Clinical Review & Education
JAMA Insights
Prophylaxis Against Pneumocystis jirovecii Pneumonia in Adults
Shiwei Zhou, MD; Samuel L. Aitken, PharmD, MPH
Pneumocystis jirovecii is an opportunistic fungal pathogen that
causes life-threatening pneumonia in immunocompromised pa-
tients. Patients with Pneumocystis pneumonia (PCP) typically present
with fever, nonproductive cough, dyspnea, and hypoxemia with dif-
fuse bilateral ground-glass opaci-
ties on chest imaging.1 PCP can
Supplemental content
be prevented by reducing immu-
nosuppression and with chemo-
CME at jamacmelookup.com prophylaxis. Effective prophy-
laxis significantly decreases the incidence of infection.2 This article
summarizes current recommendations regarding prevention of PCP
in patients who are immunocompromised.3-5
Indications for Prophylaxis
Primary prophylaxis is intended to prevent a first episode of PCP and
should be administered in patients at risk for PCP due to specific
medical conditions or treatments (Table). Primary prophylaxis for
PCP is recommended for all patients with HIV/AIDS who have CD4
T-lymphocyte count less than 200/μL.3 These patients should also
receive antiretroviral therapy (ART). Prophylaxis for PCP is also rec-
ommended for those with CD4 cell percentage less than 14% or in
patients with CD4 lymphocyte count between 200/μL and 250/μL
whose ART is delayed or who cannot receive CD4 monitoring at least
every 3 months.3
Among patients without HIV who are immunocompromised, pri-
mary PCP prophylaxis is recommended for those with acute lym-
phoblastic leukemia receiving antileukemic therapy, recipients of al-
logeneic hematopoietic cell transplant (HCT) and solid organ
transplant, and patients treated with the anti-CD52 antibody ale-
Table. Medical Conditions and Pharmaceutical Therapies Requiring Prophylaxis for Pneumocystis Pneumonia in Adults
Strength of recommendation
Indication for primary Pneumocystis prophylaxis and quality of evidence
HIV, CD4 T-lymphocyte count <200/μL AI (NIH)
HIV, CD4 count <14% of total lymphocyte count, BII (NIH)
or CD4 count 200/μL to 250/μL if ART initiation
is delayed and CD4 count monitoring (every 3 mo)
is not possible
Acute lymphoblastic leukemia 1 (NCCN)
Allogeneic stem cell transplant 1 (NCCN)
Solid organ transplant (eg, kidney, heart, lung, Strong, moderate (AST)
small bowel)
Autologous HCT for underlying hematologic 2B (NCCN)
malignancy
Chimeric antigen receptor-modified T-cell therapy No guideline consensus
Primary immunodeficiency (severe combined No guideline consensus
immunodeficiency, idiopathic CD4 T-lymphopenia,
hyper IgM syndrome)
Abbreviations: ART, antiretroviral therapy; AST, American Society of
Transplantation; CMV, cytomegalovirus; HCT, hematocrit; NIH, National
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mtuzumab, phosphatidylinositol 3-kinase inhibitors (eg, idelalisib,
duvelisib), or temozolomide with concurrent radiotherapy.5-7 Pro-
phylaxis is also recommended for patients treated with purine ana-
logue chemotherapeutic agents (eg, fludarabine, cladribine), pa-
tients with malignancy receiving autologous HCT, and recipients of
chimeric antigen receptor T-cell therapy.1,5
Patients receiving high-dose corticosteroid treatment (equiva-
lent to ⱖ20 mg of prednisone daily for ⱖ1 month) who have an ad-
ditional cause of immunodeficiency (eg, underlying malignancy, ad-
ditional immunosuppressive medication) should receive PCP
prophylaxis.5,7 Patients with antineutrophil cytoplasmic antibody–
associated vasculitis, such as granulomatosis with polyangiitis, un-
dergoing induction therapy should also receive PCP prophylaxis.8
There is no consensus regarding PCP prophylaxis for patients with
autoimmune or autoinflammatory conditions, although patients with
rheumatoid arthritis, systemic sclerosis, and giant cell arteritis treated
with high-dose corticosteroids have a lower risk for developing PCP
compared with those with granulomatosis with polyangiitis.8
An increasing number of patients are treated with immune-
modulating medications that are associated with PCP but lack con-
sensus guidelines regarding prophylaxis.9,10 These medications in-
cludecheckpointinhibitors(eg,ipilimumab,nivolumab),tumornecrosis
factor inhibitors (eg, infliximab), anti-CD20 antibodies (eg, ritux-
imab),bruton-tyrosinekinaseinhibitors(eg,ibrutinib),andJanuskinase
inhibitors (eg, ruxolitinib) (eTable in the Supplement). Although these
treatments alone do not require PCP prophylaxis, the coexistence of
an additional risk factor (eg, high-dose corticosteroids, presence of ab-
solute lymphopenia, other immunosuppressive drugs) may be an in-
dication to initiate prophylaxis. Other factors that may indicate a need
Timing and duration of prophylaxis/comments
Until CD4 increased from <200/μL to ≥200/μL for at least 3 mo in
response to ART
Consider discontinuing prophylaxis when CD4 between 100/μL to
200/μL in patients whose HIV RNA remains below limit of detection of
the assay used for ≥3 mo
For the duration of antileukemic therapy, through the end of
maintenance therapy
Begin after engraftment and continuing at least 6 mo after transplant,
longer if still receiving immunosuppressive therapy
For 6 mo to 1 y following transplant; consider restarting prophylaxis
during intensive immunosuppression for allograft rejection, CMV
infection, or prolonged neutropenia; consider lifelong prophylaxis for
recipients of lung, small bowel transplant, and those with prior PCP
For 3-6 mo after transplant
For 3 mo or until CD4 count >200/μL, whichever occurs later
Institutes of Health; NCCN, National Comprehensive Cancer Network;
PCP, Pneumocytis pneumonia.
(Reprinted) JAMA Published online June 26, 2023 E1
 Clinical Review & Education JAMA Insights

