(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
-
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.
-
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.
-
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
-
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.
-
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
-
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."
-
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
-
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.
-
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.
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K12/455
BacT/ALERT® FN Plus Culture Bottle
510(k) SUMMARY
JAN 2 5 2013
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
Name of device
BacT/ALERT®FN Plus
Device Identification
Trade Name: BacT/ALERT® FN Plus Culture Bottle
Classification Name: Blood Culturing System, Microbiology
Product Code: MDB
Regulation: 21CFR866.2560, microbial growth monitor
Device Class: Class 1, not exempt from premarket notification per 21CFR807.81
Premarket Notification Submitter
| Company Name: | bioMérieux, Inc. |
|---|---|
| Company Address: | 100 Rodolphe Street |
| Durham, NC 27712 | |
| Contact: | Patricia Murphy, Staff Regulatory Affairs Specialist |
| Telephone # | 919-620-2270 |
| Fax# | 919-620-2548 |
| Preparation Date: | May 14, 2012 |
Intended Use of the Device:
- 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.
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BacT/ALERT® FN Plus Culture Bottle
Image /page/1/Picture/1 description: The image shows the logo for bioMerieux. The logo consists of the word "BIOMERIEUX" in a blocky, sans-serif font. A black circle with a white horizontal line through it sits above the text, and a thin vertical line bisects the circle and extends down between the "E" and "R" in "BIOMERIEUX."
Description of the Device:
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.
SUBSTANTIAL EQUIVALENCE INFORMATION
Predicate device name(s):
BacT/ALERT® FN Culture Bottle
Predicate device 510(k) number(s) K020815
Comparison with predicate
The BacT/ALERT FN Plus Culture Bottle is claimed substantially equivalent to the BacT/ALERT FN Culture Bottle (K020815).
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| Culture Bottle Characteristics: Changes versus K020815 | |
|---|---|
| Specimen Sampling andHandling | Unchanged |
| Assay Types | Unchanged |
| Reaction Types | Unchanged |
| Calibration | Unchanged |
| Quality Control (by Operator) | Unchanged |
| Principles of Operation | Unchanged |
| Firmware | No changes to software code (in detection software) occurred.Released with firmware version B.40 on BacT/ALERT MicrobialDetection SystemsThe structure of the detection algorithm remains unchanged.No change was made to the initial value threshold of theBacT/ALERT® FN Plus bottle type knowledge base.Applicable variables in software controlling barcode recognition wereadjusted to enable recognition of the new bottle type. |
Table 1 Similarities and differences between the bottles are outlined below:
Performance Characteristics
Analytical Testing
Analytical Sensitivity: Growth Performance
Data represent results from in-house seeded studies with and without blood obtained from healthy human volunteers. Multiple strains were tested for each species at target inoculum levels of 125 CFU per bottle. The species listed are representatives of clinically prevalent organisms in blood cultures and sterile body. fluids.
