Version May 2024
INTRODUCTION — Pneumocystis jirovecii pneumonia (formerly called Pneumocystis carinii pneumonia or PCP) is the most common opportunistic respiratory infection in patients with acquired immunodeficiency syndrome (AIDS). It typically occurs in patients with human immunodeficiency virus (HIV) with a CD4 count <200 cells/microL who are not receiving antiretroviral therapy or appropriate prophylaxis.
This topic will review the treatment and prevention of PCP in patients with HIV infection. Topic reviews on the clinical presentation and diagnosis of PCP in patients with HIV and PCP in the HIV-uninfected host are discussed separately. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV" and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)
TREATMENT — Antimicrobial therapy directed against P. jirovecii is the mainstay of treatment for Pneumocystis pneumonia (PCP). In addition, some patients will require adjunctive corticosteroids. Antiretroviral therapy (ART) should be initiated to restore immune function. Although PCP is uncommon in those on ART, for those patients already receiving it, we continue their ART regimen while they are being treated for PCP. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and 'Timing of ART initiation' below.)
Empiric therapy for PCP should be initiated pending the results of the diagnostic evaluation if there is a high clinical suspicion for PCP (eg, CD4 count <200 cells/microL, hypoxemia, interstitial infiltrates). In certain situations, it is not possible to confirm the diagnosis, and patients are treated and monitored for clinical response (see 'Monitoring patients on treatment' below). A detailed discussion on the clinical manifestations and diagnosis of PCP is found elsewhere. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV".)
After patients complete their initial treatment regimen, antimicrobial therapy should be continued at lower doses to prevent recurrent infection (ie, secondary prophylaxis). This preventive therapy can be discontinued after immune recovery has been achieved for a prolonged period of time. (See 'Secondary prophylaxis' below.)
Initial assessment — Several factors impact the approach to treatment for patients with PCP. Thus, prior to initiating therapy, we assess the following:
●Drug allergies – Trimethoprim-sulfamethoxazole (TMP-SMX), a sulfa-containing regimen, is the preferred treatment for PCP. For patients with a sulfa allergy, a second-line regimen is generally used. However, we may desensitize certain patients to TMP-SMX, such as those with severe PCP, if their sulfa allergy is non-life threatening. (See 'Preferred regimen' below and 'Alternative regimens' below and 'Desensitization for patients with a sulfa allergy' below.)
●Respiratory status – We evaluate the patient’s respiratory status to help assess the severity of disease. We first assess the patient clinically by measuring their respiratory rate and evaluating the use of accessory muscles of respiration. We then measure arterial oxygenation using pulse oximetry. (See "Evaluation of pulmonary symptoms in persons with HIV", section on 'Pulse oximetry or arterial blood gas analysis'.)
In patients with evidence of respiratory distress, tachypnea, and/or hypoxia, the severity of disease can be further assessed by obtaining a blood gas (eg, alveolar to arterial oxygen [A-a] gradient). However, with the reliability of pulse oximetry, we no longer obtain a blood gas solely to determine the need for corticosteroids if a patient has clear evidence of hypoxemia (eg, resting room air oxygen saturation <92 percent). A blood gas may still be useful to help determine if the patient requires placement in the intensive care unit and/or if an intravenous regimen should be used. (See 'Severe disease' below.)
●Factors that impact absorption – Most patients with PCP can be treated with an oral regimen. However, some individuals may have a concurrent condition that impacts their ability to take an oral medication (eg, severe esophageal candidiasis, diarrhea). Such patients will require intravenous (IV) therapy until these other conditions have improved.
Approach — The initial approach to treatment (eg, the choice of agent, the mode of administration, and the use of adjunctive corticosteroids) is determined primarily by the level of oxygenation and/or the A-a gradient. An overview of the management of patients with mild, moderate, or severe disease is reviewed here. A discussion of the specific antimicrobial agents is found below. (See 'Antimicrobial regimens' below.)
Mild disease — Patients with mild disease have an A-a O2 gradient <35 mmHg and/or a partial pressure of arterial oxygen ≥70 mmHg.
We administer oral therapy to such patients unless they have a concurrent infection or comorbidity that would impact drug absorption. We suggest TMP-SMX for treatment of mild disease; alternative regimens include trimethoprim-dapsone, clindamycin-primaquine, or atovaquone. Such patients do not require corticosteroids. (See 'Preferred regimen' below and 'Alternative regimens for mild to moderate disease' below and 'Whom to treat with corticosteroids' below.)
Moderate disease — Patients with moderate disease have an A-a O2 gradient ≥35 and <45 mmHg and/or a partial pressure of arterial oxygen ≥60 and <70 mmHg.
As with mild disease, we administer oral therapy unless the patient has a concurrent infection or comorbidity that would impact absorption. We suggest TMP-SMX for treatment of moderate disease. Alternative regimens include trimethoprim-dapsone or clindamycin-primaquine; we generally do not use atovaquone as initial treatment for moderate disease. In addition, individuals with moderate disease require adjunctive corticosteroids. (See 'Preferred regimen' below and 'Alternative regimens for mild to moderate disease' below and 'Corticosteroid regimen' below.)
Severe disease — A patient has severe disease when the A-a O2 gradient is ≥45 mmHg, the partial pressure of arterial oxygen is <60 mmHg, and/or there is potential for fatigue leading to respiratory failure (eg, a high respiratory rate or a partial pressure of arterial carbon dioxide that is normal or higher than normal in a patient with hypoxia).
We recommend TMP-SMX for patients with severe disease. Individuals should receive intravenous therapy until they are clinically stable (eg, PaO2 ≥60 mmHg, respiratory rate <25) and are able to be transitioned to oral treatment. Adjunctive corticosteroids should also be administered. (See 'Preferred regimen' below and 'Corticosteroid regimen' below.)
For those with severe disease who cannot take TMP-SMX (eg, severe sulfonamide allergy), we typically suggest clindamycin-primaquine. For such patients, we obtain a detailed history to assess the type and severity of their past sulfonamide reaction since certain individuals can be desensitized to TMP-SMX. (See 'Alternative regimens for severe disease' below and 'Desensitization for patients with a sulfa allergy' below.)
