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K Number
K130894
Device Name
XPERT MRSA/SA BLOOD CULTURE ASSAY; GENEXPERT DX SYSTEMS (GX-I, GX-II, GX-IV, GX-XVI); GENEXPERT INFINITY-48 SYSTEM; GENE
Manufacturer
CEPHEID
Date Cleared
2013-06-20

(80 days)

Product Code
NQXNOX
Regulation Number
866.1640
AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP Authorized
Intended Use
The Cepheid® Xpert® MRSA/SA Blood Culture Assay, performed on the GeneXpert® Instrument Systems, is a qualitative in vitro diagnostic test intended for the detection of Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA) DNA directly from positive blood cultures. The assay utilizes automated real-time polymerase chain reaction (PCR) for the amplification of MRSA/SA specific DNA targets and fluorogenic target-specific hybridization probes for the real-time detection of the amplified DNA. The assay is performed directly on positive blood culture samples from BD BACTEC™ Plus Aerobic/F, BacT/ALERT® SA (Standard Aerobic) or VersaTREK REDOX 1® (aerobic) blood culture bottles that are determined by Gram Stain as Gram Positive Cocci in Clusters (GPCC) or as Gram Positive Cocci in singles (GPC). The Xpert MRSA/SA Blood Culture Assay is indicated for use in conjunction with other laboratory tests, such as culture, and clinical data available to the clinician as an aid in the detection of MRSA/SA from positive blood cultures. Subculturing of positive blood cultures is necessary to recover organisms for susceptibility testing or for epidemiological typing. The Cepheid Xpert MRSA/SA Blood Culture Assay is not intended to monitor treatment for MRSA/SA infections.
Device Description
The Cepheid Xpert® MRSA/SA Blood Culture Assay (Xpert MRSA/SA Blood Culture Assay) is a rapid, automated DNA test for the simultaneous qualitative detection of MRSA and SA DNA directly from blood culture bottle specimens that are detected as positive for microbial growth and shown to contain Gram Positive Cocci by Gram stain. The primers and probes in the Xpert MRSA/SA Assay detect nucleic acid sequences of the staphylococcal protein A (spa), the gene for methicillin/oxacillin resistance (mecA), and staphylococcal cassette chromosome (SCCmec) inserted in the SA chromosomal attB site. The test includes a Sample Processing Control (SPC) to control for adequate processing of the target bacteria and to monitor the presence of inhibitor(s) in the PCR assay. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability. The specimen for testing with the Xpert MRSA/SA Blood Culture Assay consists of an aliquot taken from a positive blood culture bottle. Using one of the disposable fixed 50 µL volume transfer pipettes provided with the test kit, an aliquot of the positive blood culture is transferred into a single-use tube of Elution Reagent, also provided with the kit. The Elution Reagent is briefly vortexed and the entire content is transferred to the "S" chamber of the disposable fluidic cartridge (the Xpert MRSA/SA Blood Culture Assay cartridge), after which the cartridge is ready to place on the instrument. The assay is performed on the Cepheid GeneXpert Instrument Systems, which automate and integrate sample purification, nucleic acid amplification of the target sequences in simple or complex samples using real-time PCR. The systems consist of an instrument, personal computer, and preloaded software for running the tests and viewing the results. The GeneXpert Instrument Systems require the use of single-use disposable cartridges that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained, crosscontamination between samples is minimized. In this platform, additional sample preparation, amplification, and real-time detection are all fully-automated and completely integrated. The Xpert MRSA/SA Blood Culture Assay performed on the GeneXpert Instrument Systems provides results in approximately 60 minutes. The GeneXpert Instrument Systems, comprised of the GeneXpert Dx Systems and the GeneXpert Infinity Systems, have 1 to 80 randomly accessible modules, depending upon the instrument, that are each capable of performing separate sample preparation and real-time PCR tests. Each module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time PCR and detection.
More Information

K101879, K071026

Not Found

No
The description focuses on automated real-time PCR and integrated sample processing, with no mention of AI or ML algorithms for data analysis or interpretation.

No

This device is a qualitative in vitro diagnostic test intended for the detection of specific bacterial DNA. It aids in diagnosis but does not provide therapy or treatment.

Yes

Explanation: The "Intended Use / Indications for Use" section explicitly states that the device is a "qualitative in vitro diagnostic test."

No

The device description explicitly states that the assay is performed on the Cepheid GeneXpert Instrument Systems, which are hardware systems that automate sample preparation, amplification, and detection. The software is preloaded on a personal computer connected to the instrument and is used for running tests and viewing results, but it is not the sole component of the medical device.

Yes, this device is an IVD (In Vitro Diagnostic).

The "Intended Use / Indications for Use" section explicitly states: "The Cepheid® Xpert® MRSA/SA Blood Culture Assay, performed on the GeneXpert® Instrument Systems, is a qualitative in vitro diagnostic test intended for the detection of Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA) DNA directly from positive blood cultures."

This statement clearly identifies the device as an in vitro diagnostic test.

N/A

Intended Use / Indications for Use

The Cepheid® Xpert® MRSA/SA Blood Culture Assay, performed on the GeneXpert® Instrument Systems, is a qualitative in vitro diagnostic test intended for the detection of Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA) DNA directly from positive blood cultures. The assay utilizes automated real-time polymerase chain reaction (PCR) for the amplification of MRSA/SA specific DNA targets and fluorogenic target-specific hybridization probes for the real-time detection of the amplified DNA. The assay is performed directly on positive blood culture samples from BD BACTEC™ Plus Aerobic/F, BacT/ALERT® SA (Standard Aerobic) or VersaTREK REDOX 1® (aerobic) blood culture bottles that are determined by Gram Stain as Gram Positive Cocci in Clusters (GPCC) or as Gram Positive Cocci in singles (GPC). The Xpert MRSA/SA Blood Culture Assay is indicated for use in conjunction with other laboratory tests, such as culture, and clinical data available to the clinician as an aid in the detection of MRSA/SA from positive blood cultures. Subculturing of positive blood cultures is necessary to recover organisms for susceptibility testing or for epidemiological typing. The Cepheid Xpert MRSA/SA Blood Culture Assay is not intended to monitor treatment for MRSA/SA infections.

Product codes (comma separated list FDA assigned to the subject device)

NQX

Device Description

The Cepheid Xpert® MRSA/SA Blood Culture Assay (Xpert MRSA/SA Blood Culture Assay) is a rapid, automated DNA test for the simultaneous qualitative detection of MRSA and SA DNA directly from blood culture bottle specimens that are detected as positive for microbial growth and shown to contain Gram Positive Cocci by Gram stain. The primers and probes in the Xpert MRSA/SA Assay detect nucleic acid sequences of the staphylococcal protein A (spa), the gene for methicillin/oxacillin resistance (mecA), and staphylococcal cassette chromosome (SCCmec) inserted in the SA chromosomal attB site.

The test includes a Sample Processing Control (SPC) to control for adequate processing of the target bacteria and to monitor the presence of inhibitor(s) in the PCR assay. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.