Table 2 Growth Performance Results
| Blood | No Blood | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Microorganism | %Recovery(n) | RangeCFU/bottle | Time to Detection(hours) | %Recovery* (n=3) | RangeCFU/bottle | Time toDetection(hours) | |||||
| Mean | Range | Mean | Range | ||||||||
| Staphylococcusaureus | 100.0(15/15) | 54 - 150 | 14.6 | 12.9 - 16.7 | 100 | 116 - 150 | 21.8 21.3 -22.0 | ||||
| Escherichia coli | 100.0(15/15) | 73 - 254 | 10.9 | 10.4 - 12.4 | 100 | 73 - 176 | 11.6 10.4 --12.9 | ||||
| Bacteroidesfraqilis | 100.0(18/18) | 9 - 154 | 29.7 | 24.3 - 43.6 | 66.7(2/3) | 19 - 154 | 97.2 79.2 -115.2 | ||||
| Streptococcus | 100.0 | 4 - 260 | 16.5 | 11.5 - 43.8 | 100 | 4 - 25 | 17.5 16.0 - |
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BIOME RIETX
BacT/ALERT® FN Plus Culture Bottle
| pneumoniae | (15/15) | 19.3 | ||||||
|---|---|---|---|---|---|---|---|---|
| Clostridiumperfringens | 100.0(18/18) | 58 - 210 | 17.3 | 12.0 - 40.1 | 100.0(8/8) | 76 - 210 | 27.1 | 14.1 -35.7 |
| Klebsiellapneumoniae | 100.0(15/15) | 89 - 123 | 11.2 | 10.4 - 13.1 | 100 | 95 - 123 | 12.6 | 12.1 -13.4 |
| Fusobacteriumnucleatum | 70.6(12/17) | 19 - 204 | 74.4 | 36.0 -108.0 | 75.0(3/4) | 19 - 116 | 56.1 | 41.2 -64.8 |
| Streptococcusagalactiae | 100.0(15/15) | 14 - 194 | 16.9 | 12.7 - 28.9 | 100 | 21 - 34 | 25.9 | 20.5 -33.4 |
| Enterococcusfaecalis | 100.0(15/15) | 63 - 259 | 13.7 | 11.9 - 19.4 | 100 | 71 - 169 | 22.4 | 17.8 -24.8 |
| Parvimonasmicra | 80.0(16/20) | 46 - 154 | 51.4 | 37.3 - 69.6 | 0.0 (0/4) | 46 - 154 | - | |
| Enterobactercloacae | 100.0(15/15) | 111 - 200 | 11.9 | 11.1 - 12.5 | 100 | 111 - 185 | 13 | 11.9 -14.7 |
| Proteus mirabilis | 100.0(15/15) | 36 - 213 | 11.4 | 10.9 - 12.5 | 100 | 36 - 213 | 11.9 | 11.5 -12.7 |
| Eggerthellalenta | 86.7(13/15) | 83 - 175 | 41 | 34.8 - 60.0 | 66.7(2/3) | 83 - 151 | 46 | 44.0 -48.0 |
| Staphylococcusepidermidis | 100.0(15/15) | 44 - 135 | 21 | 17.4 - 25.3 | 100 | 44 - 105 | 29.3 | 24.5 -36.8 |
| Listeriamonocytogenes | 100.0(15/15) | 121 - 251 | 17.1 | 15.5 - 19.3 | 100 | 121 - 251 | 19.2 | 17.7 -20.3 |
| Clostridiumtertium | 100.0(15/15) | 24 | 12.5 | 11.4 - 13.5 | 100 | 24 | 14.8 | 14.1 -16.0 |
| Clostridiumsepticum | 50.0(20/40) | 25 - 146 | 31.7 | 13.9 - 62.4 | 40.0(2/5) | 90 - 146 | 43.4 | 17.1 -69.6 |
| Peptoniphilusasaccharolyticus | 60.0(12/20) | 49 - 296 | 50.9 | 34.4 - 79.2 | 25.0(1/4) | 81 - 296 | 44.7 |
Less than 100% detection was observed for some species, to include Capnocytophaga ochracea, Cardiobacterium hominis, Haemophilus parainfluenzae, and Granulicatella adiacens.
*In case of less than 100% recovery, it is recommended to add blood such as sterile defibrinated horse blood (10% v/v) 3
Antimicrobial Neutralization
Neutralization of antimicrobials by adsorbent polymeric beads varies depending upon dosage level and timing of specimen collection. Internal studies have demonstrated that antimicrobials are effectively neutralized by the BacT/ALERT FN Plus medium based on 100% recovery of organisms tested. In these tests,
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BIOMÉRIEUX
antimicrobials were added in clinically relevant concentrations directly to culture bottles during inoculation with susceptible strains of obligate and facultative anaerobic microorganisms. The effectiveness of the antimicrobials was confirmed by parallel testing using a non-neutralizing medium as a control. Studies demonstrated that the following antimicrobials/antimicrobial categories were neutralized by the medium: imipenem, oxacillin, glycylcycline, ceftaroline, aminoglycosides, fluoroquinolones, macrolides. cefoxitin, a lincosamides, ketolides, and glycopeptides.
