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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents
(Last updated: October 28, 2014; last reviewed: October 28, 2014)
Pneumocystis pneumonia (PCP) is caused by Pneumocystis jirovecii, a ubiquitous organism that is classified as a fungus but also shares biologic characteristics with protozoa. 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. 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 ages 2 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 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 Most cases occur in patients who are unaware of their HIV infection or are not receiving ongoing care for HIV,16 and in those with advanced immunosuppression (CD4 counts <100 cells/mm3).17
In HIV-infected patients, 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 are not infected with HIV is less common.18,19
In mild cases, pulmonary examination usually is normal at rest. With exertion, tachypnea, tachycardia, and diffuse dry (cellophane) rales may be observed.19 Oral thrush is a common co infection. 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.20
Hypoxemia, the most characteristic laboratory abnormality, can range from mild (room air arterial oxygen [pO2] ≥70 mm Hg or alveolar-arterial O2 difference, [A-a] DO2 <35 mm Hg) to moderate ([A-a] DO2 ≥35 and <45 mm Hg) to severe ([A-a] DO2 ≥45 mm Hg). Oxygen desaturation with exercise is often abnormal but is non-specific.21 Elevation of lactate dehydrogenase levels to >500 mg/dL is common but non-specific.22 Chest radiograph typically demonstrates diffuse, bilateral, symmetrical interstitial infiltrates emanating from the hila in a butterfly pattern;19 however, a chest radiograph may be normal in patients with early disease.23 Atypical radiographic presentations also occur, such as nodules, blebs and cysts, asymmetric disease, upper lobe localization, and pneumothorax. Spontaneous pneumothorax in a patient with HIV infection should raise the suspicion of PCP.24,25 Cavitation, intrathoracic adenopathy, and pleural effusion are uncommon in the absence of other pulmonary pathogens or malignancy, and their presence may indicate an alternative diagnosis. Approximately 13% to 18% of patients with documented PCP have another concurrent cause of pulmonary dysfunction, such as tuberculosis (TB), Kaposi sarcoma (KS), or bacterial pneumonia.26,27
Thin-section computed tomography (CT) demonstrating patchy ground-glass attenuation28,29 increases the likelihood that a diagnostic study, such as bronchoscopy, will demonstrate PCP in patients with mild-to-moderate symptoms and normal chest radiograph and, therefore, may be useful as an adjunct.
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 samples18,26,27,30 is required for a definitive diagnosis. Spontaneously expectorated sputum has low sensitivity and should not be submitted to the laboratory to diagnose PCP. Giemsa, Diff-Quik, and Wright stains detect both the cystic and trophic forms but do not stain the cyst wall; Gomori methenamine silver, Gram-Weigert, cresyl violet, and toluidine blue stain the cyst wall. Some laboratories prefer direct immunofluorescent staining. Previous studies of stained respiratory tract samples obtained by various methods indicate the following relative diagnostic sensitivities: induced sputum <50% to >90% (the sensitivity depends on the pathogen load and specimen quality, while the specificity depends on the experience of the microbiologist or pathologist), bronchoscopy with BAL 90% to 99%, transbronchial biopsy 95% to 100%, and open lung biopsy 95% to 100%.
Polymerase chain reaction (PCR) is an emerging method for diagnosing PCP.31 The sensitivity of PCR for bronchoalveolar lavage appears to be high; the ability of PCR to distinguish colonization from disease is less clear.31-34 1,3ß-D-glucan (a component of fungal cell walls) may be elevated in patients with PCP, but the assay’s sensitivity and specificity for establishing a PCP diagnosis are problematic,35,36 and other fungal diseases can produce elevation.
Because certain processes produce similar clinical manifestations, a specific diagnosis of PCP should be sought rather than relying on a presumptive diagnosis, especially in patients with moderate-to-severe disease. Treatment can be initiated before making a definitive diagnosis because organisms persist in clinical specimens for days or weeks after effective therapy is initiated.30
Pneumocystis can be quantified in the air near patients with PCP,37 and multiple outbreaks, each caused by a distinct strain of Pneumocystis, have been documented among kidney transplant patients.5-11,38 Although these strongly suggest that high-risk patients without PCP may benefit from isolation from other patients with known PCP infection, data are insufficient to support isolation as standard practice (CIII).
