ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Dec. 1979, p. 864-868
Vol. 16, No. 6
0066-4804/79/12-0864/05$02.00/0
In Vitro Activity of LY127935, a New 1-Oxa Cephalosporin, Against Aerobic Gram-Negative Bacilli DENNIS G. DELGADO, CARMEN J. BRAU, C. GLENN COBBS, AND WILLIAM E. DISMUKES* Division of Infectious Diseases, Department ofMedicine, The University of Alabama School of Medicine, Birmingham, Alabama 35294 Received for publication 10 September 1979
A total of 434 clinical aerobic gram-negative bacillary isolates were tested against LY127935, a new 1-oxa cephalosporin, and compared with other cephalosporins, penicillins, and aminoglycosides by a broth microdilution technique. Cefotaxime (HR756), a new semisynthetic cephalosporin, and LY127935 were more active, and showed lower minimun inhibitory concentrations (rantes, -O.12 to 2.0 ,ug/ml), than cefamandole, cefoxitin, and cefazolin against Escherichia coli, Klebsiella spp., Enterobacter spp., Proteus mirabilis, indole-positive Proteus spp., Serratia marcescens, Providencia spp., and Citrobacter spp. Against P. aeruginosa, piperacillin, azlocillin, and mezlocillin were the most active betalactam agents; 64 ,ug/ml inhibited 99, 93, and 87%, of the isolates, respectively. LY127935 and cefotaxime at 16 ,ug/ml inhibited 71% of Pseudomonas isolates, whereas the aminoglycosides gentamicin, tobramycin, and amikacin at a concentration of 4 ,ug/ml inhibited 84, 88, and 93%, respectively. Minimum bactericidal concentrations were determined for all isolates and were generally the same as the minimum inhibitory concentrations.
LY127935 is a new parenteral semisynthetic 1-oxa cephalosporin antibiotic which has been shown in preliminary in vitro testing to be highly active against gram-negative microorganisms including Pseudomonas aeruginosa and Enterobacteriaceae resistant to other cephalosporins and cephamycins (4). The purpose of this study was to determine the comparative in vitro susceptibility of 434 clinical gram-negative bacillary isolates to LY127935 and nine other antimicrobial agents. Microorganisms. A total of 434 clinical gram-negative bacillary isolates were tested. All isolates were obtained from patients at University Hospital, the Birmingham Veterans Administration Hospital, and Baptist Montclair Hospital, Birmingham (kindly supplied by Katherine Hunter). Isolates of all species except three represented recent consecutive clinical isolates from different patients. Some strains of Pseudomonas aeruginosa, Serratia marcescens, and Acinetobacter calcoaceticus had been stored frozen and were included to provide an evaluation of LY127935 against known multiresistant strains. The isolates were maintained on nutrient agar slants (BBL Microbiology Systems, Cockeysville, Md.) at room temperature during testing, and stock cultures were frozen in skim milk at -600C. Antibiotics. Sterile standardized powders were kindly provided by their respective manu-
facturers: LY127935, cefamandole, and tobramycin by Eli Lilly and Co.; carbenicillin and ticarcillin by Beecham Laboratories; azlocillin and mezlocillin by Delbay Research Corporation; piperacillin by Lederle Laboratories; amikacin by Bristol Laboratories; cefazolin by Smith, Kline, and French Laboratories; cefoxitin by Merck, Sharp, and Dohme Research Laboratories; and cefotaxime (HR756) by HoechstRoussel Pharmaceuticals, Inc. Determination of MICs. Minimum inhibitory concentrations (MICs) were determined by a microdilution technique as described by Barry (1). Antibiotic dilutions were prepared in Mueller-Hinton broth. With calibrated pipettes, 50 ,ul of each antibiotic dilution was transferred to each well of a U-shaped microtiter plate (Dynatech, Inc., Alexandria, Va.), with resulting final antibiotic concentrations ranging from 0.12 to 64 ug/ml. Organisms to be tested were picked from nutrient agar slants and suspended in 1 ml of Mueller-Hinton broth. After overnight incubation at 37°C, the cultures were adjusted to 10' colony-forming units per ml with a 0.5 McFarland standard and then diluted 1:1,000 with Mueller-Hinton broth. A 0.05-ml amount of the culture dilution was added to each well of the microtiter plate, resulting in a final inoculum of 5 x 104 colony-forming units per ml. The microtiter plates were incubated for 18 h 864
VOL. 16, 1979
at 370C. The MIC was defined as the lowest concentration of antibiotic that inhibited visible growth. Determination of MBCs. The minimum bactericidal concentrations (MBCs) of the antibiotics were determined by subculturing 2 pl of the broth from each well exhibiting no visible growth onto a culture plate of Mueller-Hinton agar with a replicator-type inoculator similar to that described by Zinner (5). After overnight incubation at 370C, the MBCs were defined as the lowest concentration of antibiotic yielding less than five colonies, i.e., the concentration at which at least 99.9% of the bacteria were rendered nonculturable. The MBCs were either equal to or no more than twofold greater than the MICs for all of the isolates tested; accordingly, the detailed MBC data are not included. Microdilution studies. The activity of LY127935 against 434 gram-negative bacillary isolates was compared with that of cefotaxime,
