MICROSCAN MICROSTEP

K111394 · Siemens Healthcare Diagnostics, Inc. · LTT · Jun 22, 2011 · Microbiology

Device Facts

• Record ID: K111394
• Device Name: MICROSCAN MICROSTEP
• Applicant: Siemens Healthcare Diagnostics, Inc.
• Product Code: LTT · Microbiology
• Decision Date: Jun 22, 2011
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.1640
• Device Class: Class 2

Indications for Use

The MicroScan® MICroSTREP plus® Panel is used to determine quantitative and/or qualitative antimicrobial agent susceptibility of colonies grown on solid media of aerobic streptococci. After inoculation, panels are incubated for 20 - 24 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 the addition of the antimicrobial Daptomycin at concentrations of 0.25 to 8 µg/ml to the test panel. The organisms which may be used for Daptomycin susceptibility testing in this panel are: Streptococcus pyogenes Streptoccocus agalactiae Streptococcus dysglactiae subsp.equisimilis

Device Story

MicroScan MICroSTREP plus panels are miniaturized broth dilution susceptibility tests; dehydrated antimicrobial agents in wells. Clinical lab personnel inoculate panels with standardized organism suspensions in Mueller-Hinton broth supplemented with 2-5% lysed horse blood. Panels incubated 20-24 hours at 35°C in non-CO2 incubator. Minimum Inhibitory Concentration (MIC) determined by manual visual inspection or automated reading via MicroScan WalkAway System. Output provides quantitative/qualitative susceptibility data; assists clinicians in selecting appropriate antibiotic therapy for streptococcal infections.

Clinical Evidence

Bench testing only. Performance evaluated using fresh and stock efficacy isolates and challenge strains. Compared against CLSI frozen reference panel. Overall Essential Agreement for Daptomycin was 97%. Reproducibility and precision demonstrated for both manual and automated (WalkAway) read methods. Quality control testing met acceptance criteria.

Technological Characteristics

Miniaturized broth dilution panel; dehydrated antimicrobial agents in wells. Rehydrated with Mueller-Hinton broth + 2-5% lysed horse blood. Manual or automated (WalkAway system) optical reading. Non-CO2 incubation at 35°C. Standalone or integrated with MicroScan instrumentation.

Indications for Use

Indicated for determining antimicrobial susceptibility of aerobic streptococci (Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis) to Daptomycin (0.25–8 µg/mL). For prescription use.

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 MICroSTREP plus Panels - Levofloxacin (K020556)

Submission Summary (Full Text)

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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE

A. 510(k) Number:
k111394

B. Purpose for Submission:
To obtain a substantial equivalence determination for the addition of Daptomcyin to the MicroScan® MICroSTREP plus® Panel.

C. Measurand:
Daptomycin, concentrations of 0.25 – 8 µg/mL

D. Type of Test:
Antimicrobial Susceptibility Test (AST) Growth Based Detection Method

E. Applicant:
Siemens Healthcare Diagnostics

F. Proprietary and Established Names:
MicroScan® MICroSTREP plus® Panel

G. Regulatory Information:
1. Regulation section:
866.1640 Antimicrobial Susceptibility Test (AST) Powder
2. Classification:
II
3. Product codes:
LTT- Panels, Test, Susceptibility, Antimicrobial
LTW- Susceptibility Test Cards, Antimicrobial
JWY - Manual Antimicrobial Susceptibility Test Systems

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LRG- Instrument for AutoReader & Interpretation of Overnight Susceptibility Systems

4. Panel:

83, Microbiology

H. Intended Use:

1. Intended use(s):

MICroSTREP plus® panels are designed for use in determining quantitative and/or qualitative antimicrobial agent susceptibility of colonies grown on solid media of aerobic streptococci, including *Streptococcus pneumoniae*.

The MicroScan® MICroSTREP plus® Panel is used to determine quantitative and/or qualitative antimicrobial agent susceptibility of colonies grown on solid media of aerobic streptococci. After inoculation, panels are incubated for 20 - 24 hours at $35^{\circ}\mathrm{C} \pm 1^{\circ}\mathrm{C}$ in a non- $\mathrm{CO}_{2}$ incubator, and read either visually or with MicroScan instrumentation, according to the Package insert. This particular submission is for the addition of the antimicrobial Daptomycin at concentrations of 0.25 to $8\ \mu\mathrm{g/ml}$ to the test panel.

2. Indication(s) for use:

The MicroScan® MICroSTREP plus® Panel is used to determine quantitative and/or qualitative antimicrobial agent susceptibility of colonies grown on solid media of aerobic streptococci. After inoculation, panels are incubated for 20 - 24 hours at $35^{\circ}\mathrm{C} \pm 1^{\circ}\mathrm{C}$ in a non- $\mathrm{CO}_{2}$ incubator, and read either visually or with MicroScan instrumentation, according to the Package Insert.

