RESUMO
Antimicrobial agents may interact synergistically. But to ensure synergy in vivo, the drugs should both be present at the site of infection at sufficiently high concentrations for an adequate period of time. Coencapsulation of the drugs in a drug carrier may ensure parallel tissue distributions. Since liposomes localize preferentially at sites of infection, this mode of drug delivery could, in addition, increase drug concentrations at the focus of infection. The therapeutic efficacy of gentamicin and ceftazidime coencapsulated into liposomes was examined by monitoring survival in a rat model of an acute unilateral pneumonia caused by antibiotic-susceptible and antibiotic-resistant Klebsiella pneumoniae strains. It is shown that administration of gentamicin in combination with ceftazidime in the free form either as single dose or as 5-day treatment resulted in an additive effect on rat survival in both models. In contrast, targeted delivery of liposome-coencapsulated gentamicin and ceftazidime resulted in a synergistic interaction of the antibiotics in both models. Consequently, liposome coencapsulation of gentamicin and ceftazidime allowed both a shorter course of treatment at lower cumulative doses compared with administration of the antibiotics in the free form to obtain complete survival of rats. Liposomal coencapsulation of synergistic antibiotics may open new perspectives in the treatment of severe infections.
Assuntos
Ceftazidima/farmacologia , Quimioterapia Combinada/farmacologia , Gentamicinas/farmacologia , Infecções por Klebsiella/mortalidade , Klebsiella pneumoniae/efeitos dos fármacos , Animais , Cápsulas , Ceftazidima/administração & dosagem , Resistência Microbiana a Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada/administração & dosagem , Feminino , Gentamicinas/administração & dosagem , Infecções por Klebsiella/tratamento farmacológico , Lipossomos , Ratos , Taxa de SobrevidaRESUMO
The therapeutic efficacy of long-circulating polyethylene glycol-coated liposomal amphotericin B (AMB) (PEG-AMB-LIP) was compared with that of AMB desoxycholate (Fungizone) in a model of severe invasive pulmonary aspergillosis in persistently leukopenic rats as well as in temporarily leukopenic rats. PEG-AMB-LIP treatment (intravenous administration) consisted of a single, or double (every 72 h), or triple (every 72 h) dose of 10 mg of AMB/kg of body weight, a double dose (every 72 h) of 14 mg of AMB/kg, or a 5-day treatment (every 24 h) with 6 mg/kg/dose. AMB desoxycholate was administered for 10 consecutive days at 1 mg of AMB/kg/dose. Treatment was started 30 h after fungal inoculation, at which time mycelial growth was firmly established. Both persistently and temporarily leukopenic rats died between 4 and 9 days after Aspergillus fumigatus inoculation when they were left untreated or after treatment with a placebo. In persistently leukopenic rats, a single dose of PEG-AMB-LIP (10 mg/kg) was as effective as the 10-day treatment with AMB desoxycholate (at 1 mg/kg/dose) in significantly prolonging the survival of rats infected with A. fumigatus and in reducing the dissemination of A. fumigatus to the liver. Prolongation of PEG-AMB-LIP treatment (double or triple dose or 5-day treatment) did not further improve efficacy. For temporarily leukopenic rats no major advances in efficacy were achieved compared to those for persistently leukopenic rats, probably because the leukocyte numbers in blood were restored too late in the course of infection.
Assuntos
Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Aspergilose/tratamento farmacológico , Aspergillus fumigatus/efeitos dos fármacos , Leucopenia/complicações , Pneumopatias Fúngicas/tratamento farmacológico , Anfotericina B/sangue , Anfotericina B/farmacocinética , Animais , Antifúngicos/sangue , Antifúngicos/farmacocinética , Aspergilose/complicações , Aspergilose/microbiologia , Aspergillus fumigatus/isolamento & purificação , Portadores de Fármacos , Feminino , Humanos , Terapia de Imunossupressão , Contagem de Leucócitos , Lipossomos , Pneumopatias Fúngicas/complicações , Pneumopatias Fúngicas/microbiologia , Polietilenoglicóis/química , Ratos , Resultado do TratamentoRESUMO
Polymer (PEG-PE)-coated liposomes exhibit prolonged circulation time in blood and substantial localization in Klebsiella pneumoniae-infected lung tissue in rats. Therefore, to determine the therapeutic effect, gentamicin and ceftazidime were entrapped in these liposomes and administered to rats experimentally infected with pneumonia: Relatively high and sustained concentrations of liposome-associated antibiotic in blood were observed. Compared with antibiotics alone, one dose of liposome-entrapped gentamicin or ceftazidime increased the therapeutic effect of the drugs, survival of rats, and bacterial killing in lungs. One dose of liposome-entrapped ceftazidime was as effective as a continuous 2-day infusion of nonentrapped ceftazidime. Since antibiotic-containing liposomes are stable during circulation and liposome-entrapped ceftazidime and gentamicin have low bactericidal activity in vitro, the superior therapeutic effect of the liposome-encapsulated antibiotics results from localization and subsequent degradation of liposomes and the resulting release of entrapped antibiotic at the infection site.