MicroScan Dried Gram Negative MIC/Combo Panels with Meropenem (Mer) (0.004-32ug/mL)

K192355 · Beckman Coulter, Inc. · JWY · Nov 14, 2019 · Microbiology

Device Facts

• Record ID: K192355
• Device Name: MicroScan Dried Gram Negative MIC/Combo Panels with Meropenem (Mer) (0.004-32ug/mL)
• Applicant: Beckman Coulter, Inc.
• Product Code: JWY · Microbiology
• Decision Date: Nov 14, 2019
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.1640
• Device Class: Class 2

Indications for Use

To determine antimicrobial agent susceptibility

Device Story

MicroScan Dried Gram-Negative MIC/Combo Panels are miniaturized broth dilution susceptibility tests. Panels contain dehydrated antimicrobial agents; rehydrated with water after inoculation with standardized organism suspension. Incubated in non-CO2 incubator for 16-20 hours. Minimum inhibitory concentration (MIC) determined by identifying lowest antimicrobial concentration inhibiting growth. Used in clinical laboratories; read manually or via automated instruments (WalkAway system or autoSCAN-4). Results assist clinicians in selecting appropriate antimicrobial therapy for patients with gram-negative bacterial infections.

Clinical Evidence

Bench testing only. Performance evaluated using fresh, recent, and stock clinical isolates and challenge strains. Compared against CLSI frozen reference panels. For meropenem: Enterobacteriaceae showed 95.5% Essential Agreement (EA) and 98.8% Categorical Agreement (CA); Pseudomonas aeruginosa showed 93.1% EA and 92.4% CA. Reproducibility and precision testing confirmed acceptable performance across different inoculum methods (Turbidity, Prompt) and instruments (WalkAway, autoSCAN-4). Quality control testing met acceptance criteria.

Technological Characteristics

Miniaturized broth dilution susceptibility test; dehydrated antimicrobial agents in microtiter wells. Rehydrated with water. Dimensions: standard microtiter panel format. Connectivity: compatible with WalkAway and autoSCAN-4 automated reading instruments. Principle: growth inhibition measurement. No specific materials or software architecture details provided beyond standard laboratory panel construction.

Indications for Use

Indicated for determining quantitative and/or qualitative antimicrobial agent susceptibility of colonies grown on solid media of rapidly growing aerobic and facultative anaerobic gram-negative bacilli.

Regulatory Classification

Identification

An antimicrobial susceptibility test powder is a device that consists of an antimicrobial drug powder packaged in vials in specified amounts and intended for use in clinical laboratories for determining in vitro susceptibility of bacterial pathogens to these therapeutic agents. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.

Predicate Devices

• MicroScan Dried Gram-Negative MIC/Combo Panels Eravacycline (K190109)

Submission Summary (Full Text)

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Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
www.fda.gov

# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

## I Background Information:

A 510(k) Number
K192355

B Applicant
Beckman Coulter, Inc.

C Proprietary and Established Names
MicroScan Dried Gram Negative MIC/Combo Panels with Meropenem (Mer) (0.004-32ug/mL)

D Regulatory Information
| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| JWY | Class II | 21 CFR 866.1640 - Antimicrobial Susceptibility Test Powder | MI - Microbiology |

## II Submission/Device Overview:

A Purpose for Submission:
To obtain a substantial equivalence determination for meropenem at concentrations of 0.004 – 32 μg/mL with the MicroScan Dried Gram-Negative MIC/Combo Panels for susceptibility testing of non-fastidious gram negative organisms.

B Measurand:
Meropenem in the dilution range of 0.004-32 μg/mL

C Type of Test:
Quantitative antimicrobial susceptibility test (AST)

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## III Intended Use/Indications for Use:

### A Intended Use(s):

MicroScan Dried Gram-Negative MIC/Combo Panels are designed for use in determining quantitative and/or qualitative antimicrobial agent susceptibility of colonies grown on solid media of rapidly growing aerobic and facultative gram-negative bacilli.

### B Indication(s) for Use:

The MicroScan Dried Gram-Negative MIC/Combo Panel is used to determine quantitative and/or qualitative antimicrobial agent susceptibility of colonies grown on solid media of rapidly growing aerobic and facultative anaerobic gram-negative bacilli. After inoculation, panels are incubated for 16 - 20 hours at 35 °C +/- 1 °C in a non-CO₂ incubator, and read either visually or with MicroScan instrumentation, according to the Package Insert.

This particular submission is for updated breakpoints of Enterobacteriaceae and Pseudomonas aeruginosa for the antimicrobial meropenem (Mer) at concentrations of 0.004 to 32 ug/mL to the test panel.

Meropenem has been shown to be active in vitro against most strains of microorganisms listed below, as described in the FDA-approved package insert for this antimicrobial agent.

Active in vitro and in clinical infections against:

- Escherichia coli
- Klebsiella pneumoniae
- Proteus mirabilis
- Pseudomonas aeruginosa

Active in vitro but clinical significance is unknown:

- Citrobacter freundii
- Citrobacter koseri
- Enterobacter cloacae
- Hafnia alvei
- Klebsiella oxytoca
- Morganella morganii
- Proteus vulgaris
- Serratia marcescens

### C Special Conditions for Use Statement(s):

Rx - For Prescription Use Only

**Limitations**

The ability of the MicroScan Dried Gram Negative Panels to detect resistance to meropenem is unknown for the following species because an insufficient number of resistant strains were available at the time of comparative testing: C. koseri and P. vulgaris. Isolates yielding MIC results suggestive of a resistant interpretive category should be submitted to a reference laboratory.

