Pneumocystis pneumonia (PCP) is caused by Pneumocystis jirovecii, a ubiquitous fungus. The taxonomy of the organism has been changed; Pneumocystis carinii now refers only to the Pneumocystis that infects rats, and P. jirovecii refers to the distinct species that infects humans. However, the abbreviation PCP is still used to designate Pneumocystis pneumonia. Initial infection with P. jirovecii usually occurs in early childhood; two-thirds of healthy children have antibodies to P. jirovecii by age 2 years to 4 years.1
Rodent studies and case clusters in immunosuppressed patients suggest that Pneumocystis spreads by the airborne route. Disease probably occurs by new acquisition of infection and by reactivation of latent infection.2-11 Before the widespread use of PCP prophylaxis and antiretroviral therapy (ART), PCP occurred in 70% to 80% of patients with AIDS;12 the course of treated PCP was associated with a 20% to 40% mortality rate in individuals with profound immunosuppression. Approximately 90% of PCP cases occurred in patients with CD4 T lymphocyte (CD4) cell counts <200 cells/mm3. Other factors associated with a higher risk of PCP in the pre-ART era included CD4 cell percentage <14%, previous episodes of PCP, oral thrush, recurrent bacterial pneumonia, unintentional weight loss, and higher plasma HIV RNA levels.13,14
The incidence of PCP has declined substantially with widespread use of PCP prophylaxis and ART; recent incidence among patients with AIDS in Western Europe and the United States is <1 case per 100 person-years.15-17 Most cases of PCP now occur in patients who are unaware of their HIV infection or are not receiving ongoing care for HIV,18 and in those with advanced immunosuppression (i.e., CD4 counts <100 cells/mm3).19
In patients with HIV, the most common manifestations of PCP are subacute onset of progressive dyspnea, fever, non-productive cough, and chest discomfort that worsens within days to weeks. The fulminant pneumonia observed in patients who do not have HIV is less common among patients with HIV.20,21
In mild cases, pulmonary examination while the patient is at rest usually is normal. With exertion, tachypnea, tachycardia, and diffuse dry (cellophane) rales may be observed.21 Oral thrush is a common coinfection. Fever is apparent in most cases and may be the predominant symptom in some patients. Extrapulmonary disease is rare but can occur in any organ and has been associated with use of aerosolized pentamidine prophylaxis.22
Hypoxemia, the most characteristic laboratory abnormality, can range from mild (room air arterial oxygen [PO2] ≥70 mm Hg or alveolar-arterial PO2 gradient [A-a] DO2 <35 mm Hg) to moderate ([A-a] DO2 ≥35 to <45 mm Hg) to severe ([A-a] DO2 ≥45 mm Hg). Oxygen desaturation with exercise is often abnormal but is non-specific.23 Elevation of lactate dehydrogenase levels to >500 mg/dL is common but also non-specific.24 The chest radiograph typically demonstrates diffuse, bilateral, symmetrical “ground-glass” interstitial infiltrates emanating from the hila in a butterfly pattern;21 however, in patients with early disease, a chest radiograph may be normal.25 Atypical radiographic presentations, such as nodules, blebs and cysts, asymmetric disease, upper lobe localization, intrathoracic adenopathy, and pneumothorax, also occur. Spontaneous pneumothorax in a patient with HIV infection should raise the suspicion of PCP.26,27 Cavitation and pleural effusion are uncommon in the absence of other pulmonary pathogens or malignancy, and their presence may indicate an alternative diagnosis or an additional pathology. In fact, approximately 13% to 18% of patients with documented PCP have another concurrent cause of pulmonary dysfunction, such as tuberculosis (TB), Kaposi sarcoma, or bacterial pneumonia.28,29
Thin-section computed tomography (CT) is a useful adjunctive study, since even in patients with mild-to-moderate symptoms and a normal chest radiograph, a CT scan will be abnormal, demonstrating “ground-glass” attenuation that may be patchy, while a normal CT has a high negative predictive value.30,31
Because clinical presentation, blood tests, and chest radiographs are not pathognomonic for PCP (and because the organism cannot be cultivated routinely), histopathologic or cytopathologic demonstration of organisms in tissue, bronchoalveolar lavage (BAL) fluid, or induced sputum samples20,28,29,32 is required for a definitive diagnosis of PCP. Spontaneously expectorated sputum has low sensitivity for the diagnosis of PCP and should not be submitted to the laboratory to diagnose PCP. Giemsa, Diff-Quik, and Wright stains detect both the cystic and trophic forms of P. jirovecii but do not stain the cyst wall; Grocott-Gomori methenamine silver, Gram-Weigert, cresyl violet, and toluidine blue stain the cyst wall. Some laboratories prefer direct immunofluorescent staining. The sensitivity and specificity of respiratory samples for PCP depend on the stain being used, the experience of the microbiologist or pathologist, the pathogen load, and specimen quality. Previous studies of stained respiratory tract samples obtained by various methods indicate the following relative diagnostic sensitivities: <50% to >90% for induced sputum, 90% to 99% for bronchoscopy with BAL, 95% to 100% for transbronchial biopsy, and 95% to 100% for open lung biopsy.
Polymerase chain reaction (PCR) is an alternative method for diagnosing PCP. PCR is highly sensitive and specific for detecting Pneumocystis; however, PCR cannot reliably distinguish colonization from active disease, although higher organism loads as determined by quantitative PCR (Q-PCR) assays are likely to represent clinically significant disease.33-35 1,3 β-D-glucan (β-glucan), which is a component of the cell wall of Pneumocystis cysts, is often elevated in patients with PCP. The sensitivity of the β-glucan assay for diagnosis of PCP appears to be high, thus PCP is less likely in patients with a low level of β-glucan (e.g., <80 pg/mL using the Fungitell assay). However, the specificity of β-glucan testing for establishing a PCP diagnosis is low,36-38 since many other fungal diseases, cellulose membranes used for hemodialysis, and some drugs can elevate β-glucan levels.
Because the clinical manifestations of several disease processes are similar, it is important to seek a definitive diagnosis of PCP disease rather than rely on a presumptive diagnosis, especially in patients with moderate-to-severe disease. However, PCP treatment can be initiated before a definitive diagnosis is established because P. jirovecii persist in clinical specimens for days or weeks after effective therapy is initiated.32
Pneumocystis can be quantified in the air near patients with PCP,39 and multiple outbreaks, each caused by a distinct strain of Pneumocystis, have been documented among kidney transplant patients.5-11,40 Although these findings strongly suggest that isolating patients with known PCP from patients at high risk for PCP may be beneficial, there are insufficient data to support isolation as standard practice to prevent PCP (CIII).
