Evaluation of Antibiotic Diffusion into Cardiac Vegetations by Quantitative Autoradiography

Abstract

The reason bacterial endocarditis is difficult to cure has been controversial for many years. One explanation could be that antibiotic diffusion inside the vegetations is heterogeneous. This hypothesis was investigated by means of an autoradiographic study of diffusion of labeled antibiotics into large infected cardiac vegetations of nutritionally variant Streptococcus endocarditis in rabbits. Ten days after infection, 653 microCi of [3H]penicillin, 410 microCi of [3H]tobramycin, or 174 microCi of [14C]teicoplanin were injected iv over 30 min. Thirty minutes after the end of infusion (T30), vegetation/blood radioactivity ratios were 2.48 +/- 1.27, 2.49 +/- 0.67, and 3.94 +/- 1.19 for penicillin, tobramycin, and teicoplanin, respectively. Autoradiography clearly showed that distribution of the three drugs was different: Tobramycin was homogeneously distributed; penicillin was more concentrated at the periphery but still reached the center of vegetations; teicoplanin was concentrated only at the periphery. The same distribution pattern was observed with teicoplanin at T120 (i.e., one t1/2 beta later) and also after simultaneous infusion of a therapeutic dose (15 mg/kg) of cold teicoplanin. The diffusion gradient exhibited by some antibiotics could explain the difficulty in sterilizing vegetations despite high local concentrations, and the deleterious effect of the size of the vegetations on the therapeutic response.

Bactericidal activities of teicoplanin, vancomycin, and gentamicin alone and in combination against Staphylococcus aureus in an in vitro pharmacodynamic model of endocarditis

“…Furthermore, autoradiographic studies have evaluated the diffusion of antibiotics into rabbit endocardial vegetations (15,16 (10,22).…”

Pharmacokinetic and pharmacodynamic requirements for antibiotic therapy of experimental endocarditis

“…The first one is that obtained with 14C-teicoplanin, which remains concentrated at the periphery of the vegetation and does not diffuse into the core of the vegetation (18). The second pattern of diffusion was observed with 'C-ceftriaxone (19), which progressively diffuses into the vegetation, but a high concentration gradient persists between the periphery and the core when autoradiography is performed one elimination half-life after the first determination.…”

“…One explanation could be the hypothesis proposed by Nathanson and Liebhold (47), i.e., the heterogeneous diffusion of the antibiotic into large vegetations. To investigate this hypothesis, we devised an autoradiographic method to evaluate the pattern of diffusion of labeled compounds into infected cardiac vegetations in an animal model of streptococcal endocarditis (18). Even if indirect signs of the presence of antibiotics inside vegetations can be found by electron microscopic examination of the bacteria or by antibiotic microbiological assay of the fragment of the core of a vegetation, or even if it can be speculated by computer analysis (6,44,48), autoradiography remains the sole method that is able to give a precise and quantified image of the antibiotic's distribution pattern.…”

“…The second pattern of diffusion was observed with 'C-ceftriaxone (19), which progressively diffuses into the vegetation, but a high concentration gradient persists between the periphery and the core when autoradiography is performed one elimination half-life after the first determination. To a lesser degree, this concentration gradient is observed with 14C-penicillin (18). For these two groups of antibiotics, measurement of the concentration in homogenates by conventional methods gives a false indication of the actual level of activity at the core of the lesion.…”

“…The concentration gradient between the periphery and the core of the vegetation observed with 1"C-ceftriaxone (19) and, to a lesser degree, 14C-penicillin (18) could explain the need for local concentrations to significantly exceed the MIC and/or MBC for the offending organism (40), as assessed by determination of the drug concentration in a homogenate of the vegetation. The failure of teicoplanin to diffuse into the core of the vegetation could be one explanation for the failures observed with this antibiotic in the therapy of human staphylococcal endocarditis (35).…”