(254 days)
BacT/ALERT® FN Plus Culture Bottles are used with the BacT/ALERT® Microbial Detection System in qualitative procedures for recovery and detection of anaerobic and facultative anaerobic microorganisms from blood and other normally sterile body fluids.
The proposed resin formulation reagent (BacT/ALERT® FN Plus Culture Bottle) is an improvement upon the cleared charcoal formulation reagent (BacT/ALERT® FN Culture Bottle). The BacT/ALERT® FN Culture Bottles are used with the BacT/ALERT® Microbial Detection Systems in qualitative procedures for recovery and detection of microorganisms from blood.
The predicate BacT/ALERT® FN Culture Bottle contains charcoal in the complex growth medium for its antimicrobial neutralization properties. Charcoal is eliminated in the proposed BacT/ALERT® FN Plus Culture Bottle, and is replaced with two types of adsorbent polymeric beads in the complex growth medium. The proposed BacT/ALERT® FN Plus Culture Bottle (resin) is optimized to increase antimicrobial neutralization properties and to increase the clarity of Gram stains in comparison to the predicate BacT/ALERT® FN Culture Bottle (charcoal) while maintaining the ability to detect and recover microorganisms.
The BacT/ALERT® Microbial Detection System provides both a microbial detection system and a culture medium bottle with suitable nutritional and environmental conditions for microorganisms commonly encountered in blood or other normally sterile body fluid samples (except urine) taken from a patient suspected of having bacteremia/fungemia. An inoculated bottle is placed into the instrument where it is incubated and continuously monitored for the presence of microorganisms that will grow in the BacT/ALERT® bottles.
The BacT/ALERT® Microbial Detection System utilizes a colorimetric sensor and reflected light to monitor the presence and production of carbon dioxide (CO2) that is dissolved in the culture medium. If microorganisms are present in the test sample, carbon dioxide is produced as the microorganisms metabolize the substrates in the culture medium. When growth of the microorganisms produces CO2, the color of the gas-permeable sensor installed in the bottom of each culture bottle changes from blue-areen to vellow. The lighter color results in an increase of reflectance units monitored by the system. Bottle reflectance is monitored and recorded by the instrument every 10 minutes.
This document describes the BacT/ALERT® FN Plus Culture Bottle, a device used for the recovery and detection of anaerobic and facultative anaerobic microorganisms from blood and other normally sterile body fluids. The acceptance criteria and supporting studies are detailed below.
1. Table of Acceptance Criteria and Reported Device Performance
| Acceptance Criteria Category | Specific Criteria/Metric | Reported Device Performance |
|---|---|---|
| Analytical Sensitivity: | Growth Performance - % Recovery (various microorganisms, with & without blood, target 125 CFU/bottle) | With Blood: Staphylococcus aureus (100%), Escherichia coli (100%), Bacteroides fragillis (100%), Streptococcus pneumoniae (100%), Clostridium perfringens (100%), Klebsiella pneumoniae (100%), Fusobacterium nucleatum (70.6%), Streptococcus agalactiae (100%), Enterococcus faecalis (100%), Parvimonas micra (80%), Enterobacter cloacae (100%), Proteus mirabilis (100%), Eggerthella lenta (86.7%), Staphylococcus epidermidis (100%), Listeria monocytogenes (100%), Clostridium tertium (100%), Clostridium septicum (50%), Peptoniphilus asaccharolyticus (60%). No Blood: Staphylococcus aureus (100%), Escherichia coli (100%), Bacteroides fragillis (66.7%), Streptococcus pneumoniae (100%), Clostridium perfringens (100%), Klebsiella pneumoniae (100%), Fusobacterium nucleatum (75%), Streptococcus agalactiae (100%), Enterococcus faecalis (100%), Parvimonas micra (0%), Enterobacter cloacae (100%), Proteus mirabilis (100%), Eggerthella lenta (66.7%), Staphylococcus epidermidis (100%), Listeria monocytogenes (100%), Clostridium tertium (100%), Clostridium septicum (40%), Peptoniphilus asaccharolyticus (25%). |
| Growth Performance - Time to Detection (TTD) (various microorganisms) | Range of mean TTDs: With blood 10.9-74.4 hours, without blood 11.6-97.2 hours. (Specific ranges provided for each organism in tables 2 and 3 of the source document). | |
| Antimicrobial Neutralization | Effective neutralization of tested antimicrobials, resulting in 100% recovery of susceptible organisms. | Neutralized: Imipenem, oxacillin, glycylcycline, ceftaroline, aminoglycosides, fluoroquinolones, macrolides, cefoxitin, lincosamides, ketolides, glycopeptides. Not Achieved: Ceftazidime, ceftriaxone, cefepime. Less Than Complete Neutralization: Cefotaxime (40%-3% PSL), Cefazolin (25%-5% PSL), Ertapenem (5% PSL), Ampicillin (75% PSL for E. faecalis, 0% for C. perfringens), Penicillin (120% PSL for S. pneumoniae, 0% for C. perfringens). |
