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PREVENTION AND TREATMENT Annu. Rev. Med. 1991.42:287-295. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/26/15. For personal use only.
OF PNEUMOCYSTIS CARINII PNEUMONIA Walter T. Hughes, M.D.
Department ofInfectious Diseases, St. Jude Children's Research Hospital; and Department of Pediatrics, University of Tennessee, Memphis, Tennessee 38101 KEY WORDS:
immunocompromised
host,
trimethoprim-sulfamethoxazole,
pentamidine
ABSTRACT
Several drugs are now available for the treatment and prevention of Pneumocystis carinii pneumonia. These include trimethoprim-sulfa methoxazole and pentamidine isethionate as first-line drugs and dapsone trimethoprim, trimetrexate, piritrexim, fansidar, difluoromethylornithine, and clindamycin plus primaquine as drugs in later stages of clinical development. A hydroxynaphthoquinone, called 566C80, offers promise in preclinical studies. The use of corticosteroids in the supportive man agement of P. carinii pneumonitis is undergoing clinical study. INTRODUCTION
Significant advances in the prevention and treatment of Pneumocystis carinii pneumonitis have been achieved within the last few years, in part because of the experiences and needs of patients with the acquired immuno deficiency syndrome (AIDS). P. carinii pneumonitis was first successfully treated in the mid-1950s with injections of pentamidine isethionate. By the mid- 1960s pyrimethamine in combination with a sulfonamide was found to have some efficacy in animal studies and in the studies of a few cases of human P. carinii pneumonitis. 287 0066-42 19/9 1/0401-0287$02.00
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Both animal and human studies of the mid-1970s showed trimethoprim sulfamethoxazole to be effective and safe in the prevention and treatment of P. carinii pneumonia. As the AIDS epidemic emerged in the early 1980s, it soon became evident that neither trimethoprim-sulfamethoxazole nor pentamidine was entirely satisfactory for AIDS patients because of the high rate of adverse reactions encountered and failure of response in 2030% of cases. Within the past five years new drugs have been developed, and inno vations in the older drugs have also proven useful. This review emphasizes recent studies of therapy and prevention of P. carinii pneumonia. TREATMENT Antimicrobial Therapy IN GENERAL USE The standard treatment for P. carinii pneumonitis in both AIDS and non-AIDS patients is either trimethoprim-sulfamethoxazole (TMP-SMZ) or intravenous pentamidine isethionate. Generally, these drugs are equally effective. Recovery can be expected in about 75% of cancer patients (1). A recent controlled comparative study in AIDS patients showed that 86% of cases treated with TMP-SMZ and not requiring mechanical ventilation and 61% of those treated with pentamidine recovered from P. carinii pneumonitis (2). A similar study showed no significant differences in recovery and adverse effects of AIDS patients treated with these two drug regimens (3). Adverse reactions to pentamidine occur in at least 70% of AIDS and non-AIDS patients. A striking difference in the rate of adverse reactions is noted between the two. In non-AIDS patients, fewer than 10% of patients will have any adverse effects and, when present, these are usually mild (1). However, from 40 to 88% of AIDS patients may have adverse effects from TMP-SMZ (4). These are often rash, fever, or neutropenia.
Several drugs or drug combinations have been studied sufficiently to conclude they are effective in the treatment of P. carinii, but their relative efficacies have not been established.
IN CLINICAL TRIALS
Synergism has been demonstrated with tri and dapsone in both animal (5) and human studies (6, 7). In mild to moderately severe cases of P. carinii pneumonitis in AIDS patients, a therapeutic response occurred in 61% of those treated with dapsone alone (7) and in 100% of those given the same dose of dapsone plus trimethoprim (6). Trimethoprim alone has no discernible effect on P. carinii infection. Plasma concentrations are 40% higher in patients treated Trimethoprim-dapsone
methoprim
P.
CARINII
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with TMP-dapsone than in those treated with dapsone alone (2.1 compared with 1.5 jlg/ml) (8). In a randomized study, Medina et al (9) encountered treatment failures in only 2 of 29 patients treated with TMP-dapsone and 2 of 29 treated with TMP-SMZ. Major toxic effects were fewer in the TMP-dapsone group. The adverse effects of dapsone are similar to those of sulfonamide. Seventy percent of patients who experience adverse reac tions to TMP-SMZ are able to take TMP-dapsone (10). Dapsone is avail able only in the form of oral tablets. Studies on the use of pyrimethamine plus a sulfonamide such as sulfadoxine (Fansidar) have been limited to small numbers of cases without adequate controls. At present, no advantages to the use of this combination can be claimed over other anti-Po carinii drugs. Fansidar®
Trimetrexate Trimetrexate is a potent, lipid-soluble inhibitor of both microbial and mammalian dihydrofolate reductases. Leucovorin, a reduced folate, crosses mammalian cell membranes by a specific transport system that is absent in P. carinii. Thus, leucovorin can be given con comitantly with trimetrexate to exert a selective toxic effect on the microbe. Allegra et al ( 1 1) treated AIDS patients with P. carinii pneumonitis using trimetrexate and leucovorin. A therapeutic response and survival were achieved in 63-88% of cases respectively. However, a relapse rate of up to 60%, requirement for intravenous administration, and toxicities similar to other antifols are problems that must yet be overcome (12). Combining trimetrexate with a sulfonamide may enhance efficacy. Also, piritrexim given orally was effective in one study (13).