Indications for hospitalization — Patients with PCP sometimes worsen after two to three days of therapy. This must be taken into consideration when deciding who requires hospitalization. In general, the following are indications for inpatient therapy: disease severe enough to warrant treatment with corticosteroids, regardless of whether intravenous or oral anti-Pneumocystis therapy is used; initial treatment with intravenous pentamidine given the potential side effects of therapy (in particular, hypoglycemia and hypotension); and patients for whom compliance with therapy or laboratory monitoring is likely to be difficult.
Antimicrobial regimens
Preferred regimen — TMP-SMX is the preferred regimen for the treatment of PCP in patients with HIV (table 1). Therapy should be administered for 21 days. Trimethoprim is a dihydrofolate reductase inhibitor, and sulfamethoxazole is a dihydropteroate synthetase inhibitor; when coupled together they are synergistic in eradicating P. jirovecii. (See "Trimethoprim-sulfamethoxazole: An overview".)
The standard dose of TMP-SMX is 15 to 20 mg/kg/day orally or intravenously in three or four divided doses. Dosing of TMP-SMX is based upon the TMP component and expressed as mg/kg per day of TMP. In certain circumstances, such as in patients with comorbidities, lower doses of TMP-SMX can be considered. Dose modifications for renal impairment may be needed; detailed dosing recommendations are available in the TMP-SMX drug information monograph included within UpToDate.
The severity of disease dictates whether oral or intravenous therapy should be used:
●For patients with mild to moderate disease, we prefer oral therapy since TMP-SMX has excellent oral absorption. For most patients, this turns out to be two double-strength tablets given every six or eight hours, depending upon body weight.
●For patients with severe disease, we administer IV therapy. (See 'Severe disease' above.)
We treat with TMP-SMX even if the patient was prescribed TMP-SMX for PCP prophylaxis (see 'Preventing initial infection' below). Most patients who develop PCP while being prescribed TMP-SMX prophylaxis do so because of non-adherence to their medication [1]. Although sulfa-containing agents can result in resistance mutations in the dihydropteroate synthase gene of P. jirovecii [2], drug resistance leading to treatment failure is unlikely [3].
The efficacy of TMP-SMX for treating PCP has been most clearly demonstrated in individuals with severe disease [4-8]. As an example, in a randomized trial of 70 patients with severe PCP that compared TMP-SMX with pentamidine, the survival rate was significantly higher in those receiving TMP-SMX (86 versus 61 percent) [5]. Among those with mild to moderate disease, there are no high quality data to support the use of TMP-SMX over one of the other agents. However, based upon our clinical experience, and the experience of other experts [9], we suggest TMP-SMX for initial treatment of mild to moderate PCP. (See 'Alternative regimens for mild to moderate disease' below.)
There are accumulating data that lower doses of TMP-SMX are just as effective as standard-dose TMP-SMX at treating PCP. In a meta-analysis of three studies in patients with HIV, lower doses of TMP-SMX (10 to 12 mg/kg/day) were associated with similar three-month mortality rate compared with a historical standard-dose TMP-SMX cohort (9 versus 11 percent) [10]. A randomized, controlled trial comparing low- and standard-dose of TMP-SMX is ongoing [11].
Alternative regimens — For those who are unable to take TMP-SMX, the choice of which alternative agent to use is based upon the severity of disease, the patient’s intolerances and allergies, and the ease of administration (table 1). Dose modifications for renal impairment may be needed for certain agents; detailed dosing recommendations are available in the specific drug information monographs included within UpToDate.
Alternative regimens for mild to moderate disease — Several alternative regimens can be used for the treatment of mild to moderate disease; the available data do not favor one over the other. This was illustrated in a multicenter trial that randomly assigned 181 patients with mild to moderate PCP (defined as an A-a O2 gradient <45 mmHg) to therapy with TMP-SMX, TMP-dapsone, or clindamycin-primaquine for 21 days [1]. Patients with an A-a O2 gradient between 35 and 45 mmHg also received corticosteroids. There was no significant difference between groups in the rate of treatment failure or mortality (approximately 5 percent in each treatment arm). However, the risk of hematologic and hepatotoxicity were significantly more frequent in those receiving clindamycin-primaquine and TMP-SMX, respectively.
The following oral regimens should be administered for 21 days, and are listed in order of our preference:
●Trimethoprim-dapsone – Oral trimethoprim is administered at a dose of 5 mg/kg (typically rounded to the nearest 100 milligrams) three times per day with dapsone 100 mg per day. Dapsone is a sulfone that is usually tolerated by persons who have adverse reactions to TMP-SMX [12,13]. However, in patients who have had serious reactions to TMP-SMX (eg, Stevens Johnson syndrome/toxic epidermal necrolysis, rash with fever and systemic symptoms, serum sickness, or hemolytic anemia), it seems prudent to avoid dapsone. (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Cross-reactivity'.)
●Clindamycin-primaquine – Oral clindamycin-primaquine is administered as clindamycin (450 mg every six hours or 600 mg every eight hours) along with primaquine base 30 mg per day.
●Atovaquone – Atovaquone suspension can be used for the treatment of mild PCP (see 'Mild disease' above). The dose is 750 mg twice daily and should be taken with food [14]. In general, we do not use this agent for the initial treatment of moderate disease since atovaquone was less effective than TMP/SMX in a comparative clinical trial [15]. However, we may switch a patient with moderate to severe disease to atovaquone if they are clinically improved on a more potent agent, but have developed an adverse reaction.
Patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency when using a regimen that contains dapsone or primaquine since patients with G6PD deficiency are at risk for developing hemolytic anemia when exposed to these agents. Sulfa-intolerant patients with G6PD deficiency and mild disease should receive atovaquone. For those with G6PD deficiency and moderate disease, the decision to use atovaquone, desensitize to TMP-SMX, or switch to IV therapy with pentamidine depends upon the severity of their disease and their past reaction to TMP-SMX. Although it is best if G6PD results are available prior to initiating treatment, therapy may be initiated simultaneously with testing as the risk for this deficiency is quite low. (See "Initial evaluation of adults with HIV", section on 'G6PD deficiency' and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)
Alternative regimens for severe disease — We suggest clindamycin-primaquine for patients with severe disease who cannot take TMP-SMX. However, primaquine must be administered orally; thus, IV pentamidine must be used for patients with severe PCP who have a life-threatening sulfonamide allergy and cannot take oral medications. Such patients should be switched to a less toxic regimen as soon as they can tolerate oral therapy.
