Abstract

Background

Pneumocystis pneumonia (PCP) is a disease affecting immunocompromised patients. PCP among these patients is associated with significant morbidity and mortality.

Objectives

To assess the effectiveness of PCP prophylaxis among non‐HIV immunocompromised patients; and to define the type of immunocompromised patient for whom evidence suggests a benefit for PCP prophylaxis.

Search methods

Electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE and EMBASE (to March 2014), LILACS (to March 2014), relevant conference proceedings; and references of identified trials.

Selection criteria

Randomised controlled trials (RCTs) or quasi‐RCTs comparing prophylaxis with an antibiotic effective against PCP versus placebo, no intervention, or antibiotic(s) with no activity against PCP; and trials comparing different antibiotics effective against PCP among immunocompromised non‐HIV patients. We only included trials in which Pneumocystis infections were available as an outcome.

Data collection and analysis

Two review authors independently assessed risk of bias in each trial and extracted data from the included trials. We contacted authors of the included trials to obtain missing data. The primary outcome was documented PCP infections. Risk ratios (RR) with 95% confidence intervals (CI) were estimated and pooled using the random‐effects model.

Main results

Thirteen trials performed between the years 1974 and 2008 were included, involving 1412 patients. Four trials included 520 children with acute lymphoblastic leukemia and the remaining trials included adults with acute leukemia, solid organ transplantation or autologous bone marrow transplantation. Compared to no treatment or treatment with fluoroquinolones (inactive against Pneumocystis), there was an 85% reduction in the occurrence of PCP in patients receiving prophylaxis with trimethoprim/sulfamethoxazole, RR of 0.15 (95% CI 0.04 to 0.62; 10 trials, 1000 patients). The evidence was graded as moderate due to possible risk of bias. PCP‐related mortality was also significantly reduced, RR of 0.17 (95% CI 0.03 to 0.94; nine trials, 886 patients) (low quality of evidence due to possible risk of bias and imprecision), but in trials comparing PCP prophylaxis against placebo or no treatment there was no significant effect on all‐cause mortality (low quality of evidence due to imprecision). Occurrence of leukopenia or neutropenia and their duration were not reported consistently. No significant differences in overall adverse events or events requiring discontinuation were seen comparing trimethoprim/sulfamethoxazole to no treatment or placebo (four trials, 470 patients, moderate quality evidence). No differences between once daily versus thrice weekly trimethoprim/sulfamethoxazole were seen (two trials, 207 patients).

Authors' conclusions

Given an event rate of 6.2% in the control groups of the included trials, prophylaxis for PCP using trimethoprim/sulfamethoxazole is highly effective among non‐HIV immunocompromised patients, with a number needed to treat to prevent PCP of 19 patients (95% CI 17 to 42). Prophylaxis should be considered for patients with a similar baseline risk of PCP.

Author(s)

Anat Stern, Hefziba Green, Mical Paul, Liat Vidal, Leonard Leibovici

Abstract

Plain language summary

Antibiotic treatment for the prevention of Pneumocystis pneumonia (PCP) in non‐HIV immunocompromised patients

Pneumocystis jiroveci is a fungus causing pneumonia mainly among patients with an impaired immune system, such as those infected with the human immunodeficiency virus (HIV), cancer patients, following organ transplantation, and patients receiving immune suppressive medications. Previous evidence shows that preventive antibiotic treatment (before the onset of the disease) could reduce mortality and morbidity from PCP among patients with HIV. We assessed whether this is also true for immunocompromised non‐HIV patients.

The patients included in the 13 trials we identified were adults with acute leukemia or solid organ transplantation and children with acute leukemia. This review of randomised controlled trials (RCTs) found that prophylaxis with trimethoprim/sulfamethoxazole, an antibiotic effective against PCP, significantly reduced the occurrence of PCP by 85%. We found no evidence for a reduction in all cause mortality. Confidence in the results for PCP was moderate to high, while for mortality it was low due to paucity of data. Preventive treatment was not associated with an increased rate of adverse events. Trimethoprim/sulfamethoxazole may be administered thrice weekly as effectively as once daily.

Based on our results, the number of people that need to be treated with trimethoprim/sulfamethoxazole for a prolonged period of time (ranging between several weeks to three years in the included trials) in order to prevent one episode of PCP infection was 19; when PCP infection occurs at a rate of about 6% without prophylaxis. Given the low rate of adverse events, prophylaxis should be considered for patients at similar risk of PCP.

Author(s)

Anat Stern, Hefziba Green, Mical Paul, Liat Vidal, Leonard Leibovici

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Our review shows that TMP/SMX prophylaxis is highly effective for prevention of PCP in patients with hematological malignancies, bone marrow transplantation and solid organ transplantation, both for children and adults. The overall prevalence of severe adverse events with TMP/SMX was low and did not result in treatment discontinuations. Given the observed efficacy of TMP/SMX with regard to PCP prevention, prophylactic TMP/SMX should be considered when the risk of PCP is above the rate we observed (6.2% overall). Clinical conditions in which the rates of PCP for patients not receiving prophylaxis might be above 6.2% include the following (Rodriguez 2004).

• Allogeneic bone marrow transplantation, during the six months post‐transplantation and afterwards with continued immunosuppression.
• Solid organ transplantation, in the first six months after transplantation.
• Acute lymphoblastic leukemia.

The PCP incidence is probably lower for most patients with solid malignancies. Patients receiving corticosteroids for primary or metastatic brain tumours may be at a higher risk warranting prophylaxis (Sepkowitz 1993). Among patients with collagen vascular diseases, only Wegener's granulomatosis has been associated with PCP rates above 2.5%. Quantitative incidence or relative risk data are lacking for patients treated with corticosteroids for chronic lung disease, inflammatory bowel disease, dermatological conditions or other conditions. Similarly, incidence data are lacking for acute myeloid leukemia, treatment with anti‐TNF agents, and newer biological treatments for hematological malignancies. During outbreaks of PCP among immunocompromised patients the incidence of PCP might be high enough to justify prophylaxis.

Using the data from our review and data available from studies conducted among HIV‐positive patients, TMP/SMX may be administered thrice weekly as the efficacy is similar to once daily administration. The adult dose of TMP/SMX most commonly administered in our review was 160/800 mg.

Implications for research 

Treatment with steroids for more than a month, in a dose equivalent to 20 mg of prednisone or more, may be a risk factor for the development of PCP (Yale 1996). Patients with collagen vascular diseases or inflammatory bowel disease receiving other immunosuppressive medication (including anti‐TNFalfa antibodies) are also at risk. Trials are needed for this large population of patients. Documentation of the actual adverse event rate associated with prophylaxis in clinical practice, especially leukopenia, will assist future decisions regarding prophylaxis in immunocompromised patients. The effect of prophylaxis on Pneumocystis resistance should be assessed in longitudinal studies or when TMP/SMX prophylaxis is used in practice.

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