(113 days)
VITEK® 2 AST-Gram Negative Ciprofloxacin (≤ 0.06 -> 4 ug/mL) is designed for antimicrobial susceptibility testing of Gram negative bacilli and is intended for use with the VITEK® 2 Compact Systems as a laboratory aid in the determination of in vitro susceptibility to antimicrobial agents. VITEK® 2 AST-Gram Negative Ciprofloxacin is a quantitative test. Ciprofloxacin has been shown to be active against most strains of the microorganisms listed below, according to the FDA label for this antimicrobial.
Active both in vitro and in clinical infections Citrobacter Koseri Citrobacter freundii Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Morganella morganii Proteus mirabilis Proteus vulgaris Providencia rettgeri Providencia stuartii Pseudomonas aeruginosa Salmonella typhi Serratia marcescens Shigella sonnei
In vitro data available but clinical significance is unknown: Enterobacter aerogenes Klebsiella oxytoca Salmonella enteritidis
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.
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).Ciprofloxacin has been shown to be active against most strains of the microorganisms listed below, according to the FDA label for this antimicrobial.
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 poltions of a specific antibiotic combined with culture media. The 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 repo1t is generated that contains the MIC value along with the interpretive categoly result for each antibiotic contained on the card.
The VITEK® 2 AST-Gram Negative Ciprofloxacin (≤ 0.06 -> 4 ug/mL) device is an automated system for antimicrobial susceptibility testing of Gram-negative bacilli. The study presented aims to demonstrate its substantial equivalence to a predicate device and its acceptable performance against a reference method.
Here's a breakdown of the acceptance criteria and study details:
1. Table of Acceptance Criteria & Reported Device Performance
| Acceptance Criteria | Reported Device Performance |
|---|---|
| Overall Essential Agreement (EA) with CLSI broth microdilution reference method ≥ 90% | 97.2% Essential Agreement (overall) |
| Overall Category Agreement (CA) with CLSI broth microdilution reference method ≥ 90% | 95.5% Category Agreement (overall) |
| Reproducibility acceptable | Acceptable Reproducibility |
| Quality Control acceptable | Acceptable Quality Control |
| Essential Agreement per organism group: | |
| Enterobacteriaceae (excluding Salmonella) | 97.9% |
| Pseudomonas aeruginosa | 93.6% |
| Salmonella | 100.0% |
| Category Agreement per organism group: | |
| Enterobacteriaceae (excluding Salmonella) | 95.2% |
| Pseudomonas aeruginosa | 96.6% |
| Salmonella | 100.0% |
Note on Essential Agreement (EA): Essential Agreement is defined as the agreement between the test device's MIC (Minimum Inhibitory Concentration) results and the reference method's MIC results within a specified range (typically ±1 doubling dilution).
Note on Category Agreement (CA): Category Agreement refers to the categorical agreement between the test device's interpretive results (Susceptible, Intermediate, Resistant) and the reference method's interpretive results. It distinguishes between:
- VME (Very Major Error): False Susceptible (device says susceptible, reference says resistant).
- ME (Major Error): False Resistant (device says resistant, reference says susceptible).
- mE (Minor Error): Agreement on S/I/R, but not on the exact MIC (e.g., device says susceptible, reference says intermediate, or vice versa).
2. Sample Size and Data Provenance
- Test Set Sample Size: The exact total number of isolates used in the external evaluation is not explicitly stated as a single number. However, the study involved "fresh and stock clinical isolates, as well as a set of challenge strains." The performance data is broken down by organism group, suggesting a sufficiently diverse test set was used to meet FDA guidance for AST systems.
- Data Provenance: The document states "An external evaluation was conducted." While the specific country of origin is not explicitly mentioned, given the FDA submission, it's highly probable the data was primarily collected in the United States. The study used both "fresh and stock clinical isolates" which implies a mix of retrospective (stock) and prospective (fresh) data collection.
3. Number of Experts and Qualifications for Ground Truth
- This device is an in vitro diagnostic for antimicrobial susceptibility testing, comparing its results to a gold-standard laboratory reference method (CLSI broth microdilution). Therefore, the "experts" in this context are the laboratory technicians and microbiologists performing the CLSI broth microdilution method accurately, and the established CLSI guidelines and FDA-recognized breakpoints for interpretation. There is no mention of human readers/interpreters in the traditional sense of medical imaging or clinical diagnosis.
4. Adjudication Method for the Test Set
- Not applicable in the conventional sense. The "adjudication" is the direct comparison of the VITEK 2's automated results against the established CLSI broth microdilution reference method and the application of FDA-recognized breakpoints. Discrepancies are categorized as VME, ME, or mE.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, an MRMC comparative effectiveness study was not done. This is an in vitro diagnostic device that automates antimicrobial susceptibility testing. The study design involves comparing the device's performance to a recognized reference laboratory method, not to human interpretation of images or clinical data in a multi-reader setting.
6. Standalone Performance
- Yes, standalone performance was done. The entire study is a measure of the standalone performance of the VITEK® 2 AST-GN Ciprofloxacin system as it provides automated results, which are then compared directly against the CLSI broth microdilution reference method. There is no human-in-the-loop component in the "performance" assessment itself, although human operators are required to run the VITEK 2 system and the reference method.
7. Type of Ground Truth Used
- The ground truth used was the CLSI (Clinical and Laboratory Standards Institute) broth microdilution reference method for antimicrobial susceptibility testing, interpreted using FDA-recognized breakpoints. This is considered the gold standard for AST.
8. Sample Size for the Training Set
- The document does not explicitly state the sample size used for training the VITEK® 2 AST-GN Ciprofloxacin system. The VITEK® 2 system's core "Analysis Algorithms" are described as "Growth Pattern Analysis," which implies a rule-based or machine learning approach that would have been developed and "trained" or validated using a large dataset of bacterial growth patterns under different antimicrobial concentrations. This initial development and training would have occurred prior to this specific submission for Ciprofloxacin, likely on a broader range of antimicrobials and organisms. This submission focuses on the validation of the specific Ciprofloxacin card against the established reference method.
9. How the Ground Truth for the Training Set Was Established
- While not explicitly detailed for a "training set" in this document, the general principle for establishing ground truth for AST systems (including for algorithm development/training) would involve:
- Using known strains and clinical isolates.
- Performing parallel testing with the gold-standard CLSI broth microdilution method.
- Correlating growth patterns (e.g., turbidity changes over time) observed by the VITEK 2 system with the MIC values determined by the reference method.
- Establishing the interpretive categories (Susceptible, Intermediate, Resistant) based on FDA-recognized and CLSI breakpoints applied to the reference method MICs.
- Developing and refining the algorithms (e.g., growth pattern analysis) to accurately predict MICs and interpretive categories from the VITEK 2's optical density measurements.
§ 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.”