cefamandole, cefoxitin, cefazolin, carbenicillin, ticarcillin, gentamicin, tobramycin, and amikacin. The 75 P. aeruginosa isolates were also tested against piperacillin, azlocillin, and mezlocillin. The results of these studies are shown in Table 1. LY127935 and cefotaxime inhibited strains of Escherichia coli at lower concentrations than did any of the other cephalosporins or cephamycins tested. For example, 86 and 92% of the E. coli isolates were inhibited by 50.12 ug of LY127935 and cefotaxime per ml, respectively. Similarly, these two agents were the most active of the beta-lactam antibiotics against Kiebsiella pneumoniae, Kiebsiella oxytoca, Enterobacter aerogenes, Enterobacter cloacae, Proteus mirabilis, and indole-positive Proteus spp. Against P. aeruginosa, piperacillin, azlocillin, and mezlocillin were the most active beta-lactam agents; at a concentration of 64 ,ug/ml, these agents inhibited 99, 93, and 87% of the isolates, respectively. LY127935 and cefotaxime showed activity comparable to that of carbenicillin and ticarcillin, inhibiting 71% of the isolates at a concentration of 16 ,ug/ml. None of the other cephalosporins or cephamycins inhibited these organisms at concentrations below 64 ,g/ml. Amikacin was the most active aminoglycoside against these isolates. Twenty-two isolates of P. aeruginosa were resistant to LY127935 (MIC > 16 ,ug/ml). Of these, five may have been progeny of the same strain as determined by susceptibility patterns. LY127935 and cefotaxime were several-fold more active against S. marcescens than any of the other antibiotics tested; 2 ug of LY127935 or cefotaxime per ml inhibited 90% of the strains. Cefoxitin and cefamandole were the next most
NOTES
865
active beta-lactams; a concentration of 16 ,ug/ml inhibited 84 and 70% of the isolates, respectively. Ticarcillin and carbenicillin were the most active beta-lactam antibiotics against A. calcoaceticus: a concentration of 32 pug/ml inhibited 92 and 88% of the isolates, respectively. Cefotaxime and LY127935 were the next most active; 16 pg/ml of either drug inhibited 54 and 48%, and 32 ,ug/ ml inhibited 98 and 94% of the strains, respectively. Against Providencia spp., cefotaxime and LY127935 showed the greatest antibacterial activity among the beta-lactam drugs; 1 pug of cefotaxime and 2 ug of LY127935 per ml inhibited 100% of the isolates, respectively. Cefoxitin was more active than either cefamandole or cefazolin. Cefotaxime had the greatest activity against Citrobacter spp.; a concentration of 0.5 ,ug/ml inhibited 69% of the strains, and 2 ,ug/ml inhibited 81%. LY127935, cefamandole, and cefoxitin showed comparable activity; a concentration of 4 ug of each of these antibiotics per ml inhibited 81, 75, and 69% of the strains, respectively. In summary LY127935 is highly active against aerobic gram-negative microorganisms, including P. aerugnosa and Enterobacteriaceae resistant to other cephalosporins and cephamycins. Cefotaxime, another new cephalosporin, has been shown to inhibit aerobic gram-negative bacteria at concentrations much lower than those required by other cephalosporins (2, 3). Neu et al. (4) compared the activity of LY127935 with other beta-lactam compounds and noted that it had equal or slightly less activity than cefotaxime against members of the Enterobacteriaceae, but 8- to 32-fold more activity than the other cephalosporins against these same organisms. LY127935 was twofold more active than cefotaxime and fourfold more active than carbenicillin and ticarcillin against P. aeruginosa. LY127935 and cefotaxime were equally active against S. marcescens. Neu et al. also showed that LY127935 had significant activity against other gram-negative bacteria, including Bacteroides spp., Haemophilus influenzae, and Neisseria gonorrhoeae and against gram-positive cocci including staphylococcal and streptococcal organisms (4). In the present study, LY127935 and cefotaxime were more active than cefazolin, cefamandole, and cefoxitin against all the aerobic gramnegative isolates tested. In the lower MIC ranges, i.e., sO.5 pg/ml, cefotaxime was slightly more active than LY127935 against K. pneumoniae and E. aerogenes, and these two new cephalosporins had equal activity against E. coli, K. oxytoca, E. cloacae, P. mirabilis, indole-positive Proteus spp., and Providencia spp. In contrast
866
ANTimICROB. AGENTS CHEMOTHER.