| Potentially Interfering Substances | No interference with recovery/detection of organisms, no false positives in absence of organisms. | Studies with cerebrospinal fluid, pleural fluid, synovial fluid, plasma, blood, and blood clots (with and without WBCs and microorganisms) demonstrated no interference with organism recovery and detection, nor generation of false positives. |
| Limit of Detection (LoD) | At least 95% detection achieved at specified LoD (CFU/bottle). | LoD (CFU/bottle) for: Bacteroides fragilis (5), Clostridium perfringens (4), Enterobacter aerogenes (8), Enterococcus faecalis (4), Escherichia coli (4), Listeria monocytogenes (6), Salmonella enterica (5), Staphylococcus aureus (4), Streptococcus pneumoniae (6). At least 95% detection was achieved at these LoDs (Table 3). |
| Within Laboratory Precision (Repeatability) | High % recovery, consistent TTD. | % Recovery: B. fragilis (100%), C. perfringens (98.2%), S. aureus (100%). Mean TTD Range: B. fragilis (36.9 hrs), C. perfringens (14.5 hrs), S. aureus (17.7 hrs). (Table 4). |
| Reproducibility | High % agreement to expected across sites (instrument flag + Gram stain/subculture). | Overall % Agreement: Staphylococcus aureus (92.9%), Escherichia coli (93.3%), Enterococcus faecalis (94.3%), Clostridium perfringens (98.2%), Enterobacter aerogenes (86.5%), Listeria monocytogenes (100%), Salmonella enterica (93.6%), Streptococcus pneumoniae (100%). Overall Total: 94.8% (657/693), 95% CI: 92.9%, 96.3%. (Table 5). Excluding laboratory errors, 100% recovery was observed for all except E. aerogenes (96.3%). |
| Delayed Entry | High % recovery after specified hold times/temperatures. | 100% Recovery for control (no delay), 2-8°C/48hr, 20-25°C/24hr, 20-25°C/36hr, 35-37°C/8hr. 80% Recovery for 35-37°C/24hr (with caution to subculture). 0% False Positives for Negative Controls. (Table 6). |
| Clinical Performance (Blood Culture) | Improved detection of true positives compared to predicate. | Total Isolates Detected: FN Plus (282) vs. FN (192). Ratio of True Positives (Overall): 1.469 (95% CI: 1.317, 1.621). FN Plus detected 120 unique isolates, FN detected 30 unique isolates. Significant Isolates: FN Plus (202) vs. FN (150). Ratio of 1.347. False Positives (FN Plus): 3 (0.12% of study population). (Table 7). |
| Clinical Performance (Sterile Body Fluid Culture) | Improved detection of true positives compared to predicate. | Total Isolates Detected: FN Plus (72) vs. FN (59). Ratio of True Positives (Overall): 1.220 (95% CI: 1.044, 1.396). FN Plus detected 18 unique isolates, FN detected 5 unique isolates. Significant Isolates: FN Plus (52) vs. FN (50). Ratio of 1.040. False Positives (FN Plus): 0 (0% of study population). (Table 8). |
2. Sample Size for Test Set and Data Provenance
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Analytical Studies (Growth Performance, Antimicrobial Neutralization, Interfering Substances, LoD, Precision, Reproducibility): These were "in-house seeded studies" or "seeded studies conducted at three sites."
- Growth Performance: Varies by organism. For Staphylococcus aureus, 15 bottles with blood, 3 without. For Clostridium septicum, 40 bottles with blood, 5 without.
- Limit of Detection (LoD): Minimum of 30 replicates per species.
- Within Laboratory Precision (Repeatability): Minimum of 108 replicates per organism/antimicrobial combination.
- Reproducibility: Target of 144 replicates per site (3 sites), with actual numbers for each organism varying (e.g., 27 for S. aureus at Site 1, 33 at Site 3). Overall, 693 replicates across 8 organisms for the overall reproducibility study.
- Delayed Entry: 6 species, target 100 CFU/bottle. Control (89 bottles), 48 hr/2-8°C (65 bottles), 24 hr/20-25°C (62 bottles), 36 hr/20-25°C (62 bottles), 8 hr/35-37°C (72 bottles), 24 hr/35-37°C (80 bottles). Negative Controls (51 bottles).
- Provenance: "in-house seeded studies" or "seeded studies conducted at three sites," implying laboratory-controlled experiments. The "blood obtained from healthy human volunteers" is noted for some analytical studies. The reproducibility study was conducted at three sites, and the delayed entry study at three sites.
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Clinical Study (Blood Cultures):
- Sample Size: 2514 anaerobic bottle pairs (from 1080 adult patients).
- Data Provenance: Multi-center clinical study conducted at three different geographic sites in the U.S. This is prospective clinical data.
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Clinical Study (Sterile Body Fluid Cultures):
- Sample Size: 339 bottle pairs (from 310 adult patients).
- Data Provenance: Multi-center clinical study conducted at four different geographic sites in the U.S. and Canada. This is prospective clinical data.
3. Number of Experts and Qualifications for Ground Truth
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Analytical Studies: The document does not specify the number or qualifications of experts for establishing ground truth in the analytical studies. These studies typically rely on standard microbiological techniques (e.g., plating dilutions for CFU counts, subculture and identification for recovery) performed by trained laboratory personnel.
