(10 days)
Antimicrobial Susceptibility Test Discs are used for semi-quantitative in vitro susceptibility testing by standardized agar diffusion test procedures. Cefepime Sensi-Discs® are intended for use in determining the susceptibility of a wide range of gram-positive and gram-negative bacteria, including Enterobacter spp, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus (methicillin-susceptible strains only), Streptococcus pneumoniae, and Streptococcus pyogenes (Lancefield's Group A streptococci), to Cefepime. Zone sizes used for interpretation of tests, including control organism limits, were determined by the antimicrobic manufacturer, Bristol-Myers Squibb, and received FDA approval under NDA No. 50-679.
Use of BBL® Cefepime Sensi-Discs® for in vitro agar diffusion susceptibility testing is indicated when there is a need to determine the susceptibility of bacteria to cefepime.
Cefepime Susceptibility Test Discs are prepared by impregnating high quality paper with accurately determined amounts of Cefepime supplied by the manufacturer, Bristol-Myers Squibb Company, Princeton, New Jersey. Each Cefepime disc is clearly marked on both sides with the agent and content (FEP-30). Cefepime discs are furnished in cartridges of 50 discs each. Cefepime cartridges are packed as either a single cartridge in a single box, or in a package containing ten cartridges.
Agar diffusion methods emploving dried filter paper discs 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 National Committee for Clinical Laboratory Standards (NCCLS) and is periodically updated. The latest NCCLS documents are M2-A5 (12/93) and M100-S6 (12/95).
Discs containing a wide variety of antimicrobial agents are applied to the surface of Mueller Hinton Agar plates (or Haemophilus Test Medium Agar for H. influenzae, GC II Agar with IsoVitaleX® Enrichment for N. gonorrhoeae or Mueller Hinton Agar with 5% Sheep Blood for S. pneumoniae] inoculated with pure cultures of clinical isolates. Following incubation, the plates are examined and the zones of inhibition surrounding the discs are measured and compared with established zone size ranges for individual antimicrobial agents in order to determine the agent(s) most suitable for use in antimicrobial therapy. The determination as to whether the organism in question is susceptible (S), intermediate (I), or resistant (R) to an antimicrobial agent is made by comparing zone sizes to those found in the Standards (NCCLS) Document M2-A5 ("Performance Standards for Antimicrobial Disk Susceptibility tests - Fifth Edition, Approved Standard", 12/93) and of NCCLS Document M100-S6 ("Performance Standards for Antimicrobial Susceptibility Testing", Sixth Informational Supplement, 12/95).
Here's an analysis of the provided text, focusing on the acceptance criteria and the study details:
1. A table of acceptance criteria and the reported device performance
Based on the provided text, the acceptance criteria are not explicitly stated in a quantitative manner as would be expected for a modern medical device submission (e.g., "Sensitivity > 90%, Specificity > 80%"). Instead, the acceptance criteria are implied by adherence to established clinical laboratory standards. The "reported device performance" is not explicitly detailed in the provided text beyond the statement that "Zone sizes used for interpretation of tests, including control organism limits, were determined by the antimicrobic manufacturer, Bristol-Myers Squibb, and received FDA approval under NDA No. 50-679." This suggests the performance aligns with the existing drug's established efficacy, and the device simply provides a standardized method for testing that efficacy.
| Acceptance Criterion (Implied) | Reported Device Performance |
|---|---|
| Adherence to NCCLS M2-A5 (12/93) and M100-S6 (12/95) standards | The device uses and references the interpretative criteria (zone sizes for S, I, R) detailed in NCCLS Document M2-A5 and M100-S6. The method employs Mueller Hinton Agar (or specific alternatives for certain organisms) as standardized by these guidelines. |
| Accurate application of Cefepime | Discs are prepared by impregnating high-quality paper with accurately determined amounts of Cefepime. |
| Clear labeling | Each disc is clearly marked on both sides with the agent (FEP) and content (30). |
| Consistency with previously approved Cefepime interpretative criteria | "Zone sizes used for interpretation of tests, including control organism limits, were determined by the antimicrobic manufacturer, Bristol-Myers Squibb, and received FDA approval under NDA No. 50-679." This implies the device's output (zone sizes) will correspond to these approved interpretive criteria for susceptibility determination (S, I, R). The "performance data" section explicitly refers to the MAXIPIME® (Cefepime Hydrochloride) product insert, which would contain efficacy and susceptibility data. |
2. Sample sized used for the test set and the data provenance
The document does not explicitly state the sample size used for a "test set" in the context of validating the device itself. The testing described is more about the standardization of the method using the antifungals rather than an independent performance study of the disk itself generating new "test set" data.
The data provenance for the interpretative criteria (zone sizes) is attributed to Bristol-Myers Squibb, the manufacturer of Cefepime, and their original FDA approval under NDA No. 50-679. This suggests the underlying data originated from extensive studies supporting the drug's efficacy and susceptibility breakpoints, which would have been prospective clinical and microbiological trials for the drug itself. The document does not describe a separate, independent "test set" for the Sensi-Disc.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
This information is not provided in the document. The "ground truth" for susceptibility interpretation (S, I, R) is established by the NCCLS standards (M2-A5 and M100-S6), which are consensus documents developed by committees of experts, but the individual experts and their qualifications for this specific submission are not detailed.
4. Adjudication method for the test set
This information is not applicable/provided in the document. The process described is one of adherence to standardized laboratory methods (Bauer-Kirby, NCCLS) rather than an independent adjudication of results. The determination of S, I, or R is based on comparing measured zone sizes to the established ranges in the NCCLS documents.
5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance
No, a multi-reader multi-case (MRMC) comparative effectiveness study was not conducted or reported. This type of study (and the concept of AI assistance) is not relevant to this device, which is an antimicrobial susceptibility test disc from 1996. AI was not a factor in such submissions at that time.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
No, a standalone algorithm-only performance study was not done. The device is a physical disc used in a laboratory procedure requiring human operation and interpretation of zone sizes. There is no algorithm involved in the modern sense.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
The ground truth for interpreting susceptibility (S, I, R) is based on expert consensus embodied in the NCCLS standards (M2-A5, M100-S6). These standards effectively serve as the "ground truth" for how to conduct the test and interpret its results, referencing the known clinical efficacy and breakpoints established for the drug (Cefepime) through extensive clinical trials.
8. The sample size for the training set
The document does not specify a "training set" sample size for the device itself. The data supporting the interpretative criteria (zone sizes) would have come from the original drug development and trials by Bristol-Myers Squibb (NDA No. 50-679), which would have involved a large number of microbial isolates and clinical cases to establish breakpoints. This information is a reference to the drug, not a specific training set for the Sensi-Disc device in this submission.
9. How the ground truth for the training set was established
The ground truth for the "training" (i.e., the establishment of the interpretive zone sizes for Cefepime) was established by the antimicrobic manufacturer, Bristol-Myers Squibb, through studies supporting NDA No. 50-679. This would likely have involved:
- Correlation of in vitro Minimal Inhibitory Concentrations (MICs) with clinical outcomes.
- Pharmacokinetic/pharmacodynamic (PK/PD) modeling.
- Extensive microbiological testing across a wide range of bacterial species, including clinical isolates.
- Clinical trials to demonstrate the efficacy of Cefepime against various infections, correlating in vitro susceptibility with in vivo response.
These studies formed the basis for the interpretative breakpoints (zone sizes for S, I, R) that were then adopted and standardized by organizations like NCCLS. The Sensi-Disc device leverages these pre-established and FDA-approved interpretive criteria.
§ 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).