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Due to the occurrence of very major errors with meropenem and tubidity inoculation with all read methods, isolates of *K. pneumoniae* that provide an MIC of 1 µg/mL should be retested using an alternative/reference method.

## D Special Instrument Requirements:

MicroScan panels can be read either manually or automatically on the WalkAway or autoSCAN-4 instrument systems.

## IV Device/System Characteristics:

### A Device Description:

The MicroScan Dried Gram-Negative MIC/Combo panel with meropenem is used to determine the quantitative and/or qualitative antimicrobial agent susceptibility of aerobic and facultatively anaerobic gram-negative bacilli colonies grown on solid media. After inoculation, panels are incubated for 16-20 hours at 35°C ± 1° in a non-CO₂ incubator and read either visually or with MicroScan instrumentation according to the package insert.

Inoculation methods: Turbidity or Prompt Inoculation System

Read methods: Manual, MicroScan WalkAway System and MicroScan autoSCAN-4

### B Principle of Operation:

The antimicrobial susceptibility tests are dehydrated miniaturizations of the broth dilution susceptibility test. Various antimicrobial agents are diluted in Mueller Hinton broth supplemented with calcium and magnesium to concentrations spanning the range of clinical interest. Breakpoint Combo panels use concentrations equivalent to the categorical breakpoints of FDA and/or CLSI. After inoculation and rehydration with a standardized suspension of organism and incubation at 35°C for a minimum of 16 hours, the minimum inhibitory concentration (MIC) for the test organism is determined by observing the lowest antimicrobial concentration showing inhibition of growth.

## V Substantial Equivalence Information

### A Predicate Device Name(s):

MicroScan Dried Gram Negative MIC/Combo Panels with Eravacycline (ERV) (0.016-32 ug/mL)

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

K190109

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# C Comparison with Predicate(s):

Table 1. Comparison with Predicate

| Device & Predicate Device(s): | Device: K192355 | Predicate: K190109 |
| --- | --- | --- |
| Device Trade Name | MicroScan Dried Gram Negative MIC/Combo Panels - Meropenem | MicroScan Dried Gram Negative MIC/Combo Panels - Eravacycline |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | Determination of susceptibility to with gram-negative bacilli | Determination of susceptibility with gram-negative bacilli |
| Technology | Overnight microdilution MIC susceptibility test | Same |
| Specimen | Isolated colonies from culture | Same |
| Incubation Temperature | 35 °C ± 1°C | Same |
| Incubation Atmosphere | Aerobic | Same |
| Incubation Time | 16-20 hours | Same |
| Reading Method | Automated (WalkAway or autoSCAN-4) or Manual | Same |
| Result Reported | Report results as minimum inhibitory concentration (MIC) and categorical interpretation (SIR) | Same |
| General Device Characteristic Differences | | |
| Antimicrobial Agent | Dried Meropenem 0.004 – 32 μg/mL | Dried Eravacycline 0.016 – 32 μg/mL |

# VI Standards/Guidance Documents Referenced:

1. Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA
2. CLSI M07-A10. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. $10^{\text{th}}$ ed. (January 2015)
3. CLSI M100. Performance Standards for Antimicrobial Susceptibility Testing. $29^{\text{th}}$ ed. (January 2019)

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# VII Performance Characteristics (if/when applicable):

# A Analytical Performance:

# 1. Precision/Reproducibility:

A reproducibility study was conducted at three external sites using 10 isolates of gram-negative bacilli that were consistent with the intended use. The range of meropenem dilutions tested was $0.004 - 32\mu \mathrm{g / mL}$ . Isolates were tested in triplicate over three days for a total of 270 data points (27 data points per isolate). The isolates tested in the reproducibility study included: C. freundii complex (1 isolate), E. aerogenes (3 isolates), E. cloacae (2 isolates), E. coli (1 isolate), K. oxytoca (1 isolates) and P. aeruginosa (2 isolates).

Inocula were prepared using both the turbidity and Prompt methods and results were read manually (visually) and with the WalkAway and autoSCAN-4 instrument systems. All data points were on-scale and the majority were within $\pm$ one doubling dilution of the mode MIC (Table 2). Because all results were on-scale, only a single result is reported for each read method.

The reproducibility results are acceptable.

Table 2. Reproducibility of Meropenem with all Inoculation and Read Methods

| Read Method | Reproducibility No. within ±dilution of the mode MIC value (%) | |
| --- | --- | --- |
| | Prompt Inoculation | Turbidity Inoculation |
| WalkAway | 262/270 (97.0) | 266/270 (98.5) |
| autoSCAN-4 | 263/270 (97.4) | 268/270 (99.3) |
| Manual | 269/270 (99.6) | 270/270 (100.0) |

# 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):

Inoculum Density Check. A spectrophotometric device, the MicroScan Turbidity Meter, was used to ensure the accuracy of the turbidity inoculation method. A zero check of the turbidity meter was performed daily. The inocula prepared using the turbidity method were standardized using a reading of $0.08 \pm 0.02$ (equivalent to a $0.5\mathrm{McFarland}$ barium sulfate

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turbidity standard). The digital reading was recorded for each isolate and was considered acceptable based on recommendations in the Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems.