NOTES
TABLE 1. In vitro activity of LY127935 againt aerobic gram-negative bacili compared with other cephalosporum penicillins, and aminoglycosides Antibiotic Range of MIC (jag/mi) 50% MIC (ug/ml) 90% MIC (jg/mi) Organism (no. of strains) LY127935 sO.12 0.25 50.12-1 E. coli (50) sO.12-0.5 sO.12 s0.12 Cefotaxime 0.25-64 0.5 4 Cefamandole 8 1-16 2 Cefoxitin 2->64 4 16 Cefazolin 2->64 4 >64 Carbenicillin 1->64 2 >64 Ticarcillin 2 4 0.25-32 Gentamicin 2 4 0.5-16 Tobramycin 16 1-32 8 Amikacin
K. pneumoniae (45)
LY127935
Cefotaxime Cefamandole Cefoxitin Cefazolin Carbenicillin Ticarcillin Gentamicin Tobramycin Amikacin K. oxytoca (5)
E. aerogenes (25)
E. cloacae (22)
LY127935
Cefotaxime Cefamandole Cefoxitin Cefazolin Carbenicillin Ticarchllin Gentamicin Tobramycin Amikacin
0.25->64 0.25->64 0.5->64
c0.12-0.5 sO.12-2 0.25-64 1-4 4->64 64->64 32->64 0.5-2 0.25-0.5 1-4
0.25 c0.12 1 4 4 >64 >64 0.5 0.5 2
sO.12
-O.12 4 4 8 >64 >64 0.5 0.5 1 0.25
LY127935
50.12- 64
Cefotaxime Cefamandole Cefoxitin Cefazolin Carbenicillin TiccilHin Gentamicin Tobramycin Amikacin
SO.12-1 1-32 4->64 8->64 2->64 2->64 1-8 0.5-8 2-32
50.12
LY127935
s0.12->64
Cefotaxime Cefamandole
50.12->64
0.25 0.25 4 >64 >64 8 4 1 1 2
Cefoxitin Cefazolin
Carbenicillin Ticarcillin Gentamicin Tobramycin Amikacin P. mirabilis (50)
c0.12->64 s0.12->64 0.25->64 0.25->64 2->64 8->64 2->64
LY127935 Cefotaxime
Cefamandole Cefoxitin Cefazolin
0.5->64 16->64 16->64 2->64 2->64 0.5-8 0.5-16
2-64
50.12-0.25 50.12-0.25 0.5-8 2-16 1-64
2 32 32 4 4 2 1 4
1 0.5 64 32 64 >64 >64 4 1 4 0.5 2 >64 4 >64 >64 >64 2 0.5 4 2 0.5 8 >64 >64 >64 >64 4 4 8 2 0.5 32 >64 >64 32 32 2 2 4
50.12 50.12
50.12
1 4 16
2 4 32
0.12
NOTE3S
VOL. 16, 1979
86B7
TABLE-continued Organism (no. of straim)
Proteus
spp.
(30) (in-
dole-positive)
P. aeruginosa (75)
S.
