this invention relates to an antibiotic composition utilizing pharmacokinetic and pharmacodynamic principles and the uses thereof . the composition delivers two antibiotics one of which is a concentration dependent killing antibiotic and the other is a concentration independent killing antibiotic or time dependent killing antibiotic . more particularly , this invention relates to a composition for the parenteral delivery of two different antibiotics , their dosage schedule and the uses thereof . the terminology “ concentration dependent killing antibiotic ” means an agent that shows concentration dependent bactericidal activity in vitro ; the higher the antibiotic concentration the greater is the extent of activity . the terminology “ concentration independent killing antibiotic ” means antibiotics whose bactericidal activity is dependant on time for which it is available at the site of injection for action against the bacterium and not on concentration . in many cases , it is desirable to employ two different antibiotics in the treatment of a bacterial infection , in that such antibiotics may have complementary mechanisms of action that facilitate broad - spectrum coverage , bactericidal activity and potential synergistic effects , and to minimize the development of resistance during treatment of the severe or acute bacterial infections . as non - limiting representative examples of “ concentration independent killing antibiotic beta - lactam that can be used in working of this invention include , without being limited to , following antibiotics or their pharmaceutically acceptable and effective salts thereof of benzylpenicillin , phenoxymethylpenicillin , phenethicillin , propicllin , ampicillin , methicillin , oxacillin , cloxacillin , flucloxacillin , dicloxacillin , hetacillin , talampicillin , bacampicillin , lenampicillin , amoxicillin , ciclacillin , carbenicillin , sulbenicillin , ticarcillin , carindacillin , carfecillin , piperacillin , mezlocillin , aspoxicillin , cephaloridine , cefazolin , cefapirin , cephacetrile , ceftezole , cephaloglycin , cephalexin , cephalexin , cefatrizine , cefaclor , cefroxadine , cefadroxil , cefamandole , cefotiam , cephalothin , cephradine , cefuroxime , cefoxitin , cefotaxime , ceftizoxime , cefinenoxime , cefodizime , ceftriaxone , cefuzonam , ceftazidime , cefepim , cefpirome , cefozopran , cefoselis , ceflurenam , cefoperazone , cefpimizole , cefpiramide , cefixime , cefteram pivoxil , cefpodoxime proxetil , ceftibuten , cefetamet pivoxil , cefdinir , cefditoren pivoxil , cefcapene pivoxil , cefsulodin , cefoxitin , cefinetazole , latamoxef , cefotetan , cefbuperazone , cefminox , flomoxef , aztreonam , ertapenem , carumonam , imipenem , panipenem , meropenem , viapenem , faropenem , ritipenem acoxil , or mixtures thereof , which are non - protein synthesis inhibiting . as non - limiting representative examples of “ concentration dependent killing antibiotic aminoglycoside or a pharmaceutically accepted salt thereof which can be used in working of this invention include one or more of , gentamicin , amikacin , tobramycin ; erythromycin , streptomycin , lincomycin ; tetracycline , doxycycline , chlortetracycline , minocycline ; linezolid ; fusidic acid ; kanamycin , netilmicin and chloramphenicol and other protein synthesis inhibiting antibiotics and a pharmaceutically acceptable salt thereof which are protein synthesis inhibiting . the present invention is directed in particular to a new and improved product that delivers tobramycin or a pharmaceutically acceptable salt thereof , and ceftazidime or a pharmaceutically acceptable salt thereof , in a specific dose for the treatment of bacterial infections caused by susceptible bacteria for the treatment of severe and acute infections . in formulating the antibiotic composition of the present invention , which contains different strengths of parenteral dosage form in liquid / dry powder for reconstitution before injection , as hereinabove described , the first antibiotic , a concentration dependent killing antibiotic , such as tobramycin , generally forms about 9 - 12 percent of a concentration independent killing antibiotic such as ceftazidime by weight . in formulating the antibiotic composition of the present invention , which contains different strengths of parenteral dosage form in liquid / dry powder for reconstitution before injection , as hereinabove described , more suitably , the second antibiotic i . e . a concentration independent killing antibiotic or time dependent killing antibiotic such as ceftazidime generally forms about 800 percent to about 1200 percent of a concentration dependent killing antibiotic such as tobramycin by weight . in formulating the antibiotic composition of the present invention , which contains different strengths of parenteral dosage form in liquid / dry powder for reconstitution before injection , as hereinabove described , most suitably , the second antibiotic , a concentration independent killing antibiotic or time dependent killing antibiotic such as ceftazidime generally forms about 89 - 91 percent of the combination product by weight ; whereas a concentration dependent killing antibiotic such as tobramycin generally form about 11 - 9 percent of the combination product by weight . the antibiotics may be in the form of a pharmaceutically acceptable salt . pharmaceutically acceptable salts refer to salts which can be generally used as salts of an antibiotic in pharmaceutical industry , including for example , salts of sodium , potassium , calcium and the like , and amine salts of procaine , dibenzylamine , ethylenediamine , ethanolamine , methylglucamine , taurine , and the like , as well as acid addition salts such as hydrochlorides , sulphates and basic amino acids and the like . the invention is embodied into the antibiotic composition of this invention in one or more of the following aspects : 1 . in determining the fixed proportions of tobramycin and ceftazidime in the composition so as to minimize the toxic effects of high doses of individual components 2 . in the use of one / more stabilizing / other agents in general and the use of l - arginine and / or sodium carbonate in particular , in one embodiment of the invention , the combination of tobramycin to ceftazidime to arginine and or sodium carbonate is in ratio of 1 : 7 : 1 . in other embodiment , the combination of tobramycin to ceftazidime to arginine is in ratio of 1 : 8 : 1 to 1 : 10 : 1 . in yet another embodiment , the combination of tobramycin to ceftazidime to arginine is in ratio of 1 : 9 . 