Victorio Rodriguez

Fever and infection in leukemic patients. A study of 494 consecutive patients

All of the febrile episodes occurring in 494 adults with acute leukemia were reviewed. There were an average of 2.39 febrile episodes per patient and the patients spent 28% of their days in the hospital with fever. Sixty‐four percent of the febrile episodes were due to infection. The most common types of infection were disseminated infection and pneumonia, which together accounted for 69% of the total episodes of documented infection. The etiologic agent was identified in 73% of the documented infections and gram‐negative bacilli were responsible for the great majority. The most common gram‐negative bacilli causing infection were Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa. During the course of their leukemia, 31% of the patients had repeated episodes of infection caused by the same organism and 13% had repeated FUOs. Fever occurred most often when the patients had neutropenia (less than 500/mm3). The fatality rate from septicemia decreased from 84% in 1966 to 44% in 1972. The fatality rate for major infections caused by gram‐positive cocci was 16%, for gram‐negative bacilli was 37% and for fungi was 86%. Although infection remains a serious problem in leukemia patients, considerable progress has been made.

A randomized study of carbenicillin plus cefamandole or tobramycin in the treatment of febrile episodes in cancer patients

Patients were randomly assigned to receive carbenicillin plus tobramycin by continuous infusion (C+T), carbenicillin plus cefamandole by continuous infusion (C+CC) or carbenicillin plus cefamandole by intermittent infusion (C+IC) during 490 febrile episodes. Carbenicillin was administered over 2 hours every 4 hours. The per cent of cures achieved during the 235 documented infections was 65 per cent for C+CC, 57 per cent for C+IC and 54 per cent for C+T. Among those infections caused by single gram-negative bacilli, C+CC produced a higher cure rate than C+IC or C+T(74 per cent versus 59 per cent versus 50 per cent). C+CC was significantly more effective than C+IC among patients with persistent severe neutropenia of less than 100 neutrophils/mm3 (65 per cent versus 21 per cent, p = 0.03). If the infecting organism was sensitive to both antibiotics, the cure rate which occurred during 12 per cent to 13 per cent of the febrile episodes, regardless of antibiotic regimen. However, it occurred significantly more often during documented infections than during fevers of unknown etiology (20 per cent versus 6 per cent, p less than 0.001). C+CC appears to be the most effective of the three regimens for the treatment of infections in patients with persistent severe neutropenia.

Evaluation of high-dose versus standard FAC chemotherapy for advanced breast cancer in protected environment units: a prospective randomized study.

Fifty-nine evaluable patients under 65 years of age with measurable metastatic breast cancer and without prior chemotherapy were randomly assigned to treatment with fluorouracil, Adriamycin (Adria Laboratories, Columbus, OH), and cyclophosphamide (FAC) at standard or high doses (100% to 260% higher than standard FAC) following a dose escalation schedule. Patients randomized to the high-dose FAC received the first three cycles of therapy within a protected environment. Subsequent cycles for this group were administered at standard doses of FAC in an ambulatory setting, the same as for the control group. After reaching 450 mg/m2 of Adriamycin, patients in both groups continued treatment with cyclophosphamide, methotrexate, and fluorouracil until there was disease progression. Analysis of pretreatment patient characteristics showed an even distribution for most known pretreatment factors, although the control group had slightly (but nonsignificantly) more favorable prognostic characteristics. Fourteen patients (24%) achieved a complete remission (CR) and 32 (54%) achieved a partial remission (PR), for an overall major response rate of 78%. There were no differences in overall, CR, or PR rates between the high-dose FAC and control groups. The median response durations were 11 and 10 months for the protected environment and control groups, respectively, and the median survival was 20 months for both groups. Hematologic, gastrointestinal (GI), and infection-related complications were significantly more frequent and severe in the group treated with high-dose chemotherapy. Stomatitis, diarrhea, and skin toxicity were dose-limiting. However, there were no treatment-related deaths. High-dose induction combination chemotherapy with the agents used in this study failed to increase the response rate or survival duration, and resulted in a substantial increase in toxicity.

Infections in cancer patients on a protected environment-prophylactic antibiotic program.

A total of 102 studies were conducted on 89 patients receiving cancer chemotherapy while on a protected environment-prophylactic antibiotic program. Major infections occurred during 22 studies. The majority of both minor and major infections originated during the first five weeks after the patients entered the protected environment units. The frequency of infectious complications was inversely related to the circulating neutrophil count. The majority of infections were cases of cellulitis, pharyngitis, pneumonia and septicemia. Most of the infections were caused by gram-negative bacilli. The majority of organisms causing infection had persisted in the patients after their entry into the protected environment units despite the use of prophylactic antibiotics.

Feasibility of Administering Aminoglycoside Antibiotics by Continuous Intravenous Infusion

Eleven patients each received gentamicin sulfate, tobramycin, and sisomicin by continuous intravenous infusion after an initial loading dose. Subsequent doses of antibiotic were adjusted in an attempt to maintain constant serum concentrations. There was considerable variation in the serum concentration from patient to patient and in the same patient from day to day with each drug. Although the dosages of gentamicin sulfate and tobramycin were similar, the serum concentrations of the latter drug were consistently lower. Despite the daily administration of doses of at least 300 mg of gentamicin and tobramycin per m2 and 160 mg of sisomicin per m2, nephrotoxicity occurred in only three patients. This is a low frequency of nephrotoxicity, considering the dosages of drug administered. Although therapeutic efficacy was not an objective of this study, 8 of 11 documented infections were cured. This approach to the administration of aminoglycoside antibiotics deserves therapeutic trials.