Unfortunately, no controlled studies of the use of DFMO in P. carinii pneumonitis have been reported. No definite conclusions can be drawn from the open-label studies because they involved previously treated and nonresponsive cases. However, thrombo cytopenia occurred in 75% and neutropenia in 65% of the patients treated by Neibbart et al (14). One animal study (15) reported efficacy and another (5) found no effect of DFMO on P. carinii infection. Difluoromethylornithine (DFMO)
Primaquine combined with c1indamycin has been reported as efficacious in both rat (16) and human studies (17-19) of P. carinii pneumonitis. The early clinical studies, though limited to mild disease and uncontrolled, indicate promise in the combination. Primaquine and clindamycin
While aerosolized pentamidine has an established place in the prevention of P. carinii pneumonitis in AIDS patients, its efficacy in the treatment of the pneumonitis has not been established. Generally, the data suggest aerosolized pentamidine is less effective than Aerosol pentamidine
�
290
HUGHES
intravenous pentamidine or TMP-SMZ in AIDS patients (20-22), but it is not associated with significant side effects. IN PRECLINICAL STUDIES
Several promising drugs are in preclinical study.
A hydroxynaphthoquinone, 566C80, is highly effective in animal studies
-
and shows no discernible toxicity (23). Also, several analogu�s of pen tamidine have been effective in murine P. carinii pneumonitis (24). An
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inosine analogue, 9-deazainosine, inhibits P. carinii in cell culture and in infected rats
(25).
OPINION AND CONCLUSION
It seems prudent to initiate therapy for P.
carinii pneumonitis with TMP-SMZ for patients who can tolerate the
combination without significant adverse reactions. For those who are intolerant to TMP-SMZ or who fail to respond favorably, pentamidine isethionate is the drug of choice. When neither of these drugs are appli cable, trimethoprim-dapsone is the next choice if the patient can take oral medication, because the drug combination is easily available, has been studied in controlled trials, and is tolerated by at least two thirds of patients with adverse reactions to TMP-SMZ. Trimetrexate-leucovorin has the disadvantages of high relapse rate and limited access at present. Clin damycin and primaquine are commercially available, can be taken orally, and arc probably fairly safe, but studies are not yet adequate to judge therapeutic efficacy. In summary, a rather diverse armamentarium of therapeutic agents for P. carinii pneumonia is now available to physicians.
Corticosteroid Therapy A peculiar paradox has emerged in the supportive therapy of P. carinii pneumonia. One of the most effective means of provoking P. carinii pneumonitis in both animals and humans is the administration of a corti costeroid. In latently infected rats, cortisone acetate or dexamethasone administration triggers fatal P. carinii pneumonia in over
90% of the
animals. However, if TMP-SMZ is administered concomitantly with the steroid, the pneumonitis does not occur. Several recent reports claim improvement in clinical responses and even lower mortality rates in patients with P. carinii pneumonitis treated with a corticosteroid such as methylprednisolone or prednisone
(26-29). This
approach relies on the expectation that the steroid will diminish the inflammatory response of the alveolitis and possibly inhibit phospholipase A2, which thereby delays surfactant degradation. Although most of the reports suggest that the administration of a corticosteroid improves oxygenation, a definitive study has not been reported. The steroid therapy is not likely to elicit an adverse response from P. carinii pneumonia if the patient is receiving a specific antimicrobial, but the effect on a concomitant
-=z
P. CARINII
291
infection, such as that from cytomegalovirus, Mycobacterium species, Cryptococcus neoformans, etc, is not known. PROPHYLAXIS In General Use
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Two drugs are in general use for the prevention of P. carinii pneumonia. They are trimethoprim-sulfamethoxazole and aerosolized pentamidine.
(TMP-SMZ) TMP-SMZ has been in use for some 15 years and is highly effective in the prevention of P. carinii pneumonitis when administered daily (30) or even three days a week (31). Adverse reactions are infrequent and mild in the non-AIDS patient but frequent (40-80%) and occasionally severe in AIDS patients (4). In a two-year prospective, controlled study, Fischl et al (32) randomized 60 AIDS patients to receive either TMP-SMZ or no treatment. While 53% of the no-drug group developed P. carinii pneumonia, none of the 30 patients on TMP-SMZ developed the pneumonitis. Five patients were removed from the study because of adverse effects. A similar study and results were reported by Pierone and colleagues (33).
