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Treatment and prevention of Pneumocystis carinii (P. jirovecii) pneumonia in non-HIV-infected patients

Last literature review version 17.3: September 2009  |  This topic last updated: October 1, 2009   (More)

INTRODUCTION — Pneumocystis pneumonia (PCP) is a potentially life-threatening infection that occurs in immunocompromised individuals. The nomenclature for the species of Pneumocystis that infects humans has been changed from Pneumocystis carinii to Pneumocystis jirovecii; this was done to distinguish it from the species that infects rats.

HIV-infected patients with a low CD4 count are at the highest risk of PCP. Others at substantial risk include hematopoietic stem cell and solid organ transplant recipients; those with cancer (particularly hematologic malignancies); and those receiving glucocorticoids, chemotherapeutic agents, and other immunosuppressive medications.

The treatment and prophylaxis of PCP in patients without HIV infection will be reviewed here. PCP in HIV-infected patients and the epidemiology, clinical manifestations, and diagnosis of PCP in non-HIV-infected patients are discussed separately. (See "Prophylaxis against Pneumocystis carinii (P. jirovecii) in HIV-infected patients" and "Treatment of Pneumocystis carinii (P. jirovecii) infection in HIV-infected patients" and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis carinii (P. jirovecii) pneumonia in non-HIV-infected patients".)

TREATMENT

Trimethoprim-sulfamethoxazole — We recommend trimethoprim-sulfamethoxazole (TMP-SMX) as the treatment of choice for PCP in non-HIV-infected patients (table 1). Large randomized trials have proven the efficacy of TMP-SMX in patients with HIV infection, whereas efficacy in patients without HIV infection has only been shown in a few small observational studies [1-3] and one comparative randomized trial [4]. (See "Treatment of Pneumocystis carinii (P. jirovecii) infection in HIV-infected patients".)

The standard dose of TMP-SMX is 15 to 20 mg/kg intravenously or orally daily in three or four divided doses (table 1). Dosing of TMP-SMX is based upon the TMP component and expressed as mg/kg per day of TMP. Because TMP-SMX has excellent bioavailability, oral administration is appropriate for all patients who have a functioning gastrointestinal tract.

Other agents — Alternative drugs for the treatment of mild to moderate PCP have been studied primarily in HIV-infected patients. For patients with mild or moderate PCP who are unable to tolerate TMP-SMX, we suggest atovaquone (750 mg orally twice daily). Other regimens that may be used for mild to moderate PCP include clindamycin plus primaquine, and trimethoprim plus dapsone (table 1). Patients should be tested for glucose-6-phosphate dehydrogenase deficiency before taking dapsone or primaquine. (See "Treatment of Pneumocystis carinii (P. jirovecii) infection in HIV-infected patients".)

Patients with severe PCP who have a contraindication to TMP-SMX should receive intravenous pentamidine (table 1). In a randomized trial of 50 patients with PCP, intravenous pentamidine (4 mg/kg once daily) was as effective as TMP-SMX [4]. However, pentamidine is not often used, since it is associated with greater toxicity (eg, hypotension, hypoglycemia, nephrotoxicity, and pancreatitis) and must be administered parenterally. We reserve intravenous pentamidine for patients with severe infection who are unable to tolerate TMP-SMX. We give intravenous pentamidine to patients with mild or moderate PCP only when all of the alternative regimens are contraindicated.

Clindamycin plus primaquine may be used as an alternative regimen in patients with severe PCP who have failed TMP-SMX or intravenous pentamidine. The efficacy of this approach was illustrated in a meta-analysis of salvage treatment of 456 patients with HIV and 41 non-HIV-infected patients with confirmed PCP who did not improve with conventional antipneumocystis therapy (most commonly TMP-SMX or intravenous pentamidine) [5]. The combination of clindamycin plus primaquine was the most effective alternative treatment in such patients. (See "Treatment of Pneumocystis carinii (P. jirovecii) infection in HIV-infected patients".)

The cyst wall of P. jirovecii contains beta-D-glucan, the synthesis of which is inhibited by echinocandins (eg, caspofungin) [6]. However, the echinocandins have little documented value in the treatment of PCP in humans, and progression of PCP has been reported in patients receiving echinocandins [7].

