted to a reference laboratory for further testing.

Isolates of *H. influenzae* that provide a disc zone of inhibition ≥ 17 mm should be tested by an alternative testing method prior to reporting results.

Isolates of *S. aureus* (MSSA) that provide a disc zone of inhibition ≥ 23 mm should be tested by an alternative testing method prior to reporting results.

Isolates of *S. pneumoniae* that provide a disc zone of inhibition ≥ 17 mm should be interpreted by an alternative testing method prior to reporting results.

## D Special Instrument Requirements:
Not Applicable.

## IV Device/System Characteristics:

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# A Device Description:

Thermo Scientific Oxoid Lefamulin Disc (20μg) comprise 6mm discs prepared by impregnating high quality absorbent paper with an accurately determined amount of lefamulin. The disc is clearly marked on both sides with the code LMU20. The code designates the agent (lefamulin) and the drug content (20 μg).

Thermo Scientific Oxoid discs are supplied in cartridges containing 50 discs each, there are 5 cartridges per pack. Each cartridge is individually sealed together with a desiccant capsule in a foil covered see-through blister pack. Thermo Scientific Oxoid discs can be dispensed using a Thermo Scientific Oxoid Disc Dispenser.

# B Principle of Operation:

A suitable therapeutic agent can be determined using filter paper disks impregnated with specified concentrations of antimicrobial agents placed on the surface of a suitable test medium. The test is performed by inoculating pure cultures of clinical isolates onto the test medium and placing the AST disk on the surface of the medium. The antibiotic within the disk diffuses into the agar. After incubation, the zones of inhibition around the disks are measured and compared against recognized zone diameter ranges for the specific antimicrobial agent/organism combinations being tested.

# V Substantial Equivalence Information:

# A Predicate Device Name(s):

HardyDisk AST Lefamulin 20μg (LMU20)

# B Predicate 510(k) Number(s):

K192326

# C Comparison with Predicate(s):

| Device & Predicate Device(s): | Device: K210873 | Predicate: K192326 |
| --- | --- | --- |
| Device Trade Name | Thermo Scientific Oxoid Lefamulin Disc (20 μg) LMU20 | HardyDisk AST Lefamulin 20μg (LMU20) |
| General Device Characteristic Similarities | | |
| Intended Use/Indications for Use | Thermo Scientific Oxoid Antimicrobial Susceptibility Test Discs are used in the semi quantitative agar diffusion test method for in vitro susceptibility testing. | Same. |

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| Antimicrobial Agent | Lefamulin | Same |
| --- | --- | --- |
| Antimicrobial Agent Concentration | 20 μg | Same |
| Interpretation | The user will interpret the zone diameter according to the established interpretive criteria for the drug | Same |
| Test Method | Semi quantitative agar diffusion test method using antimicrobial discs impregnated with an antimicrobial agent. | Same |
| Result Interpretation Method. | Measurement of zone size | Same |
| General Device Characteristic Differences | | |
| Manufacturing Specifications | Oxoid’s specifications | Hardy Diagnostics’ specifications |

VI Standards/Guidance Documents Referenced:

- CLSI M02-13th ed., Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard; January 2018.
- CLSI M100-29th ed., Performance Standards for Antimicrobial Susceptibility Testing; Twenty-ninth Informational Supplement; 2019

VII Performance Characteristics (if/when applicable):

A Analytical Performance:

1. Precision/Reproducibility:

Reproducibility was conducted at one external site using 15 organisms, tested in triplicate with two disk lots on three separate days using one lot of appropriate media (Mueller Hinton agar (MHA media) for S. aureus, MHA+5% sheep blood for streptococci and Haemophilus Test Medium (HTM) for Haemophilus spp). Each test was visually read by three independent readers with results blinded, resulting in 270 data points for evaluation (15 organisms x 2 disk lots x 1 media lot x 3 days x 3 independent readers = 270 data point).

The reproducibility study included 5 Staphylococcus aureus, 5 Haemophilus influenzae and 5 Streptococcus pneumoniae isolates.

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Reproducibility was calculated as the percent of results which were within ±3 mm difference in zone diameter compared to the modal zone diameter value. Summary results between disk lots and across readers are shown in Table 1 below.