TRIMETHOPRIM-SULFAMETHOXAZOLE
During the past three years, several inves tigators have studied the use of aerosolized pentamidine for prophylaxis. Although the majority of these studies have not been controlled, efficacy of varying degrees has been demonstrated. Three studies were influential in the development of pentamidine prophylax is because of the experi mental design and number of cases. The San Francisco Community Consortium study reported by Leoung and colleagues (34) compared three dose levels of aerosolized pentamidine delivered with a Respirgard II® nebulizer. The recurrence rates for P. carinii pneumonitis were 24% with a low dose of 30 mg every two weeks significantly greater than the 13% recurrence rate at the higher dose of 300 mg every four weeks. A convincing double-blind, randomized, placebo-controlled study from the Canadian Cooperative Trial showed that when the placebo was given to AIDS patients who had had a previous case of P. carinii pneumonitis, infection recurred in 35%, while only 6% of those given 60 mg of aero solized pentamidine daily for two weeks had recurrent P. carinii pneu monitis. This study utilized the Fisoneb(li) nebulizer (35). A similar study and results were reported from Paris (36). The adverse effects from aerosolized pentamidine are limited primarily to cough and wheezing, considered to be of no major significance.
AEROSOLIZED PENTAMIDINE
292
HUGHES
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INTRAVENOUS AND INTRAMUSCULAR PENTAMIDINE In small studies, monthly intramuscular (37) or intravenous (38) injections of penta midine appeared efficacious in preventing P. carinii pneumonitis in AIDS patients, but further studies are needed for firm conclusions. CONCLUSION AND OPINION TMP-SMZ is highly effective, simple to take, and inexpensive, but it is associated with a high rate of adverse reactions. Aerosolized pentamidine is safe and reasonably effective but is expensive and more cumbersome to deliver. Also, aerosolized pentamidine has not been studied in non-AIDS patients and children. It seems reasonable to use TMP-SMZ for those who can take the drug without adverse effects and to use aerosolized pentamidine for those intolerant to the drug combination.
In Clinical Studies
What is available for those patients who for one reason or another cannot take either of these drugs? Two other drugs can be considered. These are pyrimethamine-sulfadoxine (Fansidar) and diaminodiphenylsulfone (dapsone), but neither has been approved by the Food and Drug Adminis tration in the United States. DAPSONE Metroka and others (39) showed dapsone to be a useful drug for prophylaxis of P. carinii pneumonitis in AIDS patients. Only 1.2% of 173 patients with CD4 counts less than 250 per mm3 developed P. carinii pneumonitis while receiving dapsone. Similarly none of the 43 patients given TMP-SMZ prophylaxis had recurrent infection. With no prophy laxis, 26 episodes of P. carinii pneumonitis occurred in the 23 control patients during the same period of observation. Adverse effects occurred in 10% of the dapsone patients and 38% of those given TMP-SMZ. In another study reported by Torres and colleagues (40), 1 18 AIDS patients were randomized to receive oral dapsone at 100 mg biweekly or 100 mg of aerosolized pentamidine biweekly. Recurrent P. carinii pneumonitis occurred in 6% of the 53 patients receiving dapsone and 9% of those on aerosolized pentamidine. Without prophylaxis 35% had P. carinii pneumonitis. Adverse reactions were uncommon and similar in frequency and severity for the two groups. Lucas et al (41) obtained similar results using a dose of 100 mg per week. Dapsone prophylaxis in the biweekly regimen costs about 25 cents to one dollar per month. The results of Torres' study using biweekly doses of dapsone were similar to those from animal studies. In these experiments dapsone was given in single doses as infrequently as once a month and still effectively prevented P. cariniipneumonitis in all animals studied (42). Dapsone may cause rashes, neutropenia, and anemia. However, single
P.
CARINIl
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doses at biweekly intervals may minimize these effects. Further studies are needed to place dapsone in proper perspective with other drugs. The first trial of chemoprophylaxis with Fansidar was reported in 1971 by Post and colleagues (43). They showed that the drug given weekly or biweekly to infants in an Iranian orphanage was effective in preventing endemic P. carinii pneumonitis. Within the last five years, several small groups of AIDS patients were studied under varied conditions. P. carinii pneumonitis recurred in 0 to 30% of those on Fansidar, with adverse reaction rates similar to those described for TMP-SMZ (44, 45). However; some of the adverse reactions were severe, including hepatic necrosis, Stevens-Johnson syndrome, and epidermal necrolysis that resulted in death.