marcescens
(50)
A. calcoaceticus (50)
Providencia spp. (16)
Antibiotic
Carbenicillin Ticarcillin Gentamicin Tobramycin Amikacin LY127935 Cefotaxime Cefamandole Cefoxitin Cefazolin Carbenicillin Ticarcillin Gentamicin Tobramycin Amikacin LY127935 Cefotaxime Cefamandole Cefoxitin Cefazolin Carbenicillin Ticarcillin Piperacillin Azlocillin Mezlocilhin Gentamicin Tobramycin Amikacin LY127935 Cefotaxime Cefamandole Cefoxitin Cefazolin CarbeniciUin Ticarcillin Gentamicin Tobramycin Amikacin LY127935 Cefotaxime Cefamandole Cefoxitin Cefazolin
CarbeniciUin Ticarcillin Gentamicin Tobramycin Amikacin LY127935 Cefotaxime Cefamandole Cefoxitin Cefazolin
CarbeniciUlin Ticarcillin Gentamicin Tobramycin Amikacin
Range of MIC (pg/ml) 50% MIC (jg/ml) 90% MIC (pg/ml)
s0.12-2 S0.12-2 0.5-8 0.25-8 0.5-32 0O.12-1 50.12-1 1->64 1-32 4->64 0.5->64 0.5->64 0.25-64 0.5-16 0.5-64 4->64 8->64 >64 64->64 >64
16->64 4->64 2->64 2->64 8->64 0.25->64 0.12-16 0.5-64 0.25->64
C0.12->64
2->64 4->64 64->64 2->64 1->64 0.5->64 0.25->64 2-64 1-64 0.5-64 32->64 0.5->64 2->64 2->64 2->64 0.5-64
0.5-64 1-64 50.12-2 0.25-1 0.5-32 2-8 64->64 0.5->64 0.25->64 4-32 4-64 0.5-8
1 1 2 2
4 C0.12 C0.12 2 8 >64 1 1
0.5 1 2 16 16 >64 >64 >64 64 32 4 8 16 0.5 0.5 2 0.5 _0.12 8 8 >64 16 16 1 4 2 32 16 64 64 >64 16 16 4 1 2 0.5 0.5 2 2 >64 1 1 4 8 2
1 1
4 4 16
0.25 C0.12 >64 16 >64 >64 64 4 8 4 >64 64 >64
>64 >64 >64 >64 32 32 >64 8 8 4 2 2 >64 >64 >64 >64 >64 32 >64 16 32 32 >64 >64 >64 64 32 16 4 8 2 1 16 4 >64 >64 >64
16 32 4
868
ANTIMICROB. AGENTS CHEMOTHER.
NOTES
Organism (no. of strains) Citrobacter spp. (16)
TABLE 1. Continued Range of MIC (,ug/ml) 50% MIC (pg/ml) 90% MIC (ug/ml)
Antibiotic
LY127935
Cefotaxime Cefamandole Cefoxitin Cefazolin
Carbenicillin Ticarcillin Gentamicin Tobramycin
Amilcacin to the data reported by Neu et al. (4), our results showed that cefotaxime in the lower MIC ranges had greater activity than LY127935 against S. marcescens, and at a concentration of 16,ug/ml
LY127935 and cefotaxime had equivalent activity against P. aeruginosa (71% of Pseudomonas isolates were inhibited by both agents). Our in vitro results indicate that (i) LY127935 has significant antibacterial activity against the clinically important Enterobacteriaceae and the nosocomial nonfermentative gram-negative pathogens, P. aeruginosa and A. calcoaceticus; (ii) the activity of LY127935 and cefotaxime against aerobic gram-negative bacilli is similar, and (iii) the activity of both LY127935 and cefotaxime against aerobic gram-negative bacilli exceeds that of three of the more recently introduced cephalosporins, namely, cefazolin, cefoxitin, and cefamandole. This work was supported in part by Eli Laboratories grant 8160D.
Lilly
Research
0.25->64
0.5->64 0.5->64 2->64 64->64 16->64 16->64 0.5->64 0.5-16 1->64
1 4 64 >64 >64 1
8 16 32 >64 64 >64 >64 4
1
4
4
4
1 0.5
James A. Hafner of I:li Lilly was of continuous help to us. Thanks are also due to Rebecca Cooper and Deborah Duke for secretarial assistance.
LITERATURE CITED 1. Barry, A. L. 1976. Broth dilution techniques, p. 92-104. In The antimicrobic susceptibility test: principles and practice. Lea and Febiger, Philadelphia. 2. Hamilton-Miller, J. M. T., W. Brumfitt, and A. V. Reynolds. 1978. Cefotaxime (HR756), a new cephalosporin with exceptional broad spectrum activity in vitro. J. Antimicrob. Chemother. 4:437-444. 3. Neu, H. C., N. A8wapokee, P. Aswapokee, and K. P. Fu. 1979. HR756, a new cephalosporin active against gram-positive and gram-negative aerobic and anaerobic bacteria. Antimicrob. Agents Chemother. 15:273-281. 4. Neu, H. C., N. Aswapokee, K. P. Fu, and P. Aswapokee. 1979. Antibacterial activity of a new 1-oxa cephalosporin compared with that of other ,-lactam compounds. Antimicrob. Agents Chemother. 16:141-149. 5. Zinner, S. H. 1975. New aminoglycoside antibiotics for use against pseudomonas and klebsieila, p. 109-116. In J. Klastersky (ed.), Clinical use of combinations of antibiotics. John Wiley and Sons, New York.