We prefer clindamycin-primaquine rather than IV pentamidine based upon the lower rate of severe side effects. In addition, although there are no randomized clinical trials comparing clindamycin-primaquine with pentamidine for treatment of severe PCP, the former appears to be more effective and better tolerated than pentamidine when used as second-line therapy in patients who cannot take or fail TMP-SMX [8,16,17]. (See 'Treatment failure' below.)
Specific information regarding the alternative regimens includes:
●Clindamycin-primaquine – Clindamycin can be administered intravenously at a dose of 600 mg every six hours or 900 mg every eight hours. Patients should receive intravenous therapy until they are clinically stable (eg, PaO2 ≥60 mmHg, respiratory rate <25) and have a functioning gastrointestinal tract; after that, they can transition to oral clindamycin (450 mg every six hours or 600 mg every eight hours).
Primaquine base is given orally at a dose of 30 mg daily. Patients should be tested for G6PD when initiating this regimen since patients with G6PD deficiency are at risk for developing hemolytic anemia when exposed to primaquine. (See "Initial evaluation of adults with HIV", section on 'G6PD deficiency' and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Acute hemolytic anemia'.)
●Pentamidine – Pentamidine is administered intravenously at a dose of 4 mg/kg daily. We avoid pentamidine in patients with renal insufficiency (estimated glomerular filtration rate <60 mL/min/1.73m2), as well as those with concurrent pancreatitis because of its potential toxicities. (See 'Adverse reactions' below.)
Patients who require treatment with pentamidine should be admitted to the hospital and closely monitored with bedside telemetry and frequent measurement of blood pressure. The drug should be administered over at least 60 minutes while the patient is supine and adequately hydrated.
Adverse reactions to pentamidine are common and can be severe. Individuals who improve while on pentamidine should be switched to a safer oral regimen as soon as clinically feasible. However, the pentamidine dose can be reduced to 3 mg/kg IV daily for patients who experience toxicity if no other treatment option is possible. (See 'Adverse reactions' below and 'Alternative regimens for mild to moderate disease' above.)
Although there are some reports of echinocandin use in patients intolerant to or failing TMP-SMX therapy, further study is needed to delineate their role in PCP treatment [18].
For patients with a sulfa allergy, we obtain a detailed history to assess the type and severity of their past reaction; this will allow us to determine if it is safe for them to be desensitized to TMP-SMX. Patients who undergo desensitization should continue treatment with one of these alternative regimens until they are able to tolerate treatment doses of TMP-SMX. (See 'Desensitization for patients with a sulfa allergy' below.)
Use of corticosteroids — Corticosteroids given in conjunction with anti-Pneumocystis therapy can decrease the incidence of mortality and respiratory failure associated with PCP [19]. Without steroids, patients with PCP may worsen clinically after two to three days of therapy, presumably due to increased inflammation in response to dying organisms. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Clinical Features of Pulmonary disease'.)
Several randomized trials have demonstrated the benefits of administering corticosteroids to patients with PCP who have abnormalities in oxygen exchange at the time of presentation [20-22]. These findings were illustrated in a Cochrane Database review of seven randomized controlled trials that evaluated the effects of adjunctive corticosteroids in patients with HIV with moderate to severe disease [19]. Compared with placebo, the risk ratios for overall mortality in patients receiving adjunctive corticosteroids were 0.56 (95% CI 0.32-0.98) at one month and 0.59 (95% CI 0.41-0.85) at three to four months of follow-up.
Whom to treat with corticosteroids — We recommend the use of adjunctive corticosteroids for patients with moderate to severe disease (table 1). (See 'Moderate disease' above and 'Severe disease' above.)
If blood gas data are available, we agree with guideline panels and initiate steroids in patients with [9,23]:
●A partial pressure of oxygen of <70 mmHg on room air and/or
●An alveolar-arterial (A-a) oxygen gradient of ≥35 mmHg
However, with the reliability of pulse oximetry, we no longer obtain a blood gas solely to determine the need for corticosteroids if a patient has clear evidence of hypoxemia (eg, resting room air oxygen saturation <92 percent). A blood gas may still be useful to help determine if the patient requires placement in the intensive care unit and/or if an intravenous regimen should be used. (See 'Severe disease' above.)
We also administer corticosteroids to patients with worsening respiratory symptoms after starting treatment. Although there are no controlled studies evaluating the use of corticosteroids in this setting, one case series suggested there may be some benefit [24].
Corticosteroid regimen — Corticosteroids should be initiated concurrently with anti-Pneumocystis therapy. Although studies have not demonstrated the optimal dose or duration of therapy, we administer the following 21-day oral regimen [9,23]:
●Prednisone 40 mg twice daily for 5 days
followed by
●Prednisone 40 mg daily for 5 days
followed by
●Prednisone 20 mg daily for 11 days
Intravenous methylprednisolone can be substituted for oral prednisone at 75 percent of the prednisone dose if IV therapy is necessary.
Pregnancy — TMP-SMX is the preferred therapy for PCP in pregnant women. If an alternative regimen must be used, we prefer trimethoprim-dapsone since there is clinical experience with this regimen in pregnancy [9]. (See 'Preferred regimen' above and 'Alternative regimens for mild to moderate disease' above.)
However, there are risks associated with the use of TMP-SMX and dapsone in pregnancy. As examples:
●First-trimester exposure to TMP-SMX has been associated with an increased risk for neural tube defects and cardiovascular, urinary tract, and other anomalies [25]. Folic acid supplementation may reduce this risk [26], but there are concerns that folic acid can lead to increased treatment failures in patients being treated for PCP. Thus, we administer folic acid only to women in the first trimester. In addition, we obtain a follow-up ultrasound at 18 to 20 weeks to assess fetal anatomy [9].
●If sulfa drugs or dapsone are used near delivery, neonatal providers should be informed since there is an increased risk of kernicterus.
We do not use intravenous pentamidine in pregnant women since animal studies suggest that pentamidine can cause embryonic toxicity and death when administered at doses similar to those used in humans [27]. (See 'Alternative regimens for severe disease' above.)
The indications for corticosteroids are the same as in nonpregnant patients; however, pregnant women should be followed closely for gestational diabetes when treated with corticosteroids during the third trimester. Some women may also require stress dose corticosteroids during delivery [9]. (See "The management of the surgical patient taking glucocorticoids".)
More detailed discussions on the use of TMP-SMX in pregnancy are found elsewhere. (See "Trimethoprim-sulfamethoxazole: An overview", section on 'Pregnancy and breastfeeding' and "Prenatal evaluation of women with HIV in resource-rich settings", section on 'Chemoprophylaxis for opportunistic infections'.)
