(535 days)
Not Found
No
The description focuses on real-time PCR technology and automated sample processing, with no mention of AI or ML algorithms for data analysis or interpretation.
No
This device is an in vitro diagnostic test designed to detect Group B Streptococcus DNA. It aids in determining GBS colonization status and does not provide therapy or treatment.
Yes
The "Intended Use / Indications for Use" section explicitly states that the device is "an automated qualitative in vitro diagnostic test for the detection of Group B Streptococcus (GBS) DNA". Additionally, the "Device Description" also refers to it as "an automated in vitro diagnostic test".
No
The device is an in vitro diagnostic test that utilizes a physical instrument system (GeneXpert Instrument Systems) and disposable cartridges containing reagents to perform real-time PCR. While it includes software for running tests and viewing results, it is fundamentally a hardware-based system with integrated software, not a standalone software-only medical device.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use/Indications for Use: The document explicitly states it is an "automated qualitative in vitro diagnostic test" and is "indicated as an aid in determining the GBS colonization status of antepartum women." This clearly defines its purpose as a diagnostic tool used outside of the body to assess a health condition.
- Device Description: The description details the components and process of the test, which involves analyzing biological samples (vaginal/rectal swabs) to detect specific DNA markers (GBS DNA). This aligns with the definition of an in vitro diagnostic device.
- Clinical Performance Studies: The document describes clinical studies where the device's performance was evaluated against a comparator method using human specimens. This is a standard requirement for demonstrating the effectiveness of an IVD.
N/A
Intended Use / Indications for Use
The Xpert GBS LB XC test, performed on the GeneXpert® Instrument Systems, is an automated qualitative in vitro diagnostic test for the detection of Group B Streptococcus (GBS) DNA from enriched vaginal/rectal swab specimens, using real- time polymerase chain reaction (PCR).
Xpert GBS LB XC testing is indicated as an aid in determining the GBS colonization status of antepartum women.
• The Xpert GBS LB XC test is intended for antepartum testing on enriched Lim broth cultures of vaginal/rectal swabs after 18-24 hours of incubation
• The Xpert GBS LB XC test does not provide antimicrobial susceptibility test results. Culture is necessary to obtain isolates to perform susceptibility testing as recommended for penicillin-allergic women.
This device is intended for prescription use only.
Product codes (comma separated list FDA assigned to the subject device)
NJR, OOI
Device Description
The Xpert GBS LB XC test is an automated in vitro diagnostic test for qualitative detection of DNA from Group B Streptococcus (GBS) from vaginal-rectal swab specimens obtained from pregnant women that are transported to the laboratory following enrichment in Lim broth.
The primers and probes in the Xpert GBS LB XC test are designed to simultaneously amplify and detect two unique GBS chromosomal targets: the first is a target within a coding region for a glycosyl transferase family protein and the second is within a coding region for a LysR family transcriptional regulator of Streptococcus agalactiae DNA.
The Xpert GBS LB XC test includes reagents for the detection of DNA from GBS in Lim broth-enriched vaginal/rectal swabs. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge. The SPC is present to control for adequate extraction and processing of the target sequences and to monitor for the presence of inhibitors in the PCR reaction. The PCC verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dve stability.
The single-use, multi-chambered fluidic cartridges are designed to complete sample preparation and real-time PCR for the detection of GBS genomic DNA in as little as 27 minutes with high titer specimens; GBS negative specimens generate results in approximated 43 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 and RT-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 RT-PCR and detection.
The Xpert GBS LB XC test is performed on the Cepheid GeneXpert® Instrument Systems (GeneXpert Dx, GeneXpert Infinity-48s, and GeneXpert Infinity-80 systems). The GeneXpert Instrument System platform automates sample preparation, amplification and real-time detection. The GeneXpert systems consist of an instrument, computer, and preloaded software for running tests and viewing the results.
The GeneXpert Instrument Systems require the use of single-use, disposable cartridges (the Xpert GBS LB XC cartridges) that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained and specimens never come into contact with working parts of the instrument modules, cross-contamination between samples is minimized.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
vaginal/rectal swab specimens
Indicated Patient Age Range
antecedant women (pregnant women)
Intended User / Care Setting
Not Found
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
A study was performed to evaluate the analytical reactivity of Xpert GBS LB XC test using GBS strains containing deletions in or adjacent to the chromosome that encodes the CAMP factor hemolysis gene ctb. Ten unique, well characterized GBS clinical isolates representing different c/o mutations were tested at 833 CFU/mL. All strains with c/b mutations were detected with a positivity rate of 100%.
