Moxalactam (LY127935), a new semisynthetic 1-oxa-beta-lactam antibiotic with remarkable antimicrobial activity: in vitro comparison with cefamandole and tobramycin.

Moxalactam (LY127935) exhibited greater in vitro activity than cefamandole and tobramycin against clinical isolates of Enterobacteriaceae, Aeromonas hydrophila, and Pseudomonas maltophilia. The activities of the three drugs against other microorganisms were as follows: for staphylococci, cefamandole = tobramycin greater than moxalactam; for streptococci, cefamandole greater than moxalactam greater than tobramycin; and for Pseudomonas aeruginosa, tobramycin greater than moxalactam greater than cefamandole. Moxalactam also demonstrated significant activity against the Bacteroides fragilis group and other anaerobes. Moxalactam was comparable to cefotaxime (HR756) in its inhibition of cephalothin-resistant and aminoglycoside-resistant clinical isolates.

Moxalactam also demonstrated significant activity against the Bacteroides fragilis group and other anaerobes. Moxalactam was comparable to cefotaxinme (HR756) in its inhibition of cephalothin-resistant and aminoglycoside-resistant clinical isolates.
In this collaborative six-medical center in vitro evaluation, we principally compared the antimicrobial activity of moxalactam with those of a broad-spectrum cephalosporin (cefamandole) and an aminoglycoside (tobramycin).
The study compound moxalactam and reference antimicrobial agents (cefamandole and to-bramycin) were received as a gift from Eli Lilly and Co., Indianapolis, Ind. Moxalactam was an equal mixture of D and L isomers (lot SI-113-8B).
The bacterial strains studied were those consecutive clinical strains isolated during a 45to 60-day interval at the six participating laboratories. The number of isolates tested was 8,371, including 4,679 Enterobacteriaceae, 860 nonenteric gram-negative bacilli, 851 streptococci, 1,531 staphylococci, and 150 selected antibioticresistant strains. All organisms were identified and processed by methods previously described (7,8,11,12). In addition, 248 anaerobic organisms were tested by broth microdilution and agar dilution methods (9, 13) after identification by gas-liquid chromatography and biochemical micro-tube procedures (9). The minimum inhibitory concentrations (MICs) of all study compounds were determined by agar dilution methods or microdilution broth procedures. In the broth microdilution procedure, Mueller-Hinton broth (Difco) was supplemented with 50 mg of calcium and 25 mg of magnesium per liter. Media and antibiotics were dispensed into plastic trays utilizing the MIC-2000 (Cooke Laboratory Products, Alexandria, Va.) by techniques previously reported (7,8,11,12). Agar dilution tests were performed after the method of the International Collaborative Study (4) using Mueller-Hinton agar inoculated by a Steers replicator (17) with an inoculum density of ca. 104 colony-forming units per spot. The and 107 colony-forming units per ml on the MICs antibiotic-containing agar plates and microdiluwas also determined. tion trays were incubated for 15 to 18 h at 35°C. Intra-and interlaboratory MIC variations The effect ofinoculum concentrations of 103, 105, were assessed using four quality control strains  (8).
Moxalactam demonstrates remarkable activity against all the Enterobacteriaceae ( Table 1).