Indication for Primary Prophylaxis
HIV-infected adults and adolescents, including pregnant women and those on ART, should receive chemoprophylaxis against PCP if they have CD4 counts <200 cells/mm3(AI) or a history of oropharyngeal candidiasis (AII).12,13,39 Persons who have a CD4 cell percentage of <14% or a history of an AIDS-defining illness, but who do not otherwise qualify, should be considered for prophylaxis (BII).12,13,39 Initiation of chemoprophylaxis at CD4 counts between 200 and 250 cells/mm3 also should be considered when frequent monitoring of CD4 counts, such as every 3 months, is impossible (BII).13 Patients receiving pyrimethamine-sulfadiazine for treatment or suppression of toxoplasmosis do not require additional prophylaxis for PCP (AII).40
Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended prophylactic agent (AI).39,41-43 One double-strength tablet daily is the preferred regimen (AI), but one single-strength tablet daily43 also is effective and may be better tolerated than the double-strength tablet (AI). One double-strength tablet three times weekly also is effective (BI).44 TMP-SMX at a dose of one double-strength tablet daily confers cross protection against toxoplasmosis45 and many respiratory bacterial infections.41,46 Lower doses of TMP-SMX likely also confer such protection. TMP-SMX chemoprophylaxis should be continued, if 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 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 (TEN) (AIII). Patients who have experienced adverse events, including fever and rash, may better tolerate re-introduction of the drug if the dose is gradually increased (desensitization) according to published regimens (BI)47,48 or if TMP-SMX is given at a reduced dose or frequency (CIII). As many as 70% of patients can tolerate such re-institution of therapy.46
For patients who cannot tolerate TMP-SMX, alternative prophylactic regimens include dapsone (BI),41 dapsone plus pyrimethamine plus leucovorin (BI),49-51 aerosolized pentamidine administered with the Respirgard II nebulizer (manufactured by Marquest; Englewood, Colorado) (BI),42 and atovaquone (BI).52,53 Atovaquone is as effective as aerosolized pentamidine52 or dapsone53 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),49-51 or atovaquone with or without pyrimethamine plus leucovorin (CIII).
Oral pyrimethamine plus sulfadoxine also has activity against PCP.54-56 However, this combination is associated with an increased risk of severe cutaneous reactions, including Stevens-Johnson syndrome,57 and the long half-life of both pyrimethamine and sulfadoxine results in delayed clearance when the drug is stopped. Because TMP-SMX has superior safety, widespread availability, and is low cost, oral pyrimethamine plus sulfadoxine should not be used in the United States (AIII).
The following regimens cannot be recommended as alternatives because data regarding their efficacy for PCP prophylaxis are insufficient:
Aerosolized pentamidine administered by nebulization devices other than the Respirgard II nebulizer
Clinicians can consider using these agents, however, in situations in which the recommended agents cannot be administered or are not tolerated (CIII).
Discontinuing Primary Prophylaxis
Primary Pneumocystis prophylaxis should be discontinued for 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 supporting this recommendation, most patients had CD4 counts >200 cells/mm3 for more than 3 months before discontinuing PCP prophylaxis.58-67 The median CD4 count at the time prophylaxis was discontinued was >300 cells/mm3, most patients 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 to 19 months.
Discontinuing primary prophylaxis in these patients is recommended because its preventive benefits are limited to PCP, toxoplasmosis, and bacterial infections;60,66 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 CD4 count decreases to <200 cells/mm3(AIII).
A combined analysis of 12 European cohorts68 and a case series69 found a low incidence of PCP in patients with CD4 counts between 100 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 PCP prophylaxis can be safely discontinued in selected patients with CD4 counts 100 to 200 cells/mm3 and HIV plasma RNA levels below limits of detection with commercial assays. Data on which to base recommendations for this approach are inadequate, but some experts believe it is reasonable and recommend it for their patients.
