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Recommendations for Prophylaxis Against Pneumocystis carinii Pneumonia for Adults and Adolescents Infected with Human Immunodeficiency Virus

U.S. Public Health Service Task Force on Antipneumocystis Prophylaxis for Patients with Human Immunodeficiency Virus Infection

U.S. Department of Health and Human Services Public Health Service Centers for Disease Control Atlanta, Georgia 30333

The MMWR series of publications is published by the Epidemiology Program Office, Centers for Disease Control, Public Health Service, U.S. Department of Health and Human Services, Atlanta, Georgia 30333.

SUGGESTED CITATION Centers for Disease Control. Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus. MMWR 1992;41(No. RR-4): (inclusive page numbers).

Centers for Disease Control

William L. Roper, M.D., M.P.H., Director

James W. Curran, M.D., M.P.H., Office of the Deputy Director (HIV)

The material in this report was prepared for publication by:

National Center for Infectious Diseases James M. Hughes, M.D., Director

Division of HIV/AIDS Ruth L. Berkelman, M.D., Acting Director

The production of this report as an MMWR serial publication was coordinated in:

Epidemiology Program Office Stephen B. Thacker, M.D., M.Sc., Director Richard A. Goodman, M.D., M.P.H., Editor, MMWR Series

Scientific Communications Program Public Health Publications Branch Suzanne M. Hewitt,Chief Ava W. Navin, M.A., Project Editor Morie E. Miller, Editorial Assistant

Use of trade names is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services.

This report represents the recommendations of the U.S. Public Health Service Task Force on prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus. These recommendations do not represent approval by the Food and Drug Administration (FDA) or approved labeling for the particular products or indications in question. Specifically, the terms ``safe'' and ``effective'' are not synonymous with the FDA-defined legal standards for drug approval.

Single copies of this document are available through April 3, 1993, from the Centers for Disease Control, National AIDS Clearinghouse, P.O. Box 6003, Rockville, MD 20850; telephone 800-458-5231.

Copies can be purchased from Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402-9325. Telephone: (202) 783-3238.

Contents

Members of Task Force BACKGROUND PROPHYLACTIC AGENTS Trimethoprim-Sulfamethoxazole (TMP-SMX) Aerosol Pentamidine TMP-SMX Compared with Aerosol Pentamidine Other Agents Other Considerations Summary of Studies of Prophylactic Agents RECOMMENDATIONS

  1. Primary Prophylaxis

  2. Secondary Prophylaxis

  3. Evaluation before Beginning Prophylaxis

  4. Prophylactic Regimens TMP-SMX Aerosol Pentamidine Other Drugs

  5. Choice of Regimens

  6. Adverse Reactions

  7. Monitoring of Patients Receiving Prophylaxis

  8. Breakthrough PCP: Treatment and Subsequent Prophylaxis RECOMMENDATIONS FOR CHILDREN ONGOING STUDIES References

Members of Task Force:

Henry Masur, M.D. (Chair) Clinical Center, National Institutes of Health Bethesda, MD

Judith Feinberg, M.D. (Vice-Chair) Johns Hopkins Hospital Baltimore, MD

Samuel A. Bozzette, M.D. University of California at San Diego Treatment Center San Diego, CA

Victor DeGruttola, D.Sc. Harvard University Cambridge, MA

Brian R. Edlin, M.D. Centers for Disease Control Atlanta, GA

Robert Eisinger, Ph.D. National Institutes of Health Bethesda, MD

Wafaa El-Sadr, M.D. Harlem AIDS Treatment Group New York, NY

Susan S. Ellenberg, Ph.D. National Institute of Allergy and Infectious Diseases Bethesda, MD

David Feigal, M.D. University of California at San Diego Treatment Center San Diego, CA

Peter Frame, M.D. University of Cincinnati Medical Center Cincinnati, OH

Mark Goldberger, M.D. Food and Drug Administration Rockville, MD

Richard Hafner, M.D. National Institute of Allergy and Infectious Diseases Bethesda, MD

