The fluoroquinolones enrofloxacin (Baytril) and marbofloxacin (Zeniquin) were approved for use in dogs by the US Food and Drug Administration (FDA) in December 1988, and June 1999, respectively. The originally approved label for enrofloxacin stated that it was indicated for the treatment of dermal infections (wounds and abscesses), respiratory infections, and urinary cystitis caused by susceptible strains of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Staphylococcus aureus. The dose on the original label was 2.5 mg/kg twice daily and was later expanded to 5–20 mg/kg per day, with an indication simply stated as “for the management of diseases associated with bacteria susceptible to enrofloxacin.” The approved label for oral marbofloxacin in dogs lists a dose range of 2.8–5.5 mg/kg with an indication for the treatment of infections in dogs associated with bacteria susceptible to marbofloxacin. These approvals did not indicate the bacteria that would be susceptible at these dose ranges.
The Clinical and Laboratory Standards Institute (CLSI) Veterinary Antimicrobial Susceptibility Testing (VAST) subcommittee approved methods and breakpoints for testing the susceptibility of bacterial isolates from dogs to enrofloxacin and marbofloxacin in 1999 and 2004, respectively. Those interpretive categories and breakpoints are currently in the 6th edition of the CLSI standard document Vet01(S) but will be revised in the next edition of that document.1 This document is used by laboratories to guide clinicians on the appropriate reporting of results based on the susceptibility to these agents. However, since the approval of these clinical breakpoints, we have learned a lot about antimicrobial resistance, and the importance of pharmacokinetic-pharmacodynamic (PK-PD) parameters needed to meet therapeutic targets for these drugs. These antibacterial agents were approved before pharmacokinetic-pharmacodynamic (PK-PD) criteria and therapeutic targets were applied to develop interpretive testing categories and breakpoints. The current VET02 CLSI guideline states that PK-PD should be considered as one of the primary criteria when determining the susceptibility testing breakpoint, together with the wild-type cutoff (COWT), also known as the epidemiological cutoff (ECOFF), and clinical outcome data, when available.2
We are concerned that inappropriate use of fluoroquinolones in companion animals may increase the emergence of resistant bacteria because prior antibiotic exposure and failure to meet the optimum PK-PD target are risks that contribute to the emergence of resistant bacteria. If the PK-PD target is not achieved with adequate doses, suboptimal exposure leads to the selection of resistant strains that can multiply and become the dominant population in an infection.3,4 There is evidence that prior fluoroquinolone use in small animals may have contributed to the clonal spread of methicillin-resistant strains of Staphylococcus pseudintermedius.5
Because of the recognition of these important issues, the CLSI-VAST subcommittee revised the antimicrobial susceptibility testing (AST) breakpoints for enrofloxacin and marbofloxacin, which will appear in the next (7th) edition of CLSI standard document VET01(S), scheduled for publication later in 2023.1 There was a precedent for making these changes to these veterinary fluoroquinolones. The human medicine CLSI committee revised their testing standards for testing fluoroquinolones using PK-PD analysis in 2019.6 This resulted in a lowering of the breakpoints for ciprofloxacin and levofloxacin by 4-fold for the Enterobacterales and by 2-fold for Pseudomonas aeruginosa. Therefore, there was precedence for re-examining the susceptibility testing breakpoints for the veterinary breakpoints for enrofloxacin and marbofloxacin.
Because these revised susceptibility testing breakpoints are much different from those used previously, this paper will explain the rationale and provide evidence for this change. The details described in this paper will inform microbiology laboratories, public health experts who monitor antibacterial resistance, and users—the veterinarians—of the importance of using current standards for testing. The CLSI-VAST subcommittee is committed to responsible antimicrobial stewardship in animals. Revising these breakpoints to values that more accurately reflect the current understanding of PK-PD and antimicrobial resistance may reduce the inappropriate use of these fluoroquinolones, which are considered critically important by the FDA.