Protected environment-prophylactic antibiotic program for malignant lymphoma. Randomized trial during chemotherapy to induce remission.

Fifty-eight patients with malignant lymphoma were randomly allocated to receive three courses of chemotherapy to induce remission with CHOP-Bleo on the protected environment-prophylactic antibiotic (PEPA) program (30 patients) or as controls (28 patients). The complete remission rate for all patients was 74 per cent, for patients with diffuse histiocytic lymphoma 78 per cent and for patients with nodular poorly differentiated lymphocytic lymphoma 65 per cent. There were no significant differences in response rates and duration of responses between those on the PEPA program and control patients. The frequency of infection was significantly lower among the patients on the PEPA program, and dosage escalation of the chemotherapeutic agents was accomplished more often among these patients. Dosage escalation did not increase the complete remission rate, but it did reduce the relapse rate and signficantly reduced the fatality rate. The duration of remission and survival was significantly longer for those patients who received dosage escalation.

Pharmacology of Amikacin in Humans

Amikacin is a new aminoglycoside antibiotic which is active in vitro against most isolates of gram-negative bacilli. A dose of 300 mg/m2 intramuscularly produced a highest mean serum concentration of 25.4 μg/ml with a mean serum concentration of 3.1 μg/ml at 8 h. The same dose intravenously produced a highest mean serum concentration of 52.4 μg/ml with a mean serum concentration of 2.1 μg/ml at 8 h. The mean urinary excretion during the first 6 h was 75 and 66%, respectively. When amikacin was administered at a dose of 150 mg/m2 every 6 h, there was evidence of some drug accumulation. A loading dose of 150 mg/m2 administered intravenously over 30 min followed by 200 mg/m2 administered as a continuous infusion every 6 h maintained serum concentrations of 8 μg/ml. No major toxicity was observed with any of these drug regimens.

Miconazole therapy for treatment of fungal infections in cancer patients.

The effectiveness of miconazole was evaluated in 37 documented fungal infections, 32 of which were major infections. All patients were receiving therapy for advanced malignancy, with 28 patients having acute leukemia. The overall cure rate was 41% and it was also 41% for major fungal infections. Nine of 22 patients with Candida albicans infections were cured, and 3 of 11 patients with Candida tropicalis infections were cured. A total of 183 patients who received miconazole for presumed or documented fungal infection were evaluated for toxicity. Nausea and vomiting and central nervous system toxicity were the most common side effects, occurring in 25 and 16% of the patients, respectively. Overall, the drug was tolerated well, with only four patients requiring the drug to be permanently discontinued because of toxicity.

Ticarcillin Therapy of Infections

Ticarcillin was administered as initial therapy during 73 episodes of infections occurring in 69 adults with neoplastic diseases. During the first six infections, doses of 5 gm were dissolved in 200 ml of solvent and administered intravenously over a 2-h period every 6 h. Four of six infections responded to therapy. However, two of the five Pseudomonas infections failed to respond, whereas the organisms causing the infection were sensitive to ticarcillin in vitro. During the remaining 67 infections, doses of 3.5 g were similarly dissolved and administered intravenously over a 2-h period every 4 h. The overall response to ticarcillin in these 67 infections was 43%. However, 18 of 20 Pseudomonas infections, three Proteus spp. infections, and one infection caused by H. influenzae responded. Only 1 of 7 infections caused by mixed organisms and 5 of 13 infections in which the etiologic agent could not be identified responded. Ticarcillin was ineffective against the majority of Escherichia coli and Klebsiella spp. infections, organisms which were resistant to ticarcillin in vitro. The majority of patients were neutropenic, but the response rate was not dependent on the number of circulating polymorphonuclear neutrophilic leukocytes. Superinfection occurred in seven patients. Erythematous skin rash occurred in two patients, which subsided after discontinuation of the drug. No liver or renal toxicity occurred that could be attributed to ticarcillin.

Successful control of systemic aspergillus niger infections in two patients with acute leukemia

The diagnosis and successful control of systemic Aspergillus niger infection in 2 adult patients with acute leukemia is reported. During induction therapy, the first patient developed pulmonary infiltrates, skin lesions and abnormal liver function tests. Aspergillus niger was found on skin and liver biopsy. This patient was successfully treated with Amphotericin B and granulocyte transfusions and he remains in remission. The second patient developed a pneumonitis and adynamic ileus with positive sputum and stool cultures for Aspergillus niger. The infection only responded to Amphotericin B and granulocyte transfusions and the leukemia to cytoreductive chemotherapy. The patient later relapsed and died after a febrile illness. Fungi morphologically consistent with Aspergillus were found in the liver at autopsy. Infection with A. niger is rare even in this patient population; however fungal infections have become an increasing problem. The need for a high index of suspicion, especially when an infection is unresponsive to antibacterial antibiotics, the various diagnostic tools, and the need for aggressive therapy are stressed. Amphotericin B is the chemotherapy of choice but may be insufficient in a severely neutropenic host where the simultaneous use of granulocyte transfusions might be lifesaving.