W. David Hardy, M.D. University of California at Los Angeles Medical Center Los Angeles, CA

Mark Harrington AIDS Coalition to Unleash Power (ACT-UP) New York, NY

Walter T. Hughes, M.D. St. Jude's Children's Hospital Memphis, TN

Thomas Kerkering, M.D. Medical College of Virginia Richmond, VA

Joseph Kovacs, M.D. Clinical Center, National Institutes of Health Bethesda, MD

Gifford Leoung, M.D. San Francisco, CA

Julio Montaner, M.D. St. Paul's Hospital Vancouver, British Columbia

Alvaro Munoz, Ph.D. Johns Hopkins University Baltimore, MD

John P. Phair, M.D. Northwestern University Medical School Chicago, IL

Fred Sattler, M.D. Los Angeles County-University of

Southern California Medical Center Los Angeles, CA

Stephen Spector, M.D. University of California at San Diego Medical Center San Diego, CA

Contributors:

James R. Allen, M.D., M.P.H. National AIDS Program Office Washington, D.C.

Andrew Carr, M.D. University of New South Wales Sydney, Australia

Richard Chaisson, M.D. Johns Hopkins Hospital Baltimore, MD

Ken Freedberg, M.D. Boston City Hospital Boston, MA

Jean McKay National Institute of Allergy and Infectious Diseases Bethesda, MD

Michael Polis, M.D., M.P.H. Clinical Center, National Institutes of Health Bethesda, MD

Recommendations for Prophylaxis Against Pneumocystis carinii Pneumonia for Adults and Adolescents Infected with Human Immunodeficiency Virus

Summary

In 1989, the United States Public Health Service convened a Task Force of experts to consider the expanding knowledge base about prevention of Pneumocystis carinii pneumonia (PCP) among adults and adolescents (greater than or equal to 13 years of age) with human immunodeficiency virus (HIV) infection. This Task Force concluded that the morbidity, mortality, and cost due to PCP could be substantially reduced by appropriate use of antipneumocystis prophylaxis in subgroups of HIV-infected patients known to be at high risk, and developed recommendations for the administration of prophylactic regimens (1). The recommendations state that CD4+ T-lymphocyte counts should be monitored prospectively at 3- to 6-month intervals and prophylaxis should be instituted when patients become immunologically susceptible to PCP. Susceptibility was defined by a CD4+ T-lymphocyte count less than 200 cells/uL or less than 20% of total circulating T-lymphocytes, or the occurrence of a previous episode of PCP. The goal of this approach was to reduce the frequency both of initial episodes of PCP (primary prophylaxis) and of relapses or recurrences (secondary prophylaxis). Either oral trimethoprim-sulfamethoxazole (TMP-SMX) or aerosol pentamidine was recommended for prophylaxis, but because direct comparative data were lacking, neither regimen was endorsed as ``preferred.''

Since the recommendations were issued in 1989, additional information has become available about the efficacy and safety of aerosol pentamidine and oral TMP-SMX. A trial sponsored by the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group compared these two regimens in a prospective randomized study; in August 1991, this study was terminated by an independent data and safety monitoring board because statistically significantly fewer recurrences of PCP were observed in the oral TMP-SMX group than in the aerosol pentamidine group (2). On the basis of this finding and other studies assessing PCP prophylaxis, the Task Force was reconvened on October 5, 1991. This report contains the revised recommendations issued by the Task Force.

BACKGROUND

Before antipneumocystis prophylaxis was widely prescribed, most North American patients with acquired immunodeficiency syndrome (AIDS) ultimately had one or more episodes of Pneumocystis carinii pneumonia (PCP). These episodes often resulted in hospital admission and were associated with considerable morbidity, mortality, and cost. During the 1980s, practitioners succeeded in decreasing the morbidity, mortality, and expense of these episodes by making earlier diagnoses, using outpatient oral or parenteral therapeutic regimens, continuing therapy more aggressively despite mild toxicity, using alternatives to sulfa-containing regimens (e.g., trimethoprim plus dapsone), and using corticosteroids as initial adjunctive therapy for severe disease (3-5). Despite these advances, PCP continues to be a serious problem for human immunodeficiency virus (HIV)-infected patients, and prevention of cases continues to be an important goal.

