Aerosolized pentamidine. Approved for HIV-infected individuals at high risk for Pneumocystis carinii pneumonia

Aerosolized pentamidine isethionate (NebuPent, LyphoMed Inc, Rosemont, Ill) was recently approved by the US Food and Drug Administration for use in prophylaxis against Pneumocystis carinii pneumonia in individuals infected with the human immunodeficiency virus who are at high risk for this infection. The recommended dose is 300 mg of aerosolized pentamidine isethionate administered every 4 weeks via the Respirgard II nebulizer (Marquest Medical Products Inc, Englewood, Colo). The drug is indicated for individuals infected with the human immunodeficiency virus who have a history of P carinii pneumonia or individuals with a CD4 (T4) lymphocyte count less than or equal to 0.2 x 10(9)/L with no history of P carinii pneumonia. We present information about the drug and its use, including safety information and use of the nebulizer.     

Prophylaxis for opportunistic infections in an era of effective antiretroviral therapy.

Potent antiretroviral treatment is associated with dramatic improvements in immune function in many human immunodeficiency virus-infected patients. This has led to new US Public Health Service/Infectious Diseases Society of America guidelines that suggest that in certain circumstances (primary prophylaxis for Pneumocystis carinii pneumonia and disseminated Mycobacterium avium complex infection, and secondary prophylaxis for cytomegalovirus retinitis), antimicrobial prophylaxis can be discontinued for patients whose CD4 T-cell counts rise above threshold levels for at least 3-6 months. The new guidelines are probably too conservative, and effective antiretroviral treatment almost certainly provides protection against all major opportunistic pathogens. Therefore, in the future, specific prophylaxis will be needed only for those patients who do not benefit from or fail to adhere to the current more effective treatment of human immunodeficiency virus infection.     

Prophylaxis for Pneumocystis carinii pneumonia in patients infected with human immunodeficiency virus.

Following the initial observation by Dr. Margaret Fischl that trimethoprim-sulfamethoxazole can prevent Pneumocystis carinii infection in patients with Kaposi's sarcoma, initiating prophylaxis for pneumocystic infection in all patients with less than 200 CD4+ cells/mm3 has become accepted practice. This prophylactic intervention has been found not only to reduce the development of pneumonia due to P. carinii but also to prolong life. Drs. Henry Masur and Joseph A. Kovacs first reviewed prophylaxis for P. carinii pneumonia in patients infected with the human immunodeficiency virus for the AIDS Commentary 3 years ago. They have updated that initial review for this AIDS Commentary, placing currently available information into concise clinical perspective and detailing a rational plan for the clinician to follow based on results of recent studies.     

HIV-related pulmonary infections: a review of the recent literature

Antimicrobial prophylaxis and highly active antiretroviral therapy have changed the epidemiology and impact of pulmonary infection in patients infected with the human immunodeficiency virus (HIV). However, pulmonary infection remains a significant contributor to the morbidity and mortality of such patients. Bacterial pneumonia and tuberculosis remain common lung infections in this setting, especially where appropriate prophylaxis is unavailable or when compliance with such therapy is poor. Pneumonia related to Pneumocystis carinii also remains a significant problem, especially as a presenting illness in patients not yet known to be infected with HIV. Recrudescence of "treated" infection as a manifestation of the immune reconstitution syndrome may become more commonly encountered as more patients are treated with highly active therapy.     

Atypical presentations of Pneumocystis carinii pneumonia in patients receiving inhaled pentamidine prophylaxis

Inhaled pentamidine is used commonly to prevent Pneumocystis carinii pneumonia (PCP) in patients with advanced human immunodeficiency virus infection. Case reports indicate that PCP can recur in patients who receive inhaled pentamidine and that clinical features may be atypical. To determine the magnitude of this problem, we reviewed retrospectively the medical records of patients with proven PCP during a 30-month period at two hospitals. Four (31 percent) of 13 patients with previous PCP who received inhaled pentamidine prophylaxis had recurrent P carinii infection, including one patient with widely metastatic extrapulmonary disease. Chest roentgenographic findings included cavities, pneumothoraces, bilateral and upper lobe interstitial infiltrates, and pleural effusion. False-negative bronchoalveolar lavage and induced sputum examinations were frequent. We conclude that recurrent PCP in patients maintained on a regimen of inhaled pentamidine prophylaxis occurs frequently, causes chest roentgenographic abnormalities other than interstitial infiltrates, and may be difficult to diagnose. Clinicians who choose to use this effective and convenient mode of prophylaxis should be aware of the problems attendant to its use.     

