EDITORIAL
The Era of Aerosol Pentamidine Prophylaxis: The Beginning or the End? JUDITH FALLOON, M.D., HENRY MASUR, M.D.,
Bethesda,Maryland
~or patients with moderate or severe immuno-
F suppression caused by human immunodeficien-
cy virus (HIV) infection, the widespread use of antipneumocystis prophylaxis regimens to prevent first or subsequent episodes of pneumocystis pneumonia has been one of the most beneficial advances in management strategy since the acquired immunodeficiency syndrome (AIDS) epidemic began in the early 1980s. From the beginning of the epidemic, clinicians recognized that pneumocystis pneumonia occurred in most North American patients, causing considerable morbidity and mortality, and that some patients had multiple episodes of this predominantly pulmonary process. Oral trimethoprim-sulfamethoxazole was well known to be highly efficacious in preventing pneumocystis pneumonia in pediatric cancer patients [1]. The uniquely high frequency of adverse reactions to trimethoprimsulfamethoxazole among HIV-infected patients, which has still not been explained, made clinicians wary about trying a daily or intermittent trimethoprim-sulfamethoxazole regimen as prophylaxis [2]. Since oral trimethoprim-sulfamethoxazole was thought to be intolerable by so many patients (a concept that was probably exaggerated), and since pneumocystosis was thought to be confined to the lungs (an oversimplification), the medical community and patient advocacy groups embraced the concept of aerosol delivery of pentamidine with considerable enthusiasm. The theory behind aerosol pentamidine prophylaxis was well reasoned: an effective but systemically toxic drug could be delivered locally to the lungs with little systemic absorption, producing prophylactic efficacy with little systemic toxicity. The trial of aerosol pentamidine prophylaxis sponsored by Lyphomed Inc. using the Respirgard nebulizer was a historic and pivotal trial that was completed with impressive speed by a consortium of community-based physicians in San Francisco From the Critical Care Medicine Department, Warren G. Magnuson Clinical Center. National Institutes of Health, Bethesda.Marylar{d. Requestsfor reprints should be addressedto Henry Masur, M.D.. Critical Care MedicineDepartment, NationalInstitutes of Health, Building 10, Room 7D43, Bethesda,Maryland20892. Manuscript submitted February 15. 1991, and accepted February 18, 1991.
[3]. The study showed that in patients with prior pneumocystis pneumonia, high-dose aerosol pentamidine (300 mg every 4 weeks) resulted in a 1-year estimated relapse rate of 22% compared with over 40% at 30 mg every 2 weeks. The difference in relapse rate between high dose and low dose was statistically significant. Aerosol pentamidine was extremely well tolerated. This study had a major influence on the decision by the Food and Drug Administration to approve the use of prophylactic aerosol pentamidine in June 1989. Although the costs of drug acquisition and drug delivery for treating patients with aerosolized pentamidine have been considerable, the availability of a regimen that was effective and well tolerated and could be given under monitored conditions was very appealing. The Lyphomed Inc.-sponsored aerosol pentamidine prophylaxis trial demonstrated efficacy and safety, yet it posed some major questions: was the Respirgard nebulizer the optimal delivery device for depositing a satisfactory amount of drug in all lobes of the lung; was the dosing regimen of 300 mg every 4 weeks the optimal regimen; was the high cost of aerosol pentamidine justified in an era of limited health care resources; was the prophylaxis failure rate acceptable compared to what could be achieved with oral trimethoprim-sulfamethoxazole? In this issue of The American Journal of Medicine, Murphy et al [4] have assessed a different aerosol device for delivering pentamidine to the lungs. This multicenter trial was sponsored by Fisons Corporation and carried out in the United States using a chemical compound identical to the Lyphomed product but delivered via a hand-held ultrasonic nebulizer. Performance characteristics of this Fisons ultrasonic nebulizer differ from those of the Marquest Respirgard II jet nebulizer in terms of the profile of particle sizes generated and the efficiency of drug delivery. In addition, the Fisons Corporation nebulizer produces the aerosol on demand in contrast to the continuous drug delivery provided by the Respirgard nebulizer. Because of these differences between the delivery systems, the delivery of drug to alveoli by the two nebulizers is dramatically different for a fixed drug dose. Thus, April 1991
The American Journal of Medicine Volume 90
415
AEROSOL PENTAMIDINE PROPHYLAXIS / FALLOONAND MASUR