This particular submission is for the addition of the antimicrobial Daptomycin at concentrations of 0.25 to $8\ \mu\mathrm{g/ml}$ to the test panel.

The organisms which may be used for Daptomycin susceptibility testing in this panel are:

- *Streptococcus pyogenes*
- *Streptococcus agalactiae*
- *Streptococcus dysgalactiae* subsp. *equisimilis*.

3. Special conditions for use statement(s):

For prescription use

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# 4. Special instrument requirements:

Manual readings and MicroScan® WalkAway® Instrument

# I. Device Description:

The MicroScan® MICroSTREP plus® Panel is used to determine quantitative and/or qualitative antimicrobial agent susceptibility of colonies grown on solid media of aerobic streptococci. After inoculation, panels are incubated for 20 -24 hours at $35^{\circ}\mathrm{C} + / - 1^{\circ}\mathrm{C}$ in a non- $\mathrm{CO}_{2}$ incubator, and read either visually or with MicroScan instrumentation, according to the Package insert.

Primary Read Method: Manual; Alternate Read Method: MicroScan® WalkAway System®

The MIC interpretive criteria for daptomycin are as follows:

| Organism | Susceptibility Interpretive Criteria (MIC* in μg/mL): | | |
| --- | --- | --- | --- |
| | S | I | R |
| Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus dysgalactiae subsp. equisimilis | ≤ 1 | - | ≥ |

*Currently there are no intermediate or resistant interpretive criteria for daptomycin. The current absence of data on daptomycin-resistant isolates precludes defining any categories other than "Susceptible." Isolates yielding test results suggestive of a "Non-Susceptible" category should be retested, and if the result is confirmed, the isolate should be submitted to a reference laboratory for further testing.

$^{*}\mathrm{S} =$ Susceptible: Attainable levels in blood or tissue on usual usage, including oral administration when applicable.

$\mathrm{I} =$ Intermediate: The intermediate category implies clinical efficacy in body sites where the drugs are physiologically concentrated (e.g. quinolones and B-lactams in urine), or when a higher than normal dosage of drug can be used (e.g. B-lactams). The "intermediate" category also includes a "buffer zone" which should prevent small, uncontrolled, technical factors from causing major discrepancies in interpretations, especially for drugs with narrow pharmacotoxicity margins.

$\mathrm{R} =$ Resistant to usually achievable systemic concentrations.

# J. Substantial Equivalence Information:

# 1. Predicate device name(s):

MicroScan MICroSTREP plus Panel - Levofloxacin

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2. Predicate 510(k) number(s):

k020556

3. Comparison with predicate:

| Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Intended Use | Determination of susceptibility to Daptomycin with aerobic streptococci | Determination of susceptibility to Levofloxacin with aerobic streptococci including S. pneumoniae |
| Incubation Temperature | 35° | Same |
| Inoculation | Isolated colonies from culture used | Same |
| Result | MIC | MIC |
| Incubation Atmosphere | Aerobic | Aerobic |
| Differences | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Product Name | MicroScan MICroSTREP plus - Daptomycin | MicroScan MICroSTREP plus - Levofloxacin |
| Antibiotic | Daptomycin 0.25 - 8 μg/ml | Levofloxacin 0.12 - 16 μg/ml |
| Labeling Limitations | The current absence of resistant isolates precludes defining any category other than Susceptible. Isolates yielding MIC results suggestive of Non-susceptible category should be subjected to additional testing. | The ability of the MICroSTREP plus panel to detect resistance to Levofloxacin is unknown due to the lack of sufficient resistant strains at the time of comparative testing. |
| Organisms in intended use | Aerobic streptococci | Aerobic streptococci including S. pneumoniae |

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

1. Guidance for Industry and FDA- Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; August 28, 2009.
2. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacterial That Grow Aerobically, Approved Standard- 8th Edition, Document M07-A8
3. CLSI. Performance Standards for Antimicrobial Susceptibility Testing Approved Standard-, 19th Informational Supplement, Document M100-S19

L. Test Principle:

The antimicrobial agent is diluted in water, buffer, or minute concentrations of broth to concentrations bridging the range of clinical interest. Panels are rehydrated with 115 µg Mueller-Hinton Broth supplemented with 2-5% lysed horse blood (LHB), after inoculation of the broth with a standardized suspension of the organism. After incubation in a non-CO₂ incubator for 20-24 hours, the minimum inhibitory concentration (MIC) for the test organism is manually read by visually observing the lowest antimicrobial concentration showing inhibition of growth. Alternatively, the panel can be incubated in and read by the MicroScan® WalkAway® System.

M. Performance Characteristics (if/when applicable):

1. Analytical performance:

a. Precision/Reproducibility:

A reproducibility study was conducted at three study sites.