The specimen for testing with the Xpert MRSA/SA Blood Culture Assay consists of an aliquot taken from a positive blood culture bottle. Using one of the disposable fixed 50 µL volume transfer pipettes provided with the test kit, an aliquot of the positive blood culture is transferred into a single-use tube of Elution Reagent, also provided with the kit. The Elution Reagent is briefly vortexed and the entire content is transferred to the "S" chamber of the disposable fluidic cartridge (the Xpert MRSA/SA Blood Culture Assay cartridge), after which the cartridge is ready to place on the instrument.

The assay is performed on the Cepheid GeneXpert Instrument Systems, which automate and integrate sample purification, nucleic acid amplification of the target sequences in simple or complex samples using real-time PCR. The systems consist of an instrument, personal computer, and preloaded software for running the tests and viewing the results. The GeneXpert Instrument Systems require the use of single-use disposable cartridges that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained, crosscontamination between samples is minimized. In this platform, additional sample preparation, amplification, and real-time detection are all fully-automated and completely integrated. The Xpert MRSA/SA Blood Culture Assay performed on the GeneXpert Instrument Systems provides results in approximately 60 minutes.

The GeneXpert Instrument Systems, comprised of the GeneXpert Dx Systems and the GeneXpert Infinity Systems, have 1 to 80 randomly accessible modules, depending upon the instrument, that are each capable of performing separate sample preparation and real-time PCR tests. Each module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time PCR and detection.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Not Found

Indicated Patient Age Range

Not Found

Intended User / Care Setting

Laboratory tests, clinicians.

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Analytical Inclusivity (Reactivity):

  • Sample Size: 250 SA strains (47 MSSA and 203 MRSA)
  • Data Source: Multiple sources. Selections represented primary lineages with emphasis on specific clonal complexes within which MRSA is predominantly observed. Lineages with MRSA and MSSA, and MSSA exclusively, were included. Characterized by pulsed-field gel electrophoresis (PFGE) to include USA types USA100, USA300, USA400. Strains representing "Empty Cassette" variants and heterogeneous strains (BORSA) were also tested.
  • Annotation Protocol: All strains tested in triplicate using 10 ul of stationary phase cell suspension diluted 1 million-fold. Colony forming units per assay (CFU/test) determined by plate counts in triplicate.

Limit of Detection (LoD):

  • Sample Size: For MRSA, 20 replicates for 10 individual isolates representing SCCmec types I, II, III, IVa, IVd, V, VI, VII, and VIII. USA100 and USA400 were represented. For SA, 20 replicates for 3 individual SA isolates (USA types USA900 and USA1200).
  • Data Source: SA-free whole blood and MSSE (methicillin-susceptible Staphylococcus epidermidis) cells at 10^0 CFU/mL added to blood culture medium.
  • Annotation Protocol: Evaluated at each MRSA/SA concentration (CFU/test). LoD defined as lowest CFU per sample reproducibly distinguished from negative samples with 95% confidence (19 of 20 replicates positive). Point estimates and confidence intervals determined by probit regression.

Analytical Specificity (Exclusivity):

  • Sample Size: 101 strains.
  • Data Source: 91 cultures from American Type Culture Collection (ATCC), 1 from Culture Collection, University of Göteborg, Sweden (CCUG), 1 from Teruyo Ito, Juntendo University, Tokyo, Japan, 1 carbapenemase (KPC) producing Klebsiella pneumoniae strain from National Collection of Type Cultures (NCTC), UK, and 7 strains from the Network on Antimicrobial Resistance in SA (NARSA). These strains represent species phylogenetically related to SA or those potentially encountered in the hospital environment. Organisms identified as Gram positive (74), Gram negative (24), or yeast (3). Methicillin-sensitive, coagulase negative Staphylococcus, MSCoNS (27) and methicillin- resistant, coagulase negative Staphylococcus, MRCoNS (12) were included. Organisms further classified as aerobic (94) or anaerobic (7).
  • Annotation Protocol: Three replicates of each isolate were tested at 1.7 - 3.2 McFarland units.

Potentially Interfering Substances:

  • Sample Size: Negative samples (n=8), Positive samples (n=8) per substance with two clinical isolates each of MSSA (29213 and 102-04) and MRSA (SCCmec types II and HII) spiked near analytical LoD.
  • Data Source: Anticoagulated whole blood with ACD, EDTA, Heparin, and Sodium Citrate, human plasma, three blood culture media bottles (Becton Dickinson BACTEC™ Plus Aerobic/F, BioMérieux BacT/ALERT SA (Standard Aerobic), and TREK Diagnostics VersaTREK REDOXI (Aerobic), bilirubin, y-globulin, hemoglobin, triglycerides, and sodium polyanetholesulfonate (SPS). Bilirubin, y-globulin, hemoglobin, and triglycerides tested at concentrations approximately one log higher than reference levels. SPS tested at a 10 fold higher concentration than found in blood culture media.
  • Annotation Protocol: Negative samples tested to determine effect on SPC. Positive samples tested against substances. All results compared to positive and negative buffer controls.

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Clinical Comparison Study

  • Study Type: Multi-site prospective study.
  • Sample Size: 792 specimens.
  • Standalone Performance:
    • For MRSA: 98.1% of specimens positive for MRSA identified correctly; 99.6% of specimens negative for MRSA identified correctly.
    • For SA: 99.6% of specimens positive for SA identified correctly; 99.5% of specimens negative for SA identified correctly.
  • Key Results:
    • The Xpert MRSA/SA Blood Culture Assay identified 98.1% of the specimens positive for MRSA and 99.6% of the specimens negative for MRSA relative to culture.
    • The Xpert MRSA/SA Blood Culture Assay identified 99.6% of the specimens positive for SA and 99.5% of the specimens negative for SA relative to the reference culture method.
    • Overall assay success rate was 99.6% (792/795).
      Reproducibility Study
  • Study Type: Multi-site reproducibility study at three sites.
  • Sample Size: A panel of 11 samples was tested on five different days by two different operators three times per day at three sites (11 samples x 2 operators x 5 days x 3 replicates per day x 3 sites). One lot of Xpert MRSA/SA reagents.
  • Key Results:
    • Total agreement for MRSA-1 high neg (below LOD) 61.1% (55/90).
    • Total agreement for MRSA-1 low pos (~1X LOD) 100.0% (90/90).
    • Total agreement for MRSA-1 mod pos (~2-3X LOD) 100.0% (89/89).
    • Total agreement for MRSA-2 high neg (below LOD) 55.6% (50/90).
    • Total agreement for MRSA-2 low pos (~1X LOD) 100.0% (90/90).
    • Total agreement for MRSA-2 mod pos (~2-3X LOD) 100.0% (90/90).
    • Total agreement for MSSA high neg (below LOD) 59.6% (53/89).
    • Total agreement for MSSA low pos (~1X LOD) 97.8% (88/90).
    • Total agreement for MSSA mod pos (~2-3X LOD) 100.0% (90/90).
    • Total agreement for Negative-1 and Negative-2 100% (90/90).
      Instrument System Precision Study
  • Study Type: In-house precision study comparing GeneXpert Dx, Infinity-48, and Infinity-80 Instrument Systems.
  • Sample Size: A panel of 11 specimens was tested on 12 different days by two different operators four times per day per instrument (11 specimens x 12 days x 4 replicates per day x 3 instruments). One lot of Xpert MRSA/SA reagents.
  • Key Results:
    • Total agreement for MRSA-1 high neg (below LOD) 45.6% (131/287).
    • Total agreement for MRSA-1 low pos (~1X LOD) 98.3% (283/288).
    • Total agreement for MRSA-1 mod pos (~2-3X LOD) 99.7% (287/288).
    • Total agreement for MRSA-2 high neg (below LOD) 79.5% (229/288).
    • Total agreement for MRSA-2 low pos (~1X LOD) 100.0% (288/288).
    • Total agreement for MRSA-2 mod pos (~2-3X LOD) 99.7% (287/288).
    • Total agreement for MSSA high neg (below LOD) 76.4% (220/288).
    • Total agreement for MSSA low pos (~1X LOD) 98.6% (284/288).
    • Total agreement for MSSA mod pos (~2-3X LOD) 100.0% (288/288).
    • Total agreement for Negative-1 and Negative-2 100.0% (288/288).