the efficacy and toxicity of a given dose of pentamidine administered by the Fisons ultrasonic nebulizer versus the Respirgard jet nebulizer need to be assessed separately and distinctly. The trial by Murphy et al [4] was designed to compare the efficacy and safeW of three dosing regimens as secondary prophylaxis in patients with a history of pneumocystis pneumonia: 5 rag, 60 mg, or 120 mg of aerosol pentamidine was given every 2 weeks in a double-blind fashion after loading doses. When results of the Lyphomed Respirgard trial became known, these investigators made a reasonable and appropriate change in their protocol: all patients receiving the 5-mg dose (the dose that likely would have had little efficacy) were randomized to higher doses. At the time the trial was interrupted, the 60-mg regimen appeared to be more efficacious than the 5-mg regimen and, surprisingly, the 120mg regimen as well. With further follow-up, however; the differences between 60-mg and 120-mg doses disappeared. One of the weaknesses of the trial by Murphy et al is that there was no control arm after the discontinuation of the 5-rag dose, so that the results must be compared with those in historical control subjects. Murphy et al estimate the cumulative 1-year relapse rate at 12% for the 60mg group and 7% for the 120-rag group. This compares favorably with an expected relapse rate of more than 60% for patients receiving zidovudine alone during the first 12 months after a first episode of pneumocystis pneumonia [5]. These data from Murphy et al support the efficacy and safety of this Fisons ultrasonic nebulizer regimen. The efficacy of aerosol pentamidine delivered by the Fisons nebulizer at a dose of 60 mg every 2 weeks is supported even more powerfully by a placebo-controlled study recently completed in Canada and presented only in abstract form to date, which shows a substantial difference between drug and placebo [6]. Is there any reason why clinicians should consider the use of the Fisons ultrasonic delivery system in preference to the Marquest Respirgard II jet nebulizer? Toxicities associated with these two delivery systems are mild and comparable; thus, there is no demonstrable reason to chose one device over the other in terms of patient safety. The ultrasonic nebulizer has some potential advantages: it is handheld, self-contained, and does not require compressed gas or oxygen, and thus is more portable and better suited for home use. In addition, the ultrasonic nebulizer uses 60 mg of pentamidine twice monthly instead of 300 mg once monthly, thus potentially decreasing drug acquisition costs. Published studies now show that both the Respirgard jet nebulizer and the Fisons ultrasonic nebulizer can be used .effectively to decrease the 416
April 1991 The American Journal of Medicine Volume 90
relapse rate of pneumocystis pneumonia. Until there is a study directly comparing these two approaches to delivery, it cannot be proven whether one approach has more efficacy than the other. Other delivery devices with promising and interesting features have been used as well. To prove that any one system is superior to another would require a large and expensive trial. The differences would very likely be small, and funding agencies, clinicians, and patients would be unlikely to invest their resources in the demonstration of minor differences. Thus, it seems unlikely that such trials will ever be performed. From a regulatory perspective, it is important to recognize that under the Orphan Drug Act, Lyphomed Inc. received a 7-year period of marketing exclusivity that precludes approval of an application by another sponsor for the same drug for the same indication until 1996. Fisons and Lyphomed each provide the identical isethionate salt of pentamidine. Thus, unless Fisons can find a basis for contending that aerosol pentamidine delivered by their system is a "different drug" than the Lyphomed product, or that their system is "clinically superior," their approach cannot be licensed until 1996 in the U.S. There could theoretically be some legal basis to claim that the Fisons approach is "superior," but it is conceivable that Fisons will not be successful in arguing their case and thus will not receive a license. Regardless of the outcome of the licensing issues, is this the time to be looking for better ways to deliver aerosol pentamidine? Considerable research could be done on delivery systems or techniques that provide more drug to the alveoli, more homogeneous distribution to the lungs, or more efficient, more convenient, or more economical approaches [7]. This research may well be fruitful in overcoming some of the efficacy deficiencies pointed out in the Respirgard and Fisons trials. These deficiencies include poor distribution to the upper lobes