Aerosolized pentamidine prophylaxis for Pneumocystis carinii pneumonia after allogeneic marrow transplantation

Pneumocystis carinii pneumonia (PCP) poses a serious risk to allogeneic bone marrow transplant (BMT) patients, who are often intolerant of trimethoprim‐sulfamethoxazole (TMP‐SMX), the traditional first‐line prophylactic agents. There are limited published data supporting the use of aerosolized pentamidine (AP) prophylaxis in the BMT population. We assessed the effectiveness of AP in BMT recipients by reviewing the experience at our center. We divided our review into four time periods from January 1990 to March 2000, during which approximately 700 BMTs were performed. The first period includes patients receiving AP treatments from January 1990 to July 1997 (baseline), the second from August 1997 to July 1998 (pre‐outbreak), the third from August 1998 to October 1999 (outbreak), and the fourth from November 1999 to March 2000 (post‐outbreak). At our center, TMP‐SMX is the first‐line agent for PCP prophylaxis, which is routinely continued for at least one year, or for the duration of enhanced immunosuppression. During the baseline period, 505 BMTs were performed and 192 patients (38%) received AP for part of their time at risk. Six patients (3%) experienced toxicities requiring discontinuation of AP. Three cases of PCP were diagnosed over 1114 patient‐months of treatment in the baseline period. During the last 42 months of the baseline period, 2/154 patients receiving AP and 2 of an estimated 293 patients receiving exclusively oral prophylaxis developed breakthrough PCP (p = 0.61). During the outbreak period, 9 of 180 patients receiving AP developed PCP compared to none in the group receiving exclusively oral prophylaxis. Either changes in our AP protocol during the pre‐outbreak period or pentamidine resistance may have led to this failure of prophylaxis. There were no further cases during the 5‐month post‐outbreak period. Our observed overall breakthrough rate was 12 cases out of 439 patients (2.7%). Our study shows that AP is an effective and well‐tolerated second‐line agent in preventing PCP post BMT and we recommend its continued use in this regard. However, it should be administered using a well‐studied protocol, and only when TMP‐SMX is not tolerated.     

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.     

Aerosol pentamidine for secondary prophylaxis of AIDS-related Pneumocystis carinii pneumonia. A randomized, placebo-controlled study

OBJECTIVE: To assess the safety and efficacy of aerosol pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). PARTICIPANTS: Patients recovering from a first confirmed episode of AIDS-related P. carinii pneumonia who had no evidence of either another active AIDS-defining opportunistic infection or another pulmonary abnormality were considered eligible for the study but were included only if they had received no immunomodulators or antiretroviral agents other than zidovudine within 30 days of entry. One hundred sixty-two patients were randomized and started on the study drug. INTERVENTION: Patients were randomly assigned to receive aerosol pentamidine, 60 mg per dose, or placebo, delivered using a hand-held, patient-triggered, ultrasonic nebulizer. The induction phase of treatment consisted of 5 doses over 14 days, followed by a maintenance phase beginning on day 21 and consisting of one dose every 2 weeks. RESULTS: Thirty-two cases of P. carinii pneumonia were diagnosed before the termination of the trial; 27 cases occurred among 78 patients receiving placebo and 5 occurred among 84 patients receiving aerosol pentamidine. Estimates of the cumulative relapse rate of P. carinii pneumonia by 24 weeks were 50% and 9% for the placebo and pentamidine groups, respectively (P less than 0.001). Adverse reactions attributed to the study drug occurred in 15 of 78 patients receiving placebo and in 28 of 84 patients receiving pentamidine (P = 0.04). These were all mild or moderate in severity and did not preclude continued administration of the study drug. CONCLUSION: Intermittent therapy with aerosol pentamidine is highly effective and well tolerated as secondary prophylaxis for AIDS-related P. carinii pneumonia.     

Aerosolized pentamidine: effect on diagnosis and presentation of Pneumocystis carinii pneumonia

