VITEK 2 STREPTOCOCCUS LEVOFLOXACIN

K112228 · bioMerieux, Inc. · LON · Oct 3, 2011 · Microbiology

Device Facts

• Record ID: K112228
• Device Name: VITEK 2 STREPTOCOCCUS LEVOFLOXACIN
• Applicant: bioMerieux, Inc.
• Product Code: LON · Microbiology
• Decision Date: Oct 3, 2011
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.1645
• Device Class: Class 2

Intended Use

VITEK® 2 Streptococcus Levofloxacin is designed for antimicrobial susceptibility testing of Streptococcus species. VITEK 2 Streptococcus Levofloxacin is a quantitative test intended for use with the VITEK® 2 and VITEK® 2 Compact Systems as a laboratory aid in the determination of in vitro susceptibility to antimicrobial agents. Levofloxacin has been shown to be active against most strains of the microorganisms listed below, according to the FDA label for this antimicrobial. Active in vitro and in clinical infections Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]) Streptococcus pyogenes Active in vitro but clinical significance unknown β-hemolytic Streptococcus (Group C/F) β-hemolytic Streptococcus (Group G) Streptococcus agalactiae Streptococcus milleri Viridans group Streptococci

Device Story

VITEK 2 Streptococcus Levofloxacin is an automated, miniaturized, and abbreviated version of the broth microdilution technique for determining minimum inhibitory concentrations (MIC). The device uses 64-well cards containing premeasured antibiotic concentrations (1, 2, 4, 16 µg/mL) and culture media. Bacterial isolates are diluted in saline, used to rehydrate the card, and then processed by the VITEK 2 or VITEK 2 Compact System. The system automatically fills, seals, and incubates the card. An optical scanner monitors well growth via light transmittance over 4–16 hours. The system generates an MIC value and interpretive category (Susceptible, Intermediate, Resistant). Used in clinical laboratories to aid in determining in vitro susceptibility to Levofloxacin, helping clinicians select appropriate antimicrobial therapy.

Clinical Evidence

Performance established via clinical study at four sites with 1,338 clinical isolates and 207 challenge isolates. Compared to CLSI broth microdilution reference method. Combined results showed 99.0% Essential Agreement (EA) and 97.9% Category Agreement (CA). 32 minor categorical errors (2.1%) were observed, all shifting from Susceptible to Intermediate. No major or very major errors occurred. No resistant S. pneumoniae or S. pyogenes isolates were available for testing.

Technological Characteristics

Miniaturized 64-well plastic test card containing premeasured antibiotic and culture media. Sensing principle: optical scanner measuring light transmittance to detect bacterial growth. Energy source: electrical (VITEK 2/Compact system). Connectivity: integrated with VITEK 2/Compact systems. Software: automated growth-based detection algorithm.

Indications for Use

Indicated for antimicrobial susceptibility testing of Streptococcus species (including S. pneumoniae, S. pyogenes, S. agalactiae, S. milleri, Viridans group, and β-hemolytic Group C/F/G) using isolated colonies. For prescription use only.

Regulatory Classification

Identification

A fully automated short-term incubation cycle antimicrobial susceptibility system is a device that incorporates concentrations of antimicrobial agents into a system for the purpose of determining in vitro susceptibility of bacterial pathogens isolated from clinical specimens. Test results obtained from short-term (less than 16 hours) incubation are used to determine the antimicrobial agent of choice to treat bacterial diseases.

Special Controls

*Classification.* Class II (special controls). The special control for this device is FDA's guidance document entitled “Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA.”

Predicate Devices

• VITEK 2 AST-GP Amoxicillin for S. pneumoniae (k063597)

Submission Summary (Full Text)

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

#### A. 510(k) Number:

K112228

#### B. Purpose for Submission:

To obtain a substantial equivalence determination for this premarket notification for the addition of Levofloxacin to the VITEK 2 and VITEK 2 Compact Antimicrobial Susceptibility Test (AST) Systems.

#### C. Measurand:

Levofloxacin concentrations of 1, 2, 4 and 16 ug/mL are included in the VITEK® 2 Streptococcus Levofloxacin card.

# D. Type of Test:

The minimum inhibitory concentration (MIC) is determined using qualitative growth based detection algorithm using predetermined growth threshold. The MIC reporting result range of the card is ≤ 0.25 -> 16 µg/mL.

# E. Applicant:

bioMerieux, Inc.

