Antimicrobial prophylaxis is highly successful in preventing PJP in patients with immunosuppression from a diverse range of causes, including solid-organ transplantation and malignancy.r Guidelines have been published for the use of PJP prophylaxis in patients with cancer, including blood and marrow transplant (BMT) recipients.rr In a meta-analysis of randomized trials of PJP prophylaxis in immunocompromised patients without HIV infection, it was concluded that, in adults, prophylaxis is warranted when the risk of PJP is higher than 3.5%.r
Trimethoprim/sulfamethoxazole (TMP-SMX) is the first-line prophylactic agent for PJP prevention in adults and children. The effectiveness of TMP-SMX prophylaxis was illustrated in a Cochrane review of 13 randomised controlled trials that included 1412 immunocompromised patients without HIV infection who had undergone autologous hematopoietic cell or solid organ transplantation or had a haematologic malignancy.r TMP-SMX prophylaxis was associated with an 85 % reduction in the occurrence of PJP compared with no prophylaxis or fluoroquinolone prophylaxis, which is inactive against Pneumocystis (relative risk [RR] 0.15, 95% CI 0.04-0.62). The number needed to treat to prevent one infection was 19. Mortality due to PJP was also significantly reduced (RR 0.17, 95% CI 0.03-0.94), although all-cause mortality was not. Using data from two trials included in the review, no differences in efficacy were found between once-daily and thrice-weekly administration schedules for TMP-SMX.
In addition TMP-SMX has superior efficacy and activity against pathogens other than Pneumocystis jiroveci (e.g. common bacterial infections, listeriosis, nocardiosis and toxoplasmosis), low cost and ease of access.
The optimal dose schedule for TMP-SMX is not clear due to the limited number of studies comparing regimens in patients with malignancy or undergoing stem cell transplantation.r In the absence of clear evidence to support various dosing regimens, Cooley et al support the use of once-daily dosing in adults with SS (single strength) or DS (double strength) or thrice-weekly dosing with DS.
For those who are intolerant of TMP-SMX, desensitisation should be attempted when possible. Desensitisation should be considered for all patients with TMP-SMX-associated rash however it is contraindicated in patients with a history of drug rash with eosinophilia and systemic symptoms (DRESS) or Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Desensitisation is only effective if the therapy is uninterrupted; if strict adherence is unlikely, consider an alternative to TMP-SMX.r Read more about the sulphonamide desensitisation protocol.
There are no sufficiently powered trials on which to base a recommendation for alternative prophylactic regimens in patients with malignancies.r
Dapsone is effective, but inferior to TMP/SMX, and therefore, it is only to be used as an alternative agent in patients whom TMP-SMX is contraindicated or not tolerated.
Dapsone should not be given to patients with G6PD deficiency or to patients who have experienced severe side-effects with TMP-SMX, as cross reactions can occur.
- test for glucose-6-phosphate dehydrogenase (G6PD) deficiency before starting treatment with dapsone—seek expert advice if the patient is G6PD deficient
- the cross-reactivity rate between dapsone and sulfamethoxazole is approximately 20%; do not use dapsone in patients with immediate hypersensitivity or another severe reaction (e.g. drug rash with eosinophilia and systemic symptoms [DRESS] or Stevens–Johnson syndrome / toxic epidermal necrolysis [SJS/TEN]) to sulfonamides
Given the high rates of adverse effects associated with parenteral therapy in adults, including pancreatitis, hypoglycaemia (27%) and nephrotoxicity (25%), aerosolisation is the preferred mode of delivery for prophylaxis.r
Unequal distribution in the lungs can lead to breakthrough PJP in the upper lobes. Nursing staff must wear full PPE during preparation including the wearing of a P2 or N95 respirator mask. Administration must occur in an isolated and well ventilated (ideally negative-pressure) room and health care workers should not stay in the room for the whole treatment.
Nebulised pentamidine is usually well tolerated, with the major side-effects being coughing and wheezing, which can be prevented by the use of inhaled beta-agonists.r It should be avoided in patients with a smoking or asthma history.
Few clinical trials have been undertaken in patients with malignancy. There is data to suggest that aerosolised pentamidine may be inferior when used prophylactically in allogeneic transplant recipients.r
Atovaquone is also proven but less efficacious than TMP/SMX. One such trial that compared atovaquone to TMP-SMX for PJP prophylaxis in 39 patients following autologous SCT showed that atovaquone is well tolerated in this patient population.r No firm conclusions can be reached about the relative efficacy of atovaquone since the number of patients studied was small and no patient in either arm developed PJP, although the treatment-associated adverse event rate was significantly higher in patients receiving TMP-SMX (40% vs 0%, P<0.003).
Summary of dosing schedules for PJP chemoprophylaxis
||160 + 800 mg (one DS tablet) orally, daily
80 + 400 mg (one SS tablet) orally, daily
160 + 800 mg (one DS tablet) orally, three times a week*
|Fever, rash, neutropenia, gastrointestinal upset, transaminase elevation
- in clinical practice many institutions administer one DS tablet TWICE daily TWICE weekly (e.g. Monday and Thursday)
- the pre-emptive dose during conditioning therapy differs from standard prophylaxis dosing
||100 mg orally, daily
||Fever, rash, gastrointestinal upset, methemoglobinemia, haemolytic anaemia (check for G6PD deficiency)
- addition of trimethoprim to dapsone does not appear to add to efficacy in prophylaxis and so is not recommended
- dapsone is not myelosuppressive
- reduce dapsone dose to 50 mg daily in patients who develop toxicity (methaemoglobinaemia, chemical haemolysis)
- azole antifungal agents elevate dapsone levels so concomitant use should be avoided or monitored with caution.
||300 mg inhaled through nebuliser, every 4 weeks (administered through a jet-nebuliser producing a droplet size of 1-2 microns)
||Cough, wheezing, extrapulmonary pneumocystosis
||1500 mg orally, daily with a high-fat meal
||Gastrointestinal distress, rash
*Either non-consecutive or consecutive days is acceptable. DS=double strength; SS= single strength.
Adapted from Cooley et al. Internal Medicine Journal © 2014r