STUDY OBJECTIVE: To determine the effect of previous aerosolized pentamidine therapy on diagnosis and presentation of Pneumocystis carinii pneumonia. DESIGN: A retrospective study. SETTING: A tertiary care hospital. PATIENTS: Fifty-two consecutive patients with P. carinii pneumonia and underlying infection with the human immunodeficiency virus (HIV) who had bronchoscopy. Twenty-one patients who were on aerosolized pentamidine therapy served as the study group. Thirty-one patients who had not received the drug served as the control group. MEASUREMENTS AND MAIN RESULTS: The yield of bronchoalveolar lavage for P. carinii pneumonia was 62% for the study group and 100% for the control group (P less than 0.05). This lower yield was significant for the subset of patients having their first episode of P. carinii pneumonia. The yield of transbronchial biopsy was similar for both groups of patients (81% compared with 84%). The yield of bronchoscopy was not influenced by use of zidovudine. Review of lavage specimen slides suggested that there may be fewer organisms present in patients receiving aerosolized pentamidine. An atypical roentgenographic presentation of upper lobe predominant infiltrates was seen in 38% of the study patients and 7% of the control patients. In addition, pneumothoraces and cystic changes were also frequently seen in the study patients. Gallium scans, when done, were also atypical in the study group. Markers of the severity of disease, however, were similar in both groups. CONCLUSION: The yield of bronchoalveolar lavage for P. carinii pneumonia in HIV-infected patients is lower in patients receiving aerosolized pentamidine. Unusual roentgenographic presentations and atypical gallium scans are also found in this setting.     

Risk factors for prophylaxis failure in patients receiving aerosol pentamidine for Pneumocystis carinii pneumonia prophylaxis

OBJECTIVE: The purposes of this study were (1) to determine the incidence of prophylaxis failure in HIV-infected patients receiving aerosol pentamidine (AP) for Pneumocystis carinii pneumonia (PCP) prophylaxis, and (2) to identify risk factors for PCP prophylaxis failure. SETTING AND DESIGN: In Ontario, Canada, AP has been made available for outpatient PCP prophylaxis through a centralized government program, the Ontario Drug Distribution and Monitoring Program. Data from this administrative observational database were extracted for 2,227 patients who received AP between May 1989 and December 1998. OUTCOME MEASUREMENTS: The incidence of breakthrough PCP (BPCP) was calculated from the database. A Cox regression model with time-varying covariates was created to examine factors associated with BPCP. The follow-up time was divided into three eras: 1989 to 1991, 1992 to 1994, and 1995 to 1998. These eras were meant to reflect major changes in antiretroviral medication regimens. RESULTS: The overall risk of BPCP was 16.2% over a mean follow-up of 1.67 years. The overall BPCP rate was 9.7/100 patient-years, with rates of 8.8/100, 13.1/100, and 6.3/100 patient-years in each of the three treatment eras. In the multivariate analysis, significant risk factors for prophylaxis failure were low CD4 count, previous diagnosis of PCP, history of AIDS-defining conditions other than PCP, and antiretroviral treatment era defined above. CONCLUSION: The overall rate of PCP prophylaxis failure has decreased significantly after 1995, coincident with the era of highly active antiretroviral therapies. Initiation of PCP prophylaxis remains necessary in patients with risk factors.     

High dose aerosol pentamidine for secondaryPneumocystis carinii pneumonia prophylaxis in AIDS patients

Summary In a prospective trial of aerosolized pentamidine as secondary prophylaxis forPneumocystis carinii pneumonia (PCP) 18 patients received 400 mg once weekly for a mean period of 15.5 months. Pentamidine aerosol was administered with an MA2 jet nebulizer. No PCP relapses were observed and no serious side effects occurred.

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Sekundäre Prophylaxe der Pneumocystis carinii-Pneumonie bei AIDS-Patienten mit hochdosiertem Pentamidin Aerosol

Zusammenfassung Zur sekundären Prävention einerPneumocystis carinii-Pneumonie (PCP) erhielten 18 Patienten wöchentlich über einen Zeitraum von 15,5 Monaten eine Aerosolbehandlung mit 400 mg Pentamidin. Die Studie wurde prospektiv geführt. Die Applikation erfolgte mit einem MA2 Jet-Vernebler. Rezidive der PCP oder schwere Nebenwirkungen traten nicht auf.

     

Aerosolized pentamidine as second line therapy in patients with AIDS and Pneumocystis carinii pneumonia

The use of aerosolized pentamidine was investigated in ten patients with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia (PCP) who had previous or concurrent severe adverse reactions or contraindications to trimethoprim-sulfamethoxazole or parenteral pentamidine. A dose of 600 mg pentamidine in 6 ml sterile water, aerosolized in a small-particle producing jet nebulizer was administered for 25 minutes once daily for an average of 10.5 days to these ten patients. All patients improved their arterial O2 saturation and showed clinical and roentgenographic improvement within six to 21 days of aerosol pentamidine therapy. No adverse systemic reactions occurred. The results of this small open trial indicate that aerosolized pentamidine is effective and can be given safely to AIDS patients with PCP who have had adverse reactions to trimethoprim-sulfamethoxazole or parenteral pentamidine.     

Trimethoprim-sulphamethoxazole appears more effective than aerosolized pentamidine as secondary prophylaxis against Pneumocystis carinii pneumonia in patients with AIDS.

