Comparative Antipneumococcal Activities of Sulopenem and Other Drugs

Abstract

For 297 penicillin-susceptible, -intermediate, and -resistant pneumococcal strains, the sulopenem MIC 50 s were 0.008, 0.06, and 0.25, respectively, and the sulopenem MIC 90 s were 0.016, 0.25, and 0.5 g/ml, respectively. The MIC 50 s of amoxicillin for the corresponding strains were 0.03, 0.25, and 2.0 g/ml, respectively, and the MIC 90 s were 0.03, 1.0, and 8.0 g/ml, respectively. The combination of amoxicillin and clavulanate gave MICs similar to those obtained with amoxicillin alone. The sulopenem MICs were similar to those of imipenem and meropenem. The MICs of ß-lactams increased with those of penicillin G, and among the quinolones tested, moxifloxacin had the lowest MICs. Additionally, 45 strains of drug-resistant type 19A pneumococci were tested by agar dilution and gave sulopenem MIC 50 s and MIC 90 s of 1.0 and 2.0 g/ml, respectively. Both sulopenem and amoxicillin (with and without clavulanate) were bactericidal against all 12 strains tested at 2؋ MIC after 24 h. Thirty-one strains from 10 countries with various penicillin, amoxicillin, and carbapenems MICs, including those with the highest sulopenem MICs, were selected for sequencing analysis of the pbp1a, pbp2x, and pbp2b regions encoding the transpeptidase active site and MurM. We did not find any correlations between specific penicillin-binding protein-MurM patterns and changes in the MICs.The incidence of pneumococci resistant to penicillin G and other ß-lactam and non-ß-lactam compounds has increased at an alarming rate worldwide, including the United States. The major foci of infections currently include South Africa, Spain, and Central and Eastern Europe (26,27). A 1997 survey showed that 50.4% of 1,476 clinically significant pneumococcal isolates in the United States were not susceptible to penicillin (26). Of all strains tested, approximately 33% were macrolide resistant, with the highest rate of macrolide resistance being seen among penicillin-resistant strains, for which the MICs were Ն2.0 g/ml (26). A later survey, conducted as part of the Alexander Project (27), reported that the worldwide prevalence of pneumococci isolated between 1998 and 2000 for which penicillin G MICs were Ն2 g/ml was 18.2%, with the overall macrolide resistance rate being 24.6%. It is also important to note the higher rates of isolation of penicillin-intermediate and -resistant pneumococci (approximately 30%) in middle ear fluids from patients with refractory otitis media than from other isolation sites (4). Quinolone-resistant pneumococci have also been described (6,22,31). The problem of drug-resistant pneumococci is compounded by the ability of resistant clones to spread from country to country and from continent to continent (32, 34). In a recent paper, Pichichero and Casey (40) reported on the emergence in the United States of an otopathogenic strain of pneumococcus type 19A which is not covered by the current pediatric conjugate vaccine and which is resistant to all currently FDA-approved antibiotics for the treatment of acute otitis media in children. Anothe...

Development of a Practical and Convergent Process for the Preparation of Sulopenem

“…Penems, a class of β-lactam antibiotics, have been the subject of intense research over the last three decades. − Sulopenem ( 1 ) is a novel 2-thioalkyl penem that was in development for a broad range of indications (Figure ). , In order to support this research program, a practical process for the large-scale preparation of this antibacterial was required.…”

“…1−6 Sulopenem (1) is a novel 2-thioalkyl penem that was in development for a broad range of indications (Figure 1). 7,8 In order to support this research program, a practical process for the large-scale preparation of this antibacterial was required.…”

Affinity of Ceftaroline and Other β-Lactams for Penicillin-Binding Proteins from Staphylococcus aureus and Streptococcus pneumoniae

“…All sequences obtained for pbp1A (nucleotides 870 to 1950), encoding 350 amino acids, pbp2B (nucleotides 655 to 2028), encoding 458 amino acids, pbp2X (nucleotides 301 to 2034), encoding 578 amino acids, and pbp3 (nucleotides 1 to 1242), encoding 413 amino acids, have been described previously (32,34). Their respective GenBank accession numbers are listed in Table 3.…”

Development of a Second-Generation Process to Antibacterial Candidate Sulopenem

“…In 2003, development of sulopenem resumed as multidrug resistant bacteria threatened to render existing therapies ineffective. − The combination of a high-dose daily intravenous delivery, a challenging β-lactam structure, and an aggressive clinical development plan for this candidate required the identification of scalable technology for the manufacture of increasing quantities of active pharmaceutical ingredient (API). Because sulopenem exhibits antibacterial activity and contains a β-lactam structural motif related to that seen in penicillin, − all GMP manufacture was carried out in a dedicated single-product facility to eliminate cross-contamination concerns, as recommended by ICH Q7A. , This added considerable cost and complexity to the API development effort.…”