P. Martino

Itraconazole Oral Solution as Prophylaxis for Fungal Infections in Neutropenic Patients with Hematologic Malignancies: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial

To evaluate the efficacy and safety of itraconazole oral solution for preventing fungal infections, a randomized, placebo-controlled, double-blind, multicenter trial was conducted: 405 neutropenic patients with hematologic malignancies were randomly assigned to receive either itraconazole, 2.5 mg/kg every 12 hours (201 patients), or placebo (204 patients). Proven and suspected deep fungal infection occurred in 24% of itraconazole recipients and in 33% of placebo recipients, a difference of 9 percentage points (95% confidence interval [CI], 0.6% to 22.5%; P = .035). Fungemia due to Candida species was documented in 0.5% of itraconazole recipients and in 4% of placebo recipients, a difference of 3.5 percentage points (95% CI, 0.5% to 6%; P = .01). Deaths due to candidemia occurred in none of the itraconazole recipients compared with 4 placebo recipients, a difference of 2 percentage points (95% CI, 0.05% to 4%; P = .06). Aspergillus infection was documented in four itraconazole recipients (one death) and one placebo recipient (one death). Side effects causing drug interruption occurred in 18% of itraconazole recipients and 13% of placebo recipients. Itraconazole oral solution was well-tolerated and effectively prevented proven and suspected deep fungal infection as well as systemic infection and death due to Candida species.

Preventing fungal infection in neutropenic patients with acute leukemia : fluconazole compared with oral amphotericin B