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Clinical Comparison Study:

  • MRSA:
    • PPA (Positive Percent Agreement): 98.1% (103/105, 95% CI: 93.3-99.8)
    • NPA (Negative Percent Agreement): 99.6% (684/687, 95% CI: 98.7-99.9)
  • SA:
    • PPA (Positive Percent Agreement): 99.6% (235/236, 95% CI: 97.7-99.9)
    • NPA (Negative Percent Agreement): 99.5% (553/556, 95% CI: 98.4-99.9)

Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.

K101879, K071026

Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).

Not Found

§ 866.1640 Antimicrobial susceptibility test powder.

(a)
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.(b)
Classification. Class II (performance standards).

0

130894

510(k) Summary 5.0

JUN 2 0 2013

As required by 21 CFR Section 807.92(c).

| Submitted by: | Cepheid
904 Caribbean Drive
Sunnyvale, CA 90489
Phone number: (408) 400-8460
Fax number: (847) 510-0539 |
|---------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------|
| Contact: | Kerry J. Flom, Ph.D. |
| Date of Preparation: | March 29, 2013 |
| Device: | |
| Trade name: | Xpert® MRSA/SA Blood Culture Assay |
| Common name: | Methicillin-resistant Staphylococcus aureus (MRSA) and
Staphylococcus aureus (SA) from positive blood culture
bottles assay. |
| Type of Test: | Nucleic Acid Amplification Test, DNA, Methicillin-resistant
Staphylococcus aureus (MRSA) and Staphylococcus aureus
(SA), qualitative |
| Regulation number/ | 866.1640 |
| Classification name/
Product code: | Antimicrobial susceptibility test powder
NQX |
| Classification
Advisory Panel | Microbiology (83) |
| Predicate Devices
Name(s): | Xpert MRSA/SA Blood Culture Assay (510(k) #K101879)
BD GeneOhm™ StaphSR Assay (510(k) #K071026) |

Device Description:

The Cepheid Xpert® MRSA/SA Blood Culture Assay (Xpert MRSA/SA Blood Culture Assay) is a rapid, automated DNA test for the simultaneous qualitative detection of MRSA and SA DNA directly from blood culture bottle specimens that are detected as positive for microbial growth and shown to contain Gram Positive Cocci by Gram stain. The primers and probes in the Xpert MRSA/SA Assay detect nucleic acid sequences of the staphylococcal protein A (spa), the gene for methicillin/oxacillin resistance (mecA), and staphylococcal cassette chromosome (SCCmec) inserted in the SA chromosomal attB site.

The test includes a Sample Processing Control (SPC) to control for adequate processing of the target bacteria and to monitor the presence of inhibitor(s) in the PCR assay. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.

1

The specimen for testing with the Xpert MRSA/SA Blood Culture Assay consists of an aliquot taken from a positive blood culture bottle. Using one of the disposable fixed 50 µL volume transfer pipettes provided with the test kit, an aliquot of the positive blood culture is transferred into a single-use tube of Elution Reagent, also provided with the kit. The Elution Reagent is briefly vortexed and the entire content is transferred to the "S" chamber of the disposable fluidic cartridge (the Xpert MRSA/SA Blood Culture Assay cartridge), after which the cartridge is ready to place on the instrument.

The assay is performed on the Cepheid GeneXpert Instrument Systems, which automate and integrate sample purification, nucleic acid amplification of the target sequences in simple or complex samples using real-time PCR. The systems consist of an instrument, personal computer, and preloaded software for running the tests and viewing the results. The GeneXpert Instrument Systems require the use of single-use disposable cartridges that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained, crosscontamination between samples is minimized. In this platform, additional sample preparation, amplification, and real-time detection are all fully-automated and completely integrated. The Xpert MRSA/SA Blood Culture Assay performed on the GeneXpert Instrument Systems provides results in approximately 60 minutes.

The GeneXpert Instrument Systems, comprised of the GeneXpert Dx Systems and the GeneXpert Infinity Systems, have 1 to 80 randomly accessible modules, depending upon the instrument, that are each capable of performing separate sample preparation and real-time PCR tests. Each module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time PCR and detection.

The purpose of this submission is to submit documentation to support proposed improvements to the current assay and changes to the Intended Use.

Device Intended Use:

The Cepheid® Xpert® MRSA/SA Blood Culture Assay, performed on the GeneXpert® Instrument Systems, is a qualitative in vitro diagnostic test intended for the detection of Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA) DNA directly from positive blood cultures. The assay utilizes automated real-time polymerase chain reaction (PCR) for the amplification of MRSA/SA specific DNA targets and fluorogenic targetspecific hybridization probes for the real-time detection of the amplified DNA. The assay is performed directly on positive blood culture samples from BD BACTEC™ Plus Aerobic/F, BacT/ALERT® SA (Standard Aerobic) or VersaTREK REDOX 1® (aerobic) blood culture bottles that are determined by Gram Stain as Gram Positive Cocci in Clusters (GPCC) or as Gram Positive Cocci in singles (GPC). The Xpert MRSA/SA Blood Culture Assay is indicated for use in conjunction with other laboratory tests, such as culture, and clinical data available to the clinician as an aid in the detection of MRSA/SA from positive blood cultures. Subculturing of positive blood cultures is necessary to recover organisms for susceptibility testing or for epidemiological typing. The Cepheid Xpert MRSA/SA Blood Culture Assay is not intended to monitor treatment for MRSA/SA infections.

2

Substantial Equivalence:

The Xpert MRSA/SA Blood Culture Assay is substantially equivalent to the BD GeneOhm™ StaphSR Assay (510(k) #K071026) and to the current Xpert MRSA/SA Blood Culture Assay (510(k) #K101879). All assays detect SA and MRSA from positive blood cultures and determine the presence of the target organisms through real-time PCR amplification and fluorogenic target-specific hybridization detection. A multi-center study was conducted to determine the performance characteristics of the device relative to the reference culture results and susceptibility testing (the current standard of care), and relative to the predicate devices. The test results showed the Xpert MRSA/SA Blood Culture Assay to be substantially equivalent to the current standard of care and the predicate devices.

