Prevention Of Pneumocystis Carinii Pneumonia Research Articles

Infections and immunizations in organ transplant recipients: a preventive approach.

Infections after organ transplantation can be devastating in immunocompromised patients. To review strategies for preventing infections after transplantation. Immunization remains a cornerstone of preventive practice, but the suboptimal response to vaccinations in patients receiving immunosuppressive therapy presents an ongoing challenge. More work is needed to determine which of the numerous strategies for preventing symptomatic cytomegalovirus infection is most effective and economical, and under which circumstances. Prevention of Pneumocystis carinii pneumonia remains an important issue, especially in sulfa-intolerant patients. The relationship between different immunosuppressive programs and occurrence of infectious complications such as lymphoproliferative disease is just beginning to be understood. The toxicity of amphotericin B in this population has led to a search for more effective means of preventing and treating fungal infections. Finally, a new set of possible pathogens (such as the recently recognized human herpesvirus-6) is on the horizon. The best preventive approach encompasses awareness of epidemiologic risk, early detection of infection, appropriate prophylactic or preemptive therapy for specific infections, and close collaboration between the infectious-disease clinician and the transplant team.

Pneumocystis carinii Pneumonia

Even with the availability of highly effective drugs that can prevent Pneumocystis carinii pneumonia (PCP), this infection continues to be the greatest single defining illness of acquired immunodeficiency syndrome (AIDS). Despite significant progress over the last decade in our knowledge about the diagnosis and treatment of this infection, the fact that so much of the basic biology and epidemiology of P. carinii remains unknown continues to be a source of frustration to scientists working with this parasite. Pneumocystis carinii Pneumonia, edited by Peter D. Walzer, M.D., Chief of the Infectious Diseases Section of the Cincinnati Veterans Affairs Medical Center, documents both the recent progress in our knowledge as well as the continued frustration (based principally on our inability to culture the organism) that this new knowledge has come so haltingly and at such high cost.The volume contains 31 chapters written by leading authorities on PCP.It is divided into six parts: basic biology, epidemiology, pathophysiology, clinical features, diagnosis, and treatment and prevention.

Failure of Pentamidine as Prophylaxis for Pneumocystis carinii Pneumonia in HIV-Infected Children

Use of a combination of oral trimethoprim and sulfamethoxazole (TMP-SMZ) and aerosolized pentamidine are the only medications currently approved by the Centers for Disease Control and Prevention (CDC) for the prevention of Pneumocystis carinii pneumonia (PCP) in human immunodeficiency virus (HIV)–infected children. 1 However, adverse reactions to TMP-SMZ and the difficulty of administering aerosolized pentamidine in the pediatric population often necessitate the use of alternative prophylactic regimens, such as intramuscularly (IM) or intravenously (IV) administered pentamidine or orally administered dapsone. 2,3 At our institution, HIV-positive children who require prophylaxis for PCP and are intolerant of oral TMP-SMZ have received monthly IM or IV pentamidine therapy for prophylaxis for PCP. Pneumocystis carinii pneumonia developed in three of these children who had very low CD4+ cell counts for their age in spite of this regimen. Alternative regimens are necessary to prevent PCP in these severely immunodeficient children. Further clinical studies are needed

Four different regimens for prevention of Pneumocystis carinii pneumonia and toxoplasma encephalitis in HIV-infected patients

Four different regimens for prevention of Pneumocystis carinii pneumonia and toxoplasma encephalitis in HIV-infected patients

Aerosolized pentamidine for the prevention of Pneumocystis carinii pneumonia in children with cancer intolerant or allergic to trimethoprim/sulfamethoxazole.

