Leaving previously implanted central venous catheters (ports) in place does not increase morbidity in patients undergoing autologous peripheral stem cell transplantation.

We sought to assess if leaving in place a previously inserted noncolonized or infected implantable catheter (IC) is associated with an increase in morbidity in patients undergoing autologous peripheral stem cell transplantation (APSCT). Medical records from all patients between March 1997 and January 2002 undergoing APSCT with an IC in place were reviewed. Case group (IC in place) was compared with a control group (no IC) from 6 days prior to 60 days after APSCT. In all, 43 cases were matched with 43 controls by underlying disease, age and sex. In both groups, duration of neutropenia and use of antimicrobial prophylaxis were comparable. Underlying malignancies were lymphoma (22/24), multiple myeloma (14/12), leukemia (3/3), and others (7/7) in case and control groups. Cases and controls had comparable rates of risk for fever, bloodstream infection, use of vancomycin and amphotericin B, and death, as well as comparable lengths of stay and readmissions. ICs were used in 20 of 43 patients. Using the IC did not significantly increase the risk of fever, bloodstream infection, length of stay, and/or readmissions after APSCT but was associated with increased use of antibacterial and antifungal agents. Leaving in place a previously inserted, noncolonized or infected IC did not increase morbidity in patients undergoing APSCT.

Lipid formulations of amphotericin B preserve and stabilize renal function in HSCT recipients.

The current study assessed renal function based on medical records in adult hematopoietic stem cell transplant (HSCT) recipients with proven or probable invasive fungal infection (IFI) transplanted between 1995 and 2000. We confirm that amphotericin B deoxycholate (AmB-d) is nephrotoxic in a large percentage of HSCT recipients. Due to nephrotoxicity, defined as serum creatinine (SCr) >2.5 mg/dl or a 100% increase in SCr from baseline, 88% of patients treated with AmB-d were switched to a lipid formulation of amphotericin B (LFAB). In total, 53% of patients initiated on AmB-d were switched within the first week of therapy. Significantly more patients (70.6%) treated with AmB-d experienced a 100% increase in SCr from baseline compared to patients treated with either AmBisome (44.4%) or Abelcet (41.2%). A Cox Proportional Hazards Model revealed that, compared to patients initiated on AmBisome or Abelcet, the risk of nephrotoxicity (RR=1.5 vs AmBisome; RR=1.7 vs Abelcet), dialysis (RR=2.4 vs AmBisome; RR=1.4 vs Abelcet), and death (RR=2.0 vs AmBisome; RR=1.1 vs Abelcet) were all increased for patients initiated on AmB-d. Study results suggest that renal function improves and mortality declines when an LFAB is given to HSCT patients as initial therapy rather than as second-line therapy, the current practice.

Human fusariosis.

Fusarium species frequently implicated in human infections include F. solani, F. oxysporum and F. moniliforme. Among immunocompetent patients, tissue breakdown (as caused by trauma, severe burns or foreign body) is the risk factor for fusariosis. Infections include keratitis, onychomycosis and occasionally peritonitis and cellulitis. Treatment is usually successful and requires removal of the foreign body as well as antifungal therapy. Among immunocompromised patients, mainly patients with haematological malignancies, Fusarium spp. are the second most common pathogenic mould. Risk factors for disseminated fusariosis include severe immunosuppression (neutropenia, lymphopenia, graft-versus-host disease, corticosteroids), colonisation, tissue damage, and receipt of a graft from an HLA-mismatched or unrelated donor. Clinical presentation includes refractory fever (> 90%), skin lesions and sino-pulmonary infections ( approximately 75%). Type of skin lesions includes ecthyma-like, target, and multiple subcutaneous nodules. Skin lesions lead to diagnosis in > 50% of patients and precede fungemia by approximately 5 days. In contrast to disseminated aspergillosis, disseminated fusariosis can be diagnosed by blood cultures in 40% of patients. Histopathology reveals hyaline acute-branching septate hyphae similar to those found in aspergillosis. Mortality from fusarial infections in immunocompromised patients ranges from 50% to 80%. Host immune status is the single most important factor predicting outcome. Persistent neutropenia and corticosteroid therapy significantly affect survival. Optimal treatment has not been established. Anecdotal successes have been reported with various agents (high-dose amphotericin B, lipid-based amphotericin B formulations, itraconazole, voriconazole) and with cytokine-stimulated granulocyte transfusions. Preventing fusariosis relies on detection and treatment of cutaneous damage prior to commencing immunosuppression and decreasing environmental exposure to Fusaria (via air and water).

