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A new //-lactam antibiotic, named thienamycin, was discovered in culture broths of Streptomyces MA4297. The producing organism, subsequently determined to be a hitherto unrecognized species, is designated Streptomyces cattleya (NRRL 8057). The antibiotic was isolated by adsorption on Dowex 50, passage through Dowex 1, further chromatography on Dowex 50 and Bio-Gel P2, and final purification and desalting on XAD-2. Thienamycin is zwitterionic, has the elemental composition CuHIGN2O4S (M.W.=272.18) and possesses a distinctive UV absorption (Amax=297 nm, e=7,900). Its /3-lactam is unusually sensitive to hydrolysis above pH 8 and to reaction with nucleophiles such as hydroxylamine, cysteine and, to a lesser degree, the primary amine of the antibiotic itself. The latter reaction results in accelerated inactivation at high antibiotic concentrations. * This report was presented in part at the 16th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill., 1976 (q. v. abstract #227) ** This antibiotic is the first representative of a family of des-thia-carbapenem nucleus antibiotics in which the enamine portion of the fused 5-member ring bears a thioethylamine moiety. From this structural feature , the name thienamycin (thi'en-a-mi'san) is derived. THE JOURNAL OF ANTIBIOTICS JAN.

The practical application of thienamycin, a novel ,8-lactam antibiotic with a broad activity spectrum, was compromised by problems of instability. MK0787, N-formimidoyl thienamycin, does not have this liability. As reported, bacterial species resistant to most ,8-lactam antibiotics, such as Pseudomonas aeurginosa, Serratia, Enterobacter, Enterococcus, and Bacteroides spp., are uniformly susceptible to MK0787, usually at one-half the inhibitory level of thienamycin. Bactericidal ativityusuallv occurs at the minimal inhibitory concentration endpornt. Activity was reduced ony at the highest mocuum densities tested and by a lessor factor than was observed with reference 8l-lactam antibiotics active against P. aeruginosa and ,f-lactamase-bearing strains. MK0787 exhibits a broad spectrum of in vivo actvity when evaluated parenterally for efficacy against systemic infections in mice. The order of potency in vivo, 0.03 to 0.06 mg/kg for gram-positive species and 0.65 to 3.8 mg/kg for gram-negative infections including Pseudomonas, exceeded that of thienamycin and was at least 10-fold superior to reference ,B-lactam antibiotics including two recently developed agents with antipseudomonal activity, cefotaxime and LY127935.Thienamycin, a novel ,B-lactam antibiotic (1) (Fig. 1A)

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N-Formimidoyl thienamycin (MK0787) undergoes renal metabolism by a dipeptidase, dehydropeptidase I, located on the brush border of the proximal tubular cells. The effects of two inhibitors (MK-789 and MK-791) of dehydropeptidase I on the pharmacokinetics of N-formimidoyl thienamycin were studied in 41 healthy subjects receiving various combinations of N-formimidoyl thienamycin and MK-789 or MK-791. Both inhibitors affected the plasma kinetics of N-formimidoyl thienamycin only to a small extent. Plasma concentrations and the area under the plasma concentration curve increased about 20%'o with a proportional decrease in plasma clearance. Plasma half-life was not altered significantly. Coadministration of MK-789 or MK-791 resulted in uniform and marked increases in urinary recovery and renal clearance of N-formimidoyl thienamycin. Thus, at an Nformimidoyl thienamycin/MK-791 ratio of 1:0.25 or higher, the urinary recovery was about 72% in all subjects, whereas it varied between 7.7 and 43% when Nformimidoyl thienamycin was given alone. The ratio of the N-formimidoyl thienamycin and MK-791 doses affected response. At relatively higher doses of MK-791, significant increases of N-formimidoyl thienamycin urinary recovery, renal clearance, and urine concentrations occurred during the later part of the 10-h observation period after each administration. At a 1:1 ratio of the two drugs, the inhibition of renal metabolism of N-formimidoyl thienamycin was maintained for at least 8 h, whereas renal clearance declined as soon as 4 h after the administration of a 1:0.25 ratio. The results indicated that MK-789 and MK-791 alter the renal excretion of N-formimidoyl thienamycin from glomerular filtration plus tubular secretion to glomerular ifitration only, possibly by competitively inhibiting the penetration of N-formimidoyl thienamycin into the proximal tubular cells.The human pharmacokinetics of N-formimidoyl thienamycin (MK0787) are characterized by high plasma concentrations and rapid elimination via the kidneys (3). The urinary recovery (UR) of N-formimidoyl thienamycin varies considerably between subjects, whereas the withinsubject variation is very small (3). The were included in the studies described in this report.All subjects gave their informed written consent to participate, and the protocols for the studies were 300