PHARMACEUTICAL COMPOSITIONS FOR TREATING RESISTANT BACTERIA INCLUDING ANAEROBES

Abstract: Bacteroides which are uniformly resistant to ceftazidime fail to grow when exposed to 2β-chloromethyl-2α-­ methylpenam-3α-carboxylic acid (BL-P 2013), which itself is non-inhibitory, in combination with ceftazidime. Bacteroides infections are abated by treatment of the infected mammal with this combination of substances.

Description: Field of the Invention The present invention discloses drug, bio-affecting and body treating compositions containing semi-synthetic heterocyclic active ingredients of the penicillin and cephalosporin series (USPTO Class/subclass 424/271). Description of' the Prior Art Anaerobes exist as normal flora in the oropharnyx, vagina, and intestine and are associated with 90 percent of intraabdominal abscesses, 95 percent of appendiceal abscesses, 75 percent of upper tract female pelvic infections, 90 percent of aspiration pneumonia, 95 percent of lung abscesses, and 85 percent of brain abscesses. Anaerobes of the genus Bacteroides and particularly Bacteroides fragilis are found in 70 percent of intra abdominal and pelvic infections (Gorbach, S. L,, J. Infect. Diseases 135. Supplement, March, 1977 pp. S2 and S3). Chemotherapeutic agents effective against B. fragilis are blighted by serious deficiencies. Clindamycin, the presently preferred antibiotic for the treatment Of Bacteroides infection is compromised by the problem of pseudomembranous colitis which is sometimes fatal. Tetra cycline and its congeners are relatively inactive against 30 to 50 percent of the strains of B. fragilis and intra venous treatment with large doses of the tetracyclines has serious liver, renal and intestinal complications. Chloramphenicol has a wide spectrum of activity against B. fragilis but is plagued by hernatologic complications. Carbenicillin once believed to be widely effective against B. fragilis now appears to be roughly equivalent to penicillin G and is only effective against about 10 to 20 percent of the strains of B. fragilis (Gorbach, S. L., op. cit.). A mixture of amoxicillin and clavulanic acid has recently demonstrated good activity against experimentally induced Bacteroides fragilis infection (Comber, K. R. et al., 20th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, La., Abstract No. 609 (Sept., 1980)). Penicillanic acid-l,l-dioxide (CP-45,899), a ss-lactamase inhibitor which is the subject of U.S. Patent No. 4,234,579, is reported to be highly synergistic with ampicillin and sporadically synergistic with other antibiotics against B. fragilis (R. J. Fass, ibid., Abstract No. 605 (Sept., 1980)). Ceftazidime, also referred to as GR 20263, is a new parenteral aminothiazolyl cephalosporin which has the advantages of stability to a wide range of -lactamases, a broad antibacterial spectrum, and low toxicity. Cefta zidime, however, has low activity against B. fragilis and is believed to be ineffective in treating infections caused by that organism (Wise, R. et al., Antimicrobial Agents & Chemotherapy 17, 884-889 (1980)). Ceftazidime has the following structural formula and is the subject of U.S. Patent 4,258,041 patented March 24, 1981: EMI2.1 The term 11ceftazidime" is intended to include not only the antibiotic having the foregoing structural formula but also its non-toxic salts such as the sodium salt and its non-toxic metabolically labile esters. Various salts and esters of the type contemplated are identified in the foregoing patent at column 4 beginning at line 46 and continuing to column 5 at line 20. The entire disclosure of U.S. Patent 4,258,041 is incorporated herein