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Clinical Studies (Blood and Sterile Body Fluid Cultures):
- The classification of clinical isolates (significant, contaminant, or unknown) was based on "determination by the clinical trial sites." The specific number or qualifications of experts (e.g., infectious disease physicians, clinical microbiologists) involved in this determination are not explicitly stated in the provided summary.
4. Adjudication Method for the Test Set
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Analytical Studies: Not explicitly described, but generally, positive findings are confirmed by standard microbiological methods like Gram stain and subculture. For reproducibility, "Percent recovery reflects positive flag by the instrument and . Gram stain/subculture consistent with the seeded organism."
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Clinical Studies (Blood and Sterile Body Fluid Cultures):
- For clinical studies, a bottle was determined to be a "True Positive" if "the culture was flagged positive by the BacT/ALERT System and resulted in growth of the isolate upon subculture of this bottle."
- A "pair of bottles was determined to have a positive status if subculture of either the FN Plus or FN bottle was positive." This implies a form of consensus or composite reference standard where detection by either method, confirmed by subculture, counts as a positive case for the pair. However, there isn't a specified 'adjudication panel' or voting method mentioned for resolving discrepancies between the BacT/ALERT system and subculture, or between the FN Plus and FN bottles beyond this composite definition. The "Clinical Determination" (significant, contaminant, unknown) was determined by "the clinical trial sites," suggesting site-specific standard practices rather than a centralized adjudication committee.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, an MRMC comparative effectiveness study was not done. This device is a culture bottle used with an automated microbial detection system, not an AI-assisted diagnostic imaging or interpretation tool where human readers assess cases. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not applicable in this context. The comparison was between two generations of culture bottles (FN Plus vs. FN).
6. Standalone Performance (Algorithm Only without Human-in-the-Loop)
- Yes, standalone performance was done. The BacT/ALERT® Microbial Detection System uses a colorimetric sensor and reflected light to continuously monitor for the presence and production of CO2. The "BacT/ALERT® FN Plus Culture Bottle" is the culture medium, and the "BacT/ALERT® Microbial Detection System" is the instrument that performs the detection. The various analytical studies (LoD, growth performance, precision, reproducibility) evaluate the performance of the bottle and system in detecting microorganisms, which is an automated, algorithm-driven process. Human involvement comes primarily in preparing the samples, loading the bottles, and performing confirmatory subcultures and identification after the instrument flags a positive. The "True Positive" definition states positive flag by the instrument first, then confirmed by subculture.
7. Type of Ground Truth Used
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Analytical Studies:
- Spiked/Seeded Organisms: Known strains and concentrations of microorganisms were directly introduced into the bottles.
- Culture/Subculture Confirmation: Positive instrument signals were confirmed by subculture and Gram stain to ensure the detected organism matched the seeded organism.
- CFU/bottle: Direct quantification of colony-forming units.
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Clinical Studies (Blood and Sterile Body Fluid Cultures):
- Culture/Subculture Confirmation: The primary ground truth for a positive detection was defined as the "culture was flagged positive by the BacT/ALERT System and resulted in growth of the isolate upon subculture of this bottle." So, it's a combination of the device's automated detection and traditional microbiological culture (subculture).
- Clinical Determination: For categorizing isolates as significant, contaminant, or unknown, this was based on "determination by the clinical trial sites." This implies a clinical consensus based on patient presentation, other lab results, and standard infection control criteria. It's a form of expert consensus based on clinical context.
8. Sample Size for the Training Set
- The document primarily describes validation studies for the "BacT/ALERT® FN Plus Culture Bottle" in comparison to a predicate device. It details performance characteristics and clinical results. It does not explicitly provide information about a separate "training set" sample size used to develop or train the underlying BacT/ALERT® Microbial Detection System algorithm itself. The existing BacT/ALERT® system algorithm was already established, and the "FN Plus" bottle is an improved reagent formulation. The document mentions, "No changes to software code (in detection software) occurred. ... The structure of the detection algorithm remains unchanged. ... No change was made to the initial value threshold of the BacT/ALERT® FN Plus bottle type knowledge base." This indicates minimal to no re-training of the core algorithm for this specific submission, rather an adaptation to a new bottle type.
9. How the Ground Truth for the Training Set was Established
- As mentioned above, the document does not describe a new training set for the BacT/ALERT® FN Plus bottle explicitly, as the core detection algorithm was largely unchanged from the predicate system. The original BacT/ALERT® Microbial Detection System likely used extensive historical data and various seeded studies to establish its detection algorithms. However, this specific 510(k) summary focuses on the validation of the culture bottle itself.
§ 866.2560 Microbial growth monitor.
(a)
Identification. A microbial growth monitor is a device intended for medical purposes that measures the concentration of bacteria suspended in a liquid medium by measuring changes in light scattering properties, optical density, electrical impedance, or by making direct bacterial counts. The device aids in the diagnosis of disease caused by pathogenic microorganisms.(b)
Classification. Class I. With the exception of automated blood culturing system devices that are used in testing for bacteria, fungi, and other microorganisms in blood and other normally sterile body fluids, this device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter.