AIDS TREATMENT NEWS No. 114 - November 4, 1990
Michelle Roland

In spite of recent improvements in treatment, pneumocystis pneumonia remains the most frequent cause of death in people with HIV infection. In addition, all currently available treatments have potentially serious toxicities associated with them. Therefore, the best approach to dealing with pneumocystis is to avoid getting it by properly using an effective prophylaxis (preventive treatment) in all persons at risk of developing the infection.

This article provides an overview of current information and controversies about approved and experimental prophylaxis for pneumocystis. Because no currently available option is ideal, we discuss the potential advantages and disadvantages of each approach.

When to Use Pneumocystis Prophylaxis

The official recommendation of the U. S. Public Health Service is that adults should use a prophylaxis against pneumocystis if they have: (1) a T-helper count of 200 or less, or (2) a T-helper cell percent of less than 20, or (3) a previous episode of pneumocystis.1 (The T-helper cell percent is a laboratory marker of disease severity that doctors often take into account when recommending various treatments or prophylaxis. It measures the percent of all the white blood cells known as lymphocytes that are T-helper cells.)

There are additional situations in which prophylaxis may be helpful, although there is no consensus among physicians in this area. A recent survey of over 80 physicians and other health-care providers practicing in the San Francisco Bay Area demonstrated the following trends in pneumocystis prophylaxis:2

* Seventy-seven percent of the responding health-care providers would offer prophylaxis to patients with any AIDS-defining opportunistic infection, even if they did not meet the criteria outlined in the official recommendations described above.

* Fifty-eight percent would offer prophylaxis to patients with any AIDS-related malignancy irrespective of whether or not they met the official criteria.

* While approximately 80-90 percent would offer prophylaxis to patients with under 200 T-helper cells, whether symptomatic or not, less than half of those responding would do so for patients with less than 20 percent T-helper cells and no other reason for prophylaxis.

* Approximately half would offer prophylaxis to symptomatic patients with more than 200 but less than 300 T-helper cells; only about 30 percent would offer prophylaxis to asymptomatic patients in that range. Few would recommend prophylaxis for patients with more than 300 T-helper cells.

A Note About Infants

Current recommendations suggest that all infants and children should receive pneumocystis prophylaxis when their T-helper cell count falls below 500. However, an important study presented at the Sixth International Conference on AIDS suggests that some infants (those who were infected with HIV perinatally as opposed to those infected by transfusion) may be at high risk of developing pneumocystis with well over 500 T- helper cells.3

A chart review of 38 infants in Los Angeles showed that 41 percent of the infants who acquired their HIV infection perinatally were diagnosed with pneumocystis with a T-helper cell count greater than 500. Of those who acquired their infection perinatally and developed pneumocystis when they were less than one year old, all had greater than 500 T-helper cells; in fact, many had more than 1000 T-helper cells.

Although 93 percent of the infants who acquired their HIV infection via transfusion and were diagnosed with pneumocystis did have less than 500 T-helper cells, the official recommendation for prophylaxis in some categories of infants, it seems, should be reassessed.

Which Prophylaxis?

There are currently two different drugs for pneumocystis prophylaxis in widespread use in the U. S: aerosolized pentamidine, and Bactrim (also known as Septra, trimethoprim-sulfamethoxazole, TMP-SMX, or cotrimoxazole). Both have been officially recommended by the U. S. Department of Health and Human Services in the Center for Disease Control's Morbidity and Mortality Weekly Report, although neither was suggested to be the better choice in this document.1 In addition to aerosolized pentamidine and Bactrim, dapsone and dapsone plus pyrimethamine are currently being used or considered by clinicians and patients and are being tested in clinical trials. These drugs may have the additional advantage of preventing toxoplasmosis.

Bactrim was the first successful pneumocystis prophylaxis used in adults and children with cancer or organ transplants. It was routinely used for this purpose in the late 1970s,4,5 before AIDS was recognized. It was also the first drug used to prevent pneumocystis in people with HIV infection, before the development of aerosolized pentamidine. Even though it was shown to be very effective in preventing pneumocystis,6 its toxicities (severe rash, anemia, neutropenia, nausea, etc.) encouraged doctors, researchers, and patients to search for alternative approaches.