To prevent first episodes of PCP, prophylaxis should be instituted when patients become susceptible. Retrospective and prospective studies have documented that the level of circulating CD4+ (helper) T-lymphocytes is a strong predictor of risk for PCP among patients with HIV infection (6,7). The level of circulating CD4+ T-lymphocytes can be expressed as the absolute number per microliter (formerly ``cubic millimeter'') or as the percentage of total circulating T-lymphocytes that are CD4+. Either absolute CD4+ T-cell counts or CD4+ percentages may be used effectively to monitor immunosuppression in HIV-infected patients. Some clinical researchers prefer the CD4+ percentage because this value is measured directly by flow cytometry and is less subject to variation on repeated measurements. However, it is not known whether percentage or absolute count provides a better method for effectively assessing immunosuppression and making clinical judgments about HIV-infected patients. Because recommendations for antiretroviral therapy and CDC's proposed classification system for HIV infection and expanded case definition for AIDS * are based primarily on absolute counts rather than percentages (8), these revised recommendations for PCP prophylaxis are also based on absolute CD4+ T-cell counts.

The goal of establishing a CD4+ T-cell count threshold for primary PCP prophylaxis is to achieve the largest possible reduction in episodes of PCP, while minimizing unnecessary treatment of persons at very low risk. Data from the prospective Multicenter AIDS Cohort Study (7) and other data support beginning prophylaxis when the CD4+ T-cell count falls below 200 cells/uL. However, there is a gradient of risk as the CD4+ T-cell count decreases, and the risk of PCP in patients with CD4+ T-cell counts greater than 200 cells/uL, although low, is not zero. In addition, repeated absolute CD4+ T-cell measurements in individual patients may vary considerably. Some experts on the Task Force, therefore, recommend considering prophylaxis in patients with higher CD4+ T-cell counts, e.g., 200-250 cells/uL.

Observation of rapidly declining CD4+ T-cell counts should lead the treating physician to monitor CD4+ T-cells more often and to consider initiating prophylaxis at a CD4+ level higher than is usually recommended. In addition, at least two considerations other than the CD4+ T-cell count or percentage may influence the decision to initiate PCP prophylaxis (9,10). First, HIV-related thrush and unexplained fevers may be associated with increased risk of PCP, regardless of CD4+ level (7,9). Second, prophylaxis is indicated for any patient with a prior episode of PCP, regardless of CD4+ level (10).

PROPHYLACTIC AGENTS

Trimethoprim-Sulfamethoxazole (TMP-SMX)

In pediatric cancer patients, the efficacy and safety of TMP-SMX for prevention of PCP has been established conclusively (11). Breakthrough episodes of PCP in that population are rare among patients taking TMP-SMX twice daily, either 7 days/week or 3 consecutive days/week.

The efficacy of TMP-SMX, administered in a dose of one double-strength tablet (800 mg of sulfamethoxazole plus 160 mg of trimethoprim) twice daily, for primary PCP prophylaxis in HIV-infected adults and adolescents (greater than or equal to 13 years of age) was demonstrated in a prospective, unblinded study of patients with advanced Kaposi sarcoma (12). Two large retrospective studies support the efficacy of TMP-SMX, administered as one double-strength tablet every other day, for both primary and secondary prophylaxis (13,14). Although these studies were not ideal in terms of design, controls, and size, they provide evidence that TMP-SMX is effective prophylaxis for primary and secondary prevention of PCP in adults with HIV infection. Adverse effects, often requiring drug discontinuation, were, however, frequent.