Duration of therapy — The duration of therapy for PCP in patients without HIV infection has not been adequately studied, but a 14 day regimen is usually suggested in the literature. In contrast, the duration of therapy is 21 days in patients with HIV infection due to a greater risk of relapse with 14 days of therapy and the greater organism burden and slower clinical response [8]. Given the more fulminant presentation and worse outcomes in non-HIV-infected patients, we suggest treating for 21 days despite the lack of evidence supporting this duration. (See 'Outcomes' below and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis carinii (P. jirovecii) pneumonia in non-HIV-infected patients", section on 'Clinical manifestations'.)

Non-HIV-infected patients with PCP should start to show clinical improvement by the seventh day of therapy. Patients who are not improving after seven days of therapy are considered to have treatment failure and are treated in the same way as HIV-infected patients who fail initial therapy. (See "Treatment of Pneumocystis carinii (P. jirovecii) infection in HIV-infected patients", section on 'Treatment failure'.)

Adjunctive glucocorticoids — Adjunctive glucocorticoids are recommended in HIV-infected patients with moderate or severe PCP because their use improves clinical outcomes and mortality without increasing the risk of other opportunistic infections. (See "Treatment of Pneumocystis carinii (P. jirovecii) infection in HIV-infected patients", section on 'Use of corticosteroids'.)

In contrast, there is no clear evidence of efficacy for adjunctive glucocorticoids for the treatment of PCP in HIV-negative patients as illustrated by the following observations:

  • A retrospective study of 30 non-HIV-infected patients with severe PCP showed that the 16 patients who received the equivalent of ≥60 mg of prednisone per day had a significantly shorter duration of mechanical ventilation, ICU admission, and supplemental oxygenation than the 14 patients who received the equivalent of ≤30 mg of prednisone per day or were on a glucocorticoid taper [9]. However, similar rates of mechanical ventilation and in-hospital mortality were observed.
  • A second retrospective study of 31 non-HIV-infected patients with PCP also found no difference in the need for mechanical ventilation or mortality between the glucocorticoid-treated and untreated groups [10].

The available limited data do not provide support for the routine use of adjunctive glucocorticoids in non-HIV-infected patients with PCP. On the other hand, the greater degree of inflammation in the lungs of non-HIV-infected patients provides a rationale for glucocorticoid therapy [8].

Given the fulminant course and high mortality in non-HIV-infected patients with moderate to severe PCP, we suggest the use of glucocorticoid therapy in patients who, while breathing room air, have an arterial blood gas measurement that shows a partial pressure of oxygen ≤70 mmHg or an alveolar-arterial (A-a) oxygen gradient ≥35 mmHg, or hypoxemia on pulse oximetry. The glucocorticoid regimen is shown in the Table (table 1). (See "Treatment of Pneumocystis carinii (P. jirovecii) infection in HIV-infected patients", section on 'Use of corticosteroids'.)

Patients who do not meet the above criteria for glucocorticoid therapy but are already being treated for some other reason (eg, graft-versus-host disease) should continue their current regimen.

OUTCOMES — In the absence of appropriate antibiotic therapy, the mortality rate from PCP in non-HIV-infected patients is 90 to 100 percent [1]. The outcomes in non-HIV-infected patients treated for PCP are generally worse than in HIV-infected patients; mortality from PCP in patients with HIV infection is approximately 10 to 20 percent compared with 35 to 50 percent in those without HIV [11-14]. Patients with cancer have the highest mortality rates [14,15]. Non-HIV-infected patients with PCP also have higher rates of hospitalization and intensive care unit admission [12].

Severe PCP is associated with higher mortality rates [12,16]. As an example, in a retrospective review of 30 non-HIV-infected patients with PCP and respiratory failure, the mortality rate was 67 percent [16]. Mortality was associated with an elevated APACHE III score on the day of ICU admission, delay in intubation, duration of mechanical ventilation, and the development of pneumothorax [16]. (See "Predictive scoring systems for the severity of illness in the intensive care unit", section on 'APACHE score'.)

INFECTION CONTROL — Hospitalized patients with PCP should be assigned to standard precautions, although they should not be placed in the same room with other immunocompromised individuals due to the potential for person-to-person spread [17].

PROPHYLAXIS

Indications — Guidelines have been published for the use of PCP prophylaxis among patients with cancer, including hematopoietic stem cell transplant (HCT) recipients [18,19]. Although there are no published guidelines for the use of PCP prophylaxis among solid organ transplant recipients, it is standard practice to administer prophylaxis in this population. There are no published guidelines for PCP prophylaxis among patients with rheumatologic diseases receiving immunosuppressive drugs, but some advocate its use in such patients when they are receiving high-dose immunosuppressive therapy [20,21].

