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Background: Amphotericin B deoxycholate is currently the standard empirical antifungal therapy in neutropenic patients with cancer who have persistent fever that does not respond to antibiotic therapy. However, this treatment often causes infusion-related and metabolic toxicities, which may be dose limiting. Objective: To compare the efficacy and safety of itraconazole with those of amphotericin B as empirical antifungal therapy. Design: An open randomized, controlled, multicenter trial, powered for equivalence. Setting: 60 oncology centers in 10 countries. Patients: 384 neutropenic patients with cancer who had persistent fever that did not respond to antibiotic therapy. Intervention: Intravenous amphotericin B or intravenous itraconazole followed by oral itraconazole solution. Measurements: Defervescence, breakthrough fungal infection, drug-related adverse events, and death. Results: For itraconazole and amphotericin B, the median duration of therapy was 8.5 and 7 days and the median time to defervescence was 7 and 6 days, respectively. The intention-to-treat efficacy analysis of data from 360 patients showed response rates of 47% and 38% for itraconazole and amphotericin B, respectively (difference, 9.0 percentage points [95% CI, -0.8 to 19.5 percentage points]). Fewer drug-related adverse events occurred in the itraconazole group than the amphotericin B group (5% vs. 54% of patients; P=0.001), and the rate of withdrawal because of toxicity was significantly lower with itraconazole (19% vs. 38%; P=0.001). Significantly more amphotericin B recipients had nephrotoxicity (P Conclusions: Itraconazole and amphotericin B have at least equivalent efficacy as empirical antifungal therapy in neutropenic patients with cancer. However, itraconazole is associated with significantly less toxicity.

* Objective: To evaluate the efficacy and safety of fluconazole for prevention of fungal infections. * Design: A randomized, placebo-controlled, double-blind, multicenter trial. * Patients: Adults (257) undergoing chemotherapy for acute leukemia. * Intervention: Patients were randomly assigned to receive either fluconazole (400 mg orally once daily or 200 mg intravenously every 12 hours) or placebo. The study drug was started at initiation of chemotherapy and continued until recovery of neutrophil count, development of proven or suspected invasive fungal infection, or the occurrence of a drug-related toxicity. * Measurements: Fungal colonization, proven superficial or invasive fungal infection, empiric antifungal therapy with amphotericin B, drug-related side effects, and mortality. * Main Results: Fluconazole decreased fungal colonization (83 of 122 [68%] placebo patients compared with 34 of 119 [29%] fluconazole patients colonized at end of prophylaxis, P < 0.001) and proven fungal infections (27 of 132 [21%) placebo patients compared with 11 of 123 [9%] fluconazole patients infected, P = 0.02). Superficial fungal infections occurred in 20 of 132 (15%) placebo patients but in only 7 of 123 (60%) fluconazole patients (P = 0.01), whereas invasive fungal infections developed in 10 of 132 (8%) placebo patients and in 5 of 123 (4%) fluconazole patients (P = 0.3). Fluconazole was especially effective in eliminating colonization and infection by Candida species other than Candida krusei (66 of 122 [640/o] placebo patients colonized at end of prophylaxis compared with 11 of 119 [9%] fluconazole patients, P < 0.001; 22 of 132 [17%] placebo patients infected compared with 7 of 123 [6%] fluconazole patients, P = 0.005). Aspergillus infections were infrequent in both fluconazole (3 cases) and placebo groups (3 cases). The use of amphotericin B, the incidence of drug-related side effects, and overall mortality were similar in both study groups. * Conclusion: Prophylactic fluconazole prevents colonization and superficial infections by Candida species other than Candida krusei in patients undergoing chemotherapy for acute leukemia and is well tolerated. Fluconazole could not be clearly shown to be effective for preventing invasive fungal infections, reducing the use of amphotericin B, or decreasing the number of deaths. Annals of Internal Medicine. 1993;118:495-503., Treatment with fluconazole may be an effective and safe method method for preventing fungal infections in patients undergoing chemotherapy for acute leukemia. Patients undergoing chemotherapy for acute leukemia have a higher risk of developing different types of infections than other individuals. Among 255 patients undergoing chemotherapy for acute leukemia, 123 were treated with 400 milligrams (mg) of oral fluconazole per day or 200 mg of intravenous fluconazole every 12 hours and 132 were treated with a placebo, or an inactive substance. Nine percent of the patients treated with fluconazole developed a fungal infection, compared with 21% of the patients who received a placebo. Fifteen percent of the patients in the fluconazole group experienced side effects, compared to 14% of the patients in the placebo group.

Taking the drug ganciclovir before and after bone marrow transplantation appears to lower the risk and severity of cytomegalovirus (CMV) infection in CMV-seropositive patients. CMV infection, which can cause pneumonia, fever, wasting, hepatitis and even death, frequently develops after bone marrow transplants. Of 45 CMV-seropositive patients who took a placebo, or inactive substance, before and after marrow transplant, 25 (56%) developed CMV infection compared with eight of 40 patients (20%) who took ganciclovir before and after transplant. Furthermore, CMV disease - pneumonia, gastroenteritis or wasting syndrome - developed in only 10% of the patients taking ganciclovir compared with 24% of the patients taking gancyclovir. Of the patients taking ganciclovir however, 58% had to interrupt treatment because of neutropenia, which is a decrease in the number of white blood cells known as neutrophils, compared with 28% of the patients taking placebo. Most patients taking ganciclovir were eventually able to resume treatment at either the same or a lower dose.