by reference. The ss-lactamase inhibitor BL-P 2013 is an acid which with its pharmaceutically acceptable salts and physiologically hydrolyzable esters are the subject of Belgian Patent No. 887,173. BL-P 2013 acid has the following structural formula: EMI3.1 The term "BSP 2015 conpound" when used herein is intended to include the acid having the preceding formula, its pharmaceutically acceptable salts, and the physiologically hydrolyzable esters thereof. The pharmaceutically acceptable salts referred to above include the non-toxic metallic salts such as the sodium, potassium, calcium, magnesium, and ammonium salts, and the substituted ammonium salts, e.g. salts of such non-toxic amines as trialkylamines (e.g. triethylamine), procaine, dibenzylamine, N-benzyl-ss-phenethylamine, l-ephenamine, N,N'-dibenzyl-ethylenediamine, dehydroabietylamine, N,N'-bis(dehydroabietyl)ethylenediamine, N-(lower)alkylpiperidine (e.g. N-ethylpiperidine) and other amines which have been used to form pharmaceutically acceptable salts of penicillins and cephalosporins. The most preferred salts are the alkali metal salts, i.e. the sodium and potassium salts, and the ammonium salt. The terms "physiologically hydrolyzed esters" and "metabolically labile esters" refer to those pharmaceutically acceptable esters known in the art to hydrolyze to the free acid form in vivo. Examples of such esters include phenacyl, acetoxymethyl, pivaloyloxymethyl, a-acetoxyethyl, a-acetoxybenzyl, a-pivaloyloxyethyl, phthalidyl (3-phthalidyl), indanyl (5-indanyl), methoxymethyl, benzoyloxymethyl, a-ethylbutyryloxymethyl, propionyloxymethyl, valeryloxymethyl, isobutyryloxymethyl, and others with which medicinal chemists are familiar. The preferred esters are the acetoxymethyl, pivaloyloxymethyl, methoxymethyl, 3-phthalidyl, and 5-indanyl. Summary of the Invention The present invention provides a composition for the treatment of bacteroides infections. The compositions of the present invention contain the antibiotic ceftazidime together with a BL-P 2013 compound. These compositions containing both ceftazidime and the BL-P 2013 compound are administered parenterally to a mammalian host having an infection caused by a bacteroides species. The present invention provides also pharmaceutical compositions containing a non-toxic amount of ceftazidime and separated therefrom a BL-P 2013 compound. In this case ceftazidime is administered parenterally to a mammylian host having an infection caused by a bacteroides species. The BL-P 2013 compound is concurrently administered either parenterally or orally. In both cases ceftazidime is administered in a well tolerated non-toxic dose which in itself isFineffective to inhibit the growth of the bacteroides organism. The BL-P 2013 compound is administered concurrently in an non-toxic physiologically acceptable dose of sufficient size to be effective with the ceftazidime to inhibit the growth of the bacteroides organism. Detailed Description of the Invention The presence of bacteroides infection should be presumed and treatment according to the present invention commenced when the following criteria are met (Sweet, R. L., American Journal of Obstetrics and Gynecology 122, 891-901 (1975)). 1. Systemic infections complicating manipulations of the gastrointestinal tract or female pelvic organs. 2. Foul smelling exudates containing Gram negative bacilli which fail to grow on routine aerobic cultures. 3. Presence of gas within an abscess. 4. Presence of septic pelvic thrombophlebitis or septic emboli. 5. Failure to respond to the commonly used bactericidal antibiotics such as kanamycin, gentamicin, penicillin and cephalothin. 