Vol. 16, No. 6
0066-4804/79/12-0864/05$02.00/0
In Vitro Activity of LY127935, a New 1-Oxa Cephalosporin, Against Aerobic Gram-Negative Bacilli DENNIS G. DELGADO, CARMEN J. BRAU, C. GLENN COBBS, AND WILLIAM E. DISMUKES* Division of Infectious Diseases, Department ofMedicine, The University of Alabama School of Medicine, Birmingham, Alabama 35294 Received for publication 10 September 1979
A total of 434 clinical aerobic gram-negative bacillary isolates were tested against LY127935, a new 1-oxa cephalosporin, and compared with other cephalosporins, penicillins, and aminoglycosides by a broth microdilution technique. Cefotaxime (HR756), a new semisynthetic cephalosporin, and LY127935 were more active, and showed lower minimun inhibitory concentrations (rantes, -O.12 to 2.0 ,ug/ml), than cefamandole, cefoxitin, and cefazolin against Escherichia coli, Klebsiella spp., Enterobacter spp., Proteus mirabilis, indole-positive Proteus spp., Serratia marcescens, Providencia spp., and Citrobacter spp. Against P. aeruginosa, piperacillin, azlocillin, and mezlocillin were the most active betalactam agents; 64 ,ug/ml inhibited 99, 93, and 87%, of the isolates, respectively. LY127935 and cefotaxime at 16 ,ug/ml inhibited 71% of Pseudomonas isolates, whereas the aminoglycosides gentamicin, tobramycin, and amikacin at a concentration of 4 ,ug/ml inhibited 84, 88, and 93%, respectively. Minimum bactericidal concentrations were determined for all isolates and were generally the same as the minimum inhibitory concentrations.
LY127935 is a new parenteral semisynthetic 1-oxa cephalosporin antibiotic which has been shown in preliminary in vitro testing to be highly active against gram-negative microorganisms including Pseudomonas aeruginosa and Enterobacteriaceae resistant to other cephalosporins and cephamycins (4). The purpose of this study was to determine the comparative in vitro susceptibility of 434 clinical gram-negative bacillary isolates to LY127935 and nine other antimicrobial agents. Microorganisms. A total of 434 clinical gram-negative bacillary isolates were tested. All isolates were obtained from patients at University Hospital, the Birmingham Veterans Administration Hospital, and Baptist Montclair Hospital, Birmingham (kindly supplied by Katherine Hunter). Isolates of all species except three represented recent consecutive clinical isolates from different patients. Some strains of Pseudomonas aeruginosa, Serratia marcescens, and Acinetobacter calcoaceticus had been stored frozen and were included to provide an evaluation of LY127935 against known multiresistant strains. The isolates were maintained on nutrient agar slants (BBL Microbiology Systems, Cockeysville, Md.) at room temperature during testing, and stock cultures were frozen in skim milk at -600C. Antibiotics. Sterile standardized powders were kindly provided by their respective manu-
facturers: LY127935, cefamandole, and tobramycin by Eli Lilly and Co.; carbenicillin and ticarcillin by Beecham Laboratories; azlocillin and mezlocillin by Delbay Research Corporation; piperacillin by Lederle Laboratories; amikacin by Bristol Laboratories; cefazolin by Smith, Kline, and French Laboratories; cefoxitin by Merck, Sharp, and Dohme Research Laboratories; and cefotaxime (HR756) by HoechstRoussel Pharmaceuticals, Inc. Determination of MICs. Minimum inhibitory concentrations (MICs) were determined by a microdilution technique as described by Barry (1). Antibiotic dilutions were prepared in Mueller-Hinton broth. With calibrated pipettes, 50 ,ul of each antibiotic dilution was transferred to each well of a U-shaped microtiter plate (Dynatech, Inc., Alexandria, Va.), with resulting final antibiotic concentrations ranging from 0.12 to 64 ug/ml. Organisms to be tested were picked from nutrient agar slants and suspended in 1 ml of Mueller-Hinton broth. After overnight incubation at 37°C, the cultures were adjusted to 10' colony-forming units per ml with a 0.5 McFarland standard and then diluted 1:1,000 with Mueller-Hinton broth. A 0.05-ml amount of the culture dilution was added to each well of the microtiter plate, resulting in a final inoculum of 5 x 104 colony-forming units per ml. The microtiter plates were incubated for 18 h 864
VOL. 16, 1979
at 370C. The MIC was defined as the lowest concentration of antibiotic that inhibited visible growth. Determination of MBCs. The minimum bactericidal concentrations (MBCs) of the antibiotics were determined by subculturing 2 pl of the broth from each well exhibiting no visible growth onto a culture plate of Mueller-Hinton agar with a replicator-type inoculator similar to that described by Zinner (5). After overnight incubation at 370C, the MBCs were defined as the lowest concentration of antibiotic yielding less than five colonies, i.e., the concentration at which at least 99.9% of the bacteria were rendered nonculturable. The MBCs were either equal to or no more than twofold greater than the MICs for all of the isolates tested; accordingly, the detailed MBC data are not included. Microdilution studies. The activity of LY127935 against 434 gram-negative bacillary isolates was compared with that of cefotaxime,
