Abstract
BackgroundA high incidence and mortality of plague in the past two decades occurred in the Qinghai-Tibet Plateau, China. High dose streptomycin (6–8 g/d) remained the first practical strategy for controlling the progressive, vicious clinical circumstances for patients with pneumonic plague in the Plateau, as opposed to the routine dosage recommended by the World Health Organization. To investigate whether patients with pneumonic plague truly required a large dosage of streptomycin in the hypoxic environment of the Tibetan Plateau, we investigated the hypothesis that hypoxic environment would change the pharmacokinetics of streptomycin in vivo.Methods(1) We retrospectively analyzed the data of pneumonic plague patients administered streptomycin from January 1, 2000 to December 31, 2012 in these areas, which came from the database of the Qinghai Center for Disease Control; and (2) We used a persistent hypoxia chamber to simulate the plateau hypoxic environment and fed Sprague Dawley rats in the chambers for one month. Then, we continuously administered hypoxic rats a single loading dose (200 mg/kg) of streptomycin and analyzed its concentrations by high performance liquid chromatography. The pharmacokinetic profiles were analyzed using a non-compartmental method in the Phoenix WinNonlin program.Results(1) There were 32 cases of patients with pneumonic plague in the past two decades totally and 9 of them died (all-cause mortality 28.125%, 9/32), including 7 cases died of delayed diagnosis without treatment of streptomycin, and the only 2 patients received normal dose of streptomycin. (2) The pharmacokinetic behaviors of streptomycin were different between the hypoxic and normal rats. Administration in a hypoxic state resulted in 74.81% and 29.28% decreases in maximum plasma concentration and area under the concentration-time curve from time zero to infinity compared with those values under normal condition for streptomycin.ConclusionsThese results indicated that hypoxic condition could significantly decrease the absorption rate and extent of streptomycin. Therefore, patients with pneumonic plague require higher doses of streptomycin to maintain effective drug concentrations in Qing Hai and the Tibetan Plateau.
Highlights
A high incidence and mortality of plague in the past two decades occurred in the Qinghai-Tibet Plateau, China
These results indicated that hypoxic condition could significantly decrease the absorption rate and extent of streptomycin
The local people are still suffering from plague because the herdsmen often strip and eat marmot; the locals are poorly informed about plague [14] .Cases of pneumonic plague in the Qinghai Plateau are often severe; they require large doses of streptomycin and combined antibiotics to control the progression of the disease
Summary
A high incidence and mortality of plague in the past two decades occurred in the Qinghai-Tibet Plateau, China. High dose streptomycin (6–8 g/d) remained the first practical strategy for controlling the progressive, vicious clinical circumstances for patients with pneumonic plague in the Plateau, as opposed to the routine dosage recommended by the World Health Organization. The dose of streptomycin recommended by WHO is 2 g/d [1, 3] .the effective dose of streptomycin used in the Plateau region of China is 6–8 g/d, without serious side effects [4, 5] .it may delay recovery in the Qinghai-Tibet Plateau to administrate normal dose of streptomycin for treating pneumonic plague, and/or leading to septic shock and multiple organ failure.
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