Approach
All patients with Pneumocystis pneumonia (PCP) are treated with antibiotics, but this treatment may be modified according to the severity of the disease.[98] In adults and children, the severity of PCP may be graded as follows:[32]
Mild-to-moderate PCP: arterial blood gas room air pO₂ ≥70 mmHg or an alveolar-arterial (A-a) gradient ≤35 mmHg.
Moderate-to-severe PCP: arterial blood gas room air pO₂ <70 mmHg or an alveolar-arterial (A-a) gradient >35 mmHg.
The patient treated most commonly for PCP will be:
An adult or adolescent who is HIV-positive
An adult or adolescent who is HIV-negative but otherwise immunocompromised
A child who is HIV-positive or who is at risk for HIV
Treatment duration for PCP is 21 days in HIV-positive patients and 14-21 days in all other patients.
Patients with respiratory compromise should be admitted to the hospital, possibly to the intensive care unit, and may require mechanical ventilation.
Patients who have no clinical symptoms or signs of PCP but who are HIV-positive, at risk of HIV, or otherwise immunocompromised may need primary PCP prophylaxis, depending on clinical characteristics.
Treatment of adults or adolescents with HIV infection
When PCP is suspected, treatment should be initiated immediately even prior to specific diagnosis. However, a definitive diagnosis should be sought when possible because of the potential of other opportunistic infections to have similar presentations in this group of patients.[32] The organism may still be demonstrated in sputum, fluids, and tissue after commencement of treatment.
Mild-to-moderate PCP
Defined as having both a room air pO₂ ≥70 mmHg and an A-a gradient ≤35 mmHg.
The treatment of choice is trimethoprim/sulfamethoxazole (TMP/SMX), given either intravenously or orally.[32] Adverse effects are common in HIV-positive patients.
Alternative treatments should only be used if patients are intolerant to TMP/SMX and cannot be managed supportively, or if there is evidence of treatment failure. Because patient symptoms and signs often worsen within the first 3-5 days of treatment, treatment failure is considered if the patient has worsening clinical status after at least 4-8 days of therapy.
Alternative treatment regimens include dapsone plus trimethoprim, clindamycin plus primaquine, or atovaquone. All patients should be checked for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to starting primaquine or dapsone, if possible.
The recommended duration of therapy for PCP is 21 days.[32]
Moderate-to-severe PCP
Defined by either a room air pO₂ <70 mmHg or an A-a gradient >35 mmHg.
Patients whose clinical examination reveals signs of respiratory compromise, such as tachypnea, tachycardia, cyanosis, or accessory muscle use, or hemodynamic compromise should be admitted immediately to the hospital, with consideration for admission to the intensive care unit if it appears that they will require either invasive or noninvasive mechanical ventilation.
Treatment of choice is intravenous TMP/SMX combined with a corticosteroid.[32][99] In these patients, there is good clinical evidence that adjuvant corticosteroids improve 1- and 3-month mortality and reduce the need for mechanical ventilation.[99] [
]
A short course of treatment does not usually result in significant immunocompromise. Alternative treatments should only be considered if patients are intolerant to TMP/SMX and cannot be managed supportively, or there is evidence of treatment failure. As patients often worsen within the first 3-5 days of treatment, treatment failure is considered if the patient has worsening clinical status after at least 4-8 days of therapy.
Alternative treatment regimens include either clindamycin plus primaquine, or intravenous pentamidine, both with an adjuvant corticosteroid. Clindamycin plus primaquine may be more effective and less toxic than intravenous pentamidine.[100]
All patients should be checked for G6PD deficiency prior to starting primaquine, if possible.
The recommended duration of therapy for PCP is 21 days.[32]
Treatment of children with or at risk of HIV infection
When PCP is suspected, treatment should be initiated immediately, even prior to specific diagnosis.
Mild-to-moderate PCP
Defined as having both a room air pO₂ ≥70 mmHg and an A-a gradient ≤35 mmHg.
The treatment of choice is TMP/SMX, given either intravenously or orally.[22]
Alternative treatments should only be considered if patients are intolerant to TMP/SMX and cannot be managed supportively, or if there is evidence of treatment failure after 5-7 days.
Alternative treatment regimens include intravenous pentamidine, atovaquone, dapsone plus trimethoprim, or primaquine plus clindamycin.[22]
All patients should be checked for G6PD deficiency prior to starting primaquine or dapsone, if possible.