and a relapse rate that is less than in untreated patients but still substantial, and probably include increased frequency of lung cavities, lung collapse, and e x t r a p u l m o n a r y d i s s e m i n a t i o n in patients who develop pneumocystis pneumonia after having received pentamidine by aerosol [8,9]. An increasing number of uncontrolled trials are now reporting exceedingly low relapse rates for patients who can tolerate trimethoprim-sulfamethoxazole on a daily or intermittent basis [10]. These relapse rates may be less than 5% per year. These studies are uncontrolled, and although very encouraging, they cannot be considered as showing a definitive advantage for trimethoprim-sulfamethoxazole. An evaluation of the relative merits of
AEROSOL PENTAMIDINE PROPHYLAXIS / FALLOON AND MASUR
trimethoprim-sulfamethoxazole must wait until of alternative prophylactic regimens to determine the randomized, controlled, double-blind multicen- whether aerosol pentamidine will remain a first-line ter studies comparing trimethoprim-sulfamethoxa- approach to prophylaxis, or whether it will become zole with aerosol pentamidine for primary and sec- a seldom-used alternative for patients who cannot ondary prophylaxis, sponsored by the National tolerate one of several more effective, more broadly Institute of Allergy and Infectious Diseases, which active oral agents. are now fully accrued, have been completed and analyzed in a manner that fairly compares efficacy and toxicity. In addition, attractive alternatives are REFERENCES also being considered for large prophylaxis trials 1. Hughes W'I', Rivera GK, Schell MJ, Thornton D, Loot L. Successful intermitthis year, including intermittent dapsone, weekly tent chemoprophylaxis for Pneumocystis carinii pneumoni~is. N Engl J Med dapsone-pyrimethamine, and 566C80 (an investi- 1987; 316: 1627-32. gational hydroxynaphthoquinone). These latter al- 2. Wofsy CB. Use of trimethoprim-sulfamethoxazole in the treatment o! Pneumocystis carinii pneumonitis in patients with acquired immunodeficiency synternatives could conceivably provide a higher de- drome. Rev Infect Dis 1987: 9: $184-94. gree of protection than aerosol pentamidine, 3. Leoung GS, Feigal DWJr, Montgomery AB, et al. Aerosolizedpentamidine for reasonable tolerability, and some protection prophylaxis against Pneumocystis carinii pneumonia. The San Francisco Community Prophylaxis Trial. N Engl J Med 1990; 323: 769-75. against toxoplasmosis as well. 4. Murphy RL, LavelleJP, AllanJD. et al. Aerosol pentamidine prophylaxis followThe future for aerosol pentamidine as a prophy- ing Pneumocystis carinii pneumonia in AIDS patients: results of a blinded dose lactic agent is difficult to predict. The randomized, comparison study using an ultrasonic nebulizer. Am J Med 1991; 90: 418-26. double-blind trial sponsored by the National Insti- 5. Centers for DiseaseControl. Guidelinesfor prophylaxis against Pneumocystis tute of Allergy and Infectious Diseases may con- carinii pneumonia for persons infected with human immunodeficiency virus. MMWR 1989; 38($5): I-9. ceivably show superiority of aerosol pentamidine 6. Montaner JSG, Lawson L, Falutz J, et al. Aerosolized pentamidine for the over trimethoprim-sulfamethoxazSle when both secondary prophylaxis of Pneumocystis carinii pneumonia in the acquired imtoxicity and efficacy are taken into consideration, munocleficiency syndrome: a report from the Canadian cooperative trial [Abor new delivery systems may improve the results stract]. Presented at the Fifth International Conference on AIDS, Montreal, Canada, June 4-9, 1989. presented to date with aerosol pentamidine. It 7. Baskin MI, Abd AG, llowite JS. Regional deposition of aerosolized pentamiseems quite possible, however, that the near future dine--effects of body position and breathin8 pattern. Ann Intern Med 1990: will document clear benefits for a variety of oral 113: 677-83. 8. Raviglione MC. Extrapulmonary pneumocystosis: the first 50 cases. Rev Inregimens over aerosol pentamidine. fect Dis 1990; 12: 1127-38. Aerosol pentamidine has been an important ad- 9. Newsome GS, Ward DJ, Pierce PF. Spontaneous pneumothorax in patients dition to our armamentarium of agents for prevent- with acquired immunodeficiency syndrome treated with prophylactic aerosoling pneumocystis pneumonia in patients with HIV ized pentamidine. Arch Intern Med 1990; 150: 2167-8. infection. Since 1989, it has filled a highly useful 10. Lariviere M, Ruskin J. Low dose trimethoprim/sullamethoxazole (T/S) prevents pneumocystis pneumonia (PP) in AIDS[Abstract 8]. Presented at the 30th niche in our management approach. We need to Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, watch closely for definitive, well-controlled studies Georgia, October 21-24, 1990.