Methods
Microbiology data
Antibacterial susceptibility data to generate wild-type cutoff values (COWT), also known as epidemiological cutoff values (ECOFF) are required for establishing new CLSI breakpoints.2 For the revision of enrofloxacin and marbofloxacin breakpoints, these data were obtained from surveillance programs launched post-approval in North America (NA) and the European Union (EU). The EU program isolates were collected from dogs presenting with skin-soft tissue infections (SSTI) and urinary tract infections (UTI) that had not received antibiotic treatment in the month before sampling and were collected during the periods, 2008–2010 and 2013–2014. The data from the Centre Européen d’Etudes pour la Santé Animale (CEESA), ComPath program included in our tables were also published in other sources.7–9 The NA program isolates were collected from a monitoring program that collected data from veterinary diagnostic laboratories throughout the US and Canada from 2011–2018. These isolates were limited to SSTI and UTIs, and from primary care/general care practices only. North American isolates were included regardless of prior antimicrobial therapy.
The MIC distributions (MIC50 and MIC90) and COWT values were calculated and included in the Supplementary Tables with our results. The COWT was calculated using the “ECOFF Finder,” which is available as a public access tool from the CLSI website (https://clsi.org/meetings/susceptibility-testing-subcommittees/ecoffinder/). The MIC distributions were also presented for visual inspection as histograms that correspond to the data in Supplementary Tables for each antimicrobial agent and bacterial isolate.
Pharmacokinetic data
Pharmacokinetic data was obtained from published references, and data generated by the sponsor on the approved label, or Freedom of Information summary available from the FDA.10 Published references came from a PubMed, Google Scholar, and Research Gate search using the keywords “pharmacokinetic,” “dog” (or canine), and the drug names. The detailed pharmacokinetic results are presented in the Supplementary Tables. These data represent the summary of the relevant pharmacokinetic data for each antimicrobial agent, the number of dogs in each study, and the dose. The mean and standard deviation are presented as reported in the study. In some papers, the systemic clearance value (CL/F) was not provided in the data table and was calculated from the available pharmacokinetic data and dose according to the following formula: CL/F = Dose/AUC, where CL/F is the clearance per fraction absorbed from the oral dose (L/kg/hr), and AUC is the total area-under-the-curve from time zero to infinity.
Enrofloxacin is metabolized to the active metabolite ciprofloxacin, which contributes to microbiological activity.11–14 Therefore, the contribution of ciprofloxacin to the total AUC must be accounted for. If a published study used a nonspecific microbiologic assay (bioassay) that does not quantitate enrofloxacin and ciprofloxacin pharmacokinetic values separately, it was excluded from our analysis. Enrofloxacin studies that use a bioassay method result in errors in the pharmacokinetic calculations because of differences in microbiologic activity between enrofloxacin and ciprofloxacin.15
After the pharmacokinetic data was collected from studies in dogs, the data were transformed into a single overall mean value and measure of variability (SD) for all observations. These values for enrofloxacin/ciprofloxacin and marbofloxacin account for between-study variation, within-study variation, and weighted for the number of animals in each study. Because only the clearance value (CL/F) is used for Monte Carlo Simulations (as described below), this summary was also presented in a table.
Protein binding
As only the unbound antimicrobial fraction is considered biologically active, breakpoint development must consider the amount of protein binding for the drug. To properly perform PK-PD analysis for the fluoroquinolone antimicrobial agents, only the unbound drug was used for model simulations (protein unbound, or fraction unbound).2,4 We used protein binding data from a published pharmacokinetic study16 to derive a value for the fraction unbound (fu) for each drug. The mean and variability (SD) of protein binding measurements were entered into the Monte Carlo Simulations (described below).
Monte Carlo simulations and probability of target attainment (PTA)
Monte Carlo simulations to determine whether PK-PD targets for susceptible bacteria could be reached for a range of MIC values were performed. Monte Carlo simulations are often used by clinical investigators to determine if antimicrobial dose regimens can reach therapeutic targets with a high probability.17 The use of this method is provided in guidelines by the CLSI2 and the application to derive antimicrobial susceptibility testing breakpoints was reviewed by others.17,18
where fu is the unbound fraction of marbofloxacin, enrofloxacin and ciprofloxacin canine plasma (derived from published studies), D is the dose administered, and CL/F is clearance. For Monte Carlo simulations, the clearance value corrected for bioavailability was used (CL/F); therefore, bioavailability was not included in the equation.
