(37 days)
Antimicrobial Susceptibility Test Disks are used for semi-quantitative in vitro susceptibility testing by standardized agar diffusion test procedures. Tigecycline 15ug BBL™ Sensi-Disc™ is intended for use in determining the susceptibility to Tigecycline of a wide range of bacteria, as described in the "Indications for Use" section. Zone sizes used for interpretation of tests, including control organism limits, were determined by the antimicrobic manufacturer and received FDA approval under NDA Number 21-821.
Use of Tigecycline 15µg BBL" Sensi-Disc "for in vitro agar diffusion susceptibility testing is indicated when there is a need to determine the susceptibility of bacteria to Tigecycline. The concentration of 15ug has been shown to be active in vitro against most strains of microorganisms listed below, as described in the FDA approved drug insert for this antimicrobic.
Active In Vitro and in Clinical Infections Against:
Aerobic facultative Gram-positive microorganisms
Enterococcus faecalis (vancomycin-susceptible isolates only) Staphylococcus aureus -(methicillin susceptible and resistant isolates only) Streptococcus agalactiae Streptococcus anginosus grp. -(includes S. anginosus, S. intermedius, and S. constellatus Streptococcus pyogenes
Active In Vitro Against:
Aerobic and facultative Gram-positive microorganisms
Enterococcus avium Enterococcus casseliflavus Enterococcus faecalis (vancomycin-resistant isolates) Enterococcus faecium-(vancomycin-susceptible and -resistant isolates) Enterococcus gallinarum Listeria monocytogenes Stapvlococcus epidermidis -(methicillin-susceptible and -resistant isolates) Stapylococcus haemolyticus
Aerobic and facultativeGram-negative microorganisms
Citrobacter freundii Enterobacter cloacae Escherichia coli Klebsiella oxytoca Klebsiella pneumoniae
Aerobic and facultative Gram-negative microorganisms
Acinetobacter baumannii Aeromonas hydrophila Citrobacter koseri Enterobacter aerogenes Pasteurella multocida Serratia marcescens Stenotrophomonas maltophilia
Tigecycline15ug BBL" Sensi-Disc" is prepared by impregnating high quality paper with accurately determined amounts of Tigecycline supplied by the drug manufacturer. Each Tigecycline disk is clearly marked on both sides with the agent and drug content. Tigecycline cartridges each contain 50 impregnated disks that are packed as either a single cartridge in a single box, or in a package containing ten cartridges. Tigecycline disks are used for semi-quantitative in vitro susceptibility evaluations by the agar diffusion test method.
Agar diffusion susceptibility methods employing dried filter paper disks impregnated with specific concentrations of antimicrobial agents were developed in the 1940s. In order to eliminate or minimize variability in the testing, Bauer et al. developed a standardized procedure in which Mueller Hinton Agar was selected as the test medium.
Various regulatory agencies and standards-writing organizations subsequently published standardized reference procedures based on the Bauer-Kirby method. Among the earliest and most widely accepted of these standardized procedures were those published by the U.S. Food and Drug Administration (FDA) and the World Health Organization (WHO). The procedure was adopted as a consensus standard by the Clinical and Laboratory Standards Institute (CLSI) [Formerly National Committee for Clinical Laboratory Standards (NCCLS)] and is periodically updated.
The acceptance criteria and the study proving the device meets these criteria are detailed below, based on the provided 510(k) submission.
1. Table of Acceptance Criteria and Reported Device Performance
The submission refers to established standards rather than defining specific numerical acceptance criteria in the summary. The performance is demonstrated by conformance to these standards, specifically zone size interpretation for individual antimicrobial agents.
| Acceptance Criterion | Reported Device Performance |
|---|---|
| Zone Sizes for Interpretation of Tests | Determined by the antimicrobic manufacturer and received FDA approval under NDA Number 21-821. |
| Control Organism Limits | Determined by the antimicrobic manufacturer and received FDA approval under NDA Number 21-821. |
| Categorical Interpretation (Susceptible, Intermediate, Resistant) | Established by comparing zone diameters to those found in respective organism tables of CLSI/NCCLS Document M2 ("Performance Standards for Antimicrobial Disk Susceptibility Tests") and CLSI/NCCLS Document M100 ("Performance Standards for Antimicrobial Susceptibility Testing"). The device's performance is implicit in its intended use, which is to allow for this comparison and interpretation. |
2. Sample Size Used for the Test Set and Data Provenance
The 510(k) summary references "Substantial Equivalence Testing Data: See the Tigecycline drug package insert, 'Susceptibility Tests: Diffusion Techniques' (Appendix 1)." This indicates that the specific data proving the performance of the Tigecycline 15µg BBL Sensi-Disc against the established zone size ranges and control limits would be found in the Tigecycline drug package insert.
- Sample Size for Test Set: Not explicitly stated in the provided 510(k) summary. It would be detailed in Appendix 1, the Tigecycline drug package insert.
- Data Provenance: Not explicitly stated in the provided 510(k) summary. The data would originate from the studies performed to establish the zone sizes and control limits for Tigecycline, as detailed in the drug package insert. These studies are typically prospective clinical and laboratory studies involving a range of bacterial isolates.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The ground truth for defining interpretable zone sizes and control limits for antimicrobial susceptibility testing is established through extensive scientific research and standardization efforts by organizations like CLSI (Clinical and Laboratory Standards Institute, formerly NCCLS) and regulatory bodies like the FDA.