April 1991 The American Journal of Medicine Volume 90
417
The Era of Aerosol Pentamidine Prophylaxis: The Beginning or the End? JUDITH FALLOON, M.D., HENRY MASUR, M.D.,
Bethesda,Maryland
~or patients with moderate or severe immuno-
F suppression caused by human immunodeficien-
cy virus (HIV) infection, the widespread use of antipneumocystis prophylaxis regimens to prevent first or subsequent episodes of pneumocystis pneumonia has been one of the most beneficial advances in management strategy since the acquired immunodeficiency syndrome (AIDS) epidemic began in the early 1980s. From the beginning of the epidemic, clinicians recognized that pneumocystis pneumonia occurred in most North American patients, causing considerable morbidity and mortality, and that some patients had multiple episodes of this predominantly pulmonary process. Oral trimethoprim-sulfamethoxazole was well known to be highly efficacious in preventing pneumocystis pneumonia in pediatric cancer patients [1]. The uniquely high frequency of adverse reactions to trimethoprimsulfamethoxazole among HIV-infected patients, which has still not been explained, made clinicians wary about trying a daily or intermittent trimethoprim-sulfamethoxazole regimen as prophylaxis [2]. Since oral trimethoprim-sulfamethoxazole was thought to be intolerable by so many patients (a concept that was probably exaggerated), and since pneumocystosis was thought to be confined to the lungs (an oversimplification), the medical community and patient advocacy groups embraced the concept of aerosol delivery of pentamidine with considerable enthusiasm. The theory behind aerosol pentamidine prophylaxis was well reasoned: an effective but systemically toxic drug could be delivered locally to the lungs with little systemic absorption, producing prophylactic efficacy with little systemic toxicity. The trial of aerosol pentamidine prophylaxis sponsored by Lyphomed Inc. using the Respirgard nebulizer was a historic and pivotal trial that was completed with impressive speed by a consortium of community-based physicians in San Francisco From the Critical Care Medicine Department, Warren G. Magnuson Clinical Center. National Institutes of Health, Bethesda.Marylar{d. Requestsfor reprints should be addressedto Henry Masur, M.D.. Critical Care MedicineDepartment, NationalInstitutes of Health, Building 10, Room 7D43, Bethesda,Maryland20892. Manuscript submitted February 15. 1991, and accepted February 18, 1991.
[3]. The study showed that in patients with prior pneumocystis pneumonia, high-dose aerosol pentamidine (300 mg every 4 weeks) resulted in a 1-year estimated relapse rate of 22% compared with over 40% at 30 mg every 2 weeks. The difference in relapse rate between high dose and low dose was statistically significant. Aerosol pentamidine was extremely well tolerated. This study had a major influence on the decision by the Food and Drug Administration to approve the use of prophylactic aerosol pentamidine in June 1989. Although the costs of drug acquisition and drug delivery for treating patients with aerosolized pentamidine have been considerable, the availability of a regimen that was effective and well tolerated and could be given under monitored conditions was very appealing. The Lyphomed Inc.-sponsored aerosol pentamidine prophylaxis trial demonstrated efficacy and safety, yet it posed some major questions: was the Respirgard nebulizer the optimal delivery device for depositing a satisfactory amount of drug in all lobes of the lung; was the dosing regimen of 300 mg every 4 weeks the optimal regimen; was the high cost of aerosol pentamidine justified in an era of limited health care resources; was the prophylaxis failure rate acceptable compared to what could be achieved with oral trimethoprim-sulfamethoxazole? In this issue of The American Journal of Medicine, Murphy et al [4] have assessed a different aerosol device for delivering pentamidine to the lungs. This multicenter trial was sponsored by Fisons Corporation and carried out in the United States using a chemical compound identical to the Lyphomed product but delivered via a hand-held ultrasonic nebulizer. Performance characteristics of this Fisons ultrasonic nebulizer differ from those of the Marquest Respirgard II jet nebulizer in terms of the profile of particle sizes generated and the efficiency of drug delivery. In addition, the Fisons Corporation nebulizer produces the aerosol on demand in contrast to the continuous drug delivery provided by the Respirgard nebulizer. Because of these differences between the delivery systems, the delivery of drug to alveoli by the two nebulizers is dramatically different for a fixed drug dose. Thus, April 1991
The American Journal of Medicine Volume 90
415
AEROSOL PENTAMIDINE PROPHYLAXIS / FALLOONAND MASUR