The analytical specificity of the Xpert GBS LB XC test was evaluated by testing a panel of 128 strains, representing bacterial, viral, parasite and yeast strains commonly found in vaginal/rectal flora or phylogenetically related to GBS (Table 4) in the Xpert GBS LB XC test in the absence (exclusivity) or presence (microbial interference) of GBS. Bacteria were tested at ≥ 1x10^6 CFU/ml, except as noted, and viruses and parasites were tested at a level of > 1x10^5 organisms, yeast, IU or copies/ml. Microorganisms with potential to grow to high titers in Lim broth during enrichment (Candida albicans, Enterococcus faecalis, Enterococcus faecium, Enterococcus gallinarum, Streptococcus anginosus, Streptococcus parasanguinis, Corynebacterium accolens) were tested at > 1x10^6 CFU/ml. Of the 128 strains, 121 were tested in Lim broth clinical sample matrix or in simulated sample matrix, both in presence of GBS at 3x LoD and in absence of GBS.
Seven of 128 strains (Finegoldia magna, Mobiluncus curtisii subsp. curtisii, Peptoniphilus asaccharolyticus. Fusobacterium nucleatum. Peptostreptococcus anaerobius, Anaerococcus tetradius and Anaerococcus prevotii ) were not available for in vitro testing and were evaluated by in silico analysis using the Xpert GBS LB XC primer and probe sequences as queries for organism- specific BLAST (Basic Local Alignment Search Tool) analysis of the NCBI (National Center for Biotechnology Information) Nucleotide collection (nr/nt) database.
A study was conducted to demonstrate that no carry-over contamination occurs when testing these single-use, self-contained GeneXpert cartridges in the same GeneXpert module. The study consisted of a negative sample processed in the same GeneXpert module immediately following a high GBS positive sample. Twenty-one runs alternating high titer GBS positive and GBS negative samples were performed consecutively on two GeneXpert modules, thus a total of 42 runs were executed for the study.
A panel of ten samples with varying concentrations of four different GBS strains were tested by two operators each in triplicate on six different days at three sites using 3 different lots of Xpert GBS LB XC (2 operators × 3 replicates/day × 6 days × 3 sites) including negative panel members. Three lots of Xpert GBS LB XC were used at each of the three testing sites. The source of the three strains (serotype Ia, III, IV) representing a hemolytic phenotype and one strain (serotype Ic) representing a non-hemolytic phenotype is presented in Table 6. The three levels were ~3 × LOD and ~1 × LOD and negative.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Non-Clinical Studies:
Analytical Sensitivity (Limit of Detection) and Analytical Reactivity (Inclusivity):
The analytical reactivity and limit of detection (LoD) of the Xpert GBS LB XC test were determined for 12 different strains representing 12 known serotypes of GBS, of which 2 were characterized as non-hemolytic (Table 3). Serial dilutions of each serotype were prepared in a Lim broth negative clinical sample matrix or in a simulated sample matrix. Serotypes Ia. III and V were tested with 24 replicates per dilution level for each of two reagent lots across three days. Serotypes Ib, Ic, II, IV and VI-X were tested with one reagent lot for a total of 24 replicates of each dilution level across three days. The LoD was established for each serotype and reagent lot by probit logistic regression analysis. The LoD for each serotype was verified by testing 20 replicates at the 95% confidence interval upper limit with one reagent lot across three days.
Results: The results for all serotypes except serotype V and VI were >95% (>19/20) detected. The result for serotype V and VI was 85% (17/20) detected and the claimed LoD is based on the upper level of 95% confidence interval.
Analytical Reactivity with GBS cfb Mutants:
A study was performed using GBS strains containing deletions in or adjacent to the chromosome that encodes the CAMP factor hemolysis gene ctb.
Results: All strains with c/b mutations were detected with a positivity rate of 100%.
Analytical Specificity (Exclusivity) and Microbial Interference:
The analytical specificity of the Xpert GBS LB XC test was evaluated by testing a panel of 128 strains, representing bacterial, viral, parasite and yeast strains.
Results: No cross-reactivity or microbial interference of GBS detection was observed, both in silico and in vitro, with any clinically relevant pathogens.
Interfering Substances Study:
Substances that may be present in vaginal/rectal specimens with the potential to interfere with the Xpert GBS LB XC test were evaluated. These substances include human amniotic fluid, meconium, urine, fecal material, human blood, lubricating gel, vaginal anti-itch medications, vaginal antifungal medications, anti- diarrheal medications, laxatives, stool softeners, topical hemorrhoid ointments, body oil, body powder, deodorant sprays, enema solutions, and spermicidal foam.
Results: There was no interference in the presence of the substances at the concentrations tested in this study. All positive and negative samples were correctly identified using the Xpert GBS LB XC test.
Carry-Over Contamination:
Study performed with 42 runs, alternating high-titer GBS positive and GBS negative samples.
Results: All 20 positive samples were correctly reported as GBS POSITIVE. All 22 negative samples were correctly reported as GBS NEGATIVE.
Reproducibility Study:
A panel of ten samples with varying concentrations of four different GBS strains were tested by two operators each in triplicate on six different days at three sites using 3 different lots of Xpert GBS LB XC (2 operators × 3 replicates/day × 6 days × 3 sites) including negative panel members.