TMP-SMX is the treatment of choice for PCP (AI).70,71 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. Adding leucovorin to prevent myelosuppression during acute treatment is not recommended because efficacy is questionable and some evidence exists for a higher failure rate (AII).72 Oral outpatient therapy with 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 Alveolar-arterial O2 gradient ≥35 mm Hg, should receive adjunctive corticosteroids as early 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 use them in such circumstances for patients with moderate-to-severe disease (BIII). Methylprednisolone at 75% of the respective 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 and fewer side effects, but is less convenient because of the number of pills; primaquine plus clindamycin (BI)84-86 (the clindamycin component can be administered intravenously [IV] for more severe cases, but primaquine is only available orally); and atovaquone suspension (BI),53,58,70,87 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-primaquine because of its higher degree of efficacy and lesser toxicity compared with pentamidine.86,90-92
Aerosolized pentamidine should not be used to treat PCP because its efficacy is limited and it is associated with more frequent relapse (AI).88,93,94 Trimetrexate is no longer commercially available.
The recommended duration of therapy for PCP is 21 days (AII).18 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.
The overall prognosis remains poor for patients who have such severe hypoxemia that admission to an intensive care unit (ICU) is necessary. However, in recent years, such patients have had much better survival than in the past, perhaps because of better management of comorbidities and better supportive care.95-98 Because long-term survival is possible for patients in whom ART is effective, individuals with AIDS and severe PCP should be offered ICU admission or mechanical ventilation if their functional status is such that it would be appropriate, just as with HIV-uninfected patients (AII).
Special Consideration with Regards to Starting ART
In patients not on ART, ART should be initiated, 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 PCP, a significantly lower incidence of AIDS progression or death (a secondary study endpoint) was seen in subjects randomized to early (median 12 days after initiation of therapy for OI) versus deferred initiation of ART (median 45 days).99 Of note, no patients with PCP and respiratory failure requiring intubation were enrolled in the study.99 Paradoxical immune reconstitution inflammatory syndrome (IRIS) has been reported following PCP.100 Most cases have occurred within weeks of the episode of PCP; symptoms include fever and recurrence or exacerbation of pulmonary symptoms including cough and shortness of breath. Although IRIS in the setting of PCP has only rarely been life threatening,101 patients should be closely followed for recurrence of symptoms after initiation of ART. Management of PCP-associated IRIS is not well defined; some experts would consider corticosteroids in patients with respiratory deterioration if other causes are ruled out.
Monitoring of Response to Therapy and Adverse Events (Including IRIS)
Careful monitoring during anti-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 when therapy has been with an agent other than TMP-SMX or was shortened for toxicity. PCP prophylaxis should be initiated immediately upon completion of therapy and maintained until the CD4 count is >200 cells/mm3 for at least 3 months.
In patients with AIDS, rates of adverse reaction to TMP-SMX are high (20%–85%).70,71,83,85,89,102-106 Common adverse effects are rash (30%–55%) (including Stevens-Johnson syndrome), fever (30%–40%), leukopenia (30%–40%), thrombocytopenia (15%), azotemia (1%–5%), hepatitis (20%), 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, hypo- or hyperglycemia, leukopenia, electrolyte abnormalities, and cardiac dysrhythmia with pentamidine;87-89,105 anemia, rash, fever, and diarrhea with primaquine and clindamycin;71,84,85 and headache, nausea, diarrhea, rash, and transaminase elevations with atovaquone.70,104
Managing Treatment Failure
Clinical failure is defined as lack of improvement or worsening of respiratory function documented by arterial blood gases (ABGs) after at least 4 to 8 days of anti-PCP treatment. Failure attributed to lack of drug efficacy occurs in approximately 10% of those with mild-to-moderate disease. No convincing clinical trials exist on which to base recommendations for the management of treatment failure attributed to lack of drug efficacy. Clinicians should wait at least 4 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 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;26,27 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 intravenous clindamycin (BII).85,89,106 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 to patients who experience a therapy failure with TMP-SMX.
When to Start Secondary Prophylaxis
Patients who have a history of PCP should be given chemoprophylaxis for life with TMP-SMX (i.e., secondary prophylaxis or chronic maintenance therapy) unless immune reconstitution occurs as a result of ART (see below) (AI).107 For patients who are intolerant of TMP-SMX, the alternatives are dapsone, dapsone combined with pyrimethamine, 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 to ≥200 cells mm3 for >3 months as a result of ART (AII). Reports from observational studies59,65,108,109 and from two randomized trials66,110 and a combined analysis of eight European cohorts being followed prospectively111 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 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. Prophylaxis should be reintroduced if the CD4 count decreases to <200 cells/mm3(AIII).