The clearance value used was derived from an average of the pharmacokinetic studies presented in our tables. For enrofloxacin administration, we accounted for the active metabolite, ciprofloxacin. Therefore, the AUC used in simulations was the contribution of each component from studies listed in our table, plus the variability. This mean value and Std Dev with log-normal distribution were entered into our Monte Carlo simulation software (Oracle Crystal Ball version 11.1.3.0.0, www.Oracle.com). Because there is a range of doses approved by the FDA for enrofloxacin and marbofloxacin, we used 2 doses for marbofloxacin, 2.8 and 5.5 mg/kg, representing the low and high doses of the range, and 3 doses for enrofloxacin, 5-, 10-, and 20 mg/kg, representing the low, medium, and high end of the range. Each dose was simulated for a 24-hour interval. The MIC values used in the simulation were 2-fold dilutions of 0.03, 0.06, 0.12, 0.25, 0.5, 1.0, 2.0, 4.0, and 8.0 µg/mL.
The values generated from the pharmacokinetic analysis were entered into the Monte Carlo simulation forecasting program, and simulations were generated for 10,000 trials. The PTA threshold for breakpoint development was ≥90% for the MIC values, indicating that 90% of the simulated PK were at or above the threshold considered therapeutically effective for that dose-MIC combination. The 90% value for PTA is a consistent standard used by CLSI and others.2,17–19
Results
Microbiology data
We collected data from 4001, 3770, and 2518 isolates for Staphylococcus pseudintermedius, Escherichia coli, and Proteus mirabilis, respectively. The distributions are presented for enrofloxacin and marbofloxacin (Figures 1 and 2). The sources and number of isolates for the microbiology susceptibility data are listed elsewhere (Supplementary Table S1). The entire susceptibility testing results, expressed as MICs, are presented elsewhere (Supplementary Tables S2–S7). Included in these tables are the distribution data (MIC50 and MIC90) and the COWT (listed in the table as ECOFF values). The COWT for marbofloxacin was 0.5 µg/mL, 0.06 µg/mL, and 0.12 µg/mL for S. pseudintermedius, E. coli, and P. mirabilis, shown elsewhere (Supplementary Tables S2–S4). The COWT for enrofloxacin was 0.25 µg/mL, 0.06-0.12 µg/mL, and 0.5 µg/mL for S. pseudintermedius, E. coli, and P. mirabilis, shown elsewhere (Supplementary Tables S5–S7).
Distribution of enrofloxacin MIC values for selected bacterial isolates from dogs.
Citation: American Journal of Veterinary Research 84, 11; 10.2460/ajvr.23.07.0159
Distribution of marbofloxacin MIC values for bacterial isolates from dogs.
Citation: American Journal of Veterinary Research 84, 11; 10.2460/ajvr.23.07.0159
These distributions provide a comparison between the COWT value and the PK-PD derived cutoffs (COPD) that are presented below. These values were used to avoid setting breakpoints that fell within the wild-type distribution.
Pharmacokinetic data
The pharmacokinetic data from 8 studies (enrofloxacin)11,16,20–23 and 7 studies (marbofloxacin)10,12,16,20,21,24,25 are presented elsewhere (Supplementary Tables S8 and S9). Because enrofloxacin is partially metabolized to ciprofloxacin, the values for ciprofloxacin are also listed in the table. The overall contribution of ciprofloxacin to the total fluoroquinolone concentrations (enrofloxacin + ciprofloxacin), after enrofloxacin administration, based on 8 studies and 48 observations (Supplementary Table S8) was 0.42 (0.13 SD). In other words, ciprofloxacin contributed to approximately 42% of the total fluoroquinolone AUC concentrations in these studies.