Superficial and systemic fungal infections are a major problem among neutropenic patients with acute leukemia [1] or those having bone marrow transplantation [2]. It remains a leading cause of morbidity and mortality, and many centers administer amphotericin B empirically to patients with neutropenia and fever refractory to antibacterial treatment [3, 4]. Antifungal prophylaxis is also used widely, but its efficacy in reducing systemic fungal infection is debated [5]. However, oral polyene antibiotics, usually poorly tolerated because of their bitter taste, have been shown to reduce oral candidiasis, and, in a placebo-controlled study, oral amphotericin B was shown to decrease autopsy-proven systemic candidiasis [6]. Among the imidazoles, ketoconazole and miconazole have been used with contrasting results in the prevention of systemic fungal infections, but because of their toxicities and the emergence of fungal-resistant strains, they are rarely used. Fluconazole, an oral triazole with systemic activity, tested in placebo-controlled trials in a daily oral dose of 400 mg, was found to be effective in reducing systemic fungal infections in marrow recipients [7] but did not show the same benefit in patients with acute leukemia receiving therapy to induce remission [8]. Our aim was to clarify the role of systemic and topical antifungal prophylactic agents in neutropenic patients with acute leukemia by doing a large, randomized, multicenter trial that compared the efficacy and tolerability of oral fluconazole with high-dose amphotericin B suspension. Methods Eligible patients included consecutive adults who had acute leukemia, were hospitalized at participating centers, and were receiving cytotoxic therapy likely to induce neutropenia (neutrophil count < 1000/mm3) within 7 days. Patients received remission-induction or reinduction therapy according to the GIMEMA protocols [9, 10]. We excluded from the study before randomization patients younger than 14 years, patients with a history of hypersensitivity to triazoles, patients treated with antifungal therapy in the previous 15 days, patients with evidence of a preexisting systemic fungal infection, and patients who had nasal colonization with Aspergillus spp. Study Protocol After informed consent was obtained, the patients were randomly assigned to receive either fluconazole, 150 mg as a once-daily capsule, or amphotericin B suspension, 500 mg every 6 hours. Patients were randomly assigned to treatments using random permuted blocks of 10 containing different and balanced sequences of the two regimens. Antifungal prophylaxis was started 1 to 3 days before the administration of cytotoxic chemotherapy and continued until the neutrophil count returned to 1000/L or a systemic fungal infection was proved or suspected. All patients received oral ciprofloxacin, 500 mg twice daily, as antibacterial prophylaxis [11]; antiviral prophylaxis and central venous catheters were used according to autonomous decisions made at each participating center. The patients were treated under conventional ward conditions or in single rooms, depending on the center. Prophylactic granulocyte transfusions and colony-stimulating factors were not used. All patients were examined daily for clinical signs of fungal infection. When axillary temperature increased to more than 38 C or infection was suspected, samples for microbiological cultures, including at least three separate blood specimens, were obtained, prophylactic therapy with ciprofloxacin was discontinued, and treatment with amikacin, ceftazidime, and a glycopeptide antibiotic (teicoplanin or vancomycin) was started; if fever persisted despite 4 to 6 days of systemic antibiotics, empiric intravenous amphotericin B was administered. Documented systemic fungal infections were treated with systemic antifungal agents (mainly intravenous amphotericin B), and superficial fungal infections were treated with topical antifungal agents. To compare the efficacy and tolerability of the two prophylactic regimens, the following variables were measured: documented systemic fungal infection; suspected systemic fungal infection; superficial fungal infection; the interval to the development of documented systemic fungal infection or to the use of empiric antifungal therapy; compliance; treatment interruption caused by side effects; and mortality. Definition of Fungal Infection Superficial fungal infection was defined as clinically apparent infection of the oropharynx or skin, along with positive cultures; a suspected case of systemic fungal infection was defined as any episode of fever that persisted despite 4 to 6 days of empiric antibiotic therapy, for which empiric intravenous amphotericin B therapy was administered; definite systemic fungal infection was defined as one in which there was both clinical evidence of blood or tissue infection and a culture or biopsy specimen from the involved site showing a pathogenic fungal organism [7]. Compliance Compliance was monitored by the nurse who counted capsules of fluconazole and measured the volume of amphotericin B oral suspension each day and recorded these data on the clinical report form. Compliance was defined as excellent if the patient took all the drug doses, as good if the patient missed fewer than three consecutive doses or took more than 80% of the total number of doses, and as poor if the patient missed more than three consecutive doses or took less than 80% of the total number of doses. Statistical Analysis Statistical analysis was done at the GIMEMA Infection Program Data Center with the SAS package (SAS Institute, Inc., Cary, North Carolina). Results are reported for all patients enrolled in the study (intention-to-treat analysis). Except for three patients randomly assigned to fluconazole and two patients assigned to amphotericin B who did not receive the study drugs and six additional patients in the fluconazole group and five in the amphotericin B group who had a duration of neutropenia of less than 7 days, all other patients were evaluable for the clinical efficacy analysis. The chi-square test with a correction for continuity, or the Fisher exact test when appropriate, was used to compare differences in proportions between the two groups. The log-rank test was used to compare the Kaplan-Meier survival curves. The Student unpaired t-test was used to compare the means. Confidence intervals (CIs) of 95% are given where appropriate. Results A total of 820 patients with acute leukemia and neutropenic episodes from 30 centers were studied; 420 were randomly assigned to receive fluconazole, and 400 were randomly assigned to receive oral amphotericin B. The two groups of patients were similar in sex, age, underlying diseases, type of chemotherapy, protective environment, use of central venous catheters, and duration and severity of neutropenia. Patients receiving first-induction chemotherapy were equally distributed in the two treatment groups (Table 1). Table 1. Patient Characteristics according to Treatment Group Systemic Fungal Infection Proven systemic fungal infection occurred in 11 (2.6%) fluconazole recipients and in 10 (2.5%) amphotericin B recipients (P > 0.2). The distribution of fungal isolates was similar in both groups (Table 2): Candida spp. caused 55% of systemic infections in fluconazole recipients and 70% in amphotericin B recipients; no difference was found in the isolation of different Candida spp., including C. krusei, between the two groups. Rates of infections caused by Aspergillus spp. were 45% in fluconazole recipients and 30% in amphotericin B recipients, a difference of 15 percentage points (95% CI for difference, 25% to 56%, P > 0.2), and the Aspergillus isolates were equally distributed. Fungemia caused by Candida spp. was documented in five patients receiving fluconazole and in three treated with amphotericin B. The characteristics of the patients with proven cases of systemic fungal infection and their clinical outcomes are summarized in Table 3. Table 2. Types of Fungi Isolated in Systemic Infections according to Treatment Group* Table 3. Characteristics and Outcomes of the Definite Cases of Systemic Fungal Infection according to Treatment Group Overall, the sites of infection between the two treatment groups were similar (P > 0.2). Simple fungemia caused by Candida isolates was documented in three patients in each group (two cases of C. krusei and one of C. parapsilosis in fluconazole recipients; one case each of C. albicans, C. krusei, and C. parapsilosis in amphotericin B recipients), and tissue infection was documented in three fluconazole recipients (C. tropicalis, C. albicans, and C. parapsilosis), and two amphotericin recipients (Candida spp., C. albicans). In patients receiving amphotericin B, esophagitis caused by Candida spp. and urinary tract infection caused by C. tropicalis were also documented. Tissue infection caused by Aspergillus spp. occurred in five fluconazole recipients (four cases of pneumonia and one disseminated infection) and in three amphotericin B-treated patients (two cases of pneumonia and one case of disseminated infection). Deaths from fungal infection were similar. Candida krusei fungemia and C. albicans and C. parapsilosis tissue infections caused death in three fluconazole recipients; C. albicans fungemia and Candida spp. tissue infection caused death in two amphotericin B recipients. Aspergillus pneumonia caused two deaths in the fluconazole group and one death in the amphotericin B group. The interval to the documented systemic fungal infection was 21 days in fluconazole recipients and 15 days in amphotericin B recipients, a nonstatistically significant difference (95% CI for difference, 3 to 15 days; P = 0.15). Superficial Fungal Infection Superficial infections were reported in 7 of the 420 patients receiving fluconazole (1.7%) and in 11 of 400 of those receiving amphotericin B (2.7%), a difference of 1 percentage point (CI for di