If an episode of PCP occurs at a CD4 count ≥200 cells/mm3, it would be prudent to continue PCP prophylaxis for life, regardless of how high the CD4 cell count rises as a consequence of ART (BIII).
Special Considerations During Pregnancy
PCP diagnostic considerations for pregnant women are the same as for women who are not pregnant.
Indications for therapy are the same as for non-pregnant women. Some data suggest an increased risk of PCP-associated mortality in pregnancy compared with non-pregnant adults, although there are no large, well-controlled studies evaluating the impact of pregnancy on PCP outcomes.112
The preferred initial therapy during pregnancy is TMP-SMX, although alternate therapies can be used if patients are unable to tolerate or are unresponsive to TMP-SMX (AI).113 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.114-116 One small study reported an increased risk of birth defects in infants born to women receiving ARV drugs and folate antagonists, primarily trimethoprim, whereas no increase was observed among those with exposure to either an ARV drug or a folate antagonist alone.117 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 of 0.4 mg/day is routinely recommended for all pregnant women,118 there are no trials evaluating whether supplementation at higher levels (such as the 4 mg/day recommended for pregnant women with a previous infant with a neural tube defect) would reduce the risk of birth defects associated with first-trimester TMP-SMX use. Epidemiologic data do suggest, however, that folic acid supplementation may reduce the risk of congenital anomalies.115,116 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 6 mg/day (odds ratio [OR] 1.24; 95% confidence interval [CI]: 0.94-1.62).119 Although the risk of multiple congenital anomalies associated with TMP-SMX use persisted with supplemental folic acid, the OR decreased from 6.4 (TMP-SMX, no folic acid) to 1.9 (TMP-SMX plus folic acid). As such, 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.120 Therefore, if supplemental folic acid (>0.4 mg/day routinely recommended) is to be given, its use should be limited to the first trimester during the teratogenic window (AIII). Whether or not a woman receives supplemental folic acid during the first trimester, a follow-up ultrasound is recommended at 18 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 kernicterus and mortality, specifically kernicterus, compared with infants who received oxytetracycline.121 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 nonpregnant adults (AIII).122-125 Patients with documented or suspected PCP and moderate-to-severe disease, as defined by room air pO2 <70 mm Hg or arterial-alveolar O2 gradient ≥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 increase in odds of delivering a baby with a cleft palate.126 On the other hand, other large population-based studies have not found an association between maternal use of corticosteroids and congenital anomalies. 127,128 Corticosteroid use in pregnancy may be associated with an increased risk of maternal hypertension, glucose intolerance/gestational diabetes, and infection.129 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 more than 3 weeks may have a suppressed hypothalamic-pituitary-adrenal (HPA) axis and consideration should be given to the use of stress-dose steroids during delivery (BIII). HPA axis suppression is rarely seen among neonates born to women on chronic corticosteroids during pregnancy.
Alternative therapeutic regimens for mild-to-moderate disease include dapsone and TMP, primaquine plus clindamycin, atovaquone suspension, and IV pentamidine.
Dapsone appears to cross the placenta.130,131 It has been used safely over the past several decades to treat leprosy, malaria, and various dermatologic conditions during pregnancy.131,132 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 hemolytic anemia.133
Clindamycin, which appears to cross the placenta, is a Food and Drug Administration (FDA) Pregnancy Category B medication and 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 exposed fetuses with G6PD deficiency. The degree of intravascular hemolysis appears to be associated with both dose of primaquine and severity of G6PD deficiency.134
Data on atovaquone in humans are limited but preclinical studies have not demonstrated toxicity.134
Pentamidine is embryotoxic but not teratogenic in rats and rabbits.135
Pneumonia during pregnancy increases rates of preterm labor and delivery. Pregnant women with pneumonia after 20 weeks’ gestation should be monitored for evidence of contractions (BIII).
Chemoprophylaxis for PCP should be administered to pregnant women the same as for other 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 this period (CIII) rather than withholding chemoprophylaxis.
