Advice

Technology overview

Technology overview

This briefing describes the regulated use of the technology for the indication specified, in the setting described, and with any other specific equipment referred to. It is the responsibility of healthcare professionals to check the regulatory status of any intended use of the technology in other indications and settings.

About the technology

CE marking

The Xpert Carba‑R test is classed as an in vitro diagnostic device. The manufacturer, Cepheid, received the first CE mark for the device in June 2014. The current certification is dated July 2015 and covers the updated version of the test currently supplied in the UK, which detects an increased number of carbapenemase genes.

Description

Xpert Carba‑R is an on‑demand, qualitative in vitro diagnostic test to identify people carrying CPOs, including at least 91 genes within the 5 most prevalent carbapenemase gene families (KPC, NDM, VIM, IMP‑1 and OXA‑48, updated to include the OXA‑181 and OXA‑232 variants).

The test identifies bacterial DNA from a rectal swab specimen, using fully automated real‑time polymerase chain reaction (PCR) with fluorogenic detection of the amplified DNA. Results are available in about 50 minutes.

Each test kit is designed to process 10 samples and contains 10 individual test cartridges, sample reagent vials and disposable transfer pipettes. A separate specimen collection container (not part of the kit) has a pair of swabs attached to its lid. Rectal swab samples are collected from approximately 1 cm beyond the anal sphincter using the paired swabs. The swabs are then returned to the container for transport to the laboratory. Only 1 swab is needed for Xpert Carba‑R testing. The second swab can be stored for repeat testing if necessary. Swabs in the transport container can be stored at room temperature for up to 6 hours and refrigerated for up to 7 days.

The Xpert Carba‑R test is run using the Cepheid clinical in vitro diagnostic system, which consists of 3 main components:

  • The GeneXpert molecular diagnostic system – available in 4 configurations (I, II, IV or XVI) consisting of 1, 2, 4 or 16 modules respectively, and a larger Infinity version with 16 to 80 modules. Point‑of‑care testing is more suited to the smaller 1 or 2 module versions; the larger 4 to 80 module configurations are more suitable for clinical laboratory use. Each module is loaded with 1 Xpert Carba‑R test cartridge per person. Multi‑module versions can run several on‑demand and independent tests using different test cartridges at any time.

  • A computer which runs the GeneXpert DX software and stores the results – the software is used to input the patient and test information, to monitor the automated test process, and to view, print and export the results as well as to generate reports. A barcode scanner is included to automate data entry. The computer and barcode scanner are supplied with the GeneXpert system.

  • The single‑use Xpert Carba‑R cartridge – the DNA extraction and PCR reaction is carried out within the cartridge. There are 2 automated internal quality controls in each cartridge: a probe check control and a sample processing control.

One of the Xpert Carba‑R test swabs is inserted into the sample reagent vial and mixed at high speed for 10 seconds using a standard laboratory vortex mixer. A pipette is then used to transfer approximately 1.7 ml of the liquid sample to the cartridge sample chamber. The cartridge is loaded into a GeneXpert system module, and test processing and analysis starts automatically by closing the module door.

Results are analysed by the GeneXpert DX software from measured fluorescent signals, using calculation algorithms. Results for each of the 5 gene families (detection or no detection) are reported in tabular and graphical formats in about 50 minutes.

The manufacturer also supplies a range of Xpert cartridges for 22 other in vitro diagnostic tests including additional infection control tests for Clostridium difficile (Xpert C. difficile), methicillin‑resistant Staphylococcus aureus (Xpert MRSA), vancomycin‑resistant enterococci (Xpert vanA/van B), Xpert Flu/RSV and Norovirus (Xpert Norovirus). These tests also run on the GeneXpert platform but are beyond the scope of this briefing.

Setting and intended use

The Xpert Carba‑R can be used in any suitable healthcare setting with access to the GeneXpert system. In secondary or tertiary care clinical laboratories, the Xpert Carba‑R test and GeneXpert systems would be operated by qualified laboratory staff with appropriate training on the test and system.

Xpert Carba‑R could also be used in secondary care during pre‑admission patient assessment procedures, where it would be used to provide point‑of‑care testing by appropriately trained healthcare professionals.

Current NHS options

Screening is currently not recommended in the UK for people with no known risk of CPOs, but people known to be previously colonised or who are at risk of colonisation are tested for CPOs during routine hospital admission. This includes people who have been hospital inpatients within the previous 12 months, either abroad or at a UK hospital which has problems with the spread of CPOs (Public Health England – Acute trust toolkit). The standard method for detecting CPOs in high‑risk people is by testing 3 stool samples or rectal swabs collected on days 0, 2 and 4 after admission. The samples are initially tested for CPO colonisation by microbiological culturing, typically with chromogenic agar. This process typically takes 24 hours for positive samples and 48 hours for negative samples. The person is kept in isolation until all 3 culture results are available. If all 3 culture tests are negative the person can be considered for removal from isolation. If any CPO colonies are detected following culture and incubation, additional tests are needed to determine carbapenem resistance (Public Health England 2013). This would involve antimicrobial susceptibility testing using microbiological agar plates and an indicator carbapenem such as meropenem, doripenem or imipenem. If a sample is considered resistant to the carbapenem, further supplementary tests are done to distinguish carbapenemase producers from those that have other carbapenem resistance mechanisms. Confirmatory tests can be inhibitor‑based where synergy can be demonstrated between the indicator carbapenem and various carbapenemase inhibitors. Other methods include the modified Hodge test, matrix assisted laser desorption/ionisation time‑of‑flight mass spectrometer (MALDI‑ToF), the Carba‑NP test (Biomerieux, USA) or PCR‑based assays (Public Health England 2014).

