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D J Winston

Publications and source records attributed to D J Winston.

At least 19 recordsLinked to original sources
PubMed2001

Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial.

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 < 0.001). Breakthrough fungal infections (5 patients in each group) and mortality rates (19 deaths in the itraconazole group and 25 deaths in the amphotericin B group) were similar. Sixty-five patients switched to oral itraconazole solution after receiving the intravenous formulation for a median of 9 days. 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.

Administration, Oral↗
PubMed2001

Randomized, double-blind, multicenter trial comparing clinafloxacin with imipenem as empirical monotherapy for febrile granulocytopenic patients.

In a double-blind, multicenter trial, 541 febrile granulocytopenic patients were randomized to receive either intravenous (iv) clinafloxacin (200 mg every 12 h) or i.v. imipenem (500 mg every 6 h) as empirical monotherapy. More baseline pathogens were susceptible to clinafloxacin (259 [99%] of 262 organisms) than to imipenem (253 [95%] of 265; P=.03). Initial favorable clinical response rates for clinafloxacin (88 [32%] of 272 patients) and imipenem (89 [33%] of 269) were similar. After addition of other antimicrobial agents, overall response rates were 259 (95%) of 272 for clinafloxacin and 251 (93%) of 269 for imipenem. During the study, only 13 clinafloxacin (5%) and 18 imipenem (7%) recipients died. Both drugs were generally well tolerated. Drug-related skin rash occurred more often with clinafloxacin (11% vs. 6%; P=.07), whereas nausea (2% vs. 5%; P=.16), Clostridium-difficile-associated diarrhea (3% vs. 8%; P=.02), and seizures (0% vs. 2%; P=.06) occurred more often with imipenem. These results suggest that clinafloxacin and imipenem have similar efficacy as empirical monotherapy in febrile granulocytopenic patients.

Adolescent↗
PubMed2001

A multicenter, randomized, double-blind comparison of different doses of intravenous immunoglobulin for prevention of graft-versus-host disease and infection after allogeneic bone marrow transplantation.

Intravenous immunoglobulin is approved for use in allogeneic bone marrow transplant recipients for prevention of graft-versus-host disease (GVHD) and infections, but the minimally effective dose has not been established. In this multicenter, randomized, double-blind trial, patients undergoing allogeneic marrow transplantation were randomized to receive 100 mg/kg, 250 mg/kg, or 500 mg/kg doses of intravenous immunoglobulin. Each dose was given weekly for 90 days and then monthly until 1 year after transplant. Six hundred and eighteen patients were evaluated. Acute GVHD (grades 2-4) occurred in 39% of the patients (80 of 206) in the 100 mg/kg group, 42% of the patients (88 of 208) in the 250 mg/kg group, and in 35% of the patients (72 of 204) in the 500 mg/kg group (P = 0.344). Among patients with unrelated marrow donors, a higher dose of intravenous immunoglobulin (500 mg/kg) was associated with less acute GVHD (P = 0.07). The incidences of chronic GVHD, infection and interstitial pneumonia were similar for all three doses of intravenous immunoglobulin. The dose of intravenous immunoglobulin also had no effect on the types of infection, relapse of hematological malignancy or survival. Except for more frequent chills (P = 0.007) and headaches (P = 0.015) in patients given the 500 mg/kg or 250 mg/kg dose of immunoglobulin, adverse events were similar for all three doses. These results suggest that 100 mg/kg, 250 mg/kg, and 500 mg/kg doses of intravenous immunoglobulin are associated with similar incidences of GVHD and infections in most allogeneic marrow transplants. These results should be considered when designing cost-effective strategies for the use of intravenous immunoglobulin in allogeneic marrow transplants receiving other current regimens for prophylaxis of GVHD and infection.

Adolescent↗
PubMed2000

Quinupristin/Dalfopristin therapy for infections due to vancomycin-resistant Enterococcus faecium.