Clinicians who are providing pre-conception care for HIV-infected women receiving PCP prophylaxis can discuss with their patients the option of deferring pregnancy until PCP prophylaxis can be safely discontinued; that is, until the CD4 cell count is ≥200 cells/mm3 for 3 months (BIII).
Recommendations for Prevention and Treatment of Pneumocystis Pneumonia (PCP)
Preventing 1st Episode of PCP (Primary Prophylaxis)
Indications for Initiating Primary Prophylaxis:
CD4 count <200 cells/mm3(AI)or
Oropharyngeal candidiasis (AII)or
CD4% <14% (BII) or
History of AIDS-defining illness (BII)or
CD4 count >200 but <250 cells/mm3 and if CD4 cell count monitoring (e.g., every 3 months) is not possible (BII).
Note—Patients who are receiving pyrimethamine/sulfadiazine for treatment or suppression of toxoplasmosis do not require additional prophylaxis for PCP (AII).
TMP-SMX, 1 DS PO dailya(AI)or
TMP-SMX, 1 SS PO dailya(AI).
TMP-SMX 1 DS PO three times weeklya(BI)or
Dapsoneb,c 100 mg PO daily or 50 mg PO BID (BI)or
Dapsoneb 50 mg PO daily + (pyrimethamine 50 mg + leucovorin 25 mg) PO weekly (BI)or
Aerosolized pentamidinec 300 mg via Respigard II™ nebulizer every month (BI)or
Atovaquone 1500 mg PO daily with food (BI)or
(Atovaquone 1500 mg + pyrimethamine 25 mg + leucovorin 10 mg) PO daily with food (CIII).
Indication for Discontinuing Primary Prophylaxis:
CD4 count increased from <200 cells/mm3 to ≥200 cells/mm3 for at least 3 months in response to ART (AI)
Indication for Restarting Primary Prophylaxis:
CD4 count <200 cells/mm3(AIII)
Note—Patients who develop PCP despite TMP-SMX prophylaxis usually can be treated effectively with standard doses of TMP-SMX (BIII).
For Moderate to Severe PCP—Total Duration = 21 Days (AII): Preferred Therapy:
TMP-SMX: (TMP 15–20 mg and SMX 75–100 mg)/kg/day IV given q6h or q8h (AI), may switch to PO after clinical improvement (AI).
Pentamidine 4 mg/kg IV once daily infused over at least 60 minutes (AI); may reduce the dose to 3 mg/kg IV once daily because of toxicities (BI)or
Primaquineb 30 mg (base) PO once daily + (Clindamycin [IV 600 q6h or 900 mg q8h] or [PO 450 mg q6h or 600 mg q8h]) (AI).
**Adjunctive corticosteroid may be indicated in some moderate to severe cases (see indications and dosage recommendations below)
For Mild to Moderate PCP—Total Duration = 21 days (AII): Preferred Therapy:
TMP-SMX: (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day), given PO in 3 divided doses (AI)or
TMP-SMX DS - 2 tablets TID (AI).
Dapsoneb 100 mg PO daily + TMP 15 mg/kg/day PO (3 divided doses) (BI)or
Primaquineb 30 mg (base) PO daily + Clindamycin PO (450 mg q6h or 600 mg q8h) (BI)or
Atovaquone 750 mg PO BID with food (BI)
Adjunctive Corticosteroids: For Moderate to Severe PCP Based on the Following Criteria (AI):
PaO2 <70 mmHg at room air or
Alveolar-arterial O2 gradient ≥35 mmHg
Prednisone doses (beginning as early as possible and within 72 hours of PCP therapy) (AI):
40 mg PO BID
40 mg PO daily
20 mg PO daily
IV methylprednisolone can be given as 75% of prednisone dose
Preventing Subsequent Episode of PCP (Secondary Prophylaxis)
Indications for Initiating Secondary Prophylaxis:
TMP-SMX, 1 DS PO dailya(AI)or
TMP-SMX, 1 SS PO dailya (AI).