By the late 1980s, the apparent effectiveness of aerosolized pentamidine, and the relatively fewer and milder side effects associated with it, made it the drug of choice among many patients and clinicians. Aerosolized pentamidine was preferable to some from a theoretical standpoint because delivering a toxic drug directly to the site of action seemed safer than delivering it to the whole body. This theory assumed, however, that pneumocystis only causes disease in the lungs, which we now know is not true.

Recently the following questions have been raised in an attempt to understand which of these two regimens, aerosolized pentamidine or Bactrim, may be best as a first choice for prophylaxis:

(1) Is one drug more effective than the other?

(2) Is there an increased incidence of pneumocystis infections in organs other than the lung (extrapulmonary pneumocystis) in patients using aerosolized pentamidine compared to those using the systemic drug Bactrim?

(3) Is there an increased incidence in collapsed lungs (spontaneous pneumothorax) associated with the use of aerosolized pentamidine?

(4) Can Bactrim be used more safely but just as effectively by using it less often?

(5) Does the use of aerosolized pentamidine make diagnosis of break-through pneumocystis by chest x-ray, sputum, and bronchoalveolar lavage (fluid collected during a bronchoscopy) more difficult than does a systemic prophylaxis?

(6) How do the issues of cost and convenience fit into the risk/benefit equation? While aerosolized pentamidine costs an average of $1,200 per year for the drug alone, not including the significant costs associated with administering the treatment, Bactrim (or generic equivalents) may cost as little as $12 per year.

Aerosolized Pentamidine vs. Bactrim: Relative Safety and Efficacy

The ideal way to determine which prophylaxis works best is to compare the two directly in a large, controlled, prospective clinical trial. Unfortunately, no such data is yet available. An ongoing government-sponsored trial comparing these two drugs is completing enrollment of patients at this time (ACTG 021). According to David Hardy, M. D., one of the principal investigators overseeing the study, the results are not expected to be available in the next several months. The data will be looked at periodically by a panel of experts (called a Data and Safety Monitoring Board), however, and significant results will be publicized if they are found before completion of the study.

Many physicians suspect that dapsone is comparably effective to aerosolized pentamidine or Bactrim. Enrollment of a large government-sponsored trial comparing these three drugs has been completed (ACTG 081). This trial is scheduled to run until June of 1992. The principal investigator, Sam Bozette, M. D., of the University of California at San Diego, does not expect the trial to be completed early because he does not expect to see a large difference in the incidence of pneumocystis or adverse reactions among the three groups.

Results of these two clinical trials should provide important information about the relative efficacy of these three approaches. In addition to the relative incidence of both pulmonary and extrapulmonary pneumocystis, the incidence of toxoplasmosis and bacterial infections among the different groups will also be analyzed, with the expectation that the systemic drugs may decrease the incidence of those infections as well. Finally, the incidence of anemia will be compared among the groups to see if the systemic drugs cause a significantly greater incidence of anemia than does aerosolized pentamidine.

The only controlled trial of Bactrim for prophylaxis of AIDS-related pneumocystis published in a peer-reviewed journal to date is a Bactrim vs. no-treatment trial in patients with Kaposi's sarcoma which was published in 1988.6 The treated group (2 tablets a day plus 5 mg of leucovorin calcium) experienced no pneumocystis, whereas 53 percent in the no-treatment group were diagnosed with pneumocystis. Although effective, 50 percent of those receiving Bactrim experienced toxicities (rash, nausea), and 17 percent had to discontinue the prophylaxis.

Several uncontrolled studies were presented in San Francisco at the Sixth International Conference on AIDS in June. Results from a Danish trial of 122 people who had previously had at least one episode of pneumocystis showed relapse in 8 of the 122 patients, who were using one double-strength tablet of Bactrim daily, in a mean time of 13.1 months.7 In another study, a retrospective chart review found no pneumocystis in patients taking Bactrim once per day for 3, 6, 9, and 12 months.8 The authors concluded that Bactrim was effective in preventing pneumocystis when compared to an expected rate of 13 percent at 6 months and 24 percent at 12 months in patients not using a prophylaxis. This study was small (21 patients at 12 months and 45 patients at 6 months) and uncontrolled, but strongly suggestive of Bactrim's efficacy.

A recently published controlled, randomized, dose-comparison study of aerosolized pentamidine initiated by the San Francisco County Community Consortium (now the Community Consortium) in 1987 showed a significant decrease in the incidence of pneumocystis in patients receiving 300 mg of aerosolized pentamidine once a month as compared to those receiving 30 mg every two weeks.9 According to the principal investigator of this study, Gifford Leoung, M. D., of San Francisco General Hospital, the use of 300 mg of aerosolized pentamidine once a month reduced the incidence of pneumocystis to approximately 12 to 15 percent of that previously seen in patients who used no prophylaxis. This study, which was completed in December, 1988, was instrumental in obtaining official FDA approval of aerosolized pentamidine, making prophylaxis widely available to many people with AIDS for the first time.

Clearly, both Bactrim and aerosolized pentamidine are effective in decreasing the incidence of pneumocystis. But neither is 100 percent safe and effective. Although aerosolized pentamidine has become the most common prophylactic choice in many areas of the U. S., researchers and clinicians have raised a number of concerns about its use. We spoke with Sam Bozette, M.D., the principal investigator on the U. S. government-sponsored study of aerosolized pentamidine vs. Bactrim vs. Dapsone, discussed above. Although data from that study is not yet available, and Dr. Bozette has not seen any of it, he shared the following thoughts with us based on clinical experience and his understanding of the biology of the disease and the mechanisms of the drugs available:

* He believes Bactrim should be the first line prophylaxis. In his opinion, a systemic approach makes more sense than a local approach. While acknowledging that aerosolized pentamidine is effective, Dr. Bozette doubts the ability to deliver the drug to all the areas in the lung where it is needed. He pointed out the increased incidence of pneumocystis in the top portions of the lungs in patients on aerosolized pentamidine prophylaxis.

* Dr. Bozette also pointed out the increased incidence of extrapulmonary pneumocystis associated with the use of aerosolized pentamidine, which he believes would be prevented with the use of a systemic drug like Bactrim. Although several small studies presented at the Sixth International Conference on AIDS addressed the issue of extrapulmonary pneumocystis in patients using aerosolized pentamidine, none compared the incidence in those using aerosolized pentamidine with those using a systemic drug like Bactrim or Dapsone.10 Therefore, while it may seem likely that delivering the prophylactic treatment to the whole body (as with Bactrim or dapsone) instead of only to the lung (as with aerosolized pentamidine) would reduce the incidence of extrapulmonary pneumocystis, we cannot be sure that this is, in fact, the case.

* Dr. Bozette also noted, with the same reservation about a lack of comparative data, the potential increased incidence of spontaneous pneumothorax (collapsed lung) in patients on aerosolized pentamidine. Clinicians and researchers disagree on whether aerosolized pentamidine directly causes this problem. A recent study found 12 pneumothoraces in 327 patients on aerosolized pentamidine; of these, 83 percent required a chest tube, and 6 of the 12 patients died. Seventy-five percent of those with pneumothorax had evidence of active pneumocystis. The researchers concluded that the pneumothorax was not directly caused by use of aerosolized pentamidine, but rather "represents a prophylaxis failure with a high mortality rate...[Their] pathologic and clinical observations in patients receiving aerosolized pentamidine with spontaneous pneumothorax indicate that there are areas of the lung with inadequately controlled infection with P. carinii ."11 The problem remains that there is no data to compare the rate of pneumothorax in patients treated with systemic drugs like Bactrim or dapsone to that in patients using aerosolized pentamidine.

