Thermo Scientific Oxoid Meropenem/Vaborbactam Disc (30µg) MEV30

K181975 · Oxoid Limited (Part of Thermo Fisher Scientific) · JTN · Sep 27, 2018 · Microbiology

Device Facts

• Record ID: K181975
• Device Name: Thermo Scientific Oxoid Meropenem/Vaborbactam Disc (30µg) MEV30
• Applicant: Oxoid Limited (Part of Thermo Fisher Scientific)
• Product Code: JTN · Microbiology
• Decision Date: Sep 27, 2018
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.1620
• Device Class: Class 2

Indications for Use

Thermo Scientific Oxoid Antimicrobial Susceptibility Test (AST) Discs are used in the semi-quantitative agar diffusion test method for in vitro susceptibility testing. The Thermo Scientific Oxoid Meropenem/Vaborbactam Disc (30μg) MEV30 can be used to determine susceptibility to Meropenem/Vaborbactam against the following bacteria, for which Meropenem/Vaborbactam has been shown to be active both clinically in vitro: Gram-negative bacteria: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae species complex

Device Story

Device consists of 6mm high-absorbent paper disks impregnated with 30µg Meropenem/Vaborbactam (MEV30). Used in clinical microbiology laboratories for semi-quantitative agar diffusion (Kirby-Bauer) testing. Operator inoculates agar medium with pure bacterial culture; places disk on surface. Antibiotic diffuses into agar; after incubation, user measures zone of inhibition diameter. Results compared against established interpretive criteria to categorize bacteria as susceptible, intermediate, or resistant. Output assists clinicians in selecting appropriate antimicrobial therapy for patients with infections caused by indicated Gram-negative bacteria.

Clinical Evidence

Bench testing only. Evaluated 375 isolates (300 clinical, 75 challenge) including E. coli, K. pneumoniae, and E. cloacae complex. Demonstrated 99.2% category agreement with predicate. Reproducibility study (270 data points) showed >95% agreement. QC performance >95% across multiple strains.

Technological Characteristics

6mm absorbent paper disks impregnated with 20µg Meropenem and 10µg Vaborbactam. Principle: agar diffusion. Manual reading of inhibition zones. Standardized per CLSI M02-A13 and M100-S28. No software or electronic components.

Indications for Use

Indicated for in vitro susceptibility testing of Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex using the semi-quantitative agar diffusion method.

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

• HardyDisk Meropenem/Vaborbactam 20/10 µg (MEV30) (K172621)

Submission Summary (Full Text)

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510(k) SUBSTANTIAL EQUIVALENCE DETERMINATIONS
DECISION SUMMARY
ASSAY ONLY TEMPLATE

A. 510(k) Number:
K181975

B. Purpose for Submission:
To obtain substantial equivalence determination for Meropenem/Vaborbactam Antimicrobial Test Disk

C. Measurand:
Meropenem/Vaborbactam (30 µg) MEV30

D. Type of Test:
Antimicrobial Test Disc

E. Applicant:
Oxoid Ltd.

F. Proprietary and Established Names:
Thermo Scientific Oxoid Meropenem/Vaborbactam Disc (30 µg) MEV30

G. Regulatory Information:
1. Regulation section:
21 CFR 866.1620 Antimicrobial Susceptibility Test Disc
2. Classification:
Class II
3. Product code:
JTN – Susceptibility Test Disc, Antimicrobial

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4. Panel:

83 Microbiology

H. Intended Use:

1. Intended use(s):

Thermo Scientific Oxoid Antimicrobial Susceptibility Test (AST) Discs are used in the semi-quantitative agar diffusion test method for *in vitro* susceptibility testing.

2. Indication(s) for use:

Thermo Scientific Oxoid Antimicrobial Susceptibility Test (AST) Discs are used in the semi-quantitative agar diffusion test method for *in vitro* susceptibility testing.