Prospective study of Candida colonization, use of empiric amphotericin B and development of invasive mycosis in neutropenic patients.

The association between colonization withCandida spp., subsequent occurrence of invasive candidiasis and empiric use of amphotericin B was investigated prospectively in 139 neutropenic patients with hematologic malignancies. Treatment with amphotericin B was required in 67 % of patients colonized in multiple non-contiguous body sites (multicolonized) versus 31 % of patients colonized in single or contiguous sites (monocolonized) and in 21 % of non-colonized patients (p=0.0037 and p=0.00026, respectively). Invasive candidiasis was documented in 22.2 % of multicolonized versus 4.8 % of monocolonized patients and in none of the non-colonized patients (p=0.035 and p=0.0036, respectively). Analysis of the spectrum of colonizingCandida spp. showed that multicolonized subjects were colonized with increased frequency byCandida albicans compared to monocolonized subjects, and that the association between multicolonization, invasive candidiasis and amphotericin B usage was statistically significant in patients colonized byCandida albicans but not in patients colonized by otherCandida species. The association betweenCandida multicolonization and the occurrence ofCandida infection seems to be confirmed by a double-blind placebo-controlled study performed in a small subgroup of the multicolonized patients treated with fluconazole.

Cutaneous aspergillosis in patients with haematological malignancies.

Abstract The aim of the present study was to evaluate skin infections caused by Aspergillus in patients with haematological malignancies. Fifteen cases of cutaneous aspergillosis are reported, 12 of which occurred among 4448 consecutive patients with acute leukaemia. Cutaneous involvement occurred in 4% of patients with documented Aspergillus infection. Primary cutaneous aspergillosis was diagnosed in five cases. Infection was fatal in 11 of 15 cases; the absence of additional sites of infection other than cutis at presentation appeared to be the only factor related to a favourable outcome.

Piperacillin/tazobactam/amikacin versus piperacillin/amikacin/teicoplanin in the empirical treatment of neutropenic patients

A prospective randomized trial was performed to compare the efficacy of a regimen containing a glycopeptide versus one containing a beta-lactamase inhibitor in the treatment of febrile episodes in neutropenic patients. Fifty-eight patients received piperacillin/amikacin/teicoplanin (group 1) and 56 received piperacillin/amikacin/tazobactam (group 2). In the case of persistence of fever without microbiological documentation of the cause, teicoplanin was also given empirically in group 2 on day 4, and amphotericin B in both groups on day 6. In 114 evaluable febrile episodes, the rate of success without modification of therapy was 60 % in patients on piperacillin/amikacin/teicoplanin and 41 % in patients on piperacillin/amikacin/tazobactam (p<0.03). Eleven of 34 patients in the latter group who failed to improve eventually responded upon addition of teicoplanin. Ten and nine patients in group 1 and group 2 respectively required the addition of amphotericin B for definite improvement. There were 14 episodes of gram-positive septicemia in each group: the response rate was 100 % in group 1 and 43 % in group 2. Three episodes of gram-negative breakthrough septicemia occurred in group 1 versus no cases in group 2 (p=0.1). Three deaths occurred in each group. Piperacillin/amikacin/tazobactam may be as efficacious as piperacillin/amikacin/teicoplanin in the treatment of febrile neutropenic patients provided the regimen is modified (usually by addition of teicoplanin) in unresponsive cases.

