The in vitro and in vivo antibacterial activities of sulopenem (CP-70, 429), a new parenteral penem antibiotic, were compared with those of imipenem (IPM), flomoxef, cefuzonam (CZON) and cefotaxime. Sulopenem possessed broad-spectrum activities against Gram-positive bacteria and Gram-negative bacteria. Antibacterial activities of sulopenem against methicillin-sensitive Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Streptococcus pyogenes and Streptococcus pneumoniae were equivalent to or somewhat superior to those of IPM. Against members of the family Enterobacteriaceae, sulopenem was 4- to 260-fold more active than reference antibiotics with broad-spectra. In a killing kinetics study for Haemophilus influenzae, sulopenem showed a 99.9% decrease of viable cells after 8 hours at a concentration of 0.20μg/ml. This effect was obtained at a concentration 8-fold lower than that of IPM. The protective effects of sulopenem in murine experimental systemic infections were superior to those of imipenem/cilastatin. In murine experimental mixed infection with Escherichia coli and Bacteroides fragilis, sulopenem had lower ED50, in other words stronger antimicrobial activities than IPM. The therapeutic effect of sulopenem are related well with its MIC value. In guinea pigs experimental lung infection with Klebsiella pneumoniae, sulopenem was more effective than CZON or cefotiam.

View full abstract

Eighty percent minimum inhibitory concentrations (MICK) of sulopenem against clinically isolated 12 to 80 strains of each of different bacteria were as follows: methicillin-susceptible Staphylococcus aureus (MSSA): 0.20μg/ml, methicillin-resistant S. aureus (MRSA): 50μg/ml, coagulase-negative staphylococci: 3.13μg/ml, Streptococcus pyogenes:≤0.013μg/ml, Streptococcus pneumoniae:≤0.013μg/ml, β-streptococci: 0.05μg/ml, Enterococcus faecalis: 12.5μg/ml, Enterococcus faecium:>100μg/ml, Escherichia coli CS2(R⁺): 0.10μg/ml, Klebsiella pneumoniae: 0.05μg/ml, Proteus mirabilis: 0.10μg/ml, Proteus vulgaris: 0.20μg/ml, Morganella morganii: 0.39μg/ml, Providencia rettgeri: 3.13μg/ml, Citrobacter freundii: 0.20μg/ml, Enterobacter cloacae: 0.39μg/ml, Serratia marcescens: 1.56μg/ml, Pseudomonas aeruginosa: 50μg/ml, Pseudomonas cepacia: 3.13μg/ml, Xanthomonas maltophilia: >100μg/ml, Acinetobacter calcoaceticus: 1.56μg/ml, ampicillin-resistant Haemophilus influenzae: 0.39μg/ml and Bacteroides fragilis: 0.20μg/ml, respectively. Sulopenem possesses a stronger activity than flomoxef or cefuzonam against Gram-positive bacteria, the strongest activity among the antibiotics tested against Gram-negative bacteria except P. aeruginosa.
Sulopenem has stronger affinities than imipenem to all fractions of PBPs of S. aureus, E. coli, P. vulgaris, S. marcescens, even of P. aeruginosa. Affinities of sulopenem to PBPs-1 and -3 of S. aureus, PBP-2 of E. coli were much stronger than those of imipenem (IPM).
Sulopenem generally has small Ki values to all types of β-lactamases and also has stronger permanent inactivation effect to Ia and IIb types of β-lactamases than IPM.
No synergistic bactericidal activity of sulopenem was apparent with serum complement. However, synergism of sulopenem with macrophages was prominent in bactericidal activity. The cells of E. coli were well phagocytosed and rapidly digested by cultured macrophages in the presence of a higher than 1/8 MIC of sulopenem.
Moreover, sulopenem was more stable than imipenem against swine and human dehydropeptidase-Is. Sulopenem is one of the antibiotics that do not induce the appearance of subclones resistant to the drug.