Antimicrobial neutralization was not achieved for ceftazidime, ceftriaxone, or cefepime.
Less than complete neutralization was observed for cefotaxime, cefazolin, ampicillin, penicillin, and ertapenem. Cefotaxime was neutralized at ranges of 40% peak serum level (PSL) to 3% PSL depending on the microorganism. Cefazolin was neutralized at ranges of 25% PSL to 5% PSL depending on the microorganism. Ertapenem was neutralized at 5% PSL. Ampicillin was neutralized at 75% PSL for. E. faecalis. Penicillin was neutralized at 120% PSL for S. pneumoniae. No neutralization was observed for C. perfringens at 100% PSL of either ampicillin or penicillin.
Potentially Interfering Substances .
In-house seeded studies were conducted with cerebrospinal fluid, pleural fluid, synovial fluid, plasma, blood, and blood clots, Aliquots of each of these fluids also received white blood cells at concentrations relevant to bacteremia in each given body fluid. White blood cells and blood clots were added because sepsis can lead to elevation of white blood cells and activation of the coaqulation cascade. Testing was conducted with and without microorganisms. These substances neither interfered with recovery and detection of organisms, nor did they generate false positive results in the absence of organisms.
Limit of Detection (LoD)
Data in Table 3 shows results from in-house seeded studies. A minimum of 30. replicates were tested per species. Data in Table 3 was generated using bottles at end of shelf life. Bottles inoculated with B. fragilis and S. pneumoniae received 1 ml pooled human blood supplementation. At least 95% detection was achieved at LoD.
Table 3 Summary of LoD Data
| Microorganism------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | Strain ID | LoD (CFU/bottle) |
|---|---|---|
| ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ----------- | ------------------ |
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| Bacteroides fragilis | ATCC 25285 | 5 |
|---|---|---|
| Clostridium perfringens | NCTC 8798 | 4 |
| Enterobacter aerogenes | ATCC 13048 | 8 |
| Enterococcus faecalis | NCTC 12697 | 4 |
| Escherichia coli | NCTC 12923 | 4 |
| Listeria monocytogenes | ATCC 15313 | 6 |
| Salmonella enterica | ATCC 14028 | 5 |
| Staphylococcus aureus | NCTC 10788 | 4 |
| Streptococcus pneumoniae | ATCC 6305 | 6 |
Within Laboratory Precision (Repeatability)
Data represents results from in-house seeded studies conducted on 12 days on multiple instruments by multiple operators. Organisms were grown in the presence of clinically relevant concentrations of antimicrobials to which they are susceptible. In this seeded study BacT/ALERT FN Plus bottles were subcultured at least 24 hours after being flagged positive by the instrument. A minimum of 108 replicates were tested for each organism/antimicrobial combination.
| Sample Input | CFU/bottle(range) | % Recovery | Time toDetection(hours) | |||||
|---|---|---|---|---|---|---|---|---|
| Organism | Antimicrobial | Lot 1 | Lot 2 | Lot 3 | Overall | Mean | Range | |
| B. fragilis | Imipenem | 136 - 406 | 100.0 | 100.0 | 100.0 | 100.0 | 36.9 | 30.2 -55.2 |
| C. perfringens | Vancomycin | 75 - 204 | 100.0 | 94.4 | 100.0 | 98.2 | 14.5 | 11.1 -22.0 |
| S. aureus | Oxacillin | 94 - 158 | 100.0 | 100.0 | 100.0 | 100.0 | 17.7 | 15.1 -24.3 |
Table 4 Summary of the Within-Laboratory Precision Data
Reproducibility
Data represents results from seeded studies conducted at three sites using a target of 144 replicates per site on 3 days with a minimum of two operators per site. Reproducibility was evaluated on each of 8 organisms. One organism (S. pneumoniae) was prepared via serial dilution and the other 7 organisms were prepared using BioBalls. S. pneumoniae was seeded into the FN Plus bottle at a target inoculum of 100 CFU/bottle, with an acceptable range of 30-300 CFU/bottle and the other 7 organisms at a target range of 1-17 CFU/bottle. The actual inoculum ranged from 5 CFU/bottle to 500 CFU/bottle for the 30-300
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Image /page/6/Picture/1 description: The image shows the logo for bioMerieux. The logo consists of the word "BIOMERIEUX" in a sans-serif font. Above the text is a circular symbol with a vertical line through it. A thin vertical line connects the symbol to the text.
