ETEST Piperacillin/Tazobactam (P/T) (0.016/4-256/4 ug/mL)

K190154 · Biomerieux S.A. · JWY · May 1, 2019 · Microbiology

Device Facts

• Record ID: K190154
• Device Name: ETEST Piperacillin/Tazobactam (P/T) (0.016/4-256/4 ug/mL)
• Applicant: Biomerieux S.A.
• Product Code: JWY · Microbiology
• Decision Date: May 1, 2019
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.1640
• Device Class: Class 2

Indications for Use

ETEST® is a manual, quantitative technique for determination of antimicrobial susceptibility of non-fastidious Gram-negative and Gram-positive aerobic bacteria and fastidious bacteria. 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 tested on agar media after overnight incubation. Piperacillin/Tazobactam has been shown to be active against the Gram-negative aerobic microorganisms listed below according to the FDA label for this antimicrobial agent. ETEST® P/T can be used to determine the MIC of Piperacillin/Tazobactam against the following microorganisms: Active both in vitro and in clinical infections: Acinetobacter baumannii Escherichia coli Klebsiella pneumoniae Pseudomonas aeruginosa In vitro data are available for the following microorganisms, but clinical significance is unknown: Citrobacter koseri Morganella morganii Proteus mirabilis Proteus vulgaris Serratia marcescens Providencia stuartii Providencia rettgeri Salmonella enterica

Device Story

ETEST® is a thin, inert, non-porous plastic strip with a predefined antibiotic gradient on one side and an MIC reading scale on the other. Used in clinical microbiology laboratories; operated by laboratory technicians. Strip applied to inoculated agar surface; antibiotic gradient transfers into agar, forming a stable, continuous, exponential concentration gradient. After overnight incubation, a symmetrical inhibition ellipse forms around the strip. Technician reads MIC value at the intersection of the ellipse and the strip. Provides quantitative susceptibility data to guide antibiotic therapy decisions; helps clinicians select appropriate antimicrobial treatment for bacterial infections.

Clinical Evidence

Bench testing only. Performance evaluated using 772 clinical and 89 challenge isolates across four sites. Compared to CLSI broth microdilution reference method. Combined results for Enterobacteriaceae: 95.8% Essential Agreement (EA), 93.3% Category Agreement (CA). A. baumannii: 91.6% EA, 89.2% CA. P. aeruginosa: 98.3% EA, 93.3% CA. Trending analysis identified significant MIC shifts for several species, addressed via labeling footnotes. Quality control testing met acceptance criteria.

Technological Characteristics

Manual, quantitative antimicrobial susceptibility test system. Consists of a thin, inert, nonporous plastic strip with a predefined exponential gradient of dried/stabilized antibiotic (Piperacillin/Tazobactam 0.016/4 - 256/4 μg/mL). Principle: dilution and diffusion on agar media. Incubation: 35° ± 2°C for 16-20 hours. Manual reading of MIC at inhibition ellipse intersection. No software or electronic components.

Indications for Use

Indicated for determination of antimicrobial susceptibility of non-fastidious Gram-negative and Gram-positive aerobic bacteria and fastidious bacteria. Specifically indicated for Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Citrobacter koseri, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Providencia stuartii, Providencia rettgeri, and Salmonella enterica. Prescription use only.

Regulatory Classification

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.

Predicate Devices

• ETEST® Ceftazidime/Avibactam (CZA) (K172150)

Submission Summary (Full Text)

{0}

# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

A. 510(k) Number:
K190154

B. Purpose for Submission:
To obtain a substantial equivalence determination for Piperacillin/Tazobactam at concentrations of 0.016/4 - 256/4 µg/mL for susceptibility testing of Gram-negative aerobic organisms with ETEST.