the efficacy and toxicity of a given dose of pentamidine administered by the Fisons ultrasonic nebulizer versus the Respirgard jet nebulizer need to be assessed separately and distinctly. The trial by Murphy et al [4] was designed to compare the efficacy and safeW of three dosing regimens as secondary prophylaxis in patients with a history of pneumocystis pneumonia: 5 rag, 60 mg, or 120 mg of aerosol pentamidine was given every 2 weeks in a double-blind fashion after loading doses. When results of the Lyphomed Respirgard trial became known, these investigators made a reasonable and appropriate change in their protocol: all patients receiving the 5-mg dose (the dose that likely would have had little efficacy) were randomized to higher doses. At the time the trial was interrupted, the 60-mg regimen appeared to be more efficacious than the 5-mg regimen and, surprisingly, the 120mg regimen as well. With further follow-up, however; the differences between 60-mg and 120-mg doses disappeared. One of the weaknesses of the trial by Murphy et al is that there was no control arm after the discontinuation of the 5-rag dose, so that the results must be compared with those in historical control subjects. Murphy et al estimate the cumulative 1-year relapse rate at 12% for the 60mg group and 7% for the 120-rag group. This compares favorably with an expected relapse rate of more than 60% for patients receiving zidovudine alone during the first 12 months after a first episode of pneumocystis pneumonia [5]. These data from Murphy et al support the efficacy and safety of this Fisons ultrasonic nebulizer regimen. The efficacy of aerosol pentamidine delivered by the Fisons nebulizer at a dose of 60 mg every 2 weeks is supported even more powerfully by a placebo-controlled study recently completed in Canada and presented only in abstract form to date, which shows a substantial difference between drug and placebo [6]. Is there any reason why clinicians should consider the use of the Fisons ultrasonic delivery system in preference to the Marquest Respirgard II jet nebulizer? Toxicities associated with these two delivery systems are mild and comparable; thus, there is no demonstrable reason to chose one device over the other in terms of patient safety. The ultrasonic nebulizer has some potential advantages: it is handheld, self-contained, and does not require compressed gas or oxygen, and thus is more portable and better suited for home use. In addition, the ultrasonic nebulizer uses 60 mg of pentamidine twice monthly instead of 300 mg once monthly, thus potentially decreasing drug acquisition costs. Published studies now show that both the Respirgard jet nebulizer and the Fisons ultrasonic nebulizer can be used .effectively to decrease the 416
April 1991 The American Journal of Medicine Volume 90
relapse rate of pneumocystis pneumonia. Until there is a study directly comparing these two approaches to delivery, it cannot be proven whether one approach has more efficacy than the other. Other delivery devices with promising and interesting features have been used as well. To prove that any one system is superior to another would require a large and expensive trial. The differences would very likely be small, and funding agencies, clinicians, and patients would be unlikely to invest their resources in the demonstration of minor differences. Thus, it seems unlikely that such trials will ever be performed. From a regulatory perspective, it is important to recognize that under the Orphan Drug Act, Lyphomed Inc. received a 7-year period of marketing exclusivity that precludes approval of an application by another sponsor for the same drug for the same indication until 1996. Fisons and Lyphomed each provide the identical isethionate salt of pentamidine. Thus, unless Fisons can find a basis for contending that aerosol pentamidine delivered by their system is a "different drug" than the Lyphomed product, or that their system is "clinically superior," their approach cannot be licensed until 1996 in the U.S. There could theoretically be some legal basis to claim that the Fisons approach is "superior," but it is conceivable that Fisons will not be successful in arguing their case and thus will not receive a license. Regardless of the outcome of the licensing issues, is this the time to be looking for better ways to deliver aerosol pentamidine? Considerable research could be done on delivery systems or techniques that provide more drug to the alveoli, more homogeneous distribution to the lungs, or more efficient, more convenient, or more economical approaches [7]. This research may well be fruitful in overcoming some of the efficacy deficiencies pointed out in the Respirgard and Fisons trials. These deficiencies include poor distribution to the upper lobes and a relapse rate that