The efficacy and safety of quinupristin/dalfopristin for treatment of infections due to vancomycin-resistant Enterococcus faecium were evaluated in 24 hospitalized patients with documented infections (19 bacteremias, 5 localized infections) caused by vancomycin-resistant E. faecium that was susceptible to quinupristin/dalfopristin in vitro. Patients received iv quinupristin/dalfopristin at a dosage of either 7.5 mg/kg every 8 h or 5 mg/kg every 8 h. A favorable clinical response (cure or improvement) occurred in 19 (83%) of 23 evaluable patients; bacteriologic eradication occurred in 17 (74%) of 23 evaluable patients. A favorable clinical response was observed in 12 (80%) of 15 patients who were treated with 7.5 mg/kg of quinupristin/dalfopristin every 8 h and in 7 (88%) of 8 patients treated with 5 mg/kg of quinupristin/dalfopristin every 8 h. Two of four treatment failures were associated with a decrease in the in vitro susceptibility of vancomycin-resistant E. faecium to quinupristin/dalfopristin. Superinfections developed in 6 patients (26%), but only one was caused by Enterococcus faecalis that was resistant to quinupristin/dalfopristin. Myalgias and arthralgias were the only adverse events related to quinupristin/dalfopristin. These conditions occurred in 8 (33%) of 24 patients and were dose-related (8 cases in 16 patients treated with 7.5 mg/kg of quinupristin/dalfopristin every 8 h, no cases in 8 patients treated with 5 mg/kg every 8 h). Mortality associated with vancomycin-resistant E. faecium infection was 17% (4 of 23 patients), whereas mortality from other causes was 52% (12 of 23 patients). These results suggest that quinupristin/dalfopristin is effective as treatment for vancomycin-resistant E. faecium infections in critically ill patients with serious underlying conditions. Except for myalgias and arthralgias at higher dosages, the drug is well-tolerated.

Adolescent↗
PubMed2000

A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer.

PURPOSE: To compare the efficacy and safety of fluconazole and amphotericin B as empiric antifungal therapy of febrile neutropenic patients with cancer. PATIENTS AND METHODS: A total of 317 neutropenic patients (<500 cells/mm3) with persistent or recrudescent fever despite 4 or more days of antibacterial therapy were randomly assigned to receive either fluconazole (400 mg intravenously once daily) or amphotericin B (0.5 mg/kg once daily). Patients were evaluated for the efficacy and safety of each drug by clinical criteria, frequent cultures and radiological procedures, and laboratory values. A response was classified as satisfactory at the end of therapy if the patient was afebrile, had no clinical or microbiological evidence of fungal infection, and did not require study termination due to lack of efficacy, drug toxicity, or death. RESULTS: A satisfactory response occurred in 68% of the patients treated with fluconazole (107 of 158 patients) and in 67% of patients treated with amphotericin B (106 of 159 patients). Progressive or new fungal infections during therapy occurred in 13 (8%) patients treated with fluconazole (8 with Candida, 5 with Aspergillus) and in 10 (6%) patients treated with amphotericin B (5 with Candida, 3 with Aspergillus, 2 with other fungi). Adverse events related to study drug (especially fever, chills, renal insufficiency, electrolyte disturbances, and respiratory distress) occurred more often in patients treated with amphotericin B (128 [81%] of 159 patients) than patients treated with fluconazole (20 [13%] of 158 patients, P = 0.001). Eleven (7%) patients treated with amphotericin B but only 1 (1%) patient treated with fluconazole were terminated from the study owing to an adverse event (P = 0.005). Overall mortality (27 [17%] patients treated with fluconazole versus 34 [21%] patients treated with amphotericin B) and mortality from fungal infection (7 [4%] patients treated with fluconazole versus 5 [3%] patients treated with amphotericin B) were similar in each study group. CONCLUSIONS: Intravenous fluconazole can be an effective and safe alternative to amphotericin B for empiric antifungal therapy in many febrile neutropenic patients. However, because fluconazole may be ineffective in the treatment of Aspergillus, patients at risk for that infection should be evaluated by chest radiograph, computed tomographic scanning, and cultures before the use of empiric fluconazole therapy.

Amphotericin B↗
PubMed1999

Prophylactic fluconazole in liver transplant recipients. A randomized, double-blind, placebo-controlled trial.

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 < 0.001). Fluconazole prevented both superficial infection (29 of 104 placebo recipients became infected [28%] compared with 4 of 108 fluconazole recipients [4%]; P < 0.001) and invasive infection (24 of 104 placebo recipients became infected [23%] compared with 6 of 108 fluconazole recipients [6%]; P < 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 > 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.