C. Measurand:
Piperacillin/Tazobactam 0.016/4 - 256/4 µg/mL

D. Type of Test:
Quantitative Antimicrobial Susceptibility Test growth-based detection

E. Applicant:
bioMérieux, Inc.

F. Proprietary and Established Names:
ETEST Piperacillin/Tazobactam (P/T) (0.016/4 - 256/4 µg/mL)

G. Regulatory Information:
1. Regulation section:
866.1640 Antimicrobial Susceptibility Test Powder
2. Classification:
II
3. Product code:
JWY - Manual Antimicrobial Susceptibility Test Systems
4. Panel:
83 – Microbiology (83)

{1}

H. Intended Use:

1. Intended use(s):

ETEST is a manual, quantitative technique for determination of antimicrobial susceptibility of non-fastidious Gram-negative and Gram-positive aerobic bacteria and fastidious bacteria. The system comprises a predefined antibiotic gradient which is used to determine the Minimum Inhibitory Concentration (MIC, in $\mu\mathrm{g}/\mathrm{mL}$) of different antimicrobial agents against microorganisms tested on agar media after overnight incubation.

Piperacillin/Tazobactam has been shown to be active against the Gram-negative aerobic microorganisms listed below according to the FDA label for this antimicrobial agent.

ETEST P/T can be used to determine the MIC of Piperacillin/Tazobactam against the following microorganisms:

Active both *in vitro* and in clinical infections:
- Acinetobacter baumannii
- Escherichia coli
- Klebsiella pneumoniae
- Pseudomonas aeruginosa

*In vitro* data are available for the following microorganisms, but clinical significance is unknown:
- Citrobacter koseri
- Morganella morganii
- Proteus mirabilis
- Proteus vulgaris
- Serratia marcescens
- Providencia stuartii
- Providencia rettgeri
- Salmonella enterica

2. Indication(s) for use:

Same as Intended Use

3. Special conditions for use statement(s):

For prescription use

The following limitations are included in the labeling:

- The ability of ETEST Piperacillin/Tazobactam to detect the following resistant Enterobacteriaceae isolates is unknown because resistant isolates were either not

{2}

available or an insufficient number was encountered at the time of comparative testing: Proteus mirabilis, Proteus vulgaris and Salmonella enterica.

4. Special instrument requirements:

Manual reading only

I. Device Description:

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 has the minimum inhibitory concentration (MIC) reading scale expressed in $\mu \mathrm{g} / \mathrm{mL}$. The other side of the strip contains a predefined continuous exponential gradient of antibiotic concentrations.

When the strip is applied to an inoculated agar surface, the preformed antibiotic gradient immediately transfers into the agar matrix, then forming a stable, continuous and exponential gradient of antibiotic concentrations directly underneath the strip. Bacterial growth becomes visible during incubation, and a symmetrical inhibition ellipse centered along the strip appears. The MIC value is read from the scale in terms of $\mu \mathrm{g} / \mathrm{mL}$ at complete inhibition of bacterial growth, where the pointed end of the ellipse intersects the strip.

ETEST Piperacillin/Tazobactam contains a range of piperacillin from 0.016 to $256~\mu \mathrm{g / mL}$, overlaid with a fixed concentration of $4\mu \mathrm{g} / \mathrm{mL}$ of tazobactam.

J. Substantial Equivalence Information:

1. Predicate device name(s):

ETEST Ceftazidime/Avibactam 0.016-256 $\mu \mathrm{g / mL}$

2. Predicate $510(\mathbf{k})$ number(s):

K172150

3. Comparison with predicate:

{3}

Table 1: Comparison with the Predicate Device

| Item | Device ETEST, Piperacillin/Tazobactam (K190154) | Predicate ETEST, Ceftazidime/Avibactam (K172150) |
| --- | --- | --- |
| Similarities | | |
| Intended Use | ETEST is a manual, quantitative technique for determination of antimicrobial susceptibility of non-fastidious Gram-negative and Gram-positive aerobic bacteria and fastidious bacteria. The system comprises a predefined antibiotic gradient which is used to determine the Minimum Inhibitory Concentration (MIC, in μg/mL) of different antimicrobial agents against microorganisms tested on agar media after overnight incubation. | Same |
| Test Design | Predefined exponential gradient of the dried and stabilized antibiotic covers a continuous concentration range across 15 two-fold dilutions of a conventional MIC method | Same |
| Antimicrobial Concentration Range | 0.016/4 – 256/4 μg/mL | Same |
| Inoculation | Isolated colonies from culture | Same |
| Incubation | 35° ± 2°C for 16 – 20 hours | Same |
| Result | MIC in μg/mL | Same |
| Differences | | |
| Claimed Organisms | Acinetobacter baumanniiCitrobacter koseriEscherichia coliKlebsiella pneumoniaeMorganella morganiiProteus mirabilisProteus vulgarisProvidencia stuartiiProvidencia rettgeriPseudomonas aeruginosaSalmonella entericaSerratia marcescens | Citrobacter freundiiCitrobacter koseriEnterobacter aerogenesEnterobacter cloacaeEscherichia coliKlebsiella oxytocaKlebsiella pneumoniaeMorganella morganiiProteus mirabilisProvidencia rettgeriProvidencia stuartiiPseudomonas aeruginosaSerratia marcescens |
| Antibiotic | Piperacillin/Tazobactam | Ceftazidime/Avibactam |

