hr-810 and Disease-Models--Animal

Burkholderia pseudomallei is the causative agent of melioidosis, a disease endemic in tropical and subtropical regions of South-East Asia and Northern Australia. Antimicrobial therapy regimens for treatment of acute septicemic melioidosis are of variable efficacy. Ceftazidime is the current antibiotic of choice and is commonly administered with other agents such as cotrimoxazole or doxycycline. The emergence of resistant strains of B. pseudomallei and the persistence of high mortality rates prompted the present study. Using an established mouse model of acute disseminated B. pseudomallei infection, we compared the efficacy of ceftazidime versus cefpirome in combination with cotrimoxazole or chloramphenicol therapy in vivo. Control mice that were infected but did not receive antibiotic therapy died within 96 hours of infection. No deaths occurred in treatment groups receiving either cephalosporin or cotrimoxazole, despite the demonstrated resistance of B. pseudomallei to cotrimoxazole in vitro. The mortality rate in treatment groups receiving either cephalosporin and chloramphenicol was 66%. These results demonstrate a comparable level of efficacy between ceftazidime and cefpirome for treatment of acute B. pseudomallei infection in mice.

Topics: Animals; Burkholderia pseudomallei; Cefpirome; Ceftazidime; Cephalosporins; Chloramphenicol; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Liver; Melioidosis; Mice; Mice, Inbred BALB C; Spleen; Trimethoprim, Sulfamethoxazole Drug Combination

Three female Yucatan micropigs were included and received a single dose of amikacin (15 mg/kg) by short infusion (30 min) combined either with a single dose of cefepime or cefpirome (30 mg/kg/12 h) or meropenem (7 mg/kg/8 h). The beta-lactams were administered either by intravenous intermittent injection or by continuous infusion. The mean elimination half-life and clearance value of amikacin were 1.88 h and 2.15 ml/min.kg-1 respectively. These pharmacokinetic parameters were similar to those obtained in man (t1/2 = 2,42 h et Cl = 1,61 ml/min kg-1). Furthermore, they were not affected by coadministration of cefepime, cefpirome and to meropenem. While resistant to cefepime, cefpirome and amikacin, Klebsiella pneumoniae producing ESBL was susceptible to combination of these cephalosporins with amikacin in an in vitro/ex vivo micropig model. For the six dosage regimens used in this study, the killing activities were similar and resulted in at least 4 log decrease at 6 h after drug exposure. For antimicrobial combination consisting of bolus dosing of amikacin plus continuous infusion of cefepime or cefpirome, the 12 h serum bactericidal titers (SBTs) were 1:8 for cefepime and 1:2 for cefpirome dosage regimen. When each drug administered intermittently, the 12 h SBTs were 1:4 for cefepime and 1:2 for cefpirome. The 8 h SBTs for dosing schedule containing meropenem combined with amikacin were 1:4 and 1:16 after 30 min short infusion and continuous infusion respectively. In conclusion, our study showed that the micropig model is a reliable model for pharmacokinetic investigation of amikacin. It was concluded that beta-lactam antibiotics tested with amikacin may be coadministered by using the standard recommended dosing regimen of amikacin. Continuous infusion of beta-lactams combined with once dosing of amikacin seems to be as or more effective than intermittent injection of each drug.

Topics: Amikacin; Animals; Anti-Bacterial Agents; Cefepime; Cefpirome; Cephalosporins; Disease Models, Animal; Drug Therapy, Combination; Female; Humans; In Vitro Techniques; Klebsiella pneumoniae; Meropenem; Perfusion; Serum Bactericidal Test; Swine; Thienamycins

The miniature pig exhibits physiological and anatomical similarities to man. In addition, its reduced size and its docility make it appropriate for laboratory use. Curiously, this model remains seldom used in experimental pharmacokinetics. We present here in a chronic model of catheterized micropig allowing long term investigations of antiinfective agents. We work with Yucatan adult female micropigs weighing between 20 and 40kg. A catheter (60 cm x 2 mm) is placed in the external jugular vein under general anaesthesia and exits in the midline dorsal neck. The catheter is flushed every two days with heparinized saline to retain its potency. At the time of kinetic studies, the antiinfective agent is injected in an ear vein. Blood samples are obtained using the jugular catheter. The mean time of viability of the device is 13 weeks (SD: 10 weeks). Thrombosis was the main cause of arrest of the model. In conclusion, this chronic model of catheterized micropig is suitable for long term pharmacokinetic and pharmacodynamic investigations of antiinfective agents.