forPCPprophylaxisincludeimmunosuppressionfromthepatient’sun- Duration of Prophylaxis

derlying disease process, history of previous opportunistic infec-
tions, older age, and comorbidities.
Secondary prophylaxis to prevent recurrence of PCP should be
started in all patients after successful treatment of PCP if the im-
munosuppressed state persists.
Prophylactic Therapy
Trimethoprim-sulfamethoxazole is the drug of choice for PCP pro-
phylaxis for patients with and without HIV (Table). Prophylactic dos-
ing of trimethoprim-sulfamethoxazole for patients with normal kid-
ney function is typically 1 double-strength oral tablet (800/160 mg)
daily or 3 times per week or 1 single-strength tablet (400/80 mg)
daily, and is usually well-tolerated. Exanthem and nausea are
common adverse effects.2 If trimethoprim-sulfamethoxazole is
discontinued for a mild adverse effect, reinstitution of medica-
tion should be considered after resolution of the adverse reaction.
Those with allergic reactions may require desensitization with al-
lergy consultation.3
Alternatives for PCP prophylaxis include atovaquone, dap-
sone, and monthly administration of aerosolized pentamidine. All
patients should have glucose-6 phosphate dehydrogenase levels
measured by blood test prior to initiating dapsone. According to the
National Comprehensive Cancer Network, monthly intravenous
pentamidine is an acceptable alternative for PCP prophylaxis among
HCT recipients,5 but it is not recommended by the National Insti-
tutes of Health for patients with HIV due to insufficient evidence.3
In clinical practice, the adverse effect profile, tolerability, and the
health care insurance coverage of the patient often influence selec-
tion of alternative prophylaxis regimens. Due to increased risk of my-
elosuppression in patients with hematologic malignancy or HCT, and
due to increased rates of nephrotoxicity in kidney transplant recipi-
ents, alternatives to trimethoprim-sulfamethoxazole should be con-
sidered in these patients.6
Prophylaxis for PCP should continue as long as the immunosuppres-
sive state persists. Among patients with HIV, PCP prophylaxis can
be discontinued when CD4 lymphocyte counts increase to greater
than 200/μL for more than 3 months in response to ART.3 Prophy-
laxis may also be discontinued if CD4 counts are 100/μL to 200/μL
in patients whose HIV plasma RNA levels remain below the limits of
detection for at least 3 months.3 Prophylaxis may be discontinued
in patients treated with alemtuzumab and purine analogue agents
whose CD4 count improves to greater than 200/μL.5
Patients with acute lymphoblastic leukemia should continue PCP
prophylaxis through the end of maintenance therapy.5 Allogeneic
HCT recipients begin prophylaxis at engraftment and should con-
tinue prophylaxis through at least 6 months after transplant or lon-
ger if immunosuppression is ongoing. Because the effect of immu-
nosuppressive medications (eg, rituximab, temozolomide, idelalisib)
may persist after drug discontinuation, duration of PCP prophy-
laxis should be individualized based on the medication received.
All solid organ transplant recipients should receive prophy-
laxis for at least 6 to 12 months after the transplant, after which pro-
phylaxis should be prescribed during periods of intensive immuno-
suppression for allograft rejection, infection with Cytomegalovirus,
or prolonged neutropenia.6 Lifetime prophylaxis is recommended
for recipients of lung and small bowel transplant as well as solid or-
gan transplant recipients with previous PCP infection.6
Patients requiring PCP prophylaxis usually have multiple co-
morbid health conditions and are often cared for by multiple sub-
specialists, including hematology, oncology, infectious diseases, rheu-
matology, pulmonology, and transplant. Discussion and coordination
of initiation and discontinuation of PCP prophylaxis across these cli-
nicians can be beneficial.
Patients at risk for PCP should receive safe and effective pro-
phylaxis while they are immunosuppressed; trimethoprim-
sulfamethoxazole is the agent of choice.

ARTICLE INFORMATION
Author Affiliations: Department of Internal
Medicine, Division of Infectious Diseases, Michigan
Medicine, Ann Arbor (Zhou); Department of
Pharmacy, Michigan Medicine, Ann Arbor (Aitken).
Clin North Am. Published May 2, 2023. doi:10.1016/
j.idc.2023.03.005
3. Panel on Guidelines for the Prevention and
Treatment of Opportunistic Infections in Adults and
Adolescents with HIV. Guidelines for the Prevention
7. Taplitz RA, Kennedy EB, Bow EJ, et al.
Antimicrobial prophylaxis for adult patients with
cancer-related immunosuppression: ASCO and
IDSA Clinical Practice Guideline Update. J Clin Oncol.
2018;36(30):3043-3054. doi:10.1200/JCO.18.00374

Corresponding Author: Shiwei Zhou, MD,
Michigan Medicine, University of Michigan,
1500 E Medical Center Dr, Ann Arbor, MI 48109
(shzh@med.umich.edu).
Published Online: June 26, 2023.
doi:10.1001/jama.2023.9844
Conflict of Interest Disclosures: Dr Aitken
reported receiving personal fees from bioMerieux,
F2G, Entasis, Shionogi, GSK, Melinta, AstraZeneca,
Enstasis, and Basilea outside the submitted work.
No other disclosures were reported.
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