{4}

K. Standard/Guidance Document Referenced (if applicable):

- Guidance for Industry and FDA - Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems – August 28, 2009.
- CLSI M02-A12, Performance Standards for Antimicrobial Disk Susceptibility Test; Approved Standard, January 2015.
- CLSI M07-A11 “Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard, Eleventh Edition January 2018”.
- CLSI M100-Ed28 “Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Eighth Informational Supplement, January 2018”.

L. Test Principle:

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 $\mu \mathrm{g} / \mathrm{mL}$. The other side of the strip contains a predefined continuous gradient of antibiotic concentrations.

When the strip is applied to an inoculated agar surface, the preformed antibiotic gradient immediately transfers into the agar matrix, then forming a stable, continuous and exponential gradient of antibiotic concentrations directly underneath the strip. Bacteria growth becomes visible during incubation, and a symmetrical inhibition ellipse centered along the strip appears. After incubation, the MIC value is read from the scale in terms of $\mu \mathrm{g} / \mathrm{mL}$ at complete inhibition of bacterial growth, where the pointed end of the ellipse intersects the strip. Since ETEST generates MIC values which fall between two-fold dilutions for interpretation, the MIC value read must be recorded to the next two-fold dilution.

The MIC gradient on ETEST Piperacillin/Tazobactam ranges from $0.016 / 4$ to $256 / 4~\mu \mathrm{g / mL}$.

M. Performance Characteristics (if/when applicable):

1. Analytical performance:

a. Precision/Reproducibility:

Reproducibility testing was conducted at three sites over three days using a Gram-negative panel that included two *A. baumannii*, three *E. coli*, two *K. pneumoniae*, one *M. morganii* and two *P. aeruginosa* isolates. The mode of MIC values was determined for each isolate and the reproducibility was calculated based on the number of MIC values that fell within $\pm 1$ doubling dilution of the mode.

The reproducibility results were acceptable at $100\%$.

b. Linearity/assay reportable range:

Not applicable

{5}

c. Traceability, Stability, Expected values (controls, calibrators, or methods):

Inoculum Density Check. Inoculum density checks were performed for all quality control and reproducibility organism suspensions and for $10\%$ of the suspensions prepared for susceptibility testing of the fresh (contemporary) clinical isolates.

The overall mean inoculum densities (CFU/mL) for isolates tested with the reference method ranged from $3.84 \times 10^{5}$ to $5.84 \times 10^{5}$ . The overall mean inoculum densities for isolates tested with the ETEST ranged from $5.4 \times 10^{7}$ to $1.71 \times 10^{8}$ .

The inoculum densities were acceptable.

Purity Check. Verification of isolate purity was conducted on all clinical, challenge and reproducibility organism suspensions for each ETEST and from each growth control well of the broth microdilution (BMD) reference panel.

Growth or Device Failure. No device failures occurred in the ETEST Piperacillin/Tazobactam clinical trial.

Quality Control (QC) Testing. The FDA and CLSI recommended QC strains (E. coli ATCC 25922, E. coli ATCC 35218, P. aeruginosa ATCC 27853, and K. pneumoniae ATCC 700603) were tested at least 20 times per site at four sites using both ETEST and BMD reference methods. The results are summarized in Table 2.