Table 5.1 shows the similarities and differences between the Xpert MRSA/SA Blood Culture Assay and predicate assays.

Table 5.1
Similarities and Differences Between the Xpert MRSA/SA Blood Culture Assay
and the Predicate Devices
Similarities
ItemNew Device
Xpert MRSA/SA Blood Culture AssayPredicate Devices
Current Xpert MRSA/SA Blood Culture Assay
(510(k) #K101879)BD GeneOhm™
StaphSR Assay
(510(k) #K071026)
Intended UseRapid detection of MRSA and SASameSame
Indication for UseIdentification of MRSA and SA colonizationSameSame
Specimen TypePositive Blood CultureSameSame
Technological PrinciplesFully-automated nucleic acid amplification (DNA); real-time PCRSameSame
DNA Target SequenceSequence incorporating the insertion site ( attB ) of Staphylococcal Cassette Chromosome mec (SCC mec ) for detection of MRSA.SameSame

3

Similarities
New DevicePredicate Devices
ItemXpert MRSA/SA
Blood Culture AssayCurrent Xpert
MRSA/SA Blood
Culture Assay
(510(k) #K101879)BD GeneOhm™
StaphSR Assay
(510(k) #K071026)
Clinical
Comparison
Results:Xpert MRSA/SA Blood
Culture Assay
Performance vs.
Reference Culture :
MRSA:
Positive % Agreement:
98.1%
Negative % Agreement:
99.6%
SA:
Positive % Agreement:
99.6%
Negative % Agreement:
99.5%Xpert MRSA/SA Blood
Culture Assay
Performance vs.
Reference Culture :
MRSA:
Positive % Agreement:
100.0
Negative % Agreement:
100.0
SA:
Positive % Agreement:
100.0
Negative % Agreement:
99.4BD GeneOhm™
StaphSR Assay
Performance vs.
Reference Culture
methods :
MRSA:
Positive %
Agreement: 100.0
Negative %
Agreement: 98.2 -
100.0
SA:
Positive %
Agreement: 98.8 -
100.0
Negative %
Agreement: 96.5 -
100.0
[Data obtained from
the BD GeneOhm
StaphSR Assay
510(k) Summary]

:

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:

,

  1. September 19. 1.

:

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:

:

1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 - 1999 -

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Differences
ItemNew Device
Xpert MRSA/SA Blood Culture AssayPredicate Devices
Current Xpert MRSA/SA Blood Culture Assay
(510(k) #K101879)BD GeneOhm™
StaphSR Assay
(510(k) #K071026)
Test CartridgeSame as current Xpert assay.Disposable single-use, multi-chambered fluidic cartridge.Disposable single-use PCR tube
Instrument
SystemCepheid GeneXpert Dx Systems and GeneXpert Infinity SystemsCepheid GeneXpert Dx SystemCepheid SmartCycler
Differences
New DevicePredicate Devices
ItemXpert MRSA/SA
Blood Culture AssayCurrent Xpert
MRSA/SA Blood
Culture Assay
(510(k) #K101879)BD GeneOhm™
StaphSR Assay
(510(k) #K071026)
Sample
PreparationSelf-contained and
automated after mixed
specimen is added to
cartridge. All other
reagents are contained
in the cartridge.Self-contained and
automated after mixed
specimen and two
single-dose reagents are
added to cartridge.Manual
ProbesSame as current Xpert
assay.TaqMan® ProbesMolecular Beacons
Internal
ControlsSame as current Xpert
assay.Sample processing
control (SPC) and probe
check control (PCC).One internal reagent
control and external
positive and negative
controls required per run
DNA Target
SequenceSame as current Xpert
assay.Sequence specific to
methicillin/oxacillin
resistance (mecA gene)N/A
UsersSame as current Xpert
assay.Operators with no
clinical lab experience
to experienced clinical
laboratory
technologists.CLIA High Complexity
Laboratory Users
DNA Target
SequenceSame as current Xpert
assay.Sequence specific to
Staphylococcus aureus
species (spa gene)Sequence specific to
Staphylococcus aureus
species (nuc gene)
Ability to
identify
correctly
"Empty
Cassette
Variants"Same as current Xpert
assay.Yes, sequence specific
to Staphylococcus
aureus species (mecA
gene)No
Rapid test
resultsApproximately 60
minutes to result.Approximately 50
minutes to result.Approximately 60-75
minutes to result.

4

and the comments of the comments of the comments of the contraction of the contribution of the contribution of the contribution of the contribution of the contribution of the

5

Non-Clinical Studies:

Analytical Inclusivity (Reactivity)

Two hundred fifty (250) SA strains (47 MSSA and 203 MRSA) from multiple sources were tested using the Xpert MRSA/SA Blood Culture Assay. Selections were made to represent the primary lineages with emphasis placed on the specific clonal complexes within which MRSA is predominantly observed. Lineages that contain MRSA and MSSA, as well as those that contain MSSA exclusively were included. When characterized by pulsed-field gel electrophoresis (PFGE), numerous USA types including USA100, the most common healthcare-acquired strain and USA300 and USA400, the most common communityacquired strains were also included.1 Strains representing "Empty Cassette" variants and heterogeneous strains identified as borderline oxacillin-resistant Staphylococcus aureus or BORSA were also tested.

All strains were tested in triplicate using 10 ul of stationary phase cell suspension diluted 1 million-fold. Colony forming units per assay (CFU/test) were determined by plate counts in triplicate. All results were reported correctly by the Xpert MRSA/SA Blood Culture Assay, except one specimen. The Xpert MRSA/SA Blood Culture Assay incorrectly identified one (1) SA strain (LGA251) as MSSA instead of MRSA. LGA251 contains a novel mecA gene representing a divergent mecA homologue (mecALGA25)) located in a novel staphylococcal chromosome mec element, designated SCCmec type XI. The mecA primers and probes in the MRSA/SA Blood Culture Assay will not detect the novel mecA gene in this strain due to mutations in the primer/probe binding regions. The mecA gene in this strain is only 70% homologous to the mecA gene in other known MRSA strains.

Limit of Detection

Studies were performed to determine the two-sided 95% confidence intervals for the analytical limit of detection (LoD) of SA cells and methicillin-resistant SA (MRSA) cells diluted into a blood culture matrix that can be detected by the Xpert MRSA/SA Blood Culture Assay. The matrix consisted of SA-free whole blood and MSSE (methicillinsusceptible Staphylococcus epidermidis) cells at 10° CFU/mL added to blood culture medium. The limit of detection is defined as the lowest number of colony forming units (CFU) per sample that can be reproducibly distinguished from negative samples with 95% confidence or the lowest concentration at which 19 of 20 replicates were positive.

For MRSA. 20 replicates were evaluated at each MRSA concentration tested (CFU/test) for 10 individual isolates representing SCCmec types I, II, III, IVa, IVd, V, VI, VII, and VIII. When characterized by pulsed-field gel electrophoresis (PFGE), USA100, the most common healthcare-acquired strain and USA400, one of the most common communityacquired strains were represented.