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FANSIDAR
In Preclinical Studies A promising drug for which preclinical studies have been completed is a hydroxynaphthoquinone designated 566C80. This drug totally prevented murine P. carinii pneumonitis given as infrequently as once a week (23). No significant toxicity or adverse reaction has been found and the drug is currently in early clinical trials. Also, clindamycin plus primaquine may provide yet another drug combination for chemoprophylaxis. In conclusion, the prospects are promising for effective and safe drugs with which to treat and prevent P. carinii pneumonitis in AIDS and non AIDS patients at risk for this infection. With the progression of the AIDS epidemic, the development of more intensive anticancer therapy, and the expansion of organ transplantation programs, P. carinii pneumonia will demand increasing attention from physicians. ACKNOWLEDGMENTS
This work was supported by National Institute of Allergy and Infectious Diseases Grant ROI-AI20673-07, National Cancer Institute Cancer Center Support (CORE) Grant P30CA21765, and the American Lebanese Syrian Associated Charities. Literature Cited
I. Hughes, W. T., Feldman, S., Chaud hary, S. c., Ossi, M. J., Cox, F., et al. 1978. Comparison of pentamidine ise
sulfamethoxazole compared with pen tamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: a pro spective, noncrossover study. Ann.
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3. Wharton, J. M., Coleman, D. L., Wofsy, c. B., Luce, J. M., Blumenfeld, W., et aL 1986. Trimethoprim-sulfamethoxa-
thionate and trimethoprim sulfa methoxazole in the treatment of Pneu mocystis carinii pneumonia. J. Pediatr.
Intern. Med.
109: 280--87
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zole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann. In tern. Med. 105: 37-44 4. Gordin, F. M., Simon, G. L., Wofsy, C. B., Mills, J. 1984. Adverse reactions to trimethoprim-sulfamethoxazole in pa tients with the acquired immuno deficiency syndrome. Ann. Intern. Med. 100:495-99 5. Hughes, W. T., Smith, B. L. 1984. Effi cacy of diaminodiphenylsulfone and other drugs in murine Pneumocystis cari nii pneumonitis. Antimicrob. Agents Chemother. 26: 436-40 6. Leoung, G. S., Mills, J., Hopewell, P. c., Hughes, W., Wofsy, C. 1986. Dapsone trimethoprim for Pneumocystis carinii pneumonia in the acquired immuno deficiency syndrome. Ann. Intern. Med. 105:45-48 7. Mills, J., Leoung, G., Medina, I., Hopewell, P. c., Hughes, W. T., et al 1988. Dapsone treatment of Pneumo cystis carinii pneumonia in the acquired immunodeficiency syndrome . Antimi crob. Agents Chemother. 32: 1057-60 8. Lee, B. L., Medina, I., Benowitz, N. L., Jacob, P., Wofsy, C. B., et a!. 1989. Dap sone, trimethoprim, sulfamethoxazole plasma levels during treatment of Pneumocystis pneumonia in patients with AIDS. Ann. Intern. Med. 110: 60611 9. Medina, I., Leoung, G., Mills, J., Hopewell, P., Feigel, D., et a!. 1987. Oral therapy for Pneumocystis carinii pneu monia in AIDS. A randomized double blind trial of trimethoprim-sulfa methoxazole versus dapsone-trimetho prim for first episode Pneumocystis carinii pneumonia in AIDS. In Proc. 3rd Int. Con! AIDS, Washington, DC, Abstr. F 3.3 10. Medina, I., Feigel, D., Wofsy, C. 1987. Cross-allergy to sulfonamides/sulfones (Sulfa) and folic antagonists in AIDS. See Ref. 9, Abstr. F 3.1 II. Allegra, C. I., Chabner, B. A., Tuazon, C. U., Ogata-Arakaki, D., Baird, B., et a!. 1987. Trimetrexate for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immuno deficiency syndrome. N. Engl. J. Med. 317:978-85 12. Davey, R. T., Masur, H. 1990. Recent advances in the diagnosis, treatment and prevention of Pneumocystis carinii pneu monia. Antimicrob. Agents Chemother. 34:499-504 13. Falloon, J., Allegra, c., Kovacs, I., O'Neill, D., Ogata-Arakaki, D., et al. 1990. Piritrexim with leucovorin for the
treatment of Pneumocystis pneumonia in AIDS patients. Clin. Res. 38: 361A (Abstr.) 14. Neibbart, E. P., Dembitzer, F., Ham mer, G. S., Dembitzer, R., Sacks, H. S., et al. 1989. Elflornithine in the treatment of Pneumocystis carinii pneu monia. In Proc. 5th Int. Corif'. AIDS, Montreal, Canada, Abstr. TBP 29 IS. Clarkson, A. B., Williams, D. E., Rosen berg, C. 1988. Efficacy of DL-a-di fluoromethylornithine in a rat model of Pneumocystis carinii pneumonia. Anti microb. Agents Chemother. 32: 1158-63 16. Queener, S. F., Bartlett, M. S., Rich ardson, J. D., et a!. 1988. Activity of clindamycin with primaquine against Pneumocystis carinii in vivo and in vitro. Antimicrab. Agents Chemather. 32: 80713 17. Kay, R., DuBois,- R. 1990. Clin damycin/primaquine therapy and se condary prophylaxis against Pneuma cystis carinii pneumonia in patients with AIDS. South. Med. 1. 83: 403-4 18. Ruf, B., Rohde, I., Pohle, H. D. 1990. Efficacy of clindamycin/primaquine vs. trimethoprim/sulfamethoxazole in acute treatment of Pneumocystis carinii pneu monia. Am. Rev. Respir. Dis. 141: A I54 19. Black, I. R., Feinberg, I., Fass, R. I., Plouffe, J. F., et a!. 1989. Clindamycin plus primaquine therapy for Pneumo cystis carinii pneumonia in AIDS patients. See Ref. 14, Abstr. TBP 30 20. Girard, P. M., Lecompte, T., Lazzarin, A., and the A.P. Working Group. 1989. Aerosolized pentamidine in the treat ment of PCP episodes: an open multi national trial, preliminary results of 70 patients. See Ref. 14, Abstr. TBP 23 21. Hoo Soo, G. W., Mohsenifar, Z., Meyer, R. D. 1990. Comparison of inhaled versus intravenous pentamidine for Pneumocystis carinii pneumonia in AIDS. World Conference on Lung Health. Am. Rev. Respir. Dis. 141:AlSO 22. Conte, I. E., Chernoff, D., Hollander, H., Feigal, D. 1989. Reduced dose or aerosolized pentamidine treatment for Pneumocystis carinii pneumonia. See Ref. 14, Abstr. TBP 25 23. Hughes, W. T., Gray, V. L., Gutteridge, W. E., Latter, V. S., Pudney, M. 1990. Efficacy of a hydroxynaphthoquinone, 566C80, in experimental Pneumocystis carinii pneumonitis. Antimicrob. Agents Chemolher. 34:225-28 24. Tidwell, R. R., Jones, S. K., Geratz, J. D., Ohemeng, K. A., Cory, M., et al. 1990. Analogous of 1,5-Bis(4-amidino phenyoxy) pentane (Pentamidine) in the treatment of experimental Pneumo-
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1989. Successful chemoprophylaxis for Pneuf1locystis with dapsone or bactrim. See Ref. 14, Abstr. TBO 4 Torres, R. A., Palermo, S., Gregory, G., Carlo, c., Mariamides, M., et al. 1989. Prophylaxis for Pneuf1locystis carinii pneumonia with aerosol pentamidine or oral dapsone in patients with AIDS or severe ARC. See Ref. 14, Abstr. TBP 75 Lucas, C. R., Sandland, A. M., Mijch, A., Simpson, J. M. 1989. Primary dap sone chemoprophylaxis for Pneuf1lo cystis carinii pneumonia in immuno compromised patients infected with human immunodeficiency virus. Med. J. Austr. 151: 30-33 Hughes, W. T. 1988. Comparison of dosages, intervals and drugs in the pre vention of Pneuf1lucystis carinii pneu monia. Antif1licrob. Agents Chef1lother. 32:623-25 Post, C., Fakouhi, T., Dutz, W., Ban darinzadek, B., Kohout, E. E. 1971. Prophylaxis of epidemic infantile pneumocystosis with a 20 : I sulfadoxine plus pyrimethamine combination. Curr. Ther. Res. 13: 273-77 Miller, L., Cohn, D. 1989. High rates of recurrent Pneuf1locystis pneumonia and toxicity in AIDS patients taking pyri methamine-sulfadoxine prophylaxis. See Ref. 14, Abstr. TBP 43 Ruf, B., Pohle, H. D. 1990. Pyri methamine-sulfadoxine (Fansidar) in primary and secondary chemoprophy laxis of Pneuf1locystis carinii pneumonia. Af1l. Rev. Respir. Dis. 141: A154
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PREVENTION AND TREATMENT Annu. Rev. Med. 1991.42:287-295. Downloaded from www.annualreviews.org Access provided by Technische Universiteit Eindhoven on 01/26/15. For personal use only.
OF PNEUMOCYSTIS CARINII PNEUMONIA Walter T. Hughes, M.D.