Table 2: ETEST Piperacillin/Tazobactam QC Results

| QC Organism | Piperacillin/Tazobactam Expected Range | Piperacillin Concentration (μg/mL)a | Reference (BMD) | ETEST |
| --- | --- | --- | --- | --- |
| E. coliATCC 25922 | 1/4 – 4/4 μg/mL | <1 | 0 | 0 |
| | | 1 | 2 | 0 |
| | | 2 | 79 | 79 |
| | | 4 | 4 | 6 |
| | | >4 | 0 | 0 |
| E. coliATCC 35218 | 0.5/4 – 2/4 μg/mL | <0.5 | 0 | 0 |
| | | 0.5 | 1 | 0 |
| | | 1 | 78 | 20 |
| | | 2 | 6 | 65 |
| | | >2 | 0 | 0 |

{6}

| QC Organism | Piperacillin/Tazobactam Expected Range | Piperacillin Concentration (μg/mL)^{a} | Reference (BMD) | ETEST |
| --- | --- | --- | --- | --- |
| P. aeruginosa ATCC 27853 | 1/4 – 8/4 μg/mL | <1 | 0 | 0 |
| | | 1 | 0 | 0 |
| | | 2 | 13 | 6 |
| | | 4 | 63 | 79 |
| | | 8 | 9 | 0 |
| | | >8 | 0 | 0 |
| K. pneumoniae ATCC 700603 | 8/4 – 32/4 μg/mL | <8 | 0 | 0 |
| | | 8 | 36 | 0 |
| | | 16 | 49 | 85 |
| | | 32 | 0 | 0 |
| | | >32 | 0 | 0 |

aTazobactam concentration was fixed at 4 μg/mL.

The Quality Control results were within the recommended range 100% of the time and thus acceptable.

Supplemental Quality Control Testing. To ensure the integrity of the plasmids encoding antimicrobial resistance (AR) in the quality control strains Escherichia coli ATCC 35218 and Klebsiella pneumoniae ATCC 700603, supplemental testing was conducted at four sites. The β-lactamase negative E. coli ATCC 25922 was also tested. Per the CLSI M100 standard, QC strains were evaluated by disk diffusion method by testing ampicillin (10 μg) and ceftazidime (30 μg) disks. Results are shown below in Tables 3 and 4.

Table 3: Supplemental QC Results - Ampicillin

| QC Organism (AR mechanism) | Ampicillin (10 μg) Expected Range | Zone Size (mm) | Disk Results |
| --- | --- | --- | --- |
| E. coli ATCC 25922 (β-lactamase negative) | 15 – 22 mm | <15 | 0 |
| | | 15 | 9 |
| | | 16 | 16 |
| | | 17 | 14 |
| | | 18 | 17 |
| | | 19 | 23 |
| | | 20 | 6 |
| | | 21 | 0 |
| | | 22 | 0 |
| | | >22 | 0 |
| E. coli ATCC 35218 (TEM-1) | 6 mm | <5 | 0 |
| | | 6 | 84 |
| | | >7 | 0 |

{7}

Table 4: Supplemental QC Results - Ceftazidime

| QC Organism (AR mechanism) | Ceftazidime (30 μg) Expected Range | Zone Size (mm) | Disk Results |
| --- | --- | --- | --- |
| E. coli ATCC 25922 (β-lactamase negative) | 25 – 32 mm | <25 | 0 |
| | | 25 | 0 |
| | | 26 | 2 |
| | | 27 | 7 |
| | | 28 | 5 |
| | | 29 | 6 |
| | | 30 | 23 |
| | | 31 | 23 |
| | | 32 | 19 |
| | | >32 | 0 |
| K. pneumoniae ATCC 700603 (SHV-18, OXA-2, mutations in OmpK35 and OmpK37, TEM-1) | 10 – 18 mm | <10 | 0 |
| | | 10 | 0 |
| | | 11 | 0 |
| | | 12 | 0 |
| | | 13 | 4 |
| | | 14 | 25 |
| | | 15 | 39 |
| | | 16 | 16 |
| | | 17 | 0 |
| | | 18 | 0 |
| | | >18 | 0 |
| P. aeruginosa ATCC 27853 (Inducible AmpC) | 22 – 29 mm | <22 | 0 |
| | | 22 | 0 |
| | | 23 | 0 |
| | | 24 | 0 |
| | | 25 | 0 |
| | | 26 | 6 |
| | | 27 | 12 |
| | | 28 | 27 |
| | | 29 | 40 |
| | | >29 | 0 |