* Dr. Bozette also addressed the concern that the use of aerosolized pentamidine might make diagnosis, and thus management, of pneumocystis more difficult, as the number of organisms would be decreased by the aerosolized pentamidine even if they are not eliminated completely. At the Sixth International Conference on AIDS in June, researcher Henry Masur, M.D., reported that both sputum yield and the ability to diagnose pneumocystis using bronchoalveolar lavage fluid are decreased with the use of aerosolized pentamidine. However, a study presented at the recent Thirtieth Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC, October 21-24, 1990, in Atlanta) found no difference in the ability to detect the organism in sputum samples or bronchoalveolar lavage fluid of patients using or not using aerosolized pentamidine.12 The question remains open.

When asked which prophylactic treatment he would recommend if a patient failed Bactrim, Dr. Bozette said that the following factors should be taken into account: 1) if the patient does not want to take more pills or is anemic or otherwise intolerant of anti-retroviral therapy, he would recommend aerosolized pentamidine; 2) if, however, the patient were allergic to Bactrim, and did not have any of the other problems, he would recommend dapsone as the second choice. Dr. Bozette emphasized that the patient's preference is a very important variable in this decision-making process.

Dr. Leoung, principal investigator for the San Francisco aerosolized pentamidine study referred to above, suggested several circumstances in which aerosolized pentamidine may be a better first choice than one of the systemic drugs. Because aerosolized pentamidine does not get into the circulation, it may be a better choice in pregnant women, as there is some risk to the fetus associated with the use of the systemic drugs. Also, the government only pays for aerosolized pentamidine, because Bactrim is not FDA-approved for pneumocystis prophylaxis. Although Bactrim is much less expensive than aerosolized pentamidine, this bit of bureaucratic logic may pose a problem for some patients. Also, some patients may be taking other medication which should not be combined with Bactrim. And for some, the convenience of a monthly treatment is an important factor.

If Bactrim, How Much? How Often?

Official US recommendations suggest that Bactrim should be used twice a day, together with daily leucovorin. Most physicians do not prescribe leucovorin, and many use Bactrim less often than every day. The data on Bactrim use in pediatric cancer patients demonstrated that there was no difference in its effectiveness when used daily as opposed to three times a week.4,13 In AIDS TREATMENT NEWS issue #106, Dr. Marcus Conant reported on the successful use of Bactrim two times a day, twice a week by Cooper, from Australia. A study published but not presented at the Sixth International Conference on AIDS reported a decrease in the incidence of moderate and severe side effects (rash, nausea) with one tablet per day as opposed to two tablets every day or two tablets three times a week; this study included almost 200 participants.14

Four studies presented at the recent ICAAC conference suggest that one tablet taken three times a week is safe and effective in preventing pneumocystis. Two of these studies were retrospective chart reviews which looked at the incidence of pneumocystis and side effects in patients taking one tablet thrice weekly. The first study15 found no pneumocystis in 115 patients followed for an average of 20 months (range 3-46); the second16 found one case of pneumocystis in 64 patients followed for approximately 8 months (primary prophylaxis) or over 9 months (secondary prophylaxis). Twenty-nine percent of the people in the first study experienced side effects (rash, nausea, vomit, rare fever) and 13 percent discontinued therapy; only three of the 64 patients discontinued therapy in the second study.

A third study17 compared, via retrospective chart review, daily (18 patients) vs. thrice weekly (35 patients) Bactrim. There was one case of pneumocystis. There was a higher incidence of anemia in the thrice weekly treatment group but higher incidences of neutropenia, nausea, and vomiting in the daily treatment group. The incidence of toxicity which required discontinuation of Bactrim was approximately equal in the two groups.

The fourth study, also a chart review,18 demonstrated a lower incidence of pneumocystis in patients on thrice weekly Bactrim than those on aerosolized pentamidine (7 percent vs. 20 percent with a total of almost 100 patients). All of these studies were relatively small chart reviews, as opposed to large, controlled studies, and thus provide strong suggestive, though not conclusive, data about the effectiveness of one Bactrim tablet three times per week.

Dapsone With or Without Pyrimethamine

The general consensus in the medical community is that there is not enough data to determine the efficacy of dapsone in preventing pneumocystis, but that it is expected to be approximately as effective as Bactrim. The most serious toxicity associated with dapsone is hemolytic anemia; patients should have their G6PD (glucose-6-phosphate dehydrogenase, an enzyme) levels tested before taking dapsone because the anemia can be severe in patients with a G6PD deficiency.

