Our study focused on PCP prophylaxis in patients receiving corticosteroid therapy for solid tumours or haematologic malignancy. Although the mechanisms of immune compromise in this population are multifactorial, corticosteroid therapy is a significant and readily identifiable risk factor, providing opportunity for modification of prescribing practices relevant to prophylaxis.
We have identified differences in proportion of patients with solid tumours receiving chemoprophylaxis compared to patients with haematologic malignancy. This may be attributed to the use of prescriber guidelines within some groups of haematology patients at PMCC. However, even in this group, a large proportion (36.4%) were not prescribed chemoprophylaxis, and the observed number of cases of PCP (seven out of 13) in haematology patients would suggest significant under-prescribing. Our estimation of incidence of PCP is based upon a number of assumptions, including consistency of hospital bed-days, indications for corticosteroid therapy, and proportion of solid and haematological malignancy treated at PMCC during the study period. Community-based prescription of corticosteroid therapy was not captured, leading to possible overestimation of incidence.
In our series, predisposing corticosteroid therapy was not administered in 11 patients with PCP. Only two cases had solid tumours, suggesting that the vast majority of at-risk patients with solid tumours can be identified on the basis of corticosteroid therapy. Nine cases had haematological malignancy. Given the heterogeneity of potential risk factors in this subgroup, distinct recommendations for prophylaxis must be based upon the underlying disease or predisposing chemotherapy. For example, chemoprophylaxis should be administered for 6 months following engraftment in allogeneic transplant recipients (Dykewicz, 2001
). This may be extended where immunosuppressive therapy or chronic GVHD persists beyond 6 months. Chemoprophylaxis should be considered in autologous stem cell transplant recipients with underlying lymphoma or leukaemia, intense conditioning regimens, or recently administered fludarabine or 2-chlorodeoxyadenosine (Rodriguez and Fishman, 2004
). Patients receiving alemtuzumab therapy should receive PCP chemoprophylaxis for at least 2 months after therapy (Keating et al, 2004
Trimethoprim–sulfamethoxazole prophylaxis Pneumocystis jirovecii
pneumonia prophylaxis is effective in patients not infected with HIV. Munoz et al (1997)
showed that TMP–SMX (administered on weekends only) eliminated all cases of PCP in a population of heart transplant recipients, compared to 4% incidence prior to prophylaxis. TMP–SMX has been shown to be an effective prophylaxis in patients with cancer (Hughes et al, 1977
). Daily and thrice weekly dosing regimens have demonstrated equivalence in patients with leukaemia (Hughes et al, 1987
; Rossi et al, 1987
), and twice weekly dosing has been shown to be effective in allogeneic transplant recipients (Souza et al, 1999
Precautions and contraindications
Contraindications to the TMP–SMX prophylaxis must be considered: documented hypersensitivity, megaloblastic anaemia due to folate deficiency, severe renal impairment and porphyria (Masters et al, 2003
). Caution must also be exercised in patients with impaired renal function, impaired hepatic function, severe drug allergies, glucose-6-phosphate dehydrogenase deficiency or blood dyscrasias. The potential for myelosuppression or drug interactions may necessitate consideration of an alternative prophylactic agent.
Myelosuppression has been associated with TMP–SMX use in children with acute lymphoblastic leukaemia (Woods et al, 1984
). Conversely, in a study of adult patients with acute leukaemia, no significant difference in myelosuppression was found when TMP–SMX (1 double strength tablet twice daily) was compared with placebo (Ward et al, 1993
). The original reports of efficacy of TMP–SMX for prophylaxis did not demonstrate significant myelosuppression (Hughes et al, 1977
). However, when used for prophylaxis against bacteraemia following autologous bone marrow transplantation, the time to neutrophil recovery is significantly longer in patients receiving TMP–SMX, compared to patients receiving ciprofloxacin (Imrie et al, 1995
). We recommend that an alternative prophylactic agent be used in at-risk patients with expected myelosuppression >7 days ().
