Sensititre HP MIC Susceptibility Plate with Tedizolid (0.002-4 mcg/ml)

K142338 · Thermo Fisher Scientific · JWY · Mar 2, 2015 · Microbiology

Device Facts

• Record ID: K142338
• Device Name: Sensititre HP MIC Susceptibility Plate with Tedizolid (0.002-4 mcg/ml)
• Applicant: Thermo Fisher Scientific
• Product Code: JWY · Microbiology
• Decision Date: Mar 2, 2015
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.1640
• Device Class: Class 2

Indications for Use

The Sensititre Haemophilus influenzae/Streptococcus pneumoniae plates are in vitro diagnostic products for clinical susceptibility testing of Haemophilus influenzae, Streptococcus pneumoniae and Streptococcus species.

Device Story

Sensititre HP MIC Susceptibility plate is an in vitro diagnostic device used in clinical laboratories for antimicrobial susceptibility testing. It utilizes microbroth dilution to determine the Minimum Inhibitory Concentration (MIC) of Tedizolid against specific Streptococcus species. The device consists of multi-well plates containing pre-dispensed, dried antimicrobial agents. Clinical isolates are inoculated into the wells; after incubation, growth is assessed to determine the MIC. Results assist clinicians in selecting appropriate antibiotic therapy for patients with bacterial infections. The device is intended for professional use in clinical settings.

Clinical Evidence

Performance evaluated via method comparison study at three sites using 225 clinical and 60 challenge Streptococcus isolates (S. pyogenes, S. agalactiae, S. anginosus). Overall EA was 100% (Manual) and 98.9% (Automated). CA was 100% (Manual) and 99.6% (Automated). Reproducibility >95% for both methods. No clinical data (patient outcomes) provided; performance based on bench-top comparison to CLSI reference broth microdilution.

Technological Characteristics

Multi-well plastic microtitre plates containing dried antimicrobial agents. Sensing principle: fluorescence detection of bacterial surface enzyme activity (cleavage of fluorogenic substrate). Energy source: electrical (for Autoinoculator/AIM, OptiRead, Vizion systems). Connectivity: OptiRead/ARIS systems. Sterilization: not specified. Software: automated reading algorithm for MIC determination.

Indications for Use

Indicated for clinical susceptibility testing of fastidious isolates, specifically Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus anginosus. Prescription use only.

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.

Submission Summary (Full Text)

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

A. 510(k) Number:
K142338

B. Purpose for Submission:
Addition of Tedizolid to the Sensititre HP MIC susceptibility plate for testing *Streptococcus* species

C. Measurand:
Tedizolid in the dilution range 0.002- 4μg/mL

D. Type of Test:
Quantitative Antimicrobial Susceptibility Test (AST) growth based

E. Applicant:
ThermoFisher Scientific

F. Proprietary and Established Names:
Sensititre *Haemophilus/S. pneumoniae* (HP) MIC Susceptibility plate

G. Regulatory Information:
1. Regulation section:
866.1640 Antimicrobial Susceptibility Test Powder
2. Classification:
Class II
3. Product code:
JWY- Manual Antimicrobial Susceptibility Test System
LRG- Instrument for Auto Reader and Instrumentation of Overnight Susceptibility Systems
LTT- Panels, Test, Susceptibility, Antimicrobial

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4. Panel:
Microbiology

H. Intended Use:

1. Intended use(s):
The Sensititre Haemophilus influenzae/Streptococcus pneumoniae plates are in vitro diagnostic products for clinical susceptibility testing of Haemophilus influenzae, Streptococcus pneumoniae and Streptococcus species.

2. Indication(s) for use:
The Sensititre HP MIC Susceptibility plate is in vitro diagnostic product for clinical susceptibility testing of fastidious isolates.

This 510(k) is for the newly approved Tedizolid for the dilution range of 0.002- 4μg/mL to the Sensititre HP MIC Susceptibility plate for testing Streptococcus spp.

The approved primary “Indications for Use” and clinical significance for Streptococcus spp. is for the following species:
Streptococcus pyogenes
Streptococcus agalactiae
Streptococcus anginosus

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

The ability of the Sensititre system to detect non-susceptible isolates to Tedizolid is unknown because non-susceptible isolates were not available at the time of the comparative testing. If such isolates are observed, they should be submitted to a reference lab.

4. Special instrument requirements:
The Sensititre Autoinoculator/AIM
The Sensititre OptiRead System
The Sensititre Vizion

I. Device Description:
The Sensititre 20-24 hour Haemophilus influenzae/Streptococcus pneumoniae MIC Susceptibility plate is a micro-version of the classic broth dilution method and can provide

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both qualitative and quantitative susceptibility test results in a dried microtitre plate format. Each micro-broth dilution plate is dosed with antimicrobial agents as specific concentrations and then dried.