Aerosol Pentamidine

For an aerosol approach to be clinically effective, a sufficient amount of drug must be nebulized into particles of the appropriate size so that the drug can be deposited throughout the lung parenchyma. This approach depends on the precise characteristics of the nebulization device used, the dose of drug chosen, and patient-specific factors, including ventilation mechanics, body position, and pulmonary physiology. Patients with severely abnormal pulmonary function have not been included in most trials because of uncertainty about how the aerosolized drug would be distributed in their lungs. Because different nebulizers may deliver different amounts of drug to the lung, data about safety and efficacy obtained in clinical trials of one nebulizer cannot be assumed to apply to another device. In addition, because the drug is delivered almost exclusively to the patient's lungs, there is no protection against extrapulmonary pneumocystosis, a rare event that appears to be more common among patients receiving aerosol pentamidine than among those receiving systemic or no prophylaxis (15). For patients who develop PCP during aerosol pentamidine prophylaxis, the clinical presentation may include unusual radiographic appearances (especially upper-lobe infiltrates), and the diagnosis may be more difficult to establish by induced sputum or bronchoalveolar lavage (16,17). Multiple lobe lavages, immunofluorescent staining techniques, or transbronchial biopsies may be necessary to establish the diagnosis.

Aerosol pentamidine delivered by the Respirgard II nebulizer (Marquest, Englewood, CO) at a monthly dose of 300 mg was shown to be effective for primary prophylaxis in a prospective, double-blind, placebo-controlled trial performed in Switzerland and Italy in 1989-1990 (18). Aerosol pentamidine delivered by the Respirgard II nebulizer at a monthly dose of 300 mg was also shown to be effective for secondary prophylaxis in the San Francisco Consortium Prophylaxis trial (19). Coughing and wheezing were common occurrences (36% and 11% of participants, respectively), but only 5.6% of patients had to discontinue aerosol pentamidine.

A prospective, double-blind, randomized, placebo-controlled study carried out in Canada demonstrated the efficacy of aerosol pentamidine (60 mg every 2 weeks) administered with the Fisoneb hand-held, patient-triggered, ultrasonic nebulizer (Fisons Corp., Rochester, NY) for secondary prophylaxis (20). Aerosol pentamidine delivered by the Fisoneb nebulizer was also assessed in a double-blind, randomized, dose-comparison study that did not have a placebo arm (21); the results of this study supported the conclusions of the placebo-controlled study in Canada.

A third delivery system, the Ultraneb 99 ultrasonic nebulizer (DeVilbis, Arcueil, France) was assessed in a randomized but unblinded study based on 4 mg/kg of pentamidine (pentamidine base) every 4 weeks (22). This system appeared effective and safe, but this small study was not as rigorously designed as the previously mentioned trials.

In summary, these studies demonstrate that, for secondary prophylaxis, the dosing regimens used with either the Fisoneb ultrasonic nebulizer or the Respirgard II jet nebulizer are safe and effective. Because the two systems have not been compared with each other in a single trial, no preference for either system is warranted. The Fisoneb device has the advantages of being hand held and portable, and it uses less pentamidine. The Respirgard II device is less expensive and disposable, but requires a compressed air source. The Fisoneb nebulizer has not been assessed for primary prophylaxis.

Clinicians need to be cognizant that, while aerosol pentamidine is being administered, substantial environmental contamination may result from the aerosol delivery system and coughing by the patient. Droplets containing pentamidine or infectious microorganisms from the patient's lungs may be aerosolized. Although the long-term effects of aerosol pentamidine on health-care workers are unknown, transmission of Mycobacterium tuberculosis is of particular concern (23-26).

TMP-SMX Compared with Aerosol Pentamidine

A randomized, prospective, open-label study, AIDS Clinical Trials Group (ACTG) trial 021, compared the efficacy and toxicity of TMP-SMX (one double-strength tablet daily) and aerosol pentamidine (300 mg every 4 weeks, administered by the Respirgard II nebulizer) among patients receiving zidovudine (100 mg/4 hours) who had recovered from an initial episode of PCP (2). The 1-year estimated recurrence rate for the aerosol pentamidine group was 18.5%, compared with 3.5% for the TMP-SMX group. The risk of recurrence in the pentamidine group was 3.25 times that in the TMP-SMX group. The results of this trial provide strong evidence for the superior efficacy of TMP-SMX in preventing or delaying recurrences of PCP.