Granulocytopenia, the depletion of granulocyte white blood cells, places patients at grave risk from infection. Nowadays, this condition occurs quite frequently, often as a side effect of chemotherapy or other immunosuppressive therapies. Aggressive antibiotic treatment is necessary to prevent any bacterial infection from attaining life-threatening magnitude, and therefore indications of infection such as fever are treated without necessarily waiting for laboratory confirmation of the type of bacteria and the antibiotic sensitivity of the bacteria. Many of the patients experiencing granulocytopenia are already receiving drugs which are toxic to the kidneys. Therefore, the use of additional drugs which are also toxic to the kidneys is probably unwise; unfortunately, this rules out the aminoglycosides, an important group of antibiotics. (Streptomycin and gentamicin are examples of aminoglycosides.) To make matters worse, chemotherapy seems to increase the toxicity of aminoglycosides. A study was conducted to evaluate three antibiotic regimens for the treatment of granulocytopenic patients with fever; 429 patients were entered into the study, but 26 were excluded from analysis for a variety of reasons, including infections which turned out to be viral rather than bacterial. The patients were randomly assigned to receive cefoperazone with piperacillin, ceftazidime with piperacillin, or imipenem alone. Complications were not common, but included seizures in six patients and diarrhea in 83. The lower dose of imipenem tested, 2 g per day, was found to be just as effective as the regimens containing two antibiotics. Imipenem is less costly than the other antibiotic treatments, and the results of this study provide no reason for using the more expensive combination therapy in the treatment of granulocytopenic patients with fever. (Consumer Summary produced by Reliance Medical Information, Inc.)

Granulocytopenia is an abnormal decrease in granulocytes, a type of white blood cell in the bone marrow. The disease is often associated with bacterial infections and can be controlled by antibiotics. Under normal conditions, the gastrointestinal tract has anaerobic bacteria, which prevent the growth of aerobic bacteria, that is, bacteria that require oxygen to thrive. Ofloxacin is an antibiotic that specifically attacks aerobic bacteria, such as gram-negative bacilli and gram-positive cocci, but preserves the natural anaerobic bacteria in the gastrointestinal tract. The effectiveness and safety of ofloxacin were compared with that of the antibiotic mixture vancomycin/polymyxin in treating bacterial infections in 62 patients with granulocytopenia. There were fewer numbers of gram-negative bacilli organism per patient, fewer patients with infection, and fewer cases of septicemia, or bacteria in the blood, in the group receiving ofloxacin than those receiving the antibiotic mixture. Ofloxacin was also better tolerated and caused fewer side effects. However, neither of the antibiotic preparations could eliminate infection by viridans group streptococci, coagulase-negative staphylococci, or other gram-positive organisms. Three types of bacteria that were resistant to inactivation by ofloxacin were isolated but did not cause infections. The results show that ofloxacin is a more effective and tolerable antibiotic than vancomycin/polymyxin for the prevention of infections by gram-negative bacteria in granulocytopenic patients, although more effective treatment is needed to prevent gram-positive infections.

Background: Among persons who receive solid organ transplants, liver transplant recipients have the highest incidence of invasive fungal infection; however, no antifungal prophylaxis has been proven to be effective. Objective: To evaluate the efficacy and safety of prophylactic fluconazole in liver transplant recipients. Design: Randomized, double-blind, placebo-controlled trial. Setting: University-affiliated transplantation center. Patients: 212 liver transplant recipients who received fluconazole (400 mg/d) or placebo until 10 weeks after transplantation. Measurements: Fungal colonization, proven superficial or invasive fungal infection, drug-related side effects, and death. Results: Fungal colonization increased in patients who received placebo (from 60% to 90%) but decreased in patients who received fluconazole (from 70% to 28%). Proven fungal infection occurred in 45 of 104 placebo recipients (43%) but in only 10 of 108 fluconazole recipients (9%) (P [is less than] 0.001). Fluconazole prevented both superficial infection (29 of 104 placebo recipients became infected [28%] compared with 4 of 108 fluconazole recipients [4%]; P [is less than] 0.001) and invasive infection (24 of 104 placebo recipients became infected [23%] compared with 6 of 108 fluconazole recipients [6%]; P [is less than] 0.001). Fluconazole prevented infection by most Candida species, except C. glabrata. However, infection and colonization by organisms intrinsically resistant to fluconazole did not seem to increase. Fluconazole was not associated with any hepatotoxicity. Patients receiving fluconazole had higher serum cyclosporine levels and more adverse neurologic events (headaches, tremors, or seizures in 13 fluconazole recipients compared with 3 placebo recipients; P = 0.01). Although the overall mortality rate was similar in both groups (12 of 108 [11%] in the fluconazole group compared with 15 of 104 [14%] in the placebo group; P [is greater than] 0.2), fewer deaths related to invasive fungal infection were seen in the fluconazole group (2 of 108 patients [2%]) than in the placebo group (13 of 104 patients [13%]) (P = 0.003). Conclusions: Prophylactic fluconazole after liver transplantation decreases fungal colonization, prevents superficial and invasive fungal infections, and has no appreciable hepatotoxicity. Although fluconazole prophylaxis is associated with fewer deaths from fungal infection, it does not improve overall survival. Patients receiving prophylactic fluconazole require close monitoring of serum cyclosporine levels to avoid neurologic toxicity. Ann Intern Med. 1999;131:729-737., Giving liver transplant recipients the anti-fungal drug fluconazole can prevent fungal infection. Most organ transplant recipients must take immunosuppressive drugs to prevent their immune system from rejecting the organ. But this leaves them susceptible to infection. Researchers randomly assigned 212 liver transplant recipients to take fluconazole or a placebo. Fluconazole substantially reduced the rate of fungal infections, as well as death from fungal infections. However, it increased blood levels of cyclosporine, which could increase the rate of side effects from this immunosuppressive drug.