Table 1: Reproducibility Summary
| Between Disk Lots | | | Across Readers | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Lot #1 | Lot #2 | All Lots | Reader# 1 | Reader#2 | Reader#3 | All Readers |
| 100%
(135/135) | 100%
(135/135) | 100%
(270/270) | 100%
(90/90) | 100%
(90/90) | 100%
(90/90) | 100%
(270/270) |

The reproducibility between disk lots and across readers is >95% and meets the acceptance criteria.

2. Linearity:
Not applicable.

3. Analytical Specificity/Interference:
Not applicable.

4. Assay Reportable Range:
Not applicable.

5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):

Quality Control (QC) Testing:
The CLSI-recommended quality control (QC) isolates, Staphylococcus aureus ATCC 25923 Haemophilus influenzae ATCC 49247 and Streptococcus pneumoniae ATCC 49619 were tested s (i.e., a minimum of 20 quality control test results per lot per reader and per site) on appropriate media. One predicate disk lot and two Oxoid disk lots were used. Each test was visually read by three or four independent readers. The performance is shown in Table2.

Table 2: Quality Control Performance
| | Zone Diameter in millimeter (mm) | | | |
| --- | --- | --- | --- | --- |
| QC Organism | Range | Comparator Disc^{1} | Oxoid Lot A^{2} | Oxoid Lot B^{2} |
| Staphylococcus aureus ATCC 25923
Expected Range: 26-32 mm | 21 | | | |
| | 22 | | | |
| | 23 | | | |
| | 24 | | | |
| | 25 | | 1 | |
| | 26 | 7 | 1 | 1 |
| | 27 | 9 | 5 | 7 |
| | 28 | 14 | 9 | 9 |
| | 29 | 19 | 16 | 18 |
| | 30 | 6 | 16 | 14 |
| | 31 | 7 | 12 | 12 |

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| | Zone Diameter in millimeter (mm) | | | |
| --- | --- | --- | --- | --- |
| QC Organism | Range | Comparator Disc¹ | Oxoid Lot A² | Oxoid Lot B² |
| | 32 | | 2 | 1 |
| | >33 | | | |
| Haemophilus influenzae ATCC 49247
Expected Range: 22-28 mm | 21 | | | |
| | 22 | | | |
| | 23 | | | |
| | 24 | 3 | | |
| | 25 | 20 | | |
| | 26 | 24 | 12 | 9 |
| | 27 | 13 | 28 | 31 |
| | 28 | 1 | 21 | 21 |
| | 29 | | | |
| | 30 | | | |
| | 31 | | | |
| Streptococcus pneumoniae ATCC 49619
Expected Range: 19-27 mm | 19 | | | |
| | 21 | | | 1 |
| | 22 | 3 | | |
| | 23 | 13 | 1 | |
| | 24 | 25 | 7 | 5 |
| | 25 | 16 | 24 | 23 |
| | 26 | 3 | 23 | 24 |
| | 27 | | 5 | 7 |
| | 28 | | | |
| | 29 | | | |
| | 30 | | | |
| | 31 | | | |

ATCC=American Type Culture Collection
¹One comparator disk lot
²Two Oxoid disk lots were tested (lot A and lot B)

The Oxoid disk QC performance is > 95% and is acceptable.

## Inoculum Density Check:

Colony counts were conducted for all QC and reproducibility isolates, as well as 10% of clinical isolates. All were within the expected range.

6. Detection Limit:

Not applicable.

7. Assay Cut-Off:

Not applicable.

## B Comparison Studies:

1. Method Comparison with Predicate Device:

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The Oxoid Lefamulin disc 20 µg (LMU20) was compared with an FDA cleared disc of the same antimicrobial, mass/concentration, and content. The study was conducted at one testing site. Three independent operators participated in reading of test results with isolates evenly distributed to mimic testing at multiple sites. Testing was performed with one lot of disk of each test manufacturer (Oxoid and comparator FDA-cleared disk) utilizing the appropriate media (MHA media for S. aureus (MSSA), MHA+5% sheep blood for streptococci and HTM for Haemophilus spp). following the CLSI M02 13th edition method.