For the purpose of performing Monte Carlo Simulations, a single value for clearance and the associated variability (SD) was necessary. These values were calculated to account for between- and within-study variation and weighted for the number of animals in each study. The clearance value (expressed as CL/F) from 8 data sets and 48 observations for enrofloxacin and ciprofloxacin, respectively, was 0.80 L/kg/hr (SD 0.47) and 0.79 L/kg/hr (SD 0.43). The CL/F from 7 data sets and 56 observations for marbofloxacin was 0.11 L/kg/hr (SD 0.04) This summary is presented elsewhere (Supplementary Table S10).
Protein binding
We used protein binding results from a published source.16 The values used for this analysis were enrofloxacin 34.74% (SD 2.33), ciprofloxacin 18.48% (SD 2.98), and marbofloxacin 21.81% (SD 6.26).
Monte Carlo simulations
The results from the PK-PD analysis using Monte Carlo simulation for each dose analyzed are shown for enrofloxacin and marbofloxacin (Figures 3 and 4). These figures are derived from the results for enrofloxacin and marbofloxacin (Supplementary Tables S11 and S12). Our threshold for selecting a breakpoint is a PTA of approximately 90% or greater. Based on the values for enrofloxacin (Figure 3; Supplementary Table S11), susceptible breakpoints were selected as follows: 0.06 µg/mL for the low dose of 5 mg/kg, 0.12 µg/mL for an intermediate dose of 10 mg/kg, and 0.25 µg/mL for a high dose of 20 mg/kg (Table 1). Based on the results shown for marbofloxacin (Figure 4; Supplementary Table S12), we selected a MIC breakpoint of 0.12 µg/mL for the low dose of 2.8 mg/kg, a breakpoint of 0.25 µg/mL for a high dose of 5.5 mg/kg.
Plot of the probability of target attainment (PTA) for a range of MIC values for Enrofloxacin at 3 doses administered to dogs once daily. The arrows indicate the MIC corresponding to a PTA of 90% or greater to reach a target of f AUC/MIC > 72 using PK-PD analysis and Monte Carlo simulations. AUC = Area under the curve.
Citation: American Journal of Veterinary Research 84, 11; 10.2460/ajvr.23.07.0159
Plot of the probability of target attainment (PTA) for a range of MIC values for Marbofloxacin at 2 doses administered to dogs once daily. The arrows indicate the MIC corresponding to a PTA of 90% or greater to reach a target of f AUC/MIC > 72 using PK-PD analysis and Monte Carlo simulations. AUC = Area under the curve.
Citation: American Journal of Veterinary Research 84, 11; 10.2460/ajvr.23.07.0159
New (revised) and old (prior) CLSI interpretive categories and breakpoint for enrofloxacin and marbofloxacin administered oral to dogs.
| Interpretive categories and MIC breakpoints, µg/mL | ||||
|---|---|---|---|---|
| Antimicrobial agent | S | I | SDD | R |
| Enrofloxacin (prior) | ≤ 0.5 | 1–2 | ≥ 4 | |
| Enrofloxacin (revised) | ≤ 0.06 | 0.12–0.25 | ≥ 0.5 | |
| Marbofloxacin (prior) | ≤ 1 | 2 | ≥ 4 | |
| Marbofloxacin (revised) | ≤ 0.12 | 0.25 | ≥ 0.5 | |
The value listed in each cell are the breakpoints (µg/mL) for each interpretive category. S, susceptible. I = Intermediate. SDD = Susceptible dose-dependent. R = Resistant. The “S” category refers to susceptibility at the lowest label dose of 2.8 and 5 mg/kg for marbofloxacin and enrofloxacin, respectively. The SDD category refers to a higher dose of 5.5 mg/kg for marbofloxacin, and 10–20 mg/kg for enrofloxacin.
