AmBisome: relationship between the pharmacokinetic characteristics acquired by liposomal formulation and safety/efficacy.

Amphotericin B (AMPH-B) is a polyene antifungal agent with a superior and broad fungicidal spectrum, but its administration at a dose sufficient for treatment is difficult because of dose- and duration-dependent nephrotoxicity. To solve this dilemma, a liposomal formation of AMPH-B that achieved reduction of adverse effects while maintaining the efficacy, AmBisome® (L-AMB), was developed. In L-AMB, AMPH-B molecules are stabilized by phospholipids and cholesterol in the liposomal lipid bilayer, reducing the cytotoxicity for animal cells compared with that of the free-form AMPH-B.

Therapeutic effect of meropenem on an experimental guinea pig model of meningitis with type b β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae.

The purpose of this study was to investigate the relationship between efficacy and percentage of time above the MIC (%T>MIC) in the cerebrospinal fluid (CSF) for different dosing regimens of meropenem against an experimental lethal meningitis model in guinea pigs with type b β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (Hib BLNAR). Guinea pigs were intrathecally inoculated with 10(8) CFU/head of Hib BLNAR 8 h before the start of therapy. A single dose of 20, 40, or 80 mg/kg meropenem or multiple doses of 40 mg/kg meropenem were subcutaneously administered.

Novel carbapenem antibiotics for parenteral and oral applications: in vitro and in vivo activities of 2-aryl carbapenems and their pharmacokinetics in laboratory animals.

SM-295291 and SM-369926 are new parenteral 2-aryl carbapenems with strong activity against major causative pathogens of community-acquired infections such as methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus pyogenes, Enterococcus faecalis, Klebsiella pneumoniae, Moraxella catarrhalis, Haemophilus influenzae (including β-lactamase-negative ampicillin-resistant strains), and Neisseria gonorrhoeae (including ciprofloxacin-resistant strains), with MIC(90)s of ≤ 1 μg/ml. Unlike tebipenem (MIC(50), 8 μg/ml), SM-295291 and SM-369926 had no activity against hospital pathogens such as Pseudomonas aeruginosa (MIC(50), ≥ 128 μg/ml). The bactericidal activities of SM-295291 and SM-369926 against penicillin-resistant S.

Influence of fungicidal activity against Candida tropicalis on the efficacy of micafungin and liposomal amphotericin B in a neutropenic murine lethal infection model.

Objectives: To investigate the correlation between in vitro killing activity and in vivo efficacy of micafungin (MCFG) and liposomal amphotericin B (L-AMB) against Candida tropicalis in a neutropenic murine lethal infection model.

Methods: Candida albicans (one strain) and C. tropicalis (three strains) were tested in time-kill studies.

[In vivo activity of liposomal amphotericin B against Exophiala dermatitidis in a murine lethal infection model].

This study evaluated the in vivo activity of liposomal amphotericin B (L-AMB) and deoxycholate amphotericin B (D-AMB) in a murine model of disseminated infection caused by Exophiala dermatitidis. Cyclophosphamide-treated neutropenic ddY mice were inoculated intravenously with conidial suspensions of E. dermatitidis IFM 4827 or IFM 53409.

Comparative study of the efficacy of liposomal amphotericin B and amphotericin B deoxycholate against six species of Zygomycetes in a murine lethal infection model.

The objective of this study was to investigate the efficacy of liposomal amphotericin B (L-AMB) at a clinical dose (3 mg/kg) against six species (5 genera) of Zygomycetes in a murine lethal infection model, and to compare findings with those for deoxycholate amphotericin B (D-AMB). The correlation between in-vitro activity and in-vivo efficacy of L-AMB was also investigated. Cyclophosphamide-treated mice were inoculated intravenously with conidial suspensions.

Experimental verification of the efficacy of optimized two-step infusion therapy with meropenem using an in vitro pharmacodynamic model and Monte Carlo simulation.

In this study we compared the efficacy of a theoretically optimized two-step infusion therapy (OTIT; rapid first-step infusion and slow second-step infusion) to the efficacies of prolonged infusion therapy (PIT) and traditional 0.5 h infusion therapy (TIT) with meropenem against Pseudomonas aeruginosa using an in vitro pharmacodynamic model and a Monte Carlo simulation. In the in vitro pharmacodynamic model, the bactericidal effect against P.