Prognosis — Most patients being treated for PCP will improve on therapy. However, some patients develop progressive respiratory failure, even with appropriate treatment. Studies done prior to the widespread use of antiretroviral therapy found that response to treatment depends, in part, upon the degree of hypoxia at presentation [1,22,28,29]. As examples:
●Patients with mild to moderate disease (A-a O2 gradient ≤45 mmHg) had a case fatality rate <10 percent [1], whereas patients with more severe abnormalities in gas exchange had a case fatality >20 percent [22].
●The mortality among patients with PCP and respiratory failure requiring intensive care admission or mechanical ventilation was reported to be as high as 60 percent [30-33].
Other factors that correlate with poor outcome include increasing age, a prior episode of PCP, an elevated serum lactate dehydrogenase concentration, a low CD4 cell count, and the presence of cytomegalovirus in bronchoalveolar lavage fluid [28,29,34-36].
Initiating antiretroviral therapy (ART) improves the prognosis of patients with PCP and advanced HIV-related immunosuppression [36-38]. In an observational study that included 5222 episodes of PCP occurring among 4412 patients, the 12-month survival increased from 40 percent in 1992 to 1993 to 63 percent in 1996 to 1998 (ie, after the introduction of potent ART) [36]. Administering antiretroviral therapy soon after treatment for PCP is initiated provides the best benefit. (See 'Timing of ART initiation' below.)
Monitoring patients on treatment — Patients should be monitored for adverse events related to their treatment regimen, as well as their response to therapy.
●For patients with mild to moderate disease being treated as an outpatient, we schedule a follow-up visit within one week of starting treatment to perform a clinical assessment and obtain laboratory testing. At that visit, we measure the oxygen saturation, obtain a complete blood count, and measure renal function, electrolytes, and aminotransferase levels.
●For patients with severe disease requiring hospitalization, daily clinical assessments and more frequent laboratory monitoring are needed. For such patients, we monitor complete blood counts, electrolytes, and liver function tests at least two to three times per week. Individuals receiving pentamidine should have renal function, glucose, calcium, and electrolyte concentrations monitored daily; such patients should be switched to a less toxic regimen as soon as they can tolerate oral therapy. (See 'Alternative regimens' above.)
●Individuals who receive corticosteroids should be monitored for the development of new opportunistic infections, especially candidiasis [39-42]. In an observational study of 174 patients with PCP, adjunctive corticosteroids increased the likelihood of subsequent esophageal candidiasis [41].
Adverse reactions — Several of the antimicrobial regimens used to treat PCP are associated with significant side effects. A change in regimen may be needed for patients who develop severe adverse reactions (eg, Stevens Johnson syndrome with TMP-SMX, pancreatitis or renal failure with pentamidine).
●TMP-SMX – Adverse reactions to TMP-SMX are common in patients being treated for PCP [43]. Reactions can range from mild to severe and include gastrointestinal intolerance, photosensitivity, rash, and fever. Laboratory testing can reveal leukopenia and marked hyperkalemia, as well as evidence of acute kidney injury and hepatotoxicity [44]. Sulfonamides should be immediately discontinued if any of the following conditions are present [45]:
•Persistent rash and/or fever for more than five days
•Absolute neutrophil count <500 cells/mm3
•Hypotension
•Intractable hyperkalemia
•Fever and flu-like symptoms, followed by conjunctival irritation, mucous membrane involvement, painful skin, target lesions, blistering, or desquamation of the skin
We try to continue treatment in patients who have adverse reactions to TMP-SMX that are not life threatening [9]. Antihistamines may be helpful in controlling minor reactions. Hydration or sodium polystyrene can be used to treat hyperkalemia caused by the renal tubular resorption of potassium. A more detailed discussion on adverse reactions to TMP-SMX is found elsewhere. (See "Trimethoprim-sulfamethoxazole: An overview", section on 'Adverse effects and precautions'.)
●TMP-dapsone – Side effects of TMP-dapsone include gastrointestinal upset, rash, fever, hemolytic anemia, and methemoglobinemia. Laboratory testing can also reveal neutropenia, hyperkalemia, and transaminase elevations. An interaction between trimethoprim and dapsone appears to increase the levels of both drugs in patients being treated for PCP, and this may increase the risk of side effects such as anemia and methemoglobinemia [46].
●Clindamycin-primaquine – Side effects include rash, fever, diarrhea (including Clostridioides difficile-associated colitis), hemolytic anemia, neutropenia, and methemoglobinemia.
●Atovaquone – The most common side effect is gastrointestinal distress. Other adverse reactions include fever and transaminase elevations. Rash may also occur, but is less common than with other regimens.
●Pentamidine – Adverse reactions occur in up to 70 percent of patients and include nausea, taste disturbance, cardiac arrhythmias, hyperkalemia, nephrotoxicity, pancreatitis, hypokalemia, hypocalcemia, hypoglycemia, and hyperglycemia. Patients can develop permanent insulin-requiring diabetes mellitus after treatment with pentamidine [47]. The nephrotoxicity of pentamidine is cumulative and is usually evidenced by a gradual increase in the creatinine concentration over the course of therapy. Concomitant use of other nephrotoxic drugs such as amphotericin B, aminoglycosides, and foscarnet potentiate the renal toxicity of pentamidine. Certain adverse events, particularly hypoglycemia and hypotension, may be life threatening.
Treatment failure — Patients who do not show any improvement (eg, tachypnea, hypoxemia) after four to eight days of therapy are considered treatment failures [9]. Treatment failure may be due to the severity of disease at the time of diagnosis or to a concurrent infection that was not previously identified. It is possible that P. jirovecii can develop mutations associated with resistance to sulfa drugs; however, the impact of drug resistance on treatment outcomes has not been established [2,3].
Our approach to treatment failure is as follows:
●We modify the treatment regimen for patients failing therapy, especially those with severe disease and those who do not improve after eight days. However, this approach is based upon clinical experience and the findings of uncontrolled studies, since there are no controlled clinical trials to guide whether to continue or change initial therapy. Examples of treatment modifications include:
•If a patient progresses to severe disease while receiving oral therapy, we administer an IV regimen. For those receiving oral TMP-SMX, we change to IV TMP-SMX. Patients unable to tolerate TMP-SMX should be switched to clindamycin-primaquine. (See 'Preferred regimen' above and 'Alternative regimens for severe disease' above.)