Test results demonstrated AR plasmid integrity of the QC isolates with $100\%$ (85/85) of the results within expected range.

d. Detection limit:

Not applicable

e. Analytical specificity:

Not applicable

{8}

f. Assay cut-off:

Not applicable

2. Comparison studies:

a. Method comparison with predicate device:

Results obtained with ETEST Piperacillin/Tazobactam were compared to results obtained with the CLSI broth microdilution (BMD) reference panel. The reference panel, prepared and interpreted according to recommendations outlined in the CLSI M07-A10, contained two-fold serial dilutions of piperacillin/tazobactam with a piperacillin concentration range of $0.016 - 256\ \mu\mathrm{g/mL}$ (tazobactam concentration fixed at $4\ \mu\mathrm{g/mL}$). At the end of incubation, the MIC value obtained from the ETEST (where the complete inhibition of growth intersects the strip) was compared to MIC results obtained with the reference method. The testing conditions for ETEST consisted of the following:

- Inoculum: Direct colony suspension to achieve a suspension equivalent to a 0.5 McFarland standard suspension
- Medium: Cation-adjusted Mueller Hinton agar
- Incubation: $35^{\circ}\mathrm{C} \pm 2$ for 16-20 hours (except *A. baumannii*, incubate at $35^{\circ}\mathrm{C}$ for 20-24 hours)

Clinical testing for ETEST Piperacillin/Tazobactam was evaluated at three external sites within the United States and one internal site located outside the United States. Each clinical isolate was tested one time by ETEST and BMD using the same initial standardized suspension. A total of 772 clinical isolates were tested which included 592 *Enterobacteriaceae* [C. koseri (41), E. coli (140), K. pneumoniae (167), M. morganii (39), P. mirabilis (38), P. vulgaris (31), P. rettgeri (28), P. stuartii (36), S. enterica (31) and S. marcescens (41)], 74 *A. baumannii* and 106 *P. aeruginosa* isolates. Of all of the tested clinical isolates, $49.2\%$ were considered contemporary (i.e., tested within six months of the organism’s original isolation from clinical culture) and $50.8\%$ were considered stock (i.e., no time limit on time from isolation prior to testing).

Challenge testing was performed at one internal site using ETEST and BMD. A total of 89 challenge isolates were tested which included 67 *Enterobacteriaceae* [C. koseri (5), E. coli (28), K. pneumoniae (23), M. morganii (2), P. mirabilis (3), S. marcescens (6)], 9 *A. baumannii* and 13 *P. aeruginosa* isolates.

The comparative study (both clinical and challenge) included 659 *Enterobacteriaceae* isolates [C. koseri (46), E. coli (168), K. pneumoniae (190), M. morganii (41), P. mirabilis (41), P. vulgaris (31), P. rettgeri (28), P. stuartii (36), S. enterica (31) and S. marcescens (47)]. Information on the numbers of each *Enterobacteriaceae* species is included as a footnote to the performance table in the labeling.

{9}

ETEST Piperacillin/Tazobactam performance observed for clinical, challenge and combined isolates is provided in Table 5.

Table 5: Performance of Clinical and Challenge Isolates

| Piperacillin/Tazobactam | Total | EA N | EA % | Eval. Total | Eval. EA N | Eval. EA % | CA N | CA % | #R | min | maj | vmj |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Enterobacteriaceae (all) | | | | | | | | | | | | |
| Clinical | 592 | 571 | 96.5 | 477 | 456 | 95.6 | 566 | 95.6 | 131 | 24 | 0 | 2 |
| Challenge | 67 | 60 | 89.6 | 57 | 50 | 87.7 | 49 | 73.1 | 16 | 18 | 0 | 0 |
| Combined | 659 | 631 | 95.8 | 534 | 506 | 94.8 | 615 | 93.3 | 147 | 42 | 0 | 2 |
| A. baumannii | | | | | | | | | | | | |
| Clinical | 74 | 68 | 91.9 | 49 | 43 | 87.8 | 66 | 89.2 | 26 | 8 | 0 | 0 |
| Challenge | 9 | 8 | 88.9 | 3 | 2 | 66.7 | 8 | 88.9 | 6 | 1 | 0 | 0 |
| Combined | 83 | 76 | 91.6 | 52 | 45 | 86.5 | 74 | 89.2 | 32 | 9 | 0 | 0 |
| P. aeruginosa | | | | | | | | | | | | |
| Clinical | 106 | 104 | 98.1 | 91 | 89 | 97.8 | 101 | 95.3 | 16 | 5 | 0 | 0 |
| Challenge | 13 | 13 | 100 | 12 | 12 | 100 | 10 | 76.9 | 1 | 3 | 0 | 0 |
| Combined | 119 | 117 | 98.3 | 103 | 101 | 98.1 | 111 | 93.3 | 17 | 8 | 0 | 0 |

