VITEK® 2 AST-Gram Negative Levolloxacin is designed for antimicrobial susceptibility testing of Gram-negative bacilli and is intended for use with the VITEK® 2 and VITEK® 2 Compact Systems as a laboratory aid in the determination of in vito susceptibility to antimicrobial agents. VITEK® 2 AST-Gram Negative Levofloxacin is a quantitative test. Levolloxacin has been shown to be active against most strains of the microorganisms listed below, according to the FDA label for this antimicrobial.

Active in vitro and in clinical infections: Enterchacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens

Active in vitro but clinical significance unknown: Citrobacter freundii, Enterobacter aerogenes, Klebsiella oxytoca, Morganii, Pantoea agglomerans, Proteus vulgaris, Providencia rettgeri, Providencia stuartii

VITEK® 2 AST-Gram Negative Levofloxacin also reports the susceptibility for the following additional organism as listed on the FDA Susceptibility Test Interpretive Criteria website: Salmonella spp.

The VITEK® 2 Gram-Negative Susceptibility Card is intended for use with the VITEK® 2 Systems in clinical laboratories as an in vitro test to determine the susceptibility of clinically significant aerobic Gram-negative bacilli to antimicrobial agents when used as instructed.

Device Description

The principle of the VITEK® 2 AST cards is based on the microdilution minimum inhibitory concentration (MIC) technique reported by MacLowry and Marsh (1) and Gerlach (2). The VITEK® 2 AST card is essentially a miniaturized, abbreviated and automated version of the doubling dilution technique (3).

Each VITEK® 2 AST card contains 64 wells. A control well which only contains microbiological culture media is resident on all cards. The remaining wells contain premeasured portions of a specific antibiotic combined with culture media. The bacterial or yeast isolate to be tested is diluted to a standardized concentration with 0.45 - 0.5% saline before being used to rehydrate the antimicrobial medium within the card. The VITEK® 2 System automatically fills, seals and places the card into the incubator/reader. The VITEK® 2 Compact has a manual filling, sealing and loading operation. The VITEK® 2 Systems monitor the growth of each well in the card over a defined period of time. At the completion of the incubation cycle, a report is generated that contains the MIC value along with the interpretive category result for each antibiotic contained on the card.

VITEK® 2 AST-GN Levofloxacin has the following concentrations in the card: 0.25, 0.5, 2, and 8 (equivalent standard method concentration by efficacy in ug/mL).

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study details for the VITEK® 2 AST-Gram Negative Levofloxacin device, based on the provided FDA 510(k) summary:

1. Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by the FDA Class II Special Controls Guidance Document for Antimicrobial Susceptibility Test (AST) Systems. The performance metrics reported are Essential Agreement (EA), Category Agreement (CA), Very Major Errors (VME), Major Errors (ME), and minor Errors (mE). Reproducibility and Quality Control also demonstrated acceptable results, although specific percentage thresholds for these are not provided in this summary.

Here's the table of reported device performance:

Antimicrobial	Organism Group	Essential Agreement (%EA)	Category Agreement (%CA)	VME (%)	ME (%)	mE (%)	% Reproducibility
Levofloxacin	Enterobacterales	99.7 (345/346)	98.0 (339/346)	0.0 (0/76)	0.0 (0/262)	2.0 (7/346)	100
Levofloxacin	Pseudomonas aeruginosa	96.9 (218/225)	93.3 (210/225)	0.0 (0/76)	1.6 (2/127)	5.8 (13/225)	N/A
Levofloxacin	Salmonella spp.	97.9 (47/48)	97.9 (47/48)	0.0 (0/4)	0.0 (0/40)	2.1 (1/48)	N/A

Notes on Interpretation from the document:

VITEK 2 Levofloxacin MIC values for Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa tended to be in exact agreement or at least one doubling dilution higher when compared to the reference agar dilution method.
VITEK 2 Levofloxacin MIC values for Serratia marcescens tended to be in exact agreement or at least one doubling dilution lower when compared to the reference agar dilution method.

2. Sample Size and Data Provenance

The sample sizes for the test set are embedded within the performance data (e.g., 346 for Enterobacterales, 225 for Pseudomonas aeruginosa, 48 for Salmonella spp.). These numbers represent the total number of isolates tested for each organism group.

The data provenance is described as an "external evaluation" conducted with "fresh and stock clinical isolates, as well as a set of challenge strains." The document does not specify the country of origin, but "external" implies outside of the manufacturer's immediate control. The use of "fresh and stock clinical isolates" indicates a mix of prospective (fresh) and retrospective (stock) data, augmented by specific challenge strains.