6. The presence of poorly stained Gram negative pleomorphle rods particularly when large numbers of organism are intracellular. Such infections are frequently associated with damaged epithelial surfaces or mucous membranes. The term bacteroides infection" as used herein is intended to apply to infections wherein a Bacteroides is isolated in pure or mixed culture from the infected zone. Certain infectious processes involve several strains of bacteria which behave in a cooperative fashion to produce an infection. Such conditions are also subject to treatment according to the present invention when a Bacteroides is a member of such a mixed culture. (Gorbach, S. I, et al., New England Journal of Medicine 290, 1289-94 (1974)). The culturing and identification of anaerobes from clinical specimens requires sophisticated methods and may require several days or even weeks. Treatment according to the present invention should not be delayed to await positive identification when a bacteroides infection is suspected or presumed. Empirical therapy should be commenced when the above criteria are observed. Treatment is continued as long as infection persists and for 10 days or more thereafter. The dosage employed for adult human treatment with ceftazidime is preferably in the range of from 500 to 6,ooo mg per day administered intravenously or intramuscularly. A dose is employed which is in itself ineffective to abate the infection, but which is well tolerated by the host and without toxic effect. Usually the daily dose is administered as several divided portions during each day of treatment. BL-P 2013 is useful when given orally or parenterally concomitantly with ceftazidime. Parenteral dosage compositions containing both BL-P 2013 and ceftazidime may be employed. On a weight basis the dosage of BL-P'2013 is from 1/5 to 5 times, and preferably equal to, that of ceftazidime. As indicated they may be given either in admixture or concomitantly as separate dosage units. Parenteral administration includes intramuscular, subcutaneous, intraperitoneal, and intravenous administration. A carrier or diluent is ordinarily used in administering the BL-P 2015 compound and ceftazidime and is chosen on the basis of the intended mode of administration. For example, when considering the oral mode of administration, the BL-P 2013 compound can be used in the form of tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solutions, and the like, in accordance with standard pharmaceutical practice. The proportional ratio of active ingredients to carrier will naturally depend on the chemical nature, solubility, stability and potency of the active ingredients, as well as the dosage contemplated. However, these pharmaceutical compositions will likely contain from about 5% to about 80% of carrier. In the case of tablets for oral use, carriers which are commonly used include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch, and lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, are commonly used in tablets. For oral administration in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols. When aqueous suspensions are required for oral use, the active ingredients are combined with emulsifying and suspending agents. if desired, certain sweetening and/or flavoring agents can be added. For parenteral administration, which includes intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredients are usually prepared, and the pH of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be preferably controlled to render the preparation substantially isotonic. The prescribing physician will decide