Raymond T. Testa

In vitro and in vivo antibacterial activities of the glycylcyclines, a new class of semisynthetic tetracyclines.

N,N-Dimethylglycylamido (DMG) derivatives of minocycline and 6-demethyl-6-deoxytetracycline are new semisynthetic tetracyclines referred to as the glycylcyclines. The in vitro activities of the glycylcyclines were evaluated in comparison with those of minocycline and tetracycline against strains carrying characterized tetracycline resistance determinants and against 995 recent clinical isolates obtained from geographically distinct medical centers in North America. The glycylcyclines were active against tetracycline-resistant strains carrying efflux [tet(A), tet(B), tet(C), and tet(D) in Escherichia coli and tet(K) in Staphylococcus aureus] and ribosomal protection [tet(M) in S. aureus, Enterococcus faecalis, and E. coli)] resistance determinants. Potent activity (MIC for 90% of strains, < or = 0.5 microgram/ml) was obtained with the glycylcyclines against methicillin-susceptible and methicillin-resistant S. aureus, E. faecalis, Enterococcus faecium, and various streptococcal species. The glycylcyclines exhibited good activity against a wide diversity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to minocycline and tetracycline. The activities of the glycylcyclines against most organisms tested were comparable to each other. The in vivo efficacies of the glycylcyclines against acute lethal infections in mice when dosed intravenously were reflective of their in vitro activities. The glycylcyclines had efficacies comparable to that of minocycline against infections with methicillin-susceptible and methicillin-resistant S. aureus strains, a strain carrying tet(K), and a tetracycline-susceptible E. coli strain but exceeded the effectiveness of minocycline against infections with resistant isolates, including strains harboring tet(M) or tet(B). Levels of DMG-6-deoxytetracycline in serum were higher and more sustained than those of DMG-minocycline or minocycline. Our results show that the glycylcyclines have potent in vitro activities against a wide spectrum of gram-positive and gram-negative, aerobic and anaerobic bacteria, including many resistant strains. On the basis of their in vitro and in vivo activities, the glycylcyclines represent a significant advance to the tetracycline class of antibiotics and have good potential value for clinical efficacy.

Comparative in vitro and in vivo activities of piperacillin combined with the beta-lactamase inhibitors tazobactam, clavulanic acid, and sulbactam.

Tazobactam (YTR-830H), a novel beta-lactamase inhibitor, was compared with clavulanic acid and sulbactam for enhancement of the activity of piperacillin against beta-lactamase-producing, piperacillin-resistant clinical isolates. Piperacillin MICs were determined in media containing a fixed concentration of 2 or 4 micrograms of the inhibitors per ml. The higher concentration was generally more effective. Tazobactam was superior to sulbactam in enhancing the spectrum and potency of piperacillin. Although the calvulanic acid combination was more potent, tazobactam was effective for a similar spectrum of resistant gram-negative clinical isolates containing beta-lactamase. MICs were reduced to the susceptible range for Escherichia coli, Klebsiella pneumoniae, Proteus spp., Salmonella spp., and Shigella spp. Combinations with tazobactam and sulbactam, but not clavulanic acid, were effective against Morganella spp. Some antagonism of the activity of piperacillin was observed with clavulanic acid but not with tazobactam or sulbactam. The inhibitors were similarly effective with piperacillin against beta-lactamase-positive Staphylococcus spp. and the Bacteroides fragilis group. Piperacillin-tazobactam was more effective against a broader spectrum of gram-negative enteric bacteria than ticarcillin plus clavulanic acid was. Combinations with tazobactam or clavulanic acid had a broader spectrum of activity than combinations with sulbactam against bacteria that produce characterized plasmid-mediated enzymes of clinical significance. In particular, piperacillin with tazobactam or clavulanic acid, but not with sulbactam, inhibited TEM-1, TEM-2, and SHV-1 enzymes. In vitro activity was reflected in vivo. Tazobactam and clavulanic acid were superior to sulbactam in enhancing the therapeutic efficacy of piperacillin in mice infected with beta-lactamase-positive E. coli, K. pneumoniae, Proteus mirabilis, and Staphylococcus aureus. Only combinations with tazobactam and sulbactam were effective against the Morganella infection. Tazobactam has a good potential for enhancing the clinical efficacy of piperacillin.