Results: No statistically significant difference in performance (p-value of
§ 866.3740
Streptococcus spp. serological reagents.(a)
Identification. Streptococcus spp. serological reagents are devices that consist of antigens and antisera (excluding streptococcal exoenzyme reagents made from enzymes secreted by streptococci) used in serological tests to identifyStreptococcus spp. from cultured isolates derived from clinical specimens. The identification aids in the diagnosis of diseases caused by bacteria belonging to the genusStreptococcus and provides epidemiological information on these diseases. Pathogenic streptococci are associated with infections, such as sore throat, impetigo (an infection characterized by small pustules on the skin), urinary tract infections, rheumatic fever, and kidney disease.(b)
Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 866.9.
0
Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left, there is a symbol representing the Department of Health & Human Services. To the right of the symbol, there is the FDA logo in blue, followed by the words "U.S. FOOD & DRUG" in a larger font and "ADMINISTRATION" in a smaller font below it, also in blue.
May 9, 2022
Cepheid Robert Resnick Principal Regulatory Affairs Specialist 904 Caribbean Drive Sunnyvale, California 94089
Re: K203429
Trade/Device Name: Xpert GBS LB XC. GeneXpert Dx System. GeneXpert Infinity System Regulation Number: 21 CFR 866.3740 Regulation Name: Streptococcus Spp. Serological Reagents Regulatory Class: Class I Product Code: NJR, OOI Dated: November 18, 2020 Received: November 20, 2020
Dear Robert Resnick:
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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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 Part
1
801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4. Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
for
Ribhi Shawar, Ph.D. (ABMM) Branch Chief, General Bacteriology and Antimicrobial Susceptibility Branch Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
2
Indications for Use
510(k) Number (if known) K203429
Device Name Xpert GBS LB XC
Indications for Use (Describe)
The Xpert GBS LB XC test, performed on the GeneXpert® Instrument Systems, is an automated qualitative in vitro diagnostic test for the detection of Group B Streptococcus (GBS) DNA from enriched vaginal/rectal swab specimens, using real- time polymerase chain reaction (PCR).
Xpert GBS LB XC testing is indicated as an aid in determining the GBS colonization status of antepartum women.
· The Xpert GBS LB XC test is intended for antepartum testing on enriched Lim broth cultures of vaginal/rectal swabs after 18-24 hours of incubation
· The Xpert GBS LB XC test does not provide antimicrobial susceptibility test results. Culture is necessary to obtain isolates to perform susceptibility testing as recommended for penicillin-allergic women
| Type of Use (Select one or both, as applicable) |
|---|
| ------------------------------------------------- |
× Prescription Use (Part 21 CFR 801 Subpart D)
__ Over-The-Counter Use (21 CFR 801 Subpart C)
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3
510(k) SUMMARY
As required by 21 CFR Section 807.92(c).
I. SUBMITTER
| Submitted by: | Cepheid 904 Caribbean Drive Sunnyvale, CA 90489 Phone number: (408) 541-4191 Fax number: (408) 541-4192 |
|---|---|
| Contact: | Robert Resnick. M.S. |
| Date of Preparation: | December 06, 2021 |
| II. DEVICE | |
| Trade name: | Xpert® GBS LB XC |
| Common name: | Xpert® GBS LB XC |
| Type of Test: | Qualitative real-time polymerase chain reaction (PCR) and detection test |
| Regulation number, | |
| Classification name, | |
| Product code: Definition | 21 CFR 866.3740, Streptococcus spp. serological reagents. NJR; |
| Definition: A nucleic acid amplification assay system (including probes, | |
| other reagents, and instrumentation) is an aid in the identification of | |
| group b streptococci from pre-partum and intra-partum women to | |
| establish colonization status. | |
| 21 CFR 862.2570, Instrumentation for clinical multiplex test systems, | |
| OOI; Definition: The system is a clinical multiplex instrument intended | |
| to measure and sort multiple signals generated my multiple probes, | |
| intercalating dyes, or other ligands in an assay from a clinical sample. | |
| Signals may be generated by fluorescence or other phenomena and may | |
| be measured using filters on a photodiode or other detector. It may | |
| integrate sample and/or reagent handling, amplification, dedicated | |
| instrument control, data acquisition software, raw data storage | |
| mechanisms and other essential hardware components along with the | |
| signal reader unit. The system is used with specific assays to comprise | |
| an assay test system. | |
| Classification Advisory | |
| Panel | Microbiology (83) |
| Prescription Use | Yes |
III. PREDICATE DEVICE
Predicate Device Assay: Xpert GBS LB (K121539)
4
IV. DEVICE DESCRIPTION
The Xpert GBS LB XC test is an automated in vitro diagnostic test for qualitative detection of DNA from Group B Streptococcus (GBS) from vaginal-rectal swab specimens obtained from pregnant women that are transported to the laboratory following enrichment in Lim broth.
