A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation

Colby, Christine; McAfee, Steve; Sackstein, R.; Finkelstein, DM; Ja, Fishman; Spitzer, TR

doi:10.1038/sj.bmt.1702004

Cited by 93 publications

(73 citation statements)

References 13 publications

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“…11,22 Aerosolized pentamidine, atovaquone, or disulone are acceptable alternatives in case of intolerance but are probably less effective. [23][24][25][26] It should also be remembered that bone marrow toxicity is rare with the low doses of trimethoprim-sulfamethoxazole or sulfadoxinepyrimethamine used in prophylaxis, even in bone marrow recipients. 22,27 Following this study, we spread these recommendations among our team and only one case of PCP was observed during the following 2 years, as compared to 2-3 cases per year previously.…”

Section: Discussionmentioning

confidence: 99%

Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study

Castro

Neuville

Sarfati

et al. 2005

Bone Marrow Transplant

123

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Summary:Pneumocystis jiroveci pneumonia (PCP) has become a rare opportunistic infection due to the efficacy of prophylactic regimens. We conducted a 6-year retrospective study at our institution. A total of 13 cases of PCP were diagnosed among 519 patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) (2.5%). In three patients, PCP occurred within the first 5 months following HSCT. These severely immunocompromised patients were receiving prophylaxis and had concomitant aspergillosis that caused rapid death in two of them. In 10 other patients, PCP occurred a median of 14.5 months after HSCT. In all these patients, PCP prophylaxis had been discontinued, mainly because of the suspected bone-marrow toxicity of the prophylactic regimen. Median CD4 þ T cell count was 131/ll at diagnosis. Seven of these 10 patients were receiving immunosuppressive therapy for chronic graft versus host disease and three had a relapse of their hematological malignancy. One patient died from PCP despite high doses of cotrimoxazole. We conclude that PCP is still occurring after allogeneic HSCT, mainly as a late complication in patients in whom PCP prophylaxis had been prematurely discontinued. Long-term PCP prophylaxis should be maintained in patients receiving immunosuppressive drugs, and in those with low CD4 þ T cell counts or a relapse of their hematological malignancy. Pneumocystis jiroveci is an atypical fungus causing severe pneumonia in immunocompromised patients, particularly among allogeneic hematopoietic stem cell transplant (HSCT) recipients. 1 Before the use of prophylaxis, 5-16% of patients who received allogeneic marrow transplants developed P. jiroveci pneumonia (PCP) with a median onset at 9 weeks post-transplantation and a mortality rate of up to 76%. 2,3 Since the use of effective prophylaxis with trimethoprim-sulfamethoxazole, less than 5% of HSCT recipients still develop PCP. 2,4,5 However, recent studies have reported the occurrence of late onset PCP in patients discontinuing prophylaxis after the first 6 months posttransplant. 4,6 These reports gave rise to the recommendation of prescribing PCP prophylaxis throughout all periods of immunocompromise after engraftment. 7 These recommendations, however, do not clearly define parameters that could be used to determine the best time for discontinuing prophylaxis in HSCT recipients, as recent studies have shown a long-lasting defect in CD4 þ T cells in these patients. 8,9 Following the occurrence of PCP among three HSCT recipients in our center in 2002, we decided to undertake a retrospective study of all cases of PCP diagnosed among HSCT recipients within the last 6 years. Patients and methodsIn order to describe the clinical characteristics of recent cases of PCP, we retrospectively reviewed the charts of all patients who underwent an allogeneic HSCT and who developed PCP between January 1997 and December 2002 at our institution. Patients were identified through the computerized records of the laboratory of parasitology, by the identification of P...

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Section: Discussionmentioning

confidence: 99%

Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study

Castro

Neuville

Sarfati

et al. 2005

Bone Marrow Transplant

123

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“…for developing toxoplasmosis in immunocompromised patients with antibodies to Toxoplasma gondii (Machado et al, 1998). Safety and tolerability of atovaquone prophylaxis (1500 mg daily) has been demonstrated in autologous stem cell transplant recipients (Colby et al, 1999), but studies of efficacy in non-HIV-infected patients are lacking. Use of clindamycin (300 mg daily) and primaquine (15 mg daily) for prophylaxis in HIV-infected patients is associated with a higher risk for developing PCP than the TMP -SMX prophylaxis (Barber et al, 1996).…”