8 : 1 . 3 . this invention also includes a process of making a sterile blended liquid / dry powder composition . in one embodiment the invention provides a process for the manufacture of a pharmaceutical composition that can be reconstituted by addition of a compatible reconstitution diluent prior to parenteral administration and , if desired , diluted with a compatible diluent prior to parenteral administration ; which comprises effective amounts of ( a ) tobramycin or a pharmaceutically acceptable salt thereof preferably sulphate salt , ( b ) ceftazidime or a pharmaceutically acceptable salt thereof preferably pentahydrate salt and a stabilizing agent in the form of l - arginine and / or sodium carbonate . in this case , the appropriate solvent is usually added to sterile blended composition , which preferably is distilled water for injection , but is not limited thereto in accordance with the invention . in another embodiment for a liquid dosage form , both the active ingredients are dissolved in an appropriate medium and the resulting solution is sterilized and filtered followed by filling in an appropriate ampoule or vial , and sealing . liquid injection may contain additives such as soothing agents which have local anesthetic effect , such as procaine hydrochloride , xylocaine hydrochloride , benzyl alcohol and phenol , antiseptic agents such as benzyl alcohol , phenol , methyl or propyl paraben and chlorobutanol , buffering agents such as a sodium salt of citric acid , phosphoric acid , acetic acid , solution adjuvants such as arginine hydrochloride , sodium meta bi sulphite , stabilizing agents such as l - cysteine , l - methionine , l - histidine , and chelating agents , if required . in a preferred embodiment parenteral dosage form of both the antibiotics have almost the same kinetics . in another aspect , the present invention is directed to treating a bacterial infection by administering to a host preferably mammal more preferably human beings in need thereof , an antibiotic product as herein above and hereinafter described . in another aspect , the present invention is directed to treating a bacterial infection caused by aerobes , gram negative : citrobacter spp ., including citrobacter freundii and citrobacter diversus ; enterobacter spp ., including enterobacter cloacae and enterobacter aerogenes ; escherichia coli ; haemophilus influenzae , including ampicillin - resistant strains ; klebsiella spp . ( including klebsiella pneumoniae ); neisseria meningitidisi ; proteus mirabilis ; proteus vulgaris ; pseudomonas spp . ( including pseudomonas aeruginosa ); and serratia spp . aerobes , gram positive : staphylococcus aureus , including penicillinase - and non - penicillinase - producing strains ; streptococcus agalactiae ( group b streptococci ); streptococcus pneumoniae ; and streptococcus pyogenes ( group a beta - hemolytic streptococci ). anaerobes : bacteroides spp . acinetobacter spp ., clostridium spp ., ( not including clostridium difficile ), haemophilus parainfluenzae , morganella morganii ( formerly proteus morganii ), neisseria gonorrhoeae , peptococcus spp ., peptostreptococcus spp ., providencia spp . ( including providencia rettgeri , formerly proteus rettgeri ), salmonella spp ., shigella spp ., staphylococcus epidermidis , and yersinia enterocolitica ., methicillin - resistant staphylococci , streptococcus faecalis and many other enterococci , listeria monocytogenes , campylobacter spp ., or clostridium difficile . thus , in accordance with an aspect of the present invention , there is provided a fixed dose antibiotic combination product that has contained therein as parenteral dosage form , which initiates release of antibiotic at same time and wherein includes at least a concentration dependent killing antibiotic such as tobramycin sulphate , a concentration independent killing antibiotic or time dependent killing antibiotic such as ceftazidime pentahydrate along with 1 - arginine and / or sodium carbonate . in another aspect , the present invention relates to a product that delivers tobramycin or a pharmaceutically acceptable salt thereof , along with ceftazidime or a pharmaceutically acceptable salt thereof , in a specific dose for the treatment of bacterial infections like cystic fibrosis , lower respiratory tract infections , including pneumonia , skin and skin structure infections , urinary tract infections , both complicated and uncomplicated , bacterial septicemia , bone and joint infections , gynecologic infections , including endometritis , pelvic cellulitis , and other infections of the female genital tract , intra abdominal infections , including peritonitis and polymicrobial infections , central nervous system infections , including meningitis etc . in accordance with a preferred embodiment elimination of tobramycin and ceftazidime is principally via renal excretion with an average (± sd ) half - life of 2 . 0 (± 0 . 