The Thermo Scientific Oxoid Meropenem/Vaborbactam Disc (30μg) MEV30 can be used to determine susceptibility to Meropenem/Vaborbactam against the following bacteria, for which Meropenem/Vaborbactam has been shown to be active both clinically *in vitro*:

- Gram-negative bacteria:
- Escherichia coli
- Klebsiella pneumoniae
- Enterobacter cloacae species complex

3. Special conditions for use statement(s):

For prescription use only.

4. Special instrument requirements:

Not applicable

I. Device Description:

Thermo Scientific Oxoid Meropenem/Vaborbactam Disc (30 μg) MEV30 Antimicrobial Susceptibility Test Disks are 6 mm disks prepared by impregnating high absorbent paper with accurately determined amounts of Meropenem and Vaborbactam. The disk is clearly marked on both sides with the code MEV30. The code designates the agent (Meropenem/Vaborbactam) and the drug content.

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. Oxoid discs can be dispensed using an Oxoid Disk Dispenser.

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# J. Substantial Equivalence Information:

1. Predicate device name(s):

HardyDisk Meropenem/Vaborbactam $20 / 10~\mu \mathrm{g}$ (MEV30)

2. Predicate $510(\mathbf{k})$ number(s):

K172612

3. Comparison with predicate:

Table 1: Comparison with Predicate Device

| Similarities | | |
| --- | --- | --- |
| Item | Device: K181975 Thermo Scientific Oxoid Meropenem/Vaborbactam Disk (30 μg) MEV30 | Predicate: K172621 HardyDisk Meropenem/Vaborbactam Disk 20/10 μg (MEV30) |
| Test Method | Semi-quantitative agar diffusion method using antimicrobial disks impregnated with an antimicrobial agent | Same |
| Intended Use | Antimicrobial Susceptibility Test (AST) Discs are used in the semi-quantitative agar diffusion test method for in vitro susceptibility testing | Same |
| Antimicrobial Agent | Meropenem/Vaborbactam | Same |
| Antimicrobial Agent Concentration | Meropenem 20 μg/Vaborbactam 10 μg | Same |
| Reading Method | The user will interpret the zone diameters according established interpretive criteria for the drug | Same |
| Differences | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Manufacturing Specifications | Oxoid's specifications | Hardy Diagnostics' specifications |

# K. Standard/Guidance Document Referenced (if applicable):

CLSI M02-A13, Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard- Twelfth Edition

CLSI M100-S28, Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Seventh Informational Supplement

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# L. Test Principle:

A suitable therapeutic agent can be determined using filter paper discs 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 disc on the surface of the medium. The antibiotic within the disc diffuses into the agar. After incubation, the zones of inhibition around the discs are measured and compared against recognized zone diameter ranges for the specific antimicrobial agent/organism combinations being tested.

# M. Performance Characteristics (if/when applicable):

# 1. Analytical performance:

# a. Precision/Reproducibility:

Reproducibility was conducted at an external site using 15 indicated organisms, tested with two disc lots on three separate days. Each test was visually read by 3 independent readers with results blinded, resulting in 270 data points for evaluation.

The reproducibility study included 12 strains of Klebsiella pneumoniae, and one each of Citrobacter freundii, E. coli, and Enterobacter cloacae. Reproducibility was assessed by considering $\pm 3\mathrm{mm}$ difference in zone diameter comparing test results with predetermined disk zone diameter test mode. All results were within $2\mathrm{mm}$ of the mode result. Results are shown in Table 2 below.

Table 2: Reproducibility Summary

| Between Disk Lots | | | Across Readers | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Lot A | Lot B | 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 across manual readers and disc lots is $>95\%$ and meets the acceptance criteria.

# b. Linearity/assay reportable range:

Not Applicable

# c. Traceability, Stability, Expected values (controls, calibrators, or methods):

The CLSI-recommended QC isolates were tested a sufficient number of times (i.e., at least 60 results/QC isolate). The Enterobacteriaceae QC isolates were: E. coli ATCC 25922, K. pneumoniae ATCC 700603, K. pneumoniae ATCC BAA-1705, and K. pneumoniae ATCC BAA-2814. One predicate disk lot and two Oxoid disk lots were

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used for each QC isolate in the study. The performance is shown in Table 3 below.

