Tissue Penetration

Because of the difficulties associated with measuring tissue concentrations of drugs, we generally use serum concentration as a surrogate marker in pharmacodynamic models. Although most common bacterial pathogens are extracellular, infections occur in the tissues, and it is the pharmacodynamic profile of an antibiotic at the site of infection that ultimately determines its clinical efficacy. Antibiotic concentrations can vary significantly depending on the type of tissue. Drug penetration into tissues depends on the properties of the specific tissue type, the properties of the antibiotic, and the interactions that occur at the tissue/drug interface. Protein binding, tissue permeability, tissue metabolic processes, and drug physiochemical properties such as lipid solubility, pKa, and molecular weight all influence an antibiotic's movement into human tissues. Only the free fraction (non-protein-bound) of an antibiotic is available to exert a pharmacological effect. For P-lactams, the percent tissue penetration is inversely proportional to the protein binding of the drug. Animal studies show a direct correlation between serum protein binding and penetration into peripheral lymph. The penetration into rabbit lymph of ceftriaxone, a drug that is highly protein bound, is 67.3%. In comparison, the penetration of amoxicillin, a drug with much less serum protein binding, is 97.6% [68].

Methodological problems in obtaining tissue samples are the limiting factor in characterizing antibiotic tissue concentrations. A complete pharmacodynamic picture would include a concentration-time curve for the various tissue compartments. Most studies done in humans to date, however, simply characterize drug penetration into various tissue compartments. In spite of the limitations, these studies have provided important information about the extracellular and intracel-lular disposition of these drugs. Tissue penetration studies consistently show that penicillins and cephalosporins have rapid and good penetration into interstitial fluid [69-72]. The opposite occurs in relation to intracellular space. There is essentially no uptake of P-lactams into peripheral blood mononuclear cells, poly-morphonuclear cells, or alveolar macrophages, thus explaining the ineffectiveness of P-lactams against intracellular pathogens such as Mycoplasma or Chlamydia [73,74].

Standard methods of characterizing tissue concentrations by using whole tissue homogenates tend to underestimate the interstitial concentration of P-

lactams. A promising new technique, currently being developed for studying the pharmacodynamics of drug tissue penetration in both animals and humans, has been applied to the study of P-lactams with some success. Microdialysis is an in vivo sampling technique for the continuous monitoring of drugs or other ana-lytes in the extravascular space. The advantage of microdialysis is that it can be used in a variety of tissue compartments with minimal invasiveness and can therefore be used in subjects that are awake and freely moving. Because it overcomes the limitations of other methods, microdialysis offers a unique opportunity to characterize the pharmacokinetic profile of drugs in tissue compartments such as the interstitial fluid, adipose tissue, muscle, or dermis.

Two microdialysis studies in animals have evaluated the tissue pharmacoki-netic profile of various P-lactams. In the rat thigh model, investigators found an excellent correlation between piperacillin and ceftriaxone concentrations in plasma and predicted free levels of drug in the tissue [75,76]. In a separate study using awake and freely moving rats, the investigators measured ceftriaxone and ceftazidime concentrations in two regions of the animal's brain. Interestingly, not only are the half-lives of the antibiotics in the brain different from their respective half-lives in serum, but drug distribution within the brain differs by region and is not homogenous. Based on this study, antibiotic distribution appears to differ by specific tissue compartment and region [77]. Similar differences, by tissue compartment, in equilibration rates and pharmacokinetic profiles have been observed in human subjects [78]. Microdialysis promises to be a useful tool in pharmacodynamic studies of the future.

The central nervous system presents special problems in relation to studying the pharmacodynamics of drugs. The brain is a unique tissue compartment. Tight junctions of endothelial cells and a low rate of transcellular drug transport both act to exclude antibiotics from the CNS. Impaired host defenses and the slow rate of bacterial growth in the CNS decrease the effectiveness of antibiotics. The primary determinants of antibiotic blood-brain barrier penetration are a drug's lipid solubility, degree of protein binding, ionization, and active transport into or out of the CSF [79]. Although highly lipophilic compounds pass readily into the CSF, P-lactams are hydrophilic, weak organic acids, and their penetration is normally less than 10%. This penetration significantly increases during the inflammation associated with meningitis [80-83]. An additional issue in relation to P-lactams is the active transport mechanism that pumps these drugs out of the CSF. Benzylpenicillin has the highest affinity for the transport pump, but other P-lactams are also subject to elimination by this route.

Antibiotic concentrations are especially difficult to measure in the brain due to the invasiveness in obtaining either spinal fluid (CSF) or tissue samples, and relatively few pharmacodynamic studies have examined the activity of P-lactams in the CNS. Although there is limited evidence that antibiotic pharmaco-dynamics in the brain differ from the dynamics in other tissue compartments, because we cannot easily characterize this in human subjects, antibiotic dosing in CNS infections is still largely empirical. The data we do have, have been obtained from in vitro models or animal studies.

In vitro, for cefotaxime, investigators have shown a limited PAE to E. coli of about 0.5 h in pooled human CSF. The same studies do not demonstrate a PAE for cefotaxime to E. coli in Mueller-Hinton broth (MHB), indicating that there may be a mechanism for PAE that is unique to the CSF [84,85]. There are conflicting results from animal studies measuring the PAE of P-lactams in the CSF [86]. In one study, adding P-lactamase to the CSF reversed the PAE, indicating that small amounts of residual drug in the CSF may actually be responsible for the in vivo PAE [87].

Although studies in animals have suggested that the P-lactam pharmacody-namic parameter in CSF that correlates to efficacy is actually the peak concentration rather than the time above MIC, the results from these studies are inconclusive [88-90]. Using a rabbit pneumococcal meningitis model to investigate the relationship between CSF penicillin concentration and bactericidal rate of killing, the investigators demonstrated that maximal killing occurred at 10-30 times the minimal bactericidal concentration (MBC) of the pathogen [91]. Unfortunately, they did not also determine the duration of time above MBC. As the concentration of drug increases, the time above MBC in the CSF will also increase and will most likely approach 100% of the dosing interval. When the dose of the antibiotic is high enough to provide 100% time above MIC, the pharmacodynamic parameters of time and concentration cannot be separated to determine which parameter really correlates to efficacy.

In contrast, the one study to examine the relationship between the pharma-codynamic parameters of time above MBC, peak/MBC, and AUC/MBC demonstrated that T > MIC continues to be the important pharmacodynamic parameter for P-lactams, even in the CSF. By varying the doses and dosing intervals of ceftriaxone in a rabbit meningitis model of cephalosporin-resistant S. pneumoniae (MIC and MBC = 4.0 |g/mL), the investigators determined that T > MBC is the only pharmacodynamic parameter that independently correlated with ceftriax-one's bactericidal activity. During the first 24 h, the highest rate of bactericidal killing occurred when T > MBC exceeded 95% of the dosing interval. Also, in the first 24 h, twice-daily administration of the same total ceftriaxone dose resulted in longer time > MBC and higher killing rates [92]. On the basis of this study, it appears that the same pharmacodynamic model, time-dependent killing, that defines P-lactam activity in serum and other tissue compartments also defines P-lactam efficacy in the CSF [93].

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