A study with almost 200 people presented at the June, 1990, Sixth International Conference on AIDS found a statistically non-significant difference in the incidence of pneumocystis and the length of time to infection between a group treated with aerosolized pentamidine (100 mg every two weeks) and dapsone (100 mg twice a week). Although not statistically significant, the dapsone group did have a slightly lower incidence and a slightly longer disease-free interval.19

Dapsone was compared with Bactrim in a study presented at the Fifth International Conference on AIDS in Montreal;20 two out of 173 in the dapsone group vs. none of 48 in the Bactrim group developed pneumocystis. Only 10 percent of the dapsone group experienced adverse reactions requiring termination of therapy, as opposed to 38 percent of the Bactrim group. Treatment was studied for an average of eight to nine months. Importantly, patients who were allergic to one drug generally tolerated the other.

Two short, small studies presented at the Sixth International Conference on AIDS looked at the safety and effectiveness of dapsone plus pyrimethamine.21 Anemia was the primary toxicity and was usually tolerable. Nausea, vomiting, and rash also occurred in a small number of participants. No pneumocystis developed in 20 patients with a mean follow up of 6.5 months (range 4-16 months).

Preventing Toxoplasmosis Too?

Dapsone may have the additional advantage of preventing toxoplasmosis, especially when used with pyrimethamine, one of the standard treatments for this disease. When asked by a doctor in the audience at the Sixth International Conference on AIDS if he believed Bactrim could prevent toxoplasmosis, Dr. Henry Masur from the National Institutes of Health replied that Bactrim was not effective against toxoplasmosis in animals or in the test tube, but that he expected that dapsone plus pyrimethamine or the new Burroughs-Wellcome drug 566C80 (see below) would have broad anti-parasitic activity against it, as well as against pneumocystis. Another combination he suggested for further study is dapsone plus trimethoprim for those who are allergic to the sulfamethoxazole in Bactrim. (Note that some physicians and researchers do expect that Bactrim may also prevent toxoplasmosis; this question is being addressed in the two government-sponsored trials discussed above.)

A Note on Fansidar

Fansidar (sulfadoxine-pyrimethamine) continues to be studied in some European countries, but has largely fallen out of favor as a pneumocystis prophylaxis in the U. S. because of its rare but potentially fatal side effects. It has been associated with a severe allergic reaction called Steven's-Johnson syndrome. For more information, consult the Physicians' Desk Reference.

Experimental Prophylaxis

A Promising New Drug: 566C80

566C80 is a member of an anti-parasitic class of drugs called naphthoquinones. Unlike the treatments now in use, it may be able to destroy the cysts in which pneumocystis lives in a latent state in the human body. It may also be useful in the prevention and treatment of other parasitic opportunistic infections in AIDS, such as toxoplasmosis and cryptosporidiosis.

The drug has been demonstrated by researchers at Burroughs-Wellcome and St Jude's Children's Research Hospital in Memphis, Tennessee, to be effective in test-tube and animal studies. 22,23

An early human study24 examined the safety of increasing doses of 566C80 in six groups of four people each. The only adverse reaction was a rash in one person at the highest dose; the rash cleared after the drug was discontinued. More studies are currently underway or being designed to examine the safety and efficacy of this drug in the treatment and prophylaxis of pneumocystis. Those who are interested in more information about these studies can call 800/TRIALS-A for eligibility information and referrals to the appropriate study sites.

For a more complete discussion of the research on this compound, see Treatment Issues, volume 4, number 7 (published by Gay Men's Health Crisis, Department of Medical Information, 129 West 20th Street, New York, NY 10011).

Other Experimental Approaches

The pneumocystis carinii organism which causes pneumocystis has characteristics of both protozoa and fungi. Several preliminary animal studies presented at the ICAAC conference examined the effectiveness of a group of compounds that are believed to be effective against the fungal properties of the organism. Researchers from Merck Sharp and Dohme and Eli Lilly presented data on beta-1,3-glucan synthase inhibitors. Beta glucan is a structural component of many fungal cell walls.