3. Number of Experts and Qualifications for Ground Truth

The document does not explicitly state the number of experts used or their specific qualifications (e.g., "radiologist with 10 years of experience"). However, the ground truth is established by the "CLSI agar dilution reference method incubated between 16-20 hours." This method is a standardized laboratory procedure, and implicitly requires trained laboratory professionals to perform and interpret, but it's not based on expert consensus in the typical sense of diagnostic imaging or clinical interpretation.

4. Adjudication Method

The concept of "adjudication" in the sense of multiple experts reviewing and reaching a consensus on a case (like 2+1 or 3+1) is not applicable here. The ground truth is determined by a single, standardized reference laboratory method (CLSI agar dilution). Any discrepancies would be between the VITEK 2 device's result and this reference method, leading to the error rates (VME, ME, mE) reported.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not conducted as described. This type of study typically involves human readers or clinicians making diagnoses with and without AI assistance to measure improvement in human performance. The VITEK 2 device is a fully automated laboratory device, and the study compares its performance directly against a reference laboratory method, not against human interpretation of the images/data it produces.

6. Standalone Performance Study

Yes, a standalone (algorithm only without human-in-the-loop performance) study was done. The entire performance evaluation reported in the 510(k) summary is of the VITEK 2 device's output (MIC values and interpretive categories) compared directly to the CLSI agar dilution reference method. The device is intended to be automated, and its performance is assessed independently.

7. Type of Ground Truth Used

The ground truth used is the CLSI agar dilution reference method results. This is a recognized standard laboratory method for determining antimicrobial susceptibility, considered the gold standard for this type of in vitro diagnostic test. It is not based on expert consensus, pathology, or outcomes data in the usual clinical sense, but rather a robust, objective laboratory measurement.

8. Sample Size for the Training Set

The document does not specify the sample size for the training set. It describes the data used for the "external evaluation" (test set) but provides no information about the isolates used to develop or train the VITEK® 2 AST-GN Levofloxacin system's algorithms (Discriminant Analysis).

9. How the Ground Truth for the Training Set Was Established

The document does not provide details on how the ground truth for the training set was established. However, given the nature of AST systems, it is highly probable that the training set's ground truth would have also been established using a similar, if not identical, reference method like the CLSI agar dilution method. The device's "Discriminant Analysis" algorithms would have been developed and optimized to correlate its readings with these reference standard results.

Summary

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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo in blue. Underneath the FDA logo is the word "ADMINISTRATION".

June 26, 2023

bioMerieux, Inc. Esther Hernandez Regulatory Affairs Specialist 595 Anglum Road Hazelwood, Missouri 63042

Re: K222378

Trade/Device Name: VITEK 2 AST-Gram Negative Levofloxacin (<0.125 - >8 ug/mL) Regulation Number: 21 CFR 866.1645 Regulation Name: Fully Automated Short-Term Incubation Cycle Antimicrobial Susceptibility System Regulatory Class: Class II Product Code: LON, LTT, LTW Dated: August 4, 2022 Received: August 5, 2022

Dear Esther Hernandez:

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 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR

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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 mediation-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.

Ribhi Shawar -S

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 Ouality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K222378

Device Name

VITEK® 2 AST-Gram Negative Levofloxacin (50.125 - ≥8 µg/mL)

Indications for Use (Describe)

Active in vitro and in clinical infections: Enterchacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens

VITEK® 2 AST-Gram Negative Levofloxacin also reports the susceptibility for the following additional organism as listed on the FDA Susceptibility Test Interpretive Criteria website: Salmonella spp.

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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510(k) SUMMARY

VITEK® 2 AST-GN Levofloxacin

A. 510(k) Submission Information:

Submitter's Name:	bioMérieux, Inc.
Address:	595 Anglum RoadHazelwood, MO 63042
Contact Person:	Esther HernandezRegulatory Affairs Specialist
Phone Number:	314-731-8841
Fax Number:	314-731-8689
Date of Preparation:	August 4, 2022
Formal/Trade Name:	VITEK® 2 AST-Gram Negative Levofloxacin (≤$0.125 -≥8$ µg/mL)
Classification Name:	21 CFR 866.1645Fully Automated Short-Term Incubation CycleAntimicrobial Susceptibility SystemProduct Code LON, LTT, LTW.
Common Name:	VITEK® 2 AST-GN Levofloxacin
Predicate Device:	VITEK® 2 AST-Gram Negative Levofloxacin(K072038)

D. Device Description:

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System automatically fills, seals and places the card into the incubator/reader. The VITEK® 2 Compact has a manual filling, sealing and loading operation. The VITEK® 2 Systems monitor the growth of each well in the card over a defined period of time. At the completion of the incubation cycle, a report is generated that contains the MIC value along with the interpretive category result for each antibiotic contained on the card.

VITEK® 2 AST-GN Levofloxacin has the following concentrations in the card: 0.25, 0.5, 2, and 8 (equivalent standard method concentration by efficacy in ug/mL).