EA - Essential Agreement

CA - Category Agreement

EVAL - Evaluable isolates

R - Resistant isolates

min - minor errors

maj - major errors

vmj - very major errors

Essential Agreement (EA) is when the ETEST result agrees exactly or within one doubling dilution of the reference broth microdilution result. Category Agreement (CA) is when the ETEST result interpretation agrees exactly with the reference broth microdilution result interpretation.

## Overall Performance

ETEST Piperacillin/Tazobactam performance for all Enterobacteriaceae isolates is acceptable with 95.8% EA and 93.3% CA. There were 42 minor errors, no major errors, and two very major errors. When evaluating individual species, however, performance of K. pneumoniae was unacceptable with 88.9% CA (94.2% EA). Since this species also had a very major error rate of 2% (2 VMJ / 99 resistant isolates), the following footnote is included in the performance section of the device labeling:

Categorical errors when testing Klebsiella pneumoniae isolates were mostly due to minor errors (19/190, 10%). Two of 99 resistant isolates gave a very major error. Upon repeat testing, a reference MIC value could not be confidently established for one of the isolates due to extensive variability with the reference method.

ETEST Piperacillin/Tazobactam performance for all A. baumannii isolates is acceptable with 91.6% EA and 89.2% CA. There were nine minor errors and no major or very major errors.

{10}

ETEST Piperacillin/Tazobactam performance for all *P. aeruginosa* is acceptable with 98.3% EA and 93.3% CA. There were eight minor errors and no major or very major errors.

At the time of comparative testing, resistant isolates were not available for several bacterial species. Thus, the following limitation is included in the device labeling:

The ability of ETEST Piperacillin/Tazobactam to detect the following resistant Enterobacteriaceae isolates is unknown because resistant isolates were either not available or an insufficient number was encountered at the time of comparative testing: Proteus mirabilis, Proteus vulgaris and Salmonella enterica.

To address testing of non-indicated species, the sponsor included the following statement in the Warnings and Precautions section of the device labeling:

Per the FDA-Recognized Susceptibility Test Interpretive Criteria website, the safety and efficacy of antimicrobial drugs, for which antimicrobial susceptibility is tested by this AST device, may or may not have been established in adequate and well-controlled clinical trials for treating clinical infections due to microorganisms outside of those found in the indications and usage in the drug label. The clinical significance of susceptibility information in those instances is unknown. The approved labeling for specific antimicrobial drugs provides the uses for which the antimicrobial drug is approved.

## Inoculator and ETEST Strip Applicator Options

Culture media plates for ETEST can be inoculated and streaked by swabs manually or with the RETRO C80 inoculator. ETEST strips can be applied onto inoculated media using forceps or the NEMA C88 vacuum pen.

The ETEST Piperacillin/Tazobactam studies used manual inoculation with swabs and applied ETEST strips with forceps at all test sites. The following footnote is included in the performance section of the device labeling:

Optional inoculator and ETEST strip applicator can be used for plate inoculation and applying ETEST strips onto agar media. In the ETEST Piperacillin/Tazobactam clinical studies, swabs were used for plate inoculation/streaking and forceps were used for ETEST strip application.

## Trending

A trending analysis was conducted using the combined data (clinical and challenge) for each organism species and group. This trending calculation analyzes device MIC values that are determined to be one or more doubling dilutions lower or higher than the reference method. MIC values that are off-scale for both the reference and device are not considered in the trending analysis.