Trimethoprim/sulfamethoxazole (TMP/SMX) is the drug of choice for Pneumocystis carinii pneumonia (PCP) prophylaxis in immunocompromised patients. In children with malignancy, TMP/SMX is well tolerated, but adverse reactions that necessitate discontinuation can occur. We evaluated the safety and efficacy of aerosolized pentamidine (AP) as an alternative prophylaxis modality in children with malignancy who are intolerant of or allergic to TMP/SMX. AP (200 mg/m2 every 4 weeks) was administered to 60 children with malignancy receiving chemotherapy who had experienced severe adverse reactions to TMP/SMX. Seven hundred twenty doses of AP have been administered during a 3 1/2-year period (21,600 patient-days), with 30 patients treated for > or = 12 months (range, 12 to 25). Adverse reactions occurred during 79 (10%) of the 720 treatments and included bronchospasm in 23, cough in 40, vomiting in 10, and nausea in six. Only two patients had severe bronchospasm. AP was discontinued due to toxicity in three patients (5%). None of the patients (upper 95% confidence limit, 0.049) have developed PCP. AP appears to be well tolerated and effective in the prevention of PCP in children with malignancy.

Quick Reference Guide for Clinicians Managing Early HIV Infection

This Quick Reference Guide for Clinicians contains highlights from the Clinical Practice Guideline on Evaluation and Management of Early HIV Infection, which was developed by a private‐sector panel of health care providers and consumers. Selected aspects of evaluating and managing patients, both adults and children, who are in the early stages of human immunodeficiency virus infection are presented. Topics covered include disclosure of HIV status, monitoring of CD4 lymphocyte counts, prevention of Pneumocystis carinii pneumonia and infection with Mycobacterium tuberculosis, initiation of antiretroviral therapy, treatment of syphilis, eye and oral care, performance of Papanicolaou smears. diagnosis of HIV infection in infants and children, preventive therapy for PCP and assessment of neurologic problems in HIV‐infected children, pregnancy counseling, and development of a comprehensive case management system. Algorithms are included that show the sequence of events related to evaluating and managing early HIV infection in adults and children, as well as drug dosing tables for antiretroviral. PCP, and M. tuberculosis therapies. This Quick Reference Guide for Clinicians contains excerpts from the Clinical Practice Guideline, but users should not rely on these excerpts alone. Clinicians should refer to the complete Clinical Practice Guideline for more detailed analysis and discussion of the available research, critical evaluation of the assumptions and knowledge of the field, health care decision making, and references.

Prevention of infections in patients with T cell defects.

Although no specific infection is limited entirely to hosts with T-lymphocyte defects, certain microbial organisms have an affinity for such individuals. Effective, safe, and feasible methods are available for the prevention of two of the major life-threatening infections in patients with T-lymphocyte defects, although none of these methods is ideal. Trimethoprim-sulfamethoxazole administered orally daily or thrice weekly is highly effective for the prevention of Pneumocystis carinii pneumonia. For patients who cannot tolerate this drug combination, monthly inhalation of aerosolized pentamidine is an alternative prophylactic approach. Additional drugs in clinical or preclinical trials offer promise for use in preventing this pneumonitis. Varicella is one of the most frequent serious viral infections in patients with cancer, especially children. Varicella-zoster immune globulin (VZIG) has proven effective in reducing the frequency of infection in exposed susceptible individuals; however, breakthrough infections are not uncommon. Of 358 children with acute lymphoblastic leukemia, 62 received VZIG following exposure to varicella, and 16 (26%) of these had breakthrough varicella. A live attenuated varicella-zoster virus vaccine offers promise, especially for the universal immunization of individuals before immunocompromise occurs.

Inhibition of Pneumocystis carinii dihydropteroate synthetase by para-acetamidobenzoic acid: possible mechanism of action of isoprinosine in human immunodeficiency virus infection.

