A problem in the interpretation of β-lactam antibiotic levels in tissues

Abstract

Ceftazidime was injected iv to rabbits (25 mg/kg). Samples of the whole muscle and muscle tissue fluid were removed at 0.25, 0.5, 1, 1.5, 2, 2.5 h for assay. Muscle tissue fluid was obtained using implanted cotton threads and freshly applied paper discs. The levels of ceftazidime in muscle fluid were similar to concurrent serum levels at all times tested. Ceftazidime levels in small pieces of excised muscle were significantly lower (ten-fold) than concurrent serum or tissue fluid levels. This difference between ceftazidime levels in whole tissue and tissue fluid is explained by the fact that not all antibiotics penetrate into the cellular mass of tissue but some remain confined to the much smaller interstitial tissue fluid compartment. The assumption that antibiotics will diffuse evenly throughout a tissue is an error to be avoided in the interpretation of antibiotic levels in tissues.

Distribution and Antimicrobial Activity of Fosfomycin in the Interstitial Fluid of Human Soft Tissues

“…Besides a high degree of in vitro antibiotic activity, an ideal antibiotic for soft tissue infections should be characterized by several physicochemical attributes, particularly a low level of protein binding, i.e., the ability to attain high unbound concentrations at the target site, and hydrophilicity, i.e., the ability to selectively penetrate extracellular water spaces. These characteristics are typical of several antibiotics currently recommended as treatments for soft tissue infections, particularly beta-lactams (24). An alternative, promising candidate in this regard appears to be fosfomycin, which is negligibly bound to serum proteins, has a water-soluble, hydrophilic structure, and does not undergo metabolism to an inactive portion.…”

“…One important prerequisite for an antibiotic to be clinically effective in soft tissue infections is the ability to attain unbound concentrations in the interstitial fluid high enough to exceed the MICs for the relevant pathogens (16,24). An antibiotic which might be particularly favorable in this regard is fosfomycin (6,8).…”

Antibiotic tissue penetration and its relevance: impact of tissue penetration on infection response

“…Calculations such as those in Table 1 in the accompanying paper (60a) show how drugs which do not penetrate cells but which are evenly distributed throughout blood and ECF can produce the false impression of low biophase penetration. In contrast, steadystate or postdistributive concentrations of these antibiotics in ECF obtained with cotton threads or paper disks are similar to the corresponding concentrations in serum (78)(79)(80). On the basis of ECF models, one would conclude that f-lactam antibiotics penetrate extracellular infection sites very well.…”

“…Antibiotic serum protein binding has been tabulated with the method of determination specified (17). In general, the aminoglycosides (37) and quinolones (62) (78,79). The lack of intracellular penetration of these ,-lactams explains these results.…”

Antibiotic tissue penetration and its relevance: models of tissue penetration and their meaning

“…It is generally assumed that most bacterial infections occur in what is considered the extracellular or interstitial space (1,42,43,58). Bacteria attach to the surfaces of host cells as well as to any artificial surface on which nutrients and metabolic products are available (35).…”