is less than in untreated patients but still substantial, and probably include increased frequency of lung cavities, lung collapse, and e x t r a p u l m o n a r y d i s s e m i n a t i o n in patients who develop pneumocystis pneumonia after having received pentamidine by aerosol [8,9]. An increasing number of uncontrolled trials are now reporting exceedingly low relapse rates for patients who can tolerate trimethoprim-sulfamethoxazole on a daily or intermittent basis [10]. These relapse rates may be less than 5% per year. These studies are uncontrolled, and although very encouraging, they cannot be considered as showing a definitive advantage for trimethoprim-sulfamethoxazole. An evaluation of the relative merits of
AEROSOL PENTAMIDINE PROPHYLAXIS / FALLOON AND MASUR
trimethoprim-sulfamethoxazole must wait until of alternative prophylactic regimens to determine the randomized, controlled, double-blind multicen- whether aerosol pentamidine will remain a first-line ter studies comparing trimethoprim-sulfamethoxa- approach to prophylaxis, or whether it will become zole with aerosol pentamidine for primary and sec- a seldom-used alternative for patients who cannot ondary prophylaxis, sponsored by the National tolerate one of several more effective, more broadly Institute of Allergy and Infectious Diseases, which active oral agents. are now fully accrued, have been completed and analyzed in a manner that fairly compares efficacy and toxicity. In addition, attractive alternatives are REFERENCES also being considered for large prophylaxis trials 1. Hughes W'I', Rivera GK, Schell MJ, Thornton D, Loot L. Successful intermitthis year, including intermittent dapsone, weekly tent chemoprophylaxis for Pneumocystis carinii pneumoni~is. N Engl J Med dapsone-pyrimethamine, and 566C80 (an investi- 1987; 316: 1627-32. gational hydroxynaphthoquinone). These latter al- 2. Wofsy CB. Use of trimethoprim-sulfamethoxazole in the treatment o! Pneumocystis carinii pneumonitis in patients with acquired immunodeficiency synternatives could conceivably provide a higher de- drome. Rev Infect Dis 1987: 9: $184-94. gree of protection than aerosol pentamidine, 3. Leoung GS, Feigal DWJr, Montgomery AB, et al. Aerosolizedpentamidine for reasonable tolerability, and some protection prophylaxis against Pneumocystis carinii pneumonia. The San Francisco Community Prophylaxis Trial. N Engl J Med 1990; 323: 769-75. against toxoplasmosis as well. 4. Murphy RL, LavelleJP, AllanJD. et al. Aerosol pentamidine prophylaxis followThe future for aerosol pentamidine as a prophy- ing Pneumocystis carinii pneumonia in AIDS patients: results of a blinded dose lactic agent is difficult to predict. The randomized, comparison study using an ultrasonic nebulizer. Am J Med 1991; 90: 418-26. double-blind trial sponsored by the National Insti- 5. Centers for DiseaseControl. Guidelinesfor prophylaxis against Pneumocystis tute of Allergy and Infectious Diseases may con- carinii pneumonia for persons infected with human immunodeficiency virus. MMWR 1989; 38($5): I-9. ceivably show superiority of aerosol pentamidine 6. Montaner JSG, Lawson L, Falutz J, et al. Aerosolized pentamidine for the over trimethoprim-sulfamethoxazSle when both secondary prophylaxis of Pneumocystis carinii pneumonia in the acquired imtoxicity and efficacy are taken into consideration, munocleficiency syndrome: a report from the Canadian cooperative trial [Abor new delivery systems may improve the results stract]. Presented at the Fifth International Conference on AIDS, Montreal, Canada, June 4-9, 1989. presented to date with aerosol pentamidine. It 7. Baskin MI, Abd AG, llowite JS. Regional deposition of aerosolized pentamiseems quite possible, however, that the near future dine--effects of body position and breathin8 pattern. Ann Intern Med 1990: will document clear benefits for a variety of oral 113: 677-83. 8. Raviglione MC. Extrapulmonary pneumocystosis: the first 50 cases. Rev Inregimens over aerosol pentamidine. fect Dis 1990; 12: 1127-38. Aerosol pentamidine has been an important ad- 9. Newsome GS, Ward DJ, Pierce PF. Spontaneous pneumothorax in patients dition to our armamentarium of agents for prevent- with acquired immunodeficiency syndrome treated with prophylactic aerosoling pneumocystis pneumonia in patients with HIV ized pentamidine. Arch Intern Med 1990; 150: 2167-8. infection. Since 1989, it has filled a highly useful 10. Lariviere M, Ruskin J. Low dose trimethoprim/sullamethoxazole (T/S) prevents pneumocystis pneumonia (PP) in AIDS[Abstract 8]. Presented at the 30th niche in our management approach. We need to Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, watch closely for definitive, well-controlled studies Georgia, October 21-24, 1990.
April 1991 The American Journal of Medicine Volume 90
417