Isoprinosine has been reported to decrease progression to AIDS, primarily by preventing Pneumocystis carinii pneumonia (PCP), in human immunodeficiency virus-infected patients, but the mechanism of action is unknown. para-Acetamidobenzoic acid (PAcBA), one component of isoprinosine, is structurally related to para-aminobenzoic acid (PABA), a precursor of de novo folate synthesis. This pathway is known to be important for P. carinii because sulfonamides, which are effective anti-P. carinii agents, inhibit incorporation of PABA into folate precursors by the enzyme dihydropteroate synthetase (DHPS). Inhibition of P. carinii DHPS by PAcBA was investigated by using two assays. In short-term cultures of P. carinii from rats, [3H]PABA incorporation into reduced folates was inhibited by both isoprinosine (mean +/- standard error 50% inhibitory concentration [IC50], 20 +/- 8.4 microM) and PAcBA free acid (IC50, 240 +/- 100 microM); a soluble PAcBA salt was more potent than PAcBA free acid alone (IC50, 29 +/- 48 microM). The activity of PAcBA free acid was confirmed in a cell-free DHPS inhibition assay (IC50, 120 +/- 120 microM). Inosine and dimethylaminopropanol, two other components of isoprinosine, were poor inhibitors of PABA incorporation (IC50, > 1,000 microM). PAcBA free acid also showed activity in inhibiting the DHPS of Toxoplasma gondii, but was a poor inhibitor of the DHPSs of Escherichia coli and Saccharomyces cerevisiae. In a rat model of PCP, the PAcBA salt administered intraperitoneally demonstrated no activity against established PCP either alone or when used in combination with trimethoprim; the lack of efficacy in this model may be due to the rapid metabolism of the drug. Prevention of PCP by PaCBA through inhibition of P. carinii DHPS may explain the activity of isoprinosine in decreasing the progression to AIDS in human immunodeficiency virus-infected patients.

Chronic pentamidine aerosol prophylaxis does not induce QT prolongation

Intravenous administration of pentamidine is known to cause long-QT syndrome (Torsade de pointes tachycardias and large QT prolongation) in rare cases and to cause small QT prolongation regularly. A similar pattern is seen with other drugs known to cause a long-QT syndrome. Pentamidine aerosol prophylaxis is commonly used to prevent Pneumocystis carinii pneumonia in HIV-infected persons. The goal of this study was to clarify whether pentamidine aerosol prophylaxis induces QT prolongation. We examined 100 patients receiving pentamidine aerosol prophylaxis at a rather high dose (300 mg biweekly) for at least 1 month (range 1-24) by determining the QT interval corrected for heart rate (QTc), blind for treatment. In a cross-sectional study, QTc was not different in 50 HIV-infected patients with chronic pentamidine aerosol prophylaxis (413 ms), 50 similar HIV-infected patients without pentamidine (407 ms), and 50 similar patients without HIV-infection and without pentamidine (407 ms). In a longitudinal study in another 50 HIV-infected patients, QTc was the same before (414 ms) and on long-term (median 9-month) pentamidine aerosol prophylaxis (414 ms). In contrast to the case with intravenous pentamidine, we found no QT prolongation and thereby no risk of long-QT syndrome with pentamidine aerosol prophylaxis.

Lung deposition of nebulised pentamidine in children.

Nebulised pentamidine is effective for preventing Pneumocystis carinii pneumonia in adults with acquired immunodeficiency syndrome. The nebuliser dose required to produce equivalent lung concentrations of pentamidine in children is unknown. This study was performed to measure pulmonary pentamidine deposition in children and to relate this to age, ventilation pattern, and body size. Nebulised pentamidine (50 mg in 6 ml saline) was administered to 12 children (including one with lymphocytic interstitial pneumonitis) and to six adults with human immunodeficiency virus infection using a Respirgard II nebuliser. Technetium-99m labeled colloidal human serum albumin was used as an indirect marker for pentamidine and deposition in the lungs was detected by a gamma camera. Absolute deposition of pentamidine was not related to age, height, weight, spirometry, or ventilation characteristics. Deposition, as a mean (SD) percentage of nebuliser output, was similar in children aged 8-11 years (5.5(2.4)%), teenagers aged 12-15 years (7.2(2.2)%) and adults (7.1(2.6)%). Aerosol concentration within the lungs (% nebuliser output deposited/predicted total lung capacity) was therefore higher in children (1.9(1.5)%/1) and teenagers (1.9(0.7)%/1) than in adults (1.0(0.7%)/1), and was negatively correlated with height (r = -0.69) and weight (r = -0.50). Deposition of aerosol in the region of the large central airways was particularly marked in children. Small reductions in forced expiratory volume in one second and forced vital capacity after treatment did not differ significantly between adults and children and visual analogue scores of subjective adverse effects did not vary with age. These results suggest that children probably require lower nebuliser pentamidine doses to produce lung pentamidine concentrations equivalent to those found to be effective for preventing P carinii pneumonia in adults using the Respirgard II nebuliser.