## Clinical:

Clinical testing was performed at one U.S. site with both Thermo Scientific Oxoid Lefamulin Disc and the comparator FDA cleared disk using a total of 300 clinical isolates including 100 clinical isolates of each of the indicated species.

## Challenge:

Challenge testing was performed at one U.S site. A total of 75 challenge isolates were tested which included 25 isolates of each of the three indicated species (Staphylococcus aureus MSSA, Haemophilus influenzae and Streptococcus pneumoniae.

Results for the total 375 clinical and challenge isolates are shown in Table 3.

Table 3: Performance of Oxoid Lefamulin Disc vs. Comparator Disc.

| | Total | CA# | CA% | S (#) | NS (#) | VMJ | MAJ | MIN |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Staphylococcus aureus (MSSA) ≥23 (S), -, - | | | | | | | | |
| Clinical | 100 | 100 | 100.0 | 100 | 0 | 0 | 0 | NA |
| Challenge | 25 | 25 | 100.0 | 13 | 12 | 0 | 0 | NA |
| Combined | 125 | 125 | 100.0 | 113 | 12 | 0 | 0 | NA |
| Haemophilus influenzae ≥17 (S), -, - | | | | | | | | |
| Clinical | 100 | 99 | 99.0 | 99 | 1 | 1 | 0 | NA |
| Challenge | 25 | 23 | 92.0 | 20 | 5 | 2 | 0 | NA |
| Combined | 125 | 122 | 97.6 | 119 | 6 | 3 | 0 | NA |
| Streptococcus pneumoniae ≥17 (S), -, - | | | | | | | | |
| Clinical | 100 | 100 | 100.0 | 100 | 0 | 0 | 0 | NA |
| Challenge | 25 | 25 | 100.0 | 25 | 0 | 0 | 0 | NA |
| Combined | 125 | 125 | 100.0 | 125 | 0 | 0 | 0 | NA |

NA: Not Applicable.

CA – Category Agreement
S – Susceptible isolates
NS – Non-susceptible isolates
MIN – minor errors
MAJ – major errors
VMJ – very major errors

Category Agreement (CA) is when the Thermo Scientific Oxoid disc result interpretation agrees exactly with the comparator result interpretation.

The performance of the Thermo Scientific Oxoid Lefamulin disc as compared to the FDA cleared comparator disc for Staphylococcus aureus (MSSA) is acceptable with 100% CA. There were no major and no very major discrepancies.

The performance of the Thermo Scientific Oxoid Lefamulin disc as compared to the FDA cleared comparator disc for Streptococcus pneumoniae is acceptable with 100% CA. There were no major and no very major discrepancies.

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The performance of the Thermo Scientific Oxoid Lefamulin disc as compared to the FDA cleared comparator for H. influenzae is acceptable with 97.6% CA. However, there were 3 very major errors resulting in a very major error rate of 50% (3/6 non-susceptible isolates) which does not meet FDA acceptance criteria of ≤2% very major errors. To address the very major error rate, the following limitation was included in the device labeling:

Isolates of H. influenzae that provide a disc zone of inhibition ≥ 17 mm should be tested by an alternative testing method prior to reporting results.

As required under 511A(b)(2)(C)(ii)(I) of the Federal Food, Drug and Cosmetic Act, the following statement is included as a footnote to the performance table in the device labeling to address testing of non-indicated species:

Per the FDA-Recognized Susceptibility Test Interpretive Criteria website, the safety and efficacy of antimicrobial drugs, for which antimicrobial susceptibility is tested by this AST device, may or may not have been established in adequate and well-controlled clinical trials for treating clinical infections due to microorganisms outside of those found in the indications and usage in the drug label. The clinical significance of susceptibility information in those instances is unknown. The approved labeling for specific antimicrobial drugs provides the uses for which the antimicrobial drug is approved.

## Non-susceptible Isolates Tested:

Lefamulin interpretive criteria does not have intermediate or resistant breakpoints for the indicated organisms. The following limitation was included in the device labeling:

The current absence of resistant isolates precludes defining any results other than "Susceptible". Isolates yielding results other than "Susceptible" should be submitted to a reference laboratory for further testing.