Pharmacodynamics of SMP-601 (PTZ601) against vancomycin-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus in neutropenic murine thigh infection models.

SMP-601 (also known as PTZ601, PZ-601, or SM-216601) is a novel parenteral carbapenem with potent activity against multidrug-resistant gram-positive pathogens, including vancomycin-resistant Enterococcus faecium (VREF) and methicillin-resistant Staphylococcus aureus (MRSA). The pharmacodynamics of SMP-601 against VREF and MRSA were investigated in neutropenic murine thigh infection models. The percentage of the dosing interval that the unbound SMP-601 concentration exceeded the MIC (f%T>MIC) was the pharmacokinetic-pharmacodynamic parameter that correlated most closely with efficacy with R(2) values of 0.

Comparative study on the efficacy of liposomal amphotericin B and voriconazole in a murine pulmonary aspergillosis model.

Background: No clinical studies have compared the efficacy of liposomal formulation AMB (L-AMB) and voriconazole (VRC) in the treatment of pulmonary aspergillosis. The aim of this study was to compare the efficacy of L-AMB and VRC in murine pulmonary aspergillosis.

Methods: Leucopenic mice were infected intratracheally with Aspergillus fumigatus and treated intravenously with L-AMB (once a day) or VRC (twice a day).

The mode of action of 2-(thiazol-2-ylthio)-1beta-methylcarbapenems against Pseudomonas aeruginosa: the impact of outer membrane permeability and the contribution of MexAB-OprM efflux system.

The mode of action of a series of 2-(4-dihydropyrrolylthiazol-2-ylthio) and 2-(4-tetrahydropyridinylthiazol-2-ylthio)-1beta-methylcarbapenem analogues against Pseudomonas aeruginosa was investigated with regard to contributions of the affinity for penicillin binding proteins (PBPs), the outer membrane permeability, and the effect of the MexAB-OprM efflux system. In this series of carbapenems, the introduction of a substituent in C-2 side chain with a change in physicochemical properties affected the antipseudomonal activity depending on the molecular weight. However, these structural modifications did not affect the affinity for pseudomonal PBPs significantly.

Orally active carbapenem antibiotics I. Antibacterial and pharmacokinetic potential of 2-phenyl and 2-thienylcarbapenems.

In order to design orally active carbapenem antibiotics effective against beta-lactam-resistant pathogens, such as penicillin-resistant Streptococcus pneumoniae (PRSP) and beta-lactamase non-producing ampicillin-resistant Haemophilus influenzae (BLNAR), a series of novel 2-phenylcarbapenems and some 2-thienyl derivatives were synthesized and tested for antibacterial activities. These compounds were highly active against PRSP, BLNAR, and major Gram-positive and Gram-negative bacteria that cause community-acquired infections. Their pivaloyloxymethylester-type prodrug exhibited good oral absorption in mice, suggesting that this series of carbapenems were promising as a prototype of novel orally active beta-lactams.

In vitro and in vivo antibacterial activities of SM-216601, a new broad-spectrum parenteral carbapenem.

SM-216601 is a novel parenteral 1beta-methylcarbapenem. In agar dilution susceptibility testing, the MIC of SM-216601 for 90% of the methicillin-resistant Staphylococcus aureus (MRSA) strains tested (MIC(90)) was 2 microg/ml, which was comparable to those of vancomycin and linezolid. SM-216601 was also very potent against Enterococcus faecium, including vancomycin-resistant strains (MIC(90) = 8 microg/ml).

[In vitro combined effect of meropenem and various antimicrobial agents against beta-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae and penicillin-resistant Streptococcus pneumoniae].

As a basic study of combination therapy for bacterial meningitis, in vitro combined effect of meropenem (MEPM) and various antimicrobial agents against beta-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (BLNAR) and penicillin-resistant Streptococcus pneumoniae (PRSP) was investigated. The following findings were obtained. 1.

[Bactericial activity of chlorhexidine gluconate against recent clinical isolates of various bacterial species in Japan].

The minimum inhibitory concentration (MIC) and bactericidal activity of chlorhexidine gluconate (CHG) were determined for methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), Escherichia coli, Serratia marcescens, Eterobacter cloacae, Pseudomonas aeruginosa and Burkholderia cepacia, isolated from patients in medical institutions all over Japan between 2000 and 2002. The following findings were obtained.