E. Substantial Equivalence Information

The similarities and differences of the VITEK 2 AST-GN Levofloxacin when compared to the predicate device, VITEK 2 AST-GN Levofloxacin (K072038), are described in the following table. The only difference between both devices are the Indications for Use and the breakpoints used to analyze the data performance. The below table provides the similarities and differences:

Item	Device:VITEK® 2 AST-GN Levofloxacin	Predicate:VITEK® 2 AST-GN Levofloxacin(K072038)
	Similarities
Intended Use	VITEK® 2 AST-Gram NegativeLevofloxacin is designed forantimicrobial susceptibility testing ofGram-negative bacilli and is intendedfor use with the VITEK® 2 andVITEK® 2 Compact Systems as alaboratory aid in the determination ofin vitro susceptibility to antimicrobialagents. VITEK® 2 AST-GramNegative Levofloxacin is aquantitative test. Levofloxacin hasbeen shown to be active against moststrains of the microorganisms listedbelow, according to the FDA labelfor this antimicrobial.	VITEK® 2 AST-Gram NegativeLevofloxacin is designed forantimicrobial susceptibility testing ofGram-negative bacilli and is intendedfor use with the VITEK® 2 andVITEK® 2 Compact Systems as alaboratory aid in the determination ofin vitro susceptibility to antimicrobialagents. VITEK® 2 AST-GramNegative Levofloxacin is aquantitative test. Levofloxacin hasbeen shown to be active against moststrains of the microorganisms listedbelow, according to the FDA label forthis antimicrobial.
	Active in vitro and in clinicalinfections:Enterobacter cloacaeEscherichia coliKlebsiella pneumoniaeProteus mirabilisPseudomonas aeruginosaSerratia marcescens	Active in vitro and in clinicalinfections:Enterobacter cloacaeEscherichia coliKlebsiella pneumoniaeProteus mirabilisPseudomonas aeruginosaSerratia marcescensCitrobacter koseriCitrobacter freundiiEnterobacter aerogenes
	Active in vitro but clinical significanceunknown
Citrobacter koseriCitrobacter freundiiEnterobacter aerogenesKlebsiella oxytocaMorganella morganiiPantoea agglomeransProteus vulgarisProvidencia rettgeriProvidencia stuartiiThe VITEK® 2 Gram-NegativeSusceptibility Card is intended for usewith the VITEK® 2 Systems in clinicallaboratories as an in vitro test todetermine the susceptibility of clinicallysignificant aerobic Gram-negativebacilli to antimicrobial agents whenused as instructed.	Klebsiella oxytocaMorganella morganiiPantoea agglomeransProteus vulgarisProvidencia rettgeriProvidencia stuartiiThe VITEK® 2 AntimicrobialSusceptibility Test (AST) is intended tofor use with the VITEK® 2 and VITEK® 2 Compact Systems for the automatedquantitative or qualitative susceptibilitytesting of isolated colonies for mostclinically significant aerobic Gram-negative bacilli, Staphylococcus spp.,Enterococcus spp., Streptococcusagalactiae , and S. pneumoniae .
Test Methodology	Automated quantitative antimicrobialsusceptibility test for use with theVITEK® 2 and VITEK® 2 CompactSystems to determine the in vitrosusceptibility of Gram-negative bacilli.	Same
Antimicrobial Agent	Levofloxacin	Same
Inoculum	Saline suspension of organism	Same
Test Card	VITEK® 2 Gram-negative SusceptibilityTest Card	Same
Analysis Algorithms	Discriminant Analysis	Same
Instrument	VITEK® 2 and VITEK® 2 CompactSystems	Same
Concentrations	0.25, 0.5, 2, 8	Same
Differences
Indications for Use	VITEK® 2 AST-Gram NegativeLevofloxacin also reports thesusceptibility for the followingadditional organism as listed on theFDA Susceptibility Test InterpretiveCriteria website:Salmonella spp.	Acinetobacter baumanniiAcinetobacter hvoffiiEnterobacter sakazakiiPseudomonas fluorescens
Breakpoints	Enterobacterales : ≤0.5 (S), 1 (I), ≥2(R)Pseudomonas aeruginosa : ≤1 (S), 2(I), ≥4 (R)Salmonella spp.: ≤0.125 (S), 0.25-1(I), ≥2 (R)	Acinetobacter : ≤2 (S), 4 (I), 8 (R)Enterobacteriaceae : ≤2 (S), 4 (I), 8(R)Pseudomonas : ≤2 (S), 4 (I), 8 (R)

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F. Intended Use:

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VITEK® 2 AST-Gram Negative Levofloxacin is designed for antimicrobial susceptibility testing of Gram-negative bacilli and is intended for use with the VITEK® 2 and VITEK® 2 Compact Systems as a laboratory aid in the determination of in vitro susceptibility to antimicrobial agents. VITEK® 2 AST-Gram Negative Levofloxacin is a quantitative test. Levofloxacin has been shown to be active against most strains of the microorganisms listed below, according to the FDA label for this antimicrobial.

