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Polling Place: Practical Significance of Minimum Inhibitory Concentration of Antimicrobials

Mark G. Papich, DVM, MS, Diplomate ACVCP, Fellow AAVP

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We have all read a great deal about the importance of MICs to the efficacy of antimicrobial treatment. How does this affect dosing and patient management in everyday practice?

Our Readers Say...

Too Few Data = Lots of Frustration
We are trying to use antimicrobials in a very quantitative and specific way, and we don't have the information we need to do that. There are very few antimicrobials that have published effective tissue concentrations in milligrams per unit of tissue and documented data to allow us to know what oral dose is needed to produce these levels in various tissues. Marbofloxacin is the only one I have been able to find that has published micrograms per unit of tissue reached by recommended oral doses, and it is given right in the package insert information. Even if tissue concentration information is available, often it is on the human side, and there are a number of studies that show you cannot extrapolate between humans and animals as to oral dosing and absorption/bioavailability.

The problem is that many widely used antimicrobials have been out a long time and were developed before MICs were used to assess antimicrobial efficacy. The in vitro Kirby-Bauer turbidity tests were used to assess these drugs. The frustration is compounded because the agar disk diffusion tests may show an organism as resistant to a given antimicrobial, while MIC data show it as susceptible at certain tissue levels. The bottom line is that we need a lot more data before we can intelligently use MIC values.
Roddy Roberts, DVM

Quantitative vs. Qualitative
I have found that the important factor is getting a quantitative versus a qualitative number when looking at bacterial inhibition. It plays a bigger role when I am selecting an antibiotic to use in an area where we might not have good penetration or when there is some question about organism resistance. For the most part we know that we will have good penetration in the urinary system, so when we're treating a urinary infection MICs are not as critical. But if we have an antibiotic that may have marginal penetration into the involved tissue, it is important to know what concentration we will need to get adequate concentration into that tissue, whether it is urinary, sinus, or some other. That's where MICs play a role for me. They are also important in the face of a resistant organism, as we have a very narrow selection of antibiotics to choose from in such cases.
Ron Hooley, DVM

Sense & Susceptibility
Practicing veterinarians have a pretty good sense of the appropriate antibiotic dosages for most of the common diseases that we face. Skin diseases in general, Staphylococcus intermedius infections of the skin, urinary tract infections, upper respiratory infections-most of us have developed solid regimens based on experience once we have culture data on what's growing. Thus, from a practical standpoint, I don't use MICs routinely, but I know I have them available if I encounter a particularly unusual case or an infection in a body system with which I am not accustomed to dealing, such as the central nervous system.

I had a specific case in a cat with chronic sinusitis in which the MIC was really handy. We cultured samples and came back with a pure Pseudomonas growth. We obtained the MIC concentrations on that cat. The best antibiotic available at the time was enrofloxacin, which in some cats has shown some toxicity. So we were looking for the minimum dose that would knock out the Pseudomonas, but no more than that. Data were available on peak concentrations in sinus and nasal tissues, so we were able to combine that information with the MIC numbers to calculate dosage for that cat. It was a helpful exercise and was also beneficial to the cat.
Patrick Grogan, DVM

Antimicrobial Characteristics
The biggest concern is using a drug that concentrates in the involved tissues. Based on the organism; the SIR (susceptible, intermediate, and resistant) laboratory ratings; and the characteristics of the compound, you can make an informed drug choice. You choose the one that you can send home with the client (oral), can use in the hospital, and that targets the appropriate tissue. Only if you have a really resistant infection are breakpoints important to determine. But MICs are always measured in plasma, so you may actually choose an antibiotic with an intermediate rating because it has better tissue penetration than antibiotics with susceptible ratings.
Paula Monroe, DVM

Broad Reasoning
Even if you do not get down to the level of exact number of milligrams of antibiotic needed to treat the bacteria, MIC data can be useful in broad screening of possible antimicrobials for a given infection. If you have several antimicrobials to which the organism involved shows resistance and several to which the organism tests as susceptible, you can figure out which one in the susceptible group you should use. That is, if one is at the very low end, requiring very little drug in tissue to take care of the bacteria, versus one that falls at the upper end of the susceptible level, you can be more confident about your drug choice.
Patrick Cunningham, DVM

The expert says . . .