Loss of hepatitis A virus (HAV) antibodies after peripheral stem cell transplantation (PSCT).

The majority of patients with hepatitis A have a benign course, but some may develop fulminant hepatitis and hematological complications. Peripheral stem cell transplantation (PSCT) is associated with loss of immunity. There are no data regarding loss of HAV antibodies (anti-HAV) after PSCT. We retrospectively evaluated the persistence of anti-HAV in a nonvaccinated population that underwent PSCT. Serum detection of anti-HAV was determined before and after PSCT using a qualitative commercially available enzyme immunoassay. From January 1997 to March 2001, 136 (68%) of 201 patients tested (+) for anti-HAV prior to PSCT. Subsequent investigation of anti-HAV was possible in 36 of these patients at a median of 12 months after PSCT. The median age of patients was 47 years old; they had diagnoses of hematological malignancies (33) and solid tumors (three), and underwent autologous (31) and allogenic (five) PSCT. A total of 31 (86%) of 36 patients remained anti-HAV (+) and five (14%) became (-) after PSCT. The variables age, sex, diagnosis, type of PSCT, time of testing, and number of CD34 cells infused were not predictors of loss of anti-HAV. In conclusion, 14% of 36 nonvaccinated anti-HAV (+) patients lost their antibodies at a median of 12 months after PSCT.

Valacyclovir prophylaxis for the prevention of Herpes simplex virus reactivation in recipients of progenitor cells transplantation.

HSV can cause oral lesions that exacerbate chemotherapy-related mucositis. Intravenous acyclovir is effective in preventing HSV reactivations, but expensive. Valacyclovir has good bioavailability and has not been studied for prophylaxis of HSV among PCT patients. We compared the efficacy and costs of valacyclovir in preventing HSV reactivation among HSV seropositive autologous progenitor cell transplantation (APCT) patients with historical controls in whom intravenous acyclovir or no HSV prophylaxis were used. Valacyclovir group: From October 1997 to April 1999 108 adult patients received valacyclovir 500 mg twice daily from day -3 of APCT until neutropenia recovery or day +30. Valacyclovir was switched to intravenous acyclovir in cases of oral intolerance (17 patients) or suspected HSV reactivation (five patients). Intravenous acyclovir group: From January 1996 to October 1997 43 patients received 5 mg/kg twice-daily intravenous acyclovir from day -3 until recovery from neutropenia. No prophylaxis group: 38 patients from January 1996 to October 1997 did not receive HSV prophylaxis. HSV reactivations were seen in 2.7%, 2% and 45% of patients in the valacyclovir, intravenous acyclovir, and no prophylaxis groups, respectively. Valacyclovir was well tolerated and was the least expensive strategy. Oral valacyclovir was as effective as intravenous acyclovir for the prophylaxis of HSV reactivation in APCT patients.

Fusariosis associated with pathogenic fusarium species colonization of a hospital water system: a new paradigm for the epidemiology of opportunistic mold infections.

We sought the reservoir of Fusarium species in a hospital with cases of known fusarial infections. Cultures of samples from patients and the environment were performed and evaluated for relatedness by use of molecular methods. Fusarium species was recovered from 162 (57%) of 283 water system samples. Of 92 sink drains tested, 72 (88%) yielded Fusarium solani; 12 (16%) of 71 sink faucet aerators and 2 (8%) of 26 shower heads yielded Fusarium oxysporum. Fusarium solani was isolated from the hospital water tank. Aerosolization of Fusarium species was documented after running the showers. Molecular biotyping revealed multiple distinct genotypes among the isolates from the environment and patients. Eight of 20 patients with F. solani infections had isolates with a molecular match with either an environmental isolate (n=2) or another patient isolate (n=6). The time interval between the 2 matched patient-environment isolates pairs was 5 and 11 months, and 2, 4, and 5.5 years for the 3 patient-patient isolate pairs. The water distribution system of a hospital was identified as a reservoir of Fusarium species.

[Eight years of experience in a single institution in hematopoietic stem cell autologous transplantation in malignant hematological diseases and in solid tumors]. / Ocho años de experiencia en una sola institucion en trasplante autólogo de células progenitoras hematopoyéticas en enfermedades hematológicas malignas y en tumores solidos.

