Comparison of in vitro and in vivo models to assess venous irritation of parenteral antibiotics.
The venous irritation potential of four parenteral antibiotics, tetracycline hydrochloride (TET), erythromycin lactobionate (ERY), amphotericin B (AMP), and cephaloridine (CEP), was evaluated in an in vivo model using the rabbit ear vein. Lateral ear veins of New Zealand White rabbits were infused for 1 hr with test solutions containing TET (0.25,2.5, or 10 mg/ml), ERY (2.5, 5, or 25 mg/ml), AMP (0.05, 0.1, or 0.5 mg/ml), or CEP (4 or 20 mg/ml). Control rabbits received comparable volumes of 0.9% NaCl or 5% dextrose. Approximately 24 hr postinfusion, the rabbits were evaluated for visually evident changes in the treated ears. Pathologic evaluation of the veins was performed using histologic sections and scanning electron microscopy. TET, ERY, and AMP caused concentration-dependent changes in veins characterized primarily by loss of endothelium with associated inflammation and thrombus formation, consistent with the known clinical irritancy of these antibiotics. CEP, on the other hand, was well tolerated in the rabbit ear vein, paralleling its low irritancy potential in man. Test solutions identical to those used in vivo in rabbits were also evaluated in established in vitro assays for hemolytic potential when mixed with whole blood from monkeys and for damage to L6 muscle cells as determined by loss of creatine phosphokinase. Results of the in vitro test systems paralleled those of the rabbit ear model, with TET, ERY, and AMP exhibiting dose-dependent hemolysis and muscle cell toxicity, while CEP was comparatively nontoxic. Of the three models, the rabbit ear vein had the greatest sensitivity when histopathologic evaluation was employed.(ABSTRACT TRUNCATED AT 250 WORDS)
Hoover
D M
DM
Toxicology Division, Lilly Research Laboratories, Greenfield, Indiana 46140.
Gardner
J B
JB
Timmerman
T L
TL
Klepfer
J A
JA
Laska
D A
DA
White
S L
SL
McGrath
J P
JP
Buening
M K
MK
Williams
P D
PD
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000633:toxicity*; D003402:Creatine Kinase / Q000097:blood; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D066298:In Vitro Techniques; D007509:Irritants; D008253:Macaca mulatta; D008297:Male; D008855:Microscopy, Electron, Scanning; D011817:Rabbits; D014680:Veins / Q000187:drug effects* / Q000473:pathology
D000900:Anti-Bacterial Agents; D007509:Irritants; D003402:Creatine Kinase