Understanding Breakpoints on Microbiology Susceptibility Reports
Breakpoints are specific MIC values or inhibition zone diameters that categorize bacteria as susceptible, intermediate, or resistant, and you should select antibiotics reported as "susceptible" with the lowest MIC values while considering infection site characteristics and pharmacokinetic/pharmacodynamic principles. 1
What Breakpoints Represent
Breakpoints serve as clinical decision thresholds that translate laboratory measurements into actionable treatment categories by integrating three critical factors: 1
- Microbiological data: The MIC distribution of bacterial populations and their resistance mechanisms 1
- Pharmacokinetic parameters: Achievable drug concentrations at the infection site with standard dosing regimens 2
- Clinical outcomes: Cure rates, treatment failures, and bacteriological responses from clinical trials 1
The breakpoint essentially answers: "At what MIC does this antibiotic reliably cure infections caused by this organism?" 3
The Three Clinical Categories
Susceptible (S)
- MIC at or below the breakpoint indicates the infection should respond to standard dosing regimens 4
- These organisms are expected to be eliminated with appropriate antibiotic therapy at recommended doses 1
Intermediate (I)
- MIC falls between susceptible and resistant thresholds, indicating variable or indeterminate clinical responses 1
- Infections may be eliminated if the antibiotic concentrates at the infection site (e.g., urinary tract) or if dosage is increased 1, 4
- This category also serves as a technical buffer to minimize confusion for organisms with MICs close to the breakpoint, accounting for inherent test variability 1
Resistant (R)
- MIC exceeds the breakpoint, meaning infection is highly unlikely to respond even to maximum doses 1
- Clinical failure is expected, and alternative therapy should be selected 4
How to Use Breakpoints for Antibiotic Selection
Step 1: Identify Susceptible Agents
- Review the susceptibility report and identify all antibiotics categorized as "Susceptible" 4
- Discard resistant and intermediate options unless no susceptible alternatives exist 4
Step 2: Compare MIC Values Among Susceptible Options
- Select the antibiotic with the lowest MIC value among susceptible agents, as lower MICs indicate greater bacterial susceptibility and more effective killing at lower concentrations 4
- This approach maximizes the pharmacodynamic advantage and reduces the risk of treatment failure 4
Step 3: Consider Infection Site Characteristics
- Environmental conditions at the infection site dramatically affect antibiotic activity beyond what MIC predicts 4
- For urinary tract infections: Antibiotics with high urinary concentrations can succeed despite higher MICs because drug levels in urine far exceed serum levels 4, 5
- For CNS infections: Standard MIC interpretation may not apply; select agents with proven CSF penetration 4
- For deep-seated infections: Target the higher end of PK/PD goals (8× MIC instead of 4× MIC) 4
Step 4: Apply Pharmacokinetic/Pharmacodynamic Principles
Time-dependent antibiotics (beta-lactams): 4
- Target free drug concentration ≥4-8× MIC for 40-100% of the dosing interval
- Consider extended or continuous infusion when MIC is in the intermediate range or for critically ill patients 4
Concentration-dependent antibiotics (fluoroquinolones, aminoglycosides): 4
- Target Cmax/MIC ≥8-10 or AUC/MIC >125
- Higher peak concentrations relative to MIC predict better outcomes 6
Critical Pitfalls to Avoid
Treating "Near-Breakpoint" MICs as Fully Susceptible
- Organisms with MICs close to the susceptible breakpoint have higher failure rates than those with MICs well below the breakpoint 4
- When the MIC approaches the breakpoint, consider alternative agents with lower MICs or adjust dosing strategies 1
Ignoring the Intermediate Category
- The intermediate category is not a "maybe susceptible" designation—it signals that standard dosing may be inadequate 1
- Either increase the dose, use continuous infusion, or select an alternative agent with a susceptible interpretation 4
Relying Solely on Categorical Interpretation
- Categorization as S/I/R causes information loss compared to analyzing actual MIC values 7
- Two organisms both reported as "susceptible" may have vastly different MICs (e.g., 0.5 vs. 4 μg/mL), with the lower MIC predicting better outcomes 7
Misinterpreting ">" Symbols
- The ">" symbol means the actual MIC exceeds the highest concentration tested, signaling reduced susceptibility or resistance 5
- For example, ">2 μg/mL" means the MIC is at least 2 μg/mL and likely higher, often indicating resistance depending on the organism-antibiotic combination 5
Special Considerations for Critically Ill Patients
Altered pharmacokinetics in ICU patients necessitate therapeutic drug monitoring (TDM) combined with MIC interpretation: 4
| Antibiotic | Target Cmin (mg/L) | MIC Threshold (mg/L) |
|---|---|---|
| Meropenem | 8-16 | 2 (P. aeruginosa) |
| Cefepime | 5-20 | 1 (Enterobacteriaceae) |
| Piperacillin | Css 80-160 | 16 (P. aeruginosa) |
- For beta-lactams in ICU patients, maintain 100% fT>MIC through continuous or prolonged infusion when MIC is elevated or the patient has augmented renal clearance 4
Understanding Breakpoint Limitations
Breakpoints Are Not Universal
- Different organizations (CLSI, EUCAST) may establish discrepant breakpoints for the same organism-antibiotic combination, and every effort must be made to resolve such discrepancies 1
- Breakpoints are organism-specific and infection site-specific; a breakpoint for E. coli may not apply to P. aeruginosa 1
Breakpoints Evolve Over Time
- Breakpoints are periodically revised based on new clinical data, emerging resistance mechanisms, and refined pharmacokinetic understanding 2, 3
- Older breakpoints derived by deterministic approaches tend to be too high and may classify borderline susceptible bacteria as fully susceptible, increasing resistance development and clinical failure 2