The organism to be tested must be in pure culture and identified as Streptococcus spp. The medium for testing Streptococcus spp. is Sensititre Mueller-Hinton broth with 2-5% lysed horse blood with a final organism density of 5 x 10⁵ CFU/mL. A standardized suspension is prepared from colonies in pure growth and inoculated into the microtitre plate. After 20-24 hours of incubation, the microtitre plate is examined for growth to determine the MIC using either the Sensititre OptiRead or manually using the Vizion.

## J. Substantial Equivalence Information:

1. Predicate device name(s):

MicroScan® MICroSTREP plus Panel

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

K021184

3. Comparison with predicate:

Table 1: Comparison with the Predicate Devices

| Similarities | | |
| --- | --- | --- |
| Item | Device
Sensititre
Haemophilus/Streptococcus
pneumoniae (HP) MIC
Susceptibility Plates | Predicate
MICroSTREP Plus Panel
K021184 |
| Intended Use | The Sensititre HP MIC
Susceptibility is in vitro diagnostic
product for clinical susceptibility
testing | To determine bacterial
antimicrobial agent
susceptibility |
| Test Panel | The bacterial suspension in the
appropriate broth is used to
rehydrate the plate | Same |
| Test Organism | Streptococcus spp. (S. pyogenes, S.
agalactiae, S. anginosus) | Streptococci spp. other than
S. pneumoniae |
| Incubation | 20-24 hours | Same |
| Results reported | Report results as Minimum
Inhibitory Concentration (MIC) and
interpretative criteria (S, NS) | MIC (SIR) |

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| Differences | | |
| --- | --- | --- |
| Item | Device | Predicate |
| Antibiotic | Tedizolid | Clindamycin |
| Reading Method | Automated method by detection of fluorescence. Manual method by visual read of growth | Organism turbidity growth visually or by MicroScan instrumentation |

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

1. The FDA guidance document: Guidance for Industry and FDA Staff- Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems
2. CLSI M100-S24: Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement (QC parameters only)
3. CLSI M7-A9: Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard- Ninth Edition

L. Test Principle:

The Sensititre 20-24 hour Haemophilus influenzae/Streptococcus pneumoniae MIC Susceptibility plates are multi-well plastic microtitre plates that contain doubling dilution of antibacterial agents. Each plate includes antimicrobial agents at appropriate dilutions. Results can be read manually by visual reading of growth or automatically on an autoreader via fluorescence.

The Sensititre AutoReader /OptiRead System utilize fluorescence technology to read the micro-broth dilution plates after 20 to 24 hours incubation. The technology involves the detection of bacterial growth by monitoring the activity of specific surface enzymes produced by the test organism. Growth is determined by generating a fluorescent product from a non-fluorescent (fluorogenic) substrate. The non-fluorescent substrate is prepared by conjugating a fluorescent compound to the specific enzyme substrates with a bond which prevents fluorescence. The enzymatic action of the bacterial surface enzymes on the bound non-fluorescent substrate cleaves the bond releasing the fluorescence. The amount of fluorescence detected is directly related to the activity of bacterial growth. The MIC is determined by observing the lowest dilution of antimicrobial agent that inhibits growth of the organism. The non-fluorescent (fluorogenic) substrate can be added to the inoculum broth which is dispensed into the test plate at the same time as the test organism, or, the plates can be prepared with the substrate already added to each micro-well.

Streptococcus pneumoniae and Streptococcus spp. plates can either be read manually or automatically on the AutoReader /ARIS/OptiRead. Haemophilus influenzae can only be read manually on the Vizion or manual viewer.

M. Performance Characteristics (if/when applicable):

1. Analytical performance:

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# a. Precision/Reproducibility:

A reproducibility study was conducted at three study sites using 25 organisms consisting of S. pyogenes, S. agalactiae, and S. dysgalactiae. The Sensititre plates were inoculated by the Sensititre Autoinoculator/AIM. The organisms were tested one time at each of three sites for each reading method (Vizion for manual, OptiRead for automated read). The mode MIC value was determined and the reproducibility was calculated based on MICs falling within $\pm 1$ dilution of the mode MIC value. The testing resulted in overall reproducibility results of greater than $95\%$ for both Manual and Automated read methods. The results were acceptable.

# b. Linearity/assay reportable range:

Not Applicable

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

The organism recommended by both the FDA (CDER) and the CLSI, S. pneumoniae ATCC 49619 was tested against Tedizolid. Quality control was performed at all sites using the Sensititre Autoinoculator/AIM for inoculation, read by the manual (i.e. Vizion) and the automated (i.e. OptiRead) read methods. Table 2 below represents the frequency of the results and all results were in acceptable range.