Adolescent↗
PubMed1999

Randomized, placebo-controlled, double-blind, multicenter trial of efficacy and safety of granulocyte colony-stimulating factor in liver transplant recipients.

BACKGROUND: Infection and rejection are two common complications after liver transplants. In a preliminary study, administration of granulocyte colony-stimulating factor (G-CSF) to liver transplant recipients was associated with a decrease in sepsis episodes, sepsis-related deaths, and rejection compared with a historical control group of patients. The purpose of this study was to evaluate further the efficacy of G-CSF in liver transplant patients in a randomized, placebo-controlled, double-blind, multicenter trial. METHODS: Adult patients with a United Network Organ Sharing classification of 1 or 2 were randomized to receive a placebo, 100 microg/day of G-CSF or 300 microg/day of G-CSF. The study drug was started preoperatively and then continued after the transplant for a maximum of 21 days. Patients were evaluated for microbiologically-documented infection, biopsy-proven rejection, number of treatments for rejection, length of stay in the intensive care unit and hospital, graft survival, death, and adverse events. RESULTS: During the first 30 days after the transplant, the median peak white blood cell count was 16.5x10(9)/L, 34.6x10(9)L, and 54.8x10(9)/L for the placebo, low-dose G-CSF, and high-dose G-CSF patients, respectively. The incidence of infection was 30% in G-CSF patients (34 of 114 patients) and 34% in placebo patients (20 of 58 patients). Except for more nosocomial pneumonias in the G-CSF patients (7 in 114 patients vs. 0 in 58 patients, P=0.056), the types of infections and causative organisms were also similar in both treatment groups. Although the number of treatments for clinically suspected or proven rejection was similar in the G-CSF and placebo patients, biopsy-proven rejection occurred more often in G-CSF patients (34 of 114 patients or 30%) than placebo patients (11 of 58 patients or 19%) (P=0.093). There were no cases of graft loss caused by rejection. G-CSF had no effect on length of stay in the intensive-care unit or hospital. There were 22 G-CSF patients (18%) and 10 placebo patients (15%) who died within 120 days after the transplant. No serious adverse events were attributed to G-CSF. CONCLUSION: Despite producing substantial increases in the white blood cell count after the transplant, G-CSF had no beneficial effects on infection, rejection, or survival in this study. Biopsy-proven rejection and nosocomial pneumonias were more common in patients treated with G-CSF compared with those taking the placebo. No serious adverse events were attributed to G-CSF.

Adolescent↗
PubMed1998

Randomized comparison of sulbactam/cefoperazone with imipenem as empirical monotherapy for febrile granulocytopenic patients.

In a prospective, randomized, controlled trial, we compared sulbactam/cefoperazone with imipenem as empirical monotherapy for febrile, granulocytopenic patients; 101 patients received sulbactam/cefoperazone (2 g/4 g every 12 hours) and 102 patients received imipenem (500 mg every 6 hours). Documented infections were present in 40% of patients treated with sulbactam/cefoperazone (40 of 101) and in 39% of patients receiving imipenem (40 of 102). The number of pretherapy gram-positive pathogens (52 isolates) was twice the number of pretherapy gram-negative pathogens (26 isolates). The overall favorable clinical response rates for sulbactam/cefoperazone (91 of 103 patients, or 88%) and imipenem (84 of 104 patients, or 81%) were similar. Both drugs were generally well tolerated. However, diarrhea occurred more often in patients treated with sulbactam/cefoperazone (31 of 101 patients, or 31%, vs. 15 of 102 patients, or 15%; P = .007), while seizures developed only in patients receiving imipenem (0 of 101 patients vs. 3 of 102 patients, or 3%). Superinfections developed in 16% of patients in both study groups but were infrequently caused by beta-lactam-resistant gram-negative bacilli (two cases with sulbactam/cefoperazone therapy and six cases with imipenem). These results support the efficacy and safety of either sulbactam/cefoperazone or imipenem as empirical monotherapy for febrile granulocytopenic patients.

Adolescent↗
PubMed1997

Long-term ganciclovir prophylaxis for successful prevention of primary cytomegalovirus (CMV) disease in CMV-seronegative liver transplant recipients with CMV-seropositive donors.