Discussion
We sought to develop revised breakpoints for these fluoroquinolones used in dogs because since their initial approval, the use of fluoroquinolones in animals has come under greater scrutiny. There are concerns that excessive use of these agents may contribute to multi-drug resistance among animal pathogens. Since the original breakpoints were established, there is more information about the PK-PD parameter, and target, for clinical success of these agents.3,4,19 The use of PK-PD principles for setting breakpoints and dosages for fluoroquinolones has been used previously.2–4,6,17–19 Therefore, it became necessary to revise these previous breakpoints using current guidelines. We believe that the revision of these breakpoints is essential to good clinical practice.
This report provides the data, and the approach used by CLSI-VAST to establish newly revised breakpoints for testing the susceptibility of enrofloxacin and marbofloxacin for Staphylococcus pseudintermedius, Escherichia coli, and Proteus mirabilis isolates from dogs. Because of space limitations, details of our analysis are presented in the Supplementary Tables available online. We presented the distribution of MIC values for these common bacterial pathogens in dogs (Figures 1 and 2; Supplementary Tables S2–S7), which were used to establish the wild-type cutoff (COWT) for these pathogens using criteria set forth by CLSI.2
To use PK-PD principles to establish breakpoints, pharmacokinetic data were summarized from published pharmacokinetic studies for enrofloxacin and marbofloxacin after oral administration to dogs (Supplementary Tables S8–S10). These data were used to calculate mean pharmacokinetic values, with associated distributions needed for Monte Carlo simulations. The results of the Monte Carlo simulations are shown (Figures 3 and 4; Supplementary Tables S11 and S12). Approximately 90% PTA was achieved at 3 doses of enrofloxacin and 2 doses of marbofloxacin in dogs. These values were used by CLSI-VAST to revise interpretive categories and breakpoints for these antimicrobial agents in dogs (Table 1). Original breakpoints for these agents are also listed for comparison. The new breakpoints will replace the old ones and will be published in the new 7th edition of the CLSI standard.1
The 3 interpretive categories are shown (Table 1). Susceptible (S) is a category defined by a breakpoint that implies that isolates with a MIC at or below or a zone diameter at or above the susceptible breakpoint are inhibited by the usually achievable concentrations of an antimicrobial agent when the dosage recommended to treat the site of infection is used, resulting in likely clinical efficacy.1,2 The susceptible-dose dependent (SDD), is a new category for our veterinary standards. It is defined by a breakpoint that implies that the susceptibility of an isolate depends on the dosage regimen that is used. To achieve levels that are likely to be clinically effective against isolates for which the susceptibility testing results are in the SDD category, it is necessary to use a higher dose that results in higher drug exposure than that achieved with the dose that was used to establish the susceptible breakpoint. The highest doses listed (20 mg/kg and 5.5 mg/kg for enrofloxacin and marbofloxacin, respectively) are approved by the FDA for use in dogs with safety studies to support the clinical use of these doses. The intermediate (I) category is defined by a breakpoint that includes isolates with MICs within an intermediate range. This category will no longer be used for these agents (but may still apply to other antibacterial agents listed in CLSI tables). The resistant (R) category is defined by a breakpoint that implies that isolates with a MIC at or above the resistant breakpoint are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules and/or that demonstrate MICs that fall in the range in which specific microbial resistance mechanisms are likely, and clinical efficacy of the agent against isolates has not been reliably shown in isolates with similar phenotypes.
It is noted that when comparing the old and new breakpoints (Table 1), there are large differences. Bacteria that would have been interpreted as “susceptible” using the old breakpoints will now test as “resistant” for both antimicrobial agents. To reach targets in the new SDD category, higher than minimum doses—but still within the FDA-approved doses—will be needed.