The recommended duration of therapy for PCP is 21 days.
Moderate-to-severe PCP
Defined by either a room air pO₂ <70 mmHg or an A-a gradient >35 mmHg.
Children with moderate-to-severe PCP should be hospitalized and may require admission to an intensive care unit and possible mechanical ventilation.
The treatment of choice is intravenous TMP/SMX with a corticosteroid.[22]
Pentamidine may be used as an alternative if patients are intolerant to TMP/SMX and cannot be managed supportively, or if there is evidence of treatment failure.
The recommended duration of therapy for PCP is 21 days.
Treatment of adults or adolescents or children who are immunocompromised without HIV infection
There are specific recommendations for pharmacologic treatment of PCP in patients who do not have HIV infection but are otherwise immunocompromised, for example following transplantation or malignancy.[49][98][101] Local guidelines should be consulted for information on suitable regimens.
Patients who are not solid-organ transplant recipients.
The 2010 American Thoracic Society guidelines recommend TMP/SMX as the preferred treatment for PCP in immunocompromised adults. The alternative treatment options include intravenous pentamidine, atovaquone, or clindamycin plus primaquine.[98] Alternative regimens should only be used if the patient does not tolerate TMP/SMX or if there is clinical treatment failure after 4-8 days of TMP/SMX therapy. Recommended treatment duration is 21 days.
The 2014 Australian and New Zealand consensus guidelines for patients with hematologic and solid malignancies recommend TMP/SMX as the preferred PCP treatment in children and adults.[101] For mild-moderate disease, dapsone plus trimethoprim is an alternative first-line therapy and atovaquone is the second-line alternative. For moderate-severe disease, the alternatives are clindamycin plus primaquine and intravenous pentamidine. All patients should be checked for G6PD deficiency prior to starting primaquine or dapsone, if possible. Recommended treatment duration is 21 days.
Patients who are solid-organ transplant recipients:
The 2019 American Society of Transplantation guidelines also recommend TMP/SMX as the preferred PCP treatment in children and adult solid-organ transplant recipients.[49] Oral dosing may be considered in mild infections. In severe infections, intravenous pentamidine is the preferred second-line agent after TMP/SMX; however, it should be avoided in pancreas recipients due to the potential for islet cell necrosis. Other options for mild-moderate PCP include atovaquone or clindamycin plus primaquine, and options for mild-moderate or moderate-severe PCP include dapsone plus trimethoprim, or pyrimethamine plus sulfadiazine; however, these combinations regimens have not been studied adequately in children.[49] Recommended treatment duration is 14-21 days.
The adverse event rate to TMP/SMX may be less in HIV-negative patients than in HIV-positive patients.[102] The use of adjuvant corticosteroids in HIV-negative-associated severe PCP has been controversial with meta-analyses of observational studies reporting conflicting findings regarding mortality, including in hypoxemic patients.[61][103][104][105][106][107] Stronger conclusions about adjunctive corticosteroids for HIV-negative patients are precluded by a lack of randomized trials, and selection bias and small sample size in studies to date.
Primary prophylaxis of adults or adolescents with HIV infection and children with or at risk of HIV infection
Adult or adolescent: HIV-positive[32]
HIV-positive patients who have no clinical symptoms or signs of PCP require primary chemoprophylaxis in the following circumstances:
CD4 cell count <100 cells/microliter regardless of plasma HIV levels
CD4 cell count between 100 and 200 cells/microliter is plasma HIV RNA levels are above detection limits.
Prophylactic agent of choice is TMP/SMX in the absence of contraindications. Alternatives for patients, regardless of Toxoplasma gondii serostatus, include: dapsone plus pyrimethamine plus leucovorin, or atovaquone. Alternatives for patients who are seronegative for Toxoplasma gondii include dapsone, aerosolized pentamidine, or intravenous pentamidine. All patients should be checked for G6PD deficiency prior to starting dapsone, if possible.
In patients who are seropositive for Toxoplasma gondiiand who cannot tolerate TMP/SMX, alternative options for prophylaxis against both PCP and toxoplasmosis include dapsone plus pyrimethamine plus leucovorin, or atovaquone (with or without pyrimethamine) plus leucovorin. Patients receiving pyrimethamine plus sulfadiazine for treatment or suppression of toxoplasmosis do not require additional PCP prophylaxis.