•For patients failing therapy with an alternative regimen, we determine if desensitization and changing to TMP-SMX is an option. (See 'Desensitization for patients with a sulfa allergy' below.)
•For those failing therapy with intravenous TMP-SMX, we initiate clindamycin-primaquine based upon the results of uncontrolled studies that suggest this regimen improves clinical outcomes when used as salvage therapy for the treatment of PCP [8,16,48].
●Patients with treatment failure should be evaluated for a concurrent infection since approximately 15 percent of patients with PCP will have more than one opportunistic infection. This may involve more invasive testing such as bronchoalveolar lavage. For patients with severe respiratory failure, empiric therapy directed at one or more of these infections may be indicated while the results of diagnostic tests are pending. A more detailed discussion of respiratory infections in patients with HIV is found elsewhere. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Differential diagnosis' and "Evaluation of pulmonary symptoms in persons with HIV", section on 'Invasive tests'.)
●We initiate adjunctive corticosteroids if a patient’s respiratory status worsens and they require supplemental oxygen. Some patients may be stable initially (eg, mild disease), and then worsen clinically two to three days after starting anti-Pneumocystis therapy. Such patients typically have an increase in the alveolar-arterial oxygen gradient due to increased inflammation in the lungs as the organisms are killed. However, there are no controlled studies evaluating the use of corticosteroids in this setting. (See 'Use of corticosteroids' above.)
Respiratory failure — Patients who show progressive respiratory failure (eg, increased respiratory rate, worsening oxygen saturation) may require mechanical ventilatory support. For such patients, low tidal volumes and plateau pressures should be used given the potential presence of pneumatoceles, which increase the risk of pneumothorax [49]. (See "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit".)
Patients with respiratory failure should also be assessed for pneumothorax since individuals with PCP are at risk for pneumothorax, both spontaneously or in the setting of mechanical ventilation [50-52]. Such patients who develop pneumothorax in the setting of mechanical ventilation have a poor prognosis [50]. A discussion on the management of pneumothorax in patients with HIV is found elsewhere. (See "Clinical presentation and diagnosis of pneumothorax".)
Timing of ART initiation — Most patients who present with PCP are not receiving ART at the time of their diagnosis. For such patients, we recommend ART be initiated within two weeks of starting PCP treatment [9], preferably as soon as they are stable on PCP treatment. The use of early versus deferred ART was supported in a trial that enrolled 282 patients who presented with an opportunistic infection (OI), of whom the majority (63 percent) had PCP. Patients were randomly assigned to early ART (initiation within two weeks of starting OI therapy) or deferred ART (initiation after completing OI therapy) [53]. Early therapy reduced the risk of AIDS progression and death by almost half, and was not associated with an increase in adverse events or an increase in the incidence of immune reconstitution inflammatory syndromes (IRIS). (See "Immune reconstitution inflammatory syndrome".)
A detailed discussion on selecting an antiretroviral regimen is found elsewhere. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)
Secondary prophylaxis — After completing an initial 21-day course of treatment, patients should continue to receive antimicrobial therapy at a reduced dose to prevent recurrent infection (ie, secondary prophylaxis). The risk of developing recurrent PCP without secondary prophylaxis is 60 to 70 percent per year in patients who are not receiving ART [54]. The antimicrobial regimens used for secondary prophylaxis are the same as those used to prevent initial infection and are described below. (See 'Regimens for prophylaxis' below.)
Secondary prophylaxis can be discontinued in patients receiving ART if they have an undetectable viral load and a rise in their CD4 count to ≥200 cells/microL for at least three months. Discontinuing prophylaxis is also reasonable if the CD4 count is between 100 to 200 cells/microL and the HIV ribonucleic acid (RNA) remains below the limit of detection for about six months. Several studies have evaluated when prophylaxis can be discontinued [55-58]. As an example, in a randomized trial of 113 patients with HIV with prior PCP on ART, secondary prophylaxis was safely discontinued after the CD4 cell count had increased to >200 cells/microL for more than three months [56]. Among the 60 patients who discontinued prophylaxis, there were no episodes of PCP during a median follow-up of 12 months (95% CI 0 to 4.5 episodes per 100 person-years).
It is unclear if prophylaxis should be discontinued in patients who were diagnosed with PCP when their CD4 count was ≥200 cells/microL. We discuss the option of discontinuing PCP prophylaxis with individuals who have achieved virologic suppression for a period of time (eg, at least three to six months), since control of HIV viremia improves immune function independent of the absolute CD4 cell count [59,60]. However, if PCP occurs at a CD4 count >200 cells/microL while on ART, it may be prudent to continue lifelong prophylaxis.
PREVENTING INITIAL INFECTION — Patients with advanced immune suppression are at risk for developing Pneumocystis pneumonia (PCP). PCP is most likely to occur in patients who have a CD4 count <200 cells/microL and are not receiving antiretroviral therapy (ART). A more detailed discussion of risk factors for PCP is found elsewhere. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Epidemiology'.)
The most effective way to prevent PCP is by improving immune function through use of antiretroviral therapy (ART). Antimicrobial agents should be administered for prophylaxis while awaiting immune recovery. (See 'Initiating antiretroviral therapy' below and 'Indications for antimicrobial prophylaxis' below and 'Regimens for prophylaxis' below.)
The risk of developing infection may also be reduced by avoiding exposure to P. jirovecii. As an example, we avoid having hospitalized patients with PCP share rooms with other immunocompromised patients since there are data to suggest that person-to-person transmission of PCP can occur [61]. However, there is no clear evidence that isolating patients with PCP will prevent transmission. A more detailed discussion on the transmission of PCP is found elsewhere. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Pathogenesis'.)
Initiating antiretroviral therapy — The most effective way to prevent PCP is by improving the immune system through use of ART. Thus, antiretroviral therapy should be initiated in all patients at risk of developing PCP. Immune recovery reduces the risk of developing PCP and allows prophylaxis to be discontinued. (See 'Indications for antimicrobial prophylaxis' below and 'Discontinuing primary prophylaxis' below.)
A detailed discussion on selecting an antiretroviral regimen is found elsewhere. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)
Antimicrobial prophylaxis — Antimicrobial prophylaxis reduces the risk of developing PCP ninefold in patients who have a CD4 counts <200 cells/microL and are not on ART [54]. Prophylaxis is also associated with decreased health care costs and decreased mortality in those who develop infection [54,62,63]. The most common reasons for failure of prophylaxis are nonadherence and/or a very low CD4 count (<50 cells/microL) [64].