It is important to view these revised breakpoints with consideration for the distribution of bacteria presented (Figures 1 and 2; Supplementary Tables S2–S7). CLSI-VAST requires that both the COWT and the PK-PD cutoff (COPD) are used to establish the breakpoint.2 Therefore, we considered whether the COPD would fall on either side of the COWT. CLSI avoids setting breakpoints that fall within the wild-type distribution. For enrofloxacin, it appears that most E. coli isolates from dogs will fall in the S category. However, S. pseudintermedius and P. mirabilis will likely require a higher dose of 10–20 mg/kg (depending on the MIC). For marbofloxacin, it appears that most E. coli and P. mirabilis are in the S category, but most S. pseudintermedius will fall in the SDD category. Some strains of these bacterial species will fall into the R category, even with the revised breakpoints in place (Figures 1 and 2). Therefore, it is essential that before either antimicrobial agent or dose is selected, a susceptibility test should be performed to determine the potential for positive therapeutic outcomes. This analysis was limited to the 3 bacterial species shown (Figures 1 and 2) because this was a limitation of the surveillance programs used to collect our data. However, because other bacteria of the Enterobacterales are expected to respond to the same PK-PD targets, the breakpoints presented (Table 1) should apply to all bacteria in the Enterobacterales.
P. aeruginosa was not included in this analysis because there were not enough isolates to include in our figures and distribution tables. But these breakpoints should also apply to P. aeruginosa isolates because the PK-PD targets are similar. Based on observations of the limited data available from published studies7–9 the breakpoints (Table 1) would classify most P. aeruginosa isolates from dogs in the R category. This is also the conclusion from examining the data from a published study in the US,26 where most isolates from their study have MIC values in the R interpretive category. However, some P. aeruginosa isolates may have MIC values in the SDD range, which indicates that successful treatment may be possible in specific cases if high doses are used and a susceptibility test confirms that the MIC for the isolate is in the SDD category.
In summary, this report describes the procedures and conclusions by CLSI-VAST to update and revise the interpretive categories and breakpoints used for testing S. pseudintermedius, E. coli, and P. mirabilis isolates from dogs for susceptibility to enrofloxacin and marbofloxacin. These new breakpoints will be published in the 7th edition of CLSI Vet01(S)1 and laboratories will be informed of these changes. The doses that correspond to each interpretive category will also be published in Appendix D of the CLSI document.1 This represents a major change in the breakpoints used for testing these fluoroquinolones. Some bacteria that were previously considered “susceptible” will now test R. For isolates reported as SDD, higher doses in the FDA-approved range will be needed, which some veterinarians may not be familiar with using. CLSI-VAST is committed to antimicrobial stewardship and reducing, whenever possible, the unnecessary or inappropriate use of antimicrobial agents. If PK-PD targets are not achieved after administering antimicrobial agents to animals, because the dose is too low, or the isolate tests in the R category, clinical success is less likely, and multi-drug resistance can emerge, which is a risk to both animal and human health. CLSI-VAST will use the principles and approach described in this report to revise other fluoroquinolones and evaluate breakpoints for isolates from cats in the future.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org
Acknowledgments
The authors thank the members of the Clinical and Laboratory Standards Committee Veterinary Antimicrobial Susceptibility Testing (CLSI-VAST) subcommittee for their contributions and input to this study.
Disclosures
Mark G. Papich has had consulting agreements, and received gifts, honoraria, and research support from Zoetis and Elanco (formerly Bayer). These companies are sponsors of the antimicrobials mentioned in this article. Lacie Gunnett is a Senior Scientist for Global Biologics and an employee of Zoetis, the sponsor of one of the antimicrobials mentioned in this article. Brian Lubbers has had agreements, and received gifts, honoraria, and research support from Zoetis and Elanco (formerly Bayer). These companies are sponsors of the antimicrobials mentioned in this article.
No AI-assisted technologies were used in the generation of this manuscript.
Funding
Mark G. Papich is an employee of North Carolina State University. He received no funding to support the preparation of this manuscript. He is an unpaid volunteer member of the CLSI, Veterinary Antimicrobial Susceptibility Testing Subcommittee (VAST).
Brian V. Lubbers is an employee of Kansas State University. He received no funding to support the preparation of this manuscript. He is an unpaid volunteer member of the CLSI, Veterinary Antimicrobial Susceptibility Testing Subcommittee (VAST).
Lacie Gunnett is an employee of Zoetis, Kalamazoo, Michigan. Portions of the work described in this article were conducted while she was a paid employee at Zoetis.
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