Between August 1991 and December 1998, 400 patients (lymphomas: 197; acute leukemia: 86; multiple myeloma: 70 and solid tumors: 47) were admitted for autologous transplantation. All patients were mobilized with chemotherapy plus G-CSF. The hematological recovery was similar in all disease groups. Patients with acute leukemias and multiple myeloma had a slower platelet recovery. Treatment-related death was 4.5%. The status of the disease at diagnosis was the most significant prognostic factor. With a median follow-up of 23 months the probability of event-free survival at 60 months was 46% for low grade lymphoma, 44% for intermediate and high grade lymphoma, 58% for Hodgkin's disease, 45% for acute myeloblastic leukemia, 38% for solid tumors and 15% for multiple myeloma. The probability of survival at 60 months was 67% for low grade lymphoma, 47% for intermediate and high grade lymphoma, 75% for Hodgkin's disease, 52% for acute myeloblastic leukemia, 54% for solid tumors and 25% for multiple myeloma. It can be concluded that autologous progenitor cell transplantation induces a complete and faster hematological recovery in all groups of patients without any late graft failure. Results are similar to those published in the literature. The treatment-related death was low and acceptable.

Ocho años de experiencia en una sola institucion en trasplante autólogo de células progenitoras hematopoyéticas en enfermedades hematológicas malignas y en tumores solidos. / [Eight years of experience in a single institution in hematopoietic stem cell autologous transplantation in malignant hematological diseases and in solid tumors]

Between August 1991 and December 1998, 400 patients (lymphomas: 197; acute leukemia: 86; multiple myeloma: 70 and solid tumors: 47) were admitted for autologous transplantation. All patients were mobilized with chemotherapy plus G-CSF. The hematological recovery was similar in all disease groups. Patients with acute leukemias and multiple myeloma had a slower platelet recovery. Treatment-related death was 4.5

. The status of the disease at diagnosis was the most significant prognostic factor. With a median follow-up of 23 months the probability of event-free survival at 60 months was 46

for low grade lymphoma, 44

for intermediate and high grade lymphoma, 58

for Hodgkins disease, 45

for acute myeloblastic leukemia, 38

for solid tumors and 15

for multiple myeloma. The probability of survival at 60 months was 67

for low grade lymphoma, 47

for intermediate and high grade lymphoma, 75

for Hodgkins disease, 52

for acute myeloblastic leukemia, 54

for solid tumors and 25

for multiple myeloma. It can be concluded that autologous progenitor cell transplantation induces a complete and faster hematological recovery in all groups of patients without any late graft failure. Results are similar to those published in the literature. The treatment-related death was low and acceptable.

The role of immunoreconstitution in the management of refractory opportunistic fungal infections.

Systemic fungal infections are an increasingly important threat to immunocompromised patients. In particular, invasive disease due to Candida spp., Aspergillus spp. and other moulds is associated with high mortality rates in these patients, despite the many recent advances in antifungal chemotherapy. Recent studies examining the immunopathogenesis of these infections have provided increased insights into the relative importance of the different compartments of host immune defences for these fungi. In parallel, a number of cytokines have been discovered and studies of their involvement in antifungal host defences both in vitro and in experimental animal models of fungal infections have become possible. Due to their ability to upregulate phagocyte number and/or function, the cytokines of greatest interest are granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, interferon-gamma, interleukin-1 and tumour necrosis factor-alpha. Adjuvant use of these cytokines may be of value for some refractory fungal infections, as may reconstitution of immune response by transfusion of allogeneic phagocytes. Further evaluation of the safety and efficacy of these modalities of immunotherapy is a new and promising area for research.

Treatment of neutropenia-related fungal infections with granulocyte colony-stimulating factor-elicited white blood cell transfusions: a pilot study.

Neutropenia-related fungal infections can be life-threatening despite antifungal therapy. We evaluated the role of recombinant granulocyte colony-stimulating factor (rG-CSF)-elicited white blood cell (WBC) transfusions in patients with neutropenia-related fungal infections. Adult patients with hematologic malignancies, absolute neutrophil counts (ANC) <500/microl and fungal infections refractory to amphotericin B, received daily transfusions of rG-CSF-elicited and irradiated WBC transfusions from related donors. Donors received 5 microg/kg/day of rG-CSF subcutaneously. Donors achieved a mean ANC of 29.4 x 10(3) per microliter. The mean yield of neutrophils per transfusion was 41 x 10(9) (range, 10-116). Fifteen patients received a median of eight transfusions (range, 3-16). Fourteen patients had received rG-CSF for a median of 12 days. The median ANC baseline was 20/microl. Eleven patients had favorable responses and eight of them remained free of infection 3 weeks after therapy. Favorable responses occurred among patients with better Zubrod performance status (median, 3 vs 4) and shorter duration of both profound neutropenia (median, 15 vs 25 days) and active infection (median, 8 vs 17 days). The mean 1- and 24-h post-transfusion ANCs were 594/microl (range, 98-1472/microl) and 396/microl (range, 50-1475/microl), respectively. Adverse reactions were observed in nine of 35 donors and in the recipients of six of 130 transfusions. rG-CSF-elicited WBC transfusions may be a safe and promising approach for treating neutropenia-related fungal infections.