the dosage to be used in a human subject including the ratio of the dosage weight of BL-P 2013 compound and ceftazidime. The daily oral dosage of BL-P 2013 compound will normally be in the range of from 10 to about 200 milligrams per kilogram of body weight and the daily parenteral dosage will normally be in the range of about 10 to about 100 milligrams per kilogram of body weight. In some cases it may be necessary to use dosages outside these limits and these figures are to be considered illustrative only. Biological Data BL-P 2013 as the potassium salt was tested in vitro for synergism with ceftazidime as to the minimum inhibitory concentrations of the two substances alone and in combination on an equal weight basis against a variety of bacteria. Marked synergism was found with respect to various ceftazidime resistant strains of Enterobacter cloacae, Clostridium perfringens, Enterobacter aerogenes, Clostridium freundii, Citrobacter species , and Morganella morganii. Marginal synergism was seen in some instances with the two substances tested together as above against ceftazidime sensitive strains of these and other bacteria, but not against others. Importantly, of 16 Bacteroides fragilis strains tested, all were resistant to ceftazidinie and all were inhibited by a 1:1 ceftazidime- BT-P 2013 combination. The results are given below: Table 1 Antibacterial Activity of Ceftazidime Alone and in Combination with BL-P 2013 K Salt EMI9.1 <SEP> MICb <SEP> ( g/ml) <tb> <SEP> BL-P <SEP> A:B <SEP> Ceftazidime <tb> <SEP> Organism <SEP> No. <SEP> of <SEP> 2013 <tb> <SEP> Strains <SEP> (B) <SEP> 1:1 <SEP> (A) <tb> S. <SEP> aureus <SEP> (p¯) <SEP> 9 <SEP> 100 <SEP> 7.4:7.4 <SEP> 8 <tb> S. <SEP> aureus <SEP> (p+) <SEP> 9 <SEP> 73 <SEP> 8:8 <SEP> 8 <tb> E. <SEP> aerogenes <SEP> 1 <SEP> > 125 <SEP> 8:8c <SEP> 32 <SEP> <tb> E. <SEP> cloacae <SEP> 1 <SEP> > 125 <SEP> 8:8 <SEP> c <SEP> 63 <SEP> <tb> <SEP> . <SEP> 1 <SEP> > 125 <SEP> 125:125 <SEP> > 125 <tb> Citrobacter <SEP> sp. <SEP> 1 <SEP> 8 <SEP> 1:1 <SEP> 2 <tb> C. <SEP> freundii <SEP> 1 <SEP> > 125 <SEP> 8:8 <SEP> c <SEP> 125 <tb> S. <SEP> marcescens <SEP> 2 <SEP> > 125 <SEP> 2.8:2.8 <SEP> 4 <tb> EMI10.1 <tb> <SEP> MICb( g/ml) <tb> Organism <SEP> No. <SEP> of <SEP> BL-P <tb> <SEP> 2013 <SEP> A:B <SEP> Ceftazidime <tb> <SEP> Strains <SEP> (B) <SEP> 1:1 <SEP> (A) <tb> P. aeruginosa 1 > 125 8:8 8 6 6 > 125 4:4 4 B. fragilis a 12 21 1.8:1.8c 29 li 4 25 5.7:5.7c > 125 C. perfringens 3 > 125 0.04:0.04 0.04 " 3 89 0.25:0.25 0.7 8 8 > 120 1.3:1.3 3.3 Run Nos. 1353, 1354 and 1359 a Minimum inhibitory concentration (MIC) determined by the agar dilution method using 50X dilutions of 24 hour cultures as inocula dispensed by the Steers inoculator. Assay medium composed of Brucella Agar plus 5% laked sheep blood and 10 mcg/ml vitamin K. b Geometric mean value where applicable. Anaerobe data based on 2 tests. marked synergism, marginal synergism. Table 2 Antibacterial Activity of Ceftazidime Alone and in Combination with BL-P 2013 EMI11.1 <tb> <SEP> M <SEP> I <SEP> Ca <SEP> ( g/ml) <tb> <SEP> Organism <SEP> Number <SEP> Cefta <SEP> @@@@@@@@ <SEP> @@@@@@@ <tb> <SEP> of <SEP> zidime <SEP> A:B <SEP> BL-P <SEP> 2013 <tb> <SEP> Strains <SEP> (A) <SEP> 1:1 <SEP> (B) <tb> Enterobacter <SEP> aerogenes <SEP> 2 <SEP> 22.6 <SEP> 4:4 <SEP> > 125 <tb> <SEP> 3 <SEP> 1.3 <SEP> 1.3:1.3 <SEP> > 125 <SEP> <tb> <SEP> 2 <SEP> 0.25 <SEP> 0.13:0.13 <SEP> > 125 <tb> Enterobacter <SEP> cloacae <SEP> 2 <SEP> 44.9 <SEP> 8:8 <SEP> > 125 <tb> <SEP> 3 <SEP> 5.0 <SEP> 2.5:2.5 <SEP> > 125 <tb> <SEP> 1 <SEP> 1.0 <SEP> 0.25:0.25 <SEP> > 125 <tb> <SEP> 3 <SEP> 1.3 <SEP> 1.3:1.3 <SEP> > 125 <tb> Citrobacter <SEP> species <SEP> 2 <SEP> 63 <SEP> 8:8 <SEP> > 125 <tb> <SEP> 1 <SEP> 1 <SEP> 0.5: :0.5 <SEP> > 125 <tb> <SEP> 1 <SEP> 2 <SEP> 1:1 <SEP> 4 <tb> <SEP> 3 <SEP> 1.3 <SEP> 1.3:1.3 <SEP> > 125 <tb> Serratia <SEP> marcescens <SEP> 1 <SEP> > 125 <SEP> 63:63 <SEP> > 125 <tb> <SEP> 1 <SEP> 16 <SEP> 8:8 <SEP> > 125 <tb> <SEP> 2 <SEP> 2 <SEP> 0.7:0.7 <SEP> > 125 <tb> <SEP> 1 <SEP> 1 <SEP> 0.5:0.5 <SEP> > 125 <tb> <SEP> 5 <SEP> 1.3 <SEP> 1.3:1.3 <SEP> <SEP> > 125 <tb> Morganella <SEP> morganji <SEP> 1 <SEP> 8 <SEP> 1:1 <SEP> > 125 <tb> <SEP> 1 <SEP> 1 <SEP> 0.1):0.13 <SEP> <SEP> > 125 <tb> <SEP> 2 <SEP> 0.35 <SEP> 0.06:0.06 <SEP> > 125 <tb> <SEP> 4 <SEP> 0.063 <SEP> 0.03:0.03 <SEP> > 125 <tb> <SEP> 1 <SEP> 0.063 <SEP> 0.06: :0.06 <SEP> > 125 <tb> EMI12.1 <tb> <SEP> Ca <SEP> ( g/ml) <tb> <SEP> Organism <SEP> umber <SEP> Cefta <tb> <SEP> of <SEP> zidime <SEP> A:B <SEP> BL-P <SEP> 2013 <tb> <SEP> Strains <SEP> (A) <SEP> 1:1 <SEP> (B) <tb> Proteus <SEP> vulgaris <SEP> 1 <SEP> 0.063 <SEP> 0.03:0.03 <SEP> > 125 <tb> <SEP> 4 <SEP> 0.063 <SEP> 0.06:0.06 <SEP> > 125 <tb> Providencia <SEP> rettgeri <SEP> 5 <SEP> 1 <SEP> 0.5:0.5 <SEP> > 125 <tb> <SEP> 1 <SEP> 1 <SEP> 1:1 <SEP> > 125 <tb> <SEP> 3 <SEP> 0.13 <SEP> 0.16:0.16 <SEP> > 125 <tb> <SEP> 1 <SEP> 0.063 <SEP> 0.03:0.03 <SEP> > 125 <tb> Providencia <SEP> stuartii <SEP> 1 <SEP> 1 <SEP> 2:2 <SEP> > 125 <tb> <SEP> 1 <SEP> 0.13 <SEP> 0.06:0.06 <SEP> > 125 <tb> <SEP> 27 <SEP> 0.24 <SEP> 0.24:0.24 <SEP> > 125 <tb> <SEP> 3 <SEP> 0.20 <SEP> 0.4: :0.4 <SEP> > 125 <SEP> <tb> Run Nos. 1376, and 1377 a Geometric mean MIC where applicable. ---marginal synergism; ¯ marked synergism. Note: As a rule none of the strains of the above species showed an inoculum effect with ceftazidime within the range of 104 to 2 x 105 CFUs. Table 3 Antibacterial Activity of Ceftazidime Alone and in Combination with BL-P 2013 EMI13.1 <tb> <SEP> M <SEP> I <SEP> Cb( g/ml) <tb> <SEP> No. <SEP> Ceftazidime: <tb> <SEP> Organism <SEP> of <SEP> Cefta- <SEP> BL-P <SEP> 2013 <SEP> BL-P <tb> <SEP> Strains <SEP> zidime <SEP> (1:1) <SEP> 2013 <tb> S. <SEP> aureus <SEP> (P-) <SEP> 9 <SEP> 8.6 <SEP> 7.1:7.1 <SEP> 96 <tb> S. <SEP> aureus <SEP> (P+) <SEP> 9 <SEP> 9.7 <SEP> 7.4:7.4 <tb> E. <SEP> aerogenes <SEP> 1 <SEP> 11.3 <SEP> 5.7:5.7 <SEP> > 125 <tb> E. <SEP> cloacae <SEP> 1 <SEP> 63 <SEP> 8:8 <SEP> c <SEP> > 125 <tb> E. <SEP> cloacae <SEP> 1 <SEP> > 125 <SEP> > 125: <SEP> > 125 <SEP> > 125 <tb> Citrobacter <SEP> species <SEP> 1 <SEP> 2 <SEP> 1.4:1.4 <SEP> 4 <tb> C. <SEP> freundii <SEP> 1 <SEP> 63 <SEP> 8:8 <SEP> > 125 <tb> S. <SEP> marcescens <SEP> 2 <SEP> 4 <SEP> 3.4:3.4 <SEP> > 125 <tb> P. <SEP> aeruginosa <SEP> 7 <SEP> 4.9 <SEP> 4.9:4.9 <SEP> > 125 <tb> 3. <SEP> fragilis <SEP> a <SEP> 16 <SEP> > 32 <SEP> 2.7:2.7 <SEP> c <SEP> > 32 <tb> C. <SEP> perfringens <SEP> 4 <SEP> 0.11 <SEP> 0.03:0.03c <SEP> 27 <tb> C. <SEP> perfringens <SEP> 6 <SEP> 0.1 <SEP> 0.003:0.003 <SEP> c <SEP> > 32 <tb> C. <SEP> perfringens <SEP> 1 <SEP> 2 <SEP> 0.25:0.25 <SEP> > 32 <tb> C. <SEP> perfringens <SEP> 2 <SEP> 5.7 <SEP> 4:4 <SEP> > 32 <tb> Run Nos. 1332, 1333, 1334 and 1335 a Minimum inhibitory concentration (MIC) determined by the agar dilution method using 50X dilutions of 24 hour cultures as inocula dispensed by the Steers inoculator. Assay medium composed of Brucella Agar plus 5% laked sheep blood and 10 mcg/ml vitamin K. b Geometric mean MIC value where.applicable. c ---marginal synergism, narked synergism. Operative blood concentrations of BL-P 2013 are produced in mice following oral administration of doses of 25 to 100 mg./kg. of body weight of the following BL-P 2013 compounds to mice. EMI14.1 