ETEST TELAVANCIN IN 0.002-32 UG/ML AND 0.016-256 UG/ML

K102535 · Biomerieux S.A. · JWY · May 16, 2011 · Microbiology

Device Facts

• Record ID: K102535
• Device Name: ETEST TELAVANCIN IN 0.002-32 UG/ML AND 0.016-256 UG/ML
• Applicant: Biomerieux S.A.
• Product Code: JWY · Microbiology
• Decision Date: May 16, 2011
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.1640
• Device Class: Class 2

Indications for Use

This submission is for Etest® Telavancin for MIC determinations across 0.002-32 µg/mL and 0.016-256 µg/mL with Staphylooous aureus (including methicillin-resistant isolates), Entervoous faecalis (vancomycin-susceptible isolates only), Streptocous agalactive and Streptorous anginous group. Etest® is a quantitative technique for determination of antimicrobial susceptibility of both non-fastidious Gram negative and Gram positive aerobic bacteria such as Enterbaturias, Staphylovaus and Entervoors species and fastidious bacteria, such as anaerobes, N. gonorrhoeae, S. pneumoniae, Streptorouxu and Haemophilus species. The system comprises a predefined antibiotic gradient which is used to determine the Minimum Inhibitory Concentration (MIC) in ug/mL of different antimicrobial agents against microorganisms as tested on agar using overnight incubation.

Device Story

Etest® is a quantitative antimicrobial susceptibility testing system. It consists of a predefined antibiotic gradient on a test strip. The strip is applied to an inoculated agar plate and incubated overnight. The antibiotic diffuses into the agar, creating a concentration gradient. The Minimum Inhibitory Concentration (MIC) is determined by observing the point where the bacterial growth inhibition ellipse intersects the strip. Used in clinical microbiology laboratories by trained technicians to guide antibiotic therapy decisions. The device provides a quantitative MIC value, which helps clinicians select appropriate antimicrobial treatment for patients with bacterial infections.

Clinical Evidence

Performance evaluated via method comparison study across 4 clinical sites for Staphylococci/Enterococci (n=462) and 3 sites for Streptococci (n=355). Essential agreement (EA) was 98.5% for Gram-positive organisms and 98.3% for Streptococci. Category agreement (CA) was 99.6% and 100% respectively. Quality control testing confirmed system performance within expected ranges. No clinical sensitivity/specificity studies were required as this is an AST device.

Technological Characteristics

The device consists of a reagent-impregnated plastic strip containing a predefined concentration gradient of Telavancin. It functions via passive diffusion of the antibiotic into agar media. It is a manual, in vitro diagnostic test requiring overnight incubation. No electronic components, software, or energy sources are involved in the testing process.

Indications for Use

Indicated for MIC determination of telavancin (0.002–32 μg/mL and 0.016–256 μg/mL) for Staphylococcus aureus (including MRSA), Enterococcus faecalis (vancomycin-susceptible only), Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus anginosus group.

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

• Etest® (k913459)

Submission Summary (Full Text)

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

A. 510(k) Number:
k102535

B. Purpose for Submission:
To obtain a substantial equivalence determination for Etest® strip for determining susceptibility of Gram positive organisms to telavancin

C. Measurand:
Telavancin concentrations of 0.002 – 32 µg/mL and 0.016 – 256 µg/mL

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

E. Applicant:
bioMerieux, Inc.

F. Proprietary and Established Names:
Etest® Telavancin for Antimicrobial Susceptibility Testing

G. Regulatory Information:
1. Regulation section:
866.1640 Antimicrobial Susceptibility Test (AST) Powder
2. Classification:
II
3. Product code:
JWY - Manual Antimicrobial Susceptibility Test Systems

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4. Panel:

83, Microbiology

H. Intended Use:

1. Intended use(s):

Etest® is a quantitative technique for determination of antimicrobial susceptibility of both non-fastidious Gram-negative and Gram positive aerobic bacteria such as Enterobacteriaceae, Pseudomonas, Staphylococcus and Enterococcus species and fastidious bacteria, such as anaerobes, N. gonorrhoeae, S. pneumoniae, Streptococcus and Haemophilus species. The system comprises a predefined antibiotic gradient which is used to determine the Minimum Inhibitory Concentration (MIC) in $\mu \mathrm{g} / \mathrm{mL}$ of different antimicrobial agents against microorganisms as tested on agar media using overnight incubation.