Inoculum density data for the Prompt inoculation system was collected from suspensions of the QC strain E. coli ATCC 25922 and for all reproducibility isolates. Average colony counts were within the acceptable range for the QC strain and for all reproducibility isolates except for K. oxytoca which showed an elevated colony count at one testing site; however, the reproducibility observed with K. oxytoca was acceptable.

Purity Check. Purity checks were performed on all isolates for each inoculum preparation; only results from pure cultures were included.

Growth Failure Rate. Less than 10% of isolates demonstrated no growth on the dried test panel

Quality Control Testing. The CLSI-recommended QC organisms E. coli ATCC 25922 and P. aeruginosa ATCC 27853 were tested with all inoculation and read methods using fourteen dilutions of meropenem (0.004 – 32 µg/mL). The reference panel was inoculated using the turbidity method only. In this submission, the QC range for P. aeruginosa ATCC 27853 is being updated to the current recommended range of 0.12 – 1 µg/mL from the range of 0.25 – 1 µg/mL utilized for the original meropenem clearance (K971376). For both QC strains, quality control results were within the acceptable range for all inoculation and read methods. Results of current QC testing are shown in Table 3 below and demonstrate that acceptable QC results can be obtained with this device for > 95% of tests.

Table 3. Quality Control Results for all Inoculation and Read Methods for Meropenem

| Organism | Conc. (μg/mL) | Referencea | Prompt Inoculation Method | | | Turbidity Inoculation Method | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Manual | WalkAway | AS4 | Manual | WalkAway | AS4 |
| E. coli ATCC 25922 | ≤0.004 | 1 | - | - | - | - | - | - |
| | 0.008 | 1 | - | - | - | - | - | - |
| | 0.015 | 149 | 77 | 57 | 65 | 131 | 139 | 139 |
| | 0.03 | 36 | 111 | 138 | 130 | 56 | 49 | 47 |
| | 0.06 | - | 9 | - | - | - | - | - |
| | 0.12 | 1 | 1 | 1 | 1 | - | - | - |
| | 0.25 | - | 1 | 2 | 2 | - | - | - |
| | 0.5 | - | - | - | - | - | - | - |
| | 1 | - | - | - | - | - | - | - |
| | 2 | - | - | - | - | - | - | - |
| | 4 | - | - | - | - | 1 | 1 | 1 |
| | 8 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
| | 16 | - | - | - | - | - | - | - |
| | 32 | - | - | - | - | - | - | - |
| | >32 | - | - | 1 | 1 | - | - | - |
| | | | | | | | | |
| P. aeruginosa ATCC 27853 | ≤0.004 | - | - | - | - | - | - | - |
| | 0.008 | - | - | - | - | - | - | - |
| | 0.015 | - | - | - | - | - | - | - |
| | 0.03 | - | - | - | - | - | - | - |

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| Organism | Conc. (μg/mL) | Referencea | Prompt Inoculation Method | | | Turbidity Inoculation Method | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Manual | WalkAway | AS4 | Manual | WalkAway | AS4 |
| Expected Range: 0.12 – 1.0 μg/mL | 0.06 | - | - | - | - | - | - | - |
| | 0.12 | - | - | - | - | 1 | - | - |
| | 0.25 | 122 | 179 | 142 | 154 | 171 | 132 | 149 |
| | 0.50 | 59 | 20 | 49 | 38 | 10 | 37 | 24 |
| | 1 | 7 | 2 | 11 | 8 | 4 | 16 | 11 |
| | 2 | - | - | - | - | - | - | - |
| | 4 | - | - | - | - | 1 | 1 | 1 |
| | 8 | 1 | - | - | - | - | - | - |
| | 16 | - | - | - | - | - | - | - |
| | 32 | - | - | - | - | - | - | - |
| | >32 | - | - | - | - | - | - | - |

a Reference panel was inoculated using the turbidity method and read manually

6. Detection Limit:

Not Applicable

7. Assay Cut-Off:

Not Applicable

8. Accuracy (Instrument):

No Applicable

9. Carry-Over:

Not Applicable

## B Comparison Studies:

1. Method Comparison with Predicate Device:

The results obtained with the MicroScan Dried Gram-Negative MIC/Combo Panel with meropenem (dilution range 0.004 – 32 μg/mL) were compared to results obtained using a frozen broth microdilution reference panel (dilution range 0.004 – 32 μg/mL). Clinical isolates were evaluated at three testing sites in the U.S in a single study; challenge isolates were evaluated in two separate studies performed at internal and external sites.

The reference panel was prepared as described in CLSI document M07-A10 except for the use of Pluronic-F in the inoculum water for the reference panel. A validation study was performed to demonstrate the equivalence between reference panels inoculated with organisms suspended in water supplemented with Pluronic-F and reference panels inoculated with autoclaved deionized water without Pluronic-F. The effect of Pluronic-F in the reference panel was determined with 11 replicates each of the quality control strains *E. coli* ATCC 25922 and *P. aeruginosa* ATCC 27853; 100% of results were within the expected QC range with both inoculum preparations.

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For the reference method and MicroScan panels inoculated using the turbidity method, panels were inoculated using the same standardized suspension further diluted into 25 mL of water with Pluronic-D (for the MicroScan dried panels) or Pluronic-F (for the frozen reference panels). MicroScan panels were also inoculated using the Prompt inoculation method with isolates inoculated into the Prompt inoculation bottle. Reference panels were read manually (visually); MicroScan panels inoculated with both inoculation methods were read using the WalkAway and autoSCAN-4 instruments and by manual read.