The Relationship Between Susceptibility Testing and Efficacy

Although antibacterial susceptibility testing is not necessary for every case, it can be helpful in selecting proper antibacterial therapy for patients with refractory infections, seriously ill animals, or when resistant strains of bacteria are suspected. In order to perform the testing correctly and dependably, the laboratory should adhere to standards set by the National Committee on Clinical Laboratory Standards (NCCLS).a The traditional and older method for performing the susceptibility test has been the agar disk diffusion test.b However, many laboratories now perform the
susceptibility test by determining the MIC.

The MIC (minimum inhibitory concentration) is the lowest drug concentration that inhibits the growth of a particular bacterial isolate.c MIC is not a measure of efficacy per se, but instead it is simply an in vitro measurement of bacterial susceptibility. The lower the MIC value, the more susceptible the isolate is to that drug. MICs are determined using serial two-fold dilutions of drug to which is added a standardized inoculum that is incubated for a prescribed time. If one were to start at a concentration of 256 µg/ml, the MIC dilution series would be as follows: 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.12, 0.06 µg/ml, etc. If, for example, bacterial growth occurs in a dilution or concentration of 0.12 µg/ml for a specific drug, but not at 0.25 µg/ml and above, the MIC is determined to be 0.25 µg/ml. When an MIC test is conducted, it should be performed according to strict procedural standards, including quality control, such as those in NCCLS document M31A2.1
MICs, Breakpoints, & "SIR"

Once an MIC for a bacterial isolate is determined for a particular antibiotic, it is then compared to published breakpoints from the NCCLS1 that indicate whether it is susceptible or resistant. Without these breakpoints, MIC values are meaningless; but by coupling the MIC from a laboratory report with NCCLS breakpoints and other important information-such as the virulence of the bacteria and the pharmacology of the antibiotics being considered-the clinician can make a more informed selection of an antibacterial drug.

MIC breakpoints are specific to the drug, but for some drugs there may be unique breakpoints established for different organisms. For example, for enrofloxacin the susceptible breakpoint for bovine respiratory bacteria is less than for canine bacteria. The NCCLS Subcommittee on Veterinary Antimicrobial Susceptibility Testing (VAST) uses three criteria to determine veterinary-specific breakpoints:1 1) MIC data from various populations of bacteria collected in the field (population distribution) or in clinical efficacy studies, 2) pharmacokinetic-pharmacodynamic propertiesd appropriate for the antibiotic, and 3) clinical efficacy of the drug during field trials at the standard dose. For most FDA-approved antibiotics, breakpoints are still based on interpretive criteria developed for human pathogens and human-labeled uses. This is because the drugs were originally labeled for only human use and animal-specific breakpoints have not yet been established. The NCCLS VAST has been meeting regularly to revise breakpoints for older drugs, and this situation will be improved in the future.

Veterinary Specific Breakpoints
In the case of companion animals, veterinary-specific MIC breakpoints have been established for only the four licensed fluoroquinolones (enrofloxacin, difloxacin, marbofloxacin, and orbifloxacin), gentamicin, and clindamycin (dogs only). Until veterinary-specific breakpoints are established for other antibiotics used in companion animals, we will continue to rely on the human breakpoints for drugs such as amikacin, amoxicillin-clavulanate, cephalosporins, chloramphenicol, erythromycin, carbapenems (imipenem), penicillins, sulfonamides, potentiated sulfonamides, and tetracyclines. Similarities in pharmacokinetics and pathogen susceptibilities between humans and animals allow for an acceptable approximation to extrapolate human breakpoints to animal situations for many drugs until veterinary-specific standards are available. (It is not perfect, but it's all we have!)

After a laboratory determines an MIC, it may use the NCCLS "SIR" classification for breakpoints (S, susceptible; I, intermediate; or R, resistant). In everyday practice, if the MIC for the bacterial isolate falls in the susceptible category, there is a greater likelihood of successful treatment (cure) than if the isolate were classified as resistant. It does not assure success; drug failure is still possible owing to other drug or patient factorse and interactions. If the MIC is in the resistant category, bacteriologic failure is more likely because of specific resistance mechanisms or inadequate drug concentrations in the patient. However, a patient with a competent immune system may sometimes eradicate an infection even when the isolate is resistant to the drug in the MIC test.