CFU/bottle range, and from 1 CFU/bottle to 270 CFU/bottle for the 1-17 CFU/bottle range. Percent recovery reflects positive flag by the instrument and . Gram stain/subculture consistent with the seeded organism.
| Sample Input | % Agreement to Expected* | Time toDetection | InoculumRange | ||||
|---|---|---|---|---|---|---|---|
| Site 1 | Site 2 | Site 3 | Overall | Mean | Range | (CFU/bottle) | |
| Staphylococcusaureus | 96.3%(26/27) | 79.2%(19/24) | 100.0%(33/33) | 92.9%(78/84) | 20.2 | 18.5-35.7 | 2-12 |
| Escherichia coli | 100.0%(18/18) | 79.2%(19/24) | 100.0%(33/33) | 93.3%(70/75) | 12.8 | 11.4-20.8 | 2-11 |
| Enterococcusfaecalis | 100.0%(30/30) | 83.3%(20/24) | 97.0%(32/33) | 94.3%(82/87) | 24.6 | 17.9-30.4 | 2-15 |
| Clostridiumperfringens | 100.0%(18/18) | 96.8%(61/63) | 100.0%(30/30) | 98.2%(109/111) | 12.2 | 10.2-17.3 | 3-122 |
| Enterobacteraerogenes | 90.0%(27/30) | 75.0%(18/24) | 90.5%(38/42) | 86.5%(83/96) | 14.6 | 11.9-16.7 | 1-270 |
| Listeriamonocytogenes | 100.0%(21/21) | 100.0%(24/24) | 100.0%(33/33) | 100.0%(78/78) | 22.8 | 20.6-37.0 | 1-13 |
| Salmonellaenterica | 100.0%(24/24) | 79.2%(19/24) | 100.0%(30/30) | 93.6%(73/78) | 13.3 | 12.4-14.4 | 1-16 |
| Streptococcuspneumoniae | 100.0%(30/30) | 100.0%(36/36) | 100.0%(18/18) | 100.0%(84/84) | 17.5 | 13.3-23.1 | 5-500 |
| Overall | 98.0%(194/198) | 88.9%(216/243) | 98.0%(247/252) | 94.8%(657/693) | |||
| 95% CI:94.9%,99.5% | 95% CI:84.3%,92.6% | 95% CI:95.4%,99.4% | 95% CI:92.9%,96.3% |
Table 5 Summary of Reproducibility Data
The above data includes repeat testing performed as a result of laboratory errors at a single site (i.e. contaminated bottles/reagents, colony counts out of range and site failure to change bottle status after positive instrument signal and positive subculture). Data excluding the laboratory errors, demonstrated 100% recovery with the exception of E. aerogenes which exhibited 96.3% recovery for all sites combined.
Delayed Entry
Results from seeded studies using 6 species*, at target concentrations of 100 CFU/bottle (acceptable range of 30-300 CFU/bottle) were generated at three sites. Actual inoculum levels ranged from 41 CFU/bottle to 253 CFU/bottle. All bottles contained human blood from healthy volunteers and were held at specified temperatures and times prior to loading into the BacT/ALERT instrument. Percent recovery reflects positive flag by the instrument and Gram stain/subculture consistent with the seeded organism.