## Clinical Study

To determine the performance of the MicroScan Dried Gram-Negative MIC/Combo Panel with Meropenem, a total of 528 Enterobacteriaceae clinical isolates were evaluated with all inoculation and read methods (Tables 4 and 5). The testing included the following indicated species: C. freundii (15 isolates), C. koseri (3 isolates), E. cloacae complex (41 isolates), E. coli (214 isolates), H. alvei (1 isolate), K. oxytoca (14 isolates), K. pneumoniae (71 isolates), M. morganii (16 isolates), P. mirabilis (89 isolates), P. vulgaris (2 isolates) and S. marcescens (34 isolates). An additional 28 isolates of non-indicated Enterobacteriaceae species (10% of the total number of isolates tested) were also evaluated. Of the Enterobacteriaceae isolates, 448 (84.8%) were fresh isolates (tested within seven days of isolation) and 80 (15.2%) were stock isolates.

A total of 87 clinical isolates of P. aeruginosa were evaluated, 77 of which (88.5%) were fresh isolates and 10 (11.5%) were stock isolates (Tables 4 and 5).

## Challenge Study

A total of 122 Enterobacteriaceae challenge isolates were evaluated. These included: C. freundii (4 isolates), C. koseri (9 isolates), E. cloacae complex (13 isolates), E. coli (15 isolates), H. alvei (10 isolates), K. oxytoca (3 isolates), K. pneumoniae (29 isolates), M. morganii (3 isolates), P. mirabilis (6 isolates), P. vulgaris (21 isolates) and S. marcescens (5 isolates). In addition, four isolates of the non-indicated species, K. aerogenes, were evaluated.

A total of 44 challenge isolates of P. aeruginosa were evaluated. See Tables 4 and 5.

Results for EA, CA and categorical errors for Enterobacteriaceae and P. aeruginosa for all inoculation and read methods are shown in Tables 4 and 5 below. Essential agreement of evaluable results was calculated considering MIC results that were clearly identical to reference method results or clearly ≥ one doubling dilution higher or lower than the reference method results. Overall results for Enterobacteriaceae and for P. aeruginosa with all inoculation and read methods were acceptable.

For C. koseri and P. vulgaris, no resistant isolates were available for evaluation during clinical or challenge testing. The sponsor included the following limitation in the device labeling:

The ability of the MicroScan Dried Gram Negative Panels to detect resistance to meropenem is unknown for the following species because an insufficient number of resistant strains were available at the time of comparative testing: C. koseri and P.

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vulgaris. Isolates yielding MIC results suggestive of a resistant interpretive category should be submitted to a reference laboratory.

For K. pneumoniae inoculated with the turbidity method, one very major error was observed with the WalkAway and autoSCAN-4 read method for a very major error rate of 3.3%. With the turbidity inoculation method and manual read, two very major errors with K. pneumoniae were observed (6.7%). The sponsor included the following limitation in the device labeling to address the potential for very major errors with this species:

Due to the occurrence of very major errors with meropenem and turbidity inoculation with all read methods, isolates of K. pneumoniae that provide an MIC of 1 µg/mL should be retested using an alternative/reference method.

One of two resistant isolates of H. alvei showed a very major error (50.0%) with the turbidity inoculation method and manual read. The sponsor included the following footnote to the performance table in the device labeling:

One of the two resistant Hafnia alvei strains had a discrepant result compared to the reference method when using the manual read and turbidity inoculation method.

To address the testing and reporting of meropenem results for non-indicated species, the sponsor included the following statement in the Warnings and Precautions section of the device labeling:

The safety and efficacy of antimicrobial agents tested by this 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 section in the drug label. The clinical significance in those instances is unknown. The approved labeling for specific antimicrobial agents provides the uses for which the antimicrobial drug is approved.

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Table 4. Performance of MicroScan Dried Gram-Negative Panels with Meropenem, Using Prompt Inoculation and All Read Methods