The intermediate category is intended as a buffer zone between susceptible and resistant strains. This category reflects the possibility of error when an isolate has an MIC that borders between susceptible and resistant. The intermediate category is not intended to mean "moderately susceptible." If the MIC value is in the intermediate category, therapy at the usual standard dosage is discouraged because there is a good likelihood that drug concentrations may be inadequate for a cure. However, successful therapy is possible when the drug concentrates at certain sites (in urine, or as the result of topical therapy, for example), or at doses higher than the minimum effective dose listed on the label. For example, fluoroquinolone antimicrobials have been approved with a dose range that allows increases when susceptibility testing identifies an organism in the intermediate range of susceptibility. In these cases higher drug concentrations make a cure possible if the clinician is able to safely increase the dose above the minimum labeled dose. (For example, in the case of enrofloxacin in dogs, this would be equivalent to a dose of 10 to 20 mg/kg/day, rather than the minimum dose of 5 mg/kg/day.)

Some Common Mistakes
At times, veterinarians would like information on the tissue concentration rather than the plasma concentration or would prefer that the MIC breakpoints were interpreted according to the ability (or inability) of a drug to penetrate the tissue that is affected by the bacteria. This is not a rational approach. There is no such thing as "good penetration" or "poor penetration" with respect to antibiotics, except when drugs are limited by diffusion to selected sites such as the eye, prostate, or central nervous system. Otherwise, drug concentrations at the site of infection (interstitial space) are correlated with the plasma concentrations. Fenestrations in capillaries allow rapid equilibration between protein unbound plasma drug concentrations and the fluid of tissues - where the infection occurs.

A frequent error in MIC interpretation is to compare the MIC level with published tissue concentrations that are derived from whole-tissue homogenized samples. Tissue concentration data is often published by pharmaceutical companies in their product information. These concentrations are misleading because they may either underestimate or overestimate (depending on the drug's affinity for intracellular sites) the true drug concentration at the site of infection. Individual breakpoints cannot be determined to account for differences in drug concentration from one tissue to another.

Another example of the misuse of MIC information is comparing MIC values to urine drug concentrations. Some laboratories have reported susceptibility breakpoints that are higher for urinary tract infections in small animals than for infections at other sites with the same organisms. Urinary tract pathogens from small animals do not have different breakpoints as they have never been standardized by the NCCLS. Thus, MICs should be interpreted using the same criteria as discussed above.

In conclusion, the derivation and use of MIC values to interpret susceptibility is not a perfect science, but it is currently the best information available to guide therapy for serious infections. Clinicians should not use MIC information in a vacuum; instead it should be coupled with information from the clinical history and the practitioner's experience to select the most appropriate drug and dose regimen.

A. Not all laboratories in the U.S. use NCCLS standards. It is a voluntary program. However, if a laboratory does not adhere to a public standard such as NCCLS, breakpoints may vary and as such there can be no consistency from laboratory to laboratory, or among different regions. It is therefore advisable to use a reputable laboratory that adheres to strict procedural details and public standards when performing tests.
B. The agar disk diffusion test is also known as the Kirby-Bauer test. The Kirby-Bauer test measures inhibition of bacterial growth around an antimicrobial-impregnated disk that has been placed on a culture plate. In this test, a large zone of inhibition corresponds to a high degree of susceptibility.
C. The MIC value does not guarantee that the drug will kill the bacteria at this concentration, but the lethal concentration - the minimum bactericidal concentration (MBC) - is rarely measured in diagnostic laboratories because it is more difficult and time-consuming to perform.


PRACTICAL SIGNIFICANCE OF MINIMUM INHIBITORY CONCENTRATION OF ANTIMICROBIALS • Mark G. Papich

Reference
1. NCCLS. Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated from Animals; Approved Standard - Second Edition. NCCLS document M31-A2.

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

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