Table 2: Tedizolid QC Table

| ORGANISM | Conc. (μg/mL) | Reference | Sensititre- Read Method | |
| --- | --- | --- | --- | --- |
| | | | OptiRead | Manual (Vizion) |
| | | | | |
| S. pneumoniae | 0.06 | 0 | 0 | 0 |
| ATCC 49619 | 0.12 | 48 | 53 | 39 |
| Expected Range | 0.25 | 10 | 6 | 20 |
| 0.12- 0.5 μg/mL | 0.5 | 2 | 1 | 1 |
| | 1 | 0 | 0 | 0 |

The inoculum density of the quality control organisms was determined each day of testing. A total of 46 inoculum density checks were performed; the average colony counts of the QC strain were within the recommended 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:

The CLSI recommended broth microdilution reference panel was prepared according to the CLSI recommendation. Clinical testing was performed at three sites on a total of 225 Streptococcus isolates. The isolates were comprised of 90 Streptococcus pyogenes, 90 Streptococcus agalactiae, and 45 Streptococcus anginosus at three sites and AIM auto-inoculator was used as the inoculation method. All clinical isolates were fresh and all grew. The challenge set included 25 S. pyogenes, 25 S. agalactiae, and nine S. anginosus; one challenge isolate did not grow and the overall growth rate was 99.6% (284/285) for both manual (VIZION) and automated (Optiread) reads. The performance of claimed Streptococcus spp. (i.e., S. agalactiae, S. pyogenes, and S. anginosus) was demonstrated in Tables 3-5 below:

Table 3: Performance summary of Streptococcus spp. Manual (VIZION)

| Tedizolid | EA Tot | EA N | EA % | Eval EA Tot | Eval EA N | Eval EA % | CA N | CA % | NS |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | S. agalactiae (≤0.5,-,-) | | | | | | | | |
| Clinical | 90 | 90 | 100 | 90 | 90 | 100 | 90 | 100 | 0 |
| Challenge | 25 | 25 | 100 | 25 | 25 | 100 | 25 | 100 | 0 |
| Total | 115 | 115 | 100 | 115 | 115 | 100 | 115 | 100 | 0 |
| | S. pyogenes (≤0.5,-,-) | | | | | | | | |
| Clinical | 90 | 90 | 100 | 90 | 90 | 100 | 90 | 100 | 0 |
| Challenge | 25 | 25 | 100 | 25 | 25 | 100 | 25 | 100 | 0 |
| Total | 115 | 115 | 100 | 115 | 115 | 100 | 115 | 100 | 0 |
| | S. anginosus (≤0.25,-,-) | | | | | | | | |
| Clinical | 45 | 45 | 100 | 45 | 45 | 100 | 45 | 100 | 0 |
| Challenge | 9 | 9 | 100 | 9 | 9 | 100 | 9 | 100 | 0 |
| Total | 54 | 54 | 100 | 54 | 54 | 100 | 54 | 100 | 0 |

EA - Essential Agreement
CA - Category Agreement
NS - Not susceptible

EA is when there is agreement between the reference method and the Sensititre® panel within plus or minus one serial two-fold dilution of antibiotic. Category agreement (CA) is when the Sensititre panel result interpretation agrees exactly with the reference panel result interpretation. Evaluable EA is when the MIC result is on scale for both the Sensititre® and the reference and have on-scale EA. The EA% is acceptable when compared to the reference method as described in the FDA guidance document, "Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA".

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Table 4: Performance summary of Streptococcus spp. Automated (OptiRead)

| Tedizolid | EA Tot | EA N | EA % | Eval EA Tot | Eval EA N | Eval EA % | CA N | CA% | NS |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | S. agalactiae (≤0.5,-,-) | | | | | | | | |
| Clinical | 90 | 90 | 100 | 90 | 90 | 100 | 90 | 100 | 0 |
| Challenge | 25 | 25 | 100 | 25 | 25 | 100 | 25 | 100 | 0 |
| Total | 115 | 115 | 100 | 115 | 115 | 100 | 115 | 100 | 0 |
| | S. pyogenes (≤0.5,-,-) | | | | | | | | |
| Clinical | 90 | 89 | 98.9 | 90 | 89 | 98.9 | 90 | 100 | 0 |
| Challenge | 25 | 25 | 100 | 25 | 25 | 100 | 25 | 100 | 0 |
| Total | 115 | 114 | 99.1 | 115 | 114 | 99.1 | 115 | 100 | 0 |
| | S. anginosus (≤0.25,-,-) | | | | | | | | |
| Clinical | 45 | 43 | 95.6 | 45 | 43 | 95.6 | 44 | 97.8 | 0 |
| Challenge | 9 | 9 | 100 | 9 | 9 | 100 | 9 | 100 | 0 |
| Total | 54 | 52 | 96.3 | 54 | 52 | 96.3 | 53 | 98.1 | 0 |