PCP prophylaxis should be discontinued when patients have CD4 cell count ≥200 cells/microliter for ≥3 consecutive months. Discontinuing PCP prophylaxis in patients on antiretroviral medication with suppressed viral loads and CD4 counts 100 to 200 cells/microliter for ≥3 to 6 months may be considered.
PCP prophylaxis should be restarted in patients with CD4 count <100 cells/microliter regardless of the HIV viral load, and in patients with CD4 count ≥100 cells/microliter to <200 cells/microliter who do not have suppressed viral loads.
PCP prophylaxis should be continued for life in patients who develop PCP despite CD4 count >200 cells/microliter.
Children: HIV-positive or at risk for HIV[22]
Indications for primary prophylaxis in children without clinical symptoms or signs of PCP:
Age 1-12 months who are HIV-positive regardless of CD4 cell count or percentage
HIV-positive children ages 1 to <6 years with CD4 cell count <500 cells/microliter or CD4 percentage <15%
Age ≥6 to 12 years who are HIV-positive with CD4 cell count <200 cells/microliter or CD4 percentage <15%
HIV-indeterminate infants of HIV-positive mothers
Prophylactic agent of choice is TMP/SMX in the absence of contraindications. In patients who cannot tolerate TMP/SMX, other options include dapsone, atovaquone, or aerosolized pentamidine. Intravenous pentamidine may be considered in children ages >2 years when other options are not available.
All patients should be checked for G6PD deficiency prior to starting dapsone, if possible.
Children born to HIV-positive mothers should receive prophylaxis with TMP/SMX beginning at 4-6 weeks. Children who are HIV-positive at birth should be treated through their first year of life, at which time the need for ongoing PCP prophylaxis should be reassessed based on the age-specific CD4 count and percentage thresholds described previously. HIV-indeterminate infants of HIV-positive mothers should receive prophylaxis until they are determined to be HIV-uninfected.
Consider discontinuation of PCP prophylaxis after ART has been given for ≥6 months when:
CD4 percentage is ≥15% or CD4 cell count is ≥200 cells/microliter for patients ages ≥6 years
CD4 percentage is ≥15% or CD4 cell count is ≥500 cell/microliter for patients ages 1-6 years for >3 consecutive months
PCP prophylaxis should not be discontinued in HIV-infected infants ages <1 year.
After PCP prophylaxis has been discontinued, the CD4 percentage and CD4 count should be reassessed at least every 3 months and prophylaxis resumed based on the age-specific CD4 count and percentage thresholds described previously.
Primary prophylaxis of adults or adolescents or children who are immunocompromised without HIV infection
Guidelines have been published for PCP prophylaxis in patients with benign and malignant hematologic conditions, solid tumors, and solid-organ transplant recipients.[47][48][49][101][108][109]
Patients with benign and malignant hematologic conditions or solid malignancies
The 2010 American Thoracic Society guidelines recommend PCP prophylaxis for adults with hematologic and solid malignancies receiving cytotoxic chemotherapies, organ transplant recipients, and those treated with immunosuppressive regimens for inflammatory conditions.[98] Recommended options are with TMP/SMX, atovaquone, dapsone, and dapsone plus pyrimethamine plus leucovorin. All patients should be checked for G6PD deficiency prior to starting dapsone, if possible. Prophylaxis should be instituted when corticosteroids exceed a prednisone-equivalent dose of 20 mg/day for >1 month. Duration of prophylaxis is not discussed.
The 2014 Australian and New Zealand consensus guidelines for patients with hematologic and solid malignancies recommend PCP prophylaxis for specific groups of patients: all patients with acute lymphoblastic leukemia; allogeneic hematopoietic stem cell transplant recipients; children with acute myelocytic leukemia or lymphoma; children and selected high-risk adults with autologous hematopoietic stem cell transplant; patients with brain tumors, children with solid tumors undergoing myelosuppressive chemotherapy; and specific patients receiving specific chemotherapy regimens.[101] The first-line agent for prophylaxis is TMP/SMX in the absence of contraindications with alternative agents being atovaquone, dapsone, aerosolized pentamidine, or intravenous pentamidine. All patients should be checked for G6PD deficiency prior to starting dapsone, if possible. Prophylaxis should continue for 6 weeks after cessation of corticosteroids in patients receiving corticosteroid-containing regimens and in patients with ongoing immunosuppression (e.g., graft-versus-host disease) and may be continued for up to 12 months in patients who received chemotherapy regimens with high rates of late-onset PCP (such as alemtuzumab and fludarabine plus cyclophosphamide plus rituximab).
