Pediatric Perspective on the EUCAST Definitions for S, I and R

S, I AND R CATEGORIES FOR INTERPRETATION OF SUSCEPTIBILITY TESTING RESULTS In addition to its work on standardizing and improving the validity of methods for antimicrobial susceptibility testing (AST), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) issues yearly updates on its guidance to interpret the results of these tests. Interpretation of test results generally falls into 3 categories. In 2019, EUCAST updated the definitions for the 3 categories as follows: S: Susceptible, standard dosing regimen: a microorganism is categorized as “Susceptible, standard dosing regimen,” when there is a high likelihood of therapeutic success using a standard dosing regimen of the agent. I: Susceptible, increased exposure: A microorganism is categorized as “Susceptible, Increased exposure” when there is a high likelihood of therapeutic success if exposure to the agent is increased by adjusting the dosing regimen or by its concentration at the site of infection. R: Resistant: A microorganism is categorized as “Resistant” when there is a high likelihood of therapeutic failure even when there is increased exposure. Exposure in the “I” category was defined as “a function of how the mode of administration, dose, dosing interval, infusion time, as well as distribution and excretion of the antimicrobial agent will influence the infecting organism at the site of infection.”1 Similar definitions were not adopted by the other globally leading institution offering AST guidelines [the Clinical and Laboratory Standards Institute (CLSI)] although CLSI introduced the “susceptible dose-dependent” subcategory of “I” otherwise defined as “intermediate” in 2014.2 Currently, “I” may, therefore, be read as “intermediate,” according to CLSI, or as “susceptible, increased exposure,” according to EUCAST, and it is becoming arguably more important for clinicians to understand which testing and interpretation standards their laboratory uses. CLSI’s “I” category still subsumes a variety of scenarios in which the susceptibility of a tested microorganism may remain uncertain due to drug levels at the site of infection, or due to difficulties in interpreting test results—generally results in the “area of technical uncertainty.2” Due to this uncertainty, the conservative approach clinicians generally adopt when approaching the CLSI “intermediate” category is to regard it as likely resistant to the tested antibiotic agent. With the 2019 introduction of the “susceptible, increased exposure” category, EUCAST requires a change of this approach to now regarding isolates tested as “I” for a certain antibiotic agent as susceptible to it, with the additional consideration that the antibiotic necessarily needs to achieve sufficient exposure. Guidance as to how dosing of an antibiotic is considered to influence this is published by EUCAST for adults,3 with a parallel dosing table for children currently being in development.4 TRANSLATION OF TEST RESULTS INTO SUSCEPTIBILITY CATEGORIES: CLINICAL BREAKPOINTS Both EUCAST and CLSI publish tables of clinical breakpoints that offer guidance on how test results translate into the categories above. Broadly, breakpoints are thresholds for either minimum inhibitory concentrations (MICs) or growth-free zone diameters that separate results falling into different categories. Breakpoint setting makes use of various factors, including distribution of test results in previously documented isolates of bacteria, experiences (mainly findings from clinical studies) about outcomes of patients infected with bacteria with different AST test results and expected drug levels at the site of infection. The integration of these factors results in specific breakpoints for the combination of 1 bacterial species or group (eg, Enterobacteriaceae) and 1 antibacterial agent. Breakpoints may be set differently according to the site of infection, but they do not take into consideration if an isolate has been obtained from a pediatric or adult patient. EUCAST’s updated definition means that the previously common sequence of interpretations moving from “S” via “I” to “R” with gradually increasing MICs or decreasing zone diameters no longer applies. For each combination of bacterium and agent, susceptible will either be “S” or “I,” depending on whether exposure and, by consequence, dosing are heightened concerns. AST results for Pseudomonas aeruginosa (as a common example) isolates not showing unusually high MICs to any antibiotic will now, nonetheless, show “I” for most reported agents, indicating that these agents should always be given at high doses when treating Pseudomonas spp. Consequently, there is only 1 breakpoint separating “R” from either “S” or “I.” SHOULD “S,” “I” AND “R” BREAKPOINTS EQUALLY BE APPLIED TO ISOLATES FROM PEDIATRIC PATIENTS? The meaning of the AST results applying the EUCAST “S,” “I” and “R” categories is not affected by the host from whom the bacterium was isolated. An alternative antibiotic can be selected if an isolate has been tested as “R,” or dosing can be increased above the standard if an isolate is reported as “I.” Seeing that EUCAST uses the same breakpoints for isolates from adults and children, the relevant question is if these are transferrable across patient age groups. Regarding the contributing factors for breakpoint setting, this would require (1) the circulating bacterial populations in both patient populations to be similar, (2) outcomes of patients infected with bacteria with similar AST results also to be similar and (3) expected drug levels at the site of infection to be similar. The pool of bacterial isolates that is available to describe the distribution of antibiotic concentrations able to inhibit growth (MIC) and, thereby, determine which MICs will be regarded as elevated is not equally representative for different patient age groups. The contribution of different age groups depends both on how commonly an age group is sampled and on how prevalent bacteria are in this age group. As an example, Escherichia coli is commonly found in urinary tract infections in elderly patients and adult women. Even when restricting the pool to bloodstream isolates, population-based studies suggest that about 20× and 200× more E. coli isolates will be derived from people over 75 alone than from infants under the age of 1 year and adolescents between 10 and 14 years, respectively.5 Isolates of E. coli from pediatric patients only make a very minor contribution to the previously tested bacterial population. Using 1 overall distribution of MICs to determine where elevated MICs start relies on the assumption that bacterial populations in different patient groups are all part of a single homogenous bacterial population colonizing and infecting humans. While this may be true for some bacterial species, heavily age-dependent patterns of interpersonal close contacts make it seem possible that age group-specific subpopulations may arise and be maintained.6 While patient outcome by MIC is not a frequently used endpoint in clinical studies, a limited number of studies in pediatric patients have shown an increase in adverse outcomes with higher MICs below the clinical breakpoint, that is, when the isolate would still have been classified within the “S” category.7 Although this may be indicative of the breakpoint not being appropriate for children, similar findings for Gram-negative bacteria have been reported in adults.8 This illustrates that independent of age, the category of “susceptible” still requires careful patient monitoring, especially in the treatment of more critical infections. Antibiotic drug levels at the site of infection are a function of dosing (dose and dosing interval), mode of administration (eg, oral, i.m., i.v. push, intermittent or continuous i.v. infusion) and physiologically determined pharmacokinetic processes. All of these differ substantially between pediatric and adult patients but also between age groups within the pediatric and adult populations. Currently, the breakpoint setting process is not based on common pediatric dosing regimens of antibiotics and does not take different pharmacokinetics in children and neonates into account. Maturation, and body weight and composition result in different distribution and clearance of antibiotics at different pediatric ages.9 Moreover, existing pediatric dosing recommendations for antibiotics differ widely.10 EUCAST’s “I” category places a heavy focus on adequate dosing. At the same time, dosing is the main concern regarding the applicability of current clinical breakpoints for pediatric patients. In the absence of harmonized dosing recommendations for pediatrics, and of consideration of these and pediatric pharmacokinetics in breakpoint setting, the “I” category poses a challenge for the selection of an appropriate dosing strategy for the patient in question. CONCLUSIONS AND RECOMMENDATIONS While the “S,” “I” and “R” categories are generally applicable to pediatrics, appropriate dosing is the main concern, especially where constellations of “susceptible, increased exposure” (EUCAST’s “new I”) are targeted. Dosing toward the upper end of accepted ranges should be considered where dose-dependent toxicity is of limited concern. Especially for beta-lactam antibiotics, shorter dosing intervals or extended infusion times may be necessary when managing difficult-to-treat infections. More pharmacokinetic studies will be necessary, especially in neonates and critically ill children, to reduce uncertainty regarding adequate dosing. In line with the definitions, both “susceptible” categories (S and I) only indicate a high probability of success and do not guarantee it. Especially in critical infections, close monitoring of possible treatment failure is advisable.