Treatment of Plague with Gentamicin or Doxycycline in a Randomized Clinical Trial in Tanzania

Mwengee, William; Butler, Thomas; Mgema, Samuel; Mhina, George; Almasi, Yusuf; Bradley, Charles; Formanik, James B; Rochester, C.G.

doi:10.1086/500137

Cited by 106 publications

(79 citation statements)

References 37 publications

(39 reference statements)

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“…1,2) GEM is considered an``obligatory nephrotoxin'' and even small doses have been reported by several authors to produce nephrotoxicity in man and animals. 3,4) It is an aminoglycoside antibiotic that is still commonly used in the treatment of life-threatening infections.…”

Section: Introductionmentioning

confidence: 99%

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Reno-protective Role of Flunarizine (Mitochondrial Permeability Transition Pore Inactivator) against Gentamicin Induced Nephrotoxicity in Rats

et al. 2011

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This study was aimed to evaluate the role of ‰unarizine on gentamicin (GEM) induced nephrotoxicity in rat. Administration of GEM (40 mg/kg, s.c. for 10 consecutive days) signiˆcantly increased blood urea nitrogen (BUN), Nacetyl b-d-glucosaminidase (NAG), thiobarbituric acid reactive substances (TBARS) and total calcium whereas, decreased body weight, fractional excretion of sodium (FrNa), creatinine clearance (CrCl), reduced glutathione (GSH), mitochondrial cytochrome c oxidase (Cyt-C oxidase) and ATP levels resulting in nephrotoxicity. Further, ‰unarizine (100, 200 and 300 mmol/kg, p.o.) was administered to evaluate its renoprotective eŠect against GEM induced nephrotoxicity and the results were compared with cylcosporin A (CsA, 50 mmol/kg, p.o.). Flunarizine resulted in the attenuation of renal dysfunction and oxidative marker changes in rats subjected to GEM induced nephrotoxicity in a dose dependent manner. Medium and higher doses of ‰unarizine produced signiˆcant renal protective eŠect which was comparable to cyclosporin A. The results of this study clearly revealed that ‰unarizine protected the kidney against the nephrotoxic eŠect of GEM via mitochondrial permeability transition pore (MPTP) inactivation potential.

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Section: Introductionmentioning

confidence: 99%

“…Their broad-spectrum activity, chemical stability and rapid bactericidal action have often made themˆrst-line drugs in a variety of clinical situations. 2,5,6) However, high concentrations of these antibiotics are known to be nephrotoxic. In some cases, this side eŠect is so severe that the use of the drug must be discontinued.…”

Section: Introductionmentioning

confidence: 99%

Reno-protective Role of Flunarizine (Mitochondrial Permeability Transition Pore Inactivator) against Gentamicin Induced Nephrotoxicity in Rats

et al. 2011

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“…1 and 2C through 2H). Doxycycline was ineffective in our HFPM at the dose examined, despite its proven effectiveness in in vivo experimental and clinical studies (5,23). Approximately 10 2 CFU/ml of mutants resistant to 2ϫ MIC of doxycycline were present in the HFPM systems at initiation of therapy (Fig.…”

Section: Resultsmentioning

confidence: 93%

Comparative Efficacies of Candidate Antibiotics against Yersinia pestis in an In Vitro Pharmacodynamic Model