Sulfa or sulfone prophylaxis and geographic region predict mutations in the Pneumocystis carinii dihydropteroate synthase gene

To determine factors associated with mutations in the Pneumocystis carinii dihydropteroate synthase (DHPS) gene, a prospective study of human immunodeficiency virus (HIV)-infected patients with confirmed P. carinii pneumonia was conducted in Atlanta, Seattle, and San Francisco. Clinical information was obtained from patient interview and chart abstraction. DHPS genotype was determined from DNA sequencing. Overall, 76 (68.5%) of 111 patients had a mutant DHPS genotype, including 22 (81.5%) of 27 patients from San Francisco. In multivariate analysis, sulfa or sulfone prophylaxis and study site were independent predictors of a mutant genotype. Fourteen (53.8%) of 26 patients who were newly diagnosed with HIV infection and had never taken prophylaxis had a mutant genotype. The significance of geographic location as a risk factor for mutant genotype and the high proportion of mutant genotypes among persons never prescribed prophylaxis, including those newly diagnosed with HIV infection, provide indirect evidence that these mutations are transmitted from person to person either directly or through a common environmental source.     

Spontaneous pneumothorax in AIDS patients with recurrent Pneumocystis carinii pneumonia despite aerosolized pentamidine prophylaxis

Aerosolized pentamidine prophylaxis for Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS) may predispose these patients to recurrent apical Pneumocystis infection. Bullous changes and pulmonary cysts develop in the lung apices due to repeated episodes of inflammation and cytotoxic effects of HIV on pulmonary macrophages. These changes progress despite prophylaxis against recurrent Pneumocystis infection with aerosolized pentamidine, increasing the risk of spontaneous pneumothorax. Two cases are presented of bilateral pneumothoraces in patients with AIDS and recurrent P carinii pneumonia despite aerosolized pentamidine prophylaxis. Patients receiving aerosolized pentamidine prophylaxis for Pneumocystis pneumonia appear to have an increased risk of pneumothorax due to recurrent apical infections with P carinii.     

Chronic Pneumocystis carinii pneumonia associated with extensive pneumatocele formation in a child with human immunodeficiency virus infection

We describe a 12-year-old boy with Pneumocystis carinii pneumonia complicated by extensive pneumatocele formation as the presenting manifestation of human immunodeficiency virus infection. This report emphasizes the importance of considering Pneumocystis carinii infection in the differential diagnosis of pneumonia associated with pneumatocele formation in children.     

Unusual presentation of thoracic Pneumocystis carinii infection in a patient with acquired immunodeficiency syndrome.

Pleura-based masses and hilar adenopathy were seen on a chest radiograph of a patient with acquired immunodeficiency syndrome who had a history of Pneumocystis carinii infection. The differential diagnosis of such a presentation is discussed in light of atypical and extrapulmonary manifestations of P. carinii infection in a patient receiving prophylaxis with dapsone.     

Inhaled antimicrobial therapy

Although antimicrobial therapy has been administered through the inhaled route for decades, it has always been controversial. There are relatively few accepted indications for this mode of administration. Well-controlled studies of aerosolized antibiotics in cystic fibrosis demonstrate that tobramycin on a cyclical basis may reduce sputum volume, bacterial counts, and improve pulmonary function. Preliminary data indicate that inhaled antibiotic therapy of ventilator-associated tracheobronchitis may reduce sputum volume, but the clinical significance of this finding remains to be determined. Inhaled pentamidine is used for prophylaxis of Pneumocystis carinii in patients with human immunodeficiency virus infection who are intolerant of oral prophylactic agents. Ribavirin has been used for 30 years to treat respiratory syncytial virus. The role, if any, of inhaled antifungal therapy with amphotericin B remains undetermined.     

Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS.