Cooper, J E and Feil, E J. 2006. The phylogeny of Staphylococcus aureus - which genes make the best intra-species markers? Microbiology 152:1297 - 1305.

6

For SA, 20 replicates were evaluated at each SA concentration (CFU/test) for 3 individual SA isolates. USA types USA900 and USA1200 were represented.

Point estimates and confidence intervals were determined by probit regression using data (i.e., the number of positive results per number of replicates at each level) spanning a range of CFU/test loadings. The confidence intervals were determined using maximum likelihood estimates on the probit model parameters using the large sample variancecovariance matrix. The LoD point estimates and 95% upper and lower confidence intervals for each SA and each MRSA SCCmec type tested are summarized in Tables 5.2 and 5.3.

| SA Strain
ID | PFGE ID | Confirmed
LoD
(CFU/test)
[at least 19/20
positive] | LoD Estimate (Probit Regression
Analysis) (CFU/test) | | |
|-----------------|----------|----------------------------------------------------------------|---------------------------------------------------------|--------------|-----------------|
| | | | Lower
95% CI | LoD Estimate | Upper
95% CI |
| 102-04a | USA 1200 | 100 (19/20) | 60.4 | 74.5 | 101.6 |
| 29213b | unknown | 150 (19/20) | 120.1 | 138.2 | 172.7 |
| N7129a | USA900 | 300 (19/20) | 224.2 | 255.2 | 314.8 |

Table 5.2: LoD and 95% Confidence Intervals - SA

Strain Source:

· American Type Culture Collection (ATCC), Manassas, VA., USA

Centers for Disease Control and Prevention (CDC), Atlanta, GA., USA

| MRSA Strain ID | PFGE ID | Confirmed LoD
(CFU/test)
[at least 19/20
positive] | LoD Estimate (Probit Regression Analysis)
(CFU/test) | Lower 95%
CI | LoD Estimate | Upper
95% CI |
|-------------------------|----------|-------------------------------------------------------------|---------------------------------------------------------|-----------------|--------------|-----------------|
| Type I (64/4176)a | USA500 | 350 (19/20) | | 332.3 | 366.8 | 433.5 |
| Type II (N315)b | USA100e | 175 (19/20) | | 113.7 | 137.0 | 178.1 |
| Type III (11373)b | unknown | 225 (19/20) | | 191.9 | 222.6 | 273.9 |
| Type IVa (MW2)b | USA400e | 350 (19/20) | | 313.1 | 356.1 | 427.0 |
| Type V (ST59)c | USA1000e | 250 (19/20) | | 218.2 | 243.1 | 282.3 |
| Type VI (HDE288)d,f | USA800e | 250 (19/20) | | 222.2 | 246.0 | 385.0 |
| Type VII (JCSC6082)a | unknown | 300 (19/20) | | 264.1 | 288.0 | 347.1 |
| Type VIII (WA MRSA-16)c | unknown | 400 (19/20) | | 348.7 | 386.7 | 499.1 |
| Type II (BK2464)b | USA100g | 125 (19/20) | | 94.3 | 116.1 | 162.0 |
| Type IVd (BK2529)b,f | USA500g | 200 (19/20) | | 120.8 | 148.8 | 202.5 |

Table 5.3. LoD and 95% Confidence Intervals - MRSA

Strain Source:

"Teruyo Ito, Department of Bacteriology, School of Medicine Juntendo University, Tokyo, Japan

Barry Kreiswirth, Director Public Health Research Institute (PHRI), Newark, NJ., USA

"Geoffrey Coombs, Department of Microbiology and Infectious Diseases, Royal Perth Hospital, Perth WA

1 Herminia de Lancaste, Laboratory of Molecular Genetics, Instituto de Tecnologia (ITQB), Universidade Nova de Lisboa, Oeiras, Portugal

6K, Bonnstetter, et al., J Clin Micro 2007, p. 141-146; L. McDougal, et al., J Clin Micro 2003, p. 51 13-5120

THeterogeneous oxacillin-resistant isolates

8Barry Kreiswirth, personal communication

7

The results of this study indicate that the Xpert MRSA/SA Blood Culture Assay will produce a positive SA result 95% of the time in a positive blood culture aliquot (50 µL) containing 300 CFU and a positive MRSA result 95% of the time for a positive blood culture aliquot (50 µL) containing 400 CFU.

Linearity

Not applicable, the Xpert MRSA/SA Blood Culture Assay is a qualitative assay.

Analytical Specificity (Exclusivity)

One hundred and one (101) strains were collected, quantitated, and tested using the Xpert MRSA/SA Blood Culture Assay. Of the 101 strains tested, 91 cultures were obtained from the American Type Culture Collection (ATCC), 1 was obtained from Culture Collection, University of Göteborg, Sweden (CCUG), 1 was obtained from Teruyo Ito. Juntendo University, Tokyo, Japan, 1 carbapenemase (KPC) producing Klebsiella pneumoniae strain was obtained from National Collection of Type Cultures (NCTC), UK and 7 strains were obtained from the Network on Antimicrobial Resistance in SA (NARSA). These strains represent species phylogenetically related to SA or those potentially encountered in the hospital environment.

The organisms tested were identified as either Gram positive (74), Gram negative (24), or yeast (3). Methicillin-sensitive, coagulase negative Staphylococcus, MSCoNS (27) and methicillin- resistant, coagulase negative Staphylococcus, MRCoNS (12) were included. The organisms were further classified as either aerobic (94) or anaerobic (7).

Three replicates of each isolate were tested at 1.7 - 3.2 McFarland units. Under the conditions of the study, all isolates were reported MRSA NEGATIVE; SA NEGATIVE; none of the isolates were detected by the Xpert MRSA/SA Blood Culture Assay. The analytical specificity was 100%.

Potentially Interfering Substances

Substances that may be present in blood cultures with potential to interfere with the Xpert MRSA/SA Blood Culture Assay were tested in the interfering substance study. Potentially interfering substances include, but are not limited to, anticoagulated whole blood with ACD, EDTA, Heparin, and Sodium Citrate, human plasma, three blood culture media bottles (Becton Dickinson BACTEC™ Plus Aerobic/F, BioMérieux BacT/ALERT SA (Standard Aerobic), and TREK Diagnostics VersaTREK REDOXI (Aerobic), bilirubin, y-globulin, hemoglobin, triglycerides, and sodium polyanetholesulfonate (SPS). Bilirubin, y-globulin, hemoglobin, and triglycerides were tested at concentrations approximately one log higher than reference levels. SPS was tested at a 10 fold higher concentration than found in blood culture media. Negative samples (n=8) were tested in each substance to determine the effect on the performance of the sample processing control (SPC). Positive samples (n=8) were tested per substance with two clinical isolates each of MSSA (29213 and 102-04) and MRSA (SCCmec types II and HII) spiked near the analytical LoD determined for each isolate. All results were compared to positive and negative buffer controls. All negative specimens were correctly reported "MRSA NEGATIVE; SA NEGATIVE" using the Xpert MRSA/SA Blood Culture Assay. None of the

8

potentially interfering substances had a statistically significant inhibitory effect on SPC performance in negative samples (p-value =>0.05). All of the positive MSSA specimens were correctly reported "MRSA NEGATIVE; SA POSITIVE" using the Xpert MRSA/SA Blood Culture Assay. All of the positive MRSA specimens were correctly reported "MRSA POSITIVE: SA POSITIVE" using the Xpert MRSA/SA Blood Culture Assay. None of the potentially interfering substances resulted in a Ct difference of ≥1 cycle relative to the buffer controls and no false-negative results were reported.