Decreased Efficacy of Inhaled Pentamidine in the Prevention of Pneumocystis carinii Pneumonia Among HIV-infected Patients With Severe Immunodeficiency

To determine the relationship between the degree of immune deficiency and the risk of Pneumocystis carinii pneumonia (PCP) among HIV-infected patients receiving inhaled pentamidine prophylaxis. Retrospective chart review. AIDS clinic of inner-city hospital. Patients attending inhaled pentamidine clinic between 1989 and 1991. Review of medical records of patients receiving inhaled pentamidine, 300 mg/month, via nebulizer (Respirgard II) as primary or secondary prophylaxis of PCP. Statistical analysis of lymphocyte subset results and selected clinical data. Ten of 57 patients developed PCP during the period of analysis. Patients with CD4 counts less than 60/mm3 were significantly more likely to develop PCP (p = 0.01; Fisher's exact test) with a relative risk of 7.55 compared to patients with CD4 lymphocyte counts greater than 60/mm3. Failure of inhaled pentamidine prophylaxis is seen almost exclusively among patients with CD4 lymphocyte counts below 60/mm3.

Intramuscular Pentamidine for the Prevention of Pneumocystis carinii Pneumonia in Patients Infected with Human Immunodeficiency Virus

We retrospectively reviewed the charts of 96 patients infected with human immunodeficiency virus (HIV) who received intramuscular pentamidine for the prevention of Pneumocystis carinii pneumonia (PCP). These patients, all of whom had either a history of PCP or a CD4 lymphocyte count of < or = 0.2 x 10(9)/L, were intolerant of sulfa drugs, neutropenic, or intolerant of aerosolized treatment. Intramuscular pentamidine was given monthly by the Z-track technique at a dosage of 300 mg (4 mg/kg if the patient weighed < 50 kg). During a total of 350 months of primary prophylaxis in 47 patients and 426 months of secondary prophylaxis in 49 patients, only three cases of PCP occurred. More than 73% of the patients were receiving zidovudine concomitantly. Adverse reactions to intramuscular pentamidine included two episodes of hypotension, three of sterile abscess, two of glucose intolerance, and one of asymptomatic hypoglycemia. The administration of intramuscular pentamidine by the Z-track technique for PCP prophylaxis appears to be highly effective and minimally toxic.

Prophylaxis of Pneumocystis carinii pneumonia in human immunodeficiency virus–infected adults

In 1992, the feasibility and benefit of preventing Pneumocystis carinii pneumonia are well demonstrated in human immunodeficiency virus–infected patients. Although indications for prophylaxis are also well defined, the incidence of P. carinii pneumonia remains exceedingly high. Among the two recommended agents, trimethoprimsulfamethoxazole appears more effective but also less well tolerated than pentamidine aerosols. Large comparative trials using these agents and others such as dapsone, alone or in combination, are still ongoing; their results may offer alternatives, especially in trimethoprim-sulfamethoxazole–intolerant patients. The next step is to develop new agents or combinations in order to extend the spectrum of prophylactic strategies to other acquired immunodeficiency syndrome–related major opportunistic infections.

Current status of HIV therapy: II. Opportunistic diseases.