BL-P 2013 potassium salt R is K BL-P 2024 BL-P 2036 EMI14.2 Mice may be infected according to established technique with B. fragilis and PD50 values (protective dose for 50% of the animals) determined employing various combinations of the foregoing substances with ceftazidime in various proportions. InSectlble Compositions Ceftazidime 500 mg. BL-P 2013 K salt 500 mg. Sodium Carbonate 47 mg. The foregoing materials, all having approximately the same particle size are dry-blended and then loaded into glass vial which is sterilized and sealed. This material is constituted for use by dissolution aseptically in from 4 to 10 ml. of water for inspection

Claims: Claims: 1. Pharmaceutical composition comprising a non-toxic amount of Ceftazidim and a BL-P 2013 compound selected from the group consisting of the acid having the formula: EMI15.1 a pharmaceutically acceptable salt of said acid and a physiologically hydrolyzable ester of said acid in an amount effective with said amount of ceftazidime to inhibit the growth of Bacteroides. 2. Pharmaceutical composition according to claim 1, characterized in that the BL-P 2013 compound is the potassium salt of BL-P 2013. 3. Pharmaceutical composition comprising a non-toxic amount of ceftazidime and separated therefrom a BL-P 2013 compound selected from the group consisting of the acid having the formula: EMI16.1 a pharmaceutically acceptable salt of said acid and a physiologically hydrolyzable ester of said acid in an amount effective with said amount of ceftazidime to inhibit the growth of Bacteroides. 4. Pharmaceutical composition according to claim 3, characterized in that the BL-P 2013 compound is the potassium salt of BL-P 2013. 5. Pharmaceutical composition according to claim 3, characterized in that the the BL-P 2013 compound has the following formula: EMI16.2 6. Pharmaceutical composition according to claim 3, characterized in that the BL-P 2013 compound has the following formula: EMI17.1 7. A two-part composition characterized in that one part contains a non-toxic dose of ceftazidime and the second part contains a BL-P 2013 compound according to claims 3 to 7. Claims for Austria: 1. Process for preparing a pharmaceutical composition characterized in that one mixes a non-toxic amount of ceftazidime with a BL-P 2013 compound selected from the group consisting of the acid having the formula: EMI18.1 a pharmaceutically acceptable salt of said acid and a physiologically hydrolizable ester of said acid in an amount effective with said amount of ceftazidime to inhibit the growth of Bacteroides. 2. Process according to claim 1, charactrized in that the BL-P 2013 compound used is the potassium salt of BL-p 2013. 3. Process for preparing a pharmaceutical composition wherein a. non-toxic amount of ceftazidime and a 311-P 2013 compound selected from the group consisting of the acid having the formula EMI19.1 a pharmaceutically acceptable salt of said acid and a physiologically hydrolyzable ester of said acid in an amount effective with said amount of ceftazidime to inhibit the growth of Bacteroides are formulated separately to form a two-part composition. 4. Process according to claim 3, characterized in that the BL-P 2013 compound used is the potassium salt of BL-P 2013. 5. process according to claim 3, characterized in that the BL-P 2013 compound used has the following formula: EMI19.2 6. Process according to claim 3, characterized in that the BL-P 2013 compound used has the following formula: EMI20.1

Inventors: GORDON, MAXWELL, PACHTER, IRWIN J.
Applicants: BRISTOL-MYERS COMPANY
Application year: 1983
Main classification: A61K31
IPC codes: A61K31