Section: Alternative Agentsmentioning

confidence: 99%

An analysis of the utilisation of chemoprophylaxis against Pneumocystis jirovecii pneumonia in patients with malignancy receiving corticosteroid therapy at a cancer hospital

et al. 2005

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Pneumocystis jirovecii pneumonia (PCP) is associated with high mortality in immunocompromised patients without human immunodeficiency virus infection. However, chemoprophylaxis is highly effective. In patients with solid tumours or haematologic malignancy, several risk factors for developing PCP have been identified, predominantly corticosteroid therapy. The aims of this study were to identify the potentially preventable cases of PCP in patients receiving corticosteroid therapy at a tertiary care cancer centre and to estimate the frequency of utilisation of chemoprophylaxis in these patients. Two retrospective reviews were performed. Over a 10-year period, 14 cases of PCP were identified: no cases were attributable to failed chemoprophylaxis, drug allergy or intolerance. During a 6-month period, 73 patients received high-dose corticosteroid therapy (X25 mg prednisolone or X4 mg dexamethasone daily) for X4 weeks. Of these, 22 (30%) had haematologic malignancy, and 51 (70%) had solid tumours. Fewer patients with solid tumours received prophylaxis compared to patients with haematologic malignancy (3.9 vs 63.6%, Po0.0001). Guidelines for PCP chemoprophylaxis in patients with haematologic malignancy or solid tumours who receive corticosteroid therapy are proposed. Successful primary prevention of PCP in this population will require a multifaceted approach targeting the suboptimal prescribing patterns for chemoprophylaxis.

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“…2,6 Atovaquone was generally well tolerated in patients intolerant to TMP/ SMX in that only 11% of patients were discontinued from the study. The potential benefit of TMP/SMX therapy against other pathogens will not be observed except for possible activity against toxoplasmosis.…”

Section: Discussionmentioning

confidence: 99%

“…Discontinuation of TMP/SMX therapy in up to 30% to 40% of cases had led to consideration of alternative drugs. 2,3 Atovaquone was previously shown to be effective for PCP prophylaxis at a dose of 1,500 mg once daily, 4-6 with a trend for lower efficacy at a dose of 750 mg once daily. 5 Reduced efficacy may have been related to poor tablet absorption.…”

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confidence: 99%

Pneumocystis carinii pneumonia prophylaxis with atovaquone in trimethoprim-sulfamethoxazole–intolerant orthotopic liver transplant patients: A preliminary study

Meyers

Borrego

Papanicolaou

2001

Liver Transplantation

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Pneumocystis carinii pneumonia (PCP) is an opportunistic infection associated with increased morbidity and mortality in solid-organ and bone-marrow transplant recipients. Side effects of trimethoprim-sulfamethoxazole (TMP/SMX) are frequent; therefore, we performed a preliminary study using atovaquone suspension, 750 mg once daily, for 1 year for the prevention of PCP in liver transplant recipients intolerant to TMP/SMX therapy. Twenty-eight patients were treated, and data were analyzed for efficacy and toxicity. Adverse events occurred in 14 subjects, mainly related to the gastrointestinal tract. P neumocystis carinii pneumonia (PCP) is an opportunistic infection associated with increased morbidity and mortality in solid-organ and bone-marrow transplant recipients. Before instituting PCP prophylaxis, the incidence in this population was reported to be up to 10%. 1 Trimethoprim-sulfamethoxazole (TMP/SMX) is almost 100% effective in preventing PCP in immunosuppressed patients, but its use is limited by the high incidence of adverse reactions (in up to 50% of patients), in particular, bone-marrow suppression and skin manifestations, both major concerns in transplant patients. Discontinuation of TMP/SMX therapy in up to 30% to 40% of cases had led to consideration of alternative drugs. 2,3 Atovaquone was previously shown to be effective for PCP prophylaxis at a dose of 1,500 mg once daily, 4-6 with a trend for lower efficacy at a dose of 750 mg once daily. 5 Reduced efficacy may have been related to poor tablet absorption. The new suspension formulation used in this study produced greater serum levels and efficacy. All these studies were performed in patients with HIV rather than in solid-organ transplant recipients, with presumably greater T 4 cell counts, and bone marrow transplant recipients. Our study, the first efficacy study in transplant patients, was designed to test the effectiveness of PCP prevention and monitor adverse effects of atovaquone at a dose of 750 mg/d of suspension formulation in this population that was intolerant to TMP/SMX. MethodsThis is a prospective study in which we enrolled 28 patients with solid-organ transplants (liver) who had been started on the standard PCP prophylaxis with TMP/SMX (80/400 mg/d), but because of drug-related side effects, the drug was withdrawn. Institutional review board approval was obtained. Intolerance to TMP/SMX included rash in 9 of 28 patients (32%); 1 patient each with Stephens-Johnson syndrome and angioedema; bone-marrow suppression in 14 of 28 patients (50%); diarrhea in 1 of 28 patients (3.5%); and elevated creatinine levels in 1 of 28 patients (3.5%; Table 1).Patients were treated with atovaquone suspension, 750 mg once daily or 250 mg three times daily, for 1 year. Patients who were pregnant, unable to ingest oral medication, or had diarrhea (Ͼ3 loose bowel movements a day for Ͼ4 days) were excluded. All patients were followed up prospectively. The total length of follow-up was 37 months. Adverse effects were observed at each patient's clinical follow-u...

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A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation

Cited by 93 publications

References 13 publications

Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study

Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study

An analysis of the utilisation of chemoprophylaxis against Pneumocystis jirovecii pneumonia in patients with malignancy receiving corticosteroid therapy at a cancer hospital

Pneumocystis carinii pneumonia prophylaxis with atovaquone in trimethoprim-sulfamethoxazole–intolerant orthotopic liver transplant patients: A preliminary study

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