Indications for antimicrobial prophylaxis — We agree with guidelines that recommend primary PCP prophylaxis for patients with any of the following [9]:
●CD4 count <200 cells/microL
●CD4 count percentage <14 percent
●CD4 cell count between 200 and 250 cells/microL when frequent monitoring (eg, every three months) of CD4 cell counts is not possible
We also administer PCP prophylaxis to individuals with a history of an AIDS-defining illness if they have not initiated ART or are not virologically suppressed on an ART regimen.
We would not initiate prophylaxis based on the CD4 count criteria above in patients who meet criteria for discontinuation of prophylaxis (prolonged viral suppression and CD4 count between 100 and 200 cells/microL) (see 'Discontinuing primary prophylaxis' below). This approach is supported by an observational study of 23,412 patients receiving ART where 253 cases of PCP occurred over approximately five years [58]. Antimicrobial prophylaxis significantly reduced the risk of developing PCP in patients who had a CD4 count <100 cells/microL (adjusted incidence rate ratio 0.41, 95% CI 0.27-0.60). However, among patients with a CD4 count between 100 to 200 cells/microL and a viral load <400 copies/mL, there was no significant difference in the incidence of PCP among those who did or did not receive antimicrobial prophylaxis (2.1 versus 1.2 cases per 1000 person years of follow-up).
Regimens for prophylaxis — Several oral regimens are available for PCP prophylaxis (table 2). Which regimen to use, and the recommended dose, are influenced by concurrent or prior infection with toxoplasmosis.
There have been many trials comparing the efficacy of different regimens for PCP prophylaxis [12,13,64-67]. Taken together, they suggest that TMP-SMX is the most effective agent for prophylaxis in patients who can tolerate it. This was best illustrated in a meta-analysis of 35 studies of PCP prophylaxis in 6583 patients [64]. TMP-SMX was superior to dapsone or aerosolized pentamidine for the prevention of PCP. However, there was no statistically significant survival advantage seen in those taking TMP-SMX compared with alternative agents.
Patients without a sulfa allergy — We recommend trimethoprim-sulfamethoxazole (TMP-SMX) as the treatment of choice for primary PCP prophylaxis in patients without a history of sulfa allergy. TMP-SMX also decreases this risk of toxoplasmosis and bacterial infections (including many respiratory bacterial infections) [64,68,69].
The dose of TMP-SMX used for PCP prophylaxis depends upon the patient’s risk for developing toxoplasmosis. The doses listed above are for patients with normal renal function; dose modifications for renal impairment may be needed. Detailed dosing recommendations are available in the drug information monograph included within UpToDate.
●We administer one double-strength (DS) tablet daily to patients who require antimicrobial therapy to prevent toxoplasmosis (ie, those who have a CD4 count <100 cells/microL and are IgG-positive for Toxoplasma gondii). (See "Toxoplasmosis in patients with HIV", section on 'Primary prophylaxis'.)
●We administer one single-strength (SS) tablet daily to patients who do not require preventive therapy for toxoplasmosis. An alternative option for such patients is one DS tablet three times per week.
We prefer the lower doses of TMP-SMX (eg, one SS tablet daily) in patients who do not require prophylaxis for toxoplasmosis since they have been found to be effective in preventing PCP and are better tolerated. Severe adverse effects requiring discontinuation of prophylaxis have been reported in 25 to 50 percent of patients receiving TMP-SMX [12,66]. Approximately 40 percent of reactions that require discontinuation of TMP-SMX occur in the first month of therapy [70]. (See 'Adverse reactions' above.)
A randomized trial of 260 patients with HIV with a CD4 count <200 cells/microL and no history of PCP compared daily treatment with TMP-SMX SS and TMP-SMX DS [71]. Patients were followed for a median of 376 days, and no patient in either group developed PCP. However, more adverse reactions requiring treatment discontinuation were seen with the DS regimen (hazard ratio 1.4, 95% CI 0.95-2.02).
Another randomized trial with a median follow-up of 22 months compared TMP-SMX DS daily with TMP-SMX DS three times per week in 2625 patients with HIV with a CD4 cell count <200 cells/microL [70]. In an intention-to-treat analysis, the yearly rate of PCP was similar in the two groups (3.5 versus 4.1 percent), although there were trends in favor of daily TMP-SMX for PCP, death, and bacterial pneumonia. However, discontinuation due to adverse events was more common in the daily therapy group (relative risk 2.14, 95% CI 1.73-2.66).
Patients with a sulfa allergy — For most patients unable to tolerate TMP-SMX, we use dapsone over atovaquone since it is a less expensive alternative and has comparable efficacy to atovaquone [72,73]. Dapsone is a sulfone that is usually tolerated by persons who have adverse reactions to TMP-SMX [12,13]. However, it may be prudent to avoid dapsone in patients who have had serious reactions to TMP-SMX (eg, Stevens Johnson syndrome/toxic epidermal necrolysis, rash with fever and systemic symptoms, serum sickness, or hemolytic anemia). (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Cross-reactivity'.)
Aerosolized pentamidine (AP) is our last choice. Although AP is generally well tolerated, it is less effective than other regimens, requires special equipment, and is associated with transmission of other respiratory pathogens [12,74]. In addition, AP is only effective locally; if dispersal of the aerosol does not reach all portions of the lungs, untreated areas remain at risk for PCP. Another option for TMP-SMX-allergic patients is desensitization to TMP-SMX. This is discussed below. (See 'Desensitization for patients with a sulfa allergy' below.)
The alternative regimens are dosed as follows:
●Dapsone – The usual regimens for dapsone when used for PCP prophylaxis are:
•Dapsone 50 mg orally twice daily
•Dapsone 100 mg orally once daily
•Dapsone 50 mg orally once daily plus pyrimethamine 50 mg once weekly and leucovorin 25 mg one weekly
•(Dapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg) orally once weekly
If dapsone is going to be prescribed, patients should be screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency since patients with G6PD-deficiency are at risk for developing hemolytic anemia with dapsone (see "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency"). More detailed discussions of dapsone are found above. (See 'Alternative regimens for mild to moderate disease' above and 'Adverse reactions' above.)