| | Tot | No. EA | EA % | Eval EA Tot | No. Eval EA | Eval EA % | No. CA | CA % | No. R | No. S | min | maj | vmj |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| WalkAway Read | | | | | | | | | | | | | |
| Enterobacteriaceae | | | | | | | | | | | | | |
| Clinical | 528 | 506 | 95.8 | 526 | 504 | 95.8 | 528 | 100.0 | 18 | 510 | 0 | 0 | 0 |
| Challenge | 122 | 115 | 94.3 | 109 | 103 | 94.5 | 114 | 93.4 | 51 | 65 | 8 | 0 | 0 |
| Combined | 650 | 621 | 95.5 | 635 | 607 | 95.6 | 642 | 98.8 | 69 | 575 | 8 | 0 | 0 |
| P. aeruginosa | | | | | | | | | | | | | |
| Clinical | 87 | 79 | 90.8 | 82 | 75 | 91.5 | 81 | 93.1 | 12 | 71 | 5 | 1 | 0 |
| Challenge | 44 | 43 | 97.7 | 20 | 19 | 95.0 | 40 | 90.9 | 34 | 7 | 3 | 1 | 0 |
| Combined | 131 | 122 | 93.1 | 102 | 94 | 92.2 | 121 | 92.4 | 46 | 78 | 8 | 2 | 0 |
| | | | | | | | | | | | | | |
| autoSCAN-4 Read | | | | | | | | | | | | | |
| Enterobacteriaceae | | | | | | | | | | | | | |
| Clinical | 528 | 508 | 96.2 | 526 | 506 | 96.2 | 528 | 100.0 | 18 | 510 | 0 | 0 | 0 |
| Challenge | 122 | 115 | 94.3 | 109 | 103 | 94.5 | 114 | 93.4 | 51 | 65 | 8 | 0 | 0 |
| Combined | 650 | 623 | 95.8 | 635 | 609 | 95.9 | 642 | 98.8 | 69 | 575 | 8 | 0 | 0 |
| P. aeruginosa | | | | | | | | | | | | | |
| Clinical | 87 | 76 | 87.4 | 84 | 73 | 86.9 | 80 | 92.0 | 12 | 71 | 6 | 0 | 1 |
| Challenge | 44 | 43 | 97.7 | 21 | 20 | 95.2 | 40 | 90.9 | 34 | 7 | 3 | 1 | 0 |
| Combined | 131 | 119 | 90.8 | 105 | 93 | 88.6 | 120 | 91.6 | 46 | 78 | 9 | 1 | 1 |
| | | | | | | | | | | | | | |
| Manual Read | | | | | | | | | | | | | |
| Enterobacteriaceae | | | | | | | | | | | | | |
| Clinical | 528 | 507 | 96.0 | 526 | 505 | 96.0 | 527 | 99.8 | 18 | 510 | 1 | 0 | 0 |
| Challenge | 122 | 114 | 93.4 | 108 | 101 | 93.5 | 113 | 92.6 | 51 | 65 | 9 | 0 | 0 |
| Combined | 650 | 621 | 95.5 | 634 | 606 | 95.6 | 640 | 98.5 | 69 | 575 | 10 | 0 | 0 |
| P. aeruginosa | | | | | | | | | | | | | |
| Clinical | 87 | 79 | 90.8 | 85 | 77 | 90.6 | 82 | 94.3 | 12 | 71 | 5 | 0 | 0 |
| Challenge | 44 | 43 | 97.7 | 21 | 20 | 95.2 | 40 | 90.9 | 34 | 7 | 3 | 1 | 0 |
| Combined | 131 | 122 | 93.1 | 106 | 97 | 91.5 | 122 | 93.1 | 46 | 78 | 8 | 1 | 0 |

EA - Essential Agreement (± 1 dilution)
min - minor discrepancies
CA - Category Agreement
maj - major discrepancies
EVAL - Evaluable isolates
vmj - very major discrepancies
NS - Non-Susceptible isolates

Essential agreement (EA) occurs when the result of the reference method and that of the MicroScan Dried Gram-Negative MIC/Combo Panel are within plus or minus one serial two-fold dilution of the antibiotic. Evaluable results are those that are on scale for both the reference method and the MicroScan Dried Gram-Negative MIC/Combo Panel. Category agreement (CA) occurs when the interpretation of the result of the reference method agrees exactly with the interpretation provided by the MicroScan Dried Gram-Negative MIC/Combo Panel.

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Table 5. Performance of MicroScan Dried Gram-Negative Panels with Meropenem, Using Turbidity Inoculation and All Read Methods

| | Tot | No. EA | EA % | Eval EA Tot | No. Eval EA | Eval EA % | No. CA | CA % | No. R | No. S | min | maj | vmj |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| WalkAway Read | | | | | | | | | | | | | |
| Enterobacteriaceae | | | | | | | | | | | | | |
| Clinical | 528 | 518 | 98.1 | 526 | 516 | 98.1 | 525 | 99.4 | 18 | 510 | 2 | 1 | 0 |
| Challenge | 122 | 112 | 91.8 | 110 | 101 | 91.8 | 112 | 91.8 | 51 | 65 | 8 | 1 | 1 |
| Combined | 650 | 630 | 96.9 | 636 | 617 | 97.0 | 637 | 98.0 | 69 | 575 | 10 | 2 | 1 |
| P. aeruginosa | | | | | | | | | | | | | |
| Clinical | 87 | 80 | 92.0 | 84 | 77 | 91.7 | 85 | 97.7 | 12 | 71 | 2 | 0 | 0 |
| Challenge | 45 | 45 | 100.0 | 21 | 21 | 100.0 | 42 | 93.3 | 35 | 7 | 3 | 0 | 0 |
| Combined | 132 | 125 | 94.7 | 105 | 98 | 93.3 | 127 | 96.2 | 47 | 78 | 5 | 0 | 0 |
| | | | | | | | | | | | | | |
| autoSCAN-4 Read | | | | | | | | | | | | | |
| Enterobacteriaceae | | | | | | | | | | | | | |
| Clinical | 528 | 517 | 97.9 | 526 | 515 | 97.9 | 526 | 99.6 | 18 | 510 | 1 | 1 | 0 |
| Challenge | 122 | 114 | 93.4 | 110 | 102 | 92.7 | 112 | 91.8 | 51 | 65 | 8 | 1 | 1 |
| Combined | 650 | 631 | 97.1 | 636 | 617 | 97.0 | 638 | 98.2 | 69 | 575 | 9 | 2 | 1 |
| P. aeruginosa | | | | | | | | | | | | | |
| Clinical | 87 | 78 | 89.7 | 85 | 76 | 89.4 | 84 | 96.6 | 12 | 71 | 3 | 0 | 0 |
| Challenge | 45 | 45 | 100.0 | 23 | 23 | 100.0 | 42 | 93.3 | 35 | 7 | 3 | 0 | 0 |
| Combined | 132 | 123 | 93.2 | 108 | 99 | 91.7 | 126 | 95.5 | 47 | 78 | 6 | 0 | 0 |
| | | | | | | | | | | | | | |
| Manual Read | | | | | | | | | | | | | |
| Enterobacteriaceae | | | | | | | | | | | | | |
| Clinical | 528 | 519 | 98.3 | 526 | 517 | 98.3 | 523 | 99.1 | 18 | 510 | 2 | 1 | 2 |
| Challenge | 122 | 115 | 94.3 | 110 | 103 | 93.6 | 114 | 93.4 | 51 | 65 | 6 | 1 | 1 |
| Combined | 650 | 634 | 97.5 | 636 | 620 | 97.5 | 637 | 98.0 | 69 | 575 | 8 | 2 | 3 |
| P. aeruginosa | | | | | | | | | | | | | |
| Clinical | 87 | 80 | 92.0 | 84 | 77 | 91.7 | 85 | 97.7 | 12 | 71 | 2 | 0 | 0 |
| Challenge | 45 | 45 | 100.0 | 24 | 24 | 100.0 | 40 | 88.9 | 35 | 7 | 5 | 0 | 0 |
| Combined | 132 | 125 | 94.7 | 108 | 101 | 93.5 | 125 | 94.7 | 47 | 78 | 7 | 0 | 0 |