# F. Proprietary and Established Names:

VITEK® 2 Streptococcus Levofloxacin

# G. Regulatory Information:

| Product Code | Classification | Regulation Section | Panel |
|--------------|----------------|--------------------|--------------|
| LON | Class II | 21 CFR 866.1645 | Microbiology |

#### H. Intended Use:

- 1. Intended use(s):
VITEK® 2 Streptococcus Levofloxacin is designed for antimicrobial susceptibility testing of Streptococcus species. VITEK 2 Streptococcus

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Levofloxacin is a quantitative test intended for use with the VITEK® 2 and VITEK® 2 Compact Systems as a laboratory aid in the determination of in vitro susceptibility to antimicrobial agents. Levofloxacin has been shown to be active against most strains of the microorganisms listed below, according to the FDA label for this antimicrobial.

Active in vitro and in clinical infections Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]) Streptococcus pyogenes

Active in vitro but clinical significance unknown β-hemolytic Streptococcus (Group C/F) B-hemolytic Streptococcus (Group G) Streptococcus agalactiae Streptococcus milleri Viridans group Streptococci

#### 2. Indication(s) for use:

VITEK® 2 Streptococcus Levofloxacin is designed for antimicrobial susceptibility testing of Streptococcus species. VITEK 2 Streptococcus Levofloxacin is a quantitative test intended for use with the VITEK® 2 and VITEK® 2 Compact Systems as a laboratory aid in the determination of in vitro susceptibility to antimicrobial agents. Levofloxacin has been shown to be active against most strains of the microorganisms listed below, according to the FDA label for this antimicrobial.

Active in vitro and in clinical infections Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]) Streptococcus pyogenes

Active in vitro but clinical significance unknown B-hemolytic Streptococcus (Group C/F) B-hemolytic Streptococcus (Group G) Streptococcus agalactiae Streptococcus milleri Viridans group Streptococci

The VITEK® 2 Antimicrobial Susceptibility Test (AST) is intended to be used with the VITEK® 2 System for the automated quantitative or qualitative susceptibility testing of isolated colonies for the most clinically significant aerobic gram-negative bacilli, Staphylococcus spp., Enterococcus spp., Streptococcus spp. and clinically significant yeast.

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- 3. Special conditions for use statement(s):
For prescription use only.

The ability of the VITEK 2 Streptococcus to detect resistance to Levofloxacin in S. pneumoniae and S. pyogenes is unknown because resistant organisms were not available at the time of comparative testing.

- 4. Special instrument requirements:
For use with the VITEK® 2 and VITEK® 2 Compact Systems

# I. Device Description:

The VITEK 2 AST card is essentially a miniaturized, abbreviated and automated version of the doubling dilution technique for determining the minimum inhibitory concentration (MIC). Each VITEK 2 AST card contains 64 wells. A control well which only contains microbiological culture media is resident on all cards. The remaining wells contain premeasured portions of a specific antibiotic combined with culture media. The bacterial or yeast isolate to be tested is diluted to a standardized concentration with 0.45 - 0.5% saline before being used to rehydrate the antimicrobial medium within the card. The VITEK 2 System automatically fills, seals and places the card into the incubator/reader. The VITEK 2 Compact has a manual filling, sealing and loading operation. The VITEK 2 Systems monitor the growth of each well in the card over a defined period of time. At the completion of the incubation cvcle, a report is generated that contains the MIC value along with the interpretive category result for each antibiotic contained on the card.

The VITEK 2 Streptococcus Levofloxacin has the following concentrations in the card: 1. 2. 4 and 16 ug/mL (equivalent standard method concentration by efficacy in ug/mL). The MIC result range for the VITEK 2 card is ≤ 0.25 -> 16ug/mL.

| VITEK 2<br>Streptococcus<br>Levofloxacin | Equivalent<br>Standard Method<br>Concentration by<br>Efficacy in µg/mL | FDA Interpretive Categories<br>MIC in µg/mL:<br>S | FDA Interpretive Categories<br>MIC in µg/mL:<br>I | FDA Interpretive Categories<br>MIC in µg/mL:<br>R |
|------------------------------------------|------------------------------------------------------------------------|---------------------------------------------------|---------------------------------------------------|---------------------------------------------------|
| Levofloxacin | 1, 2, 4, 16 | ≤ 2 | 4 | ≥ 8 |

The MIC ranges, interpretive criteria and equivalent concentrations are as follows:

S = Susceptible, I = Intermediate, R = Resistant.