Indication for Primary Prophylaxis
Adults and adolescents with HIV, including pregnant women and those on ART, with CD4 counts <200 cells/mm3 should receive chemoprophylaxis against PCP(AI).12,13,41 Persons who have a CD4 cell percentage <14% should also be considered for PCP prophylaxis (BII).12,13,41 If ART initiation must be delayed and frequent monitoring of CD4 counts (e.g., every 3 months) is impossible, some experts recommend starting PCP chemoprophylaxis at CD4 counts ≥200 cells/mm3 to ≤250 cells/mm3 (BII).13 Patients receiving pyrimethamine-sulfadiazine for treatment or suppression of toxoplasmosis do not require additional prophylaxis for PCP (AII).42
Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended prophylactic agent for PCP (AI).41,43-45 One double-strength TMP-SMX tablet daily is the preferred regimen (AI), but one single-strength tablet daily45 is also effective and may be better tolerated than the double-strength tablet (AI). One double-strength TMP-SMX tablet three times weekly also is effective (BI).46 TMP-SMX at a dose of one double-strength tablet daily confers cross protection against toxoplasmosis47 and many respiratory bacterial infections.43,48 Lower doses of TMP-SMX may also confer such protection, potentially with less toxicity, though randomized controlled data addressing this possibility are unavailable. TMP-SMX chemoprophylaxis should be continued, when clinically feasible, in patients who have non life threatening adverse reactions. In those who discontinue TMP-SMX because of a mild adverse reaction, re-institution of the drug should be considered after the reaction has resolved (AII). Therapy should be permanently discontinued (with no rechallenge) in patients with life-threatening adverse reactions including possible or definite Stevens-Johnson syndrome or toxic epidermal necrolysis (AIII). Patients who have experienced adverse events, including fever and rash, may better tolerate re-introduction of TMP-SMX if the dose is gradually increased according to published regimens (BI)49,50 or if the drug is given at a reduced dose or frequency (CIII). As many as 70% of patients can tolerate such re-institution of TMP-SMX therapy.48
For patients who cannot tolerate TMP-SMX, alternative prophylactic regimens include dapsone (BI),43 dapsone plus pyrimethamine plus leucovorin (BI),51-53 aerosolized pentamidine administered with the Respirgard II nebulizer (manufactured by Marquest; Englewood, Colorado) (BI),44 and atovaquone (BI).54,55 Atovaquone is as effective as aerosolized pentamidine54 or dapsone55 but substantially more expensive than the other regimens. For patients seropositive for Toxoplasma gondii who cannot tolerate TMP-SMX, recommended alternatives for prophylaxis against both PCP and toxoplasmosis include dapsone plus pyrimethamine plus leucovorin (BI),51-53 or atovaquone, with or without pyrimethamine, plus leucovorin (CIII).
The following regimens cannot be recommended as alternatives to TMP-SMX because data regarding their efficacy for PCP prophylaxis are insufficient:
- Aerosolized pentamidine administered by nebulization devices other than the Respirgard II nebulizer
- Intermittently administered parenteral pentamidine
- Oral clindamycin plus primaquine
Clinicians can consider using these agents, however, in situations in which TMP-SMX or the recommended alternative prophylactic regimens cannot be administered or are not tolerated (CIII).
Discontinuing Primary Prophylaxis
Primary Pneumocystis prophylaxis should be discontinued in adult and adolescent patients who have responded to ART with an increase in CD4 counts from <200 cells/mm3 to >200 cells/mm3 for >3 months (AI). In observational and randomized studies whose findings support this recommendation, most patients had CD4 counts >200 cells/mm3 for >3 months before discontinuing PCP prophylaxis.56-65 At discontinuation of prophylaxis, the median CD4 count was >300 cells/mm3, most participants had a CD4 cell percentage ≥14%, and many had sustained suppression of HIV plasma RNA levels below detection limits for the assay employed. Median follow-up was 6 months to 19 months.
Discontinuation of primary prophylaxis in patients with CD4 count increase to >200 cells/mm3 as a result of ART is recommended because its preventive benefits against PCP, toxoplasmosis, and bacterial infections are limited;58,64 stopping the drugs reduces pill burden, cost, and the potential for drug toxicity, drug interactions, and selection of drug-resistant pathogens. Prophylaxis should be reintroduced if the patient’s CD4 count decreases to <200 cells/mm3 (AIII).
A combined analysis of European cohorts,16,66 a small randomized trial,67 and a case series68 found a low incidence of PCP in patients with CD4 counts between 100 cells/mm3 and 200 cells/mm3, who were receiving ART and had HIV plasma viral loads <50 to 400 copies/mL, and who had stopped or never received PCP prophylaxis, suggesting that primary and secondary PCP prophylaxis can be safely discontinued in patients with CD4 counts between 100 cells/mm3 to 200 cells/mm3 and HIV plasma RNA levels below limits of detection of commercial assays. Data on which to base specific recommendations are inadequate, but one approach would be to stop primary prophylaxis in patients with CD4 counts of 100 cells/mm3 to 200 cells/mm3 if HIV plasma RNA levels remain below limits of detection for ≥3 months to 6 months (BII). Similar observations have been made with regard to stopping primary prophylaxis for Toxoplasma encephalitis.69
TMP-SMX is the treatment of choice for PCP (AI).70,71 Standard doses are summarized in the table; lower doses may also be effective, potentially with less toxicity, though randomized controlled data addressing this possibility are unavailable. The dose must be adjusted for abnormal renal function. Multiple randomized clinical trials indicate that TMP-SMX is as effective as parenteral pentamidine and more effective than other regimens for PCP treatment. Adding leucovorin to prevent myelosuppression during acute treatment is not recommended because efficacy in preventing this toxicity is questionable and some evidence exists for a higher failure rate in preventing PCP (AII).72 Outpatient therapy with oral TMP-SMX is highly effective in patients with mild-to-moderate disease (AI).71
Mutations associated with resistance to sulfa drugs have been documented, but their effect on clinical outcome is uncertain.73-76 Patients who have PCP despite TMP-SMX prophylaxis usually can be treated effectively with standard doses of TMP-SMX (BIII).
Patients with documented or suspected PCP and moderate-to-severe disease, defined by room air PO2 <70 mm Hg or PAO2-PaO2 ≥35 mm Hg, should receive adjunctive corticosteroids as soon as possible and certainly within 72 hours after starting specific PCP therapy (AI).77-82 The benefits of starting steroids later are unclear, but most clinicians would administer them even after 72 hours for patients with moderate-to-severe disease (BIII). Intravenous (IV) methylprednisolone at 75% of the corresponding oral prednisone dose can be used if parenteral administration is necessary.
Alternative therapeutic regimens for mild-to-moderate disease include: dapsone and TMP (BI),71,83 which may have efficacy similar to TMP-SMX with fewer side effects, but is less convenient given the number of pills; clindamycin plus primaquine (BI)84-86 (clindamycin can be administered IV for more severe cases, but primaquine is only available in an oral formulation); and atovaquone suspension (BI),70,87 which is less effective than TMP-SMX for mild-to-moderate disease but has fewer side effects. Whenever possible, patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency before primaquine or dapsone is administered.
Alternative therapeutic regimens for patients with moderate-to-severe disease include clindamycin-primaquine or IV pentamidine (AI).86,88,89 Some clinicians prefer clindamycin plus primaquine because this combination is more effective and less toxic than pentamidine.86,90-92
Aerosolized pentamidine should not be used to treat PCP because it has limited efficacy and is associated with more frequent relapse (AI).88,93,94
The recommended duration of therapy for PCP (irrespective of regimen) is 21 days (AII).20 The probability and rate of response to therapy depend on the agent used, number of previous PCP episodes, severity of pulmonary illness, degree of immunodeficiency, timing of initiation of therapy, and comorbidities.
