Cephalosporin penetration into soft tissue of paralyzed limbs

Abstract

Poor penetration of antibiotics into paralyzed tissue may contribute to the difficulty of curing soft tissue infections in paralyzed limbs. A novel model of spinal cord hemisection was used to induce paralysis of one hind leg in mice. Five, 10, or 20 days after induction of paralysis, six groups of 10 mice were injected intravenously with a single dose or with four sequential doses of cefepime, a new broad-spectrum cephalosporin, and then sacrificed. High-performance liquid chromatography was used to compare cefepime levels in soft tissue homogenates of paralyzed and normal hind legs; no significant differences were found in any group. Factors other than antibiotic delivery may be responsible for difficulty in curing infections in paralyzed soft tissue.Soft tissue infections frequently occur in patients with spinal cord injury and are difficult to treat (5,17,18). Reduced delivery of antibiotics to paralyzed tissue could be responsible, although local factors may also play a role (11). We elected to investigate the effect of paralysis on antibiotic distribution by developing a hitherto undescribed mouse model that caused unilateral paralysis of one hind leg. By using high-performance liquid chromatography, we measured the concentration of cefepime, a new broad-spectrum cephalosporin, in soft tissue homogenates, comparing in each mouse the paralyzed limb with the normal limb. MATERIALS AND METHODSAnimals. Swiss albino Sprague-Dawley mice (approximate weight, 30 g) were used. Mice were anesthetized with methoxyflurane (Pitman-Moore Inc., Washington Crossing, N.J.), and a 0.5-cm incision was made over the midthoracic spine of each mouse. A #15 scalpel blade was gently introduced posterolaterally through soft tissue into the vertebral column. The scalpel was aimed medially to achieve hemisection of the spinal cord. Unilateral paralysis of one hind leg occurred in nearly one-half of the mice; approximately one-third of these animals regained function in the paralyzed leg within a few days, and these were excluded from the study. Cages were modified to provide easy access to food and water.Experimental design. Five, 10, or 20 days after induction of paralysis, groups of 10 mice each were injected intravenously with a single dose, or with four doses at 1-h intervals, of 200 mg of cefepime (Bristol-Myers Company, Wallingford, Conn.) per kg. A pilot study had shown that the serum half-life of cefepime in mice was about 17 min. At 1 h after the last cefepime dose, mice were anesthetized and sacrificed by aspirating as much blood as possible via a cardiac puncture. The heart and great vessels were then severed in order to minimize blood in the peripheral tissue. After removing overlying skin and subcutaneous tissues, both hind legs were resected, rinsed to remove adhering blood, and blotted dry. The soft tissue, which consisted largely of muscle, was dissected from bone, minced, weighed, and placed in polypropylene tubes (17 by 100 mm). Phosphatebuffered saline was added in a volume:weight ratio of 3:1. * Corresponding aut...

Cefepime Clinical Pharmacokinetics

“…limbs compared with normal limbs (Darouiche et al 1989). After 5, 10 or 20 days of paralysis, normal limb concentrations were 7.8, 11.4 and 15.4 mgjL compared with paralysed limb concentrations of 10.5, 13.4 and 15.9 mgjL, respectively.…”