The 2016 European Conference on Infections in Leukaemia guidelines provide recommendations for PCP prophylaxis in children and adults with benign and malignant hematologic conditions.[108] Indications for prophylaxis in children include acute lymphoblastic leukemia, allogeneic hematopoietic stem cell transplant, treatment with alemtuzumab, severe combined immunodeficiency, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, HLA II combined immunodeficiency, and corticosteroid use (>0.4 mg/kg or 16 mg/day for ≥1 month) with consideration for prophylaxis for acute myeloid leukemia and solid tumors. In adults, indications for prophylaxis include acute lymphoblastic leukemia, allogeneic hematopoietic stem cell transplant, treatment with alemtuzumab, chemotherapy with fludarabine plus cyclophosphamide plus rituximab, and corticosteroid use (>20 mg/day prednisone equivalent for 4 weeks) with prophylaxis suggested for lymphoma treated with certain regimens, regimens containing nucleoside analogs (fludarabine, cladribine, mycophenolate), and brain tumors treated with high-dose corticosteroids and irradiation. TMP/SMX is the drug of choice for PCP prophylaxis, while atovaquone, dapsone, aerosolized pentamidine, or intravenous pentamidine are second-line agents. All patients should be checked for G6PD deficiency prior to starting dapsone, if possible. Duration of PCP prophylaxis for children and adults varies based on indication.
The 2020 German Society for Hematology and Medical Oncology guidelines for patients with hematologic malignancies and solid tumors recommend PCP prophylaxis in adults treated for acute lymphoblastic leukemia, those undergoing allogeneic hematopoietic stem cell transplant, and those treated with fludarabine plus cyclophosphamide plus rituximab, corticosteroids (>20 mg/day prednisone equivalent for 4 weeks), alemtuzumab, idelalisib, or temozolomide plus radiotherapy.[109] Prophylaxis should be considered in patients with lymphoma treated with certain regimens, patients treated with nucleoside analogs or long-term anti-CD20 monoclonal antibody therapy, patients with brain tumors treated with high-dose corticosteroids plus radiotherapy, and patients with CD4 count <200 cells/microliter. TMP/SMX is the first-choice agent and atovaquone, dapsone, and aerosolized pentamidine are second-line alternatives. All patients should be checked for G6PD deficiency prior to starting dapsone, if possible. Timing of initiation and duration of prophylaxis are not discussed except for idelalisib (where PCP prophylaxis should be initiated at the beginning of therapy and continued for 2-6 months after therapy is completed).
The 2018 American Society of Clinical Oncology and Infectious Diseases Society of America guidelines on antimicrobial prophylaxis in adults with cancer-related immunosuppression recommend PCP prophylaxis in those receiving chemotherapy regimens that are associated with a >3.5% risk for PCP infection (e.g., patients receiving ≥20 mg/day prednisone equivalents for ≥1 month or those receiving purine analogs).[47] TMP/SMX is the agent of choice with atovaquone, dapsone, and aerosolized pentamidine as alternative agents. All patients should be checked for G6PD deficiency prior to starting dapsone, if possible. Prophylaxis timing is related to postmyeloid reconstitution or engraftment after stem cell transplant, especially in the setting of post-engraftment augmented immunosuppression for the treatment of graft-versus-host disease.
Patients who are hematologic cell transplant recipients or solid-organ transplant recipients
The 2009 multisociety-sponsored North American and European guidelines for preventing infective complications following hematopoietic cell transplantation recommend PCP prophylaxis for all allogeneic hematopoietic cell transplant recipients and for autologous hematopoietic cell transplant recipients with significant immunosuppression (i.e., patients with underlying hematologic malignancies, those receiving intensive conditioning regimens or graft manipulation, or those who have recently received purine analogs or high-dose corticosteroids).[48] For allogeneic hematopoietic cell transplant recipients, PCP prophylaxis is recommended from engraftment until at least 6 months after transplantation. Initiating PCP prophylaxis for 1-2 weeks prior to transplantation may be considered on the basis of underlying disease, prior chemotherapy, and pretransplant conditioning regimens. For autologous hematopoietic cell transplant recipients with significant immunosuppression, PCP prophylaxis is recommended from engraftment until 3-6 months after transplantation. PCP prophylaxis should be extended for longer than 6 months in allogeneic or autologous hematopoietic cell transplant recipients who continue to receive immunosuppressive drugs (e.g., prednisone or cyclosporine) or have chronic graft-versus-host disease. The agent of choice is TMP/SMX in the absence of contraindications. In patients who cannot tolerate TMP/SMX, alternative options include atovaquone, dapsone, aerosolized pentamidine, or intravenous pentamidine. All patients should be checked for G6PD deficiency prior to starting dapsone, if possible.
