Michael J. Keating

A Randomized Study of Tobramycin Plus Ticarcillin, Tobramycin Plus Cephalothin and Ticarcillin, or Tobramycin Plus Mezlocillin in the Treatment of Infection in Neutropenic Patients with Malignancies

Two hundred twenty-five patients with 358 febrile episodes were treated with tobramycin and ticarcillin (TT), tobramycin and mezlocillin (TM), or tobramycin, ticarcillin and cephalothin (TTC). There were no satistically significant differences in the response rates for patients who were proven to have infection (67% with TT, 69% with TTC and 53% with TM). Patients were more often cured of their infection if their neutrophil count rose during therapy. In this study, the addition of cephalothin to TT did not increase the frequency of azotemia (10% and 12%, respectively). Although mezlocillin has a broader spectrum of activity in vitro than ticarcillin, it was not more efficacious when combined with tobramycin than ticarcillin plus tobramycin for the treatment of infections in neutropenic patients.

Hypocalcemia with hypoparathyroidism and renal tubular dysfunction associated with aminoglycoside therapy.

Seventeen patients with malignant disease developed a complex metabolic syndrome of 2–8 weeks duration characterized by hypocalcemia, hypomagne‐semia and hypokalemia following administration of the aminoglycoside group of antibiotics. Gentamicin, Tobramycin, Amikacin, and Sisomicin were all involved. Other features noted were hypoalbuminemia, hypophosphatemia, and hypouricemia. Low immunoreactive parathyroid hormone (i‐PTH) levels in the presence of hypocalcemia and absence of hyperplastic changes in the parathyroid gland examined at postmortem confirmed a diagnosis of hypoparathyroidism. Immunoreactive calcitonin levels (i‐CT) were not elevated. Renal tubular wasting of potassium and magnesium was documented in six patients and excessive urinary loss of sodium, phosphate, and uric acid was noticed. Twelve patients died before recovering from the metabolic stress and five patients developed progressive renal impairment. A possible potentiating action of chemotherapeutic agents, especially Adriamycin, is suggested.

Radiation exposure as a possible etiologic factor in hairy cell leukemia (leukemic reticuloendotheliosis)

The frequency of prior occupational, accidental, or therapeutic radiation exposure was significantly higher for hairy cell leukemia patients than for a control group of solid tumor patients (8/23 vs. 4/56, P < 0.01). Hairy cell leukemia patients were also more frequently involved in occupations at high risk of radiation exposure such as chemist, engineer, physicist, and health care facility worker (7/23 vs. 4/56, P < 0.01). The observation that the incidence of thyroid disorders among hairy cell leukemia patients was also unusually high (5/23 vs. 2/56, P < 0.05) was interpreted as further indirect evidence of excessive radiation exposure. It appears that radiation exposure may be an important contributing factor in the development of some case of hairy cell leukemia.

Ticarcillin plus clavulanic acid in the treatment of patients with cancer

Since the combination of ticarcillin with clavulanic acid is active against many otherwise resistant organisms that commonly affect patients with cancer, a therapeutic trial with ticarcillin disodium plus clavulanate potassium for treating infections in cancer patients was conducted. A total of 127 evaluable patients were treated with this antibiotic. Of these, 63 percent were women with breast carcinoma, 28 percent were patients with leukemia, and the remainder were patients with sarcomas and lung cancer. The median duration of therapy was 7.7 days. There were 63 documented infections, with bacteriologic documentation in 39 episodes. Because of the high incidence of gram-positive infections and after the failure of ticarcillin plus clavulanate potassium in two of these episodes, vancomycin was added to the regimen. The overall response rate was 75 percent. In microbiologically proved infections, the response rate was 79 percent. Thirteen of 17 gram-negative infections responded (76 percent), including four of four episodes caused by Pseudomonas aeruginosa. The only failures in this group were two episodes with Klebsiella species, one episode with Escherichia coli, and one episode with Enterobacter species. Of the gram-positive infections treated without vancomycin, five of eight (63 percent) responded and only two episodes due to Staphylococcus aureus and one due to JK diphtheroid bacteria failed. All episodes treated with the combination of ticarcillin plus clavulanate potassium and vancomycin responded. Seven of eight (88 percent) polymicrobial infections and 73 percent of those infections without identified organisms responded as well. The overall response rates for septicemia, pneumonia, soft tissue infections, and urinary tract infections were 71, 50, 71, and 83 percent, respectively. Of five microbiologically proved superinfections, three were fungal, and one each was due to Klebsiella species and S. aureus. No toxicity was observed. For 12 organisms, the minimal inhibitory concentration was lower for ticarcillin plus clavulanate potassium than for ticarcillin alone; in six it was identical. Five organisms were resistant to both, and three that were resistant to ticarcillin were sensitive to ticarcillin plus clavulanate potassium. Ticarcillin plus clavulanate potassium is a safe drug with an expanded spectrum of activity. More therapeutic trials need to be conducted to better define its role in the therapy of serious infections in cancer patients.

Antibody responses of remission leukemia patients receiving active specific and nonspecific immunotherapy

A solid‐phase radioimmunoassay was utilized to evaluate the antibody response of 21 acute myelogenous leukemia (AML) patients to active specific immunotherapy with either pooled allogeneic AML blast cells or leukemia‐associated antigen (LAA), admixed with BCG cell‐wall skeleton (CWS). Five of 13 patients treated with LAA had a significant antibody response to LAA after immunotherapy. Antibody response correlated with an increased remission duration (159+ vs. 75+ weeks) and an increased survival (164+ vs. 98+ weeks). Two of eight patients treated with cells responded to LAA, and three patients had initially high anti‐LAA antibody levels. In the total study, eight of 11 patients surviving longer than 2½ years and six of seven patients maintaining a complete remission longer than 2 years were antibody responders. Neither protocol induced significant antibody to a normal spleen extract, BCG‐CWS, or a measles recall antigen. However, five of seven patients with initially high levels of antibody to BCG (following weekly BCG scarification) were long‐term survivors. These data suggest that the humoral immune response to immunotherapeutic agents may be a useful parameter for monitoring immunotherapy of AML patients.