Fluconazole treatment ofBlastoschizomyces capitatus meningitis in an allogeneic bone marrow recipient

The first known case ofBlastoschizomyces capitatus meningitis occurring in an allogeneic bone marrow recipient on steroid and cyclosporine therapy for chronic graft-versus-host disease is reported. An 11-month course of treatment with oral fluconazole resulted in resolution of the meningeal syndrome and eradication ofBlastoschizomyces capitatus from the cerebrospinal fluid. Three months after discontinuation of fluconazole the patient died due to idiopathic interstitial pneumonia and bilateral pneumothorax, without clinical signs of meningitis. Post mortem examination showed meningeal fungus invasion consistent withBlastoschizomyces capitatus infection. Oral fluconazole treatment thus did not eradicate the fungal infection, but achieved significant control of the meningitis on an outpatient basis.

Domiciliary treatment of febrile episodes in cancer patients: a prospective randomized trial comparing oral versus parenteral empirical antibiotic treatment

Abstract Hospitalization and empirical broad-spectrum, intravenous antibiotics are the standard treatment for febrile cancer patients. Recent evidence supports the suggestion that febrile episodes in a low-risk population can be managed successfully in an outpatient setting, but the optimal drug regimen is unknown. In a prospective randomized clinical trial we compared ciprofloxacin 750 mg p.o. twice a day with ceftriaxone 2 g i.v. as a single daily dose for the empiric domiciliary treatment of febrile episodes in low-risk neutropenic and nonneutropenic cancer patients. A total of 173 patients, accounting for 183 febrile episodes, were enrolled in the study. Overall, successful outcomes were recorded for 76 of 93 (82%) febrile episodes in patients who were randomized to the oral regimen and for 68 of 90 (75%) febrile episodes in patients randomized to the i.v. regimen: this difference was not statistically significant. The success rate was similar in all subgroups of patients: neutropenic and nonneutropenic, with documented infection and with fever of unknown origin. There were 3 deaths in the group of patients treated with the parenteral regimen, and two of these were related to treatment failure. Both treatments were well tolerated, and the cost of the oral regimen was lower. This prospective study suggests that domiciliary antibiotic empiric monotherapy is feasible in febrile nonneutropenic or low-risk neutropenic outpatients in whom a bacterial infection is suspected, and that either an oral or a parenteral regimen can be used. A number of factors may influence the choice between an orally and an i.v.-administered antibiotic, but owing to the easier administration and lower cost, the oral regimen seems to be preferable.

Association between Antifungal Prophylaxis and Rate of Documented Bacteremia in Febrile Neutropenic Cancer Patients

Published data have suggested a correlation between antifungal prophylaxis and bacteremia in febrile neutropenia. This correlation was investigated among 3002 febrile neutropenic patients enrolled in 4 trials during 1986-1994. Globally, 1322 patients (44%) did not receive antifungal prophylaxis; 835 (28%) received poorly absorbable antifungal agents and 845 (28%) received absorbable antifungal agents. The rates of bacteremia for these groups were 20%, 26%, and 27%, respectively (P=.0001). In a multivariate model without including antifungal prophylaxis, factors associated with bacteremia were: age, duration of hospitalization, duration of neutropenia before enrollment, underlying disease, presence of an intravenous catheter, shock, antibacterial prophylaxis, temperature, and granulocyte count at onset of fever. When antifungal prophylaxis was included, the adjustment quality of the model improved slightly (P=.05), with an odds ratio of 1.19 (95% confidence interval [CI], 0.92-1.55) for patients receiving nonabsorbable and 1.42 (95% CI, 1.07-1.88) for those who were receiving absorbable antifungal agents. Antifungal prophylaxis with absorbable agents might have an impact on the rate of documented bacteremia in febrile neutropenia. This effect should be confirmed prospectively.

