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The early bactericidal activity of a low-clearance liposomal amikacin in pulmonary tuberculosis
P R Donald1, F A Sirgel, A Venter
1Department of Paediatrics and Child Health, University of Stellenbosch, Cape Town, South Africa.
Abstract:
The early bactericidal activity (EBA) of a liposomal preparation of amikacin (MiKasome) with a long plasma half-life of 120-200 h was examined in seven patients with newly diagnosed, smear-positive pulmonary tuberculosis. Liposomal amikacin was given in slow iv infusions of 30 mg total amikacin/kg body weight on three successive days. Cfu counts were set up on 16 h sputum collections preceding the first dose and following each dose and were used for calculating the EBA. Despite the high concentrations of total amikacin, >1000 mg/L, obtainable in plasma, no evidence of EBA was obtained. In view of the considerable activity of liposomal amikacin in experimental murine tuberculosis, this finding indicates that liberation of amikacin from the long-life liposomes occurs only in macrophages that are not usually present in the vicinity of the large extracellular clumps of bacilli in the cavity caseum.
Insights
Liposomal amikacin showed no early bactericidal activity in tuberculosis patients, despite high plasma levels. This suggests amikacin release from liposomes may be limited to intracellular environments, not extracellular bacterial clumps.
Area of Science:
- Pharmacology
- Infectious Diseases
- Tuberculosis Research
Background:
- Tuberculosis remains a major global health challenge, necessitating novel treatment strategies.
- Liposomal drug delivery systems offer potential for improved therapeutic outcomes.
- Amikacin is a potent aminoglycoside antibiotic used against Mycobacterium tuberculosis.
Purpose of the Study:
- To evaluate the early bactericidal activity (EBA) of liposomal amikacin (MiKasome) in patients with newly diagnosed pulmonary tuberculosis.
- To investigate the relationship between plasma amikacin concentrations and EBA.
- To understand the pharmacokinetic and pharmacodynamic profile of liposomal amikacin in tuberculosis treatment.
Main Methods:
- Seven patients with smear-positive pulmonary tuberculosis received liposomal amikacin (30 mg/kg) intravenously over three days.
- Sputum samples were collected for 16 hours before and after each dose to determine colony-forming unit (cfu) counts.
- Early bactericidal activity (EBA) was calculated based on the reduction in cfu counts.
Main Results:
- High plasma concentrations of total amikacin (>1000 mg/L) were achieved.
- No significant early bactericidal activity (EBA) was observed in sputum samples.
- This lack of EBA contrasts with promising results in experimental murine tuberculosis models.
Conclusions:
- Liposomal amikacin's efficacy in tuberculosis may be limited by its release mechanism.
- Amikacin liberation from liposomes appears restricted to intracellular compartments (macrophages).
- Extracellular bacterial aggregates in tuberculous lesions may not be effectively targeted by this formulation.