Table 3: Enterobacteriaceae QC Performance

| QC Isolate | Zone Diameter in mm | | |
| --- | --- | --- | --- |
| | | Predicate a | Oxoid b |
| E. coliATCC 25922Expected Range:31 – 37 mm | 30 | 1 | |
| | 31 | 3 | 4 |
| | 32 | 21 | 10 |
| | 33 | 18 | 39 |
| | 34 | 13 | 34 |
| | 35 | 7 | 26 |
| | 36 | 2 | 11 |
| | 37 | 1 | 5 |
| | 38 | | 1 |
| | 39 | | 2 |
| | | | |
| K. pneumoniaeATCC 700603 cExpected Range:29 – 35 mm | 29 | | |
| | 30 | 6 | 1 |
| | 31 | 19 | 7 |
| | 32 | 27 | 25 |
| | 33 | 11 | 20 |
| | 34 | 3 | 9 |
| | 35 | | 4 |
| | | | |
| K. pneumoniaeATCC BAA-1705 c, dExpected Range:21 – 27 mm | 21 | | |
| | 22 | 1 | |
| | 23 | 2 | 2 |
| | 24 | 6 | 6 |
| | 25 | 28 | 44 |
| | 26 | 21 | 51 |
| | 27 | 8 | 21 |
| | 28 | | 8 |
| | | | |
| K. pneumoniaeATCC BAA-2814 dExpected Range:16 – 20 mm | 16 | | |
| | 17 | | |
| | 18 | 9 | 4 |
| | 19 | 43 | 67 |
| | 20 | 13 | 52 |
| | 21 | 1 | 8 |
| | 22 | | 1 |
| | | | |

a One predicate disk lot
b Two Oxoid disk lots
c Refer to the current CLSI M100 document for $\beta$ -Lactam combination agents QC integrity maintenance information
d Either strain may be used for routine QC of this antimicrobial agent

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The Oxoid disc QC performance is >95% (96.2%, 508/528) and was considered acceptable. However, the Oxoid disc QC results tended to be on the high end of the approved QC range and this trend was seen for all strains.

Colony counts were conducted for the four QC isolates and were within expected range.

d. Detection limit:

Not applicable

e. Analytical specificity:

Not applicable

f. Assay cut-off:

Not applicable

2. Comparison studies:

a. Method comparison with predicate device:

The Oxoid disk was compared with a FDA cleared disc (predicate) 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. The study included 300 clinical isolates recovered during the drug development clinical trials. An additional 75 challenge isolates from the CDC and FDA AR Bank included Enterobacteriaceae isolates harboring multiple resistance determinants.

The following species were evaluated as clinical isolates in the study: Citrobacter freundii/C. freundii spp. complex (4), Klebsiella (Enterobacter) aerogenes (1), Enterobacter cloacae/E. cloacae spp. complex (23), E. coli (111), K. oxytoca (1), K. pneumoniae (149), Morganella morganii (4), Providencia stuartii (3), and Serratia marcescens (3). Seventy-five isolates were included in the challenge study: Citrobacter freundii (1), Enterobacter aerogenes (3), Enterobacter cloacae/E. cloacae spp. complex (12), E. coli (9), K. oxytoca (2), K. pneumoniae (32), Kluyvera ascorbate (1), Morganella morganii (1), P. mirabilis (3), and Serratia marcescens (8). A total of 340 isolates from the drug indicated species (K. pneumoniae, E. coli and E. cloacae spp. Complex) were tested. The performance of the Oxoid disc for Enterobacteriaceae is shown in Table 4 below.