Other Agents

Dapsone, dapsone with pyrimethamine, dapsone with trimethoprim, and sulfadoxine with pyrimethamine have been used in various doses and schedules for prevention of PCP among patients with HIV infection (27-30). Randomized, prospective trials assessing these agents have not been completed; however, a controlled trial assessing daily dapsone for primary prophylaxis is under way in the United States, and a trial assessing once weekly dapsone-pyrimethamine for secondary prophylaxis is under way in Europe. Intermittent parenteral pentamidine, oral clindamycin with primaquine, and oral BW566C80 are additional regimens that have theoretical potential as useful preventive agents.

Other Considerations

Aerosol pentamidine is unlikely to provide protection against any other HIV-associated opportunistic infections. Data from one retrospective study (A. Carr, M.D.; B. Tindall, M.D.; and B. Brew, M.D., personal communications) and the prospective ACTG 021 Study (2) have suggested that TMP-SMX may offer some protection against cerebral toxoplasmosis, but the data are inconclusive. There are no data concerning any protection that TMP-SMX prophylaxis may provide adults or children against Salmonella sp., Streptococcus pneumoniae, or Haemophilus influenzae infection.

The wholesale monthly costs of items discussed in these recommendations, as published in the 1991 Red Book (31), are as follows: generic TMP-SMX (30 double-strength tablets), $19; pentamidine (300-mg vial), $99; and Respirgard nebulizer, $3 (the Fisoneb nebulizer is reusable and the cost is not known). Prices at specific hospital or retail pharmacies may vary substantially. The true cost of prophylaxis includes the cost of drug delivery (labor, equipment, and supplies), laboratory monitoring, and management of adverse reactions. The cost effectiveness of aerosol pentamidine is strongly influenced by the cost of administering the aerosol. The cost of pentamidine may be substantially reduced in 1992 as a result of increased competition among suppliers.

Summary of Studies of Prophylactic Agents

Both TMP-SMX and aerosol pentamidine are effective for primary and secondary prophylaxis. TMP-SMX is more effective and less expensive than aerosol pentamidine. The results of ACTG 021 show that initiating secondary prophylaxis with TMP-SMX results in superior overall prophylactic efficacy, even though many patients with advanced HIV disease cannot tolerate prolonged courses of TMP-SMX. For patients receiving primary prophylaxis, the risk of PCP is much less, so the increased toxicity of TMP-SMX may be a more substantial concern than its possible greater efficacy. A prospective study (ACTG 081) comparing TMP-SMX, dapsone, and aerosol pentamidine for primary prophylaxis is under way.

RECOMMENDATIONS

Based on a review of available data, the Task Force developed the following recommendations for the prevention of PCP in adults and adolescents with HIV infection. Physicians should be aware that TMP-SMX has not been approved by the Food and Drug Administration for the prevention of PCP. The Fisoneb device is not approved for any indication and is not currently available in the United States.

  1. Primary Prophylaxis

For HIV-infected patients with counts greater than 200 cells/uL, CD4+ T-lymphocyte counts should be monitored at least every 3-6 months. CD4+ T-cell counts may be desirable at more frequent intervals in certain situations, such as a recent rapid decline in CD4+ T-cell count or a CD4+ T-cell count approaching 200 cells/uL. Patients with less than 200 CD4+ T-cells/uL should receive PCP prophylaxis. Patients with constitutional symptoms such as thrush or unexplained fever greater than 100 F for greater than or equal to 2 weeks should also receive prophylaxis, regardless of their CD4+ T-cell count. Prophylaxis should be continued for the patient's lifetime.

2. Secondary Prophylaxis

Any patient who has recovered from a documented episode of PCP should receive prophylaxis.

3. Evaluation Before Beginning Prophylaxis

Prior to the administration of either primary or secondary antipneumocystis prophylaxis, patients should be assessed to ascertain that they do not have active pulmonary disease (e.g., PCP, tuberculosis, or histoplasmosis) that requires specific therapy.