Department ofInfectious Diseases, St. Jude Children's Research Hospital; and Department of Pediatrics, University of Tennessee, Memphis, Tennessee 38101 KEY WORDS:
immunocompromised
host,
trimethoprim-sulfamethoxazole,
pentamidine
ABSTRACT
Several drugs are now available for the treatment and prevention of Pneumocystis carinii pneumonia. These include trimethoprim-sulfa methoxazole and pentamidine isethionate as first-line drugs and dapsone trimethoprim, trimetrexate, piritrexim, fansidar, difluoromethylornithine, and clindamycin plus primaquine as drugs in later stages of clinical development. A hydroxynaphthoquinone, called 566C80, offers promise in preclinical studies. The use of corticosteroids in the supportive man agement of P. carinii pneumonitis is undergoing clinical study. INTRODUCTION
Significant advances in the prevention and treatment of Pneumocystis carinii pneumonitis have been achieved within the last few years, in part because of the experiences and needs of patients with the acquired immuno deficiency syndrome (AIDS). P. carinii pneumonitis was first successfully treated in the mid-1950s with injections of pentamidine isethionate. By the mid- 1960s pyrimethamine in combination with a sulfonamide was found to have some efficacy in animal studies and in the studies of a few cases of human P. carinii pneumonitis. 287 0066-42 19/9 1/0401-0287$02.00
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Both animal and human studies of the mid-1970s showed trimethoprim sulfamethoxazole to be effective and safe in the prevention and treatment of P. carinii pneumonia. As the AIDS epidemic emerged in the early 1980s, it soon became evident that neither trimethoprim-sulfamethoxazole nor pentamidine was entirely satisfactory for AIDS patients because of the high rate of adverse reactions encountered and failure of response in 2030% of cases. Within the past five years new drugs have been developed, and inno vations in the older drugs have also proven useful. This review emphasizes recent studies of therapy and prevention of P. carinii pneumonia. TREATMENT Antimicrobial Therapy IN GENERAL USE The standard treatment for P. carinii pneumonitis in both AIDS and non-AIDS patients is either trimethoprim-sulfamethoxazole (TMP-SMZ) or intravenous pentamidine isethionate. Generally, these drugs are equally effective. Recovery can be expected in about 75% of cancer patients (1). A recent controlled comparative study in AIDS patients showed that 86% of cases treated with TMP-SMZ and not requiring mechanical ventilation and 61% of those treated with pentamidine recovered from P. carinii pneumonitis (2). A similar study showed no significant differences in recovery and adverse effects of AIDS patients treated with these two drug regimens (3). Adverse reactions to pentamidine occur in at least 70% of AIDS and non-AIDS patients. A striking difference in the rate of adverse reactions is noted between the two. In non-AIDS patients, fewer than 10% of patients will have any adverse effects and, when present, these are usually mild (1). However, from 40 to 88% of AIDS patients may have adverse effects from TMP-SMZ (4). These are often rash, fever, or neutropenia.
Several drugs or drug combinations have been studied sufficiently to conclude they are effective in the treatment of P. carinii, but their relative efficacies have not been established.
IN CLINICAL TRIALS
Synergism has been demonstrated with tri and dapsone in both animal (5) and human studies (6, 7). In mild to moderately severe cases of P. carinii pneumonitis in AIDS patients, a therapeutic response occurred in 61% of those treated with dapsone alone (7) and in 100% of those given the same dose of dapsone plus trimethoprim (6). Trimethoprim alone has no discernible effect on P. carinii infection. Plasma concentrations are 40% higher in patients treated Trimethoprim-dapsone
methoprim
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with TMP-dapsone than in those treated with dapsone alone (2.1 compared with 1.5 jlg/ml) (8). In a randomized study, Medina et al (9) encountered treatment failures in only 2 of 29 patients treated with TMP-dapsone and 2 of 29 treated with TMP-SMZ. Major toxic effects were fewer in the TMP-dapsone group. The adverse effects of dapsone are similar to those of sulfonamide. Seventy percent of patients who experience adverse reac tions to TMP-SMZ are able to take TMP-dapsone (10). Dapsone is avail able only in the form of oral tablets. Studies on the use of pyrimethamine plus a sulfonamide such as sulfadoxine (Fansidar) have been limited to small numbers of cases without adequate controls. At present, no advantages to the use of this combination can be claimed over other anti-Po carinii drugs. Fansidar®
Trimetrexate Trimetrexate is a potent, lipid-soluble inhibitor of both microbial and mammalian dihydrofolate reductases. Leucovorin, a reduced folate, crosses mammalian cell membranes by a specific transport system that is absent in P. carinii. Thus, leucovorin can be given con comitantly with trimetrexate to exert a selective toxic effect on the microbe. Allegra et al ( 1 1) treated AIDS patients with P. carinii pneumonitis using trimetrexate and leucovorin. A therapeutic response and survival were achieved in 63-88% of cases respectively. However, a relapse rate of up to 60%, requirement for intravenous administration, and toxicities similar to other antifols are problems that must yet be overcome (12). Combining trimetrexate with a sulfonamide may enhance efficacy. Also, piritrexim given orally was effective in one study (13).