Exogenous Lipid Clearance in Compensated Liver Cirrhosis

The tolerance to exogenous fats has been evaluated in patients with liver cirrhosis. A three-stage lipid clearance test with continuous infusion (3 hr) of a triglyceride emulsion, Intralipid, was performed on 10 patients with well compensated liver cirrhosis and 10 normolipidemic volunteers. During the infusion, blood samples were collected for the measurement of particulate triglycerides (TG) by nephelometry; samples were also collected for total TG, free fatty acids (FFA) and free tryptophan (TRP) determinations. Plasma endogenous triglycerides were calculated as the total minus exogenous, particulate, TG. The fractional removal rate (K2) and the maximal clearing capacity (K1) for exogenous TG were lower in patients than in controls, though a significant difference (p less than 0.05) was found only for K1. Endogenous TG and FFA showed a comparable rise in patients and controls during Intralipid infusion. A significant increase in free TRP was noted in cirrhotics upon maximal infusion rate. It is concluded that: in patients with well compensated liver cirrhosis the maximal clearing capacity (K1) for exogenous TG is impaired. Nonetheless, moderate amounts of fat may be removed at a normal rate from the bloodstream; a normal synthesis rate of exogenous TG may be maintained even in a severely damaged liver; considering the possible role of free TRP in the pathogenesis of hepatic encephalopathy (HE), the use of large amounts of lipids should be discouraged in patients with decompensated liver cirrhosis, or even avoided in those with impending or overt HE.

Superinfections during antimicrobial treatment with betalactam-aminoglycoside combinations in neutropenic patients with hematologic malignancies

SummaryThe frequency, etiology and risk factors of superinfections during and/or within one week after antibiotic therapy with betalactam-aminoglycoside combinations were evaluated in 631 patients with hematologic malignancies admitted to the Institute of Hematology of Rome from January 1982 to December 1984. 356 patients (56%) developed 402 episodes of proven or presumed infection. Of these patients, 78 developed 102 superinfections. Overall, superinfections responded less satisfactorily to antibiotic therapy than the primary febrile episodes (63% vs. 85%). The distribution of etiologic agents of superinfections differed from those responsible for primary infections, since fungi and anaerobes (especiallyClostridium difficile) were mostly isolated after antibiotic therapy had begun. Moreover, among aerobic bacteria, frequently antibiotic-resistant species, such asPseudomonas aeruginosa, Streptococcus faecalis andStaphylococcus epidermidis were the leading etiologic agents of superinfection. The risk of superinfection appeared to increase with the depth and persistence of granulocytopenia. On the other hand, the length of hospitalization, length of previous antibiotic therapy, previous chemoprophylaxis and presence of indwelling venous catheter did not affect the risk of superinfection.ZusammenfassungBei 631 Patienten mit malignen hämatologischen Erkrankungen, die von Januar 1982 bis Dezember 1984 am hämatologischen Institut Rom zur Behandlung kamen, wurde eine Auswertung bezüglich der Häufigkeit, Ursache und der Risikofaktoren von Superinfektionen während und/oder innerhalb einer Woche nach Behandlung mit Betalactam-Aminoglykosid-Kombinationen vorgenommen. Bei 356 Patienten (56%) traten 402 Episoden einer erwiesenen oder vermuteten Infektion auf. 78 dieser Patienten bekamen 102 Episoden von Superinfektionen. Insgesamt sprachen Superinfektionen weniger befriedigend auf die Antibiotika-Therapie an als die primären febrilen Episoden (63% gegenüber 85%). Die Verteilung der kausalen Erreger der Superinfektionen war gegenüber den primären Infektionen verschieden; Pilze und Anaerobier (vor allemClostridium difficile) wurden vorwiegend nach Beginn der Antibiotika-Therapie isoliert. Unter den aeroben Erregern waren häufig Antibiotika-resistente Spezies wiePseudomonas aeruginosa, Streptococcus faecalis undStaphylococcus epidermidis die führenden kausalen Erreger von Superinfektionen. Das Risiko für eine Superinfektion schien mit dem Grad und der Dauer der Granulozytopenie zuzunehmen. Die Dauer der stationären Behandlung, Dauer einer vorausgegangenen Antibiotikatherapie, frühere Chemoprophylaxe und Anwesenheit eines intravenösen Verweilkatheters hatte hingegen keinen Einfluß auf das Risiko für eine Superinfektion.