Table 5: Overall Performance Summary of Streptococcus spp (Clinical+ Challenge)

| Tedizolid | EA Tot | EA N | EA % | Eval EA Tot | Eval EA N | Eval EA % | CA N | CA% | NS |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Manual (Vizion) | 284 | 284 | 100 | 284 | 284 | 100 | 284 | 100 | 0 |
| Automated (OptiRead) | 284 | 281 | 98.9 | 284 | 281 | 98.9 | 283 | 99.6 | 0 |

Table 5 above demonstrated acceptable performance (EA and CA) for both manual and automated reads when comparing to the reference method as described in the FDA guidance document, "Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA".

Using the data provided by the sponsor in the diagonal table format as recommended in the AST Guidance, an analysis was conducted to evaluate MIC values trending in Tables 6 and 7 below:

Table 6: Trending (Clinical+ challenge) by manual read (VIZION)

| Tedizolid | Total | ≥1 dil. lower | Exact | ≥1 dil. higher |
| --- | --- | --- | --- | --- |
| S. agalactiae | 115 | 13.0% (15/115) | 44.3% (51/115) | 42.6% (49/115) |
| S. pyogenes | 115 | 17.4% (20/115) | 47.8% (55/115) | 34.8% (40/115) |
| S. anginosus | 54 | 9.3% (5/54) | 38.9% (21/54) | 51.9% (28/54) |
| Overall | 284 | 14.1% (40/284) | 44.7% (127/284) | 41.2% (117/284) |

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Table 7: Trending (Clinical+ challenge) by automated read (OptiRead)

| Tedizolid | Total | ≥1 dil. lower | Exact | ≥1 dil. higher |
| --- | --- | --- | --- | --- |
| S. agalactiae | 115 | 13.9%
(16/115) | 47.8%
(55/115) | 38.3%
(44/115) |
| S. pyogenes | 115 | 8.7%
(10/115) | 57.4%
(66/115) | 33.9%
(39/115) |
| S. anginosus | 54 | 5.6%
(3/54) | 53.7%
(29/54) | 40.7%
(22/54) |
| Overall | 284 | 10.2%
(29/284) | 52.8%
(150/284) | 37.0%
(105/284) |

The data from Tables 6 and 7 demonstrated trending of one doubling dilution higher 41.2% (117/284) on manual read and 37.0% (105/284) on automated read when compared to the reference MIC values. The “exact” reading compared to the reference was 44.7% (127/284) for the manual and 52.8% (150/284) for the automated read. For manual read, the “exact” and one doubling dilution higher was alike at 44.7% and 41.2% respectively.

There were eight Streptococcus agalactiae and two Streptococcus pyogenes tested at the Tedizolid reference susceptible breakpoint of 0.5μg/mL. The Sensititre results tended to be one dilution lower (70%, 7/10) when compared to the reference on both the manual and automated read.

There were ten Streptococcus anginosus tested at the reference susceptible breakpoint of 0.25μg/mL; the Sensititre tended to be one dilution lower (40%, 4/10) by the manual read and (30%, 3/10) by the automated read when compared to the reference MIC values.

The following footnote was added to the “Interpretation of Results” section of the Technical Product Information:

Sensititre Tedizolid MIC values for Streptococcus agalactiae, Streptococcus pyogenes and Streptococcus anginosus tended to be one doubling dilution higher than the reference MIC values. At the reference Tedizolid susceptible breakpoint of 0.5μg/mL (S. agalactiae, S. pyogenes) or 0.25μg/mL (S. anginosus), Sensititre MIC values tended to be one doubling dilution lower.

b. Matrix comparison:

Not Applicable

3. Clinical studies:

a. Clinical Sensitivity:

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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:

The FDA interpretative criteria were used to evaluate all performance data:

Table 8: Tedizolid FDA interpretative criteria

| Organism | Susceptibility Interpretive Criteria (MIC in μg/mL) | | |
| --- | --- | --- | --- |
| | S | I | R |
| Streptococcus agalactiae and Streptococcus pyogenes | ≤0.5 | - | - |
| Streptococcus anginosus group (including S. anginosus, S. intermedius, and S. constellatus) | ≤0.25 | - | - |

N. Proposed Labeling:

The labeling is sufficient and it 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.