The primers and probes in the Xpert GBS LB XC test are designed to simultaneously amplify and detect two unique GBS chromosomal targets: the first is a target within a coding region for a glycosyl transferase family protein and the second is within a coding region for a LysR family transcriptional regulator of Streptococcus agalactiae DNA.
The Xpert GBS LB XC test includes reagents for the detection of DNA from GBS in Lim broth-enriched vaginal/rectal swabs. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge. The SPC is present to control for adequate extraction and processing of the target sequences and to monitor for the presence of inhibitors in the PCR reaction. The PCC verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dve stability.
The single-use, multi-chambered fluidic cartridges are designed to complete sample preparation and real-time PCR for the detection of GBS genomic DNA in as little as 27 minutes with high titer specimens; GBS negative specimens generate results in approximated 43 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 and RT-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 RT-PCR and detection.
The Xpert GBS LB XC test is performed on the Cepheid GeneXpert® Instrument Systems (GeneXpert Dx, GeneXpert Infinity-48s, and GeneXpert Infinity-80 systems). The GeneXpert Instrument System platform automates sample preparation, amplification and real-time detection. The GeneXpert systems consist of an instrument, computer, and preloaded software for running tests and viewing the results.
The GeneXpert Instrument Systems require the use of single-use, disposable cartridges (the Xpert GBS LB XC cartridges) that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained and specimens never come into contact with working parts of the instrument modules, cross-contamination between samples is minimized.
5
V. DEVICE INTENDED USE:
The Xpert® GBS LB XC test, performed on the GeneXpert® Instrument Systems, is an automated qualitative in vitro diagnostic test for the detection of Group B Streptoccus (GBS) DNA from enriched vaginal/rectal swab specimens, using real-time polymerase chain reaction (PCR).
Xpert GBS LB XC testing is indicated as an aid in determining the GBS colonization status of antepartum women.
- . The Xpert GBS LB XC test is intended for antepartum testing on enriched Lim broth cultures of vaginal/rectal swabs after 18-24 hours of incubation.
- . The Xpert GBS LB XC test does not provide antimicrobial susceptibility test results. Culture is necessary to obtain isolates to perform susceptibility testing as recommended for penicillin-allergic women.
This device is intended for prescription use only.
6
VI. COMPARISON OF TECHNOLOGICAL CHARACTERISTICS WITH THE PREDICATE DEVICE
Substantial Equivalence:
The Xpert GBS LB XC test is substantially equivalent to the Xpert GBS LB Assay [510(k) # K121539].
The performance of the Xpert GBS LB XC test was evaluated in a multi-site clinical study in which the performance of the Xpert GBS LB XC test was determined relative to a composite comparator reference method using both results from culture and a FDA cleared nucleic acid test. The results of the study demonstrated that the performance of the Xpert GBS LB XC is substantially equivalent to the predicate device.
The following tables compare Xpert® GBS LB XC test to Xpert® GBS LB Assay (K121539). Table 1 shows similarities between the new device and the predicate, while Table 2 shows the differences.
| Comparison | ||
|---|---|---|
| Attribute | New Device | |
| Xpert® GBS LB XC | Predicate Device | |
| Xpert GBS LB (K121539) | ||
| Regulation | Same | 21CFR 866.3740 |
| Streptococcus spp. serological | ||
| reagents | ||
| Product Code | Same | NJR |
| Nucleic acid amplification assay | ||
| system, group b streptococcus, direct | ||
| specimen test | ||
| Device Class | Same | I (non-exempt) |
| Intended Use | The Xpert GBS LB XC test, | |
| performed on the GeneXpert® | ||
| Instrument Systems, is an automated | ||
| qualitative in vitro diagnostic test for | ||
| the detection of Group B | ||
| Streptococcus (GBS) DNA from | ||
| enriched vaginal/rectal swab | ||
| specimens, using real-time | ||
| polymerase chain reaction (PCR). |
Xpert GBS LB XC testing is
indicated as an aid in determining the
GBS colonization status of
antepartum women.
• The Xpert GBS LB XC test is
intended for antepartum testing on
enriched Lim broth cultures of
vaginal/rectal swabs after 18–24
hours of incubation | The Cepheid Xpert GBS LB Assay,
performed on the GeneXpert®
Instrument Systems, is a qualitative in vitro diagnostic test designed to detect
Group B Streptococcus (GBS) DNA
from enriched vaginal/rectal swab
specimens, using fully automated
real-time polymerase chain reaction
(PCR) with fluorogenic detection of
the amplified DNA.
Xpert GBS LB Assay testing is
indicated as an aid in determining
GBS colonization status in
antepartum women.