TMP-SMX 1 DS PO three times weeklya(BI)or
Dapsoneb,c 100 mg PO daily or 50 mg PO BID (BI)or
Dapsoneb 50 mg PO daily + (pyrimethamine 50 mg + leucovorin 25 mg) PO weekly (BI)or
(Dapsoneb 200 mg + pyrimethamine 75 mg + leucovorin 25 mg) PO weekly (BI) or
Aerosolized pentamidinec 300 mg via Respigard II¿ nebulizer every month (BI)or
Atovaquone 1500 mg PO daily with food (BI)or
(Atovaquone 1500 mg + pyrimethamine 25 mg + leucovorin 10 mg) PO daily with food (CIII)
Indications for Discontinuing Secondary Prophylaxis:
CD4 count increased from <200 cells/mm3 to ≥200 cells/mm3 for >3 months as a result of ART (AII)or
If PCP diagnosed when CD4 count ≥200 cells/mm3, prophylaxis should be continued for life regardless of CD4 cell count rise as a consequence of ART (BIII).
Indications for Restarting Secondary Prophylaxis:
CD4 count falls to <200 cells/mm3 (AIII) or
If PCP recurred at a CD4 count ≥200 cells/mm3, lifelong prophylaxis should be administered (BIII).
For patients with non-life-threatening adverse reactions to TMP-SMX, the drug should be continued if clinically feasible.
If TMP-SMX is discontinued because of a mild adverse reaction, re-institution should be considered after the reaction has resolved (AII). The dose can be increased gradually (desensitization) (BI) or given at a reduced dose or frequency (CIII).
Therapy should be permanently discontinued, with no rechallenge, in patients with possible or definite Stevens-Johnson Syndrome or toxic epidermal necrolysis (AIII).
a TMP-SMX DS once daily also confers protection against toxoplasmosis and many respiratory bacterial infections; lower dose also likely confers protection. b Whenever possible, patients should be tested for G6PD deficiency before administration of dapsone or primaquine. Alternative agent should be used if the patient is found to have G6PD deficiency. c Aerosolized pentamidine or dapsone (without pyrimethamine) should not be used for PCP prophylaxis in patients who are seropositive for Toxoplasma gondii.
Acronyms: BID = twice daily; DS = double strength; IV = intravenously; PCP = Pneumocystis pneumonia; PO = orally; q “n” h = every “n” hour; SS = single strength; TID = three times daily; TMP = trimethoprim; TMP-SMX = trimethoprim-sulfamethoxazole
Pifer LL, Hughes WT, Stagno S, Woods D. Pneumocystiscarinii infection: evidence for high prevalence in normal and immunosuppressed children. Pediatrics. Jan 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. Aug 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. Dec 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. Oct 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. May 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. Dec 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. Jan–Feb 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. Feb 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. Jul 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. Mar 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. Aug 15 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. Jan 18 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. Oct 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. Sep 28 2001;15(14):1831-1836. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11579245
Buchacz K, Baker RK, Palella FJ, Jr., et al. AIDS-defining opportunistic illnesses in US patients, 1994-2007: a cohort study. AIDS. Jun 19 2010;24(10):1549-1559. Available at http://www.ncbi.nlm.nih.gov/pubmed/20502317.
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. Nov 10 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. Dec 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. May 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. May 28 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. Jul 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. Nov 5 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. Apr 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. Jan 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. Oct 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. Mar 15 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. Dec 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. Jul 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. Oct 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. European Radiology. 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. Feb 1998;26(2):509-510. Available at http://www.ncbi.nlm.nih.gov/pubmed/9502487.
Harris JR, Marston BJ, Sangrujee N, DuPlessis D, Park B. Cost-effectiveness analysis of diagnostic options for pneumocystis pneumonia (PCP). PLoS One. 2011;6(8):e23158. Available at http://www.ncbi.nlm.nih.gov/pubmed/21858013.
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. Jan 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. Feb 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. May 1 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. Jun 15 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. Jul 15 2011;53(2):197-202. Available at http://www.ncbi.nlm.nih.gov/pubmed/21690628.
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. Aug 1 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. Sep 2012;31(9):2429-2437. Available at http://www.ncbi.nlm.nih.gov/pubmed/22402816.
Centers for Disease Controm and Prevention. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. MMWR Morb Mortal Wkly Rep. Jun 16 1989;38 Suppl 5(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. Nov 15 1991;115(10):760-763. Available at http://www.ncbi.nlm.nih.gov/pubmed/1929023.