OBJECTIVE: We compared the efficacies of low-dose trimethoprim-sulphamethoxazole (TMP-SMX; one tablet: TMP, 160 mg, SMX, 800 mg, twice daily, twice a week) and aerosolized pentamidine (300 mg every 4 weeks) as secondary prophylaxis against Pneumocystis carinii pneumonia (PCP) in patients with HIV infection. DESIGN: A retrospective controlled study. SETTING: The study was performed at St Vincent's Hospital, Sydney, Australia, which is a tertiary referral university hospital. PATIENTS, PARTICIPANTS: Over a 4-year period, following primary episodes of PCP, 60 patients received TMP-SMX and 73 aerosolized pentamidine. Thirty-eight patients who received no secondary prophylaxis served as historical controls. MAIN OUTCOME MEASURES: The rate of and time to PCP relapse was recorded for patients receiving low-dose TMP-SMX, aerosolized pentamidine, or no prophylaxis. RESULTS: Only one (1.7%) patient in the TMP-SMX-treated group relapsed, compared with 31 (42.5%) of those in the aerosolized pentamidine group and 21 (55.1%) of those in the control group (P less than 0.0001). Median PCP-free survival times were greater than 1153 days in the TMP-SMX group, 496 days in the pentamidine group, and 265 days in the control group (P less than 0.0001 between all groups). The rate of or time to relapse was not influenced by CD4+ lymphocyte count at the start of prophylaxis, primary therapy of PCP, history of allergy to TMP-SMX, or zidovudine therapy during the period of secondary prophylaxis in any patient group. Both therapies were well tolerated, with three (5%) of those receiving TMP-SMX and four (5%) of those receiving pentamidine discontinuing therapy as a result of side-effects. CONCLUSIONS: Low-dose TMP-SMX appears to be more effective compared with aerosolized pentamidine as secondary prophylaxis against PCP in HIV-infected patients. Zidovudine was well tolerated by both groups, but did not influence the rate of or time to relapse.     

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.     

Apical Pneumocystis carinii pneumonia in AIDS patients not receiving inhaled pentamidine prophylaxis

Isolated apical Pneumocystis carinii pneumonia might develop in AIDS patients receiving aerosolized pentamidine prophylaxis. Demonstrated here are two cases of apical P carinii pneumonia occurring in patients not receiving inhaled pentamidine prophylaxis. Such isolated apical localization of P carinii should be differentiated from tuberculosis and fungal infection.     

Ultrasonic nebulised pentamidine for Pneumocystis carinii pneumonia

Our retrospective study for ultrasonic nebulised pentamidine in 13 patients shows that 7 of 8 patients with Pneumocystis carinii pneumonia (PCP), proven by biopsy examination, were cured (recovery rate, 88%). Two of these 8 patients were mainly treated by nebulised pentamidine and the other 5 patients were administered parenteral pentamidine before the nebulised pentamidine therapy and the final 1 patient died on day 9 without clinical improvement with nebulised pentamidine as well as conventional therapy (trimethoprim-sulphamethoxazole, parenteral pentamidine). No relapse occurred in the 7 cured patients. The inhalation increased the cough in 4 of 13 cases and caused vomiting in 1 patient. Two patients discontinued the nebulisation because of the side-effect. No extra-pulmonary side-effects of nebulised pentamidine were seen. These results show that an efficacy of nebulised pentamidine is at least equal to conventional therapy with fewer side-effects and that only patients with mild PCP without severe hypoxaemia are eligible for the inhalation therapy.     

Bilateral upper lobe Pneumocystis carinii pneumonia in a patient receiving inhaled pentamidine prophylaxis

A 46-year-old man with AIDS, receiving inhaled pentamidine for Pneumocystis carinii pneumonia (PCP) prophylaxis, developed bilateral upper lobe infiltrates. Bronchoalveolar lavage confirmed the diagnosis of PCP. Therapy with intravenous trimethoprim-sulfamethoxazole (TMP-SMX) was begun, with gradual resolution of these infiltrates noted. An explanation for the development of upper lobe PCP, despite aerosol chemoprophylaxis, is presented and emphasizes the importance of aerosol particle size (and therefore of nebulizer type) on the distribution of inhaled pentamidine.     

Pneumocystis carinii pleuropneumonia after aerosolized pentamidine prophylaxis

Summary We observed an atypicalPneumocystis infection with spontaneous pneumothorax, bronchopleural fistulae, an apical cyst andPneumocystis pleuritis after aerosolized pentamidine prophylaxis in an AIDS patient. These findings suggest a failure of pentamidine aerosol in controlling activePneumocystis infection in peripheral pulmonary areas. A relapse ofPneumocystis carinii pneumonia (PCP) must be suspected when pneumothorax occurs during secondary prophylaxis with aerosolized pentamidine. It should always be confirmed by bronchoalveolar lavage or transbronchial or open biopsy. Cases presenting as atypicalPneumocystis pneumonia may additionally reveal extrapulmonary dissemination ofPneumocystis infection.