SCH 51048, a new antifungal triazole active against hematogenous Candida krusei infections in neutropenic mice.

Candida krusei is increasingly recognized as an opportunistic pathogen in immunocompromised patients and is inherently resistant to fluconazole. We tested the in vivo efficacy of SCH 51048, an investigational antifungal triazole, in experimental hematogenous murine infection caused by two C. krusei isolates and compared its activity with those of amphotericin B and fluconazole. CF1 mice were immunosuppressed with cyclophosphamide and cortisone acetate and were challenged intravenously with infecting inocula of each C. krusei isolate. Treatment with SCH 51048 (50 or 100 mg/kg of body weight per day orally) or amphotericin B (2 mg/kg/day intraperitoneally) significantly prolonged the survival of infected mice and significantly reduced fungal titers in the kidneys (P < or = 0.05). Treatment with fluconazole (100 mg/kg/day orally) had no effect. Both dosages of SCH 51048 were as effective as amphotericin B in improving survival, but the higher dosage was significantly (P < or = 0.05) better in reducing the fungal burden in the kidneys of infected animals. A dose-dependent response was observed with SCH 51048 treatment, especially in organ clearance. Our results indicate that SCH 51048 is the first triazole that has in vivo activity against experimental infection with C. krusei and deserves further evaluation.

Activities of D0870, a novel triazole, against Candida lusitaniae and Trichosporon beigelii in experimental murine infections.

Candida lusitaniae and Trichosporon beigelii may cause life-threatening infections in the immunocompromised host and may be resistant to amphotericin B. We assessed the activities of a new triazole, D0870, against one T. beigelii and four C. lusitaniae strains, in comparison with those of fluconazole and amphotericin B. Immunosuppressed CF1 mice, intravenously infected with each fungal strain, received 3 days of therapy with oral D0870 (5 or 25 mg/kg of body weight daily), fluconazole (5 to 50 mg/kg daily), or parenteral amphotericin B (1 or 2 mg/kg daily). Survival was significantly prolonged and kidney fungus titers were reduced in mice treated with D0870 compared with untreated mice (P < or = 0.05). Treatment with D0870 was significantly more effective than that with amphotericin B or fluconazole in animals infected with two of the C. lusitaniae strains and equally effective for the remaining two C. lusitaniae strains and the T. beigelii strain. Fluconazole and amphotericin B failed to improve the survival of mice infected with one and two C. lusitaniae strains, respectively. D0870 was active against all the organisms tested, including those resistant to fluconazole and amphotericin B.

Collection and transfusion of granulocyte concentrates from donors primed with granulocyte stimulating factor and response of myelosuppressed patients with established infection.

Fifteen patients with prolonged neutropenia (a median of 23 days with granulocyte [PMN] < or = 500/microliters) and established fungal infections that had not responded to adequate antifungal therapy were transfused with PMN concentrates collected from 35 cytokine-primed granulocyte colony-stimulating factor (GCSF) donors. Patients received a median of six transfusions. Leukocytosis and granulocytosis were observed within 24 hours of the first GCSF injection, which yielded concentrates averaging 55 x 10(9) white blood cells and 41 x 10(9) PMN. Data analysis suggested that response might be related to the duration of neutropenia and known infection, as patients given PMN tx earlier in the infectious course tended to have a better response. No significant toxicity was observed in donors.

Comparative efficacies of amphotericin B, triazoles, and combination of both as experimental therapy for murine trichosporonosis.