2. Indication(s) for use:

Etest® is a quantitative technique for determination of antimicrobial susceptibility of both non-fastidious Gram-negative and Gram positive aerobic bacteria such as Enterobacteriaceae, Pseudomonas, Staphylococcus and Enterococcus species and fastidious bacteria, such as anaerobes, N. gonorrhoeae, S. pneumoniae, Streptococcus and Haemophilus species. The system comprises a predefined antibiotic gradient which is used to determine the Minimum Inhibitory Concentration (MIC) in $\mu \mathrm{g} / \mathrm{mL}$ of different antimicrobial agents against microorganisms as tested on agar media using overnight incubation.

This 510(k) submission is for Etest® Telavancin for MIC determination across concentrations of $0.002 - 32\ \mu \mathrm{g/mL}$ and $0.016 - 256\ \mu \mathrm{g/mL}$ with Staphylococcus aureus (including methicillin-resistant isolates), Enterococcus faecalis (vancomycin-susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus anginosus group.

3. Special conditions for use statement(s):

For prescription use

4. Special instrument requirements:

Manual readings only

I. Device Description:

Etest® consists of a thin, inert and non-porous plastic strip, 5mm wide and 60 mm

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long. One side of the strip carries a two-letter code designating the identity of the antibiotic and is calibrated with MIC values in terms of $\mu \mathrm{g} / \mathrm{mL}$ . A predefined exponential gradient of the dried and stabilized antibiotic covers a continuous concentration range across 15 two-fold dilutions of a conventional MIC method.

The MIC interpretive criteria for telavancin are as follows:

| Organism | Susceptibility Interpretive Criteria (MIC* in μg/mL): | | |
| --- | --- | --- | --- |
| | S | I | R |
| Staphylococcus aureus | ≤1 | - | z |
| Enterococcus faecalis (vancomycin-susceptible isolates only) | ≤1 | - | z |
| Streptococcus pyogenes | ≤0.12 | - | z |
| Streptococcus agalactiae | | | |
| Streptococcus anginosus group | | | |

*Currently there are no intermediate or resistant interpretive criteria for telavancin. The absence of resistant strains precludes defining any results categories other than "susceptible." For strains yielding results suggestive of a "non-susceptible" category, organism identification and antimicrobial susceptibility test results should be confirmed. Subsequently, the isolates should be saved and submitted to a reference laboratory that will confirm results using a reference dilution method.

$^{*}\mathrm{S} =$ 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): Etest®
2. Predicate 510(k) number(s): k913459
3. Comparison with predicate:

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| Similarities | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Intended Use | Quantitative susceptibility to antimicrobial agents | Same |
| Incubation Temperature | 35° | Same |
| Inoculation | Isolated colonies from culture used | Same |
| Result | MIC | MIC |
| Incubation Atmosphere | Aerobic and microaerophilic | Aerobic and microaerophilic |
| Differences | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Antibiotic | Telavancin | Other antibiotics |
| | | |

# 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- $8^{\text{th}}$ Edition, Document M07-A8
3. CLSI. Performance Standards for Antimicrobial Susceptibility Testing Approved Standard-, $19^{\text{th}}$ Informational Supplement, Document M100-S19

# L. Test Principle:

The Etest® gradient technology is based on a combination of the concepts of dilution and diffusion test methods for susceptibility testing. Etest® directly quantifies antimicrobial susceptibility in terms of discrete MIC values. When the Etest® strip is applied to an inoculated agar plate, the antibiotic is immediately released from the plastic surface into the agar. A predefined, continuous gradient of antibiotic concentrations is created and maintained directly underneath the strip. After incubation whereby bacterial growth becomes visible, a symmetrical inhibition ellipse centered along the strip will be seen. The MIC value in $\mu \mathrm{g} / \mathrm{mL}$ is read where the ellipse edge intersects the strip. Since Etest® generates MIC values which fall between two-fold dilutions for interpretation; the MIC value read must be recorded to the next two-fold dilution.