Bozzette SA, Finkelstein DM, Spector SA, et al; with the NIAID AIDS Clinical Trials Group. A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection. N Engl J Med. Mar 16 1995;332(11):693-699. Available at http://www.ncbi.nlm.nih.gov/pubmed/7854375.
Schneider MM, Hoepelman AI, Eeftinck Schattenkerk JK, et al; with the The Dutch AIDS Treatment Group. A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. N Engl J Med. Dec 24 1992;327(26):1836-1841. Available at http://www.ncbi.nlm.nih.gov/pubmed/1360145.
Schneider MM, Nielsen TL, Nelsing S, et al; with Dutch AIDS Treatment Group. Efficacy and toxicity of two doses of trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus. J Infect Dis. Jun 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; with Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected persons. Clin Infect Dis. Oct 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. Jul 15 1992;117(2):106-111. Available at http://www.ncbi.nlm.nih.gov/pubmed/1351371.
Hardy WD, Feinberg J, Finkelstein DM, et al; with AIDS Clinical Trials Group Protocol 021. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med. Dec 24 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. Aug 1 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. Oct 15 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. May 15 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. Mar 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. Aug 1999;180(2):369-376. Available at http://www.ncbi.nlm.nih.gov/pubmed/10395851.
El-Sadr WM, Murphy RL, Yurik TM, et al; with Community Program for Clinical Research on AIDS and the AIDS Clinical Trials Group. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. N Engl J Med. Dec 24 1998;339(26):1889-1895. Available at http://www.ncbi.nlm.nih.gov/pubmed/9862944.
Payen MC, De Wit S, Sommereijns B, Clumeck N. A controlled trial of dapsone versus pyrimethamine-sulfadoxine for primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmosis in patients with AIDS. Biomed Pharmacother. 1997;51(10):439-445. Available at http://www.ncbi.nlm.nih.gov/pubmed/9863502.
Schurmann D, Bergmann F, Albrecht H, et al. Twice-weekly pyrimethamine-sulfadoxine effectively prevents Pneumocystis carinii pneumonia relapse and toxoplasmic encephalitis in patients with AIDS. J Infect. Jan 2001;42(1):8-15. Available at http://www.ncbi.nlm.nih.gov/pubmed/11243747.
Schurmann D, Bergmann F, Albrecht H, et al. Effectiveness of twice-weekly pyrimethamine-sulfadoxine as primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in patients with advanced HIV infection. Eur J Clin Microbiol Infect Dis. May 2002;21(5):353-361. Available at http://www.ncbi.nlm.nih.gov/pubmed/12072919.
Navin TR, Miller KD, Satriale RF, Lobel HO. Adverse reactions associated with pyrimethamine-sulfadoxine prophylaxis for Pneumocystis carinii infections in AIDS. Lancet. Jun 8 1985;1(8441):1332. Available at http://www.ncbi.nlm.nih.gov/pubmed/2860516.
Furrer H, Egger M, Opravil M, et al; Swiss HIV Cohort Study. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy. N Engl J Med. Apr 29 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. Aug 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. May 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. Jan 16 1999;353(9148):201-203. Available at http://www.ncbi.nlm.nih.gov/pubmed/9923876.
Weverling GJ, Mocroft A, Ledergerber B, et al; with the EuroSIDA Study Group. Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in HIV-1 infection. Lancet. Apr 17 1999;353(9161):1293-1298. Available at http://www.ncbi.nlm.nih.gov/pubmed/10218526.
Yangco BG, Von Bargen JC, Moorman AC, Holmberg SD; with the HIV Outpatient Study (HOPS) Investigators. Discontinuation of chemoprophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection. Ann Intern Med. Feb 1 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. Mar 9 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. Sep 10 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; with the Grupo de Estudio del SIDA 04/98. 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. N Engl J Med. Jan 18 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. Jul 2004;5(4):278-283. Available at http://www.ncbi.nlm.nih.gov/pubmed/15236617.
Opportunistic Infections Project Team of the Collaboration of Observational HIVERiE, 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. Sep 1 2010;51(5):611-619. Available at http://www.ncbi.nlm.nih.gov/pubmed/20645862.
