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Wise use of Antibiotics

May, 2018

Interpreting Minimum Inhibitory Concentrations

 

Angela Myers, MD, MPH | Director, Infectious Diseases Fellowship Program | Medical Director, Travel Medicine | Associate Professor of Pediatrics

Last week when I was rounding on the ID consult service, our team saw a neonate with bullous impetigo. Culture results from the wound are shown in table 1. Questions often arise in this type of scenario regarding the best antibiotic to treat the infection. This determination is made based on knowledge of several factors including: the bacteria causing the infection, the concentration of drug at the site of infection (e.g., lung or skin), the route of administration (e.g., parenteral or enteral), elimination (e.g., renal or hepatic), drug protein binding, and perhaps most importantly,1 the antibiotic susceptibility of the organism. Susceptibility information includes the minimum inhibitory concentration (MIC) and an interpretation of susceptible (S), intermediate (I), or resistant (R), to indicate which antibiotics are likely to successfully treat a given bacterial infection. 

How is susceptibility determined? 

Before an antibiotic is used in the patient care setting, MIC breakpoints for SI and R are established and published by the Clinical and Laboratory Standards Institute (CLSI) and the Food and Drug Administration.2Antibiotic breakpoints are based on the drug level achieved in the blood using the recommended dosing from the package insert.3 Two different testing methods are used to determine these breakpoints depending on the antibiotic.

The first is the micro-broth dilution method (Image 1) in which decreasing drug concentrations (µg/ml) of a specific antibiotic (e.g., oxacillin) are inoculated with a standardized concentration of a specific bacteria (e.g., S. aureus). The lowest antibiotic concentration which prevents the growth of the bacteria is deemed the MIC. For example, for S. aureus, the oxacillin MIC breakpoint for S is ≤ 2 µg/ml and R is ≥ 4 µg/ml.

Image 1



The second method is called disc diffusion (image 2), which is a measurement of the diameter of bacterial growth inhibition (mm) around an antibiotic-impregnated disc on an agar plate of bacteria. The diameter of growth inhibition is measured and recorded. The measurement is then compared against the known zone diameter breakpoints for the specific antibiotic in order to interpret S, I or R. For example, values for the size of the zone of inhibition for clindamycin are: S is ≥ 21 mm, I is 15-20 mm and R is ≤ 14 mm. Thus, if the diameter without bacterial growth around the antibiotic disc is ≤ 14 mm, the bacteria is resistant to clindamycin. 

Image 2



These assays tell us that if the concentration of drug required to inhibit bacterial growth (micro-broth dilution) is too high or the zone of inhibition is too small (disc diffusion), we should expect that the level of antibiotic needed to effectively treat the bacteria is not achievable in the human body at standard doses. In some situations, drug resistance can be overcome based on the other factors mentioned above (e.g., cystitis with known primary renal elimination of the drug and thus very high concentrations at the site of infection). However, oftentimes the resistance cannot be overcome and a different option must be chosen for effective treatment.

Each antibiotic has specific breakpoints that can differ for each bacterial species. For example, as noted previously, the breakpoint for susceptibility for oxacillin is ≤ 2 µg/ml for S. aureus, but oxacillin’s breakpoint for Staphylococcus epidermidis is ≤ 0.25 µg/ml. This means that resistance in S. epidermidis occurs at a lower drug concentration than in S. aureus, and oxacillin is less active against S. epidermidis than S. aureus.
  
Additionally, MICs (recall that these are based on achievable serum concentrations) cannot be compared across drugs; both since different drugs achieve different serum levels at recommended dosages; and because concentrations needed to halt bacterial growth will vary from drug to drug. For example, our patient’s culture result indicates that the infection is caused by methicillin-resistant Staphylococcus aureus (MRSA), since it is resistant to oxacillin. The MIC to linezolid was 2 µg/ml (breakpoint for S ≤ 4 µg/ml), and the MIC to vancomycin was 1 µg/ml (breakpoint for S ≤ 2 µg/ml). While the MIC of vancomycin is a lower number than linezolid, this does not necessarily indicate that vancomycin is a better drug to treat the infection. All the factors mentioned previously should be taken into account (e.g., serum drug concentration, infection site, etc.) when the drug is chosen. The MIC should always be evaluated in the context of the breakpoints for that particular drug with a specific organism. 

Our patient’s isolate was not only MRSA, but also resistant to clindamycin. He improved with topical treatment, as well as a short course of linezolid. 

Table 1. Antibiotic, MIC of the culture result, and interpretation

Antibiotic

MIC

Interpretation

Clindamycin

8

R

Doxycycline

≤ 0.5

S

Linezolid

2

S

Oxacillin

≥ 4

R

Rifampin

≤ 0.5

S

Tetracycline

≤ 1

S

Trimethoprim-Sulfamethoxazole

≤ 10

S

Vancomycin

1

S


References:

  1. Optimizing Antimicrobial Susceptibility Test Reporting. Schreckenberger PC, Binnicker MJ. J. Clin Microbiol. 2011; 49:S15-19. 

  2. CLSI M100-ED28:2018 Performance Standards for Antimicrobial Susceptibility Testing, 28th Edition. Accessed on May 10th, 2018. http://em100.edaptivedocs.info/GetDoc.aspx?doc=CLSI M100 ED28:2018&sbssok=CLSI M100 ED28:2018 TABLE 2C&format=HTML#CLSI M100 ED28:2018 TABLE 2C.

  3. Setting and Revising Antibacterial Susceptibility Breakpoints. Turnidge J, Paterson DL. Clin. Microbiol. Rev. 2007; 20:391-408.