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 μg/ml and 55% of patients with “trough” levels exceeding 10 μg/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.

During the last 2 decades, Gram-negative rod bacteremia has become the leading infectious disease problem in American hospitals. With improvements in conventional microbiologic techniques, bacteremic infection can be diagnosed reliably within 3 days using only three sets of cultures. Clinical management still requires aggressive, presumptive use of antimicrobials in patients with the most adverse host factors. In the latter group, the use of combinations of antibiotics that interact synergistically in vitro has improved clinical results. In bacteremia due to anaerobes, particularly Bacteroides species, drainage of infected sites is probably more important than specific drug therapy. Various host defects have been associated with Gram-negative bacteremia; the most common in the nonleukopenic patient is impaired opsonization. The evidence that endotoxins are involved in the pathophysiology of Gram-negative bacillemia is inferential. Nevertheless, both clinical and experimental evidence suggest that active or passive immunization with endotoxin components or antigens similar to Gram-negative polysaccharides may be protective.

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A B S T R A C T To assess the phagocytic and bactericidal function of neutrophils in the acute stages of gramnegative 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.

To identify mechanisms whereby antibody to mannose-sensitive pili of Escherichia coli might enhance host defenses, we evaluated the activity of antibody to pili in four antibacterial immune processes. Antiserum to pili and Fab' fragments of IgG antibody to pili inhibited the ability of homologous piliated organisms to adhere to buccal epithelial cells. However, this antiserum did not enhance intravascular clearance, complement-dependent bacteriolysis, or opsonophagocytosis. The addition of antiserum to pili to polymorphonuclear leukocytes and piliated E. coli reduced the rate of killing from 52% to 5%. The addition of complement restored the rate to 52%, but this was much less than the 99% rate achieved with polymorphonuclear leukocytes and either fresh serum or antibody to the whole bacteria. These observations suggest that the principal anti-bacterial property of antibody to mannose-sensitive pili of E. coli is inhibition of bacterial attachment. Whether the anti-opsonic effect of antibody to pili is detrimental to host defense remains to be determined.