The moxalactam modal MIC was cO.5 ,ug/ml for all species, compared to the range of s0.5 to >32 ,ug/ml for cefamandole and cO.5 to 4 ,Lg/ml for tobramycin. The increased in vitro activity of moxalactam over both cefamandole and tobramycin statistically significant (P = < 0.001) for Enterobacter cloacae, E. coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, and S. marcescens. Lesser degrees of significance (P = < 0.05 or P = < 0.01) were found favoring moxalactam against Enterobacter agglomerans and Providencia stuartii compared to cefamandole, and moxalactam against Enterobacter aerogenes and Klebsiella oxytoca when pneumoniae, and P. mirabilis. Only one significant moxalactam media MIC difference involving the "other gram-negative bacteria" was noted; it favored higher moxalactam activity against P. aeruginosa when tested by the agar dilution procedures. The anti-staphylococcal activity of moxalac-tam was markedly less than that of cefamandole or tobramycin (  VOL. 17,1980 ity of all three drugs was poor against most Streptococcus species, especially the enterococci. Cefamandole was generally from 4to >16-fold more active than moxalactam (P = < 0.001) against Streptococcus agalactiae, Streptococcus pyogenes, other beta-streptococci, and the Streptococcus viridans group. Among the other gram-positive bacteria, all tested strains of Listeria monocytogenes and Bacillus species were resistant (>32 ,tg/ml) to moxalactam, whereas the corynebacteria were generally susceptible to the lower concentrations tested. Moxalactam demonstrated equal or slightly superior in vitro activity as compared to cefamandole and tobramycin against only three non-Enterobacteriaceae species, e.g., Aeromonas hydrophila, Moraxella sp., and Pseudomonas maltophilia. For all other tabulated species and species groups, tobramycin was significantly (P = < 0.001) more active than either moxalactam or cefamandole. Though moxalactam P. aeruginosa MICs were much lower (mode = 16 ,ug/ml) than those of cefamandole, only 27.6 and 77.9% of the strains were inhibited at 8 and 32 of moxalactam per ml, respectively.
Moxalactam showed antimicrobial activity similar to that of cefoxitin against most of the 248 strict anaerobes shown in Table 3. Moxalactam inhibited 92% of the tested Bacteroides fragilis group strains at c8 ,ug/ml. Against other anaerobes, moxalactam had equal or fourfold less activity when compared with cefoxitin. Two antibiotic-resistant populations of bacteria were also tested against 13 antimicrobial agents ( Table 4). The cephalothin-resistant strains were selected from each of the participating laboratories, and their numbers were adjusted to simulate the clinical incidence of cephalothinresistant isolates. Cefotaxime (72% inhibited at s ,ug/ml) and moxalactam (69% inhibited at c8 ,ug/ml) were the most active among the "cephalosporins" tested; amikacin (92% inhibited at S16 ,ug/ml) was the most active aminoglycoside; and piperacillin (86% inhibited at s64 aLg/ml)  and meziocillin (81% inhibited at '64,tg/ml) were the most active new penicillins. The aminoglycoside-resistant strains were those obtained from previous studies (7,8) and others kindly supplied by G. Miller of Schering Corp. and K. Price of Bristol Laboratories. The rank order of in vitro activity against this latter resistant population was piperacillin (68% inhibited at s64 ,ug/ml) > moxalactam (66% inhibited at c8 ug/ml > carbenicillin (62% inhibited at l128 ytg/ml) > mezlocillin (60% inhibited at s64 ug/ml) = cefotaxime (60% inhibited at s8 ,ug/ml).
The effect of raising the inoculum concentration from 103 to 105 colony-forming units per ml was minimal with moxalactam, cefamandole, and tobramycin (not shown). However, MICs of all three antibiotics with an inoculum of 107 colony-forming units per ml were generally in the resistant range. The moxalactam and tobramycin MICs were also less affected than those of cefamandole when compared to the results with an inoculum of 105 colony-forming units per ml.
Moxalactam and cefotaxime appear to offer promise for the treatment of some resistant populations of bacteria prevalent in certain institutions (7,8,14). Cefotaxime and moxalactam were among the most active beta-lactams against both the cephalothinand aminoglycoside-resistant strains. The newer semisynthetic penicillins, piperacillin and mezlocillin, also appear effective against both of these resistant populations. This 1-oxa-/i-lactam antibiotic, moxalactam (LY127935), inhibited 76.8 and 87.2% of all fac-ultative bacteria tested in this series of MICs of '8 and c32 ,ug/ml, respectively. This compared favorably with the two most active (on a weight basis) representatives of the currently available aminoglycosides and cephalosporins, e.g., tobramycin and cefamandole. Tobramycin inhibited 82.5% of the isolates at 54 ,ug/ml, and cefamandole inhibited 72.2% of the strains at c8 ,ug/ml. Further in vitro and in vivo investigations are considered appropriate. LITERATURE CITED