• The Xpert GBS LB Assay is used
for antepartum testing on enriched
Lim broth cultures of vaginal/rectal
swabs after 18–24 hours of incubation
• The Xpert GBS LB Assay does not
provide susceptibility results. Culture |
Table 1. Similarities between New Device and Predicate Device
7
| Comparison | ||
|---|---|---|
| Attribute | New Device | Predicate Device |
| Xpert® GBS LB XC | Xpert GBS LB (K121539) | |
| • The Xpert GBS LB XC test does | ||
| not provide antimicrobial | ||
| susceptibility test results. Culture is | ||
| necessary to obtain isolates to | ||
| perform susceptibility testing as | ||
| recommended for penicillin-allergic | ||
| women, | isolates are needed for performing | |
| susceptibility testing as recommended | ||
| for penicillin-allergic women. | ||
| Instrument Systems | Same | Cepheid GeneXpert Instrument |
| Systems | ||
| Laboratory Users | Same | CLIA Moderate Complexity |
| Specimen Type | Same | Enriched Lim broth cultures prepared |
| from vaginal/rectal swabs after 18-24 | ||
| hours of incubation | ||
| Collection and Transport | ||
| Media | Same | Cepheid Swab Collection Device or |
| equivalent swab in non-nutritive | ||
| transport medium | ||
| Assay Technology | Same | Real-Time PCR |
| Self-Contained System | ||
| Assay | Same | Yes |
| Single Use | Same | Yes |
| Automated Extraction, | ||
| detection and result | ||
| interpretation | Same | Yes |
| Fluidics | Same | Self-contained |
| External Assay Controls | Same | Materials available but not required |
| Built in Lysis Control | Same | Yes |
| Assay Results | Same | Qualitative |
| Time to Result | ||
| (after enrichment) | Same | 95% (>19/20) detected. The result for serotype V and VI was 85% (17/20) detected and the claimed LoD is based on the upper level of 95% confidence interval. |
| Serotype | LoD (CFU/mL) Probit Result | 95% CI Probit Result | Percent Detected | LoD (CFU/mL) Verified | LoD (CFU/swab) Verified |
|---|---|---|---|---|---|
| Ia | 663 | 492-835 | 100% | 663 | 50 |
| Ib | 40 | 32-49 | 95% | 40 | 3 |
| Ica | 301 | 231-370 | 100% | 301 | 23 |
| IIa | 173 | 132-213 | 100% | 173 | 13 |
| III | 540 | 409-670 | 100% | 540 | 41 |
| IV | 429 | 324-533 | 95% | 429 | 32 |
| V | 618 | 384-618 | 85% | 618b | 46 |
| VI | 544 | 353-544 | 85% | 544b | 41 |
| VII | 620 | 512-728 | 100% | 620 | 47 |
| VIII | 682 | 509-855 | 100% | 682 | 51 |
| IX | 465 | 354-575 | 100% | 465 | 35 |
| X | 677 | 525-829 | 95% | 677 | 51 |
Table 3. GBS Limit of Detection (LoD)
ª Non-hemolytic strain
b Claimed LoD corresponds to upper 95% upper CI
10
Analytical Reactivity with GBS cfb Mutants
A study was performed to evaluate the analytical reactivity of Xpert GBS LB XC test using GBS strains containing deletions in or adjacent to the chromosome that encodes the CAMP factor hemolysis gene ctb. Ten unique, well characterized GBS clinical isolates representing different c/o mutations were tested at 833 CFU/mL. All strains with c/b mutations were detected with a positivity rate of 100%.
Analytical Specificity (Exclusivity) and Microbial Interference
The analytical specificity of the Xpert GBS LB XC test was evaluated by testing a panel of 128 strains, representing bacterial, viral, parasite and yeast strains commonly found in vaginal/rectal flora or phylogenetically related to GBS (Table 4) in the Xpert GBS LB XC test in the absence (exclusivity) or presence (microbial interference) of GBS. Bacteria were tested at ≥ 1x106 CFU/ml, except as noted, and viruses and parasites were tested at a level of > 1x105 organisms, yeast, IU or copies/ml. Microorganisms with potential to grow to high titers in Lim broth during enrichment (Candida albicans, Enterococcus faecalis, Enterococcus faecium, Enterococcus gallinarum, Streptococcus anginosus, Streptococcus parasanguinis, Corynebacterium accolens) were tested at > 1x10° CFU/ml. Of the 128 strains, 121 were tested in Lim broth clinical sample matrix or in simulated sample matrix, both in presence of GBS at 3x LoD and in absence of GBS.
Seven of 128 strains (Finegoldia magna, Mobiluncus curtisii subsp. curtisii, Peptoniphilus asaccharolyticus. Fusobacterium nucleatum. Peptostreptococcus anaerobius, Anaerococcus tetradius and Anaerococcus prevotii ) were not available for in vitro testing and were evaluated by in silico analysis using the Xpert GBS LB XC primer and probe sequences as queries for organism- specific BLAST (Basic Local Alignment Search Tool) analysis of the NCBI (National Center for Biotechnology Information) Nucleotide collection (nr/nt) database.
