SECTION A
Pharmacology Guidelines

Chapter 1: Understanding Minimum Inhibitory Concentrations (MICs)

The National Committee on Clinical Laboratory Standards and the Clinical and Laboratory Standards Institute (CLSI) help to determine the susceptibility testing guidelines for most common organisms and antimicrobial agents in each species. Minimum Inhibitory Concentration (MIC) ranges for sensitive organisms are then set for specific antibiotics. To obtain an MIC for a bacteria, antibiotic concentrations are doubled in concentrations between the range of 0.06-512 µg/mL (0.06, 0.12, 0.25, etc.) to determine the susceptibility of bacteria. As antibiotic concentrations are increased, bacteria stop dividing or are killed. Bacteria that continue to proliferate at concentrations that are inhibitory for the same species are considered resistant. Typically, laboratories report susceptibilities as sensitive, intermediately sensitive or resistant to a particular antibiotic. In general, if a bacterium is resistant to an antibiotic in vitro, it should not be considered for in vivo (clinical) use. If an organism is considered to have "intermediate" sensitivity to an antibiotic the antibiotic may still be efficacious in vivo (clinically) in situations where high concentrations can be achieved (urine, topical therapy). If bacteria are susceptible to a particular antibiotic then it may be useful in vivo (clinically) if other variables are favorable (pharmacokinetics, toxicity, penetration to the site of action, etc.). When comparing between antibiotics that are both sensitive, the "breakpoint" must be considered. The breakpoint is also set by the National Committee on Clinical Laboratory Standards. The breakpoint is the concentration of antibiotic that cannot be exceeded in vivo (clinically) due to its pharmacokinetics and toxicity. The greater the difference between the MIC of the organism and the breakpoint helps to determine which antibiotic may be more efficacious.

Chapter 2: Static versus Cidal Antibiotics

The definitions of "bacteriostatic" and "bactericidal" antibiotics appear to be straightforward. A "bacteriostatic" antibiotic implies that it only produces "static" effects on bacteria versus a "bactericidal" antibiotic that kills the organisms. However, these categories are not absolute and drugs can act as either "static" or "cidal" under different conditions. Their mechanism of action may be influenced by growth conditions, bacterial density, test duration, and extent of reduction in bacterial numbers. Often agents that are "cidal" may fail to kill every organism in a large inoculum within 18-24 h. Furthermore, agents that are "static" may only kill some bacteria over 18-24 h, but may continue to kill organisms after the test period, but not enough to be called "cidal" (>99.9% in 24 h). Clinically, this is even more arbitrary. Most antibacterials are better described as potentially being both bactericidal and bacteriostatic depending on the organism and the concentrations achieved at the site of action. For theoretical purposes the following description of each is presented.

Bacteriostatic

For bacteriostatic antibiotics (those that prevent growth) the percent time that serum antibiotic concentrations are above the MIC of the organism should be >50% for most patients or closer to 100% for severely ill patients with immunosuppression or with debilitated patients. The dose here can remain the same but the dosing frequency can be increased to improve efficacy (i.e., from BID to TID). These are considered time dependent antibiotics. This differs from concentration dependent (or dose dependent) antibiotics that are considered "cidal". Examples of antibiotics categorized primarily as bacteriostatic agents include: Chloramphenicol, macrolides, tetracyclines, clindamycin, linezolide, and rifampin.

Bactericidal

For bactericidal antibiotics, the peak concentrations of antibiotic are important and should approximate 4-8 times the MIC concentrations of the organism. To maximize the clinical efficacy here, the dose must be increased and the frequency can stay the same. Examples of antibiotics that are considered bactericidal include: Aminoglycosides, penicillins, cephalosporins, carbapenems,vancomycin, fluoroquinolones, metronidazole, nitrofurantoin, and co-trimazole.

Chapter 3: In Vitro versus In Vivo Efficacy

In vitro culture and sensitivity will assist in antibiotic selection but may not always dictate in vivo efficacy. Many other factors also play a role in determining the in vivo outcome. Poor owner compliance, administration of an unstable compounded product, poor gastrointestinal absorption (altered formulation, drug/drug, drug/food interactions, variable gastrointestinal transit time, malabsorption, etc.) may all affect the ability of a drug to be absorbed. Following absorption, the distribution of drugs to the site of the infection may also be a challenge. Penetration of drugs into some physiological spaces including the eye, CNS, prostate, intracellular spaces, and into abscesses is often very difficult and is dependent on protein binding, lipophilicity, size, and degree of ionization of the drug molecule. A good example of this is the third generation cephalosporins. While all cephalosporins may appear to be effective judged on their MICs, if being used for CNS disease only cephalosporins with low protein binding can penetrate across the blood brain barrier in sufficient quantities to maintain therapeutic levels (Table 3.1). In addition, some organisms such as Staphylococcus spp. that appear to be sensitive in vitro to trimethoprim/sulfamethoxazole (TMS) combinations are able to circumvent the drug in vivo by utilizing the host's folate rendering the drug inactive. This is also true for Enterococcus spp. where both TMS and cephalosporins appear sensitive in vitro but should not be used clinically.

Table 3.1 Properties of Cephalosporins