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M. Performance Characteristics (if/when applicable):

1. Analytical performance:

a. Precision/Reproducibility:

A reproducibility study was conducted at three study sites. Twenty five Staphylococcus species (10 S. aureus, 4 S. epidermidis, 4 S. haemolyticus, 5 E. faecalis, and 1 Coagulase Negative Staphylococci) and Thirty three Streptococcus species (14 S. pyogenes Gr A, 1 S. milleri, 6 S. viridans, 2 Beta hemolytic Streptococcus spp., Streptococcus Gr C, 6 S. agalactiae Gr B, and 3 S. viridans) were tested at each site. Reference method plates were read visually in accordance with CLSI standard. 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 sites.

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. There were no off-scale results in this study, only one value for overall reproducibility is reported.

The overall reproducibility was 100% for all organisms with on-scale results tested by Etest at 3 sites. These results met the acceptance criteria and are acceptable.

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 Etest® results demonstrate that the system can produce QC results in the recommended range.

Telavancin quality control data from combined sites is shown below. For S. pneumoniae, the data is from 3 testing sites. For S. aureus and E. faecalis, the data is from 4 testing sites because of the addition of a fourth site to test additional fresh isolates. At least 20 test results per QC organism at each site were available, except for site 4 which had 10 results. This number of QC runs is acceptable, given that this site was added later to test additional fresh isolates. Telavancin Etest quality control data for Streptococcus species were

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compared to two reference methods, broth microdilution and agar dilution.

| QC Organism | MIC range (μg/mL) | MIC value (μg/mL) | Reference Frequency | Etest Frequency |
| --- | --- | --- | --- | --- |
| S. aureus ATCC 29213 | 0.125 - 1 | 0.06 | 0 | 0 |
| | | 0.125 | 57 | 59 |
| | | 0.25 | 10 | 11 |
| | | 0.5 | 3 | 0 |
| | | 1 | 0 | 0 |
| | | 2 | | |
| | | | | |
| E. faecalis ATCC 29212 | 0.125-0.5 | 0.06 | | |
| | | 0.125 | 16 | 52 |
| | | 0.25 | 51 | 17 |
| | | 0.5 | 4 | 2 |
| | | 1 | | |
| QC Organism | MIC range (μg/mL) | MIC value (μg/mL) | Broth Micro Dilution Reference Frequency | Agar Dilution Frequency | Etest Frequency |
| --- | --- | --- | --- | --- | --- |
| S. pneumoniae ATCC 49619 | 0.004 – 0.032 | 0.002 | | | |
| | | 0.004 | | | |
| | | 0.008 | 10 | 25 | 4 |
| | | 0.016 | 36 | 13 | 73 |
| | | 0.032 | 18 | 0 | 0 |
| | | 0.064 | | | |

All QC values were in the expected range.

Inoculum density checks showed acceptable results for QC organisms, as well as a select number of challenge and clinical isolates. The results were based on colony count values representing 20 tests for each QC organism and 38 tests for selected challenge and clinical isolates. All results were within the expected range.

d. Detection limit:

Not Applicable

e. Analytical specificity:

Not Applicable

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f. Assay cut-off:

Not Applicable

2. Comparison studies:

a. Method comparison with predicate device:

CLSI recommended reference methods were used to determine susceptibility. Clinical testing was performed at four sites for Staphylococci and Enterococci and at three sites for Streptococci. Etest and CLSI reference broth microdilution results were compared based on the guidelines provided in the AST Guidance Document. Essential agreement (EA) is when the Etest agree with the reference test panel results exactly or within one doubling dilution of the reference method. Category agreement (CA) is when the Etest result interpretation agrees exactly with the reference panel result interpretation based on interpretive criteria. The %EA and %CA results were acceptable.