Unfortunately, no controlled studies of the use of DFMO in P. carinii pneumonitis have been reported. No definite conclusions can be drawn from the open-label studies because they involved previously treated and nonresponsive cases. However, thrombo cytopenia occurred in 75% and neutropenia in 65% of the patients treated by Neibbart et al (14). One animal study (15) reported efficacy and another (5) found no effect of DFMO on P. carinii infection. Difluoromethylornithine (DFMO)
Primaquine combined with c1indamycin has been reported as efficacious in both rat (16) and human studies (17-19) of P. carinii pneumonitis. The early clinical studies, though limited to mild disease and uncontrolled, indicate promise in the combination. Primaquine and clindamycin
While aerosolized pentamidine has an established place in the prevention of P. carinii pneumonitis in AIDS patients, its efficacy in the treatment of the pneumonitis has not been established. Generally, the data suggest aerosolized pentamidine is less effective than Aerosol pentamidine
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intravenous pentamidine or TMP-SMZ in AIDS patients (20-22), but it is not associated with significant side effects. IN PRECLINICAL STUDIES
Several promising drugs are in preclinical study.
A hydroxynaphthoquinone, 566C80, is highly effective in animal studies
-
and shows no discernible toxicity (23). Also, several analogu�s of pen tamidine have been effective in murine P. carinii pneumonitis (24). An
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inosine analogue, 9-deazainosine, inhibits P. carinii in cell culture and in infected rats
(25).
OPINION AND CONCLUSION
It seems prudent to initiate therapy for P.
carinii pneumonitis with TMP-SMZ for patients who can tolerate the
combination without significant adverse reactions. For those who are intolerant to TMP-SMZ or who fail to respond favorably, pentamidine isethionate is the drug of choice. When neither of these drugs are appli cable, trimethoprim-dapsone is the next choice if the patient can take oral medication, because the drug combination is easily available, has been studied in controlled trials, and is tolerated by at least two thirds of patients with adverse reactions to TMP-SMZ. Trimetrexate-leucovorin has the disadvantages of high relapse rate and limited access at present. Clin damycin and primaquine are commercially available, can be taken orally, and arc probably fairly safe, but studies are not yet adequate to judge therapeutic efficacy. In summary, a rather diverse armamentarium of therapeutic agents for P. carinii pneumonia is now available to physicians.
Corticosteroid Therapy A peculiar paradox has emerged in the supportive therapy of P. carinii pneumonia. One of the most effective means of provoking P. carinii pneumonitis in both animals and humans is the administration of a corti costeroid. In latently infected rats, cortisone acetate or dexamethasone administration triggers fatal P. carinii pneumonia in over
90% of the
animals. However, if TMP-SMZ is administered concomitantly with the steroid, the pneumonitis does not occur. Several recent reports claim improvement in clinical responses and even lower mortality rates in patients with P. carinii pneumonitis treated with a corticosteroid such as methylprednisolone or prednisone
(26-29). This
approach relies on the expectation that the steroid will diminish the inflammatory response of the alveolitis and possibly inhibit phospholipase A2, which thereby delays surfactant degradation. Although most of the reports suggest that the administration of a corticosteroid improves oxygenation, a definitive study has not been reported. The steroid therapy is not likely to elicit an adverse response from P. carinii pneumonia if the patient is receiving a specific antimicrobial, but the effect on a concomitant
-=z
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infection, such as that from cytomegalovirus, Mycobacterium species, Cryptococcus neoformans, etc, is not known. PROPHYLAXIS In General Use
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Two drugs are in general use for the prevention of P. carinii pneumonia. They are trimethoprim-sulfamethoxazole and aerosolized pentamidine.
(TMP-SMZ) TMP-SMZ has been in use for some 15 years and is highly effective in the prevention of P. carinii pneumonitis when administered daily (30) or even three days a week (31). Adverse reactions are infrequent and mild in the non-AIDS patient but frequent (40-80%) and occasionally severe in AIDS patients (4). In a two-year prospective, controlled study, Fischl et al (32) randomized 60 AIDS patients to receive either TMP-SMZ or no treatment. While 53% of the no-drug group developed P. carinii pneumonia, none of the 30 patients on TMP-SMZ developed the pneumonitis. Five patients were removed from the study because of adverse effects. A similar study and results were reported by Pierone and colleagues (33).
TRIMETHOPRIM-SULFAMETHOXAZOLE
During the past three years, several inves tigators have studied the use of aerosolized pentamidine for prophylaxis. Although the majority of these studies have not been controlled, efficacy of varying degrees has been demonstrated. Three studies were influential in the development of pentamidine prophylax is because of the experi mental design and number of cases. The San Francisco Community Consortium study reported by Leoung and colleagues (34) compared three dose levels of aerosolized pentamidine delivered with a Respirgard II® nebulizer. The recurrence rates for P. carinii pneumonitis were 24% with a low dose of 30 mg every two weeks significantly greater than the 13% recurrence rate at the higher dose of 300 mg every four weeks. A convincing double-blind, randomized, placebo-controlled study from the Canadian Cooperative Trial showed that when the placebo was given to AIDS patients who had had a previous case of P. carinii pneumonitis, infection recurred in 35%, while only 6% of those given 60 mg of aero solized pentamidine daily for two weeks had recurrent P. carinii pneu monitis. This study utilized the Fisoneb(li) nebulizer (35). A similar study and results were reported from Paris (36). The adverse effects from aerosolized pentamidine are limited primarily to cough and wheezing, considered to be of no major significance.