## Resistance Mechanism Characterization

Challenge isolates of Enterobacteriaceae and P. aeruginosa harboring various molecular mechanisms of resistance noted in the FDA approved drug label were tested with meropenem. Isolates from the following CDC and FDA Antibiotic Resistance Isolate Bank panels were evaluated: Enterobacteriaceae Carbapenem Breakpoint Panel, Enterobacteriaceae Carbapenemase Diversity Panel and the Gram Negative Carbapenemase Detection Panel.

## Trending

An analysis of trending was conducted using the combined clinical and challenge data for each organism group and for each inoculation and read method. This trending calculation takes into account MIC values that are determined to be one or more doubling dilution lower or higher compared to the reference method irrespective of whether the device MIC values are on scale or not. Results that are not clearly at least one dilution lower, at least one dilution higher or in exact agreement with the CLSI reference method are not considered in the trending analysis.

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Trending results for indicated species were evaluated to determine if species-specific trends were observed. Species or organism groups for which the difference between the percentage of isolates with higher vs. lower readings was $>30\%$ and for which the confidence interval was determined to be statistically significant were considered to show evidence of trending. Trending that provides higher or lower MIC values compared to the reference is addressed in labeling.

A trend toward lower MIC readings was observed for $P$ aeruginosa using the manual read method with the turbidity inoculation method. While no trending was observed overall for Enterobacteriaceae, a trend toward higher readings was observed for $C$ koseri and $E$ coli with Prompt inoculation and all read methods, for $P$ mirabilis with Prompt inoculation and WalkAway and manual reads and for $P$ vulgaris with Prompt and manual read. A trend toward lower readings was observed for $M$ morganii with turbidity inoculation and all read methods and for $P$ vulgaris with turbidity and autoScan-4 read. The sponsor included the following footnote to the performance table in the device labeling:

Meropenem MIC values for Enterobacteriaceae and Pseudomonas aeruginosa were most frequently in exact agreement with the reference method. When not in agreement, results tended to be one doubling dilution lower for $P$ aeruginosa (turbidity, manual read), $P$ vulgaris (Turbidity, AutoScan-4 read) and $M$ morganii (Turbidity, all read methods). Results tended to be one doubling dilution higher for $C$ koseri and $E$ coli (Prompt, all read methods, $P$ vulgaris (Prompt, manual read) and $P$ mirabilis (Prompt, WalkAway and manual read).

