No abstract

A total of 91 multiply resistant bacterial strains, including Klebsiella pneumoniae (32 strains), Pseudomonas aeruginosa (16 strains), and Serratia marcescens (43 strains), were collected during hospital epidemics of nosocomial infection from 1975 to 1979. These strains were resistant to gentamicin, tobramycin, cephalothin, chloramphenicol, and ampicillin. Their susceptibility to three new broad-spectrum f-lactams, LY127935 (a 1-oxa-p-lactam), cefotaxime (HR 756), and cefoperazone (T 1551), was compared with the susceptibility of random strains of nine species of aerobic gram-negative bacilli collected in the same hospital in 1979. Susceptibility to cefamandole and ticarcillin was also determined. Strains of staphylococci and streptococci from that hospital and two nearby city-county hospitals were also compared for the three new cephalosporins and other effective antibiotics. The agar dilution method was used to measure the minimum inhibitory concentration for each antibiotic. The multiply resistant strains (minimum inhibitory concentration for gentamicin 2 8 ,ug/ml) usually were as susceptible to the three new broad-spectrum ,B-lactams as were non-multiply resistant strains.Both Klebsiella pneumoniae and Serratia marcescens, including multiply resistant and non-multiply resistant strains, were most susceptible to the 1-oxa-/ilactam LY127935 and cefotaxime. P. aeruginosa (both multiply resistant and non-multiply resistant strains) were most susceptible to cefoperazone. All three new B-lactams were active against non-multiply resistant strains of Escherichia coli, Enterobacter spp., Proteus spp., and Citrobacter spp. Providencia stuartii were most susceptible to cefotaxime and the 1-oxa-,-lactam LY127935. The three new ,6-lactams were all less active against staphylococci (especially methicillinresistant Staphylococcus aureus) than cephalothin. Streptococcus pyogenes and S. pneumoniae were very susceptible to cefotaxime and cefoperazone, though less susceptible to LY127935. None of the three new ,B-lactams was active against S. faecalis. All were very active against both penicillinase-positive and -negative strains of Neisseria gonorrhoeae.

To study the penetration of antibiotics into peritoneal tissue fluid, a subcutaneous tissue capsule model was modified by implanting multiple, perforated spherical capsules in the peritoneal cavity ofrabbits. Capsules became vascularized, encased in connective tissue, and filled with fluid having a mean protein concentration of 3.6 g/100 ml. Capsular fluid was obtained by percutaneous needle aspiration and assayed for antibiotic by the disk plate bioassay technique. Cephalosporins were administered intramuscularly at a dose of30 mg/kg. Mean peak concentrations of cephaloridine and cefazolin were significantly higher than cephalothin and cephapirin in capsular fluids, but the percent penetration (ratio of capsular mean peak to serum mean peak) ranged from 8.7 to 16.9% and was not significantly different among the cephalosporins. At 24 h the capsular concentration of cefazolin was significantly greater than for the other cephalosporins (P < 0.001). Lower rabbit serum protein binding observed at high in vivo concentrations may have enabled cefazolin to penetrate capsular fluid, but in vitro protein binding studies did not confirm a decrease in serum protein binding at high concentrations within the clinical range. Kanamycin and amikacin showed comparable capsular fluid peak concentrations as did gentamicin and tobramycin. The percent penetration ranged from 15.2 to 34.5% for the aminoglycosides. The only statistical difference was that amikacin penetration was significantly higher than that for tobramycin. Mean capsular concentrations of amikacin, cefazolin, and cephaloridine compared most favorably with the minimum inhibitory concentration of gram-negative bacilli at the dosages used in this study.

Staphylococcus aureus resistant to bactericidal activity of antibiotics caused sepsis in three patients. Bacteriological and clinical responses were not achieved until serum and tissue fluid levels of administered antibiotics exceeded the minimum bactericidal concentration (MBC) of the infecting organism. Fifteen clinical isolates of S. aureus were tested in brain heart infusion broth and MuellerHinton broth for the MBC of gentamicin, vancomycin, clindamycin, oxacillin, cefazolin, and cephalothin. Results showed significant eightfold or greater brothdependent differences in the MBC of at least one antibiotic against 87% (13/15) of strains tested. The MBC was unpredictable and varied with the strain, antibiotic, and medium used. No controlled studies are available to indicate the clinical significance of the MBC demonstrated in different media. The necessity for treating serious infection with bactericidal drugs has not yet been established; however, in septicemia such as that caused by bacterial endocarditis, bacteriostatic antibiotics have generally failed to eradicate the infection, whereas bactericidal agents have often been curative. Therefore, in patients unresponsive to usual antistaphylococcal therapy, we suggest that MBC testing be performed in at least two media and that treatment be instituted with antibiotics demonstrating the lowest MBC in all media used.In vitro antimicrobial susceptibility testing has been considered essential for appropriate antibiotic usage (20). Medium-dependent variation in the minimum inhibitory concentration (MIC) of tetracyclines, aminoglycosides, and polymyxins has been reported (2,5,19,20,24). Similar medium-dependent differences in minimum bactericidal concentration (MBC) have rarely been described for bacteria against which the tested antibiotics have an equal MIC (16 MATERIALS AND METHODSPatients. The first patient, a 60-year-old male, had septicemia and septic arthritis due to S. aureus. Studies performed in brain heart infusion (BHI) broth revealed the MIC of oxacillin to be 0.25 ,tg/ml and that of cephalothin to be 4.0 ,ug/ml. Intravenous therapy with 6 g of oxacillin per day for 7 days failed to eradicate the organisms from involved joints in spite of serum and joint oxacillin levels that ranged from 24 to 44 ug/ml. The MBC in BHI broth was 64 ytg of oxacillin per ml and 16 yg of cephalothin per ml. Intravenous therapy was therefore changed to cephalothin at 12 g/day, resulting in serum and joint fluid levels ranging from 95 to 200 ug/ml. The infection was controlled, the patient was afebrile, and cultures were sterile 24 h after the beginning of cephalothin therapy.Patient 2 was a 61-year-old male with endocarditis caused by S. aureus with numerous culture-positive septic emboli to skin, pericardium, and synovium. The patient continued to be febrile, and cultures remained positive, in spite of therapy with intravenous nafcillin at 12 g/day for 8 days. The MIC of nafcillin in MuellerHinton (MH) broth was 0.25 tig/ml with a MBC of 64 yg/ml. Therapy was changed to ce...