(90 days)
Etest® is a quantitative technique for determination of antimicrobial susceptibility of both non-fastive and Gram positive aerobic bacteria such as Enterobacteriaceae, Pseudomonas, Staphylococcus, species and fastidious bacteria, such as anaerobes, N. gonorrhoeae, S. pneumoniae, Streptococcus and Haemophilus species. The system comprises a predefined antibiotic gradient which is used to determine the Minimum Inhibitory Concentration (MIC), in ug/mL, of different antimicrobial agents against microorganisms as tested on agar media using overnight incubation.
This submission is for additional indications for the antimicrobial Etest® Ceftaroline at concentrations of 0.002 – 32 µg/ mL. Etest® Ceftaroline has been shown to be active in vitro against fastidious strains of the microorganisms listed below, according to the FDA label for this antimicrobial agent:
Streptococcus pneumoniae, Streptococcus agalactiae. Haemophilus influenzae.
The Etest gradient technology is based on a combination of the concepts of dilution and diffusion principles for susceptibility testing.
The Etest consists of a thin, inert, nonporous plastic strip that is used to determine the antimicrobial susceptibility of bacteria. One side of the strip carries the minimum inhibitory concentration (MIC) reading scale expressed in ug/mL. The other side of the strip contains a predefined continuous exponential gradient of antibiotic concentrations.
When the Etest strip is applied to an inoculated agar surface, an immediate and effective transfer of the preformed antibiotic gradient on the plastic carrier surface into the agar matrix occurs. Following incubation, a symmetrical inhibition ellipse centered along the strip is seen. The MIC value is read from the scale in term of ug/mL where the ellipse edge intersects the strip.
Here's a breakdown of the acceptance criteria and study information for the Etest® Ceftaroline device, based on the provided document:
Acceptance Criteria and Device Performance Study
The submission details the performance of the Etest® Ceftaroline for determining antimicrobial susceptibility against specific bacteria. The key metrics reported are Essential Agreement (EA) and Category Agreement (CA) when compared to a reference method.
1. Table of Acceptance Criteria and Reported Device Performance
The document states that the Etest® Ceftaroline demonstrated acceptable performance for overall Essential Agreement (EA) and for overall Category Agreement (CA) with the reference method. While explicit numerical acceptance criteria for EA and CA are not stated in the provided text as standalone thresholds, the reported percentages are presented as meeting the acceptable performance standard. However, based on typical FDA guidance for AST devices, an Essential Agreement of ≥ 90% and a Category Agreement of ≥ 90% (often nearing 95-100% for category) are generally expected. The device's performance aligns with these general expectations.
Below is a table summarizing the reported device performance:
FDA Breakpoints. Broth Microdilution Reading at 18 hr. Clinical and Challenge Combined
| Organism Group | Total Tested | # EA | % EA | # CA | % CA |
|---|---|---|---|---|---|
| S. pneumoniae | 283 | 269 | 95.1% | 283 | 100.00% |
| S. agalactiae | 276 | 259 | 93.8% | 276 | 100.00% |
| H. influenzae | 285 | 265 | 93.0% | 285 | 100.00% |
| All Organisms | 844 | 793 | 94.0% | 844 | 100.00% |
FDA Breakpoints. Broth Microdilution Reading at 23 hr. Clinical and Challenge Combined
| Organism Group | Total Tested | # EA | % EA | # CA | % CA |
|---|---|---|---|---|---|
| S. pneumoniae | 283 | 272 | 96.1% | 283 | 100.00% |
| S. agalactiae | 276 | 269 | 97.5% | 276 | 100.00% |
| H. influenzae | 285 | 270 | 94.7% | 285 | 100.00% |
| All Organisms | 844 | 811 | 96.1% | 844 | 100.00% |
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size for Test Set: The total number of isolates tested across all organisms was 844. This was broken down as:
- S. pneumoniae: 283 isolates
- S. agalactiae: 276 isolates
- H. influenzae: 285 isolates
- Data Provenance: The external evaluations were conducted using fresh and stock clinical isolates, as well as a set of challenge strains. The document does not specify the country of origin, but the use of "clinical isolates" suggests real-world samples, and "challenge strains" implies strains selected for their specific resistance profiles or difficulty of testing.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications
This information is not provided in the document. The ground truth method, CLSI broth microdilution, is a standardized laboratory procedure, not typically an expert consensus reading in the same way an image interpretation might be. Therefore, the concept of "experts" to establish its "ground truth" doesn't directly apply here in the way it would for, say, radiology reads. The accuracy of the reference method relies on adherence to the CLSI protocol.
4. Adjudication Method for the Test Set
The concept of an adjudication method (like 2+1 or 3+1) is typically used when human readers are involved in interpreting results and their interpretations need to be reconciled for ground truth. Since the ground truth is established by a standardized laboratory reference method (CLSI broth microdilution), no adjudication method between human readers/interpreters is mentioned or likely applicable in this context.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No MRMC comparative effectiveness study was done because this is an in vitro diagnostic device for antimicrobial susceptibility testing. It directly measures Minimum Inhibitory Concentration (MIC) and categorizes susceptibility (e.g., susceptible, intermediate, resistant). Its performance is compared to a reference lab method, not to human readers interpreting complex medical cases with and without AI assistance. Therefore, there is no effect size reported for human readers improving with AI.
6. Standalone (Algorithm Only Without Human-in-the-Loop Performance)
Yes, a standalone performance study was done. The Etest® Ceftaroline device's results (MIC values and categorical interpretations) were directly compared to the CLSI broth microdilution reference method's results. This comparison assesses the device's accuracy independently, without a human "interpreter" making a diagnosis based on the device's output and then having that diagnosis compared to a human-made ground truth. The Etest strip itself provides the MIC reading, which is then interpreted by a trained laboratory professional in the context of breakpoints.
7. The Type of Ground Truth Used
The ground truth used was the CLSI (Clinical and Laboratory Standards Institute) M07-A9 January 2012 broth microdilution reference method. This is a laboratory reference standard widely accepted as the gold standard for determining antimicrobial susceptibility.
8. The Sample Size for the Training Set
The document does not specify a separate "training set" sample size. In the context of antimicrobial susceptibility testing devices, the "training" (or development) often involves internal testing during the design phase to optimize the device's performance characteristics. The reported numbers (844 isolates) are for the "external evaluations" which serve as the primary performance validation against the reference method.
9. How the Ground Truth for the Training Set Was Established
As mentioned above, a distinct "training set" with established ground truth is not explicitly detailed for this type of device. The development and validation of the Etest® Ceftaroline would have followed established microbiological practices and standards, likely comparing preliminary versions to the same CLSI broth microdilution reference method during its development. The "ground truth" would consistently be the CLSI reference method.
§ 866.1640 Antimicrobial susceptibility test powder.
(a)
Identification. An antimicrobial susceptibility test powder is a device that consists of an antimicrobial drug powder packaged in vials in specified amounts and intended for use in clinical laboratories for determining in vitro susceptibility of bacterial pathogens to these therapeutic agents. Test results are used to determine the antimicrobial agent of choice in the treatment of bacterial diseases.(b)
Classification. Class II (performance standards).