## Resistance Mechanisms in Challenge Isolates:

Challenge isolates harboring the resistance mechanisms against which lefamulin has been shown to be active were not tested. The following footnote was included in the device labeling:

The performance of the Thermo Scientific Oxoid Lefamulin 20 µg disc was not evaluated with challenge isolates harboring resistance mechanisms listed in the FDA drug label.

## Secondary Analysis:

A secondary analysis of the total 375 combined clinical and challenge isolates was also performed (including 125 isolates of each of the indicated species). The analysis was conducted to compare qualitative categorical agreement of the Thermo Scientific Oxoid disc and the CLSI broth microdilution reference MIC values (based on historical data from testing performed at the initial recovery of isolates during the drug clinical trials).

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Analysis of the Oxoid disk data for S. aureus (MSSA) isolates was acceptable with 98% CA. There were no major errors. However, there were two very major errors out of 14 non-susceptible isolates (14.29%) observed with the Thermo Scientific Oxoid disc compared to MIC values which does not meet the FDA acceptance criteria of ≤2% very major error rate.

Due to the occurrence of potential very major errors with the Lefamulin and the Thermo Scientific Oxoid disc with MSSA isolates, the following limitation was included in the device labeling:

Isolates of S. aureus (MSSA) that provide a disc zone of inhibition ≥ 23 mm should be tested by an alternative testing method prior to reporting results.

Analysis of the Oxoid disk data for Streptococcus pneumoniae isolates was acceptable with 97% CA. There were no major errors. However, there were 4 very major errors out of 4 non-susceptible isolates (100%) observed with the Thermo Scientific Oxoid disc compared to MIC values which does not meet the FDA acceptance criteria of ≤2% VMJ rate.

Due to the occurrence of potential very major errors with the lefamulin and the Thermo Scientific Oxoid disc with Streptococcus pneumoniae isolates, the following limitation was included in the device labeling:

Isolates of S. pneumoniae that provide a disc zone of inhibition ≥ 17 mm should be tested by an alternative testing method prior to reporting results.

Analysis of the Oxoid disk data for H. influenzae isolates was acceptable with 92.8% CA. There were no major errors. However, the were 9 very major errors out of 12 non-susceptible isolates (75%) observed with the Thermo Scientific Oxoid disc compared to MIC values. In these instances, 2 out of the 9 very major errors were 1mm close to the breakpoints. After EA adjustment, the adjusted VMJ is 7/12 non-susceptible isolates (58.3%) which still does not meet the FDA acceptance criteria of ≤2% VMJ rate. Due to the occurrence of potential very major errors with the Lefamulin and the Thermo Scientific Oxoid disc with H. influenzae isolates, a limitation was included in the device labeling (refer to the limitation listed in section B1 above).

2. Matrix Comparison:

Not applicable.

C Clinical Studies:

1. Clinical Sensitivity:

Not applicable.

2. Clinical Specificity:

Not applicable.

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3. Other Clinical Supportive Data (When 1. and 2. Are Not Applicable):

Not applicable.

# D Clinical Cut-Off:

Not applicable.

# E Expected Values/Reference Range:

The FDA identified susceptibility interpretive criteria for Lefamulin are listed in Table 4.

Table 4: FDA- Identified Interpretative Criteria Lefamulin ${}^{1}$

| Pathogen | Minimum Inhibitory Concentrations (μg/mL) | | | Disk Diffusion (mm) | | |
| --- | --- | --- | --- | --- | --- | --- |
| | S | I | R | S2 | I | R |
| Staphylococcus aureus (MSSA isolates) | ≤0.25 | - | - | ≥23 | - | - |
| Streptococcus pneumoniae | ≤0.5 | - | - | ≥17 | - | - |
| Haemophilus influenzae | ≤2 | - | - | ≥17 | - | - |

S = Susceptible; I = Intermediate; R = Resistant
1 According to FDA STIC Website.
2The current absence of resistant isolates precludes defining any results other than "Susceptible". Isolates yielding MIC results other than "Susceptible" should be submitted to a reference laboratory for further testing.

# VIII Proposed Labeling:

The labeling supports the finding of substantial equivalence for this device.

# IX Conclusion:

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.

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