Guidelines: PCP prophylaxis for patients with malignancy who receive corticosteroid therapy
In patients receiving chemotherapy with methotrexate, pancytopenia may occur if prophylactic TMP–SMX is used concurrently. The sulphamethoxazole component may increase toxicity of methotrexate by displacement from binding sites or reduced renal excretion (Masters et al, 2003
; Mathew and Grossman, 2003
). Small studies of children with acute leukaemia have demonstrated both increased free methotrexate (Ferrazzini et al, 1990
) and no change in plasma concentration of methotrexate (Beach et al, 1981
) when co-administered with TMP–SMX. In a study of patients with rheumatoid arthritis treated with up to 25
mg methotrexate per week who received TMP–SMX prophylaxis, no patient developed myelosuppression (Langford et al, 2003
). Conversely, there are a number of case reports of significant adverse events with the combination (Groenendal and Rampen, 1990
; Govert et al, 1992
; Steuer and Gumpel, 1998
; Saravana and Lalukotta, 2003
). We therefore recommend an alternative prophylactic agent in the setting of concurrent methotrexate therapy ().
Prophylaxis with TMP–SMX may not be tolerated in patients with advanced malignancy and reduced oral intake due to nausea or dysphagia. This may not have been a significant contributor to duration of prophylaxis in our series as only one out of 13 cases of PCP were utilising palliative care services at the time of diagnosis. Further study is required to address the question of appropriateness of commencing prophylaxis in the setting of palliation.
As demonstrated in HIV-infected patients (Martin et al, 1993
; Warnock and Rimland, 1996
; El-Sadr et al, 1998
), alternative prophylactic agents may be used, but are associated with higher rates of failure. Dapsone prophylaxis (50
mg three times per week) in allogeneic transplant recipients has a significantly higher incidence of failure when compared to TMP–SMX (Souza et al, 1999
). Aerosolised pentamidine (150
mg every 2 weeks or 300
mg per month) used after bone marrow transplantation has been shown to be inferior to TMP–SMX for PCP prophylaxis (Vasconcelles et al, 2000
) and associated with an increased risk 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
). Efficacy of clindamycin/primaquine for prophylaxis in patients with malignancy has not been reported.
Due to ease of administration and medical costs, we recommend that dapsone be used as second-line prophylaxis if TMP–SMX is contraindicated or not tolerated (). Nebulised pentamidine may also be used, and atovaquone may be considered in patients unable to tolerate TMP–SMX or dapsone.
Duration of prophylaxis
Although some have recommended that prophylaxis continue for 1 month after discontinuation of corticosteroids (Sepkowitz, 2002
), extended duration may be required with other concurrently administered immunosuppressive therapies. For example, cytarabine (Hughes et al, 1975
), cyclophosphamide (Kulke and Vance, 1997
), methotrexate (Kane et al, 1993
), fluorouracil (Hardy et al, 1987
) and fludarabine (Bastion et al, 1991
) have all been associated with development of PCP in the absence of corticosteroid treatment, although the absolute risk is unclear. We recommend continued primary prophylaxis or lifelong secondary prophylaxis in the setting of ongoing immunosuppression ().
Improving utilisation and prescriber practices
Suboptimal prescribing patterns for PCP chemoprophylaxis have been described in HIV-infected patients (Montaner et al, 1996
; Schwarcz et al, 1997
). Reasons are multifactorial, including patient reluctance or inability to access healthcare services (Schwarcz et al, 1997
), and failure of a treating clinician to identify the need for prophylaxis (Auperin et al, 1994
). In our patient population, it appears that prescriber factors are a greater barrier to PCP prophylaxis than poor access to healthcare, as no case of noncompliance was identified in the series of PCP cases, and patients were otherwise attending the regular review for treatment of underlying malignancy.
We have formulated guidelines for PCP chemoprophylaxis in patients receiving corticosteroid therapy for malignancy (). If applied to the cases of PCP observed at PMCC, 11 out of 13 cases (85%) could potentially have been prevented. Successful primary prevention of PCP in this population will require a multifaceted approach including academic detailing (one-on-one education of clinicians and hospital pharmacists). This has previously been successfully implemented to enhance the use of preventive medication for corticosteroid-induced osteoporosis (Naunton et al, 2004
). Novel strategies, such as generation of computerised clinical reminders (Kralj et al, 2003
) from pharmacy records of dispensed corticosteroid, should also be considered.