OBJECTIVE: To determine the efficacy of low-dose trimethoprim-sulfamethoxazole (trimethoprim, 160 mg plus sulfamethoxazole, 800 mg; one tablet twice daily, 2 days per week) as primary prophylaxis against toxoplasmic encephalitis in patients with human immunodeficiency virus (HIV) infection and previous Pneumocystis carinii pneumonia. DESIGN: A retrospective study. SETTING: Tertiary referral teaching hospital. PATIENTS: During a 3-year period after primary episodes of P. carinii pneumonia, 60 patients received trimethoprim-sulfamethoxazole, and 95 patients received pentamidine (aerosolized in 78 patients and intravenous in 17 patients) as secondary prophylaxis. RESULTS: No patient in the trimethoprim-sulfamethoxazole group and no patient seronegative for Toxoplasma gondii developed toxoplasmic encephalitis, compared with 12 of 36 (33%; 95% Cl, 19% to 51%) seropositive patients in the pentamidine group (trimethoprim-sulfamethoxazole compared with pentamidine, P = 0.008). A significant difference was seen in the time to development of toxoplasmic encephalitis between the trimethoprim-sulfamethoxazole group (no case at 1153 days) and the pentamidine group (median time, 460 days) (P = 0.004). Neither the CD4+ lymphocyte count at the start of prophylaxis nor zidovudine therapy during the period of prophylaxis influenced the rate of toxoplasmic encephalitis in any group. CONCLUSIONS: Low-dose trimethoprim-sulfamethoxazole (four tablets per week) appears to be effective prophylaxis against toxoplasmic encephalitis in HIV-infected patients with previous P. carinii pneumonia. A prospective, randomized, controlled study is needed to further evaluate these findings.     

Pneumocystis carinii

This article covers the biology, epidemiology, and pathology of infection with Pneumocystis carinii. The clinical presentation, course, and treatment of pneumonia caused by this organism in patients infected with the human immunodeficiency virus is discussed.     

Spontaneous pneumothorax in patients with acquired immunodeficiency syndrome treated with prophylactic aerosolized pentamidine

Spontaneous pneumothorax is a known complication of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. To evaluate the possible pathogenesis and natural history of pneumothorax in patients receiving aerosolized pentamidine prophylaxis, we retrospectively reviewed 327 outpatients positive for human immunodeficiency virus receiving aerosolized pentamidine. There were 12 spontaneous pneumothoraces in this group of patients. Seventy-five percent of patients with pneumothorax had roentgenographic evidence of fibrocystic lung parenchyma and clinical evidence of active Pneumocystis pneumonia. The majority (83%) required chest tube evacuation. There was a 50% mortality rate associated with this complication. These findings suggest that spontaneous pneumothorax in patients treated with aerosolized pentamidine most commonly represents a prophylaxis failure associated with a high mortality rate.     

AIDS-related Pneumocystis carinii pneumonia with disappearance of cystic lesions after treatment

A 21-year-old hemophiliac with human immunodeficiency virus (HIV) infection was admitted to our hospital because of bilateral pneumothoraces associated with Pneumocysis carinii pneumonia (PCP). He underwent chest tube drainages and intravenous pentamidine therapy, resulting in clinical improvement. Two months after treatment for PCP, cystic lesions that had existed before treatment disappeared on chest computed tomography. We concluded that Pneumocystis carinii infection might be associated with lung destruction and cyst formation, and that inflammatory exudates in the small bronchioles might act as a ball-valve with subsequent spontaneous pneumothoraces.     

Pneumocystis carinii pneumonia among patients with neoplastic disease.

Pneumocystis carinii pneumonia (PCP) emerged in the 1980s as the most common opportunistic infection among patients with the acquired immunodeficiency syndrome (AIDS). Because of this, the presentation and clinical course of PCP has become well-known to many physicians. However, PCP continues to occur among patients not infected with the human immunodeficiency virus, generally those who receive immunosuppressive therapy as treatment for neoplastic disease. A review from Memorial Sloan-Kettering Cancer has shown that a new group of patients, those receiving corticosteroid therapy for brain neoplasm, are also at risk for the development of PCP and should receive PCP prophylaxis. Previously defined patient groups--people with acute lymphocytic leukemia or allogeneic bone marrow transplantation--also should continue to receive prophylaxis. In addition, the clinical course and outcome of patients with neoplastic disease who develop PCP may differ from those with AIDS and PCP: the disease may be much more fulminant among patients with neoplastic disease, and the mortality rate much higher, approaching 50% in the Memorial Sloan-Kettering Cancer Center series. Wider use of prophylaxis should decrease the frequency of this disease, whereas prompt initiation of therapy in patients with a compatible syndrome should help to improve mortality rates.     

Extrapulmonary pneumocystosis: clinical features in human immunodeficiency virus infection

Pneumocystis carinii infection is reported with increasing frequency as a cause of disease outside of the respiratory tract in patients with human immunodeficiency virus (HIV) infection. Extrapulmonary pneumocystosis is not limited to patients in any discrete risk group for HIV infection. Patients with HIV infection who develop extrapulmonary pneumocystosis frequently do not have concurrent P. carinii pneumonia. Signs and symptoms of extrapulmonary pneumocystosis are nonspecific but when present are frequently referable to the tissues or organs involved. Extrapulmonary pneumocystosis can be diagnosed by examination of tissue biopsies from affected sites using standard histologic techniques. Therapy with antimicrobial agents used to treat P. carinii pneumonia has been effective in some patients. An association between use of aerosolized pentamidine for prevention of P. carinii pneumonia and development of extrapulmonary pneumocystosis has been suggested but remains unconfirmed. Other factors such as the use of zidovudine and duration of immunodeficiency may also be important to the pathogenesis of extrapulmonary pneumocystosis. Further studies are needed to better identify risk factors that may predispose patients to the development of extrapulmonary pneumocystosis.     