Although overall the prognosis for patients with respiratory failure due to PCP is poor, over the past decades, survival for patients who require ICU care has improved as management of respiratory failure and HIV co-morbidities has improved.95-98 Special attention is necessary regarding the use of ART in such critically ill patients.99
Special Consideration with Regards to Starting ART (Including IRIS)
If not already started, ART should be initiated in patients, when possible, within 2 weeks of diagnosis of PCP (AI). In a randomized controlled trial of 282 patients with opportunistic infections (OIs) other than TB, 63% of whom had definite or presumptive PCP, the incidence of AIDS progression or death (a secondary study endpoint) was significantly lower among participants who initiated ART early than among those who delayed ART (median 12 days and 45 days after OI therapy initiation, respectively).100 Of note, none of the participants with PCP enrolled in the study had respiratory failure requiring intubation;100 initiating ART in such patients is problematic given the lack of parenteral preparations and unpredictble absorption of oral medications, as well as potential drug interactions with agents commonly used in the ICU.101
Paradoxical immune reconstitution inflammatory syndrome (IRIS) following an episode of PCP is rare but has been reported.102,103 Most cases occurred within weeks of the episode of PCP; symptoms included fever and recurrence or exacerbation of pulmonary symptoms including cough and shortness of breath, as well as worsening of a previously improving chest radiograph. Although IRIS in the setting of PCP has only rarely been life-threatening,104 patients should be closely followed for recurrence of symptoms after initiation of ART. Management of PCP-associated IRIS is not well defined; some experts recommend use of corticosteroids in patients with respiratory deterioration if other causes are ruled out.
Monitoring of Response to Pneumocystis Pneumonia Therapy and Adverse Events
Careful monitoring during PCP therapy is important to evaluate response to treatment and to detect toxicity as soon as possible. Follow-up after therapy includes assessment for early relapse, especially if therapy has been with an agent other than TMP-SMX or was shortened because of toxicity.
In patients with HIV, rates of adverse reaction to TMP-SMX are high (20% to 85% of patients).70,71,83,85,89,105-109 Common adverse effects are rash (30% to 55% of patients) (including Stevens-Johnson syndrome), fever (30% to 40% of patients), leukopenia (30% to 40% of patients), thrombocytopenia (15% of patients), azotemia (1% to 5% of patients), hepatitis (20% of patients), and hyperkalemia. Supportive care for common adverse effects should be attempted before TMP-SMX is discontinued (AIII). Rashes often can be “treated through” with antihistamines, nausea can be controlled with antiemetics, and fever can be managed with antipyretics.
The most common adverse effects of alternative therapies include methemoglobinemia and hemolysis with dapsone or primaquine (especially in those with G6PD deficiency); rash and fever with dapsone;71,83 azotemia, pancreatitis, hypoglycemia or hyperglycemia, leukopenia, electrolyte abnormalities, and cardiac dysrhythmia with pentamidine;87-89,108 anemia, rash, fever, and diarrhea with primaquine and clindamycin;71,84,85 and headache, nausea, diarrhea, rash, and transaminase elevations with atovaquone.70,107
Managing Treatment Failure
Clinical failure is defined as lack of improvement or worsening of respiratory function documented by arterial blood gases after ≥4 days to 8 days of anti-PCP treatment. Failure attributed to lack of drug efficacy occurs in approximately 10% of patients with mild-to-moderate PCP disease. However, there are not any convincing clinical trial data on which to base recommendations for the management of PCP treatment failure due lack of drug efficacy.
Clinicians should wait ≥4 days to 8 days before switching therapy for lack of clinical improvement (BIII). In the absence of corticosteroid therapy, early and reversible deterioration within the first 3 days to 5 days of therapy is typical, probably because of the inflammatory response caused by antibiotic-induced lysis of organisms in the lung. Other concomitant infections must be excluded as a cause of clinical failure;28,29 bronchoscopy with BAL should be strongly considered to evaluate for this possibility, even if the procedure was conducted before initiating therapy.
Treatment failure attributed to treatment-limiting toxicities occurs in up to one-third of patients.71 Switching to another regimen is the appropriate management for treatment-related toxicity (BII). When TMP-SMX is not effective or cannot be used for moderate-to-severe disease because of toxicity, the common practice is to use parenteral pentamidine or oral primaquine combined with IV clindamycin (BII).85,86,89 For mild disease, atovaquone is a reasonable alternative (BII). Although a meta-analysis, systematic review, and cohort study concluded that the combination of clindamycin and primaquine might be the most effective regimen for salvage therapy,86,91,92 no prospective clinical trials have evaluated the optimal approach for patients who experience a therapy failure with TMP-SMX.
When to Start Secondary Prophylaxis
Secondary PCP prophylaxis with TMP-SMX should be initiated immediately upon successful completion of PCP therapy and maintained until immune reconstitution occurs as a result of ART (see below) (AI).110 For patients who are intolerant of TMP-SMX, the alternatives are dapsone, dapsone plus pyrimethamine plus leucovorin, atovaquone, and aerosolized pentamidine.
When to Stop Secondary Prophylaxis
Secondary prophylaxis should be discontinued in adult and adolescent patients whose CD4 counts have increased from <200 cells/mm3 to >200 cells/mm3 for >3 months as a result of ART (AII). Reports from observational studies57,63,111,112 and from two randomized trials64,113 and a combined analysis of European cohorts being followed prospectively66,114 support this recommendation. In these studies, patients responded to ART with an increase in CD4 counts to ≥200 cells/mm3 for >3 months. At the time secondary PCP prophylaxis was discontinued, the median CD4 count was >300 cells/mm3 and most patients had a CD4 cell percentage >14%. Most patients had sustained suppression of plasma HIV RNA levels below the limits of detection for the assay employed; the longest follow-up was 40 months. Based on results from the COHERE study, secondary prophylaxis in patients with CD4 counts of 100 cells/mm3 to 200 cells/mm3 can potentially be discontinued if HIV plasma RNA levels remain below limits of detection for ≥3 months to 6 months (BII).66
When to Restart Primary or Secondary Prophylaxis
Primary or secondary PCP prophylaxis should be reintroduced if the patient’s CD4 count decreases to <100 cells/mm3 (AIII) regardless of the HIV plasma viral load. Prophylaxis should also be reintroduced for patients with CD4 counts of 100 cells/mm3 to 200 cells/mm3 with HIV plasma viral load above detection limits of the assay used (AIII). Based on results from the COHERE study, primary or secondary PCP prophylaxis may not need to be restarted in patients with CD4 counts of 100 cells/mm3 to 200 cells/mm3 who have had HIV plasma RNA levels below limits of detection for ≥3 to 6 months (BII).16,66
If an episode of PCP occurs at a CD4 count >200 cells/mm3 while a patient is on ART, it would be prudent for the patient to continue PCP prophylaxis for life, regardless of how high their CD4 cell count rises as a consequence of ART (BIII). For patients in whom PCP occurs at a CD4 count >200 cells/mm3 while not on ART, discontinuation of prophylaxis can be considered once HIV plasma RNA levels are suppressed to below limits of detection for ≥3 to 6 months, although there are no data to support recommendations in this setting (CIII).
Special Considerations During Pregnancy
PCP diagnostic considerations for pregnant women are the same as for women who are not pregnant.
Indications for PCP therapy are the same for pregnant women as for non-pregnant women. Some data suggest an increased risk of PCP-associated mortality in pregnancy, although there are no large, well-controlled studies evaluating the impact of pregnancy on PCP outcomes.115
The preferred initial therapy for PCP during pregnancy is TMP-SMX, although alternate therapies can be used if patients are unable to tolerate or are unresponsive to TMP-SMX (AI).116 In case-control studies, trimethoprim has been associated with an increased risk of neural tube defects and cardiovascular, urinary tract, and multiple anomalies after first-trimester exposure.117-119 One small study reported an increased risk of birth defects in infants born to women receiving antiretrovirals and folate antagonists, primarily trimethoprim; by contrast, no such increase was observed among infants exposed to either an antiretroviral or a folate antagonist alone.120 Although a small increased risk of birth defects may be associated with first-trimester exposure to trimethoprim, women in their first trimester with PCP still should be treated with TMP-SMX because of its considerable benefit (AIII).