Table 6. Trending for all Species with all Inoculation and Read Methods

| Inoculation/ Read Method | Organism | Total Evaluable for Trending | ≥1 Dilution lower No. (%) | Exact No. (%) | ≥1 Dilution Higher No. (%) | Percent Difference (CI) | Trending Noted |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Prompt/ WalkAway | Enterobacteriaceae | 603 | 41 (6.8) | 367 (60.9) | 195 (32.3) | 25.5 | No |
| | C. freundii | 19 | 2 (10.5) | 15 (79.0) | 2 (10.5) | 0 | No |
| | C. koseri | 12 | 0 | 7 (58.3) | 5 (41.7) | 41.7 | Yes |
| | E. cloacae complex | 53 | 8 (15.1) | 30 (56.6) | 15 (28.3) | 13.2 | No |
| | E. coli | 225 | 7 (3.1) | 133 (59.1) | 85 (37.8) | 34.7 | Yes |
| | H. alvei | 11 | 1 (9.1) | 6 (54.6) | 4 (36.4) | 27.3 | No |
| | K. oxytoca | 17 | 0 | 13 (76.5) | 4 (23.5) | 23.5 | No |
| | K. pneumoniae | 95 | 7 (7.4) | 68 (71.6) | 20 (21.1) | 13.7 | No |
| | M. morganii | 19 | 3 (15.8) | 12 (63.2) | 4 (21.1) | 5.3 | No |
| | P. mirabilis | 94 | 9 (9.6) | 43 (45.7) | 42 (44.7) | 35.1 | Yes |
| | P. vulgaris | 23 | 4 (17.4) | 12 (52.2) | 7 (30.4) | 13.0 | No |
| | S. marcescens | 35 | 0 | 28 (80.0) | 7 (20.0) | 20.0 | No |
| | P. aeruginosa | 103 | 33 (32.0) | 45 (43.7) | 25 (24.3) | -7.8 | No |
| | | | | | | | |
| Prompt/ autoSCAN-4 | Enterobacteriaceae | 603 | 55 (9.1) | 357 (59.2) | 191 (31.7) | 22.6 | No |
| | C. freundii | 19 | 2 (10.5) | 15 (79.0) | 2 (10.5) | 0 | No |
| | C. koseri | 12 | 0 | 7 (58.3) | 5 (41.7) | 41.7 | Yes |
| | E. cloacae complex | 53 | 7 (13.2) | 29 (54.7) | 17 (32.1) | 18.9 | No |
| | E. coli | 225 | 7 (3.1) | 127 (56.4) | 91 (40.4) | 37.3 | Yes |
| | H. alvei | 11 | 1 (9.1) | 7 (63.6) | 3 (27.3) | 18.2 | No |
| | K. oxytoca | 17 | 0 | 13 (76.5) | 4 (23.5) | 23.5 | No |
| | K. pneumoniae | 95 | 7 (7.4) | 66 (69.5) | 22 (23.2) | 15.8 | No |
| | M. morganii | 19 | 4 (21.1) | 12 (63.2) | 3 (15.8) | -5.3 | No |
| | P. mirabilis | 94 | 11 (11.7) | 45 (47.9) | 38 (40.4) | 28.7 | No |
| | P. vulgaris | 23 | 8 (34.8) | 13 (56.5) | 2 (8.7) | -26.1 | No |