BACKGROUND: We conducted a trial of long-term ganciclovir prophylaxis for prevention of primary cytomegalovirus (CMV) disease in CMV-seronegative liver transplant recipients with CMV-seropositive donors. METHODS: Patients received intravenous ganciclovir at a dose of 6 mg/kg once a day from day 1 to day 30 after transplant, and then at a dose of 6 mg/kg once a day, Monday through Friday, until day 100. Forty-seven consecutive patients were evaluated. Due to the primary physician's decision or administrative error, 10 patients received less than 7 weeks of ganciclovir (mean duration, 3 weeks). RESULTS: Four of the 10 (40%) patients who received less than 7 weeks of ganciclovir developed CMV disease (hepatitis). In contrast, none of the 37 patients given 100 days of prophylactic ganciclovir developed CMV disease while receiving ganciclovir. Two patients (5.4%) subsequently developed CMV disease (hepatitis) 21 and 88 days, respectively, after completing their ganciclovir prophylaxis. Reversible neutropenia in three patients (8.1%) was the only side effect associated with long-term ganciclovir. Complications from central intravenous catheters did not occur. CONCLUSIONS: These results reaffirm the efficacy and safety of long-term ganciclovir prophylaxis for prevention of primary CMV disease in a large number of high-risk CMV-seronegative liver transplant recipients with CMV-seropositive donors.

Adolescent↗
PubMed1997

Randomized comparison of ganciclovir plus intravenous immune globulin (IVIG) with IVIG alone for prevention of primary cytomegalovirus disease in children receiving liver transplants.

A randomized placebo-controlled trial was conducted to determine the benefit of ganciclovir (5 mg/[kg x d]) for 30 days in addition to intravenous immune globulin (IVIG) for 16 weeks for prevention of primary cytomegalovirus (CMV) disease in children receiving liver transplants. Patients were monitored for 6 months after transplantation. The two groups of patients (recipients of 29 ganciclovir plus IVIG and 27 recipients of IVIG alone) were similar in terms of age, sex, and underlying disease. The incidence of CMV disease among the ganciclovir plus IVIG recipients and the IVIG alone recipients was 17% and 26%, respectively, and the time to disease in these recipients was 46 days and 32 days, respectively. There was no difference between groups in terms of survival; episodes of rejection, bacteremia, or fungemia; use of immunosuppressive agents; and incidence of leukopenia or thrombocytopenia. These results suggest that a 4-week course of ganciclovir with IVIG is not more effective than IVIG alone for prevention of primary CMV disease. Since short-term prophylaxis with ganciclovir may delay the onset of CMV disease, further studies with a longer course of ganciclovir prophylaxis are warranted.

Adolescent↗
PubMed1997

Coccidioidomycosis in liver transplant patients.

Eight (0.59%) of 1,347 patients who underwent liver transplantation at the UCLA Medical Center (Los Angeles) developed coccidioidomycosis. Whereas only one case occurred during the first 8 years and 10 months of the UCLA Liver Transplant Program (February 1984 to December 1992), seven cases occurred within the following 23-month period (December 1992 to November 1994). The median time of onset for infection after transplantation was 8 weeks (range, 4-312 weeks). Clinical presentations of patients with coccidioidomycosis included pneumonia (six cases), pneumonia with meningitis (one case), hepatitis (one case), and monoarticular arthritis (one case). Despite therapy with amphotericin B alone (six cases) or amphotericin B plus fluconazole (two cases), infection was fatal in four of eight cases. As of this writing, the four surviving patients are receiving chronic maintenance therapy with either fluconazole (three patients) or itraconazole (one patient). These experiences show that coccidioidomycosis can be a serious and frequently fatal infection after liver transplantation and that the incidence of this disease appears to be increasing.

Adult↗
PubMed1996

Failure of ganciclovir prophylaxis to prevent allograft reinfection following orthotopic liver transplantation for chronic hepatitis B infection.