# J. Substantial Equivalence Information:

- 1. Predicate device name(s):

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VITEK 2 AST-GP Amoxicillin for S. pneumoniae

- 2. Predicate K number(s):
k063597

- 3. Comparison with predicate:

| Item | Device | Predicate |
|----------------------------------|--------------------------------------------------------------------|-----------|
| Intended Use | Determining<br>susceptibility to<br>antimicrobial agents | Same |
| Inoculation and test<br>organism | Isolated colonies of<br><i>Streptococcus</i> species | Same |
| Instrument | Test are run on both the<br>VITEK 2 and VITEK 2<br>Compact Systems | Same |
| Test Card | The VITEK 2 card,<br>including base broth | Same |

| Differences | | |
|-------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Item | Device | Predicate |
| Test Method | Automated qualitative<br>antimicrobial<br>susceptibility test for<br>use with the VITEK® 2<br>and<br>VITEK® 2 Compact<br>Systems to<br>determine the in vitro<br>susceptibility of<br><i>Streptococcus</i><br>species. | Automated quantitative<br>antimicrobial<br>susceptibility test for<br>use with the VITEK® 2<br>and<br>VITEK® 2 Compact<br>Systems to<br>determine the in vitro<br>susceptibility of<br><i>Streptococcus</i><br>species. |
| Antibiotic | Levofloxacin-specific<br>concentrations | Amoxicillin-specific<br>concentrations |
| Reading algorithm | Unique to Levofloxacin | Unique to Amoxicillin |

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

"Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA"

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guid anceDocuments/ucm071462.pdf

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Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, Approved Standard -8th Edition, Document M7-A8.

Performance Standards for Antimicrobial Susceptibility Testing - 19th Informational Supplement, M100-S19.

# L. Test Principle:

Automated growth based detection using attenuation of light measured by an optical scanner. The optics used in the systems use visible light to directly measure organism growth. Transmittance optics are based on an initial light reading of a well before significant growth has begun. Periodic light transmittance samplings of the same well measure organism growth by how much light is prevented from going through the well. The VITEK 2 System monitors the growth of each well in the card over a defined period of time. An interpretive call is made between 4 and 16 hours for a "rapid" read but may be extended to 18 hours in some instances. At the completion of the incubation cycle, a report is generated that contains the MIC value along with the interpretive category result for each antibiotic on the card. The VITEK 2 Streptococcus Levofloxacin has the following concentrations in the card: 1, 2, 4 and 16 ug/mL (equivalent standard method concentration by efficacy in ug/mL). The MIC result range for the VITEK 2 card is < 0.25 -> 16 ug/mL.

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

- 1. Analytical performance:
- a. Precision/Reproducibility:

A reproducibility study was conducted at three external clinical sites. Ten Streptococcus species isolates were tested at each site and testing was performed in triplicate over three days with the VITEK 2 Streptococcus Levofloxacin card. The testing was performed using both the manual and the automated dilution methods. Testing was conducted on the VITEK 2 instrument.

All reproducibility isolates were inhibited at concentrations in the susceptible range for Levofloxacin and all MIC values were on-scale. Reproducibility was 100% with by both manual dilution and automated dilution.

- b. Linearity/assay reportable range:
Not applicable

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- c. Traceability, Stability, Expected values (controls, calibrators, or methods):
The recommended Streptococcus pneumonia QC organism was tested on every test occasion with the reference method and the VITEK 2 System. Ancillary quality control testing was also performed. Two gram-positive organisms were tested throughout comparative testing at each study site by the reference method only. This was done to perform further quality control of the broth microdilution panels using E. faecalis ATCC 29212 and S. aureus ATCC 29213 which have a QC range of 0.25 -2 ug/mL and 0.06-0.5 ug/mL respectively for Levofloxacin.

The reference method QC results were in range for every day tested. The VITEK 2 was tested a sufficient number of times to demonstrate that the system can produce acceptable QC results.

Quality Control was performed during the studies using both the auto-dilution and the manual method of diluting the organisms on the VITEK 2 System. Results demonstrated that methods were comparable.

| Organism | Concentration<br>(µg/mL) | Auto Dilution | | Manual Dilution | |
|--------------------------------------------------|--------------------------|---------------|---------|-----------------|---------|
| | | Reference | VITEK 2 | Reference | VITEK 2 |
| <i>Streptococcus<br/>pneumonia</i><br>ATCC 49619 | ≤0.125 | | | | |
| | 0.25* | | | | |
| | 0.5* | 164 | 208 | 166 | 212 |
| | 1* | 48 | 4 | 48 | 2 |
| Acceptable<br>MIC range:<br>0.5-2 µg/mL | 2* | | | | |
| | 4* | | | | |
| | 8* | | | | |
| | 16* | | | | |
| | ≥32 | | | | |

Quality Control Results with the VITEK 2 System for Levofloxacin:

* VITEK Card Result Range is < 0.25 -> 16

At least one Quality control organism was in control in the reference on all days. Quality Control results for the VITEK 2 System using either inoculation dilution method demonstrated that the VITEK 2 System could produce the expected quality control results.