View full abstract

Sulopenem, a new penem antibiotic, was compared with other antibiotics with regard to in vitro antibacterial and bactericidal activities, stabilization against β-lactamases, and effect on the release of lipopolysaccharide from Gram-negative bacteria. The results are summarized as follows.
1. Sulopenem showed more potent activities than other antibiotics against both Gram-positive and Gram-negative bacteria except Pseudomonas aeruginosa.
2. Sulopenem showed potent bactericidal activities (MIC/MBC) against both Gram-positive and Gram-negative bacteria. Time kill studies against Staphylococcus aureus, Escherichia coli, Enterobacter cloacae and Citrobacter freundii showed potent bactericidal activities of sulopenem.
3. Sulopenem was found to possess a stronger activity than other antibiotics against β-lactamase-producing strains except P. aeruginosa and Stenotrophomonas maltophilia.
4. In particular, sulopenem was found to be more stable to the hydrolysis by various β-lactamases produced by Gram-negative bacteria than any other antibiotics tested. Vmax/Km values of sulopenem were smaller than those of cefotiam for all tested β-lactamases, which reflected a broad antibacterial spectrum of sulopenem.
5. E. coli ML4707 exposed to sulopenem and imipenem released less endotoxin than did controls at all concentration ranges tested. In contrast, the strain exposed to ceftazidime at bacteriostatic concentrations released a large amount of endotoxin.

View full abstract

The in vitro and in vivo antibacterial activities of sulopenem, a new penem, were evaluated in comparison with imipenem (IPM), meropenem (MEPM), ceftazidime (CAZ) and flomoxef (FMOX).
Sulopenem had broad and potent antibacterial spectra against Gram-positive and Gram-negative bacteria, including Enterococcus faecalis, Proteus vulgaris, Morganella morganii, Enterobacter spp. and Citrobacter freundii. Sulopenem showed concentration-dependent bactericidal activities against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Acinetobacter calcoaceticus. Morphological observation using phase-contrast microscope revealed that sulopenem induced spherical cell formation with E. coli and K. pneumoniae at lower concentrations and bacteriolysis at higher concentrations. Therapeutic efficacies of sulopenem against systemic infections in mice were almost equal to those of imipenem against Streptococcus pneumoniae. While its therapeutic efficacies were superior to those of meropenem, ceftazidime and flomoxef against S. aureus and S. pneumoniae, they were inferior to those of imipenem/cilastatin against S. aureus, K. pneumoniae and A. calcoaceticus.

View full abstract

In vitro activities of sulopenem, a novel parenteral penem, was compared with those of imipenem, flomoxef, cefuzonam, cefoperazone and sulbactam/ampicillin against 66 reference strains (19 genera, 61 species) and 392 recent clinical isolates of anaerobic bacteria and fastidious aerobic bacteria. Sulopenem had a very broad spectrum against anaerobic bacteria. In general, this compound was active against anaerobic reference strains with MICs of 0.78μg/ml, while being the least active against Bifidobacterium spp. and less active than imipenem against Lactobacillus spp. Sulopenem was more active against Bacteroides fragilis isolates than imipenem and had the highest activities against Bacteroides thetaiotaomicron, Prevotella intermedia, Porphyromonas gingivalis, Fusobacterium spp. and Peptostreptococcus spp. among the antibiotics tested.
Sulopenem was not hydrolyzed by oxyiminocephalosporinase type 1 produced by B. fragilis GAI-0558, GAI-7955 and GAI-10150 and its stability was comparable to imipenem. Its susceptibilities to hydrolysis by a metallo-β-lactamase from B. fragilis GAI-30144 was less than imipenem.
Sulopenem (120mg/kg, 3 times a day for 4 days) was as effective as imipenem/cilastatin against a mixed intraabdominal mice infection due to E. coli and B. fragilis. Sulopenem (20mg/kg twice a day for 5 days) did not induce an overgrowth of Clostridium difficile in the caecum of mice.