In a meta-analysis of randomized trials of PCP prophylaxis in immunocompromised patients without HIV infection, it was concluded that prophylaxis is warranted when the risk of PCP is higher than 3.5 percent in adults, and might be indicated at lower incidence rates in children since children experience fewer medication-related adverse effects [22].

Individuals with the following risk factors should receive PCP prophylaxis based upon the evidence for substantial risk of PCP:

  • Patients receiving a glucocorticoid dose equivalent to ≥20 mg of prednisone daily for one month or longer who also have another cause of immunocompromise (eg, certain hematologic malignancies or a second immunosuppressive drug) [13,18,19,23-25].
  • Patients receiving alemtuzumab should receive PCP prophylaxis for a minimum of two months after completion of therapy or until the CD4 count is >200 x 10(7) cells/microL, whichever occurs later [19,26].
  • Patients receiving concomitant temozolomide and radiotherapy, until recovery of lymphopenia [19,27].
  • Patients with acute lymphocytic leukemia [19].
  • Allogeneic HCT recipients beginning after engraftment and continuing for as long as immunosuppressive therapy is given and/or the CD4 count is <200 cells/microL [18,19].
  • Selected autologous HCT recipients, including those who have an underlying hematologic malignancy, such as lymphoma, myeloma, or leukemia, have received intense conditioning regimens, have undergone graft manipulations (eg, CD34 selection), or have recently received purine analogs [18,19].
  • Solid organ transplant recipients, often for at least six months to one year following transplantation and during periods of high doses of immunosuppressive medications (eg, during treatment for acute rejection).
  • Patients with certain primary immunodeficiencies (eg, severe combined immunodeficiency, idiopathic CD4 T-lymphocytopenia, hyper-IgM syndrome) [28,29].
  • Some experts also recommend PCP prophylaxis for patients receiving a purine analog, such as fludarabine, or another T-cell depleting agent [19].
  • Some authorities recommend PCP prophylaxis for patients receiving certain combinations of immunosuppressive drugs. As an example, PCP prophylaxis should be considered in patients treated with TNF-alpha inhibitors who are also receiving high-dose glucocorticoids or other intensive immunosuppression. (See "Tumor necrosis factor-alpha inhibitors: Risk of bacterial, viral, and fungal infections", section on 'Pneumocystis carinii (jirovecii)',).

Among patients with rheumatologic diseases, prophylaxis is usually given to those who are treated with significant doses of glucocorticoids (eg, ≥20 mg of prednisone daily for one month or longer) in combination with a second immunosuppressive drug, particularly a cytotoxic agent (eg, cyclophosphamide), as is commonly used in Wegener's granulomatosis [20,21,24,25,30-32]. Patients with polymyositis/dermatomyositis who have interstitial pulmonary fibrosis may be at increased risk for PCP with glucocorticoids alone [33]. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis carinii (P. jirovecii) pneumonia in non-HIV-infected patients", section on 'Immunosuppressive drugs' and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis carinii (P. jirovecii) pneumonia in non-HIV-infected patients", section on Rheumatologic disease.)

The risk with methotrexate alone or in combination with low doses of glucocorticoids, as is often used in rheumatoid arthritis, does not appear to warrant prophylaxis [31]. In contrast, patients with Wegener's granulomatosis receiving methotrexate in combination with high doses of glucocorticoids should receive prophylaxis [32].

Some clinicians have been hesitant to use TMP-SMX for PCP prophylaxis in patients receiving methotrexate due to concern for myelosuppression. However, prophylactic doses of TMP-SMX appear to be safe in patients with Wegener's granulomatosis receiving methotrexate [32,34].

PCP prophylaxis should be considered in patients with other conditions that cause immunocompromise based upon their risk of PCP. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis carinii (P. jirovecii) pneumonia in non-HIV-infected patients", section on 'Risk factors'.)

Efficacy — PCP prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) is highly effective and it is therefore considered the first-line agent. This approach has been recommended in several guidelines by major organizations [18,19,23]. In a retrospective study from Denmark that identified 50 cases of PCP in patients without HIV infection during 2002-2004, the majority of patients (82 percent) never received PCP prophylaxis, whereas 16 percent had PCP prophylaxis discontinued months prior to diagnosis [35].