We assessed the activities of amphotericin B deoxycholate, liposomal amphotericin B, fluconazole, and SCH 39304 against 10 strains of Trichosporon beigelii in mice with hematogenous infections. Cyclophosphamide-immunosuppressed CF1 male mice were challenged intravenously with a lethal inoculum of T. beigelii (5 x 10(6) conidia per mouse) and were assigned to different treatment groups or were left untreated. Amphotericin B deoxycholate (1 mg/kg of body weight and liposomal amphotericin B (1, 5, and 10 mg/kg) were given parenterally once daily. Escalating doses (5, 10, and 20 mg/kg/day) of fluconazole and SCH 39304 were tested. We also compared the activity of amphotericin B deoxycholate plus fluconazole (1 and 10 mg/kg/day, respectively) with that of each agent alone. Fluconazole significantly prolonged the survival of mice infected with each of the 10 strains tested. Amphotericin B deoxycholate achieved various responses, improving the outcomes in mice infected with seven of the strains. Liposomal amphotericin B was not more effective than amphotericin B deoxycholate against the two strains tested. Both fluconazole and SCH 39304 reduced the kidney fungal counts in a dose-dependent pattern, with SCH 39304 being more active than fluconazole against one of the two strains tested. The activity of the combination of amphotericin B deoxycholate plus fluconazole appeared to be superior to that of either agent alone, especially in reducing the kidney fungal burden. Fluconazole is more active than amphotericin B deoxycholate against experimental murine trichosporonosis.

Taxonomy, biology, and clinical aspects of Fusarium species.

There are several taxonomic systems available for identifying Fusarium species. The philosophy used in each taxonomic system is discussed as well as problems encountered in working with Fusarium species in culture. Fusarium species are toxigenic, and the mycotoxins produced by these organisms are often associated with animal and human diseases. The implications for the association of the carcinogens, fumonisins, produced by Fusarium moniliforme and other Fusarium species with human diseases are discussed. Foreign-body-associated fusarial infection such as keratitis in contact lens wearers, onychomycosis, skin infections, and disseminated multiorgan infections are discussed. Disseminated fusarial hyalohyphomycosis has emerged as a significant, usually fatal infection in the immunocompromised host. Successful outcome is determined by the degree of immunosuppression, the extent of the infection, and the presence of a removable focus such as an indwelling central venous catheter. These infections may be clinically suspected on the basis of a constellation of clinical and laboratory findings, which should lead to prompt therapy, probably with one of the newer antifungal agents. Perhaps the use of such agents or the use of colony-stimulating factors may improve the outcome of this devastating infection. However, until new approaches for treatment develop, effective preventive measures are urgently needed.

Correlation between in vitro and in vivo activity of antifungal agents against Candida species.

The correlation between antifungal susceptibility testing and in vivo response to antifungal therapy was examined in experimental murine candidiasis. In vitro susceptibility testing was done using a microbroth dilution method. Twenty-two Candida albicans, 4 Candida lusitaniae, and 2 Candida krusei isolates were tested against fluconazole, flucytosine, and amphotericin B. In vivo antifungal activity was tested in murine hematogenous candidiasis. Normal CF1 mice were infected with each of the C. albicans strains; immunosuppressed CF1 mice were inoculated with C. lusitaniae or C. krusei. Mice received various doses of antifungal agents, and survival was monitored for 21 days. Kidney fungal burden was examined on day 4. Antifungal therapy significantly prolonged survival and reduced tissue counts in animals infected with organisms susceptible to the agent tested (P < .05). In vitro resistance to a drug predicted its lack of in vivo activity. These results appear to correlate well with outcome of murine hematogenous candidiasis.

Comparison of the efficacy of polyenes and triazoles against hematogenous Candida krusei infection in neutropenic mice.

Candida krusei is reported to cause serious infections in immunocompromised patients, particularly those receiving prophylaxis with antifungal azoles. Treatment of this infection can be very challenging. The efficacy of amphotericin B, liposomal amphotericin B (three dosages), fluconazole, and D0870 (a new experimental oral bis-triazole) was assessed in a CF1 mouse model of hematogenous C. krusei infection. Increased survival time and reduced kidney fungal burden were achieved with treatment with amphotericin B at 2 mg/kg/day and liposomal amphotericin B at 8 and 15 mg/kg/day. D0870 at 25 mg/kg/day increased survival time but had no effect on clearance from organs, while the survival and clearance from organs of mice treated with fluconazole at a dose of 100 mg/kg/day did not differ from those of untreated animals. These findings suggest that deoxycholate and liposome-encapsulated amphotericin B are active against disseminated C. krusei infection in neutropenic mice and confirm the in vitro and in vivo resistance of this species to fluconazole.