●Atovaquone – The dose of atovaquone suspension for PCP prophylaxis is 1500 mg daily given with food. More detailed discussions of atovaquone are found above. (See 'Alternative regimens for mild to moderate disease' above and 'Adverse reactions' above.)
●Aerosolized pentamidine – We administer AP for PCP prophylaxis only when other therapies cannot be used. The recommended dose of AP is 300 mg monthly via a nebulizer. AP is generally administered with two puffs of albuterol to reduce cough and bronchospasm.
Screening for active tuberculosis, including a baseline chest x-ray, should be performed before AP is administered since there is a concern about transmission of tuberculosis to health care workers and other patients through pentamidine-induced bronchospasm [75,76]. In addition, AP should be administered in a negative pressure room in order to contain both aerosolized particles of the drug and any microbes that may be expectorated. When AP needs to be administered in an individual patient's hospital room, a HEPA-filtered containment tent should be used and the airflow into this room should be temporarily altered to negative pressure, if possible.
The major side effects of AP are cough and bronchospasm. The use of AP is also a risk factor for developing a pneumothorax [77]. (See "Clinical presentation and diagnosis of pneumothorax".)
Dapsone alone and aerosolized pentamidine do not provide sufficient protection to prevent reactivation of T. gondii [78]. Thus, additional agents must be used for patients who require treatment to prevent toxoplasmosis. A discussion on the prevention of toxoplasmosis is found elsewhere. (See "Toxoplasmosis in patients with HIV", section on 'Prevention'.)
Patients being treated for toxoplasmosis — Patients who are receiving initial or maintenance therapy for toxoplasmosis with pyrimethamine/sulfadiazine do not require additional preventive therapy for PCP. (See "Toxoplasmosis in patients with HIV", section on 'Preferred regimens'.)
Pregnant women — A detailed discussion on the prevention of PCP in pregnant women is found elsewhere. (See "Prenatal evaluation of women with HIV in resource-rich settings", section on 'Chemoprophylaxis for opportunistic infections'.)
Discontinuing primary prophylaxis
CD4 count >200 cells/microl — We discontinue primary PCP prophylaxis in patients who are receiving ART and have an undetectable viral load if the CD4 count ≥200 cells/microL for three months or longer. This recommendation is consistent with guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV [9] and is supported by several studies suggesting a low risk of PCP in this population [79-82]. As an example, in a meta-analysis that evaluated 12 studies with 3035 subjects who discontinued primary PCP prophylaxis following immune reconstitution on ART (mainly defined by CD4 cell count >200 cells/microL), seven cases of PCP occurred with a cumulative incidence of 0.23 percent (95% CI 0.09-0.48) [82].
CD4 count 100-200 cells/microl — We discontinue primary PCP prophylaxis in patients with a CD4 count between 100 and 200 cells/microL if they are receiving ART and have had an undetectable viral load for six months or longer. The risk of PCP appears extremely low in such patients if virologic suppression is maintained [58,83]. In a cohort study that followed approximately 5000 patients for a median duration of 3.5 years, no cases of PCP occurred in patients who were virologically suppressed and discontinued prophylaxis with a CD4 count between 100 and 200 cells/microL (95% CI 0.0-2.7 cases per 1000 person-years of follow-up) [58].
CD4 count <100 cells/microL — We generally prefer to continue primary PCP prophylaxis in patients with a CD4 count <100 cells/microL. This recommendation is consistent with guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV [9]. Since most patients starting on ART with low CD4 cell counts gain on average 100 to 200 cells/microL per year, they usually meet the threshold to consider discontinuation (ie, CD4 cell count ≥100 cells/microL and prolonged virologic suppression) within several months. However, if patients are receiving ART, have had an undetectable viral load for six months or longer, and the CD4 cell count remains below 100 cells/microL, it may be reasonable to discontinue primary prophylaxis, although we do not routinely do this because the risk of PCP is highest at these CD4 cell count levels.
In a cohort study that followed approximately 5000 patients on ART for a median duration of 4.3 years, there was no significant difference in incidence of PCP in patients who stopped primary PCP prophylaxis when CD4 >200 cells/microL compared with those who stopped when viral load was undetectable for three months or longer, regardless of CD4 cell count (adjusted hazard ratio 0.8, 95% CI 0.6-1.1) [84]. However, patients with CD4 cell count <100 cells/microL comprised 67 percent of new PCP cases, suggesting that CD4 counts <100 cells/microL is still a risk factor for PCP even in those with an undetectable viral load.
Restarting primary prophylaxis — Prophylaxis should be reintroduced if:
●CD4 count falls to <100 cells/microL
●CD4 count falls between 100-200 cells/microL and the viral load becomes detectable
These recommendations reflect the patient populations that are at highest risk of PCP infection. We do not recommend restarting primary prophylaxis in patients with CD4 counts between 100 to 200 cells/microL if their viral load has remained undetectable for six months or longer. (See 'Indications for antimicrobial prophylaxis' above.)
DESENSITIZATION FOR PATIENTS WITH A SULFA ALLERGY — Trimethoprim-sulfamethoxazole (TMP-SMX) can be reintroduced to certain individuals with a history of an isolated cutaneous reaction to sulfa (ie, without systemic involvement). More detailed discussions on the manifestations and management of sulfonamide allergies are found elsewhere. (See "Sulfonamide allergy in HIV-uninfected patients" and "Trimethoprim-sulfamethoxazole: An overview", section on 'Adverse effects and precautions'.)
For such patients, we attempt to "desensitize" the patient to TMP-SMX using a gradual dose escalation. We administer the following desensitization protocol using TMP-SMX pediatric suspension (TMP 8 mg/mL and SMX 40 mg/mL) [85]:
●Day 1: 1.25 mL once
●Day 2: 1.25 mL twice daily
●Day 3: 1.25 mL three times daily
●Day 4: 2.5 mL twice daily
●Day 5: 2.5 mL three times daily
●Day 6: one SS tablet
One SS tablet daily can be used for prophylaxis. For those who require full treatment doses, the dose can then be gradually increased over several days (see 'Preferred regimen' above).
For example, the protocol above can be continued as below:
●Day 7: one SS tablet three times daily
●Day 8: One DS tablet twice daily
●Day 9: Two DS tablets twice daily
●Day 10: Two DS tablets three times daily (for a target dose of approximately 15 mg/kg/day for a 60 kg person)
An alternative PCP regimen should be used until a patient is able to tolerate treatment doses. (See 'Alternative regimens' above.)