No cross-reactivity or microbial interference of GBS detection was observed, both in silico and in vitro, with any clinically relevant pathogens.
| Organism | ||
|---|---|---|
| Arcanobacterium (Trueperella) pyogenes | Haemophilus influenzae | Serratia marcescens |
| Atopobium (Fannyhessea) vaginae | Hafnia alvei | Shigella flexneri |
| Abiotrophia defectiva | Hepatitis B virus | Shigella sonnei |
| Acinetobacter baumannii | Hepatitis C virus | Staphylococcus aureusc |
| Acinetobacter lwoffii | Human immunodeficiency | |
| virus | Staphylococcus epidermidis | |
| Actinobacillus pleuropneumoniae | Human Papillomavirus 18b | Staphylococcus haemolyticus |
| Organism | Organism | Organism |
| Aeromonas hydrophila | Klebsiella (Enterobacter) | |
| aerogenes | Staphylococcus intermedius | |
| Alcaligenes faecalis | Klebsiella oxytoca | Staphylococcus lugdunensis |
| Anaerococcus lactolyticus | Klebsiella pneumoniae | Staphylococcus saprophyticus |
| Anaerococcus prevotiia | Lactobacillus acidophilus | Staphylococcus simulans |
| Anaerococcus tetradiusa | Lactobacillus casei | Stenotrophomonas maltophilia |
| Bacillus cereus | Lactobacillus delbrueckii lactis | Streptococcus acidominimus |
| Bacillus coagulans | Lactobacillus gasseri | Streptococcus anginosus |
| Bacteroides fragilis | Lactobacillus plantarum | Streptococcus bovis |
| Bifidobacterium adolescentis Reuter | Lactobacillus reuteri | Streptococcus canis |
| Bifidobacterium brevis | Listeria monocytogenes | Streptococcus constellatus |
| BK virus | Micrococcus luteus | Streptococcus criceti |
| Blastocystis hominisb | Mobiluncus curtisii subsp. | |
| Curtisiia | Streptococcus cristatus | |
| Bordetella pertussis | Moraxella atlantae | Streptococcus downei |
| Burkholderia cepacia | Moraxella catarrhalis | Streptococcus dysgalactiae |
| subsp. dysgalactiae | ||
| Campylobacter jejuni | Morganella morganii | Streptococcus dysgalactiae |
| subsp. equisimilis | ||
| Candida albicans | Mycoplasma genitaliumb | Streptococcus equi subsp. equi |
| Candida glabrata | Neisseria gonorrhoeae | Streptococcus gordonii |
| Candida tropicalis | Norovirus | Streptococcus intermedius |
| Chlamydia trachomatis | Pantoea agglomerans | Streptococcus mitis |
| Citrobacter freundii | Pasteurella aerogenes | Streptococcus mutans |
| Clostridium difficile | Peptoniphilus | |
| asaccharolyticusa | Streptococcus oralis | |
| Cytomegalovirus | Peptostreptococcus | |
| anaerobiusa | Streptococcus parasanguinis | |
| Corynebacterium accolens | Porphyromonas | |
| asaccharolytica | Streptococcus pneumoniae | |
| Corynebacterium sp. (genitalium) | Prevotella bivia | Streptococcus pseudoporcinus |
| Corynebacterium urealyticum | Prevotella melaninogenica | Streptococcus pyogenesb |
| Cryptococcus neoformans | Prevotella oralis | Streptococcus ratti |
| Enterobacter cloacae | Propionibacterium acnes | Streptococcus salivarius |
| Organism | ||
| Enterococcus durans | Proteus mirabilis | Streptococcus sanguinis |
| Enterococcus faecalis | Proteus vulgaris | Streptococcus sobrinus |
| Enterococcus faecium | Providencia stuartiib | Streptococcus suis |
| Enterococcus gallinarum | Pseudomonas aeruginosa | Streptococcus uberis |
| Epstein-Barr virus | Pseudomonas fluorescens | Streptococcus vestibularis |
| Escherichia coli | Rhodococcus equi | Toxoplasma gondii |
| Finegoldia magnaa | Rubella virus | Trichomonas vaginalis |
| Fusobacterium nucleatuma | Salmonella enterica subsp. enterica ser. Dublin (group D) | Vibrio cholerae |
| Gardnerella vaginalis | Salmonella enterica subsp. typhimurium | Yersinia enterocolitica |
| Giardia lambliab | Serratia liquefaciens | |
| a Evaluated in silico | ||
| b Evaluated with DNA |
Table 4. Analytical Specificity of the Xpert GBS LB XC Test
11
12
Interfering Substances Study
Substances that may be present in vaginal/rectal specimens with the potential to interfere with the Xpert GBS LB XC test were evaluated. Potentially interfering endogenous and exogenous substances include human amniotic fluid, meconium, urine, fecal material, human blood, lubricating gel, vaginal anti-itch medications, vaginal antifungal medications, anti- diarrheal medications, laxatives, stool softeners, topical hemorrhoid ointments, body oil, body powder, deodorant sprays, enema solutions, and spermicidal foam.