According the approved drug label for telavancin, only a susceptible interpretive category is defined. There are no intermediate or resistance interpretive categories. In this study, two isolates were noted to have MICs outside the susceptible category. There were 2 cases in this study in which Etest results gave a categorical interpretation that was not in agreement with the reference broth dilution MIC. The MIC results were for the two isolates were as follows:

For *E. faecalis* (Vancomycin-Susceptible), the telavancin MIC was 0.5 µg/mL (Susceptible) by Etest and 2 µg/mL (non-susceptible) by broth microdilution reference. This was considered a Very Major Error.

For *S. aureus* (Methicillin-Resistant), the telavancin MIC was 1.5 µg/mL (non-susceptible) by Etest. Triplicate testing by broth microdilution showed the MIC as 0.5, 0.5 and 1 µg/mL (Susceptible). This was considered a Major Error.

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

A total of 462 Gram positive aerobic organisms (challenge and clinical isolates) were evaluated at four clinical study sites (n=462). A total of 355 Streptococcus spp. (challenge and clinical isolates) were evaluated at 3 clinical study sites.

The performance evaluation summary of essential and category agreement results for challenge and clinical strains is shown in the tables below.

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# Gram-Positive Organisms

Clinical data

| Organism group | Total Tested | #EA | %EA Total | Total Evaluable | #EA of Evaluable | %EA Evaluable | #CA | %CA | #NS | #vmj | #maj | #min |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| S. aureus MR | 135 | 133 | 98.5 | 135 | 133 | 98.5 | 135 | 100 | 0 | 0 | 0 | 0 |
| S. aureus MS | 65 | 65 | 100 | 65 | 65 | 100 | 65 | 100 | 0 | 0 | 0 | 0 |
| S. epidermidis MR | 33 | 32 | 97.0 | 33 | 32 | 97.0 | 33 | 100 | 0 | 0 | 0 | 0 |
| S. epidermidis MS | 22 | 22 | 100 | 22 | 22 | 100 | 22 | 100 | 0 | 0 | 0 | 0 |
| Coag neg staph MR | 30 | 30 | 100 | 30 | 30 | 100 | 30 | 100 | 0 | 0 | 0 | 0 |
| Coag neg staph MS | 25 | 25 | 100 | 25 | 25 | 100 | 25 | 100 | 0 | 0 | 0 | 0 |
| S. haemolyticus MR | 6 | 6 | 100 | 6 | 6 | 100 | 6 | 100 | 0 | 0 | 0 | 0 |
| E. faecalis VS | 65 | 63 | 97 | 65 | 63 | 97 | 64 | 98 | 1 | 1 | 0 | 0 |
| E. faecium VS | 15 | 14 | 93.3 | 15 | 14 | 93.3 | 15 | 100 | 0 | 0 | 0 | 0 |
| Total | 396 | 390 | 98.5 | 396 | 390 | 98.5 | 395 | 99.7 | 1 | 1 | 0 | 0 |

## Challenge

| S. aureus MR | 21 | 20 | 95.2 | 21 | 20 | 95.2 | 20 | 95.2 | 0 | 0 | 1 | 0 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| S. aureus MS | 9 | 9 | 100.0 | 9 | 9 | 100.0 | 9 | 100 | 0 | 0 | 0 | 0 |
| S. epidermidis MR | 6 | 6 | 100.0 | 6 | 6 | 100.0 | 6 | 100 | 0 | 0 | 0 | 0 |
| S. epidermidis MS | 3 | 3 | 100.0 | 3 | 3 | 100.0 | 3 | 100 | 0 | 0 | 0 | 0 |
| Coag neg staph MR | 10 | 10 | 100.0 | 10 | 10 | 100.0 | 10 | 100 | 0 | 0 | 0 | 0 |
| Coag neg staph MS | 9 | 9 | 100.0 | 9 | 9 | 100.0 | 9 | 100 | 0 | 0 | 0 | 0 |
| S. haemolyticus MR | 2 | 2 | 100.0 | 2 | 2 | 100.0 | 2 | 100 | 0 | 0 | 0 | 0 |
| E. faecalis VS | 6 | 6 | 100.0 | 6 | 6 | 100.0 | 6 | 100 | 0 | 0 | 0 | 0 |
| Total | 66 | 65 | 98.5 | 66 | 65 | 98.5 | 65 | 98.5 | 0 | 0 | 1 | 0 |