Although a majority of patients may be able to tolerate TMP-SMX when rechallenged with the full dose [85,86], dose escalation over one to two weeks reduces the risk of developing an adverse reaction [85,87]. As an example, a randomized trial compared dose escalation of TMP-SMX with immediate resumption of a SS tablet daily in 190 patients with HIV who had previously discontinued TMP-SMX for an adverse reaction [85]. The trial was stopped early by a monitoring board since more patients who received dose escalation remained on TMP-SMX at six months (75 versus 57 percent).
Desensitization to TMP-SMX is reviewed in more detail separately. (See "Sulfonamide allergy in HIV-uninfected patients", section on 'Protocols for past rash/fever'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults with HIV".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Pneumocystis pneumonia (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Overview − Pneumocystis jirovecii pneumonia (formerly called Pneumocystis carinii pneumonia or PCP) is the most common opportunistic respiratory infection in patients with HIV. It typically occurs in patients with HIV with a CD4 count <200 cells/microL who are not receiving antiretroviral therapy or appropriate prophylaxis. Antimicrobial therapy directed against P. jiroveci is the mainstay of treatment for PCP. (See 'Introduction' above.)
●Approach to treatment − The approach to treatment (eg, the choice of agent, the mode of administration, and the use of adjunctive corticosteroids) is based upon the severity of disease. Preferred and alternative regimen dosing and duration are presented in the table (table 1). (See 'Preferred regimen' above and 'Alternative regimens' above.)
•Severe disease − For patients with severe disease, we recommend treatment with intravenous (IV) trimethoprim-sulfamethoxazole (TMP-SMX) rather than IV pentamidine (Grade 1A). For patients with severe disease who are unable to take TMP-SMX, we suggest clindamycin-primaquine rather than IV pentamidine (Grade 2B). However, for such patients who cannot take medications orally, pentamidine is the only IV option. If pentamidine is used, patients should be switched to a less toxic regimen as soon as they can tolerate oral therapy. (See 'Severe disease' above.)
•Mild to moderate disease − For individuals with mild to moderate disease, we suggest treatment with oral TMP-SMX rather than oral trimethoprim-dapsone (Grade 2B). For most individuals with mild to moderate disease who are unable to take TMP-SMX, we suggest dapsone plus trimethoprim or clindamycin plus primaquine rather than atovaquone (Grade 2B). Treatment with atovaquone for PCP should preferentially be limited to patients with mild disease, or to complete a course of therapy in patients improving on TMP-SMX who develop an adverse reaction and need to stop it. (See 'Mild disease' above and 'Moderate disease' above.)
•Indications for hospitalization − Patients with PCP sometimes worsen after two to three days of therapy. In general, hospitalization for therapy is warranted in patients who need treatment with corticosteroids, initial treatment with IV pentamidine given the potential side effects of therapy (eg, hypoglycemia, hypotension), and patients for whom compliance with therapy or laboratory monitoring is likely to be difficult. (See 'Indications for hospitalization' above.)
●Use of adjunctive corticosteroids − For patients with moderate to severe disease (eg, a partial pressure of oxygen of <70 mmHg on room air and/or an alveolar-arterial (A-a) oxygen gradient of ≥35 mmHg), we recommend initiating corticosteroids (Grade 1A). We also administer corticosteroids to patients with clear evidence of hypoxemia (eg, resting room air oxygen saturation <92 percent). Corticosteroids should be administered concurrently with anti-Pneumocystis therapy in this setting to decrease the incidence of mortality and respiratory failure associated with PCP. (See 'Use of corticosteroids' above.)
●Approach to pregnant patients − TMP-SMX is the preferred therapy for PCP in pregnant women. If an alternative therapy must be used, trimethoprim-dapsone can be administered since there is clinical experience with this regimen in pregnancy. (See 'Pregnancy' above.)
●Monitoring patients on treatment − Patients should be monitored for adverse events related to their treatment regimen and their response to therapy. A change in regimen may be needed for patients who develop severe adverse reactions (eg, Stevens-Johnson syndrome with TMP-SMX, pancreatitis, or renal failure with pentamidine). We also modify the treatment regimen for patients failing therapy (no improvement after four to eight days of therapy), especially those with severe disease who do not improve after eight days. (See 'Monitoring patients on treatment' above.)
●Timing of ART initiation − For patients with PCP who are not receiving antiretroviral therapy (ART) at the time of their diagnosis, we recommend ART be initiated within two weeks of PCP treatment (Grade 1B). Early ART (versus starting therapy after PCP treatment) can reduce the risk of AIDS progression and death in patients presenting with PCP. (See 'Timing of ART initiation' above.)
●Secondary prophylaxis − After completing their initial 21-day course of treatment, patients should continue to receive antimicrobial therapy at a reduced dose to prevent recurrent infection (ie, secondary prophylaxis). Secondary prophylaxis can be discontinued in patients receiving ART if they have an undetectable viral load and a rise in their CD4 count to ≥200 cells/microL for at least three months. (See 'Secondary prophylaxis' above.)
●Preventing initial infection − The most effective way to prevent PCP is by improving the immune system through use of ART. (See 'Preventing initial infection' above.)
•Indications for prophylaxis − We administer PCP prophylaxis to patients with any of the following characteristics:
-CD4 count <200 cells/microL
-CD4 percentage <14 percent
-History of an AIDS-defining illness if they have not initiated ART or are not virologically suppressed while receiving an ART regimen.
-CD4 count between 200 and 250 cells/microL when frequent monitoring of CD4 counts is not possible. (See 'Indications for antimicrobial prophylaxis' above.)
•Regimens for prophylaxis − For patients who meet criteria for PCP prophylaxis, we recommend TMP-SMX rather than dapsone (Grade 1A). For individuals who cannot take TMP-SMX or dapsone, atovaquone is preferred over aerosolized pentamidine (table 2). (See 'Regimens for prophylaxis' above.)
•Discontinuation of prophylaxis − We discontinue primary PCP prophylaxis in patients receiving ART if they have an undetectable viral load and a rise in their CD4 count to ≥200 cells/microL for at least three months or have prolonged viral suppression and a CD4 count between 100 and 200 cells/microL. (See 'Discontinuing primary prophylaxis' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Patricia Tietjen, MD, who contributed to an earlier version of this topic review.
UpToDate also gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.
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