The penem BRL 42715, C6-(N1-methyl-1,2,3-triazolylmethylene)penem, is a potent inhibitor of a broad range of bacterial P-lactamases, including the plasmid-mediated TEM, SHV, OXA, and staphylococcal enzymes, as well as the chromosomally mediated enzymes of Bacteroides, Enterobacter, Citrobacter, Serratia, Morganella, Escherichia, Klebsiella, and Proteus species. The concentration of BRL 42715 needed to reduce the initial rate of hydrolysis of most P-lactamase enzymes by 50% was <0.01 ,ug/ml, which was 10-to 100-fold lower than for other l-lactamase inhibitors. These potent inhibitory activities were reflected in the low concentrations of BRL 42715 needed to potentiate the antibacterial activity of ,-lactamase-susceptible Il-lactams. Concentrations of 0.25 ,ug/ml or less considerably enhanced the activity of amoxicillin against many jI-lactamase-producing strains. The MIC50 (MIC for 50% of strains tested) of amoxicillin for 412 ,3-lactamase-producing members of the family Enterobacteriaceae fell from >128 to 2 ,ug/ml in the presence of 1 jig of BRL 42715 per ml, whereas 5 jig of clavulanic acid per ml brought the MIC5. down to 8 jig/ml. Among these 412 strains were 73 Citrobacter and Enterobacter strains, and 1 ,ig of BRL 42715 per ml reduced the M1C50 of amoxicillin from >128 to 2 ,ug/mI for the 48 cefotaxime-susceptible strains and from >128 to 8 ,ig/ml for the 25 cefotaxime-resistant strains.The ,B-lactamase enzymes form a large and diverse group (3,19) and are recognized as a major cause of bacterial resistance to P-lactam antibiotics (14). This resistance can often be overcome either by using P-lactam antibiotics that are stable to hydrolysis by P-lactamases or by combining labile 3-lactams with enzyme inhibitors which may not themselves be useful antibacterial agents but which have the ability to inactivate P-lactamases. The first ,-lactamase inhibitor to have clinical application was clavulanic acid (8, 16), and formulations of amoxicillin plus clavulanic acid and of ticarcillin plus clavulanic acid are available which protect the antibiotics amoxicillin and ticarcillin from hydrolysis by many P-lactamase-producing organisms. More recently described P-lactamase inhibitors include sulbactam (5) and tazobactam (YTR 830; 1). Clavulanic acid is highly active against a broad range of P-lactamases, including the Ic enzymes produced by Proteus vulgaris and Bacteroides fragilis, but is only weakly active against other class I enzymes. Sulbactam is generally less potent than clavulanic acid (9), although it does have some activity against most class I enzymes, while tazobactam is similar in potency to clavulanic acid and also has moderate activity against the class I enzymes.Studies done in our laboratories on the structural modification of the penem nucleus culminated in the synthesis of compounds containing an alkylidene moiety at the C6 position of the penem ring system (I.

(15). Experimental animal models have been of significant value in studying the pathogenesis of chlamydial infection, particularly the immunopathological sequelae of untreated asymptomatic infection in females-salpingitis, ectopic pregnancy, and tubal infertility. Nonhuman primate models resemble the human disease most closely (19), but these animals are costly and in restricted supply. Guinea pigs, rabbits, and cats have also been used (11,20,21 on fertility. The mouse pneumonitis biovar of C. trachomatis, MoPn, is genetically and antigenically distinct from human biovars (32) but has the advantage that it is a natural mouse pathogen, particularly of the respiratory tract. To our knowledge, the use of this strain in experimental genital tract chemotherapy has been restricted to two studies involving intrabursal inoculation of mice to induce hydrosalpinx and infertility (5, 26) and a third in which C. trachomatis MoPn was introduced intravaginally to progesterone-treated mice. In the last study, therapy experiments were terminated after 12 days and long-term sequelae were not described (3).We report here, for the first time, the development of an upper genital tract infection in progesterone-treated outbred mice caused by intravaginal inoculation with C. trachomatis MoPn, in which salpingitis, hydrosalpinx formation, and loss of fertility were observed. We have used the model to assess the effects of minocycline, doxycycline, amoxicillin-clavulanic acid, and azithromycin on chlamydial shedding and preservation of fertility. MATERUILS AND METHODS Organism

. Agents Chemother. 33:1580Chemother. 33: -1587Chemother. 33: , 1989. The pharmacokinetics of BRL 42715 were studied following oral and parenteral administration in inice, rats, rabbits, beagle dogs, and cynomolgus monkeys. The elimination half-life (tQ12) of BRL 42715 following intravenous administration was 7 min in rats, 6.2 min in rabbits, 11 min in dogs, and 18 min in cynomolgus monkeys; and interspecies scaling indicated a tj12 of 31 min in humans. Urinary recovery was 24 to 43% in the three species studied. A linear relationship was observed between the dose and the theoretical concentration in blood at time zero and between the dose and area under the concentration-time curve following intravenous administration to mice. Extravascular dosing in mice, rats, and dogs resulted in an increase in t1/2, suggesting a depot effect.BRL 42715 was absorbed in mice following an oral dose (bioavallability of 0.2), but was not absorbed in rats, dogs, or cynomolgus monkeys to any significant extent. The binding of BRL 42715 in serum was 27 to 38% in mouse, rat, and dog sera but was somewhat higher (68 to 70%) in primate and human sera. BRL 42715 was not readily hydrolyzed by the renal dehydropeptidase enzymes of any of the five species studied.BRL 42715 is a penem derivative which is a potent inhibitor of a broad range of ,B-lactamases, including the chromosomally mediated enzymes of Enterobacter, Citrobacter, and Pseudomonas species, against which all other Plactamase inhibitors have poor activity (9). The pharmacokinetics of BRL 42715 were studied in laboratory animals, and these data are reported here.The enzyme renal dehydropeptidase I (RDHP) is known to be a major cause of metabolic inactivation of carbapenems such as imipenem in both laboratory animals and humans. Inhibition of this enzyme by the RDHP inhibitor cilastatin resulted in a six-to eightfold increase in the urinary recovery of imipenem and reduced nephrotoxic potential (12). Certain penem antibiotics are also known to be hydrolyzed by RDHP (11), and it was considered necessary in the early stages of evaluation to determine the stability of BRL 42715 compared with those of the Schering penems SCH 29482 and SCH 34343 and the carbapenems BRL 13902 (3) and imipenem in various kidney homogenates. The results of that study are also reported here. MATERIALS AND METHODSTest compounds. BRL 13902 and BRL 42715 were prepared by SmithKline Beecham Pharmaceuticals. Cilastatin and imipenem were gifts from Merck Sharp & Dohme, Rahway, N.J. SCH 29482 and SCH 34343 were gifts from Schering-Plough Corp., Bloomfield, N.J.Binding of drug to serum. Duplicate samples of BRL 42715 were diluted in pooled fresh serum to a final concentration of 100 ,ug/ml, and the solution was left at room temperature for 15 min, following which samples were centrifuged in an Amicon micropartition system at 1,500 x g for 20 min. BRL 42715 was assayed by high-pressure liquid chromatography using a Waters MicrobondaPak C18 RP column in an RCM-* Corresponding author. 100 unit and was eluted with ...