4. Prophylactic Regimens

TMP-SMX

Oral TMP-SMX is recommended for prevention of PCP at a dose of one double-strength tablet (800 mg of sulfamethoxazole and 160 mg of trimethoprim) once a day, 7 days/week. Leucovorin does not need to be administered with this regimen; based on recent data (2), the Task Force has changed its 1989 recommendations for leucovorin. However, a substantial proportion of patients will not be able to tolerate TMP-SMX because of pruritus, rash, cytopenias, and transaminase elevations. Available data do not allow the Task Force to recommend that TMP-SMX be administered fewer than 7 days/week.

Aerosol Pentamidine

For primary or secondary prophylaxis, aerosol pentamidine administered by either the Respirgard II regimen (300 mg once/month) or the Fisoneb nebulizer (an initial loading regimen of five 60-mg doses over a 2-week period, followed by a 60-mg dose every 2 weeks) is recommended. Aerosol pentamidine trials have not been carried out among patients with severe pulmonary function abnormalities, and therefore its efficacy and safety for those patients have not been established (32).

For the Respirgard II jet nebulizer, 300 mg of pentamidine isethionate should be diluted in 6 mL of sterile water and delivered with an air flow of 6 L/min from a 50-PSI compressed air source until the reservoir is dry. Patients who develop cough, wheezing, or chest pain should receive immediate intervention with an inhaled beta2 agonist (e.g., albuterol, two puffs, each delivering 100 ug) and pretreatment 10 minutes before each subsequent pentamidine administration.

For the Fisoneb ultrasonic hand-held nebulizer, 60 mg of pentamidine should be dissolved in 3 mL of sterile water. The patient should inhale for 15-20 minutes until the reservoir is dry. The patient should receive five doses spaced 24-72 hours apart during the first 2 weeks and one dose every 2 weeks thereafter. Inhaled beta2 agonist pretreatment or therapy is also useful for this delivery system.

Before aerosol pentamidine is initiated, patients should be evaluated for tuberculosis by medical history, tuberculin skin test, chest radiograph, and, if cough or pulmonary infiltrate is present, acid-fast bacilli smears and cultures of sputum. Before each subsequent treatment, patients should be evaluated for symptoms suggestive of tuberculosis or another active disease process; if such symptoms are identified, a diagnostic evaluation should be initiated. Aerosol pentamidine should be administered to patients with tuberculosis only under strict adherence to published recommendations (26). Health-care workers administering aerosol pentamidine should wear particulate respirators whenever they must be in the room or booth during administration of aerosol pentamidine to a patient who has, or is at high risk of having, tuberculosis (26). Ideally, all patients should receive treatments in individual rooms or booths with negative-pressure ventilation relative to adjacent areas, with room or booth air exhausted directly to the outside and away from all windows and air-intake ducts (26). After receiving aerosol pentamidine, patients should not return to common waiting areas until coughing subsides. After the treatment room or booth has been used, adequate time should be allowed for removal of residual pentamidine and any infectious organisms from the air before use by another patient (26). Physicians and other health-care workers should be familiar with and adhere to published recommendations for prevention of tuberculosis in health-care settings (24,26).

Other Drugs

Because data are insufficient, the following are not generally recommended as prophylactic regimens: aerosol pentamidine administered by other nebulization devices; intermittent parenteral pentamidine; oral dapsone; oral pyrimethamine plus dapsone; oral pyrimethamine-sulfadoxine; oral clindamycin plus primaquine; oral quinolone; and oral BW566C80. These agents may be considered in unusual situations in which neither TMP-SMX nor aerosol pentamidine can be administered.