Louie

VanScoy

Liu

et al. 2011

Antimicrob Agents Chemother

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Yersinia pestis, the bacterium that causes plague, is a potential agent of bioterrorism. Streptomycin is the "gold standard" for the treatment of plague infections in humans, but the drug is not available in many countries, and resistance to this antibiotic occurs naturally and has been generated in the laboratory. Other antibiotics have been shown to be active against Y. pestis in vitro and in vivo. However, the relative efficacies of clinically prescribed regimens of these antibiotics with streptomycin and with each other for the killing of Yersinia pestis are unknown. The efficacies of simulated pharmacokinetic profiles for human 10-day clinical regimens of ampicillin, meropenem, moxifloxacin, ciprofloxacin, and gentamicin were compared with the gold standard, streptomycin, for killing of Yersinia pestis in an in vitro pharmacodynamic model. Resistance amplification with therapy was also assessed. Streptomycin killed the microbe in one trial but failed due to resistance amplification in the second trial. In two trials, the other antibiotics consistently reduced the bacterial densities within the pharmacodynamic systems from 10 8 CFU/ml to undetectable levels (<10 2 CFU/ml) between 1 and 3 days of treatment. None of the comparator agents selected for resistance. The comparator antibiotics were superior to streptomycin against Y. pestis and deserve further evaluation.Yersinia pestis is the causative agent of plague. Rodents are the natural reservoir for Y. pestis, but this microbe can be transmitted to humans through the bite of an infected flea, resulting in bubonic, septicemic, and pneumonic plagues (1,3,25). Untreated bubonic plague is associated with a 40% mortality rate, while untreated septicemic and pneumonic plagues are both associated with 100% mortality rates (9). Streptomycin is considered the "gold standard" for the treatment of all forms of plague. A regimen of streptomycin (1 g given intramuscularly or intravenous every 12 h for 10 days), usually in combination with other antimicrobial agents, reduces the mortalities of bubonic, septicemic, and pneumonic plagues to 14, 22, and 57%, respectively (6).Y. pestis has been used as a bioweapon and has the potential to be used as an agent of bioterrorism (17). Furthermore, Y. pestis isolates that are resistant to streptomycin have been generated in the laboratory and exist in nature (13,20,27). Thus, there is a need to identify other drugs that have activity against Y. pestis.If it were used as an agent of bioterrorism, it is likely that the microbe would be disseminated via aerosol, resulting in inhalation-induced pneumonic plague (17). Gentamicin, ciprofloxacin, moxifloxacin, ampicillin, meropenem, and doxycycline demonstrate in vitro activity against Y. pestis and have demonstrated efficacy in murine infection models (2, 5, 12, 28). Gentamicin, doxycycline, and ciprofloxacin have been successful in the treatment of human plague (3, 18, 23).Since naturally occurring pneumonic plague is rare and it is unethical to intentionally infect people with this p...

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“…The purpose of this review is to examine the importance of plague during the first decade of this century with an emphasis on novel events and progress of clinical knowledge (Table 1). [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] Relevant literature was obtained by searching Pubmed for papers covering the years 2000-2009.…”

Section: Introductionmentioning

confidence: 99%

Plague Gives Surprises in the First Decade of the 21st Century in the United States and Worldwide

Butler¹

2013

The American Society of Tropical Medicine and Hygiene

111

105

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Abstract. Plague is an ancient disease caused by the bacterium Yersinia pestis and transmitted by rodent flea bites that continues to surprise us with first-ever events. This review documents plague in human cases in the 1st decade of the 21st century and updates our knowledge of clinical manifestations, transmission during outbreaks, diagnostic testing, antimicrobial treatment, and vaccine development. In the United States, 57 persons were reported to have the disease, of which seven died. Worldwide, 21,725 persons were affected with 1,612 deaths, for a case-fatality rate of 7.4%. The Congo reported more cases than any other country, including two large outbreaks of pneumonic plague, surpassing Madagascar, which had the most cases in the previous decade. Two United States scientists suffered fatal accidental exposures: a wildlife biologist, who carried out an autopsy on a mountain lion in Arizona in 2007, and a geneticist with subclinical hemochromatosis in Chicago, who was handling an avirulent strain of Y. pestis in 2009. Antimicrobial drugs given early after the onset of symptoms prevented many deaths; those recommended for treatment and prophylaxis included gentamicin, doxycycline, and fluoroquinolones, although fluoroquinolones have not been adequately tested in humans. Fleas that do not have their guts blocked by clotted blood meals were shown to be better transmitters of plague than blocked fleas. Under development for protection against bioterrorist use, a subunit vaccine containing F1 and V antigens of Y. pestis was administered to human volunteers eliciting antibodies without any serious side effects. These events, although showing progress, suggest that plague will persist in rodent reservoirs mostly in African countries burdened by poverty and civil unrest, causing death when patients fail to receive prompt antimicrobial treatment.

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Treatment of Plague with Gentamicin or Doxycycline in a Randomized Clinical Trial in Tanzania

Abstract: Both gentamicin and doxycycline were effective therapies for adult and pediatric plague, with high rates of favorable responses and low rates of adverse events.

Cited by 106 publications

References 37 publications

Reno-protective Role of Flunarizine (Mitochondrial Permeability Transition Pore Inactivator) against Gentamicin Induced Nephrotoxicity in Rats

Reno-protective Role of Flunarizine (Mitochondrial Permeability Transition Pore Inactivator) against Gentamicin Induced Nephrotoxicity in Rats

Comparative Efficacies of Candidate Antibiotics against Yersinia pestis in an In Vitro Pharmacodynamic Model

Plague Gives Surprises in the First Decade of the 21st Century in the United States and Worldwide

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