Trimethoprim-sulfamethoxazole — The effectiveness of TMP-SMX prophylaxis was illustrated in a meta-analysis of 12 randomized controlled trials that included 1245 immunocompromised patients without HIV infection who had undergone autologous bone marrow or solid organ transplantation or had a hematologic malignancy [22]. Two of the trials compared TMP-SMX to another agent with activity against Pneumocystis (atovaquone in one trial and sulfadoxine with pyrimethamine in one trial). The remaining trials compared various dosing regimens of TMP-SMX, or compared TMP-SMX to placebo, an agent without activity against Pneumocystis (eg, ciprofloxacin in renal transplant recipients for urinary tract infection prevention), or no prophylaxis.

TMP-SMX prophylaxis was associated with a 91 percent reduction in the occurrence of PCP (RR 0.09, 95% CI 0.02-0.32). The number needed to treat to prevent one infection was 15. Mortality due to PCP was also significantly reduced (RR 0.17, 95% CI 0.03-0.94), although all-cause mortality was not. No differences in efficacy were found between once-daily and thrice-weekly administration schedules for TMP-SMX.

A cost-effectiveness analysis in patients with Wegener's granulomatosis receiving immunosuppressive drugs suggested that PCP prophylaxis with TMP-SMX increased quality-adjusted life expectancy and reduced costs [36].

TMP-SMX is generally well-tolerated in patients without HIV infection, as a meta-analysis found that adverse events necessitating cessation of therapy occurred in only 3.1 percent of patients [22]. In contrast, TMP-SMX has a high rate of adverse effects in HIV-infected patients. (See "Prophylaxis against Pneumocystis carinii (P. jirovecii) in HIV-infected patients", section on 'Adverse reactions'.)

Other drugs — Other drugs that can been used for PCP prophylaxis in non-HIV-infected patients include atovaquone, dapsone with or without pyrimethamine, aerosolized or intravenous pentamidine, clindamycin plus primaquine, and sulfadoxine plus pyrimethamine (table 2).

Randomized trials in non-HIV-infected patients are limited [37,38].

One such trial that compared atovaquone to TMP-SMX for PCP prophylaxis in 39 patients following autologous hematopoietic stem cell transplantation showed that atovaquone is well-tolerated in this patient population [37]. 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 PCP.

The comparative efficacy of PCP prophylaxis regimens has been more extensively studied in HIV-infected patients. (See "Prophylaxis against Pneumocystis carinii (P. jirovecii) in HIV-infected patients", section on 'Comparative efficacy'.)

Regimens — Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended first-line agent for PCP prophylaxis based upon its proven efficacy [18,19,22,23,25]. It may be given as one double-strength tablet daily or three times per week or as one single-strength tablet daily. For those who are intolerant of TMP-SMX, desensitization should be attempted when possible. (See "Prophylaxis against Pneumocystis carinii (P. jirovecii) in HIV-infected patients", section on 'Rechallenge'.)

We suggest atovaquone as the agent of choice for patients who cannot tolerate TMP-SMX, particularly in hematopoietic stem cell transplant recipients given its lack of bone marrow toxicity. Dapsone (with or without pyrimethamine) is a reasonable alternative. Other possible regimens include aerosolized or intravenous pentamidine, clindamycin plus primaquine, and sulfadoxine plus pyrimethamine (table 2). (See "Prophylaxis against Pneumocystis carinii (P. jirovecii) in HIV-infected patients", section on 'Regimens'.)

An additional benefit of TMP-SMX, and dapsone in combination with pyrimethamine, is that these regimens provide protection against toxoplasmosis. TMP-SMX also prevents some bacterial infections, such as pneumococcal, nocardial, and listerial infections.

PCP prophylaxis should be continued until the risk factor for the disease is no longer present [18,19,23]. (See 'Indications' above.)

Caution should be exercised in discontinuation of PCP prophylaxis in patients who have received high-dose glucocorticoids and/or cyclophosphamide, since prolonged immunosuppression may persist after discontinuation of such agents. Although the CD4 count has not been shown to correlate with risk of PCP in non-HIV-infected patients, some experts have suggested discontinuing prophylaxis only in patients who have had a CD4 count >200 cells/microL for at least six months [21].