- Number of Experts: Not explicitly stated in the provided 510(k) summary. However, the establishment of such standards involves numerous clinical microbiologists, infectious disease physicians, and pharmacologists from academic institutions, industry, and government agencies and is a consensus-driven process.
- Qualifications of Experts: These experts would typically be highly qualified professionals in microbiology, infectious diseases, and pharmacology, with significant experience in antimicrobial susceptibility testing and clinical outcomes.
4. Adjudication Method for the Test Set
The concept of "adjudication" in the traditional sense of multiple reviewers resolving discrepancies isn't directly applicable to the establishment of predefined zone size interpretive criteria for antimicrobial susceptibility discs. The ground truth (zone size breakpoints) is established through large-scale correlation studies involving minimum inhibitory concentration (MIC) testing, pharmacokinetic/pharmacodynamic (PK/PD) data, and clinical outcomes.
Instead of adjudication, the method involves:
- Correlation Studies: Comparing disk diffusion zone diameters to MIC values, which are considered the gold standard for antimicrobial susceptibility.
- Clinical Efficacy Data: Ensuring that the breakpoints correlate with successful clinical outcomes in patients treated with the antimicrobial.
- Consensus Process: CLSI (formerly NCCLS) and similar bodies use a consensus process involving expert committees to review and approve these breakpoints.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done
No, an MRMC comparative effectiveness study in the context of human readers improving with AI vs without AI assistance was not performed. This device is an antimicrobial susceptibility test disk, not an AI-assisted diagnostic tool for image interpretation. Its function is to provide a physical measurement (zone of inhibition) that is then interpreted against established standards, not to assist human interpretation of complex medical images or data.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done
This refers to a standalone performance of the device itself (the antimicrobial disk) which is then interpreted by a human against a standard. The device's performance as a "standalone" system is in producing a consistent zone of inhibition that can be accurately measured. The interpretation of that zone (Susceptible, Intermediate, Resistant) always involves a human reading against established criteria.
The "standalone" performance of the disk would be assessed through studies ensuring:
- Accurate and consistent impregnation of Tigecycline at 15µg.
- Stability of the antimicrobial agent on the disk.
- Reproducibility and accuracy of zone diameters when tested with control strains.
7. The Type of Ground Truth Used
The ground truth for the Tigecycline 15µg BBL Sensi-Disc is based on:
- Expert Consensus / Standardized Breakpoints: Established by organizations like CLSI/NCCLS, which define the zone diameters corresponding to Susceptible, Intermediate, and Resistant categories. These breakpoints are derived from extensive research.
- Correlation with MIC Values: The gold standard for antimicrobial susceptibility, where disk diffusion results are correlated with Minimum Inhibitory Concentrations.
- Clinical Outcome Data: The breakpoints are designed to predict clinical efficacy.
- Pathology/Microbiological Confirmation: The isolates used in the studies would be pure cultures of confirmed bacterial species.
8. The Sample Size for the Training Set
The concept of "training set" as it relates to machine learning algorithms is not directly applicable here. In the context of antimicrobial susceptibility testing, the "training set" would indirectly refer to the vast amount of data and isolates used over many years to establish the general principles of disk diffusion, the Mueller Hinton Agar method, and later, the specific breakpoints for new antimicrobial agents like Tigecycline. This would encompass thousands of isolates across numerous studies. The specific number of isolates used to determine the breakpoints for Tigecycline would be in the drug package insert (Appendix 1).
9. How the Ground Truth for the Training Set Was Established
For antimicrobial susceptibility testing, the "ground truth" for establishing the interpretive criteria (analogous to a training set's ground truth) is established through:
- Minimum Inhibitory Concentration (MIC) Testing: This is the reference method, determining the lowest concentration of an antimicrobial agent that inhibits the visible growth of a microorganism.
- Pharmacokinetic/Pharmacodynamic (PK/PD) Studies: These studies correlate drug concentrations in the body with their antimicrobial effect and help predict clinical success.
- Clinical Outcome Studies: Observing patient responses to treatment to ensure that the in vitro susceptibility results accurately predict therapeutic efficacy.
- Regression Analysis: Statistical methods are used to correlate zone diameters obtained from disk diffusion with MIC values to establish the interpretive breakpoints (zone diameter cutoffs).
- Expert Review and Consensus: As mentioned before, committees of experts review all available data (MICs, PK/PD, clinical outcomes) to arrive at the final standardized breakpoints.
§ 866.1620 Antimicrobial susceptibility test disc.
(a)
Identification. An antimicrobial susceptibility test disc is a device that consists of antimicrobic-impregnated paper discs used to measure by a disc-agar diffusion technique or a disc-broth elution technique the in vitro susceptibility of most clinically important bacterial pathogens to antimicrobial agents. In the disc-agar diffusion technique, bacterial susceptibility is ascertained by directly measuring the magnitude of a zone of bacterial inhibition around the disc on an agar surface. The disc-broth elution technique is associated with an automated rapid susceptibility test system and employs a fluid medium in which susceptibility is ascertained by photometrically measuring changes in bacterial growth resulting when antimicrobial material is eluted from the disc into the fluid medium. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.(b)
Classification. Class II (performance standards).