Active in vitro and in clinical infections:

Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa Serratia marcescens

Active in vitro but clinical significance unknown:

Citrobacter koseri Citrobacter freundii Enterobacter aerogenes Klebsiella oxytoca Morganella morganii Pantoea agglomerans Proteus vulgaris Providencia rettgeri Providencia stuartii
VITEK® 2 AST-Gram Negative Levofloxacin also reports the susceptibility for the following additional organism as listed on the FDA Susceptibility Test Interpretive Criteria website:

Salmonella spp.

G. Performance Overview:

VITEK® 2 AST-GN Levofloxacin demonstrated substantially equivalent performance when compared with the CLSI agar dilution reference method, as defined in the FDA Class II

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Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA (Issued August 28, 2009).

The Premarket Notification (Traditional 510[k]) presents data in support of VITEK® 2 AST-GN Levotloxacin. An external evaluation was conducted with fresh and stock clinical isolates, as well as a set of challenge strains. The external evaluations were designed to confirm the acceptability of VITEK® 2 AST-GN Levofloxacin by comparing its performance with the CLSI agar dilution reference method incubated between 16-20 hours. The data is representative of performance on both the VITEK 2 and VITEK® 2 Compact instrument platforms.

VITEK® 2 AST-GN Levofloxacin demonstrated acceptable performance as presented in the table below.

Antimicrobial	An imicrobialCode	AntibioticVersion	Bp1	Comment	Essential Agreement			Category Agreement				% Reproducibility
					% Error			% Error
					% EA	VME	ME	mE	% CA	VME	ME	mE
Levofloxacin	LEV	lev02n	CLSI(FDA)	#, EEnterobacterales	(345/346) 99.7	N/A	N/A	N/A	(339/346)98.0	(0/76)0.0	(0/262)0.0	(7/346)2.0	100
				#, EPseudomonasaeruginosa	(218/225) 96.9	N/A	N/A	N/A	(210/225)93.3	(0/76)0.0	(2/127)1.6	(13/225)5.8
				#, ESalmonella spp.	(47/48)97.9	N/A	N/A	N/A	(47/48)97.9	(0/4)0.0	(0/40)0.0	(1/48)2.1
	VITEK 2 Levofloxacin MIC values for Escherichia coli, Klebsiella pneumoniae pneumoniae, andPseudomonas aeruginosa tended to be in exact agreement or at least one doubling dilution higherwhen compared to the reference agar dilution method. VITEK 2 Levofloxacin MIC values forSerratia marcescens tended to be in exact agreement or at least one doubling dilution lower whencompared to the reference agar dilution method.

Abbreviations - Bp = breakyout comminee; EA = essental agreement; CA = category agreement; VME = Very Major Error (suscept with reference readt); ME Major Erro (resistantes until); n.E = mor Error (susceptble or resistant result with an micronation reference result, or an intermediate result with a susceptible or resistent reference result)

#=US Food and Drug Administration 510(k) cleared

CI.SI = Clinical and Laboratory Standards Insti

E = External performance data

N/A = Not applicable

Reproducibility and Quality Control demonstrated acceptable results.

H. Conclusion:

The performance data presented in this submission support a substantial equivalence decision. VITEK® 2 AST-Gram Negative Levofloxacin (≤0.125 ->8 µg/mL) is substantially equivalent to VITEK® 2 AST-Gram Negative Levofloxacin (K072038).

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References:

1. MacLowry, J.D. and Marsh, H.H., Semi-automatic Microtechnique for Serial Dilution Antibiotic Sensitivity Testing in the Clinical laboratory, Journal of Laboratory Clinical Medicine, 72:685-687, 1968.
1. Gerlach, E.H., Microdilution 1: A Comparative Study, p. 63-76. Current Techniques for Antibiotic Susceptibility Testing. A. Balows (ed.), Charles C. Thomas, Springfield, IL, 1974.
1. Barry, A.L., The Antimicrobic Susceptibility Test, Principles and Practices, Lea and Febiger, Philadelphia, PA, 1976.

Regulation Number and Section

§ 866.1645 Fully automated short-term incubation cycle antimicrobial susceptibility system.

(a)
Identification. A fully automated short-term incubation cycle antimicrobial susceptibility system is a device that incorporates concentrations of antimicrobial agents into a system for the purpose of determining in vitro susceptibility of bacterial pathogens isolated from clinical specimens. Test results obtained from short-term (less than 16 hours) incubation are used to determine the antimicrobial agent of choice to treat bacterial diseases.(b)
Classification. Class II (special controls). The special control for this device is FDA's guidance document entitled “Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA.”