Ralph J. Weinstein

Amikacin was used in 77 treatment courses at a dosage of >/=7.5 mg/kg every 8 h, and patients were monitored for ototoxicity by following serial audiograms, serum creatinine, and amikacin blood levels. Patients were leukopenic (58), were infected by gentamicin-resistant organisms (11), or had cystic fibrosis (8). Three patients developed tinnitus, but none had vertigo or nystagmus. Of 55 courses with pre- and post-treatment audiogram, 13 (24%) were associated with development of high-frequency hearing loss, which was usually bilateral. No patient had conversational hearing loss, and audiograms reverted to normal in three patients. Onset of cochlear damage occurred in one patient after therapy was stopped. The group with high-tone hearing loss, in comparison to the group without audiographic changes, received a larger mean total dose (24 versus 9.6 g), were treated for a longer duration (19 versus 9 days), and more frequently had previous aminoglycosides. Fifty-seven percent of patients with a "peak" serum level exceeding 32 mug/ml and 55% of patients with "trough" levels exceeding 10 mug/ml developed cochlear damage. There was no difference between the groups in age, body weight, previous cochlear damage, renal disease before or during therapy, or average daily dose. Both monitoring of blood levels and limiting duration of therapy may prevent amikacin ototoxicity.

Infections with Pseudomonas aeruginosa and Serratia marcescens are often difficult to treat because of the narrow therapeutic ratio of available antimicrobials. Synergistic inhibitory and bactericidal activity for gentamicin and carbenicillin against P. aeruginosa has been documented in vitro. The purpose of this study was to compare 4 methods of determining in vitro synergism between several aminoglycosides and penicillins. The agar dilution method using an inoculum replicator was employed, and a drug combination showing inhibition equal to or less than one-fourth of the individual minimal inhibitory concentrations was termed synergistic. Combinations using amikacin and BL-P1654 showed synergism against a greater per cent of strains of P. aeruginosa and S. marcescens than combinations using gentamicin or carbenicillin. Additionally, the "checkerboard" broth dilution method using both minimal inhibitory concentration and minimal bactericidal concentration as endpoints and killing curves according to the methods of Jawetz was studied. Comparison of the results of these 4 methods showed excellent correlation, verifying the consistency of the 4 techniques for determining in vitro synergism.

To assess the phagocytic and bactericidal function of neutrophils in the acute stages of gram-negative rod bacteremia, cells from 30 nonleukopenic patients were studied in a test system utilizing plasma obtained simultaneously with culture-positive blood, the autologous infecting strain, and two laboratory test strains of Staphylococcus aureus and Pseudomonas aeruginosa. Results were compared to those obtained with normal neutrophils and plasma. Patient and control plasma were simultaneously tested with each source of phagocytic cells to localize any abnormalities. Four patients had a defect against their infecting strain, 33% of the inoculum phagocytized and killed versus 80% by controls. In these cases differences were localized to the patients' plasma, as normal plasma tested with patients' cells reversed the defect. Thus, four patients had impaired opsonization when compared to normal controls, but we also observed that 11 of 30 bacteremic isolates, all Escherichia coli, showed absolute or relative resistance to phagocytosis in the patient and control assay system. No intrinsic granulocyte killing abnormalities were noted. There was poor correlation between results obtained with infecting strains compared to laboratory test organisms. We conclude that in patients without evidence of an inherited neutrophil bactericidal disorder, recurrent infection, or treatment with cytotoxic drugs, intrinsic bactericidal defects are uncommon at the onset of gram-negative bacteremia, and impaired opsonization is the most commonly encountered cause of neutrophil dysfunction.

Blood culture isolates from 133 episodes of Escherichia coli bacteremia were typed for K-1 capsular antigen by immunodiffusion, utilizing equine antiserum raised against meningococcal group B polysaccharide. Twenty-six percent (34 of 133) of these isolates were positive for K-1 antigen. These 133 strains, 34 K-1 and 99 non-K-1, were tested for susceptibility to phagocytosis. K-1 strains were found to be more resistant to clearance (27%) than non-K-1 strains (71%) when tested in an in vitro opsonophagocytic/killing assay containing normal human granulocytes and plasma. Additional studies demonstrated that resistance was due to decreased phagocytosis rather than diminished intraleukocytic killing. K-1 strains obtained from stool showed a similar degree of resistance to phagocytosis when compared with K-1 blood isolates. A comparison of clinical data on non-neonatal patients with E. coli K-1 and non-K-1 bacteremia showed no significant differences in mortality for these two groups. The incidence of shock for patients bacteremic with K-1 strains (74%) was significantly greater than that for patients bacteremic with non-K-1 strains (33%). These differences are attributed to the increased resistance to phagocytosis observed for K-1 versus non-K-1 E. coli isolates.