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Table 4: Performance of Oxoid Meropenem/Vaborbactam with Enterobacteriaceae

| | Total | CA# | CA% | S (#) | I (#) | R (#) | Vmj | Maj | Min |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Clinical | 300 | 299 | 99.7 | 294 | 4 | 2 | 0 | 0 | 1 |
| Challenge | 75 | 73 | 97.3 | 65 | 1 | 9 | 0 | 0 | 2 |
| Combined | 375^{a} | 372 | 99.2 | 359 | 5 | 11 | 0 | 0 | 3 |

* Includes drug indicated organisms: K. pneumoniae (184), Escherichia coli (121), and Enterobacter cloacae spp. complex (35).

CA - Category Agreement
S - Susceptible isolates
I - Intermediate isolates
R - Resistant isolates

maj - major discrepancies
vmj- very major discrepancies
min- minor discrepancies

The performance of the Oxoid Meropenem/Vaborbactam disc as compared to the predicate is acceptable (99.2%); there were three minor discrepancies and no major or very major discrepancies. There was a total of 340 isolates from indicated species that included K. pneumoniae (184 isolates), E. coli (121 isolates) and E. cloacae (35 isolates). To address the testing of non-indicated species the following footnote is included in the device labeling:

The safety and efficacy of meropenem/vaborbactam in treating clinical infections due to Gram-Negative organisms other than Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex may or may not have been established in adequate and well-controlled clinical trials. The clinical significance of such susceptibility information in those instances is unknown.

A total of 11 resistant strains were tested including 10 strains of K. pneumoniae and one strain of E. coli. To address the lack of testing of resistant strains of species other than K. pneumoniae, the following limitation was included in the device labelling:

The ability of the Oxoid Meropenem/Vaborbactam disc to detect resistance in species other than K. pneumoniae is unknown because resistant strains were not available at the time of comparative testing. If such a strain is observed, it should be submitted to a reference laboratory for further testing.

## Resistance Mechanisms in Challenge Isolates

The 75-isolate challenge set included Enterobacteriaceae isolates harboring extended spectrum βeta-Lactamases (ESBLs) (CTX-M, SHV, TEM, AmpC including pAmpC (ACT, CMY, DHA), and cAmpC) and carbapenemases (KPC, NDM, OXA, IMI, VIM, and SME).

Isolates that exhibit overexpression of efflux pumps or lower expression of porins were not available for evaluation. Information regarding these resistance mechanisms is addressed in device labeling by the following footnote:

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The performance of Oxoid Meropenem/Vaborbactam disk (30 μg) MEV30 is unknown for Enterobacteriaceae with the following resistance mechanisms: overexpression of efflux pumps and/or lower expression of porins.

## Secondary Analysis

A secondary analysis of the 375 isolates was also performed. The analysis was conducted to compare qualitative categorical agreement of the Oxoid disc and the predicate disk with the reference MIC values (based on historical data from testing performed at the initial recovery of isolates during the drug clinical trials). The analysis showed a CA of 98.1% and 98.4% for the Oxoid and the predicate discs, respectively. There were two very major errors observed; however, because testing was not performed concurrently with disk testing and no further investigation was performed, the reason for these errors remains unknown. Given that these errors were observed by both the test disk and predicate and no errors were observed in the primary analysis (based on disk comparisons), these results did not raise additional concerns.

b. Matrix comparison:

Not applicable

3. Clinical studies:

a. Clinical Sensitivity:

Not applicable

b. Clinical specificity:

Not applicable

c. Other clinical supportive data (when a. and b. are not applicable):

Not applicable

4. Clinical cut-off:

Not applicable

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# 5. Expected values/Reference range:

Table 5: FDA- Identified Interpretative Criteria Meropenem/Vaborbactama

| Pathogen | MIC (μg/mL) | | | Disk Diffusion (mm) | | |
| --- | --- | --- | --- | --- | --- | --- |
| | S | I | R | S | I | R |
| Enterobacteriaceae | ≤4/8 | 8/8 | ≥16/8 | ≥17 | 14-16 | ≤13 |

a FDA-Recognized Antimicrobial Susceptibility Test Interpretive Criteria Website https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm410971.htm. The QC strains and expected ranges are the same as recommended in CLSI M100 28th Edition.

# N. Proposed Labeling:

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

# O. Conclusion:

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