AEROSOLIZED PENTAMIDINE
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INTRAVENOUS AND INTRAMUSCULAR PENTAMIDINE In small studies, monthly intramuscular (37) or intravenous (38) injections of penta midine appeared efficacious in preventing P. carinii pneumonitis in AIDS patients, but further studies are needed for firm conclusions. CONCLUSION AND OPINION TMP-SMZ is highly effective, simple to take, and inexpensive, but it is associated with a high rate of adverse reactions. Aerosolized pentamidine is safe and reasonably effective but is expensive and more cumbersome to deliver. Also, aerosolized pentamidine has not been studied in non-AIDS patients and children. It seems reasonable to use TMP-SMZ for those who can take the drug without adverse effects and to use aerosolized pentamidine for those intolerant to the drug combination.
In Clinical Studies
What is available for those patients who for one reason or another cannot take either of these drugs? Two other drugs can be considered. These are pyrimethamine-sulfadoxine (Fansidar) and diaminodiphenylsulfone (dapsone), but neither has been approved by the Food and Drug Adminis tration in the United States. DAPSONE Metroka and others (39) showed dapsone to be a useful drug for prophylaxis of P. carinii pneumonitis in AIDS patients. Only 1.2% of 173 patients with CD4 counts less than 250 per mm3 developed P. carinii pneumonitis while receiving dapsone. Similarly none of the 43 patients given TMP-SMZ prophylaxis had recurrent infection. With no prophy laxis, 26 episodes of P. carinii pneumonitis occurred in the 23 control patients during the same period of observation. Adverse effects occurred in 10% of the dapsone patients and 38% of those given TMP-SMZ. In another study reported by Torres and colleagues (40), 1 18 AIDS patients were randomized to receive oral dapsone at 100 mg biweekly or 100 mg of aerosolized pentamidine biweekly. Recurrent P. carinii pneumonitis occurred in 6% of the 53 patients receiving dapsone and 9% of those on aerosolized pentamidine. Without prophylaxis 35% had P. carinii pneumonitis. Adverse reactions were uncommon and similar in frequency and severity for the two groups. Lucas et al (41) obtained similar results using a dose of 100 mg per week. Dapsone prophylaxis in the biweekly regimen costs about 25 cents to one dollar per month. The results of Torres' study using biweekly doses of dapsone were similar to those from animal studies. In these experiments dapsone was given in single doses as infrequently as once a month and still effectively prevented P. cariniipneumonitis in all animals studied (42). Dapsone may cause rashes, neutropenia, and anemia. However, single
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doses at biweekly intervals may minimize these effects. Further studies are needed to place dapsone in proper perspective with other drugs. The first trial of chemoprophylaxis with Fansidar was reported in 1971 by Post and colleagues (43). They showed that the drug given weekly or biweekly to infants in an Iranian orphanage was effective in preventing endemic P. carinii pneumonitis. Within the last five years, several small groups of AIDS patients were studied under varied conditions. P. carinii pneumonitis recurred in 0 to 30% of those on Fansidar, with adverse reaction rates similar to those described for TMP-SMZ (44, 45). However; some of the adverse reactions were severe, including hepatic necrosis, Stevens-Johnson syndrome, and epidermal necrolysis that resulted in death.
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FANSIDAR
In Preclinical Studies A promising drug for which preclinical studies have been completed is a hydroxynaphthoquinone designated 566C80. This drug totally prevented murine P. carinii pneumonitis given as infrequently as once a week (23). No significant toxicity or adverse reaction has been found and the drug is currently in early clinical trials. Also, clindamycin plus primaquine may provide yet another drug combination for chemoprophylaxis. In conclusion, the prospects are promising for effective and safe drugs with which to treat and prevent P. carinii pneumonitis in AIDS and non AIDS patients at risk for this infection. With the progression of the AIDS epidemic, the development of more intensive anticancer therapy, and the expansion of organ transplantation programs, P. carinii pneumonia will demand increasing attention from physicians. ACKNOWLEDGMENTS
This work was supported by National Institute of Allergy and Infectious Diseases Grant ROI-AI20673-07, National Cancer Institute Cancer Center Support (CORE) Grant P30CA21765, and the American Lebanese Syrian Associated Charities. Literature Cited
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