Each site tested a minimum of 10 on-scale reproducibility organisms per antimicrobial agent. Selection of isolates included organisms with on-scale expected results for each antimicrobial agent included in this study. These isolates may have been selected from the challenge isolates.

Reproducibility was performed using plates with long dilution range and shortened dilution range (mapped). Because mapped dilutions have narrow range, several MIC values were off-scale. Only reproducibility calculations from the long dilution range are presented here.

Reproducibility was calculated as the percent of results for the combined sites which were within +/- one doubling dilution of the mode MIC value for all

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sites. Each reproducibility organism was tested in triplicate on the dried Test panel and singly on the frozen reference panel on three different days at each site. Dried test panels were tested with the turbidity inoculation method and read manually and on the MicroScan WalkAway System.

For reproducibility calculations, off-scale values are handled in two ways; "best case" and "worst case" scenarios. Best case calculation for reproducibility assumes the off-scale result is within one well from the mode MIC value. Worst case calculation for reproducibility assuming the off-scale result is greater than one well from the mode MIC value.

The overall best case and worst case reproducibility values for manual read and WalkAway for long dilution range are shown below. These results met the acceptance criteria.

| Inoculation Method | Read Method | % Reproducible (Best case-all sites) | % Reproducible (Worst case-all sites) |
| --- | --- | --- | --- |
| Turbidity | Manual | 98.5 | 98.5 |
| | WalkAway | 97.4 (94.8)* | 94.8 |

* Value in parentheses reflect the calculation made for off-scale values which were not included in the "Best Case" calculation because the off-scale results were several doubling dilutions from the mode and values are confirmed to be greater than one well from the mode.

b. Linearity/assay reportable range:

Not applicable

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

The recommended QC isolates were tested a sufficient number of times with acceptable results with the reference method. The MICroSTREP plus - Daptomycin test results demonstrate that the system can produce QC results in the recommended range.

Daptomycin quality control data from combined sites is shown below. For S. pneumoniae, the data is from 3 testing sites. QC data was analyzed for the long dilution range and shortened dilution range (mapped). At least 25 test results were available at each site. The combined QC data is shown in the following table.

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| QC Organism | MIC range (μg/mL) | MIC value (μg/mL) | Broth Micro Dilution Reference Frequency | Microscan Manual Read | Microscan Walk-Away Read |
| --- | --- | --- | --- | --- | --- |
| S. pneumoniae ATCC 49619 | 0.06 - 0.5 | 0.03 | | | |
| | | 0.06 | 5 | | |
| | | 0.12 | 88 | 19 | 23 |
| | | 0.25 | 17 | 83 | 79 |
| | | 0.5 | 1 | 7 | 5 |
| | | 1.0 | 0 | 2 | 2 |

All QC values were in the expected range except for two results by each reading method, which were one doubling dilution above the range. For the Manual read, 109/111 (98.2%) test results were in range and for Microscan WalkAway, 107/109 (98.2%) test results were in range. QC test results with the new device were within the expected range >95% of the time, which is acceptable.

Inoculum density checks showed acceptable results for QC organisms, as well as a select number of challenge and clinical isolates. All results were within the 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:

Clinical testing was performed at three sites using fresh isolates supplemented with stock isolates of *Streptococcus* spp. A comparison of the MICroSTREP plus - Daptomycin test panel results was made to the reference method as recommended in the CLSI standard M7-A6 with the following deviations from that recommendation: Pluronic-F was used as the inoculum in the frozen reference panels. This is composed of water which contains a very small amount (0.1) of Pluronic to provide a smoother draw of liquid into the inoculator. Testing of the reference method and the MicroScan panels was

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performed at the same time. A challenge set was also tested at one site and compared to the reference broth dilution result mode that was determined by previous testing of each isolate multiple times in the recommended reference panel. All isolates tested grew in the MicroScan panels.

MicroScan MICroSTREP plus - Daptomycin and CLSI reference broth microdilution results were compared based on the guidelines provided in the AST Guidance Document. Essential agreement (EA) is when the MICroSTREP plus agree with the reference test panel results exactly or within one doubling dilution of the reference method. Category agreement (CA) is when the MICroSTREP plus result interpretation agrees exactly with the reference panel result interpretation based on interpretive criteria. The %EA and %CA results were acceptable.

According to the approved drug label for daptomycin, only a susceptible interpretive category is defined. There are no intermediate or resistance interpretive categories. In this study, no isolates were noted to have MICs outside the susceptible category by the reference method. There were 2 cases in this study in which MicroScan MICroSTREP plus results gave a Daptomycin categorical interpretation that was not in agreement with the reference broth dilution MIC (Reference interpretation was "susceptible" while the MicroScan MICroSTREP plus interpretation was "non-susceptible).