Clinical Studies

Clinical Comparison Study

· Performance characteristics of the Xpert MRSA/SA Blood Culture Assay were determined in a multi-site prospective study at eight US institutions by comparing the Xpert MRSA/SA Blood Culture Assay with culture.

Subjects included individuals whose routine care called for blood culture testing. If the blood culture sample was positive for microbial growth and the Gram stain showed Gram positive cocci (singles or in clusters), the sample was eligible for inclusion in the clinical study, and aliquots of leftover culture material were obtained for testing by the Xpert MRSA/SA Blood Culture Assay. Culture and Gram stain procedures, and patient management continued at the sites per the standard practice. Susceptibility testing was performed in accordance with the CLSI documents M2-A11 and M100-S22. Cefoxitin disc was used as a surrogate for detecting methicillin/oxacillin resistance.

Performance of the Xpert MRSA/SA Blood Culture Assay was calculated relative to the reference culture results.

Overall Results

A total of 792 specimens were tested for MRSA and SA by Xpert MRSA/SA Blood Culture Assay and culture.

The Xpert MRSA/SA Blood Culture Assay identified 98.1% of the specimens positive for MRSA and 99.6% of the specimens negative for MRSA relative to culture.

The Xpert MRSA/SA Blood Culture Assay identified 99.6% of the specimens positive for SA and 99.5% of the specimens negative for SA relative to the reference culture method. The performance of the Xpert MRSA/SA Blood Culture Assay is summarized in Table 5.4.

9

Culture
MRSA+SA+/MRSA-Neg/No
GrowthTotal
XpertMRSA+10321106
SA+/MRSA-21282132
SA-01553554
Total105131556792
Xpert PerformanceMRSA:
PPA: 98.1% (103/105, 95% CI: 93.3-99.8)
NPA: 99.6% (684/687, 95% CI: 98.7-99.9 )
SA:
PPA: 99.6% (235/236, 95% CI: 97.7-99.9 )
NPA: 99.5% (553/556, 95% CI: 98.4-99.9)

Table 5.4. MRSA/SA Performance vs. Reference Culture

Of the Xpert MRSA/SA Blood Culture Assay runs on eligible specimens, 96.1% (764/795) were successful on the first attempt. The remaining 31runs gave indeterminate results on the first attempt (1 "INVALID", 22 "ERROR" and 8 "NO RESULT"). Thirty of the 31 indeterminate cases were retested; one specimen was not retested. Twenty-eight of the 30 indeterminate cases that were retested yielded valid results upon repeat assay. The overall rate of assay success was 99.6% (792/795).

Reproducibility Study

Reproducibility of the Xpert MRSA/SA Assay was evaluated at three sites using samples comprised of cultured material spiked into a simulated matrix. The samples were prepared at concentration levels representing high negative (below LoD), low positive (~1 X LoD) and moderate positive (~2-3X LoD) for both MRSA and MSSA. Two different strains of MRSA were used. Negative panel members were also included and were comprised of Staphylococcus epidermidis spiked into a simulated matrix. A panel of 11 samples was tested on five different days by two different operators three times per day at three sites (11 samples x 2 operators x 5 days x 3 replicates per day x 3 sites). One lot of Xpert MRSA/SA reagents was included in the study. Xpert MRSA/SA Assays were performed according to the Xpert MRSA/SA Assay procedure. The rate of agreement for each panel member is presented in Table 5.5.

10

| Sample | Site 1/
GX Dx | Site 2/
Inf-80 | Site 3/
Inf-48 | % Total Agreement |
|-----------------------------|-------------------|-------------------|-------------------|--------------------|
| MRSA-1 high neg (below LOD) | 56.7%
(17/30) | 60.0%
(18/30) | 66.7%
(20/30) | 61.1%
(55/90) |
| MRSA-1 low pos (~1X LOD) | 100.0%
(30/30) | 100.0%
(30/30) | 100.0%
(30/30) | 100.0%
(90/90) |
| MRSA-1 mod pos (~2-3X LOD) | 100.0%
(30/30) | 100.0%
(30/30) | 100.0%
(29/29) | 100.0%
(89/89)a |
| MRSA-2 high neg (below LOD) | 43.3%
(13/30) | 53.3%
(16/30) | 70.0%
(21/30) | 55.6%
(50/90) |
| MRSA-2 low pos (~1X LOD) | 100.0%
(30/30) | 100.0%
(30/30) | 100.0%
(30/30) | 100.0%
(90/90) |
| MRSA-2 mod pos (~2-3X LOD) | 100.0%
(30/30) | 100.0%
(30/30) | 100.0%
(30/30) | 100.0%
(90/90) |
| MSSA high neg (below LOD) | 60.0%
(18/30) | 48.3%
(14/29) | 70.0%
(21/30) | 59.6%
(53/89)b |
| MSSA low pos (~1X LOD) | 96.7%
(29/30) | 100.0%
(30/30) | 96.7%
(29/30) | 97.8%
(88/90) |
| MSSA mod pos (~2-3X LOD) | 100.0%
(30/30) | 100.0%
(30/30) | 100.0%
(30/30) | 100.0%
(90/90) |
| Negative-1 | 100%
(30/30) | 100%
(30/30) | 100%
(30/30) | 100%
(90/90) |
| Negative-2 | 100%
(30/30) | 100%
(30/30) | 100%
(30/30) | 100%
(90/90) |

Table 5.5. Summary of Reproducibility Results - Agreement by Study Site/Instrument

"One sample indeterminate after initial and retest.

One sample mistakenly not run.

The reproducibility of the Xpert MRSA/SA Assay was also evaluated in terms of the fluorescence signal expressed in cycle threshold (Ct) values for each target detected. The mean, standard deviation (SD), and coefficient of variation (CV) between-sites, betweenlots, between-days, and between-runs for each panel member are presented in Table 5.6.