Infections and malignancies account for most deaths in patients with AIDS and will continue to do so as long as HIV-induced immunosuppression is progressive and irreversible. Co-trimoxazole has emerged as the preferred agent for prevention of Pneumocystis carinii pneumonia. As appropriate broad-spectrum agents are developed, multiple opportunistic pathogen prophylaxis could become effective.

Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs.

Over a 7-year period, we analyzed 261 dose regimens of antimicrobial drugs in the treatment and prevention of Pneumocystis carinii pneumonia in an immunosuppressed rat model. These compounds ranged from drugs in clinical use to newly synthesized agents. Drug efficacy was expressed as the magnitude of the reduction in median P. carinii cyst or nucleus counts on a scale ranging from inactive (less than 5-fold) to very markedly active (greater than or equal to 1,000-fold). The classification system was reproducible and allowed drugs studied at different times to be compared with each other. The system demonstrated a hierarchy of anti-P. carinii activity not only among classes of compounds but also among individual members of a drug class. Sulfonamides, sulfones, and diamidines were the most active agents; some purine nucleosides and nitrofurans also showed promising activity; and most antiparasitic, antifungal, antibacterial, and antiviral drugs were inactive. We conclude that this classification system represents a simple, quantitative method of comparing the activities of antimicrobial drugs against P. carinii. Information gained from this system should be helpful in developing new anti-P. carinii compounds and establishing standard procedures for their evaluation.

Advances in the treatment of children with human immunodeficiency virus infection

Over the past decade a number of significant advances have been made in the diagnosis and management of human immunodeficiency virus infection in children. Using virologic methods, it is now possible to make a specific diagnosis within the first few months after birth (more than 95% of infected children can be diagnosed by 3 to 6 months of age). In addition, a better understanding of the normal “development” of CD4 lymphocyte counts in infants and children has shown that these values are distinctly different than in adults and that values change with advancing age. This is important in monitoring human immunodeficiency virus-infected children and in determining thresholds for instituting intervention strategies. Human immunodeficiency virus infection in children is now a treatable disease. Two antiretroviral agents have been approved for use in pediatric patients and a host of studies are underway to investigate the optimal regimens of these agents and alternative new agents. Standard recommendations are in place for prevention of Pneumocystis carinii pneumonia, the most common and often fatal opportunistic infection in human immunodeficiency virus-infected children. Advances have been made in supportive care, including the prevention of bacterial infections in some categories of patients.

Effectiveness of low-dose cotrimoxazole prophylaxis against Pneumocystis carinii pneumonia after renal and/or pancreas transplantation.

We retrospectively examined the effectiveness of prophylaxis with cotrimoxazole in preventing Pneumocystis carinii pneumonia in recipients of kidney and combined kidney-pancreas transplants between 1985 and 1989. Cotrimoxazole prophylaxis (480 mg daily or 300 mg/m2), when used, was started within 2 months after transplantation and usually continued until 6 months after surgery. Eight (3.7%) of the 214 patients who were not given prophylaxis were infected with Pneumocystis carinii, and there were 4 fatalities (50% mortality). There were no cases among the 161 patients given prophylaxis (P less than or equal to 0.03). No serious adverse effects were noted in the prophylaxis group. It is concluded that prophylaxis against Pneumocystis carinii infection is well tolerated and should be given as soon as possible to all organ transplant recipients for at least 6 months.