5. Choice of Regimens

The final choice of regimens for an individual patient should rest on analysis of studies of comparable patients and consideration of factors unique to each patient, such as drug intolerance, gastrointestinal absorption, pulmonary physiology, and ability to adhere to prescribed regimens. However, for patients who have had no history of serious adverse reactions to sulfa or trimethoprim, the Task Force recommends oral TMP-SMX (one double-strength tablet once daily, 7 days/week, without leucovorin) rather than aerosol pentamidine (Figure 1) for both primary and secondary prophylaxis. Aerosol pentamidine should be administered by either the Respirgard or Fisoneb nebulizer at the appropriate doses.

6. Adverse Reactions

TMP-SMX is frequently associated with substantial pruritus, rash, leukopenia, transaminase elevation, and nausea. These adverse reactions are rarely life threatening; severe exfoliative rashes (such as Stevens-Johnson syndrome) occur only rarely. There is little information about the effect of dose reduction on the frequency or severity of adverse reactions in the range of doses used for prophylaxis. Experts on the Task Force differ in their opinions about the safety of rechallenging a patient who has had a non-life-threatening reaction to TMP-SMX. In the ACTG 021 study, the frequencies of severe adverse reactions among patients assigned to TMP-SMX were similar, regardless of whether they had a history of mild TMP-SMX intolerance (32% vs. 26%) (2); this finding suggests that a mild reaction is not a contraindication to subsequent use of TMP-SMX for secondary prophylaxis. However, some Task Force experts remain concerned that such rechallenges could produce severe adverse reactions. Desensitization protocols may allow some patients with previous adverse reactions to tolerate TMP-SMX (33).

Aerosol pentamidine should not be administered to a patient who has had hypoglycemia, pancreatitis, arrhythmia, or severe hypotension associated with any form of pentamidine. This regimen should be administered to patients with severe pulmonary function abnormalities with caution and only after consideration of the feasibility of alternatives (32). Most bronchospastic complications (wheezing, cough, chest pain) can be alleviated and subsequently prevented by inhalational beta2 agonists such as albuterol (two puffs, each delivering 100 ug) (32).

7. Monitoring of Patients Receiving Prophylaxis

Patients receiving prophylaxis should be monitored closely for the development of pneumocystosis, since no regimen is 100% effective for HIV-infected patients. Physicians should be alert for extrapulmonary pneumocystosis and for unusual radiologic presentations of PCP that may occur during aerosol pentamidine prophylaxis, including upper-lobe infiltrates or pneumothorax. Moreover, the diagnostic yield of bronchoalveolar lavage and induced sputum is substantially reduced. If prophylaxis is discontinued, the patient will again be at high risk for developing PCP.

8. Breakthrough PCP: Treatment and Subsequent Prophylaxis

At present, it is not possible to determine whether breakthrough episodes of PCP in patients who have adhered to their prophylaxis regimens result from resistance to the prophylactic agent. Causes of breakthrough PCP during TMP-SMX treatment may include poor adherence to the regimen by the patient and poor gastrointestinal absorption. Causes during aerosol pentamidine treatment may include poor adherence to the regimen, inability to use the aerosol device properly, and poor pulmonary ventilatory distribution. Some Task Force experts prefer to treat breakthrough episodes of PCP with an agent different from the prophylactic agent (i.e., parenteral pentamidine therapy for breakthroughs during oral TMP-SMX prophylaxis and TMP-SMX therapy for patients receiving aerosol pentamidine). However, there are no data to support such an approach, and in anecdotal cases acute episodes have been successfully treated by using the prophylactic agent at higher doses. Drug intolerance and past treatment or prophylaxis failure may warrant consideration of experimental therapies.

After successful therapy of a breakthrough episode, the choice of prophylactic regimen should be determined by the same considerations as the initial choice: TMP-SMX is still preferred over aerosol pentamidine if the patient can tolerate the oral regimen, can take the drug reliably, and can absorb it from the gastrointestinal tract.