Although folic acid supplementation at 0.4 mg/day is routinely recommended for all pregnant women,121 there are no trials evaluating whether supplementation at higher levels (e.g., 4 mg/day as recommended for pregnant women who previously had an infant with a neural tube defect) would reduce the risk of birth defects associated with first-trimester TMP-SMX use in women with HIV. Epidemiologic data suggest that folic acid supplementation may reduce the risk of congenital anomalies.118,119 In a large, population-based, case-control study, the increased odds of congenital cardiovascular anomalies associated with TMP-SMX use in pregnancy were not seen in women also receiving folic acid supplementation, most of whom received folic acid 6 mg/day (odds ratio [OR] 1.24; 95% CI, 0.94–1.62).117 Although the risk of multiple congenital abnormalities associated with TMP-SMX use persisted despite supplemental folic acid, the OR decreased from 6.4 for TMP-SMX without folic acid to 1.9 for TMP-SMX plus folic acid. On the basis of these findings, clinicians can consider giving supplemental folic acid (>0.4 mg/day routinely recommended) to women in their first trimester who are on TMP-SMX (BIII). On the other hand, a randomized, controlled trial demonstrated that adding folinic acid to TMP-SMX treatment for PCP was associated with an increased risk of therapeutic failure and death.72 In addition, there are case reports of failure of TMP-SMX prophylaxis in the setting of concurrent folinic acid use.122 Therefore, if supplemental folic acid (>0.4 mg/day routinely recommended) is given, its use should be limited to the first trimester during the teratogenic window (AIII). Whether a woman receives supplemental folic acid during the first trimester, a follow-up ultrasound is recommended at 18 weeks to 20 weeks to assess fetal anatomy (BIII).
A randomized, controlled trial published in 1956 found that premature infants receiving prophylactic penicillin/sulfisoxazole were at significantly higher risk of mortality, specifically kernicterus, than infants who received oxytetracycline.123 Because of these findings, some clinicians are concerned about the risk of neonatal kernicterus in the setting of maternal sulfonamide or dapsone use near delivery, although no published studies to date link late third-trimester exposure to either drug with neonatal death or kernicterus.
Adjunctive corticosteroid therapy should be used to improve the mother’s treatment outcome as indicated in non-pregnant adults (AIII).124-127 Patients with documented or suspected PCP and moderate-to-severe disease, as defined by room air PO2 <70 mm Hg or PAO2 - PaO2 >35 mm Hg, should receive adjunctive corticosteroids as early as possible. A systematic review of case-control studies evaluating women with first-trimester exposure to corticosteroids found a 3.4 increased odds of delivering a baby with a cleft palate.128 On the other hand, other large population-based studies have not found an association between maternal use of corticosteroids and congenital anomalies.129,130 Corticosteroid use in pregnancy may be associated with an increased risk of maternal hypertension, glucose intolerance or gestational diabetes, and infection.131 Maternal glucose levels should be monitored closely when corticosteroids are used in the third trimester because the risk of glucose intolerance is increased (AIII). Moreover, women receiving 20 mg/day of prednisone (or its dosing equivalent for other exogenous corticosteroids) for >3 weeks may have hypothalamic-pituitary-adrenal (HPA) axis suppression and use of stress-dose corticosteroids during delivery should be considered (BIII). HPA axis suppression is rarely seen among neonates born to women who received chronic corticosteroids during pregnancy.
Alternative therapeutic regimens for mild-to-moderate PCP disease include dapsone and TMP, primaquine plus clindamycin, atovaquone suspension, and IV pentamidine.
Dapsone appears to cross the placenta.132,133 For several decades, dapsone has been used safely to treat leprosy, malaria, and various dermatologic conditions during pregnancy.133,134 Long-term therapy is associated with a risk of mild maternal hemolysis, and exposed fetuses with G6PD deficiency are at potential risk (albeit extremely low) of acute hemolytic anemia.135
Clindamycin, which appears to cross the placenta, is a Food and Drug Administration (FDA) Pregnancy Category B medication and is considered safe for use throughout pregnancy.
Primaquine generally is not used in pregnancy because of the risk of maternal hemolysis. As with dapsone, there is potential risk of hemolytic anemia in a primaquine-exposed fetus with G6PD deficiency. The degree of intravascular hemolysis appears to be associated with both dose of primaquine and severity of G6PD deficiency.136
Data on atovaquone in human pregnancy are limited but preclinical studies have not demonstrated toxicity.136
Pentamidine is embryotoxic but not teratogenic in rats and rabbits.137
All-cause pneumonia during pregnancy increases rates of preterm labor and delivery. Women at >20 weeks gestation who have with pneumonia should be closely monitored for evidence of contractions (BIII).
Chemoprophylaxis for PCP should be administered to pregnant women as for non-pregnant adults and adolescents (AIII). TMP-SMX is the recommended prophylactic agent. Given theoretical concerns about possible teratogenicity associated with first-trimester drug exposures, health care providers may consider using alternative prophylactic regimens such as aerosolized pentamidine or oral atovaquone during the first-trimester (CIII) rather than withholding chemoprophylaxis.
Clinicians who are providing pre-conception care for women with HIV receiving PCP prophylaxis can discuss with their patients the option of deferring pregnancy until PCP prophylaxis can be safely discontinued (i.e., CD4 cell count >200 cells/mm3 for 3 months) (BIII).
Recommendations for Preventing and Treating Pneumocystis Pneumonia
|Preventing First Episode of PCP (Primary Prophylaxis)
Indications for Initiating Primary Prophylaxis:
For Mild to Moderate PCP: Total Duration of Treatment is 21 Days (AII)
For Moderate to Severe PCP Based on the Following Criteria (AI):
|Preventing Subsequent Episode of PCP (Secondary Prophylaxis)
Indications for Initiating Secondary Prophylaxis:
Indications for Restarting Secondary Prophylaxis:
aTMP-SMX DS once daily also confers protection against toxoplasmosis and many respiratory bacterial infections; a lower dose also likely confers protection.
- Pifer LL, Hughes WT, Stagno S, Woods D. Pneumocystis carinii infection: evidence for high prevalence in normal and immunosuppressed children. Pediatrics. 1978;61(1):35-41. Available at: http://www.ncbi.nlm.nih.gov/pubmed/400818.
- Keely SP, Stringer JR, Baughman RP, Linke MJ, Walzer PD, Smulian AG. Genetic variation among Pneumocystis carinii hominis isolates in recurrent pneumocystosis. J Infect Dis. 1995;172(2):595-598. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7542688.
- Helweg-Larsen J, Tsolaki AG, Miller RF, Lundgren B, Wakefield AE. Clusters of Pneumocystis carinii pneumonia: analysis of person-to-person transmission by genotyping. QJM. 1998;91(12):813-820. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10024946.
- Huang L, Beard CB, Creasman J, et al. Sulfa or sulfone prophylaxis and geographic region predict mutations in the Pneumocystis carinii dihydropteroate synthase gene. J Infect Dis. 2000;182(4):1192-1198. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10979917.
- Sassi M, Ripamonti C, Mueller NJ, et al. Outbreaks of Pneumocystis pneumonia in 2 renal transplant centers linked to a single strain of Pneumocystis: implications for transmission and virulence. Clin Infect Dis. 2012;54(10):1437-1444. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22431811.