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| Inoculation/ReadMethod | Organism | TotalEvaluableforTrending | ≥1DilutionlowerNo. (%) | Exact No.(%) | ≥1DilutionHigherNo. (%) | PercentDifference(CI) | TrendingNoted |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | S. marcescens | 35 | 8 (22.9) | 23 (65.7) | 4 (11.4) | -11.4 | No |
| | P. aeruginosa | 105 | 35 (34.7) | 49 (46.7) | 21 (20.0) | -13.3 | No |
| | | | | | | | |
| Prompt/Manual | Enterobacteriaceae | 603 | 42 (7.0) | 366 (60.8) | 194 (32.2) | 25.3 | No |
| | C. freundii | 19 | 3 (15.8) | 14 (73.7) | 2 (10.5) | -5.3 | No |
| | C. koseri | 12 | 0 | 7 (58.3) | 5 (41.7) | 41.7 | Yes |
| | E. cloacae complex | 53 | 8 (15.1) | 29 (54.7) | 16 (30.2) | 15.1 | No |
| | E. coli | 224 | 6 (2.7) | 132 (59.0) | 86 (38.4) | 35.7 | Yes |
| | H. alvei | 11 | 1 (9.1) | 7 (63.6) | 3 (27.3) | 18.2 | No |
| | K. oxytoca | 17 | 0 | 12 (70.6) | 5 (29.4) | 29.4 | No |
| | K. pneumoniae | 95 | 8 (8.4) | 68 (71.6) | 19 (20.0) | 11.6 | No |
| | M. morganii | 19 | 4 (21.1) | 12 (63.2) | 3 (15.8) | -5.3 | No |
| | P. mirabilis | 94 | 6 (6.4) | 51 (54.3) | 37 (39.4) | 33.0 | Yes |
| | P. vulgaris | 23 | 2 (8.7) | 9 (39.1) | 12 (52.2) | 43.5 | Yes |
| | S. marcescens | 35 | 4 (11.4) | 25 (71.4) | 6 (17.1) | 5.7 | No |
| | P. aeruginosa | 105 | 48 (45.7) | 39 (37.1) | 18 (17.1) | -28.6 | No |
| | | | | | | | |
| Turbidity/WalkAway | Enterobacteriaceae | 604 | 77 (12.8) | 410 (67.9) | 117 (19.4) | 6.6 | No |
| | C. freundii | 19 | 3 (15.8) | 14 (73.7) | 2 (10.5) | -5.26 | No |
| | C. koseri | 12 | 1 (8.3) | 9 (75.0) | 2 (16.7) | 8.3 | No |
| | E. cloacae complex | 54 | 12 (22.2) | 36 (66.7) | 6 (11.1) | -11.1 | No |
| | E. coli | 225 | 17 (7.6) | 157 (69.8) | 51 (22.7) | 15.1 | No |
| | H. alvei | 11 | 2 (18.2) | 7 (63.6) | 2 (18.2) | 0 | No |
| | K. oxytoca | 17 | 1 (5.9) | 14 (82.4) | 2 (11.8) | 5.9 | No |
| | K. pneumoniae | 95 | 16 (16.8) | 66 (69.5) | 13 (13.7) | -3.2 | No |
| | M. morganii | 19 | 7 (36.8) | 11 (57.9) | 1 (5.3) | -31.6 | Yes |
| | P. mirabilis | 94 | 11(11.7) | 53 (56.4) | 30 (31.9) | 20.2 | No |
| | P. vulgaris | 23 | 5 (21.7) | 14 (60.9) | 4 (17.4) | -4.4 | No |
| | S. marcescens | 35 | 2 (5.7) | 29 (82.9) | 4 (11.4) | 5.7 | No |
| | P. aeruginosa | 105 | 32 (30.5) | 52 (49.5) | 21 (20.0) | -10.5 | No |
| | | | | | | | |
| Turbidity/autoSCAN-4 | Enterobacteriaceae | 607 | 89 (14.7) | 409 (67.1) | 111 (18.3) | 3.6 | No |
| | C. freundii | 19 | 3 (15.8) | 14 (73.7) | 2 (10.5) | -5.26 | No |
| | C. koseri | 12 | 1 (8.3) | 9 (75.0) | 2 (16.7) | 8.3 | No |
| | E. cloacae complex | 54 | 10 (18.5) | 38 (70.4) | 6 (11.1) | -7.4 | No |
| | E. coli | 225 | 17 (7.6) | 155 (68.9) | 53 (23.6) | 16.0 | No |
| | H. alvei | 11 | 3 (27.3) | 8 (72.7) | 0 | -27.3 | No |
| | K. oxytoca | 17 | 1 (5.9) | 14 (82.4) | 2 (11.8) | 5.9 | No |
| | K. pneumoniae | 95 | 15 (15.8) | 68 (71.6) | 12 (12.6) | -3.2 | No |
| | M. morganii | 19 | 7 (36.8) | 11 (57.9) | 1 (5.3) | -31.6 | Yes |
| | P. mirabilis | 94 | 13 (13.8) | 50 (53.2) | 31 (33.0) | 19.2 | No |
| | P. vulgaris | 23 | 11 (47.8) | 12 (52.2) | 0 | -47.8 | Yes |
| | S. marcescens | 38 | 8 (21.1) | 28 (73.7) | 2 (5.3) | -15.8 | No |
| | P. aeruginosa | 108 | 32 (29.6) | 60 (55.6) | 16 (14.8) | -14.8 | No |
| | | | | | | | |
| Turbidity/Manual | Enterobacteriaceae | 604 | 72 (11.9) | 423 (70.0) | 109 (18.1) | 6.1 | No |
| | C. freundii | 19 | 4 (21.1) | 14 (73.7) | 1 (5.3) | -15.8 | No |
| | C. koseri | 12 | 1 (8.3) | 9 (75.0) | 2 (16.7) | 8.3 | No |
| | E. cloacae complex | 54 | 14 (25.9) | 34 (63.0) | 6 (11.1) | -14.8 | No |
| | E. coli | 225 | 14 (6.2) | 159 (70.7) | 52 (23.1) | 16.9 | No |
| | H. alvei | 11 | 3 (27.3) | 8 (72.7) | 0 | -27.3 | No |
| | K. oxytoca | 17 | 1 (5.9) | 13 (76.5) | 3 (17.7) | 11.8 | No |
| | K. pneumoniae | 95 | 15 (15.8) | 66 (69.5) | 14 (14.7) | -1.1 | No |
| | M. morganii | 19 | 7 (36.8) | 11 (57.9) | 1 (5.3) | -31.6 | Yes |
| | P. mirabilis | 94 | 6 (6.4) | 65 (69.2) | 23 (24.5) | 18.1 | No |
| | P. vulgaris | 23 | 3 (13.0) | 18 (78.3) | 2 (8.7) | -4.4 | No |
| | S. marcescens | 35 | 4 (11.4) | 26 (74.3) | 5 (14.3) | 2.9 | No |
| | P. aeruginosa | 107 | 47 (43.9) | 51 (47.7) | 9 (8.4) | -35.5 | Yes |

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2. Matrix Comparison:

Not Applicable

# C Clinical Studies:

1. Clinical Sensitivity:

Not Applicable

2. Clinical Specificity:

Not Applicable

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

Not Applicable

# D Clinical Cut-Off:

Not Applicable

# Expected Values/Reference Range:

Table 7. FDA-Recognized Interpretive Criteria for Meropenem

| Organism | Interpretive Criteria for Meropenem MIC (μg/mL)a | | |
| --- | --- | --- | --- |
| | Susceptible | Intermediate | Resistant |
| Enterobacteriaceae | ≤1 | 2 | ≥4 |
| P. aeruginosa | ≤2 | 4 | ≥8 |

a FDA STIC Webpage
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm410971.htm

# F Other Supportive Instrument Performance Characteristics Data:

Not applicable

# 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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{14}

To support the implementation of changes to FDA-recognized susceptibility test interpretive criteria (i.e., breakpoints), this submission included a breakpoint change protocol that was reviewed and accepted by FDA. This protocol addresses future revisions to device labeling in response to breakpoint changes that are recognized on the FDA STIC webpage (https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm410971.htm). The protocol outlined the specific procedures and acceptance criteria that Beckman Coulter intends to use to evaluate the MicroScan Dried Gram-Negative MIC/Combo Panels with Meropenem (Mer) (0.004 - 32 µg/mL) when revised breakpoints for meropenem are published on the FDA STIC webpage. The breakpoint change protocol included with the submission indicated that if specific criteria are met, Beckman Coulter will update the meropenem device label to include (1) the new breakpoints, (2) an updated performance section after re-evaluation of data in this premarket notification with the new breakpoints, and (3) any new limitations as determined by their evaluation.

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