Ocular penetration of N-formimidoyl thienamycin (MK-787) and potentiation by dipeptidase inhibitor (MK-791).
N-formimidoyl thienamycin (MK-787) is a new beta-lactam with potent activity against both aerobic and anaerobic gram-positive and gram-negative bacteria. Its spectrum and activity suggest it may be useful in treatment of complicated intraocular infections. Its ocular penetration was studied in New Zealand white rabbits immediately before and after the third dose of 40 mg/kg administered intravenously at q6h intervals. Plasma, aqueous humor, and vitreous humor were obtained by direct aspiration, and antibiotic levels were assayed using an agar well diffusion method. MK-787 penetrated uninflamed intraocular fluids, including vitreous humor, although vitreous concentrations achieved (0.1-0.2 micrograms/ml) were significantly lower than the mean peak plasma (15 micrograms/ml) and aqueous concentrations (7 micrograms/ml). Nevertheless, the intraocular levels attained approached or exceeded the MIC90 for most sensitive organisms including some gram-negative bacilli important in bacterial endophthalmitis. When administered in combination with the renal enzyme inhibitor MK-791, plasma and aqueous concentrations of MK-787 were markedly potentiated, although vitreous concentrations were minimally affected. The potential usefulness of MK-787 in conjunction with MK-791 in the infected eye should be examined further in an animal model of bacterial endophthalmitis.
D000818:Animals; D001082:Aqueous Humor / Q000032:analysis; D015377:Cilastatin; D003521:Cyclopropanes / Q000494:pharmacology*; D004150:Dipeptidases / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D005123:Eye / Q000032:analysis / Q000378:metabolism*; D005260:Female; D015378:Imipenem; D011817:Rabbits; D013845:Thienamycins / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D014822:Vitreous Body / Q000032:analysis
D003521:Cyclopropanes; D013845:Thienamycins; D015377:Cilastatin; D015378:Imipenem; D004150:Dipeptidases