11

Table 5.6. Summary of Reproducibility Data
TargetSampleConcAgree/NAgrmt
(%)Mean
CtBetween-
InstrumentBetween-
DayBetween-
Run1Within-RunTotal
SDCV
(%)SDCV
(%)SDCV
(%)SDCV
(%)SDCV
(%)
spaMRSA-1high neg55/9061.135.60.180.50.210.60.000.00.952.70.992.8
MRSA-1low pos90/90100.032.80.270.80.000.00.000.00.621.90.672.1
MRSA-1mod pos89/89100.031.20.110.40.000.00.000.00.581.90.591.9
MRSA-2high neg50/9055.635.30.150.40.000.00.000.00.992.81.002.8
MRSA-2low pos90/90100.032.30.110.40.000.00.130.40.631.90.652.0
MRSA-2mod pos90/90100.030.70.000.00.000.00.000.00.551.80.551.8
MSSAhigh neg53/8959.636.30.000.00.000.00.000.01.263.51.263.5
MSSAlow pos88/9097.833.50.070.20.180.50.000.00.892.70.912.7
MSSAmod pos90/90100.031.70.080.20.200.60.170.60.481.50.561.8
NEG-1Neg90/90100.0NANANANANANANANANANANA
NEG-2Neg90/90100.0NANANANANANANANANANANA
mecMRSA-1high neg55/9061.135.80.000.00.361.00.000.00.832.30.912.5
MRSA-1low pos90/90100.033.40.120.40.190.60.000.00.551.60.591.8
MRSA-1mod pos89/89100.031.90.080.20.000.00.000.00.461.40.471.5
MRSA-2high neg50/9055.635.80.000.00.340.90.000.01.032.91.083.0
MRSA-2low pos90/90100.032.80.110.30.000.00.160.50.511.60.541.7
MRSA-2mod pos90/90100.031.50.000.00.160.50.000.00.491.50.511.6
MSSAhigh neg53/8959.6NANANANANANANANANANANA
MSSAlow pos88/9097.8NANANANANANANANANANANA
MSSAmod pos90/90100.0NANANANANANANANANANANA
NEG-1Neg90/90100.0NANANANANANANANANANANA
NEG-2Neg90/90100.0NANANANANANANANANANANA
SCCMRSA-1high neg55/9061.137.20.200.50.371.00.351.00.822.20.982.6
MRSA-1low pos90/90100.034.50.190.50.230.70.000.00.591.70.661.9
MRSA-1mod pos89/89100.033.00.160.50.000.00.000.00.451.40.481.5
MRSA-2high neg50/9055.636.80.230.60.240.60.100.31.002.71.062.9
MRSA-2low pos90/90100.033.70.110.30.000.00.260.80.571.70.641.9
MRSA-2mod pos90/90100.032.40.000.00.090.30.000.00.451.40.461.4
MSSAhigh neg53/8959.6NANANANANANANANANANANA
MSSAlow pos88/9097.8NANANANANANANANANANANA
MSSAmod pos90/90100.0NANANANANANANANANANANA
NEG-1Neg90/90100.0NANANANANANANANANANANA
NEG-2Neg90/90100.0NANANANANANANANANANANA
SPCMRSA-1high neg55/9061.132.70.000.00.000.00.200.60.652.00.682.1
MRSA-1low pos90/90100.033.00.000.00.160.50.100.30.611.80.631.9
MRSA-1mod pos89/89100.033.00.270.80.000.00.000.00.832.50.872.6
MRSA-2high neg50/9055.633.10.230.70.000.00.100.30.852.60.892.7
MRSA-2low pos90/90100.032.90.150.50.000.00.000.00.782.40.792.4
MRSA-2mod pos90/90100.032.80.000.00.230.70.000.00.662.00.702.1
MSSAhigh neg53/8959.632.80.180.50.150.50.000.00.742.20.772.4
MSSAlow pos88/9097.832.90.000.00.000.00.000.00.722.20.722.2
MSSAmod pos90/90100.033.00.000.00.310.90.000.00.692.10.762.3
NEG-1Neg90/90100.0NANANANANANANANANANANA
NEG-2Neg90/90100.0NANANANANANANANANANANA

Summary of Reproducibility Data Table 56

Agreement, Conc-concentration, CV=coefficient of variation, NA=Not Applicable for negative samples, SD=standard deviation Note: The variance estimate from some ically negative, which can occur if the variability due to those factors is very small. When this occurs, the variability as measured with SD and CV is set to 0.

1 A run is defined as the three samples per panel member run by one operator at one site on one day.

Instrument System Precision Study

An in-house precision study was conducted to compare the performance of the GeneXpert Dx, the Infinity-48 and the Infinity-80 Instrument Systems using samples comprised of cultured material spiked into a simulated matrix. The samples were prepared at concentration levels representing high negative (below LoD), low positive (~1X LoD) and moderate positive (~2-3X LoD) for both MRSA and MSSA. Two different strains of MRSA were used. Negative panel members were also included and were comprised of Staphylococcus epidermidis spiked into a

12

simulated matrix. A panel of 11 specimens was tested on 12 different days by two different operators four times per day per instrument (11 specimens x 12 days x 4 replicates per day x 3 instruments). One lot of Xpert MRSA/SA reagents was included in the study. Xpert MRSA/SA Assays were performed according to the Xpert MRSA/SA Assay procedure. The rate of agreement for each panel member is presented in Table 5.7.

SampleGX DxInf-48Inf-80% Total Agreement
MRSA-1 high neg (below LOD)50.0%
(48/96)51.6%
(49/95)35.4%
(34/96)45.6%
(131/287)a
MRSA-1 low pos (~1X LOD)96.9%
(93/96)99.0%
(95/96)99.0%
(95/96)98.3%
(283/288)
MRSA-1 mod pos (~2-3X LOD)100.0%
(96/96)100.0%
(96/96)99.0%
(95/96)99.7%
(287/288)
MRSA-2 high neg (below LOD)80.2%
(77/96)78.1%
(75/96)80.2%
(77/96)79.5%
(229/288)
MRSA-2 low pos (~1X LOD)100.0%
(96/96)100.0%
(96/96)100.0%
(96/96)100.0%
(288/288)
MRSA-2 mod pos (~2-3X LOD)100.0%
(96/96)100.0%
(96/96)99.0%
(95/96)99.7%
(287/288)
MSSA high neg (below LOD)76.0%
(73/96)71.9%
(69/96)81.3%
(78/96)76.4%
(220/288)
MSSA low pos (~1X LOD)96.9%
(93/96)99.0%
(95/96)100.0%
(96/96)98.6%
(284/288)
MSSA mod pos (~2-3X LOD)100.0%
(96/96)100.0%
(96/96)100.0%
(96/96)100.0%
(288/288)
Negative-1100.0%
(96/96)100.0%
(96/96)100.0%
(96/96)100.0%
(288/288)
Negative-2100.0%
(96/96)100.0%
(96/96)100.0%
(96/96)100.0%
(288/288)

Table 5.7: Summary of Precision Results - Agreement by Instrument

One sample was indeterminate after initial and retest.

The precision study results were also evaluated in terms of the fluorescence signal expressed in Ct values for each target detected. The mean, standard deviation (SD), and coefficient of variation (CV) between-instruments, between-days, and between-runs for each panel member are presented in Table 5.8.