3 ) hours and the mean renal clearance of approximately 100 . 0 (± 10 . 0 ) ml / min and calculated plasma clearance is approx - 115 . 0 ml / min in healthy volunteers . in accordance with one preferred embodiment of the invention , the average period of the treatment with tobramycin and ceftazidime equaled to 7 days ( 5 to 10 ). in general , the invention is available as sterile blend of two or more dry powders in fixed ratios to be reconstituted before injection with suitable solvent . however , it can also be formulated and sealed as liquid composition . in a preferred embodiment the administration of the antibiotic product is a concentrate that is diluted before administration in suitable infusions ; such as sterile water for injection , 0 . 9 % sodium chloride , 5 % dextrose injection . in an embodiment of this invention , the composition of this invention is sterile packed in a sealed container which has an interior comprising a fill volume occupied by the suitable solvent and a headspace volume occupied by a micro atmosphere having a nitrogen pressure of not more than about 5 %, wherein the ratio of reconstituted fill volume to headspace volume is not less than about 1 : 1 . in another embodiment of this invention , wherein a pharmaceutically effective unit / multiple dose of said combination is provided in a sealed airtight container which is selected from the group consisting of a vial , a mono vial , an ampoule , a syringe , a packet , a pouch and an auto - injector , wherein said container has a head space volume sufficient for introduction of appropriate volume of an aqueous solvent sufficient to form a unit / multiple dose in the form of an appropriate reconstituted solution of said combination . in yet another embodiment of this invention , wherein said pharmaceutical composition is packed in a sealed container wherein said container has a headspace sufficient for introduction of a volume of aqueous solvent sufficient to form a concentrated solution of said pharmaceutical composition . the antibiotic composition of the present invention may be administered by the following routes of administration : parenteral , by intramuscular or intravenous administration and the preferred regimen is that the product is administered 2 - 3 times for intramuscular injection and intravenous infusion over a 24 hour period . examples which illustrate various embodiments of this invention are given in the following , without limiting the scope of invention as claimed . this test was performed by disc diffusion test for ceftazidime and tobramycin on müeller - hinton agar medium purchased from hi media . the medium was prepared and used as per manufacturer &# 39 ; s instructions . ceftazidime alone , tobramycin alone and the combination of ceftazidime and tobramycin , on different micro - organisms was taken . different concentrations of the antibiotics or their combinations were selected mentioned to as highest ( 10 mg / ml ceftazidime , 1 . 2 mg / ml tobramycin and 10 mg / ml + 1 . 2 mg / ml as combination of the two ), high ( 1 mg / ml ceftazidime , 0 . 12 mg / ml tobramycin and 1 mg / ml + 0 . 12 mg / ml as combination of the two ), low ( 0 . 1 mg / ml ceftazidime , 0 . 012 mg / ml tobramycin and 0 . 1 mg / ml + 0 . 012 mg / ml as combination of the two ) and lowest ( 0 . 01 mg / ml ceftazidime , 0 . 001 mg / ml tobramycin and 0 . 01 mg / ml + 0 . 001 mg / ml as combination of the two in the data and discs . zone size was determined in mm . the activity of ceftazidime and tobramycin is best seen in p . auerignosa , e . coli , klebsiella pneumoniae , staphylococcus ( mssa ), c . albicanus , mrsa . the three strength tested were 560 mg ( 500 mg ceftazidime and 60 mg tobramycin ), 1120 mg ( 1000 mg ceftazidime and 120 mg tobramycin ) and 2180 mg ( 2000 mg ceftazidime and tobramycin 180 mg ). for each concentration the three zones were observed i . e for combination , ceftazidime alone and tobramycin alone and tested for efficacy against various types of micro - organisms . average hospitalization time of conventional treatment using ceftazidime before or after tobramycin was 14 to 21 days . in conventional treatment , tobramycin was given at 40 mg to 80 mg bd and ceftazidime 1 g to 2 g bd for 14 - 21 days . average hospitalization time for treatment of this invention is reduced to 25 %. due to reduced hospitalization and treatment time cost to patient / treatment is reduced . it is obvious that with less treatment time and decreased hospitalization time , cost of treatment was less and relief to the patient was significantly improved with treatment of this invention . the composition of this invention was subjected to accelerated stability test . all procedures were carried out as per standard testing procedures . the results show that the compositions of this invention of tobramycin and ceftazidime are stable . phenol was added with continuous stirring and nitrogen purging . the volume was made up with water for injection and ph was readjusted whenever required . charcoal treatment during filtration with 0 . 2 micron is required to get colourless solution
the present invention provides a pharmaceutical composition comprising antibiotic combination products for delivering two or more different antibiotics simultaneously , wherein the two different antibiotics comprise one which consisting of concentration dependent killing and the other concentration independent killing or time dependant killing activity . the invention has been worked out utilizing pharmacokinetic and pharmacodynamic principles to optimize antibiotic regimen , to improve clinical results and to potentially decrease the development of resistance . combination of ceftazidime and tobramycin has been evolved to specifically illustrate the invention .