Topics: Adult; Animals; Antibiotics, Antitubercular; Antifungal Agents; Catheterization, Peripheral; Cefepime; Cefpirome; Ceftriaxone; Cephalosporins; Disease Models, Animal; Female; Humans; Injections, Intravenous; Meropenem; Swine; Thienamycins

Results of in vitro time-kill synergy studies using subinhibitory, inhibitory, or suprainhibitory concentrations of bactericidal agents were compared with treatment outcomes of experimental infective endocarditis due to a methicillin-susceptible strain of Staphylococcus aureus. For rifampin-cephalosporin combinations, in vitro synergy testing using recommended fractions of the MIC failed to predict antagonism in vivo while concentrations above the MIC corresponded with antagonism in vivo.

Topics: Animals; Cefazolin; Cefpirome; Cephalosporins; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Endocarditis, Bacterial; Gentamicins; Microbial Sensitivity Tests; Nafcillin; Predictive Value of Tests; Rabbits; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Time Factors

The most appropriate therapy for meningitis caused by Streptococcus pneumoniae strains resistant to the extended-spectrum cephalosporins is unknown. We evaluated ceftriaxone, vancomycin, and rifampin alone and in different combinations and meropenem, cefpirome, and clinafloxacin alone in the rabbit meningitis model. Meningitis was induced in rabbits by intracisternal inoculation of one of two pneumococcal strains isolated from infants with meningitis (ceftriaxone MICs, 4 and 1 microgram/ml, respectively). Two doses, 5 h apart, of each antibiotic were given intravenously (except that ceftriaxone was given as one dose). Cerebrospinal fluid bacterial concentrations were measured at 0, 5, 10, and 24 h after therapy was started. Clinafloxacin was the most active single agent against both strains. Against the more resistant strain, ceftriaxone or meropenem alone was ineffective. The combination of vancomycin and ceftriaxone was synergistic, suggesting that this combination might be effective for initial empiric therapy of pneumococcal meningitis until results of susceptibility studies are available.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Cefpirome; Ceftriaxone; Cephalosporins; Disease Models, Animal; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Fluoroquinolones; Male; Meningitis, Pneumococcal; Meropenem; Microbial Sensitivity Tests; Penicillin Resistance; Quinolones; Rabbits; Rifampin; Thienamycins; Vancomycin

The transferability of cefpirome (HR810, CPR) to cerebrospinal fluid (CSF) was studied employing rabbits with experimental meningitis caused by Staphylococcus aureus. The mean serum concentration was 362 +/- 6.63 micrograms/ml at 15 minutes after intravenous administration of the drug at a dose level of 100 mg/kg. The mean concentration in CSF was maximum at 60 minutes after administration, and the mean maximum concentration was 14.6 +/- 2.85 micrograms/ml. Pharmacokinetic parameters calculated from these values were as follows, Cmax (CSF/serum): 4.04%; AUC (CSF/serum): 5.14% between 15 and 60 minutes, 8.12% between 15 and 120 minutes and 10.4% between 15 and 180 minutes; T 1/2 for CPR in CSF: 154 minutes; T 1/2 (CSF/serum): 3.96. In comparison to those of other beta-lactam antibiotics which were obtained in the same way, the transferability of CPR was intermediate, but the peak CSF level was high, and in consideration of the antimicrobial potency against the main pathogens of meningitis, it appears worthwhile of running clinical trials for this drug.

Topics: Animals; Cefpirome; Cephalosporins; Disease Models, Animal; Injections, Intravenous; Meningitis; Rabbits; Staphylococcal Infections