In vitro and in vivo activities of LJC10,627, a new carbapenem with stability to dehydropeptidase I.

The activity of LJC10,627 was compared with the activities of imipenem and other antibiotics. LJC10,627 was more active against most members of the family Enterobacteriaceae, Pseudomonas spp., and Acinetobacter spp. but slightly less active than imipenem against staphylococci and streptococci. LJC10,627 showed stability to mouse dehydropeptidase I and was more effective in vivo than imipenem plus cilastatin against gram-negative bacterial infections and as effective against staphylococcal infections.

Peptidic prodrugs of novel aminomethyl-THF 1β-methylcarbapenems

Abstract Peptidic prodrugs of the five most active aminomethyl-THF 1β-methylcarbapenems were synthesized. Of these, only L-amino acid derivatives from 1a demonstrated an improved oral activity. These results indicate that the L-amino acid derivatives from 1a are orally absorbed most likely through the dipeptide and tripeptide transport mechanism.

Synthesis and structure-activity relationships of novel THF 1β-methylcarbapenems II

Abstract A series of twelve highly active aminomethyl-THF 1β-methylcarbapenems 3a-1 were synthesized. Of these, carbapenems 3a-f demonstrated a spectrum of antimicrobial activity comparable to those of imipenem and meropenem with the exception of only moderate anti-pseudomonal activity. Most importantly, they demonstrated moderate intrinsic oral activity against an E. coli infection in mice.

Mono and bis double ester prodrugs of novel aminomethyl-THF 1β-methylcarbapenems

Mono and bis double ester prodrugs of aminomethyl THF 1β-methylcarbapenems 1 were synthesized. Mono double ester derivatives (2, 4 and 7) did not demonstrate significantly improved oral activity due to the presence of the charged species. However, bis double ester derivatives (3 and 5) demonstrated enhanced oral activity.

In vitro activity of piperacillin/tazobactam against isolates from patients enrolled in clinical trials

The in vitro activity of piperacillin alone or titrated with a constant concentration of 4 mug/ml tazobactam was evaluated against 3962 baseline pathogens isolated from 1899 patients enrolled in 9 clinical trial studies in North America. Tazobactam increased susceptibility rates of piperacillin for Enterobacteriaceae from 81% to 96%, Staphylococcus (methicillin susceptible) spp. from 6% to 100%, Bacteroides fragilis group from 79% to >99% and Haemophilus from 85% to 98%. The excellent activity of piperacillin against Pseudomonas, Streptococcus and Enterococcus was maintained in the presence of tazobactam. Overall piperacillin/tazobactam had better activity than ticarcillin/clavulanic acid, ceftazidime, and in general equaled the activity of imipenem. The excellent in vitro, extended-spectrum activity of piperacillin/tazobactam suggests its utility for various infections.

In Vitro and In Vivo Efficacy of YTR-830H and Piperacillin Combinations Versus β-Lactamase-Producing Bacteria

YTR-830H, a beta-lactamase inhibitor, is a non-amino penicillanic sulfone. In vitro synergistic activity with piperacillin was determined for 226 beta-lactamase producing clinical cultures. Combination of piperacillin: YTR in ratios of 2:1, 4:1, and 8:1 were highly effective vs Escherichia coli, Proteus, Providencia, Morganella, Staphylococcus, and Bacteroides. Minimum inhibitory concentrations (MICs) of piperacillin were reduced from the resistant to susceptible range. The higher ratios were less effective vs Enterobacter, Serratia, and Citrobacter. YTR-830H was not antagonistic with piperacillin. Combinations of 2:1, 4:1, and 8:1 increased the therapeutic effectiveness of piperacillin 8 - to 36 - fold against acute lethal infections produced in mice with piperacillin-resistant Escherichia coli, Klebsiella pneumoniae, Morganella morganii, and Staphylococcus aureus.