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Table 6 Summary of Delayed Entry Data
| SampleInput | IncubationTemperature(°C) | Hold Time(hours) | % Recovery | Time to Detection from SampleInoculation(Hold Time + Instrument TTD inhours) | |
|---|---|---|---|---|---|
| Control | No delay | 100.0%(89/89) | Mean | Range | |
| 2-8 | 48 | 100.0%(65/65) | 63.3 | 50.1 - 90.4 | |
| InoculatedTestBottles | 20-25 | 24 | 100.0%(62/62) | 34.7 | 26.0 - 79.2 |
| 20-25 | 36 | 100.0%(62/62) | 43.6 | 38.0 - 78.6 | |
| 35-37 | 8 | 100.0%(72/72) | 17.7 | 10.0 - 53.4 | |
| 35-37 | 24 | 80.0%(64/80) | 28.6 | 26.0 - 52.3 | |
| NegativeControls | All conditions | 0.0%(0/51) | - | - |
- Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Enterococus faecium, Bacteroides fragilis, Clostridium perfringens
CAUTION: Culture bottles held at 35 to 37°C for 24 hours or longer before loading may not detect microorganisms and should be subcultured.
Clinical Study Results (Blood Culture)
A multi-center clinical study was conducted at three different geographic sites in the U.S. comparing performance of the FN Plus and FN blood culture bottles for anaerobic culture pairs that received blood volumes between 6 ml and 10 ml (compliant pairs). A total of 2514 anaerobic bottle pairs were obtained from 1080 adult patients suspected of blood stream bacterial/yeast infections. Subcultures of both bottles were performed for any bottle in the set determined to be positive by the BacT/ALERT system. A pair of bottles was determined to have a positive status if subculture of either the FN Plus or FN bottle was positive. A culture 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
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of this bottle. True positive rates were calculated for the FN Plus and FN culture bottles and the ratio of FN Plus true positives to FN true positives was calculated to compare performance. Clinical Isolates recovered were classified as significant, contaminant, or unknown based on determination by the clinical trial sites.
A total of 312 isolates were recovered from all compliant anaerobic blood culture pairs with a positive status. There were a total of 289 bottle pairs that recovered at least 1 isolate by subculture of FN Plus or FN bottles. A total of 266 bottle pairs recovered a single isolate and 23 bottle pairs recovered two isolates. The total population reported in Table 7 comprises the 312 isolates recovered from positive bottle pairs and 2225 negative bottle pairs for a total of 2537 results. The FN Plus bottle detected a total of 282 isolates compared to the FN bottle that detected 192 isolates. Of the significant isolates, the FN Plus bottle detected a total of 202 isolates compared to the FN bottle that detected 150 significant isolates. Three false positives were identified on subculture of positive FN Plus bottles and comprised 0:12% (3/2537) of the study population.
| ClinicalDetermination | FN Plus TruePositives | % of FN Plus TruePositives inPopulation | FN TruePositives | % of FN TruePositives inPopulation | Ratio ofTruePositives |
|---|---|---|---|---|---|
| Significant | 202 | 8.0% (202/2514) | 150 | 6.0% (150/2514) | 1.347 |
| Contaminant | 58 | 2.3% (58/2514) | 30 | 1.2% (30/2514) | 1.933 |
| Unknown | 22 | 0.9% (22/2514) | 12 | 0.5%(12/2514) | 1.833 |
| Total | 282 | 11.2% (282/2514) | 192 | 7.6% (192/2514) | 1.469 |
Table 7 All Compliant Pairs With Single and Multiple Isolates Combined (Blood Cultures)
One hundred sixty two (162) isolates were detected by both FN Plus and FN. 120 isolates were detected only by FN Plus and 30 isolates were detected only by FN. *The ratio of true positive rates for overall isolates was 1.469 (282/192) with a 95% Cl of (1.317, 1.621)'
Clinical Study Results - (Sterile Body Fluid Cultures)
A multi-center clinical study was conducted at four different geographic sites in the U.S. and Canada comparing the performance of the FN Plus and FN culture bottles with sterile body fluid specimens (SBF). A total of 339 bottle pairs were obtained from 310 adult patients suspected of SBF bacterial/yeast infections. Sterile body fluid types evaluated were amniotic fluid, continuous ambulatory peritoneal dialysis (CAPD) fluid, cerebrospinal fluid (CSF), peritoneal fluid, pleural fluid, and synovial fluid. Clinical Isolates recovered were classified as significant, contaminant, or unknown based on determination by the clinical trial sites.