The following samples should also be sent to the Reference Laboratory at Public Health England for further testing, to assess outbreaks and identify transmission pathways:

  • all enterobacteriaceae suspected of producing a carbapenemase

  • all Pseudomonas sp. suspected of producing a carbapenemase

  • all Acinetobacter sp. suspected of producing a metallo‑carbapenemase.

NICE is aware of the following CE‑marked devices that appear to fulfil a similar function to the Xpert Carba‑R:

Costs and use of the technology

The Xpert Carba‑R system consists of several essential components and optional accessories. List prices (excluding VAT) for the essential components are as follows:

  • Xpert Carba‑R cartridge: £30 per single test

  • sample collection device (transport container with dual swab): £37 per pack of 50

  • GeneXpert molecular diagnostic system (1–16 modules) including computer system and barcode scanner costs from £18,077 for a single‑module system to £121,308 for a 16‑module system.

List prices for optional accessories (excluding VAT) are:

  • uninterruptible power supply for the GeneXpert system: £1522

  • laser printer with USB cable: £110

  • GeneXpert 16‑cartridge tray: £8

  • GeneXpert 32‑cartridge tray: £12.

The GeneXpert system has an anticipated lifespan of at least 10 years. The manufacturer offers annual maintenance contracts from £2103 to £7107 depending on the number of modules in the system. The annual service includes preventative maintenance and module calibration. On‑site and telephone technical support are available.

Training covers sample collection, preparing the cartridge and analysing the results. Standardised training material and training guides are also provided. Training takes about 30 minutes and is offered during the initial installation and on request. Experienced staff already familiar with the process may train new staff members.

Likely place in therapy

The Xpert Carba‑R would be used to detect the presence of CPOs in people who are suspected of colonisation or infection. It would deliver results faster than the standard culture technique used to identify colonisation and would be used in placed of standard culture‑based tests and an adjunct to the supplementary and confirmatory tests such as antimicrobial resistance testing. This could therefore result in a quicker diagnosis of CPO colonisation and allow healthcare providers to implement local infection control protocols to prevent transmission to other susceptible people.

Specialist commentator comments

One specialist commentator indicated that, because most people tested would not be colonised with CPOs, the main purpose and value of using Xpert Carba‑R in a screening programme is likely to be in excluding (rather than diagnosing) colonisation. The group of people to be tested would be determined locally and may include patients with risk factors (for example people transferred from certain hospitals or previous CPO colonisation); patients having a high‑risk type of care (for example ICU); or regular screening of patients during an outbreak. This specialist commentator was aware that in some parts of the country, all new admissions to hospital are tested. However another specialist commentator highlighted that the Xpert Carba‑R test would be too expensive for universal screening of all admissions.

One specialist commentator suggested other instances when the Xpert Carba‑R test result could be useful, such as when a patient identified as being at increased risk of CPO colonisation becomes septic. In this case CPO colonisation could be determined at the onset of sepsis and a different antibiotic therapy could be provided much sooner. Additionally, the rapid availability of results could also help when a patient who is not in isolation is identified as carrying CPOs, allowing infection control teams to screen contacts for evidence of spread. This could potentially bring any outbreak under control faster, allowing a closed ward to be re‑opened and could help in the identification of people who might need a different antibiotic treatment if they become unwell.

One specialist commentator highlighted that there are many other diagnostic tests that can be run on the GeneXpert System and a fair number of hospitals will already be using this platform.

One specialist commentator indicated that because the Xpert Carba‑R uses bespoke rectal swabs, there may be implications in the supply of swabs to wards. They also indicated that standard practice is to take rectal samples at 48‑hour intervals until 3 negative screens are obtained, so the culture screening process will always take approximately 96 hours from admission. They suggested that a quick turnaround time for any test would be beneficial and will speed up the process with possible transfer out of isolation. Another specialist commentator advised that repeated sampling (3 times) to prove a negative result is not commonly practicable and in most cases, clinicians rely on the first result.

One specialist commentator highlighted that the main evidence supporting the Xpert Carba‑R test is dominated by enterobacteriaceae, with few non‑fermenting bacteria. They considered that there is scant evidence on the utility of the Xpert Carba‑R test for the detection of carbapenemase genes in bacteria other than enterobacteriaceae, for example important genera such as Acinetobacter which produces OXA‑23. The specialist commentator also noted that the performance characteristics of the Xpert Carba‑R for individual genes reported in the evidence could be misleading. The sensitivity figure of 71% related solely to the detection of the IMP carbapenemase gene from a single study and in the UK, this carbapenemase gene is present in no more than 1% of CPOs.

Equality considerations

NICE is committed to promoting equality, eliminating unlawful discrimination and fostering good relations between people with particular protected characteristics and others. In producing guidance and advice, NICE aims to comply fully with all legal obligations to:

  • promote race and disability equality and equality of opportunity between men and women

  • eliminate unlawful discrimination on grounds of race, disability, age, sex, gender reassignment, marriage and civil partnership, pregnancy and maternity (including women post‑delivery), sexual orientation, and religion or belief (these are protected characteristics under the Equality Act 2010).