Rifabutin for the treatment of acinetobacter baumannii

Abstract

To identify novel agents to treat carbapenem-resistant Acinetobacter baumannii . the Inventors used a nutrient-depleted medium with serum to mimic the in vivo environment. In RPMI with serum, the screen identified rifabutin (RBT) as being 133-fold more potent than rifampin (RIF) against A. baumannii , with MICs of 0.031 μg/ml and 4 μg/ml respectively. No difference in RBT vs. RIF activity was observed when MHII was used as the culture media. RBT possesses markedly superior in efficacy to RIF in murine models of lethal iv and pneumonia models of infection with a hyper-virulent, clinical lung and blood isolate of extreme-drug resistant (XDR) A. baumannii . In both models, RBT significantly improved survival and lowered bacterial burden compared to RIF. RBT is a promising, novel therapeutic option for A. baumannii infections.

1 . A method of treatment treating a mammalian subject infected with  Acinetobacter , comprising:
 administering rifabutin to the mammalian subject, wherein the rifabutin is administered as a sole therapeutically active agent to treat the  Acinetobacter , or the rifabutin is not co-administered with any other therapeutically active agent that is being administered to treat the same  Acinetobacter  infection.   
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the rifabutin is administered as sole therapeutically active agent to treat said  Acinetobacter  infection. 
     
     
         4 . The method of  claim 1 , wherein the rifabutin is not co-administered with any other therapeutically active agent that is being administered to treat the same  Acinetobacter  infection. 
     
     
         5 . The method of  claim 1 , wherein  Acinetobacter  infection is  Acinetobacter baumannii.    
     
     
         6 . The method of  claim 1 , wherein rifabutin is administered to a human patient. 
     
     
         7 . The method of  claim 4 , wherein the method comprises a time lag of at least about 48 h, preferably at least about 24 h, more preferably at least about 12 h, again more preferably about at least 8 h, again more preferably at least about 4 h is between administration of the rifabutin and administration of another antibiotic that is administered to treat the same  Acinetobacter  infection in a human patient. 
     
     
         8 . The method of  claim 7 , wherein the  Acinetobacter  infection is caused by multi-drug resistant  Acinetobacter  bacteria. 
     
     
         9 . The method of  claim 8 , wherein the  Acinetobacter  infection is an infection in respiratory tract, blood, circulation system, urinary tract, skin, surgical-site, or a combination thereof, of the human patient, or wherein meningitis is identified in the human patient. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 10 , wherein the rifabutin is administered in a dose of 60 mg to 600 mg per day. 
     
     
         12 . A method of treating an  Acinetobacter  infection, comprising:
 administering rifabutin to a human subject in need thereof, wherein rifabutin is administered in a daily dose of 60 mg to 600 mg and wherein the rifabutin is administered as a sole therapeutically active agent or the rifabutin is not co-administered with any other therapeutically active agent that is being administered to treat the same  Acinetobacter  infection.   
     
     
         13 . The method of  claim 12 , wherein the  Acinetobacter  infection is an infection caused by bacteria selected from the group consisting of  Acinetobacter baumannii, Acinetobacter lwoffii, Acinetobacter calcoaceticus, Acinetobacter nosocomialis , and  Acinetobacter pittii.    
     
     
         14 . The method of  claim 12 , wherein the  Acinetobacter  infection is caused by multi-drug resistant  Acinetobacter  bacteria. 
     
     
         15 . The method of  claim 12 , wherein the  Acinetobacter  infection is an  Acinetobacter  infection of the respiratory tract, blood (i.e. bacteremia), circulation system, urinary tract, skin, surgical-site, catheter-site, or a combination thereof, of the human subject, or wherein meningitis is identified in the human subject. 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 12 , wherein the rifabutin is administered as the sole therapeutically active agent. 
     
     
         18 . The method of  claim 12 , wherein the rifabutin is administered sequentially to another therapeutically active agent that is not co-administered to treat the same  Acinetobacter  infection. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the mammalian subject after receiving an administered dosage of the rifabutin has a greater reduction in  Acinetobacter  amount compared to that in a control mammalian subject infected with the  Acinetobacter  but treated with rifampicin at the same dosage instead of the rifabutin. 
     
     
         21 . The method of  claim 20 , wherein the  Acinetobacter  amount in a log 10 scale in the mammalian subject after receiving the rifabutin is about 7-fold lower than that in the control mammalian subject treated with the rifampicin. 
     
     
         22 . The method of  claim 1 , further comprising measuring  Acinetobacter  amount in blood of the mammalian subject after the administration of the rifabutin. 
     
     
         23 . The method of  claim 1 , further comprising measuring  Acinetobacter  density in a sample of infected organ of the mammalian subject after the administration of the rifabutin. 
     
     
         24 . The method of  claim 1 , further comprising detecting that the  Acinetobacter  amount in the mammalian subject after the administration of the rifabutin (i) is reduced compared to before the administration, (ii) the reduction in the mammalian subject is greater than that in a control mammalian subject infected with the  Acinetobacter  but treated with rifampicin at a same dosage as the rifabutin, or both (i) and (ii).