cefamandole, cefoxitin, cefazolin, carbenicillin, ticarcillin, gentamicin, tobramycin, and amikacin. The 75 P. aeruginosa isolates were also tested against piperacillin, azlocillin, and mezlocillin. The results of these studies are shown in Table 1. LY127935 and cefotaxime inhibited strains of Escherichia coli at lower concentrations than did any of the other cephalosporins or cephamycins tested. For example, 86 and 92% of the E. coli isolates were inhibited by 50.12 ug of LY127935 and cefotaxime per ml, respectively. Similarly, these two agents were the most active of the beta-lactam antibiotics against Kiebsiella pneumoniae, Kiebsiella oxytoca, Enterobacter aerogenes, Enterobacter cloacae, Proteus mirabilis, and indole-positive Proteus spp. Against P. aeruginosa, piperacillin, azlocillin, and mezlocillin were the most active beta-lactam agents; at a concentration of 64 ,ug/ml, these agents inhibited 99, 93, and 87% of the isolates, respectively. LY127935 and cefotaxime showed activity comparable to that of carbenicillin and ticarcillin, inhibiting 71% of the isolates at a concentration of 16 ,ug/ml. None of the other cephalosporins or cephamycins inhibited these organisms at concentrations below 64 ,g/ml. Amikacin was the most active aminoglycoside against these isolates. Twenty-two isolates of P. aeruginosa were resistant to LY127935 (MIC > 16 ,ug/ml). Of these, five may have been progeny of the same strain as determined by susceptibility patterns. LY127935 and cefotaxime were several-fold more active against S. marcescens than any of the other antibiotics tested; 2 ug of LY127935 or cefotaxime per ml inhibited 90% of the strains. Cefoxitin and cefamandole were the next most
NOTES
865
active beta-lactams; a concentration of 16 ,ug/ml inhibited 84 and 70% of the isolates, respectively. Ticarcillin and carbenicillin were the most active beta-lactam antibiotics against A. calcoaceticus: a concentration of 32 pug/ml inhibited 92 and 88% of the isolates, respectively. Cefotaxime and LY127935 were the next most active; 16 pg/ml of either drug inhibited 54 and 48%, and 32 ,ug/ ml inhibited 98 and 94% of the strains, respectively. Against Providencia spp., cefotaxime and LY127935 showed the greatest antibacterial activity among the beta-lactam drugs; 1 pug of cefotaxime and 2 ug of LY127935 per ml inhibited 100% of the isolates, respectively. Cefoxitin was more active than either cefamandole or cefazolin. Cefotaxime had the greatest activity against Citrobacter spp.; a concentration of 0.5 ,ug/ml inhibited 69% of the strains, and 2 ,ug/ml inhibited 81%. LY127935, cefamandole, and cefoxitin showed comparable activity; a concentration of 4 ug of each of these antibiotics per ml inhibited 81, 75, and 69% of the strains, respectively. In summary LY127935 is highly active against aerobic gram-negative microorganisms, including P. aerugnosa and Enterobacteriaceae resistant to other cephalosporins and cephamycins. Cefotaxime, another new cephalosporin, has been shown to inhibit aerobic gram-negative bacteria at concentrations much lower than those required by other cephalosporins (2, 3). Neu et al. (4) compared the activity of LY127935 with other beta-lactam compounds and noted that it had equal or slightly less activity than cefotaxime against members of the Enterobacteriaceae, but 8- to 32-fold more activity than the other cephalosporins against these same organisms. LY127935 was twofold more active than cefotaxime and fourfold more active than carbenicillin and ticarcillin against P. aeruginosa. LY127935 and cefotaxime were equally active against S. marcescens. Neu et al. also showed that LY127935 had significant activity against other gram-negative bacteria, including Bacteroides spp., Haemophilus influenzae, and Neisseria gonorrhoeae and against gram-positive cocci including staphylococcal and streptococcal organisms (4). In the present study, LY127935 and cefotaxime were more active than cefazolin, cefamandole, and cefoxitin against all the aerobic gramnegative isolates tested. In the lower MIC ranges, i.e., sO.5 pg/ml, cefotaxime was slightly more active than LY127935 against K. pneumoniae and E. aerogenes, and these two new cephalosporins had equal activity against E. coli, K. oxytoca, E. cloacae, P. mirabilis, indole-positive Proteus spp., and Providencia spp. In contrast
866
ANTimICROB. AGENTS CHEMOTHER.