Labeling will recommend that isolates yielding a "non-susceptible" category should be submitted to a reference laboratory for further testing.

A total of 281 (214 fresh/67 stock) clinical isolates of Streptococcus spp. were evaluated at 3 clinical study sites. There were 107 Streptococcus pyogenes, 145 Streptococcus agalactiae and 29 other beta hemolytic streptococci belonging to Group C and Group G (Streptococcus dysgalactiae subsp. equisimilis). A total of 50 stock challenge isolates were also included and were tested at one site.

Combined results from clinical and challenge studies demonstrated an overall EA of 97% (321/331) and an overall CA of 99.3% (329/331) for the mapped (shortened) dilution range.

The performance evaluation summary of essential and category agreement results for challenge and clinical strains is shown in the tables below. Only results from manual read (primary method) are shown below for the long and short (mapped) dilution range. WalkAway read gave similar results to manual read.

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# Streptococci (long dilution-Manual)

Clinical data

| Organism group | Total Tested | #EA | %EA Total | Total Evaluable | #EA of Evaluable | %EA Evaluable | #CA | %CA | #NS | Categorical Error (%) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Other B-hemolytic Str | 29 | 24 | 82.8* | 29 | 24 | 82.8* | 28 | 96.6 | 0 | 1 (3.4%) |
| S. agalactiae (Group B) | 145 | 136 | 93.8 | 145 | 136 | 93.8 | 144 | 99.3 | 0 | 1 (0.7) |
| S. pyogenes (Group A) | 107 | 105 | 98.1 | 107 | 105 | 98.1 | 107 | 100 | 0 | 0 |
| Total | 281 | 265 | 94.3 | 281 | 265 | 94.3 | 279 | 99.3 | 0 | 2 (0.7%) |

Challenge

| S. agalactiae (Group B) | 19 | 17 | 89.5 | 19 | 17 | 89.5 | 19 | 100 | 0 | 0 (0%) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| S. dysgalactiae | 13 | 12 | 92.3 | 13 | 12 | 92.3 | 13 | 100 | 0 | 0 (0%) |
| S. pyogenes (Group A) | 18 | 18 | 100 | 18 | 18 | 100 | 18 | 100 | 0 | 0 (0%) |
| Total | 50 | 47 | 94.0 | 50 | 47 | 94.0 | 50 | 100 | 0 | 0 (0%) |

Clinical and Challenge Combined

| All Organisms | 331 | 312 | 94.3 | 331 | 312 | 94.3 | 329 | 99.4 | 0 | 2 (0.6%) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |

*Daptomycin MIC values that were 2 doubling dilutions above the reference MIC were obtained for 5 isolates. However, this did not cause a categorical error except for 1 isolate. This data is acceptable because of the high category agreement.

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# Streptococci (mapped dilution-Manual)

Clinical data

| Organism group | Total Tested | #EA | %EA Total | Total Evaluable | #EA of Evaluable | %EA Evaluable | #CA | %CA | #NS | Categorical Error (%) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Other B-hemolytic Str | 29 | 28 | 96.6 | 1 | 1 | 100 | 28 | 96.6 | 0 | 1 (3.4%) |
| S. agalactiae (Group B) | 145 | 138 | 95.2 | 42 | 42 | 100 | 144 | 99.3 | 0 | 1 (0.7) |
| S. pyogenes (Group A) | 107 | 107 | 100 | 4 | 4 | 100 | 107 | 100 | 0 | 0 |
| Total | 281 | 273 | 97.2 | 47 | 47 | 100 | 279 | 99.3 | 0 | 2 (0.7%) |

Challenge

| S. agalactiae (Group B) | 19 | 17 | 89.5 | 1 | 1 | 100 | 19 | 100 | 0 | 0 (0%) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| S. dysgalactiae | 13 | 13 | 100 | . | . | . | 13 | 100 | 0 | 0 (0%) |
| S. pyogenes (Group A) | 18 | 18 | 100 | . | . | . | 18 | 100 | 0 | 0 (0%) |
| Total | 50 | 48 | 96.0 | 1 | 1 | 100 | 50 | 100 | 0 | 0 (0%) |

Clinical and Challenge Combined

| All Organisms | 331 | 321 | 97.0 | 48 | 48 | 100 | 329 | 99.3 | 0 | 2 (0.6%) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |

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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

5. Expected values/Reference range:
Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus dysgalactiae subsp. equisimilis are considered susceptible to daptomycin at ≤ 1 µg/mL*
The current absence of data for resistant isolates precluded defining any results other than "susceptible". Isolates yielding MIC results suggestive of a "non-susceptible" category should be submitted to a reference laboratory for further testing.

N. Proposed Labeling:
The labeling is sufficient and satisfies the requirements of 21 CFR Part 809.10.

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