13

Tamle 3.0. Outlimary of I 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
TargetSampleСопсAgree/NAgrmt
(%)Mean
CtBetween-Between-Between-Within-RunTotal
InstrumentDayRun'
SDCVSDCVSDCVSDCVSDCV
(%)(%)(%)(%)(%)
spaMRSA-Ihigh neg131/28745.634.40.000.00.000.00.000.01.093.21.093.2
MRSA-Ilow pos283/28898.332.90.020.10.160.50.000.00.782.40.802.4
MRSA-1mod pos287/28899.732.00.060.20.100.30.000.00.621.90.632.0
MRSA-2high neg229/28879.536.20.140.40.000.00.000.01.193.31.353.7
MRSA-2low pos288/288100.032.40.030.10.000.00.000.00.571.80.621.9
MRSA-2mod pos287/28899.731,10.120.40.000.00.000.00.491.60.211.7
MSSAhigh neg220/28876.436.40.2 10.60.000.00.000.01.363.7। 'ਤੇਖੋ4.4
MSSAlow pos284/28898.633.80.090.30.180:50.000.00.872.60.902.7
MSSAmod pos288/288100.032.20.080.30.000.00.000.00.702.20.742.3
NEG-INeg288/288100.0NANANANANANANANANANANA
NEG-2Neg288/288100.0NANANANANANANANANANANA
MRSA-Ihigh neg131/28745.634.50.000.00.110.30.000.00.862.50.872.5
mecMRSA-Ilow pos283/28898.333.40.070.20.140.40.000.00.611.80.631.9
MRSA-Imod pos287/28899.732.50.080.20.000.00.000.00.551.70.561.7
MRSA-2high neg229/28879.535.90.000.00.280.80.000.01.022.81 .062.9
MRSA-2low pos288/288100.032.80.060.20.000.00.000.00.49ાં .ડ0.531.6
MRSA-2mod pos287/28899.731.50.140. ર0.050.20.000.00.451.40.47રે
MSSAhigh neg220/28876.4NANANANANANANANANANANA
MSSAlow pos284/28898.6NANANANANANANANANANANA
MSSAmod pos288/288100.0NANANANANANANANANANANA
NEG-INeg288/2881 00.0NANANANANANANANANANANA
NEG-2Neg288/288100.0NANANANANANANANANANANA
MRSA-1high neg131/28745.636.70.180.50.000.00.000.01 .5 l4.11.524.1
MRSA-Ilow pos283/28898.334.70.000.00.200.60.000.01.113.21,133.2
SCCMRSA-1mod pos287/28899.733.70.120.30.000.00.000.00.782.30.782.3
MRSA-2high neg229/28879.537.30.000.00.320.80.000.01.032.81.173.1
MRSA-2low pos288/2881 00.034.20.020.10.000.00.000.00.441.30.50। .ડ
MRSA-2mod pos287/28899.733.00.120.40.030.10.000.00.491.50.501.5
MSSAhigh neg220/28876.4NANANANANANANANANANANA
MSSAlow pos284/288૭૪.6NANANANANANANANANANANA
MSSAmod pos288/288100.0NANANANANANANANANANANA
NEG-1Neg288/288100.0NANANANANANANANANANANA
NEG-2Neg288/288100.0NANANANANANANANANANANA
SPCMRSA-1high neg131/28745.633.40.000.00.170.50.000.00.842.50.862.6
MRSA-Ilow pos283/28898.333.40.100.30.210.60.000.00.772.30.802.4
MRSA-1mod pos287/28899.733.40.080.20.150.50.000.00.722.20.742.2
MRSA-2high neg229/28879.533.40.000.00.000.00.000.00.822.40.822.4
MRSA-2low pos288/288100.033.40.020. I0.000.00.000.00.732.20.772.3
MRSA-2mod pos287/28899.733.30.000.00.090.30.000.00.742.20.752.2
MSSAhigh neg220/28876.433.40.000.00.200.60.000.00.832.50.852.6
MSSAlow pos284/28898.633.50.000.00.000.00.000.00.862.60.872.6
MSSAmod pos288/288100.033.10.110.30.000.00.000.00.752.20.772.3
NEG-1Neg288/288100.033.40.000.00.130.40.000.00.852.60.872.6
NEG-2Neg288/288100.033.50.000.00.020.10.000.00.842.50.842.5

Table 58. Summary of Precision Data

Agrow=Agreement, Conc=concentration, CV=coefficient of variation, N/A=Not Applicable for negative samples, SD=standard deviation

Note: The variance estimate from some factors may be numerically negative, which can occur if the variability due to those factors is very small. When this occurs, the variability as measured with SD and CV is set to 0.

I A run is defined as the four samples per panel member run by one operator at one site on one day.

Conclusions

The results of the nonclinical analytical and clinical performance studies summarized above demonstrate that the Xpert MRSA/SA Blood Culture Assay is substantially equivalent to the predicate devices.

14

Image /page/14/Picture/0 description: The image shows the logo for the U.S. Department of Health and Human Services. The logo is a circular seal with the words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" around the perimeter. Inside the circle is an emblem of an eagle with three lines representing the bird's body and wings.

DEPARTMENT OF HEALTH & HUMAN SERVICES

Public Health Service

Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G60 Silver Spring, MD 20993-0002

RAINER ZIERMANN, PH.D. VICE PRESIDENT, CLINICAL AFFAIRS CEPHEID 904 CARRIBEAN DRIVE SUNNYVALE CA 94089

June 20, 2013

Re: K130894

Trade/Device Name: Xpert MRSA/SA Blood Culture Assay Regulation Number: 21 CFR 866.1640 Regulation Name: Antimicrobial susceptibility test powder Regulatory Class: II Product Code: NOX Dated: March 29, 2013 Received: April 02, 2013

Dear Dr. Ziermann:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug. and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050. .

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If you desire specific advice for your device on our labeling regulations (2) CFR Parts 801 and 809), please contact the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Uwe Scherf - S for

Sally A. Hojvat, M.Sc., Ph.D. Director, Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use ·4.0

Indications for Use Form

510(k) Number (if known): K130894

Device Name: Xpert® MRSA/SA Blood Culture Assay

Indications for Use:

The Cepheid Xpert® MRSA/SA Blood Culture Assay, performed on the GeneXpert® Instrument Systems, is a qualitative in vitro diagnostic test intended for the detection of Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA) DNA directly from positive blood cultures. The assay utilizes automated real-time polymerase chain reaction (PCR) for the amplification of MRSA/SA specific DNA targets and fluorogenic target-specific hybridization probes for the real-time detection of the amplified DNA. The assay is performed directly on positive blood culture samples from BD BACTEC™ Plus Aerobic/F, BacT/ALERT® SA (Standard Aerobic) or VersaTREK REDOX 1® (aerobic) blood culture bottles that are determined by Gram stain as Gram Positive Cocci in Clusters (GPCC) or as Gram Positive Cocci in singles (GPC). The Xpert MRSA/SA Blood Culture Assay is indicated for use in conjunction with other laboratory tests, such as culture, and clinical data available to the clinician as an aid in the detection of MRSA/SA from positive blood cultures. Subculturing of positive blood cultures is necessary to recover organisms for susceptibility testing or for epidemiological typing. The Cepheid Xpert MRSA/SA Blood Culture Assay is not intended to monitor treatment for MRSA/SA infections.

Prescription Use XAND/OROver-The-Counter Use
(Part 21 CFR 801 Subpart D)(21 CFR 801 Subpart C)

(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)

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Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)

John Holosen 2013.06 18 13.06 si -04'00'

Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety

510(k)_k130894

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