(MICg, 0.25 ,ug/ml), cefuroxime axetil (MIC90, '0.5 ,ug/ml), cefprozil (MIC90, .0.5 ,ug/ml), cefaclor (MIC90, 0.5 ,ug/ml), and loracarbef (MIC90, 1.0 ,ug/ml). Most strains of the other species remained susceptible to the study drugs other than amoxicillin.

Broth microdilution tests and an antimicrobial interaction (synergy) studies using various combinations of cefoperazone and sulbactam were performed in an effort to determine the most appropriate in vitro dilution test system. The test results with cefoperazone and sulbactam were categorized as synergistic (complete or partial) for nearly 80% of the strains isolated from clinical trial patients. The results indicate that the cefoperazone-sulbactam fixed ratio (2:1) maximized the cefoperazone spectrum of activity and best approximated the parenteral formulation of the drug. The cefoperazone-sulbactam combination had a greater antimicrobial activity than did the other comparison beta-lactams, except for imipenem, tested against strains of the family Enterobacteriaceae. To be consistent with the National Committee for Clinical Laboratory Standards interpretive breakpoints for cefoperazone alone, the following MIC breakpoints should be applied to the combination (2:1 ratio): less than or equal to 16/8 micrograms/ml, susceptible; 32/16 micrograms/ml, moderately susceptible; and greater than or equal to 64/32 micrograms/ml, resistant.

Enterobacteriaceae strains having elevated minimal inhibitory concentrations (.2.0 to s32 ,ug/ml) of cefoperazone, cefotaxime, ceftazidime, and moxalactam were synergistically inhibited by amikacin combinations (54.1 to 69.6% occurrence). Indifference was rare (8.1% for moxalactam), and true antagonistic interactions were not observed. Strains resistant or susceptible to these new cephalosporins were also synergistically inhibited by the addition of amikacin, reducing resistant cephalosporin minimal inhibitory concentrations to clinically achievable levels.Amikacin has been recognized as the currently available aminoglycoside most refractory to bacterial enzyme inactivation (18). This stability has generally limited the use of amikacin to those clinical bacterial strains resistant to kanamycin, gentamicin, and tobramycin by enzyme plasmid-mediated mechanisms. Similarly, the recently introduced third-generation cephalosporins have substantial stability to bacterial plactamases and a potent antimicrobial activity (2, 3, 6-9, 15, 16). The bacteria most likely to harbor the higher minimal inhibitory concentrations (MICs) for these new ,B-lactams are the nonfermentative bacilli and the serogroup D Streptococcus spp.; however, a few strains of Enterobacteriaceae may have MICs of 2.0 to 32 ,ug/ml (3,(7)(8)(9). These latter organisms represent a very different population of enteric bacilli only moderately susceptible (MS) to these highly active new drugs. Very few Enterobacteriaceae are currently considered resistant (MICs, .64 ,g/ml) to cefoperazone,' cefotaxime, ceftazidime, or moxalactam.To determine the possibility of using antimicrobial combinations to treat infections caused by these MS strains of Enterobacteriaceae (cefoperazone, cefotaxime, ceftazidime, or moxalactam MICs, 2.0 to 32 ,ug/ml), we screened over 6,000 organisms to find strains having elevated MICs as described above. These recent clinical isolates from The Cleveland Clinic Foundation (Cleveland, Ohio), St. Francis Hospital (Wichita, Kans.), St. Vincent Hospital and Medical Center (Portland, Oreg.), and Northwestern Memorial Hospital (Chicago, Ill.) were collected and then retested for their susceptibility to the new ,-lactams singly and in combination with amikacin. Synergy analysis was determined by the checkerboard broth dilution technique, confirmed by a limited number of bactericidal concentration isobolograms and kill curves. Some additional organisms were tested, including several with resistance to one or more of the five broad-spectrum drugs to detect their possible conversion from resistantto-susceptible MIC results by the addition of another antimicrobial agent.MATERALS AND METHODS Antibiotics. The broad-spectrum drugs utilized in all phases of this study were supplied by the following manufacturers: amikacin, Bristol Laboratories, Syracuse, N.Y.; cefoperazone, Pfizer Inc., New York, N.Y.; cefotaxime, Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J.; ceftazidime, Glaxo Inc., Research Triangle Park, N.C.; moxalactam, Eli Lilly & Co., ...

Tests with 52 strains of Staphylococcus aureus compared ceforanide and cefonicid. Addition of 50% human serum to the test system reduced the bacteriostatic and bactericidal activities of cefonicid, but ceforanide was not affected as greatly.Cefonicid is a cephalosporin with a prolonged serum half-life of approximately 3.5 to 4 h (1, 7). Ceforanide is another cephalosporin with a similar spectrum of antibacterial activity (5) and a serum half-life of approximately 2.5 to 3 h (12). Protein binding of cefonicid has been estimated to be approximately 98% (8), compared with 81% for ceforanide and 92% for cefazolin (12). Binding to serum proteins affects the pharmacokinetic properties of such drugs, resulting in prolonged half-lives; it may also reduce the bioavailability of free unbound drug during the course of therapy.The purpose of this study was to determine the extent to which serum proteins might affect the in vitro antistaphylococcal activity of ceforanide and cefonicid. Microdilution susceptibility tests were performed with 52 methicillin-susceptible isolates of Staphylococcus aureus. Doubling dilutions of both drugs. (0.12 to 32 jig/ml) were prepared in cation-supplemented Mueller-Hinton broth and in the same broth diluted with equal volumes of human serum. The serum was collected from a normal healthy male volunteer and was heat inactivated at 56°C for 15 min before addition of the system. Growth control wells containing Mueller-Hinton broth and broth with 50% serum were inoculated with each strain. We observed no evidence of inhibition by the serum. The inocula were prepared by diluting logarithmic-phase broth cultures to achieve approximately 105 CFU/ml in each well. MICs were recorded after 18 to 20 h of incubation of 35°C.An estimate of the bactericidal activity of the two drugs against 10 randomly selected strains was also determined. After the MICs were recorded, the trays were vigorously shaken to dislodge the buttons of growth and then reincubated for another 4 h. From wells with no visible evidence of growth, 25-,ul samples were subcultured to a quarter of a blood agar plate and spread to minimize the effect of drug carry-over (2, 10). MBCs were not influenced when a concentrated K-1 P-lactamase preparation was added to the system before subculturing. Furthermore, no inhibition could be demonstrated when 25 ,ul samples from wells containing 32 jig of either drug per ml in uninoculated trays were spotted onto plates seeded with a control strain of S. aureus. Thus, carry-over of a drug was not a problem with the range of concentrations that was tested. The inocula * Corresponding author. ranged from 3.0 x 105 to 4.6 x 105 CFU/ml. The MBC was defined as the lowest concentration yielding .0.1% of the viable cells in the initial inoculum (99.9% kill). The calculated end points ranged from c7 to <12 colonies for the MBC, depending on the inoculum density. Most strains demonstrated a paradoxical effect when either drug was tested in broth alone; i.e., heavy growth was often observed when wells containing ...

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