The effect of ganciclovir prophylaxis on reinfection of hepatic allografts by hepatitis B virus (HBV) was studied in 26 patients undergoing orthotopic liver transplantation (OLT) for decompensated cirrhosis due to HBV. Patients were randomized to receive either ganciclovir (6 mg/kg/day intravenously for a total of 100 days) or acyclovir (10 mg/kg every 8 hours intravenously until discharged and then 800 mg orally every 6 hours) for a total of 100 days after OLT as part of a study of prophylaxis against cytomegalovirus infection. All patients received hepatitis B immunoglobulin (HBIG), 10,000 units intravenously, during the anhepatic phase, daily for the first 7 days, after OLT, and then every 4 weeks for 6 months, Seven of 12 (58%) patients in the ganciclovir group developed recurrent HBV, compared with 6/14 (46%) of the acyclovir group (nonsignificant). No significant difference was observed in time to recurrent HBV in the ganciclovir group (mean 13.2 months) compared to the acyclovir group (mean 11 months). Our results suggest that ganciclovir administered prophylactically for 100 days after OLT does not prevent or delay graft reinfection by HBV.

Acyclovir↗
PubMed1995

Long-term ganciclovir prophylaxis eliminates serious cytomegalovirus disease in liver transplant recipients receiving OKT3 therapy for rejection.

We conducted a trial of long-term ganciclovir prophylaxis for prevention of cytomegalovirus (CMV) disease in liver transplant recipients receiving OKT3 therapy for rejection. Intravenous ganciclovir (6 mg/kg once a day, Monday through Friday) was initiated on the same day OKT3 therapy was started and continued for 4 or more weeks. Fifty-one consecutive adult patients (80% CMV seropositive, 20% CMV seronegative) were evaluated. Due to the patient's noncompliance or the primary physician's decision, 6 patients received less than 2 weeks of ganciclovir. Three of these 6 (50%) developed CMV disease (hepatitis 1, CMV syndrome 2). In contrast, of 45 patients receiving 4 or more weeks of prophylactic ganciclovir, only 1 (2.2%) developed CMV disease (hepatitis). There were no cases of CMV disease among 29 patients who received 6 or more weeks of ganciclovir. Reversible neutropenia in 2 patients (4.4%) was the only side effect associated with long-term ganciclovir. Complications from central intravenous catheters did not occur. These results suggest that CMV can be eliminated as a significant pathogen in liver transplant recipients receiving OKT3 for rejection by the long-term administration of prophylactic gnaciclovir, which is safe.

Adult↗
PubMed1995

Randomised comparison of ganciclovir and high-dose acyclovir for long-term cytomegalovirus prophylaxis in liver-transplant recipients.

Despite current approaches to prophylaxis, cytomegalovirus (CMV) continues to be a common cause of infection and disease in solid-organ-transplant patients. Thus, we conducted a controlled trial comparing long-term administration of ganciclovir with high-dose acyclovir for prevention of CMV infection and disease in liver transplant recipients. At the time of transplant, patients were randomised to receive either ganciclovir (6 mg/kg body weight per day intravenously from postoperative day 1 to day 30, then 6 mg/kg per day Monday through Friday until day 100) or acyclovir (10 mg/kg intravenously every 8 h from postoperative day 1 to day of discharge, then 800 mg orally four times a day until day 100). Patients were followed for development of CMV infection, CMV disease, and drug-related toxicity by frequent cultures, serological tests, laboratory measurements, and tissue biopsies. During the first 120 days after transplant, CMV infection occurred in 48 of 126 (38%) acyclovir patients but in only 6 of 124 (5%) ganciclovir patients (p < 0.0001). Similarly, symptomatic CMV disease developed in 12 of 126 (10%) acyclovir patients but in only 1 of 124 (0.8%) ganciclovir patients (p = 0.002). Ganciclovir reduced the incidence of CMV infection in both CMV antibody positive (37 vs 4%, p = 0.001) and negative patients (42 vs 11%, p = 0.06). In a multivariate analysis of donor-recipient CMV antibody status and other risk factors, prophylactic ganciclovir was the most significant factor protecting against CMV infection (p < 0.0001) and disease (p = 0.001). Ganciclovir and acyclovir were generally well-tolerated. Incidences of leukopenia, thrombocytopenia, renal failure, and other adverse events were similar in the two groups. CMV can be eliminated almost completely as a significant pathogen in liver transplant recipients by the long-term administration of prophylactic ganciclovir. In addition, the treatment is safe.

Acyclovir↗