These substances are listed in Table 5. All liquid substances were tested by adding 100% of the substance to the swab, solid substances by covering swab head to 75% and tablets were dissolved to their highest soluble concentration in simulate sample matrix and added to the swab. Five exogenous substances (Aquasonic® gel, Floraplus, Pepto Bismol®, Skin oil and Xyloproct) were tested at lower concentration to determine the highest tolerated amount on swab (Table 5). The interferents were tested in the absence of GBS or in the presence of GBS at 3x LoD.
There was no interference in the presence of the substances at the concentrations tested in this study. All positive and negative samples were correctly identified using the Xpert GBS LB XC test.
13
| Substance (Source) | Substance Form | Concentration on Swab |
|---|---|---|
| Human Amniotic Fluid (Lee Biosolutions Inc.) | Liquid | 60% (v/v) |
| Human Urine (Novakemi) | Liquid | 60% (v/v) |
| Human Whole Blood - EDTA (BioChemed) | Liquid | 80%(v/v) |
| Human Whole Blood - Na Citrate (BioChemed) | Liquid | 80% (v/v) |
| Leukocytes, Buffy coat, 2x107 WBCs/ml | ||
| (Karolinska University Hospital) | Liquid | 80% (v/v) |
| Meconium (Lee Biosolutions) | Solid | 100% (w/v) |
| Mucus (Sigma-Aldrich/Merck) | Solid | 30% (w/v) |
| Human Feces - Pool of 10 donors | Solid | 100 % (w/v) |
| Anti-Diarrheal Medication (Pepto Bismol) | Liquida | 40 % (v/v) |
| Anti-Diarrheal Medication (Dimor Comp | ||
| [Dimeticone] from Nordic Drugs) | Tablet | 0.03% loperamid + |
| 2% dimetkon (w/v) | ||
| Lubricant (RFSU Klick Ultra Glide) | Solid | 100% (w/v) |
| Lubricant (Sense Me Aqua Glide) | Solid | 100% (w/v) |
| Lubricant (KY-Jelly) | Solid | 100% (w/v) |
| Body Oil (ACO Repairing Skin Oil) | Liquidb | 100% (w/v) |
| Dialon Baby (Dialon Baby powder) | Solid | 100% (w/v) |
| Deodorant Powder (Vagisil® Deodorant Powder) | Solid | 100% (w/v) |
| Deodorant Spray (LN Intimate Deo) | Liquid | 60% (v/v) |
| Deodorant Suppositories (Norforms Feminine | ||
| Deodorant Suppositories) | Solid | 28.5% (w/v) |
| Enema solution (Microlax mikrolavemang – | ||
| McNeil) | Solid | 100% (w/v) |
| Oral Laxative (Inolaxol – Mylan) | Solid | 25% (w/v) |
| Oral Laxative (Phillips Milk of Magnesia - Bayer) | Liquid | 60% (w/v) |
| Oral Laxative (Pursennid Ex-Lax - GSK) | Tablet | 0.64% (w/v) |
| Spermicidal Foam (Caya preventivgel) | Solid | 100% (v/v) |
| Stool Softener (Laktulos - Meda | Liquid | 60% (v/v) |
| Stool Softener (Movicol – Norgine) | Solid | 11% (w/v) |
| Topical Hemorrhoid Ointment (Xyloproct Rectal | ||
| Ointment - Aspen) | Solidc | 10% (w/v) |
| Topical Hemorrhoid Ointment (Scheriproct | ||
| rektalsalva / Prednisolone Ointment- Bayer) | Solid | 100% (v/v) |
| Ultrasound Transmission Gel (Aquasonic Gel - | ||
| Parker) | Solidc | 25% /w/v) |
| Vaginal Antifungal Gel (Multi-Gyn Actigel) | Solid | 100% (v/v) |
| Vaginal Antifungal Gel (Multi-Gyn Floraplus) | Solidc | 75% (w/v) |
| Vaginal Anti-itch Cream (Ellen Probiotisk Utvärtes | ||
| Intim Creme) | Solid | 100% (v/v) |
| Vaginal Antifungal Cream (Canesten - Bayer) | Solid | 100% (v/v) |
| Vaginal Antifungal Cream (Daktar – McNeil) | Solid | 100% (v/v) |
Table 5. Potentially Interfering Substances Tested
Pepto Bismol® diluted to 50% in background simulated background matrix and no interference observed.
b Skin oil tolerated when 67% of swab head covered (tested as solid substance).
b Skin oil tolerated when 67% of swab head covered (tested as solid substance).
c Substances were diluted into a simulated background matrix prior to testing: Xyloproot Rectal at 10%, Aquasonic Gel was tested at 25% and MultiGyn Floraplus was tested at 75%. No interference was detection after dilution.