- de Boer MG, Kroon FP, le Cessie S, de Fijter JW, van Dissel JT. Risk factors for Pneumocystis jirovecii pneumonia in kidney transplant recipients and appraisal of strategies for selective use of chemoprophylaxis. Transpl Infect Dis. 2011;13(6):559-569. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21689251.
- Arichi N, Kishikawa H, Mitsui Y, et al. Cluster outbreak of Pneumocystis pneumonia among kidney transplant patients within a single center. Transplant Proc. 2009;41(1):170-172. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19249506.
- Gianella S, Haeberli L, Joos B, et al. Molecular evidence of interhuman transmission in an outbreak of Pneumocystis jirovecii pneumonia among renal transplant recipients. Transpl Infect Dis. 2010;12(1):1-10. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19744285.
- Mori S, Cho I, Sugimoto M. A cluster of Pneumocystis jirovecii infection among outpatients with rheumatoid arthritis. J Rheumatol. 2010;37(7):1547-1548. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20595296.
- Schmoldt S, Schuhegger R, Wendler T, et al. Molecular evidence of nosocomial Pneumocystis jirovecii transmission among 16 patients after kidney transplantation. J Clin Microbiol. 2008;46(3):966-971. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18216217.
- Yazaki H, Goto N, Uchida K, Kobayashi T, Gatanaga H, Oka S. Outbreak of Pneumocystis jiroveci pneumonia in renal transplant recipients: P. jiroveci is contagious to the susceptible host. Transplantation. 2009;88(3):380-385. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19667941.
- Phair J, Munoz A, Detels R, Kaslow R, Rinaldo C, Saah A. The risk of Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. Multicenter AIDS Cohort Study Group. N Engl J Med. 1990;322(3):161-165. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1967190.
- Kaplan JE, Hanson DL, Navin TR, Jones JL. Risk factors for primary Pneumocystis carinii pneumonia in human immunodeficiency virus-infected adolescents and adults in the United States: reassessment of indications for chemoprophylaxis. J Infect Dis. 1998;178(4):1126-1132. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9806044.
- Kaplan JE, Hanson DL, Jones JL, Dworkin MS. Viral load as an independent risk factor for opportunistic infections in HIV-infected adults and adolescents. AIDS. 2001;15(14):1831-1836. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11579245.
- Buchacz K, Baker RK, Palella FJ, Jr., et al. AIDS-defining opportunistic illnesses in US patients, 1994-2007: a cohort study. AIDS. 2010;24(10):1549-1559. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20502317.
- Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE), Mocroft A, Reiss P, et al. Is it safe to discontinue primary Pneumocystis jiroveci pneumonia prophylaxis in patients with virologically suppressed HIV infection and a CD4 cell count <200 cells/microL? Clin Infect Dis. 2010;51(5):611-619. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20645862.
- Buchacz K, Lau B, Jing Y, et al. Incidence of AIDS-defining opportunistic infections in a multicohort analysis of HIV-infected persons in the United States and Canada, 2000-2010. J Infect Dis. 2016;214(6):862-872. Available at: http://www.ncbi.nlm.nih.gov/pubmed/27559122.
- Lundberg BE, Davidson AJ, Burman WJ. Epidemiology of Pneumocystis carinii pneumonia in an era of effective prophylaxis: the relative contribution of non-adherence and drug failure. AIDS. 2000;14(16):2559-2566. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11101068.
- Wolff AJ, O'Donnell AE. Pulmonary manifestations of HIV infection in the era of highly active antiretroviral therapy. Chest. 2001;120(6):1888-1893. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11742918.
- Kovacs JA, Hiemenz JW, Macher AM, et al. Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med. 1984;100(5):663-671. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6231873.
- Selwyn PA, Pumerantz AS, Durante A, et al. Clinical predictors of Pneumocystis carinii pneumonia, bacterial pneumonia and tuberculosis in HIV-infected patients. AIDS. 1998;12(8):885-893. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9631142.
- Ng VL, Yajko DM, Hadley WK. Extrapulmonary pneumocystosis. Clin Microbiol Rev. 1997;10(3):401-418. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9227859.
- Smith DE, McLuckie A, Wyatt J, Gazzard B. Severe exercise hypoxaemia with normal or near normal X-rays: a feature of Pneumocystis carinii infection. Lancet. 1988;2(8619):1049-1051. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2903279.
- Zaman MK, White DA. Serum lactate dehydrogenase levels and Pneumocystis carinii pneumonia. Diagnostic and prognostic significance. Am Rev Respir Dis. 1988;137(4):796-800. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3258483.
- Opravil M, Marincek B, Fuchs WA, et al. Shortcomings of chest radiography in detecting Pneumocystis carinii pneumonia. J Acquir Immune Defic Syndr. 1994;7(1):39-45. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8263751.
- Metersky ML, Colt HG, Olson LK, Shanks TG. AIDS-related spontaneous pneumothorax. Risk factors and treatment. Chest. 1995;108(4):946-951. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7555166.
- Sepkowitz KA, Telzak EE, Gold JW, et al. Pneumothorax in AIDS. Ann Intern Med. 1991;114(6):455-459. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1994791.
- Baughman RP, Dohn MN, Frame PT. The continuing utility of bronchoalveolar lavage to diagnose opportunistic infection in AIDS patients. Am J Med. 1994;97(6):515-522. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7985710.
- Stover DE, Zaman MB, Hajdu SI, Lange M, Gold J, Armstrong D. Bronchoalveolar lavage in the diagnosis of diffuse pulmonary infiltrates in the immunosuppressed host. Ann Intern Med. 1984;101(1):1-7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6375497.
- Gruden JF, Huang L, Turner J, et al. High-resolution CT in the evaluation of clinically suspected Pneumocystis carinii pneumonia in AIDS patients with normal, equivocal, or nonspecific radiographic findings. AJR Am J Roentgenol. 1997;169(4):967-975. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9308446.
- Hidalgo A, Falco V, Mauleon S, al. e. Accuracy of high-resolution CT in distinguishing between Pneumocystis carinii pneumonia and non-Pneumocystis carinii pneumonia in AIDS Patients. Eur Radiol. 2003;13(??):1179-1184.
- Roger PM, Vandenbos F, Pugliese P, et al. Persistence of Pneumocystis carinii after effective treatment of P. carinii pneumonia is not related to relapse or survival among patients infected with human immunodeficiency virus. Clin Infect Dis. 1998;26(2):509-510. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9502487.
- Torres J, Goldman M, Wheat LJ, et al. Diagnosis of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients with polymerase chain reaction: a blinded comparison to standard methods. Clin Infect Dis. 2000;30(1):141-145. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10619742.
- Larsen HH, Masur H, Kovacs JA, et al. Development and evaluation of a quantitative, touch-down, real-time PCR assay for diagnosing Pneumocystis carinii pneumonia. J Clin Microbiol. 2002;40(2):490-494. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11825961.
- Larsen HH, Huang L, Kovacs JA, et al. A prospective, blinded study of quantitative touch-down polymerase chain reaction using oral-wash samples for diagnosis of Pneumocystis pneumonia in HIV-infected patients. J Infect Dis. 2004;189(9):1679-1683. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15116305.
- Pisculli ML, Sax PE. Use of a serum beta-glucan assay for diagnosis of HIV-related Pneumocystis jiroveci pneumonia in patients with negative microscopic examination results. Clin Infect Dis. 2008;46(12):1928-1930. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18540807.