{11}

Trending results were stratified by species to determine if species-related trends were observed (Table 6). Species for which the difference between the percentage of isolates with higher versus lower MIC values was $\geq 30\%$ and for which the confidence interval was determined to be statistically significant were considered to have evidence of significant trending and is addressed in labeling.

A trend toward lower MIC values was observed for $K$ pneumoniae while a trend toward higher MIC values was observed for $A$ baumannii, $M$ morganii, $P$ mirabilis, $P$ rettgeri, $P$ stuartii and $S$ marcescens. The following footnotes are included in the performance section of the device labeling to address the trending:

ETEST Piperacillin/Tazobactam MIC values tended to be in exact agreement or at least one doubling dilution lower when testing Klebsiella pneumoniae compared to the CLSI reference broth microdilution.

ETEST Piperacillin/Tazobactam MIC values tended to be in exact agreement or at least one doubling dilution higher when testing A. baumannii, M. morganii, P. mirabilis, P. rettgeri, P. stuartii and S. marcescens compared to the CLSI reference broth microdilution.

Table 6. Trending by Species (clinical and challenge isolates combined)

| Organism | Total Evaluable for Trending | ≥1 dil. Lower # (%) | Exact # (%) | ≥1 dil. Higher # (%) | Percent Difference (95% CI) | Trending Noted |
| --- | --- | --- | --- | --- | --- | --- |
| C. koseri | 37 | 8 | 26 | 3 | -13.51% | No |
| E. coli | 163 | 28 | 88 | 47 | 11.66% | No |
| K. pneumoniae | 109 | 52 | 42 | 15 | -33.94% (-44.62 to -21.99) | Yes |
| M. morganii | 40 | 1 | 20 | 19 | 45.00% (27.11 to 60.14) | Yes |
| P. mirabilis | 41 | 4 | 15 | 22 | 43.90% (24.26 to 59.36) | Yes |
| P. vulgaris | 31 | 7 | 17 | 7 | 0.00% | No |
| P. rettgeri | 22 | 2 | 6 | 14 | 54.55% (26.64 to 72.42) | Yes |
| P. stuartii | 33 | 3 | 13 | 17 | 42.42% (20.62 to 59.48) | Yes |
| S. enterica | 31 | 3 | 19 | 9 | 19.35% | No |
| S. marcescens | 43 | 5 | 16 | 22 | 39.53% (20.23 to 55.19) | Yes |
| Enterobacteriaceae (all) | 550 | 113 | 262 | 175 | 11.27% | No |
| A. baumannii | 53 | 2 | 20 | 31 | 54.72% (38.59 to 67.27) | Yes |
| P. aeruginosa | 104 | 17 | 60 | 27 | 9.62% | No |

{12}

# Resistance Markers

Resistance markers for indicated isolates were provided in the submission. They consisted of $\beta$ -lactamses including AmpC (CIT, CMY, DHA, FOX), ESBL (CTX-M, SHV, TEM) and carbapenemases (IMP, KPC, NDM, OXA, VIM).

b. Matrix comparison:

Not applicable

3. Clinical studies:

a. Clinical Sensitivity:

Not applicable

b. Clinical specificity:

Not applicable

c. Other clinical supportive data (when a. and b. are not applicable):

Not applicable

4. Clinical cut-off:

Not applicable

5. Expected values/Reference range:

The FDA-recognized susceptibility interpretive criteria for piperacillin/tazobactam are listed in Table 7.

Table 7: FDA Recognized Interpretive Criteria for Piperacillin/Tazobactam $(\mu \mathrm{g} / \mathrm{mL})^{\mathrm{a}}$

| Organism | S | I | R |
| --- | --- | --- | --- |
| Enterobacteriaceae | ≤16/4 | 32/4 - 64/4 | ≥128/4 |
| Pseudomonas aeruginosa | ≤16/4 | 32/4 - 64/4 | ≥128/4 |
| Acinetobacter spp. | ≤16/4 | 32/4 - 64/4 | ≥128/4 |

aAccording to CLSI M100-Ed28 and FDA STIC Website https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm410971.htm

# N. Proposed Labeling:

The labeling supports the finding of substantial equivalence for this device.

{13}

O. Conclusion:

The submitted information in this premarket notification is complete and supports a finding of substantial equivalence.