The 2010 American Thoracic Society guidelines recommend PCP prophylaxis for adults with hematologic and solid malignancies receiving cytotoxic chemotherapies, organ transplant recipients, and those treated with immunosuppressive regimens for inflammatory conditions.[98] Recommended options are TMP/SMX, atovaquone, dapsone, and dapsone plus pyrimethamine plus leucovorin. All patients should be checked for G6PD deficiency prior to starting dapsone, if possible. Prophylaxis should be instituted when corticosteroids exceed a prednisone-equivalent dose of 20 mg/day for >1 month. Duration of prophylaxis is not discussed.
The 2016 European Conference on Infections in Leukaemia guidelines provide recommendations for PCP prophylaxis in children and adults with benign and malignant hematologic conditions.[108] Indications for prophylaxis in children are acute lymphoblastic leukemia, allogeneic hematopoietic stem cell transplant, treatment with alemtuzumab, severe combined immunodeficiency, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, HLA II combined immunodeficiency, and corticosteroids (>0.4 mg/kg or 16 mg/day prednisone for ≥1 month) with consideration for prophylaxis for acute myeloid leukemia and solid tumors. In adults, indications for prophylaxis are acute lymphoblastic leukemia, allogeneic hematopoietic stem cell transplant, treatment with alemtuzumab, chemotherapy with fludarabine plus cyclophosphamide plus rituximab, and corticosteroids (>20 mg/day prednisone equivalent for 4 weeks) with prophylaxis suggested for lymphoma treated with R-CHOP-14 or escalated BEACOPP, regimens containing nucleoside analogs (fludarabine, cladribine, mycophenolate), and brain tumors treated with high-dose corticosteroids and irradiation. TMP/SMX is the drug of choice for PCP prophylaxis, while atovaquone, dapsone, aerosolized pentamidine, or intravenous pentamidine are second-line agents. All patients should be checked for G6PD deficiency prior to starting dapsone, if possible. Duration of PCP prophylaxis for children and adults varies based on indication: from induction to end of maintenance (acute lymphoblastic leukemia in children and adults); from engraftment to ≥6 months and as long as immunosuppression is ongoing (allogeneic hematopoietic stem cell transplant in children and adults); >6 months after completion of treatment (alemtuzumab in adults); ≥6 months after completion of treatment (fludarabine plus cyclophosphamide plus rituximab in adults); life-long or until restoration of underlying defect (severe combined immunodeficiency, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia, and HLA II combined immunodeficiency in children); and duration of chemotherapy (acute myeloid leukemia and solid tumors in children).
The 2019 American Society of Transplantation guidelines recommend PCP prophylaxis for all children and adults who are solid-organ transplant recipients for at least 6-12 months and for programs with incidence of PCP infection among recipients of at least 3% to 5%.[49] Lifelong prophylaxis may be indicated for small bowel and lung transplant recipients and patients with a history of previous PCP infection. Continuation or resumption of prophylaxis is generally indicated for patients treated with augmented immunosuppression for graft rejection, those with cytomegalovirus infection, patients receiving corticosteroids (e.g., >20 mg/day of prednisone for ≥2 weeks) and during prolonged neutropenia or flares of autoimmune disease. The agent of choice is TMP/SMX in the absence of contraindications. In patients who cannot tolerate TMP/SMX, other options include dapsone, atovaquone, aerosolized pentamidine, or clindamycin plus pyrimethamine (the latter for adults only).
Secondary prophylaxis
Patients who have had PCP infection, who have been treated and are without symptoms, receive secondary prophylaxis, which conforms to the same schedule as primary prophylaxis for each patient group.
Secondary prophylaxis is recommended for HIV-positive patients who have had PCP and should be started after completion of PCP treatment and continued until immune reconstitution occurs with ART.[22][32]
Secondary prophylaxis can be discontinued for most patients using the same criteria as for discontinuing primary prophylaxis. PCP prophylaxis should not be discontinued in HIV-infected infants ages <1 year. Prophylaxis should be continued for life in patients who develop PCP despite CD4 count >200 cells/microliter.
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