The most compelling data25 compared the effects of one of these drugs, L671,329, with Bactrim and pentamidine in treating rats with pneumocystis. More than 98 percent of the cysts were eliminated in those rats treated with L671,329 after 4 days; those rats treated with the other two drugs showed no significant differences in cyst load after 4 days as compared to control rats.

A second beta-1, 3-glucan synthase inhibitor, L687,781, was shown to be less potent, but effective, in eliminating cysts (greater than 83 percent after five days of treatment).26 L671,329 was also reported to be an effective prophylaxis in the immunosuppressed rats.

A third study27 evaluated cilofungin and echinocandin B in rats and found that the cysts in the lungs were swollen and that the nuclei indicated cell death. The authors of this study suggested that these compounds were effective in both treatment and prophylaxis.

We expect continuing improvement in pneumocystis prevention and treatment, as more information becomes available through pre-clinical research (laboratory and animal studies) and clinical trials.

References

1. U. S. Department of Health and Human Services, Public Health Service. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. Morbidity and Mortality Weekly Report (MMWR) Recommendations and Reports. June 16, 1989; volume 38, number S-5.

2. Pneumocystis prophylaxis survey results reported in The Synopsis of the Community Consortium. July 3, 1990; volume 3, number 7. [The Community Consortium is a group of health-care providers who are involved in community-based clinical research. The majority of these providers practice in the San Francisco Bay Area.]

3. Kovacs A, Church J, Mascola L, and others. CD4 counts as predictors of Pneumocystis carinii pneumonia in infants and children with HIV infection [abstract F. B. 24]. Sixth International Conference on AIDS, San Francisco, June 20-24, 1990.

4. Hughes WT, Kuhn S, Chaudhary S, and others. Successful chemoprophylaxis for Pneumocystis carinii pneumonia. The New England Journal of Medicine. December 29, 1977; volume 297, pages 1419-1426.

5. Harris RE, McCallister JA, Allen SA, Barton AS, and Baehner RL. Prevention of pneumocystis pneumonia. Use of continuous sulfamethoxazole-trimethoprim therapy. American Journal of Diseases of Children. 1980; volume 134, number 1, pages 35-38.

6. Fischl M A, Dickinson G M, and La Voie L. Safety and efficacy of sulfamethoxazole and trimethoprim chemoprophylaxis for Pneumocystis carinii pneumonia. Journal of the American Medical Association. February 26, 1988; volume 259, pages 1185-1189.

7. Nielsen T L, Jensen B N, Nelsing S and others. Sulfamethoxazole/trimethoprim as secondary prophylaxis against Pneumocystis carinii pneumonia [abstract Th.B. 412]. Sixth International Conference on AIDS, San Francisco, June 20- 24, 1990.

8. Kelly J, Keyes C, Marte C, Wolbert J, and Chieffe R. Once daily trimethoprim/sulfamethoxazole as prophylaxis for Pneumocystis carinii pneumonia [abstract Th.B. 413]. Sixth International Conference on AIDS, San Francisco, June 20-24, 1990.

9. Leoung GS, Feigal DW, Montgomery AB, and others. Aerosolized pentamidine for prophylaxis against Pneumocystis carinii pneumonia. The New England Journal of Medicine. September 20, 1990; volume 323, number 12.

10. McCabe R and Edelstein H. Atypical Pneumocystis carinii pneumonia in patients receiving inhaled pentamidine prophylaxis [abstract 426]. Also Denis M, Guidet B, and Lebas J. Clinical data of disseminated Pneumocystis carinii infection in 6 AIDS patients receiving secondary prophylaxis with aerosolized pentamidine abstract 427]. Also Noskin G, Murphy R L, Finn W G, and Timins M. Extrapulmonary Pneumocystis carinii in patients receiving aerosolized Pentamidine [abstract 428]. Sixth International Conference on AIDS, San Francisco, June 20-24, 1990.

11. Newsome GS, Ward DJ, and Pierce PF. Spontaneous pneumo-thorax in patients with acquired immunodeficiency syndrome treated with prophylactic aerosolized pentamidine. Archives of Internal Medicine. October 1990; volume 150, pages 2167-2168.