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Carry-Over Contamination
A study was conducted to demonstrate that no carry-over contamination occurs when testing these single-use, self-contained GeneXpert cartridges in the same GeneXpert module. The study consisted of a negative sample processed in the same GeneXpert module immediately following a high GBS positive sample. Twenty-one runs alternating high titer GBS positive and GBS negative samples were performed consecutively on two GeneXpert modules, thus a total of 42 runs were executed for the study. All 20 positive samples were correctly reported as GBS POSITIVE. All 22 negative samples were correctly reported as GBS NEGATIVE.
Reproducibility Study
A panel of ten samples with varying concentrations of four different GBS strains were tested by two operators each in triplicate on six different days at three sites using 3 different lots of Xpert GBS LB XC (2 operators × 3 replicates/day × 6 days × 3 sites) including negative panel members. Three lots of Xpert GBS LB XC were used at each of the three testing sites. The source of the three strains (serotype Ia, III, IV) representing a hemolytic phenotype and one strain (serotype Ic) representing a non-hemolytic phenotype is presented in Table 6. The three levels were ~3 × LOD and ~1 × LOD and negative.
| Strain | Phenotype | Panel Member |
|---|---|---|
| Not applicable | Not applicable | Negative |
| GBS Serotype Ia - ATCC12386 | Hemolytic | Low Positive (~1X LoD) |
| Moderate Positive (~3X LoD) | ||
| GBS Serotype Ic -ATCC13813 | Non-emolytic | Low Positive (~1X LoD) |
| Moderate Positive (~3X LoD) | ||
| GBS Serotype III - ATCC12403 | Hemolytic | Low Positive (~1X LoD) |
| Moderate Positive (~3X LoD) | ||
| GBS Serotype IV -ATCC49446 | Hemolytic | Low Positive (~1X LoD) |
| Moderate Positive (~3X LoD) |
Table 6. Reproducibility Panel
Xpert GBS LB XC testing was performed on the GeneXpert Instrument Systems according to the Xpert GBS LB XC test procedure.
The percent agreement of the qualitative results for GBS detection for each sample calculated for each of the six operators and for each site is shown in Table 7. In addition, the overall percent agreement for each sample (total agreement) and the 95% two-sided Wilson Score confidence interval are shown in the last column.
15
| | Sample | Site 1 | | | Site 2 | | | Site 3 | | | Total Agreement by
Sample with
95% CI | |
|----|-------------------------------|-------------------|-------------------|-------------------|-------------------|-------------------|-------------------|-------------------|-------------------|-------------------|---------------------------------------------|--|
| | | OP 1 | OP 2 | Subtotal | OP 1 | OP 2 | Subtotal | OP 1 | OP 2 | Subtotal | | |
| 01 | Negative 1ª | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(108/108)
96.6-100.0 | |
| 02 | Negative 2ª | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(108/108)
96.6-100.0 | |
| 03 | GBS
serotype
Ia1xLoD | 100.0%1xLoD | 100%
(18/18) | 94.4%
(17/18) | 97.2%
(35/36) | 100.0%
(18/18) | 94.4%
(17/18) | 97.2%
(35/36) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 98.1%
(106/108)
93.5-99.5 | |
| 04 | GBS
serotype
Icb
(18/18) | 100%
(18/18) | 100%
(36/36) | 100%
(18/18) | 100%
(18/18) | 100%
(36/36) | 100%
(18/18) | 100%
(18/18) | 100%
(36/36) | 100.0%
(108/108)
96.6-100.0 | |
| 05 | GBS
serotype
III~1xLoD | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(108/108)
96.6-100.0 | |
| 06 | GBS
serotype IV
~1xLoD | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 94.0%
(17/18) | 94.0%
(17/18) | 94.0%
(34/36) | 100.0%
(18/18) | 94.0%
(17/18) | 97.0%
(35/36) | 97.2%
(105/108)
92.1-99.4 | |
| 07 | GBS
serotype Ia
3xLoD | 100.0%3xLoD | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(108/108)
96.6-100.0 | |
| 08 | GBS
serotype
Icb
(17/17) | 100.0%
(18/18) | 100.0%
(35/35) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(107/107)
96.5-100.0 | |
| 09 | GBS
serotype III
3xLoD | 100.0%3xLoD | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(108/108)
96.6-100.0 | |
| 10 | GBS
serotype
IV
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(18/18) | 100.0%
(18/18) | 100.0%
(36/36) | 100.0%
(108/108)
96.6-100.0 | |
Table 7: Summary of Reproducibility and Precision Results
Testing with Serotype Ic was performed separately from testing by the other panel members. Negative panel a. members were included in both rounds of testing and are represented separately in the performance table above.
b. Serotype Ic is characterized as non-hemolytic.
No statistically significant difference in performance (p-value of