- Sax PE, Komarow L, Finkelman MA, et al. Blood (1->3)-beta-D-glucan as a diagnostic test for HIV-related Pneumocystis jirovecii pneumonia. Clin Infect Dis. 2011;53(2):197-202. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21690628.
- Li WJ, Guo YL, Liu TJ, Wang K, Kong JL. Diagnosis of Pneumocystis pneumonia using serum (1-3)-beta-D-Glucan: a bivariate meta-analysis and systematic review. J Thorac Dis. 2015;7(12):2214-2225. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26793343.
- Choukri F, Menotti J, Sarfati C, et al. Quantification and spread of Pneumocystis jirovecii in the surrounding air of patients with Pneumocystis pneumonia. Clin Infect Dis. 2010;51(3):259-265. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20572759.
- Pliquett RU, Asbe-Vollkopf A, Hauser PM, et al. A Pneumocystis jirovecii pneumonia outbreak in a single kidney-transplant center: role of cytomegalovirus co-infection. Eur J Clin Microbiol Infect Dis. 2012;31(9):2429-2437. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22402816.
- Centers for Disease Control and Prevention. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. MMWR Morb Mortal Wkly Rep. 1989;38(Suppl 5):1-9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2524643.
- Heald A, Flepp M, Chave JP, et al. Treatment for cerebral toxoplasmosis protects against Pneumocystis carinii pneumonia in patients with AIDS. The Swiss HIV Cohort Study. Ann Intern Med. 1991;115(10):760-763. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1929023.
- Bozzette SA, Finkelstein DM, Spector SA, et al. A randomized trial of three antiPneumocystis agents in patients with advanced human immunodeficiency virus infection. NIAID AIDS Clinical Trials Group. N Engl J Med. 1995;332(11):693-699. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7854375.
- Schneider MM, Hoepelman AI, Eeftinck Schattenkerk JK, et al. A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. The Dutch AIDS Treatment Group. N Engl J Med. 1992;327(26):1836-1841. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1360145.
- Schneider MM, Nielsen TL, Nelsing S, et al. Efficacy and toxicity of two doses of trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus. Dutch AIDS Treatment Group. J Infect Dis. 1995;171(6):1632-1636. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7769306.
- El-Sadr WM, Luskin-Hawk R, Yurik TM, et al. A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected persons. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). Clin Infect Dis. 1999;29(4):775-783. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10589887.
- Carr A, Tindall B, Brew BJ, et al. Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med. 1992;117(2):106-111. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1351371.
- Hardy WD, Feinberg J, Finkelstein DM, et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trials Group Protocol 021. N Engl J Med. 1992;327(26):1842-1848. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1448121.
- Para MF, Finkelstein D, Becker S, Dohn M, Walawander A, Black JR. Reduced toxicity with gradual initiation of trimethoprim-sulfamethoxazole as primary prophylaxis for Pneumocystis carinii pneumonia: AIDS Clinical Trials Group 268. J Acquir Immune Defic Syndr. 2000;24(4):337-343. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11015150.
- Leoung GS, Stanford JF, Giordano MF, et al. Trimethoprim-sulfamethoxazole (TMP-SMZ) dose escalation versus direct rechallenge for Pneumocystis Carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ. J Infect Dis. 2001;184(8):992-997. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11574913.
- Podzamczer D, Salazar A, Jimenez J, et al. Intermittent trimethoprim-sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of Pneumocystis pneumonia and toxoplasmosis in patients infected with HIV. Ann Intern Med. 1995;122(10):755-761. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7717598.
- Opravil M, Hirschel B, Lazzarin A, et al. Once-weekly administration of dapsone/pyrimethamine vs. aerosolized pentamidine as combined prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus-infected patients. Clin Infect Dis. 1995;20(3):531-541. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7756472.
- Girard PM, Landman R, Gaudebout C, al. e. Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. The PRIO Study Group. N Engl J Med. 1993;328(21):1514-1520. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8479488&query_hl=14&itool=pubmed_docsum.
- Chan C, Montaner J, Lefebvre EA, et al. Atovaquone suspension compared with aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfonamides. J Infect Dis. 1999;180(2):369-376. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10395851.
- El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. Community Program for Clinical Research on AIDS and the AIDS Clinical Trials Group. N Engl J Med. 1998;339(26):1889-1895. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9862944.
- Furrer H, Egger M, Opravil M, et al. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy. Swiss HIV Cohort Study. N Engl J Med. 1999;340(17):1301-1306. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10219064.
- Dworkin MS, Hanson DL, Kaplan JE, Jones JL, Ward JW. Risk for preventable opportunistic infections in persons with AIDS after antiretroviral therapy increases CD4+ T lymphocyte counts above prophylaxis thresholds. J Infect Dis. 2000;182(2):611-615. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10915098.
- Mussini C, Pezzotti P, Govoni A, et al. Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus type I-infected patients: the changes in opportunistic prophylaxis study. J Infect Dis. 2000;181(5):1635-1642. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10823763.
- Schneider MM, Borleffs JC, Stolk RP, Jaspers CA, Hoepelman AI. Discontinuation of prophylaxis for Pneumocystis carinii pneumonia in HIV-1-infected patients treated with highly active antiretroviral therapy. Lancet. 1999;353(9148):201-203. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9923876.
- Weverling GJ, Mocroft A, Ledergerber B, et al. Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in HIV-1 infection. EuroSIDA Study Group. Lancet. 1999;353(9161):1293-1298. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10218526.
- Yangco BG, Von Bargen JC, Moorman AC, Holmberg SD. Discontinuation of chemoprophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection. HIV Outpatient Study (HOPS) Investigators. Ann Intern Med. 2000;132(3):201-205. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10651600.
- Furrer H, Opravil M, Rossi M, et al. Discontinuation of primary prophylaxis in HIV-infected patients at high risk of Pneumocystis carinii pneumonia: prospective multicentre study. AIDS. 2001;15(4):501-507. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11242147.
- Kirk O, Lundgren JD, Pedersen C, Nielsen H, Gerstoft J. Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy? AIDS. 1999;13(13):1647-1651. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10509565.
- Lopez Bernaldo de Quiros JC, Miro JM, Pena JM, et al. A randomized trial of the discontinuation of primary and secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with HIV infection. Grupo de Estudio del SIDA 04/98. N Engl J Med. 2001;344(3):159-167. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11172138.
- Green H, Hay P, Dunn DT, McCormack S, Investigators S. A prospective multicentre study of discontinuing prophylaxis for opportunistic infections after effective antiretroviral therapy. HIV Med. 2004;5(4):278-283. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15236617.
- Furrer H, for the OI working group of COHERE in EuroCoord. HIV Replication is a Major Predictor of Primary and Recurrent Pneumocystis Pneumonia - Implications for Prophylaxis Recommendations. Presented at: 15th European AIDS Conference; 2015; Barcelona.
- Chaiwarith R, Praparattanapan J, Nuntachit N, Kotarathitithum W, Supparatpinyo K. Discontinuation of primary and secondary prophylaxis for opportunistic infections in HIV-infected patients who had CD4+ cell count <200 cells/mm(3) but undetectable plasma HIV-1 RNA: an open-label randomized controlled trial. AIDS Patient Care STDS. 2013;27(2):71-76. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23373662.
- D'Egidio GE, Kravcik S, Cooper CL, Cameron DW, Fergusson DA, Angel JB. Pneumocystis jiroveci pneumonia prophylaxis is not required with a CD4+ T-cell count < 200 cells/microl when viral replication is suppressed. AIDS. 2007;21(13):1711-1715. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17690568.