12. Geaghan S, Fahey J, McGinty E, and others. Impact of prophylactic aerosolized pentamidine on the laboratory diagnosis of Pneumocystis carinii pneumonia [abstract 850]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 21-24, 1990.

13. Hughes, WT and others. Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonia. New England Journal of Medicine. 1987; volume 316, pages 1627-1632.

14. Wolbert J, Keyes C, Chieffe R, Marte C, Kelly J, and Holzman R S. Side effects of prophylactic trimethoprim/sulfa- methoxazole are diminished with once daily dosing [abstract 2086]. Sixth International Conference on AIDS, San Francisco, June 20-24, 1990.

15. Lariviere M and Ruskin J. Low dose trimethoprim/sulfamethoxazole prevents Pneumocystis carinii pneumonia [abstract 8]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 21-24, 1990.

16. Stein D S, Terry D, Palte S, Lancaster D J, and Weems J J. Thrice weekly dosing of trimethoprim/sulfamethoxazole for primary and secondary prophylaxis of Pneumocystis carinii pneumonia [abstract 854]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 21- 24, 1990.

17. Morgan A, Graziani A, and MacGregor R R. Daily versus intermittent trimethoprim/sulfamethoxazole for Pneumocystis carinii pneumonia [abstract 856]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 21-24, 1990.

18. Catena W, De Luca A, and Perez G. Efficacy of low dose trimethoprim/sulfamethoxazole in pneumocystis prophylaxis [abstract 857]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 21-24, 1990.

19. Torres R, Thorn M, Newlands J, and others. Randomized trial of intermittent dapsone versus aerosolized pentamidine for primary and secondary prophylaxis of Pneumocystis carinii pneumonia [abstract Th.B. 407]. Sixth International Conference on AIDS, San Francisco, June 20-24, 1990.

20. Metroka C, Jacobus D, and Lewis N. Successful chemoprophylaxis for pneumocystis with dapsone or Bactrim [abstract T. B. 0.4]. Fifth International Conference on AIDS, Montreal, June 4-9, 1989.

21. Ogata-Arakaki D, Falloon J, Lavelle J, and others. The safety of weekly dapsone and weekly dapsone and pyrimethamine as pneumocystis prophylaxis [abstract Th.B. 411]. Also Clotet B, Sirera G, Romeu J, Velasco P, Gimeno J M, and Tor J. Twice weekly dapsone-pyrimethamine for preventing Pneumocystis carinii pneumonia relapses in HIV infected patients [abstract Th.B. 414]. Sixth International Conference on AIDS, San Francisco, June 20-24, 1990.

22. Rogers M D and Lafon S W. In vivo and in vitro anti-Pneumocystis carinii activity of the hydroxynaphthoquinone, 566C80 [abstract 588]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 21- 24, 1990.

23. Hughes WT and others. Efficacy of a hydroxynaphthoquinone, 566C80, in experimental Pneumocystis carinii pneumonia. Antimicrobial Agents and Chemotherapy. 1990; volume 34, pages 225-228.

24. Hughes W, Kennedy W, Shenep J, and others. Safety and pharmacokinetics of 566C80, a hydroxynaphthoquinone with anti- Pneumocystis carinii activity [abstract 861]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 21-24, 1990.

25. Romancheck J A, Pittarelli L A, and Schmatz D M. A comparative study of the anti-pneumocystis activity of L671,329, trimethoprim/sulfamethoxazole and pentamidine isethionate [abstract 586]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 21- 24, 1990.

26. Schmatz D M, Romancheck M A, Pittarelli L A, Nollstadt K, Bartizal K, and Turner M J. The use of ' 1,3 glucan synthesis inhibitors for the treatment and prevention of Pneumocystis carinii pneumonia [abstract 585]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 21-24, 1990.

27. Rogers M D and Lafon S W. In vivo and in vitro anti-Pneumocystis carinii activity of the hydroxynaphthoquinone, 566C80 [abstract 588]. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 21-24, 1990.

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