A comparison of the effectiveness of three regimens in the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients

Background.— Pneumocystis carinii pneumonia (PCP) is a major cause of morbidity and the leading cause of death in patients with the acquired immunodeficiency syndrome. The prevention of the occurrence and recurrence of PCP is a cornerstone in the treatment of patients infected with the human immunodeficiency virus. There are few studies comparing PCP prophylactic regimens. Methods.— The efficacy of three regimens for prophylaxis against PCP was assessed in a retrospective chart review of 211 human immunodeficiency virus—infected patients at risk for the disease. Over the course of the 2-year study period, 133 patients were prescribed trimethoprimsulfamethoxazole (one double-strength tablet twice a day, thrice weekly) for a mean of 7.4 months (range, 1 to 25 months). Seventy-seven patients received dapsone (50 mg daily) for a mean of 5.7 months (range, 1 to 23 months), and 125 patients received aerosolized pentamidine (300 mg via nebulizer once monthly) for a mean of 9.3 months (range, 1 to 21 months). The majority of patients (62%) received primary prophylaxis; 38% had one or more previous episodes of PCP; and 73% were receiving concomitant antiretroviral therapy. Results.— Pneumocystis Pneumocystis carinii pneumonia did not develop in any patient receiving trimethoprimsulfamethoxazole in 981 patient-months. Five patients receiving dapsone for 437 patient-months and 17 patients receiving aerosolized pentamidine for 1166 patient-months developed PCP. Fifty-six percent of the trimethoprimsulfamethoxazole group and 55% of the dapsone group changed drug due to adverse reactions, while only 2% in the aerosolized pentamidine group required drug change. Conclusion.— Despite its adverse reaction profile, trimethoprim-sulfamethoxazole is the most effective agent to prevent the occurrence and recurrence of PCP. ( Arch Intern Med . 1992;152:523-528)

A Comparison of the Effectiveness of Three Regimens in the Prevention of Pneumocystis carinii Pneumonia in Human Immunodeficiency Virus-Infected Patients

Pneumocystis carinii pneumonia (PCP) is a major cause of morbidity and the leading cause of death in patients with the acquired immunodeficiency syndrome. The prevention of the occurrence and recurrence of PCP is a cornerstone in the treatment of patients infected with the human immunodeficiency virus. There are few studies comparing PCP prophylactic regimens. The efficacy of three regimens for prophylaxis against PCP was assessed in a retrospective chart review of 211 human immunodeficiency virus-infected patients at risk for the disease. Over the course of the 2-year study period, 133 patients were prescribed trimethoprim-sulfamethoxazole (one double-strength tablet twice a day, thrice weekly) for a mean of 7.4 months (range, 1 to 25 months). Seventy-seven patients received dapsone (50 mg daily) for a mean of 5.7 months (range, 1 to 23 months), and 125 patients received aerosolized pentamidine (300 mg via nebulizer once monthly) for a mean of 9.3 months (range, 1 to 21 months). The majority of patients (62%) received primary prophylaxis; 38% had one or more previous episodes of PCP; and 73% were receiving concomitant antiretroviral therapy. Pneumocystis carinii pneumonia did not develop in any patient receiving trimethoprim-sulfamethoxazole in 981 patient-months. Five patients receiving dapsone for 437 patient-months and 17 patients receiving aerosolized pentamidine for 1166 patient-months developed PCP. Fifty-six percent of the trimethoprim-sulfamethoxazole group and 55% of the dapsone group changed drug due to adverse reactions, while only 2% in the aerosolized pentamidine group required drug change. Despite its adverse reaction profile, trimethoprim-sulfamethoxazole is the most effective agent to prevent the occurrence and recurrence of PCP.

Treatment options for human immunodeficiency virusinfected pregnant women

The increasing seroprevalence of human immunodeficiency virus (HIV) among women of reproductive age and the risks of vertical transmission of HIV have led to recommendations for routine prenatal HIV counseling and testing. The incentive to undergo such testing is related not only to fetal concerns, but also to the potential benefit of early and comprehensive therapy for women. Treatments that should be considered for use during pregnancy include the antiretroviral agent zidovudine and prophylactic agents to prevent Pneumocystis carinii pneumonia, the most common opportunistic infection seen in patients progressing to AIDS. Assessment of the risks and benefits of these treatments during pregnancy is complex and requires discussions between physician and patient. This paper reviews current information and provides recommendations for incorporating therapies into obstetric practice.