Appropriate Versus Inappropriate Antimicrobial Therapy

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Definition
• Successful antimicrobial therapy relies on administering sufficient doses so that pathogens at the site of infection are killed or sufficiently suppressed and can be eliminated by the host's immune system.
• Pharmacokinetics (PK) is what the body does to a drug. It is the mathematical description of absorption, distribution to the various tissues, metabolism of lipid-soluble drugs into water-soluble metabolites, and finally renal excretion.
• Pharmacodynamics (PD) is what the antimicrobial agent does to the bacteria. It describes the drug action and responses of the bacteria.
• Pharmacokinetics and pharmacodynamics are interrelated-PK determines the amount of drug that reaches the site of action, and the intensity of a PD effect is associated with the drug concentration at the site of action.
• Benefits of the PK/PD approach include increased efficacy of antimicrobial therapy and minimized antimicrobial resistance.

Treatment

MICs & Susceptibility Testing
• The minimum inhibitory concentration (MIC) is the lowest drug concentration that inhibits bacterial growth.
• The minimum bactericidal concentration is the lowest drug concentration that kills 99.9% of bacteria.
• The Clinical Laboratory Standards Institute (CLSI) defines MICs as serially doubling concentrations (in µg/ml). Susceptible (S), intermediate (I), and resistant (R) designations are derived from "breakpoints" assigned by CLSI based on safely achievable plasma concentrations and results of clinical trials.
- For susceptible pathogens, the recommended dosage of the antimicrobial will reach plasma or tissue concentrations that will inhibit bacterial growth in vivo.
- For a resistant pathogen, inhibitory antimicrobial concentrations are not safely attainable in the patient.
- If the pathogen is categorized as intermediate, administering the antimicrobial at higher than recommended doses may result in effective therapy.
• The CLSI breakpoints were originally established with bacterial isolates from humans, using human PK data and clinical trials in humans. A veterinary subcommittee was established only in 1993, and it has only recently proposed veterinary-specific guidelines for susceptibility tests for some antimicrobials. Therefore, the true relevance of any in vitro MIC predicting the in vivo results of drug therapy is questionable. But by convention, drug dosage regimens use a target plasma drug concentration that is based on some multiple (usually 4 to 10) of the in vitro MIC.

Postantibiotic Effect
• For some bacteria-drug interactions, bacterial growth remains suppressed for a period after the drug concentration has decreased below the MIC. This is called the postantibiotic effect.
• The postantibiotic effect may be the reason that dosage regimens that fail to maintain drug concentration above the MIC are still efficacious. The postantibiotic effect depends on the antimicrobial and the bacterial pathogen (Table 2).
- Only the fluoroquinolones show a long postantibiotic effect for both gram-positive and gram-negative bacteria, which supports their once-daily dosing.
- Penicillins and cephalosporins have long postantibiotic effects for gram-positive bacteria, so they are efficacious even with the intermittent dosing that allows drug concentrations to drop below the MIC.

Pharmacokinetic & Pharmacodynamic Relationships
• A successful antimicrobial dosage regimen depends on both PK and PD.
• The PK parameters used in drug dosage design are the area under the plasma concentration versus time curve (AUC) from 0 to 24 hours, the maximum plasma concentration (Cmax), and the length of time the antimicrobial concentration exceeds a defined PD threshold (T).
• The most commonly used PD parameter is the MIC.
• In relating the PK and PD parameters to clinical efficacy, antimicrobial drug action is classified as concentration dependent or time dependent.

Concentration-Dependent Drugs
• For concentration-dependent antimicrobials, high plasma concentrations relative to the MIC of the pathogen (Cmax:MIC) and the AUC that is above the bacterial MIC during the dosage interval (area under the inhibitory curve, (AUC0-24 hr:MIC) are the major determinants of clinical efficacy (Figure 1).
- These drugs also have prolonged postantibiotic effects, thereby allowing once-daily dosing while maintaining maximum clinical efficacy.
- For fluoroquinolones (enrofloxacin, orbifloxacin, difloxacin, marbofloxacin), clinical efficacy is associated with achieving an AUC0-24 hr:MIC greater than 125 or a Cmax:MIC greater than 10. This allows once-daily dosing, which improves client compliance with the treatment regimen.
- For aminoglycosides (gentamicin, amikacin), achieving a Cmax:MIC greater than 10 is considered optimal for efficacy. This allows once-daily dosing and minimizes the risk for nephrotoxicity associated with high trough concentrations of aminoglycosides.
- Other antimicrobials that appear to have concentration-dependent activity include metronidazole (Cmax:MIC > 10 to 25) and azithromycin (AUC0-24 hr:MIC > 25).