Hematopoietic stem cell transplant recipients — PCP prophylaxis regimens in hematopoietic stem cell transplant (HCT) recipients vary according to protocols at different transplantation centers. Despite its proven efficacy, many hematologists/oncologists avoid using TMP-SMX in HCT recipients because of concern for bone marrow toxicity. However, evidence for myelosuppression at prophylactic doses is lacking. Some have suggested using folinic acid supplementation (leucovorin) in HCT recipients who are receiving TMP-SMX to prevent bone marrow toxicity, although others avoid leucovorin due to reports of reduced efficacy of TMP-SMX when combined with folinic acid in the treatment of PCP [18,39,40].

Despite the limited data in HCT recipients, many prefer atovaquone to TMP-SMX because it does not cause myelosuppression. However, atovaquone does not possess antibacterial activity (in contrast to TMP-SMX) and is significantly more expensive than other regimens.

With respect to dapsone, there are concerns about methemoglobinemia and other hematologic toxicity, although a case-control study in HCT recipients failed to identify any hematologic toxicity with dapsone among patients allergic to TMP-SMX [41]. The usual dose is 100 mg/day but, to minimize toxicity, some use dapsone at a dose of 50 mg/day plus pyrimethamine 50 mg orally twice weekly. Patients should be tested for glucose-6-phosphate dehydrogenase deficiency before taking dapsone.

Other options include aerosolized or intravenous pentamidine, and sulfadoxine in combination with pyrimethamine, which is a folic acid antagonist (table 2). Patients given pyrimethamine with either sulfadoxine or dapsone should therefore also receive folinic acid. These agents are discussed in detail separately. (See "Prophylaxis against Pneumocystis carinii (P. jirovecii) in HIV-infected patients", section on 'Regimens'.)

Systemic lupus erythematosus — Some data suggest that sulfonamide-containing antibiotics, including TMP-SMX, can cause exacerbations of systemic lupus erythematosus (SLE), particularly in patients with adverse reactions to these agents. As a result, many rheumatologists avoid TMP-SMX prophylaxis in patients with SLE. We suggest atovaquone as an alternative agent in such patients who require PCP prophylaxis (table 2). (See "Overview of the therapy and prognosis of systemic lupus erythematosus in adults", section on 'Avoidance of specific medications'.)

SUMMARY AND RECOMMENDATIONS

PCP treatment

  • Pneumocystis pneumonia (PCP) is a potentially life-threatening infection that occurs in immunocompromised individuals, especially in those with HIV, but also in hematopoietic stem cell and solid organ transplant recipients; those with cancer (particularly hematologic malignancies); and those receiving glucocorticoids, chemotherapeutic agents, and other immunosuppressive medications. (See 'Introduction' above.)

  • We suggest using adjunctive glucocorticoids in non-HIV-infected patients who, while breathing room air, have an arterial blood gas measurement that shows a partial pressure of oxygen ≤70 mmHg or an alveolar-arterial (A-a) oxygen gradient ≥35 mmHg, or hypoxemia on pulse oximetry. (Grade 2B). (See 'Adjunctive glucocorticoids' above.)

Outcomes of PCP

  • The outcomes for immunocompromised patients without HIV infection treated for PCP are generally worse than in those with HIV infection; mortality from PCP in patients with HIV is approximately 10 to 20 percent compared with 35 to 50 percent in those without HIV. (See 'Outcomes' above.)

Infection control for PCP

  • Hospitalized patients with PCP should be assigned to standard precautions, although they should not be placed in the same room with other immunocompromised individuals due to the potential for person-to-person spread. (See 'Infection control' above.)

PCP prophylaxis

  • We recommend PCP prophylaxis for the following high-risk groups: Patients receiving a glucocorticoid dose equivalent to ≥20 mg of prednisone daily for one month or longer who also have another cause of immunocompromise; allogeneic hematopoietic stem cell and solid organ transplant recipients; patients with acute lymphocytic leukemia; patients receiving certain immunosuppressive drugs (eg, alemtuzumab, temozolomide in conjunction with radiotherapy); and selected autologous hematopoietic stem cell transplant recipients (Grade 1A). (See 'Indications' above.)

  • We suggest PCP prophylaxis for patients with rheumatologic diseases who are treated with significant doses of glucocorticoids (eg, ≥20 mg of prednisone daily for one month or longer) in combination with a second immunosuppressive drug, particularly a cytotoxic agent (eg, cyclophosphamide), as is commonly used in Wegener's granulomatosis (Grade 2B). (See 'Indications' above.)

  • We suggest using an agent other than TMP-SMX, such as atovaquone, in patients with systemic lupus erythematosus (SLE) who require prophylaxis due to the risk that TMP-SMX may cause an SLE flare (Grade 2C).

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