View full abstract

In order to evaluate the antimicrobial activity of meropenem (MEPM), minimum inhibitory concentrations (MICs) of MEPM and control drugs were determined against clinical isolates from blood and cerebrospinal fluid that were obtained from January, 1993 to December, 1994.
The results are summarized as follows;
1. The MIC-range, 50% MIC (MIC₅₀) and 90% MIC (MIC₉₀) of MEPM were equal to those of imipenem (IPM) and panipenem (PAPM) against Streptococcus pneumoniae including benzylpenicillin (PCG)-insensitive or -resistant S. pneumoniae, Streptococcus agalactiae and Listeria monocytogenes which are Gram-positive strains, and were stronger than those of ampicillin (ABPC) and cefotaxime (CTX).
2. The MIC-range, MIC₅₀ and MIC₉₀ of these 3 drugs of carbapenems (MEPM, IPM and PAPM) were different against Escherichia coli and Haemophilus influenzae which are Gram-negative strains. The MIC₉₀ of MEPM was ≤0.025μg/ml and those of IPM and PAPM were 0.2μg/ml against E. coli. The MIC₉₀ of MEPM was 0.1μg/ml, that of IPM was 25μg/ml and that of PAPM was 6.25μg/ml against H. influenzae. Thus, the antimicrobial activity of MEPM was stronger than those of IPM and PAPM.
The MIC₉₀'s of IPM and PAPM against H. influenzae were high with the MIC of IPM at 12.5-25μg/ml and the MIC of PAPM at 3.13-12.5μg/ml against 3 IPM-resistant strains among 17 isolates.
3. The MIC₉₀ of ABPC was 0.39μg/ml and that of CTX was 0.1μug/ml against 20 strains of S. pneumoniae including 6 strains of PCG-insensitive or resistant S. pneumoniae. The MIC₉₀ of ABPC and CTX were higher than those of 3 carbapenem drugs. There were E. coil of 8 strains with ABPC-high resistance (the MIC of ABPC was > 100μ/ml) and 2 strains for which MIC of CTX were 0.39μg/ml and 3.13μg/ml.
It was found that 29.4% of H. infiuenzae were 13-lactamase producing strains.
4. It appeared that antimicrobial activities of carbapenems, particularly MEPM were strong against clinical isolates from blood and cerebrospinal fluid.
MEPM will be first choice drug by empiric therapy in infections including sepsis and purulent meningitis.

View full abstract

Clinical and bacteriological studies were carried out on cefditoren pivoxil (CDTR-PI) granule in infantile purulent acute otitis media treated at general practice settings and the following findings were obtained:
1. Two hundred forty eight strains were isolated from 210 patients, almost all of which (81.1%) harbored the following two strains: Streptococcus pneumoniae (42.3%) and Haemophilus influenzae (38.8%). Among S. pneumoniae, benzylpenicillin (PCG)-insensitive S. pneumoniae (PISP) or PCG-resistant S. pneumoniae (PRSP) was 36.2%, corresponding to 15.3% of all the isolates and found in 18% of all patients.
2. The bacteria in the middle ear discharge and the nasopharyngeal swabs were correlated with conformity rate of more than 80% with regard to Streptococcus pyogenes, S. pneumoniae and H. influenzae but no Staphylococcus aureus was detected simultaneously from the two sources in any of the patients. S. aureus and coagulase-negative staphylococci (CNS) were considered to be contaminants that were originated from the external auditory meatus at the time of sampling.
3. Frequencies of isolation of S. pneumoniae from different age groups were higher in a lower age group between 0 and 4 years and those of PISP or PRSP had the similar tendency.
4. Antibacterial activities were determined for CDTR and related oral antibiotics against the strains of S. pneumoniae and H. influenzae as representative isolates. CDTR had stronger antibacterial activities against both bacteria than the reference antibiotics. CDTR was found to be transferred into the otorrhea at a mean concentration of 0.58 μg/ml after single administration of CDTR-PI granule formulation at 3 mg(potency)/kg.
5. As for bacterial eradication efficacies in the middle ear cavity and the nasopharynx, eradication rates were higher than 80% in the middle ear cavity in all cases without large differences among bacterial species but eradication rate of PISP was 30% in the nasopharynx, and it was significantly lower than those of PSSP and other bacteria.
6. In view of clinical effectiveness, the efficacy rate was 89.4% and bacteriological effects was 92.2%; in view of safety, adverse reactions were; observed in 9.5% and the rate of usefulness was 89.4%.
7. From above-stated results, CDTR-PI was considered as a useful oral antibiotic for infantile acute otitis media including PISP infections.

View full abstract

Clinical efficacy of fluconazole was evaluated against fungal infections complicated with hematological diseases. Fluconazole 200-400mg was administered intravenously to 20 suspected fungal infections occurring in patients with hematological diseases (acute leukemia 6, malignant lymphoma 11, adult T cell leukemia 2, chronic myelogenous leukemia blastic crisis 1). These mycoses included 8 cases of suspected pulmonary fungal infection, 10 cases suspected fungemia, and two cases of suspected hepatic fungal abscess. The clinical response rate was 60.0%. Side effects were observed in two cases, one with transient liver function test abnormality and the other with nausea. Fluconazole is considered to be a potent, safe antifungal agent for the treatment of suspected fungal infections associated with hematological diseases.

View full abstract