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. Aug 20 2007;21(13):1711-1715. Available at http://www.ncbi.nlm.nih.gov/pubmed/17690568.
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. May 27 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. May 1 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. Oct 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. May 20 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. Oct 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 jirovecii pneumonia. Emerg Infect Dis. Oct 2004;10(10):1760-1765. Available at http://www.ncbi.nlm.nih.gov/pubmed/15504261.
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. Sep 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. Nov 22 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. Nov 22 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. Jul 1 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. Nov 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. Sep 20 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. Jun 1994;18(6):905-913. Available at http://www.ncbi.nlm.nih.gov/pubmed/8086551.
Toma E, Thorne A, Singer J, et al; with the CTN-PCP Study Group. 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). Clin Infect Dis. Sep 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. Jun 25 2001;161(12):1529-1533. Available at http://www.ncbi.nlm.nih.gov/pubmed/11427101.
Dohn MN, Weinberg WG, Torres RA, et al; with the Atovaquone Study Group. Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Ann Intern Med. Aug 1 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. Aug 1 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. Jul 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. Oct 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. Dec 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. May 1 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. Aug 1 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. Apr 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. May 1 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. Jan 3 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. Aug 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. Jan 2009;135(1):11-17. Available at http://www.ncbi.nlm.nih.gov/pubmed/18719058.
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.
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.
Jagannathan P, Davis E, Jacobson M, Huang L. Life-threatening immune reconstitution inflammatory syndrome after Pneumocystis pneumonia: a cautionary case series. AIDS. Aug 24 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. May 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. Apr 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. May 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. Mar 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. Jul 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. Sep 3 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. Mar 10 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. Oct 21 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. Mar 1 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. Jan 18 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. Aug 2001;120(2):666-671. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11502676.
Connelly RT, Lourwood DL. Pneumocystis carinii pneumonia prophylaxis during pregnancy. Pharmacotherapy. Jul–Aug 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. Nov-Dec 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. Nov 30 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. American Journal of Epidemiology. May 15 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? Sexually Transmitted Infections. Dec 2001;77(6):441-443. Available at http://www.ncbi.nlm.nih.gov/pubmed/11714944.
Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep. Sep 11 1992;41(RR-14):1-7. Available at http://www.ncbi.nlm.nih.gov/pubmed/1522835.
Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study. Reproductive Toxicology. Nov–Dec 2001;15(6):637-646. Available at http://www.ncbi.nlm.nih.gov/pubmed/11738517.
Razavi B, Lund B, Allen BL, Schlesinger L. Failure of trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis carinii pneumonia with concurrent leucovorin use. Infection. Jan 2002;30(1):41-42. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=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. Oct 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 of a successful outcome. Obstet Gynecol. May 1994;83(5 Pt 2):823-824. Available at http://www.ncbi.nlm.nih.gov/pubmed/8159362.
Madinger NE, Greenspoon JS, Ellrodt AG. Pneumonia during pregnancy: has modern technology improved maternal and fetal outcome? Am J Obstet Gynecol. Sep 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. Mar 3 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. Oct 15 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. Dec 2000;62(6):385-392. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11091360.
Czeizel AE, Rockenbauer M. Population-based case-control study of teratogenic potential of corticosteroids. Teratology. Nov 1997;56(5):335-340. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9451758.
Kallen B. Maternal drug use and infant cleft lip/palate with special reference to corticoids. Cleft Palate Craniofac J. Nov 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/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16712713.
Zuidema J, Hilbers-Modderman ES, Merkus FW. Clinical pharmacokinetics of dapsone. Clin Pharmacokinet. Jul-Aug 1986;11(4):299-315. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=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/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=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. Jun 2003;8(6):488-506. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12791054.
Thornton YS, Bowe ET. Neonatal hyperbilirubinemia after treatment of maternal leprosy. South Med J. May 1989;82(5):668. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2717998.
Nosten F, McGready R, d'Alessandro U, et al. Antimalarial drugs in pregnancy: a review. Curr Drug Saf. Jan 2006;1(1):1-15. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=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. Sep 1990;163(3):912-916. Available at http://www.ncbi.nlm.nih.gov/pubmed/2403167.