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

A multicenter open, randomized, controlled trial was conducted to determine whether primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis can be discontinued in patients infected with human immunodeficiency virus type 1 (HIV-1) whose CD4+ T cell counts have increased to >200 cells/mm3 (and who have remained at this level for at least 3 months) as a result of highly active antiretroviral therapy (HAART). Patients were randomized to either the discontinuation arm (i.e., those who discontinued prophylaxis; n=355) or to the continuation arm (n=353); the 2 arms of the study were similar in terms of demographic, clinical, and immunovirologic characteristics. During the median follow-ups of 6.4 months (discontinuation arm) and 6.1 months (continuation arm) and with a total of 419 patient-years, no patient developed P. carinii pneumonia or toxoplasmic encephalitis. The results of this study strongly indicate that primary prophylaxis for P. carinii pneumonia and toxoplasmic encephalitis can be safely discontinued in patients whose CD4+ T cell counts increase to >200 cells/mm3 during HAART.     

Pneumocystis carinii infection of the thyroid in a hypothyroid patient with AIDS: diagnosis by fine needle aspiration biopsy

A 49-yr-old homosexual man with acquired immunodeficiency syndrome presented with a left-sided neck mass. He was found to have a firm goiter. He was clinically euthyroid, but had laboratory evidence of primary hypothyroidism. Radioactive iodine scan of the thyroid showed homogeneous uptake over an enlarged right lobe and absence of uptake over the left lobe. Two fine needle aspiration biopsies of the thyroid revealed the presence of Pneumocystis carinii (P. carinii) organisms on the Gomori's methenamine silver strain. After courses of iv and oral therapy with trimethoprim-sulfamethoxazole, a third fine needle aspiration biopsy failed to reveal any organisms. A repeated radioactive iodine scan of the thyroid showed return of uptake over the left lobe. Thyroid function tests normalized with levothyroxine, and the goiter decreased in size. To our knowledge, this is the first report of hypothyroidism associated with P. carinii infection of the thyroid. P. carinii infection should be considered in the differential diagnosis of human immunodeficiency virus infected individuals presenting with cold thyroid nodules. Fine needle aspiration biopsy is a valuable tool in assessing these patients.     

Effect of aerosolized pentamidine prophylaxis on the diagnosis of Pneumocystis carinii pneumonia by induced sputum examination in patients infected with the human immunodeficiency virus

This study assessed the effect of aerosolized pentamidine prophylaxis on the clinical presentation and diagnostic sensitivity of induced sputum examination for Pneumocystis carinii pneumonia. Between January 1, 1988 and October 27, 1990, 348 induced sputum examinations were performed as the initial diagnostic procedure for P. carinii pneumonia in patients infected with the human immunodeficiency virus (HIV). Medical records were reviewed for all induced sputum examinations, and the study group consisted of patients who either had not received prophylactic therapy (n = 193) or had received aerosolized pentamidine prophylaxis (n = 126). A total of 29 induced sputum examinations in patients receiving either other prophylactic regimens or ongoing therapy for previously documented P. carinii pneumonia were excluded from the study group. A total of 72 consecutive episodes of P. carinii pneumonia were subsequently documented by induced sputum examination (n = 54), bronchoalveolar lavage (n = 16), thoracocentesis (n = 1), or autopsy (n = 1). A total of 44 episodes occurred in patients who had not received antipneumocystis prophylaxis, and 28 episodes occurred in patients who had received aerosolized pentamidine. Of patients capable of producing a sputum specimen for analysis, induced sputum examination had a significantly lower diagnostic yield of 64.3% in patients who had received aerosolized pentamidine prophylaxis compared with 92.3% in patients who did not receive prophylaxis (p less than 0.02, Fisher's exact test). When the data were analyzed on an intention to treat basis, although there was a trend suggesting a lower overall yield in the aerosolized pentamidine patients, the difference was not statistically significant (64.3 versus 81.8%, p = 0.17, Fisher's exact test).(ABSTRACT TRUNCATED AT 250 WORDS)