- Miro J, Esteve A, Furrer H, Opportunistic Infection Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. Safety of Stopping Primary T. gondii Prophylaxis With Suppressed Viremia and CD4>100. Presented at: CROI; 2016; Boston, Massachusetts. Available at: http://www.croiconference.org/sessions/safety-stopping-primary-t-gondii-prophylaxis-suppressed-viremia-and-cd4100.
- Hughes W, Leoung G, Kramer F, et al. Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med. 1993;328(21):1521-1527. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8479489.
- Safrin S, Finkelstein DM, Feinberg J, et al. Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine. ACTG 108 Study Group. Ann Intern Med. 1996;124(9):792-802. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8610948.
- Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. 1994;170(4):912-917. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7930736.
- Crothers K, Beard CB, Turner J, et al. Severity and outcome of HIV-associated Pneumocystis pneumonia containing Pneumocystis jirovecii dihydropteroate synthase gene mutations. AIDS. 2005;19(8):801-805. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15867494.
- Huang L, Crothers K, Atzori C, et al. Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance. Emerg Infect Dis. 2004;10(10):1721-1728. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15504256.
- Stein CR, Poole C, Kazanjian P, Meshnick SR. Sulfa use, dihydropteroate synthase mutations, and Pneumocystis jiroveccii pneumonia. Emerg Infect Dis. 2004;10(??):1760-1765.
- Alvarez-Martinez MJ, Miro JM, Valls ME, et al. Prevalence of dihydropteroate synthase genotypes before and after the introduction of combined antiretroviral therapy and their influence on the outcome of Pneumocystis pneumonia in HIV-1-infected patients. Diagn Microbiol Infect Dis. 2010;68(1):60-65. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20727472.
- Nielsen TL, Eeftinck Schattenkerk JK, Jensen BN, et al. Adjunctive corticosteroid therapy for Pneumocystis carinii pneumonia in AIDS: a randomized European multicenter open label study. J Acquir Immune Defic Syndr. 1992;5(7):726-731. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1613673.
- Bozzette SA, Sattler FR, Chiu J, et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group. N Engl J Med. 1990;323(21):1451-1457. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2233917.
- The National Institutes of Health-University of California Expert Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia. Consensus statement on the use of corticosteroids as adjunctive therapy for Pneumocystis pneumonia in the acquired immunodeficiency syndrome. N Engl J Med. 1990;323(21):1500-1504. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2136587.
- Montaner JS, Lawson LM, Levitt N, Belzberg A, Schechter MT, Ruedy J. Corticosteroids prevent early deterioration in patients with moderately severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrome (AIDS). Ann Intern Med. 1990;113(1):14-20. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2190515.
- Gallant JE, Chaisson RE, Moore RD. The effect of adjunctive corticosteroids for the treatment of Pneumocystis carinii pneumonia on mortality and subsequent complications. Chest. 1998;114(5):1258-1263. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9823998.
- Briel M, Bucher HC, Boscacci R, Furrer H. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV-infection. Cochrane Database Syst Rev. 2006;3:CD006150(3):CD006150. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16856118.
- Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med. 1990;323(12):776-782. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2392131.
- Black JR, Feinberg J, Murphy RL, et al. Clindamycin and primaquine therapy for mild-to-moderate episodes of Pneumocystis carinii pneumonia in patients with AIDS: AIDS Clinical Trials Group 044. Clin Infect Dis. 1994;18(6):905-913. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8086551.
- Toma E, Thorne A, Singer J, et al. Clindamycin with primaquine vs. Trimethoprim-sulfamethoxazole therapy for mild and moderately severe Pneumocystis carinii pneumonia in patients with AIDS: a multicenter, double-blind, randomized trial (CTN 004). CTN-PCP Study Group. Clin Infect Dis. 1998;27(3):524-530. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9770152.
- Smego RA, Jr., Nagar S, Maloba B, Popara M. A meta-analysis of salvage therapy for Pneumocystis carinii pneumonia. Arch Intern Med. 2001;161(12):1529-1533. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11427101.
- Dohn MN, Weinberg WG, Torres RA, et al. Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Atovaquone Study Group. Ann Intern Med. 1994;121(3):174-180. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7880228.
- Conte JE, Jr., Chernoff D, Feigal DW, Jr., Joseph P, McDonald C, Golden JA. Intravenous or inhaled pentamidine for treating Pneumocystis carinii pneumonia in AIDS. A randomized trial. Ann Intern Med. 1990;113(3):203-209. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2197911.
- Wharton JM, Coleman DL, Wofsy CB, et al. Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A prospective randomized trial. Ann Intern Med. 1986;105(1):37-44. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3521428.
- Kim T, Kim SH, Park KH, et al. Clindamycin-primaquine versus pentamidine for the second-line treatment of Pneumocystis pneumonia. J Infect Chemother. 2009;15(5):343-346. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19856077.
- Helweg-Larsen J, Benfield T, Atzori C, Miller RF. Clinical efficacy of first- and second-line treatments for HIV-associated Pneumocystis jirovecii pneumonia: a tri-centre cohort study. J Antimicrob Chemother. 2009;64(6):1282-1290. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19858161.
- Benfield T, Atzori C, Miller RF, Helweg-Larsen J. Second-line salvage treatment of AIDS-associated Pneumocystis jirovecii pneumonia: a case series and systematic review. J Acquir Immune Defic Syndr. 2008;48(1):63-67. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18360286.
- Soo Hoo GW, Mohsenifar Z, Meyer RD. Inhaled or intravenous pentamidine therapy for Pneumocystis carinii pneumonia in AIDS. A randomized trial. Ann Intern Med. 1990;113(3):195-202. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2197910.
- Montgomery AB, Feigal DW, Jr., Sattler F, et al. Pentamidine aerosol versus trimethoprim-sulfamethoxazole for Pneumocystis carinii in acquired immune deficiency syndrome. Am J Respir Crit Care Med. 1995;151(4):1068-1074. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7697233.
- Dworkin MS, Hanson DL, Navin TR. Survival of patients with AIDS, after diagnosis of Pneumocystis carinii pneumonia, in the United States. J Infect Dis. 2001;183(9):1409-1412. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11294675.
- Morris A, Wachter RM, Luce J, Turner J, Huang L. Improved survival with highly active antiretroviral therapy in HIV-infected patients with severe Pneumocystis carinii pneumonia. AIDS. 2003;17(1):73-80. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12478071.
- Miller RF, Allen E, Copas A, Singer M, Edwards SG. Improved survival for HIV infected patients with severe Pneumocystis jirovecii pneumonia is independent of highly active antiretroviral therapy. Thorax. 2006;61(8):716-721. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16601092.
- Powell K, Davis JL, Morris AM, Chi A, Bensley MR, Huang L. Survival for patients With HIV admitted to the ICU continues to improve in the current era of combination antiretroviral therapy. Chest. 2009;135(1):11-17. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18719058.
- Andrade HB, Shinotsuka CR, da Silva IRF, et al. Highly active antiretroviral therapy for critically ill HIV patients: A systematic review and meta-analysis. PLoS One. 2017;12(10):e0186968. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29065165.
- Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 2009;4(5):e5575. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19440326.
- Akgun KM, Miller RF. Critical Care in Human Immunodeficiency Virus-Infected Patients. Semin Respir Crit Care Med. 2016;37(2):303-317. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26974306.
- Grant PM, Komarow L, Andersen J, et al. Risk factor analyses for immune reconstitution inflammatory syndrome in a randomized study of early vs. deferred ART during an opportunistic infection. PLoS One. 2010;5(7):e11416. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20617176.