## Clinical and Challenge Combined

| All Organisms | 462 | 455 | 98.5 | 462 | 455 | 98.5 | 460 | 99.6 | 1 | 1 | 1 | 0 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |

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# Streptococci

Clinical data

| Organism group | Total Tested | #EA | %EA Total | Total Evaluable | #EA of Evaluable | %EA Evaluable | #CA | %CA | #NS | #vmj | #maj | #min |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| S. pyogenes gr A | 155 | 151 | 97.4 | 155 | 151 | 97.4 | 155 | 100 | 0 | 0 | 0 | 0 |
| S. agalactiae gr B | 55 | 55 | 100 | 55 | 55 | 100 | 55 | 100 | 0 | 0 | 0 | 0 |
| β-Streptococcus gr C | 14 | 14 | 100 | 14 | 14 | 100 | 14 | 100 | 0 | 0 | 0 | 0 |
| β-Streptococcus gr G | 14 | 14 | 100 | 14 | 14 | 100 | 14 | 100 | 1 | 0 | 0 | 0 |
| β-Streptococcus spp. | 10 | 10 | 100 | 10 | 10 | 100 | 10 | 100 | 1 | 0 | 0 | 0 |
| S. viridans | 41 | 41 | 100 | 41 | 41 | 100 | 41 | 100 | 0 | 0 | 0 | 0 |
| S. milleri | 12 | 12 | 100 | 12 | 12 | 100 | 12 | 100 | 0 | 0 | 0 | 0 |
| Total | 301 | 297 | 98.7 | 301 | 297 | 98.7 | 301 | 100 | 2 | 0 | 0 | 0 |

Challenge

| S. pyogenes gr A | 24 | 24 | 100 | 24 | 24 | 100 | 24 | 100 | 0 | 0 | 0 | 0 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| S. agalactiae gr B | 5 | 5 | 100 | 5 | 5 | 100 | 5 | 100 | 0 | 0 | 0 | 0 |
| β-Streptococcus gr C | 5 | 5 | 100 | 5 | 5 | 100 | 5 | 100 | 0 | 0 | 0 | 0 |
| β-Streptococcus gr G | 5 | 5 | 100 | 5 | 5 | 100 | 5 | 100 | 0 | 0 | 0 | 0 |
| β-Streptococcus spp. | 1 | 1 | 100 | 1 | 1 | 100 | 1 | 100 | 0 | 0 | 0 | 0 |
| S. viridans | 9 | 8 | 88.9 | 9 | 8 | 88.9 | 9 | 100 | 0 | 0 | 0 | 0 |
| S. anginosus | 2 | 1 | 50.0 | 2 | 1 | 50.0 | 2 | 100 | 0 | 0 | 0 | 0 |
| S. intermedius | 3 | 3 | 100 | 3 | 3 | 100 | 3 | 100 | 0 | 0 | 0 | 0 |
| Total | 54 | 52 | 96.3 | 54 | 52 | 96.3 | 54 | 100 | 0 | 0 | 0 | 0 |

Clinical and Challenge Combined

| All Organisms | 355 | 349 | 98.3 | 355 | 349 | 98.3 | 355 | 100 | 2 | 0 | 0 | 0 |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |

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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:

| MIC Interpretive Standards (μg/mL) | |
| --- | --- |
| | Susceptible |
| Staphylococcus aureus | ≤1 |
| Enterococcus faecalis | ≤1 |
| Streptococcus spp. | ≤0.12 |

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 expected value range, interpretive criteria and QC ranges are in the package insert. 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.