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Image /page/9/Picture/1 description: The image shows the logo for bioMérieux. The logo consists of the word "BIOMÉRIEUX" in a sans-serif font. Above the text is a circular graphic that is divided into two halves, one black and one white. A thin line extends from the bottom of the circle down between the "É" and "R" in the company name.
A total of 77 isolates were recovered from all anaerobic SBF culture pairs with a positive status. There were a total of 61 bottle pairs that recovered at least 1 isolate by subculture of FN Plus or FN bottles. A total of 50 bottle pairs recovered a single isolate, 7 bottle pairs recovered two isolates, 3 bottle pairs recovered 3 isolates, and 1 bottle pair recovered 4 isolates. The total population reported in Table 8 comprises the 77 isolates recovered from positive bottle pairs and 278 negative bottle pairs for a total of 355 results. The FN Plus bottle detected a total of 72 isolates compared to the FN bottle that detected 59 isolates. Of the significant isolates, the FN Plus bottle detected a total of 52 isolates compared to the FN bottle that detected 50 isolates. No false positives were identified for the FN Plus bottle from the study population (0/355).
Table 8 below compares results of the BacT/ALERT FN Plus to BacT/ALERT FN SBF cultures that yielded single or multiple isolates on subculture.
| ClinicalDetermination | FN PlusTruePositives | % of FN TruePositives inPopulation | FN TruePositives | % of FN TruePositives inPopulation | Ratio of TruePositives |
|---|---|---|---|---|---|
| Significant | 52 | 15.3% (52/339) | 50 | 14.7% (50/339) | 1.040 |
| Contaminant | 12 | 3.5% (12/339) | 2 | 0.6% (2/339) | 6.000 |
| Unknown | 8 | 2.5% (8/339) | 7 | 2.1% (7/339) | 1.143 |
| Total | 72 | 21.2% (72/339) | 59 | 17.4% (59/339) | 1.220 |
Table 8 All Pairs With Single and Multiple Isolates Combined (Sterile Body Fluid Cultures)
Fifty four (54) isolates were detected by both FN Plus and FN. 18 isolates were detected only by FN Plus and 5 isolates were detected only by FN. The ratio of true positive rates for overall isolates was 1.220 (72/59) with a 95% CI of (1.044, 1.396)
Proposed Labeling
The proposed labeling is complete.
Conclusion:
The information in the premarket notification is complete and supports a substantial equivalence decision.
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DEPARTMENT OF HEALTH & HUMAN SERVICES
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Public Health Service
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-002
JAN 2 5 2013
bioMerieux. Inc. c/o Patricia (Trish) Murphy Staff Regulatory Affairs Specialist 100 Rodolphe Street Durham, NC 27712
Re: K121455
Trade/Device Name: BacT/ALERT® FN Plus Culture Bottle Regulation Number: 21 CFR 866.2560 Regulation Name: Microbial Growth Monitor Regulatory Class: Class I Product Code: MDB Dated: January 11, 2013 Received: January 14, 2013
Dear Ms. Murphy:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set
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Page 2 - Ms. Murphy
forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
If you desire specific advice for your device on our labeling regulation (21 CFR Parts 801 and 809), please contact the Office of In Vitro Diagnostics and Radiological Health at (301) 796-5450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.
Sincerely yours,
Sally A. Hojvat
Sally A. Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
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INTENDED USE STATEMENT
510(k) Number (if known): K121455
Device Name: BacT/ALERT® FN Plus Culture Bottles
Intended Use:
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.
Prescription Use X (Part 21 CFR 801 Subpart D)
AND/OR
Over-The-Counter Use (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE OF NEEDED)
Concurrence of CDRH, Office of Device Evaluation (ODE)
Sabara
Division Sign-Off
Page 1 of 1
Office of In Vitro Diagnostics and Radiological Health
K1 21455
510(k)
§ 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.