Time-Dependent Drugs
• For time-dependent antimicrobials, the time during which the antimicrobial concentration exceeds the MIC of the pathogen determines clinical efficacy (T > MIC) (Figure 2).
• The penicillins, cephalosporins, most macrolides and lincosamides, tetracyclines, chloramphenicol, and potentiated sulfonamides are considered time-dependent antimicrobials.
• How much and for what percentage of the dosing interval the concentrations should be above the MIC are debatable; it is probably specific for individual bacteria-drug combinations.
- Typically, exceeding the MIC by 1 to 5 multiples for 40% to 100% of the dosage interval is appropriate for time-dependent killers.
- The T > MIC should be closer to 100% for bacteriostatic antimicrobials and for patients that are immunosuppressed.

Designing the Drug Dosage Regimen
• High plasma antimicrobial concentrations are assumed to be advantageous in that a large concentration of drug will diffuse into various tissues and body fluids.
• Antimicrobial dosage regimens are designed in 1 of 2 ways: to maximize plasma concentration or to provide a plasma concentration above the bacterial MIC for some percentage of the dosage interval.
- For concentration-dependent killers with a prolonged postantibiotic effect whose PK/PD relationship is to have an ideal Cmax:MIC (and if the volume of distribution [Vd] of the antimicrobial is known), a precise drug dosage regimen for the pathogen can be calculated from the following equation:

Dose = Vd × desired plasma concentration (where the desired plasma concentration is some multiple of the MIC [usually 8 to 10] and once-daily dosing is assumed).

- For concentration-dependent killers whose PK/PD relationship is to have an ideal AUC0-24 hr:MIC, the following equation can be used to calculate a dose per day:

Dose = (AUC0-24:MIC) × MIC × Cl

F × 24 hr

(where AUC0-24 hr:MIC is > 100, Cl is clearance [volume of blood cleared of drug per day in ml/kg], and F is bioavailability).

- For time-dependent killers, the objective is to keep the average plasma drug concentration above the pathogen's MIC for the duration of the dosage interval. Again, using Vd and elimination half-life information, you can precisely calculate a dosing regimen:

Dose = desired avg plasma conc × Vd × dosage interval 1.44 × t1/2

Practical Considerations
Antimicrobials can be categorized as either concentration dependent or time dependent (Table 1).
• For concentration-dependent antimicrobials (fluoroquinolones such as enrofloxacin, orbifloxacin, difloxacin, and marbofloxacin; aminoglycosides such as gentamicin and amikacin), regimens should be high-dose, once-daily for optimal efficacy. Cost and toxicity are the only real limitations to how high the dose can be.
- For some bacteria with very high minimum inhibitory concentrations (MICs), such as Pseudomonas aeruginosa, achieving the optimum pharmacokinetic/pharmacodynamic ratios may be impossible with label dosages or higher-than-label dosages of fluoroquinolones. In such cases, underdosing is ineffective and merely contributes to antimicrobial resistance.
• For time-dependent antimicrobials (penicillins, cephalosporins, most macrolides and lincosamides, tetracyclines, chloramphenicol, and potentiated sulfonamides), keeping the plasma concentration of the drug above the bacterial MIC is important for optimal efficacy.
- These drugs typically require frequent dosing or constant rate infusions for appropriate therapy, unless they have been formulated to be "long acting."
- In sequestered infections, penetration of a time-dependent antimicrobial to the site of infection may require high plasma concentrations to achieve a sufficient concentration gradient.

APPROPRIATE VERSUS INAPPROPRIATE ANTIMICROBIAL THERAPY • Patricia M. Dowling

Suggested Reading
Antimicrobial Therapy in Veterinary Medicine, 4th ed. Giguere S, Prescott JF, Baggot JD, et al-Ames: Iowa State University Press, 2006.
Pharmacokinetic/pharmacodynamic relationships of antimicrobial drugs used in veterinary medicine. McKellar QA, Sanchez Bruni SF, Jones DG. J Vet Pharmacol Ther 27:503-514, 2004.