NOTES
TABLE 1. In vitro activity of LY127935 againt aerobic gram-negative bacili compared with other cephalosporum penicillins, and aminoglycosides Antibiotic Range of MIC (jag/mi) 50% MIC (ug/ml) 90% MIC (jg/mi) Organism (no. of strains) LY127935 sO.12 0.25 50.12-1 E. coli (50) sO.12-0.5 sO.12 s0.12 Cefotaxime 0.25-64 0.5 4 Cefamandole 8 1-16 2 Cefoxitin 2->64 4 16 Cefazolin 2->64 4 >64 Carbenicillin 1->64 2 >64 Ticarcillin 2 4 0.25-32 Gentamicin 2 4 0.5-16 Tobramycin 16 1-32 8 Amikacin
K. pneumoniae (45)
LY127935
Cefotaxime Cefamandole Cefoxitin Cefazolin Carbenicillin Ticarcillin Gentamicin Tobramycin Amikacin K. oxytoca (5)
E. aerogenes (25)
E. cloacae (22)
LY127935
Cefotaxime Cefamandole Cefoxitin Cefazolin Carbenicillin Ticarchllin Gentamicin Tobramycin Amikacin
0.25->64 0.25->64 0.5->64
c0.12-0.5 sO.12-2 0.25-64 1-4 4->64 64->64 32->64 0.5-2 0.25-0.5 1-4
0.25 c0.12 1 4 4 >64 >64 0.5 0.5 2
sO.12
-O.12 4 4 8 >64 >64 0.5 0.5 1 0.25
LY127935
50.12- 64
Cefotaxime Cefamandole Cefoxitin Cefazolin Carbenicillin TiccilHin Gentamicin Tobramycin Amikacin
SO.12-1 1-32 4->64 8->64 2->64 2->64 1-8 0.5-8 2-32
50.12
LY127935
s0.12->64
Cefotaxime Cefamandole
50.12->64
0.25 0.25 4 >64 >64 8 4 1 1 2
Cefoxitin Cefazolin
Carbenicillin Ticarcillin Gentamicin Tobramycin Amikacin P. mirabilis (50)
c0.12->64 s0.12->64 0.25->64 0.25->64 2->64 8->64 2->64
LY127935 Cefotaxime
Cefamandole Cefoxitin Cefazolin
0.5->64 16->64 16->64 2->64 2->64 0.5-8 0.5-16
2-64
50.12-0.25 50.12-0.25 0.5-8 2-16 1-64
2 32 32 4 4 2 1 4
1 0.5 64 32 64 >64 >64 4 1 4 0.5 2 >64 4 >64 >64 >64 2 0.5 4 2 0.5 8 >64 >64 >64 >64 4 4 8 2 0.5 32 >64 >64 32 32 2 2 4
50.12 50.12
50.12
1 4 16
2 4 32
0.12
NOTE3S
VOL. 16, 1979
86B7
TABLE-continued Organism (no. of straim)
Proteus
spp.
(30) (in-
dole-positive)
P. aeruginosa (75)
S.