A similar QC study was conducted to evaluate the VITEK 2 Compact System. Results were compared to the expected FDA/CLSI QC results. All results for the VITEK 2 Compact System were within the expected QC ranges 100% of the time.

Inoculum density control was monitored using the DensiChek2 instrument. This was standardized weekly with all results recorded and in the expected

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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:

Performance was established through a clinical study which was conducted at four external study sites. A total of 1338 clinical isolates were tested by VITEK® 2 Streptococcus Levofloxacin with the VITEK® 2 System. The majority of the isolates were recently isolated from clinical specimens and the growth rate was 100%. Two hundred and nine of the 1338 clinical isolates tested were stock isolates (15.6%). A challenge set consisting of 207 isolates was evaluated with VITEK® 2 Streptococcus Levofloxacin panel at one external site.

Testing of clinical isolates was performed using the automated method of inoculation and the challenge organisms were tested with both the manual dilution and automatic dilution. Each isolate was tested by the VITEK 2 Levofloxacin Streptococcus panel and the CLSI broth microdilution reference method. The inoculum was prepared with direct colony suspension. A comparison was provided to the reference method with the following agreement. Thirty-two minor errors were seen.

| | EA<br>Tot | EA<br>N | EA<br>% | Eval<br>EA<br>Tot | Eval<br>EA<br>N | Eval<br>EA<br>% | CA<br>N | CA<br>% | #R | #<br>vmj | #<br>maj | #<br>min |
|--------------------------------------------|-----------|---------|---------|-------------------|-----------------|-----------------|---------|---------|----|----------|----------|----------|
| Organism<br>Group | | | | | | | | | | | | |
| <i>Streptococcus species</i> | | | | | | | | | | | | |
| CLINICAL | 1338 | 1323 | 98.9 | 1152 | 1143 | 99.2 | 1307 | 97.7 | 19 | 0 | 0 | 31 |
| CHALLENGE | 207 | 207 | 100 | 190 | 190 | 100 | 206 | 99.5 | 0 | 0 | 0 | 1 |
| COMBINED<br>(CLINICAL<br>AND<br>CHALLENGE) | 1545 | 1530 | 99.0 | 1342 | 1333 | 99.3 | 1513 | 97.9 | 19 | 0 | 0 | 32 |

#### AutoDilution

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EA-Essential Agreement CA-Category Agreement maj-major discrepancies vmj-very major discrepancies min-minor discrepancies

> A CA of 97.7%/99.5 % was observed for clinical/challenge isolates, respectively. An EA of 98.9%/100 % was observed for clinical/challenge isolates, respectively. However, a right shift in MIC occurred around the intermediate breakpoint.

No major or very major categorical errors occurred but a total of 32 (2.1%) minor categorical errors were seen. Of note is that all of the minor errors seen shifted the interpretation from "Susceptible" by the reference method to "Intermediate" by VITEK. Those minor errors were as follows: 17 were with S. pyogenes, 6 were with S. agalactiae, 6 were with S. mitis/oralis, 2 were with S. dysgalactiae and 1 was with S. oralis. No Levofloxacin-resistant S. pneumoniae or S. pyogenes isolates were tested in this evaluation.

Performance of the VITEK® 2 and the VITEK® 2 Compact was also evaluated with the same 207 challenge organisms using the manual dilution method. Results from those two studies showed CA of 99.5% and 98.1% and EA of 100% and 98.6% respectively for VITEK® 2 and the VITEK® 2 Compact.

All ranges were acceptable as defined in the AST Guidance Document.

- 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:

FDA Interpretive criteria for Levofloxacin when testing Streptococcus species, including S. pneumoniae are:

S= ≤ 2 μg/mL, I = 4 μg/mL, R= ≥8 μg/mL

#### N. Proposed Labeling:

The labeling is sufficient and it satisfies the requirements of 21 CFR section 809.10.

# O. Conclusion:

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