- Roade Tato L, Burgos Cibrian J, Curran Fabregas A, et al. Immune reconstitution inflammatory syndrome in HIV-infected patients with Pneumocystis jirovecii pneumonia. Enferm Infecc Microbiol Clin. 2018;36(10):621-626. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29187293.
- Jagannathan P, Davis E, Jacobson M, Huang L. Life-threatening immune reconstitution inflammatory syndrome after Pneumocystis pneumonia: a cautionary case series. AIDS. 2009;23(13):1794-1796. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19684486.
- Eeftinck Schattenkerk JK, Lange JM, van Steenwijk RP, Danner SA. Can the course of high dose cotrimoxazole for Pneumocystis carinii pneumonia in AIDS be shorter? A possible solution to the problem of cotrimoxazole toxicity. J Intern Med. 1990;227(5):359-362. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2341830.
- Gordin FM, Simon GL, Wofsy CB, Mills J. Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1984;100(4):495-499. Available at: http://www.ncbi.nlm.nih.gov/pubmed/6230976.
- Hughes WT, LaFon SW, Scott JD, Masur H. Adverse events associated with trimethoprim-sulfamethoxazole and atovaquone during the treatment of AIDS-related Pneumocystis carinii pneumonia. J Infect Dis. 1995;171(5):1295-1301. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7751706.
- Klein NC, Duncanson FP, Lenox TH, et al. Trimethoprim-sulfamethoxazole versus pentamidine for Pneumocystis carinii pneumonia in AIDS patients: results of a large prospective randomized treatment trial. AIDS. 1992;6(3):301-305. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1567574.
- Sattler FR, Frame P, Davis R, et al. Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter investigation of the AIDS Clinical Trials Group Protocol 029/031. J Infect Dis. 1994;170(1):165-172. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8014493.
- Masur H, Kaplan JE, Holmes KK, Service USPH, Infectious Diseases Society of A. Guidelines for preventing opportunistic infections among HIV-infected persons--2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. Ann Intern Med. 2002;137(5 Pt 2):435-478. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12617574.
- Soriano V, Dona C, Rodriguez-Rosado R, Barreiro P, Gonzalez-Lahoz J. Discontinuation of secondary prophylaxis for opportunistic infections in HIV-infected patients receiving highly active antiretroviral therapy. AIDS. 2000;14(4):383-386. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10770540.
- Zellweger C, Opravil M, Bernasconi E, et al. Long-term safety of discontinuation of secondary prophylaxis against Pneumocystis pneumonia: prospective multicentre study. AIDS. 2004;18(15):2047-2053. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15577626.
- Mussini C, Pezzotti P, Antinori A, et al. Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients: a randomized trial by the CIOP Study Group. Clin Infect Dis. 2003;36(5):645-651. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12594647.
- Ledergerber B, Mocroft A, Reiss P, et al. Discontinuation of secondary prophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection who have a response to antiretroviral therapy. Eight European Study Groups. N Engl J Med. 2001;344(3):168-174. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11188837.
- Ahmad H, Mehta NJ, Manikal VM, et al. Pneumocystis carinii pneumonia in pregnancy. Chest. 2001;120(2):666-671. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11502676.
- Connelly RT, Lourwood DL. Pneumocystis carinii pneumonia prophylaxis during pregnancy. Pharmacotherapy. 1994;14(4):424-429. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7937279.
- Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study. Reprod Toxicol. 2001;15(6):637-646. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11738517.
- Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med. 2000;343(22):1608-1614. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11096168.
- Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol. 2001;153(10):961-968. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11384952.
- Jungmann EM, Mercey D, DeRuiter A, et al. Is first trimester exposure to the combination of antiretroviral therapy and folate antagonists a risk factor for congenital abnormalities? Sex Transm Infect. 2001;77(6):441-443. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11714944.
- Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep. 1992;41(RR-14):1-7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1522835.
- Razavi B, Lund B, Allen BL, Schlesinger L. Failure of trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis carinii pneumonia with concurrent leucovorin use. Infection. 2002;30(1):41-42. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11876516.
- Andersen DH, Blanc WA, Crozier DN, Silverman WA. A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens. Pediatrics. 1956;18(4):614-625. Available at: http://www.ncbi.nlm.nih.gov/pubmed/13370229.
- Albino JA, Shapiro JM. Respiratory failure in pregnancy due to Pneumocystis carinii: report a successful outcome. Obstet Gynecol. 1994;83(5 Pt 2):823-824.
- Madinger NE, Greenspoon JS, Ellrodt AG. Pneumonia during pregnancy: has modern technology improved maternal and fetal outcome? Am J Obstet Gynecol. 1989;161(3):657-662. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2782348.
- Koonin LM, Ellerbrock TV, Atrash HK, et al. Pregnancy-associated deaths due to AIDS in the United States. JAMA. 1989;261(9):1306-1309. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2783746.
- Benedetti TJ, Valle R, Ledger WJ. Antepartum pneumonia in pregnancy. Am J Obstet Gynecol. 1982;144(4):413-417. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7124859.
- Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology. 2000;62(6):385-392. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11091360.
- Czeizel AE, Rockenbauer M. Population-based case-control study of teratogenic potential of corticosteroids. Teratology. 1997;56(5):335-340. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9451758.
- Kallen B. Maternal drug use and infant cleft lip/palate with special reference to corticoids. Cleft Palate Craniofac J. 2003;40(6):624-628. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14577813.
- Ostensen M, Khamashta M, Lockshin M, et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther. 2006;8(3):209. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16712713.
- Zuidema J, Hilbers-Modderman ES, Merkus FW. Clinical pharmacokinetics of dapsone. Clin Pharmacokinet. 1986;11(4):299-315. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3530584.
- Brabin BJ, Eggelte TA, Parise M, Verhoeff F. Dapsone therapy for malaria during pregnancy: maternal and fetal outcomes. Drug Saf. 2004;27(9):633-648. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15230645.
- Newman RD, Parise ME, Slutsker L, Nahlen B, Steketee RW. Safety, efficacy and determinants of effectiveness of antimalarial drugs during pregnancy: implications for prevention programmes in Plasmodium falciparum-endemic sub-Saharan Africa. Trop Med Int Health. 2003;8(6):488-506. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12791054.
- Thornton YS, Bowe ET. Neonatal hyperbilirubinemia after treatment of maternal leprosy. South Med J. 1989;82(5):668. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2717998.
- Nosten F, McGready R, d'Alessandro U, et al. Antimalarial drugs in pregnancy: a review. Curr Drug Saf. 2006;1(1):1-15. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18690910.
- Harstad TW, Little BB, Bawdon RE, Knoll K, Roe D, Gilstrap LC, 3rd. Embryofetal effects of pentamidine isethionate administered to pregnant Sprague-Dawley rats. Am J Obstet Gynecol. 1990;163(3):912-916. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2403167
Recommendations for Preventing and Treating Pneumocystis Pneumonia
|Preventing First Episode of PCP (Primary Prophylaxis)
Indications for Initiating Primary Prophylaxis:
For Mild to Moderate PCP: Total Duration of Treatment is 21 Days (AII)
For Moderate to Severe PCP Based on the Following Criteria (AI):
|Preventing Subsequent Episode of PCP (Secondary Prophylaxis)
Indications for Initiating Secondary Prophylaxis:
Indications for Restarting Secondary Prophylaxis:
aTMP-SMX DS once daily also confers protection against toxoplasmosis and many respiratory bacterial infections; a lower dose also likely confers protection.