marcescens
(50)
A. calcoaceticus (50)
Providencia spp. (16)
Antibiotic
Carbenicillin Ticarcillin Gentamicin Tobramycin Amikacin LY127935 Cefotaxime Cefamandole Cefoxitin Cefazolin Carbenicillin Ticarcillin Gentamicin Tobramycin Amikacin LY127935 Cefotaxime Cefamandole Cefoxitin Cefazolin Carbenicillin Ticarcillin Piperacillin Azlocillin Mezlocilhin Gentamicin Tobramycin Amikacin LY127935 Cefotaxime Cefamandole Cefoxitin Cefazolin CarbeniciUin Ticarcillin Gentamicin Tobramycin Amikacin LY127935 Cefotaxime Cefamandole Cefoxitin Cefazolin
CarbeniciUin Ticarcillin Gentamicin Tobramycin Amikacin LY127935 Cefotaxime Cefamandole Cefoxitin Cefazolin
CarbeniciUlin Ticarcillin Gentamicin Tobramycin Amikacin
Range of MIC (pg/ml) 50% MIC (jg/ml) 90% MIC (pg/ml)
s0.12-2 S0.12-2 0.5-8 0.25-8 0.5-32 0O.12-1 50.12-1 1->64 1-32 4->64 0.5->64 0.5->64 0.25-64 0.5-16 0.5-64 4->64 8->64 >64 64->64 >64
16->64 4->64 2->64 2->64 8->64 0.25->64 0.12-16 0.5-64 0.25->64
C0.12->64
2->64 4->64 64->64 2->64 1->64 0.5->64 0.25->64 2-64 1-64 0.5-64 32->64 0.5->64 2->64 2->64 2->64 0.5-64
0.5-64 1-64 50.12-2 0.25-1 0.5-32 2-8 64->64 0.5->64 0.25->64 4-32 4-64 0.5-8
1 1 2 2
4 C0.12 C0.12 2 8 >64 1 1
0.5 1 2 16 16 >64 >64 >64 64 32 4 8 16 0.5 0.5 2 0.5 _0.12 8 8 >64 16 16 1 4 2 32 16 64 64 >64 16 16 4 1 2 0.5 0.5 2 2 >64 1 1 4 8 2
1 1
4 4 16
0.25 C0.12 >64 16 >64 >64 64 4 8 4 >64 64 >64
>64 >64 >64 >64 32 32 >64 8 8 4 2 2 >64 >64 >64 >64 >64 32 >64 16 32 32 >64 >64 >64 64 32 16 4 8 2 1 16 4 >64 >64 >64
16 32 4
868
ANTIMICROB. AGENTS CHEMOTHER.
NOTES
Organism (no. of strains) Citrobacter spp. (16)
TABLE 1. Continued Range of MIC (,ug/ml) 50% MIC (pg/ml) 90% MIC (ug/ml)
Antibiotic
LY127935
Cefotaxime Cefamandole Cefoxitin Cefazolin
Carbenicillin Ticarcillin Gentamicin Tobramycin
Amilcacin to the data reported by Neu et al. (4), our results showed that cefotaxime in the lower MIC ranges had greater activity than LY127935 against S. marcescens, and at a concentration of 16,ug/ml
LY127935 and cefotaxime had equivalent activity against P. aeruginosa (71% of Pseudomonas isolates were inhibited by both agents). Our in vitro results indicate that (i) LY127935 has significant antibacterial activity against the clinically important Enterobacteriaceae and the nosocomial nonfermentative gram-negative pathogens, P. aeruginosa and A. calcoaceticus; (ii) the activity of LY127935 and cefotaxime against aerobic gram-negative bacilli is similar, and (iii) the activity of both LY127935 and cefotaxime against aerobic gram-negative bacilli exceeds that of three of the more recently introduced cephalosporins, namely, cefazolin, cefoxitin, and cefamandole. This work was supported in part by Eli Laboratories grant 8160D.
Lilly
Research
0.25->64
0.5->64 0.5->64 2->64 64->64 16->64 16->64 0.5->64 0.5-16 1->64
1 4 64 >64 >64 1
8 16 32 >64 64 >64 >64 4
1
4
4
4
1 0.5
James A. Hafner of I:li Lilly was of continuous help to us. Thanks are also due to Rebecca Cooper and Deborah Duke for secretarial assistance.
LITERATURE CITED 1. Barry, A. L. 1976. Broth dilution techniques, p. 92-104. In The antimicrobic susceptibility test: principles and practice. Lea and Febiger, Philadelphia. 2. Hamilton-Miller, J. M. T., W. Brumfitt, and A. V. Reynolds. 1978. Cefotaxime (HR756), a new cephalosporin with exceptional broad spectrum activity in vitro. J. Antimicrob. Chemother. 4:437-444. 3. Neu, H. C., N. A8wapokee, P. Aswapokee, and K. P. Fu. 1979. HR756, a new cephalosporin active against gram-positive and gram-negative aerobic and anaerobic bacteria. Antimicrob. Agents Chemother. 15:273-281. 4. Neu, H. C., N. Aswapokee, K. P. Fu, and P. Aswapokee. 1979. Antibacterial activity of a new 1-oxa cephalosporin compared with that of other ,-lactam compounds. Antimicrob. Agents Chemother. 16:141-149. 5. Zinner, S. H. 1975. New aminoglycoside antibiotics for use against pseudomonas and klebsieila, p. 109-116. In J. Klastersky (ed.), Clinical use of combinations of antibiotics. John Wiley and Sons, New York.