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Pleuro-Pneumonie durch Pneumocystis carinii unter Pentamidin-Inhalations-Prophylaxe

Zusammenfassung Wir beschreiben eine ausgedehnte atypische Pneumocystose mit Pneumothoraxbildung und Nachweis bronchopleuraler Fisteln, einer apikalen Zyste sowie einer Pneumocystis-Pleuritis bei einem AIDS-Patienten. Diese Manifestationen sind offensichtlich Ausdruck mangelhafter Suppression der Pneumocystis-Infektion durch inhaliertes Pentamidin-Aerosol in der Lungenperipherie. Jeder Spontanpneumothorax unter Pentamidin-Sekundärprophylaxe muß als verdächtig auf ein Pneumocystis-carinii-Pneumonie (PCP)-Rezidiv gelten. Diese Verdachtsdiagnose sollte den Versuch einer Diagnosesicherung durch bronchoalveoläre Lavage, transbronchiale oder offene Lungenbiopsie zur Folge haben. Bei atypischen Pneumocystis-Pneumonien muß mit dem Vorliegen einer extrapulmonalen Dissemination gerechnet werden.

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Presented in part at the 3. Deutscher AIDS-Kongreß in Hamburg, 1990.     

The use of aerosolized pentamidine for prophylaxis of Pneumocystis carinii pneumonia in children with leukemia

We report our experience giving aerosolized pentamidine as prophylaxis for Pneumocystis carinii pneumonia (PCP) to 9 children (mean age, 7.33 years; range 3–17 years) with leukemia who were unable to tolerate trimethoprim-sulfamethoxazole (TMP-SMX) due to allergy or myelosuppression. The dose of pentamidine was modified for each child to correct for weight and approximate alveolar ventilation. We were able to administer the drug to younger children by using a cushioned face mask in place of the standard mouthpiece. One child experienced moderate coughing with administration of pentamidine. He and four others with a past medical history suggestive of reactive airways disease were pretreated with inhaled albuterol. No other adverse effects were noted. Treatment lasted an average of 8.11 ± 4.1 months per child; no case of PCP occurred. We conclude that aerosolized pentamidine can be administered to even very young children and may be of benefit to all immunosuppressed children unable to use TMP-SMX prophylaxis. The adjusted dose used here appears to be safe, but further studies regarding drug delivery and efficacy are needed. Pediatr Pulmonol. 1994;18:226–231 . ©1994 Wiley-Liss, Inc.     

Oral dapsone versus nebulized pentamidine for Pneumocystis carinii pneumonia prophylaxis: an open randomized prospective trial to assess efficacy and haematological toxicity.

OBJECTIVE: To compare the haematological toxicity and efficacy of oral dapsone and nebulized pentamidine as Pneumocystis carinii pneumonia (PCP) prophylaxis in HIV-infected patients receiving zidovudine. DESIGN: Randomized, prospective. SETTING: Infectious diseases hospital with participants drawn from both inpatient and outpatient departments. PATIENTS: Those eligible were starting treatment with zidovudine, needed PCP prophylaxis (CD4+ count < 200 x 10(6)/l or < 20% total lymphocyte count or previous episode of PCP), and had a normal glucose-6-phosphate dehydrogenase screen. Of the 98 patients enrolled, 96 returned for follow-up. INTERVENTIONS: Fifty patients received dapsone (100mg orally twice weekly) and 46 pentamidine (400 mg nebulized monthly). Follow-up was for a median of 18 months. MAIN OUTCOME MEASURES: The development of PCP, transfusion requirements, monthly complete blood cell counts, serious adverse reactions and death were recorded. RESULTS: Nine (18%) dapsone and eight (17%) pentamidine recipients developed PCP. There was no significant difference in number of patients transfused (12 dapsone and nine pentamidine recipients) or transfusion-free survival. At exit from the study, mean haemoglobin (11.7 versus 12.4 g/dl), white blood cell (3.9 versus 3.7 x 10(9)/l) and platelet (195 versus 184 x 10(9)/l) counts did not differ for the dapsone and pentamidine arms, respectively. There was no significant difference in the occurrence of serious adverse reactions (six in the dapsone and eight in the pentamidine arm). CONCLUSIONS: Dapsone can be recommended in preference to pentamidine as PCP prophylaxis on the basis of equivalent efficacy, absence of excessive haematological toxicity, low cost and ease of administration.