RECOMMENDATIONS FOR CHILDREN

The Working Group on Pneumocystis carinii pneumonia prophylaxis for children recently published age-specific recommendations for administration of prophylactic regimens. Although no controlled trials of prophylaxis have been completed among HIV-infected children, the Working Group agreed that prophylaxis was warranted and that TMP-SMX was the preferred regimen, given the demonstrated efficacy of TMP-SMX in non-HIV-infected immunosuppressed children and the difficulty of administering aerosolized drugs to young children. Physicians should refer to the working group report (34,35) for specific recommendations on management of prophylaxis for children. These recommendations for children greater than or equal to 6 years of age are similar to the current recommendations of the Task Force for adults and adolescents, although a twice-daily dosing regimen Monday-Tuesday-Wednesday each week is preferred for children.

ONGOING STUDIES

Physicians and patients are encouraged to participate actively in organized, controlled studies that can answer crucial questions and improve the effectiveness, safety, and cost of health care for HIV-infected persons. Information about these studies can be obtained from the U.S. Public Health Service-sponsored AIDS Clinical Trials Information Service (1-800-TRIALS-A) or the American Foundation for AIDS Research (212-333-3118).

References

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  18. Hirschl B, Lazzarin A, Chopard P, et al. A controlled study of inhaled pentamidine for primary prevention of Pneumocystis carinii pneumonia. N Engl J Med 1991;324:1079-83.

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  20. Montaner JSG, Lawson LM, Gervais A, et al. Aerosol pentamidine for secondary prophylaxis of AIDS-related Pneumocystis carinii pneumonia. Ann Intern Med 1991;114:948-53.

  21. Murphy R, Lavelle J, Allan J, et al. Aerosol pentamidine prophylaxis following Pneumocystis carinii pneumonia in AIDS patients. Am J Med 1991;90:418-26.

  22. Girard PM, Gaudebout C, Lottin P, et al. Prevention of Pneumocystis carinii pneumonia relapse by pentamidine aerosol in zidovudine-treated AIDS patients. Lancet 1989;1:1348-53.

  23. CDC. Mycobacterium tuberculosis transmission in a health clinic--Florida, 1988. MMWR 1989;38:256-8, 263-4.

  24. CDC. Nosocomial transmission of multidrug-resistant tuberculosis among HIV-infected persons--Florida and New York, 1988-1991. MMWR 1991;34:585-91.

  25. Nardell EA. Dodging droplet nuclei: reducing the probability of nosocomial tuberculosis transmission in the AIDS era. Am Rev Resp Dis 1990;142:501-5.

  26. CDC. Guidelines for preventing the transmission of tuberculosis in health-care settings with special focus on HIV-related issues. MMWR 1990;39(No. RR-17):1-29.

  27. Hughes WT, Kennedy W, Dugdale M, et al. Prevention of Pneumocystis carinii pneumonitis in AIDS patients with weekly dapsone. Lancet 1990;336:1066.

  28. Kemper CA, Tucker RM, Lang OS, et al. Low-dose dapsone prophylaxis of Pneumocystis carinii pneumonia in AIDS and AIDS-related complex. AIDS 1990;4:1145-8.

  29. Lavelle J, Falloon J, Morgan A, et al. Weekly dapsone and dapsone/pyrimethamine for pneumocystis pneumonia prophylaxis. (Abstract WB2207). VII International Conference on AIDS. Florence, Italy: June 16-21, 1991.

  30. Hardy WD, Wolfe PR, Gottlieb MS, Knight S, Mitsuyasu R, Young LS. Long-term follow-up of fansidar prophylaxis for Pneumocystis carinii in patients with AIDS (Abstract TP 232). International Conference on AIDS, Washington, DC. June 1-5, 1987.

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  33. Smith RM, Iwamoto GK, Richerson HB, Flaherty JP. Trimethoprim-sulfamethoxazole desensitization in the acquired immunodeficiency syndrome. Ann Intern Med 1987;106:335.

  34. CDC. Guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with human immunodeficiency virus. MMWR 1991;40(No. RR-2).

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    • CDC. 1992 Revised classification system for HIV infection and expanded AIDS surveillance case definition for adolescents and adults (draft for public comment). Available from the Centers for Disease Control, National AIDS Clearinghouse, P.O. Box 6003, Rockville, MD 20850; telephone 800-458-5231.




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