Prophylaxis In Immunocompromised Patients Research Articles

The sulfone syndrome secondary to dapsone prophylaxis in a patient undergoing unrelated hematopoietic stem cell transplantation

Dapsone is commonly used for pneumocystis carinii pneumonia (PCP) prophylaxis in immunocompromised patients. It has been used as an alternative therapy in the hematopoietic stem cell transplant (HSCT) setting in patients who can't tolerate trimethoprim-sulfamethoxazole. The Sulfone syndrome is not a well-known sequela of dapsone therapy and occurs at various doses, ranging from 50-300 mg/d. In all cases the syndrome occurs within 2 months of initiating therapy. Its clinical manifestations include: fever, methemoglobinemia, hemolytic anemia, exfoliative dermatitis and transaminits. A 51-year old female underwent a matched unrelated hematopoiectic stem cell transplant for acute mylogenous leukemia. Dapsone therapy was initiated on day +28 at a dose of 100 mg/day for PCP prophylaxis secondary to the patient's history of a sulfonamide allergy. On day +59, one month after initiation of therapy she developed hepatitis, hemolytic anemia, fever and methemoglobinemia of 8%. She was transferred to the intensive care unit and subsequently developed an exfoliative dermatitis. We conclude that the clinical presentation of this patient after HSCT on dapsone therapy coincide with the sulfone syndrome not previously described in a patients after HSCT.

Novel preventative strategies against invasive aspergillosis.

Invasive fungal infections, such as invasive aspergillosis (IA) represent a major threat to immunocompromised patients, especially patients with hematological malignancies or who receive hematopoietic stem cell transplantation. Hence, prevention of IA is a critical strategy that requires a clear understanding of the mould's environmental sources and how it is transmitted to immunocompromised patients. Knowledge of the exposure, mechanisms of transmission, and host susceptibility to IA are vital in selecting appropriate preventive strategies to those settings where infection is more likely to occur. Among the strategies to reduce the incidence of IA is the maintenance of high quality air, i.e. air with low spore counts in hospital areas visited by patients at risk. Housing patients in laminar airflow facilities with high-energy particulate air-filtered rooms helps prevent IA, but it is only realistic and cost-effective for the highest-risk groups and for limited time periods. Air filtration is a costly preventive strategy of questionable value when done with portable filtration units. Moreover, air control measures outside the hospital are extremely difficult to implement and this is important since the majority of cases of IA after allogeneic stem cell transplantation occurs during the post-engraftment period. For these reasons, targeted antifungal prophylaxis remains the most promising of the potential prevention strategies against IA. Many older and newer antifungal agents have been used for this purpose. Amphotericin B, being the oldest and most widely used antifungal, has been used prophylactically in various doses and schedules, but has largely been replaced by its lipid and liposomal formulations that have improved safety profile. Although prophylactic fluconazole prevents candidiasis, this drug has no activity against moulds, including Aspergillus spp. On the other hand itraconazole appears to prevent IA in those patients who can tolerate the drug, since its poor tolerability limits its use. The newer extended spectrum triazole posaconazole has been used in prophylactic trials with encouraging results in selected populations of patients at risk. Voriconazole, another extended spectrum triazole that has emerged as the treatment of choice for IA has been used as secondary prophylaxis in immunocompromised patients with history of IA. Echinocandins, such as caspofungin and micafungin appear to be extremely safe and effective for primary and secondary prophylaxis of IA. Patients undergoing transplantation for hematological malignancies from mismatched or unrelated donors are clearly at higher risk of IA compared to patients undergoing autologous transplantation, since among other risk factors they frequently receive moderate doses of corticosteroids for extended periods for Graft vs. Host Disease (GvHD), a well-known risk factor for IA. Hence, results of studies in specific populations should be analyzed with caution and prophylaxis should be applied to similar patients, because antifungals are not devoid of side effects and overuse selects for resistant fungi. In conclusion, more studies are clearly needed to better define patient populations who will clearly benefit from prophylactic antifungal therapy against IA.

Methemoglobinemia in children with acute lymphoblastic leukemia (ALL) receiving dapsone for pneumocystis carinii pneumonia (PCP) prophylaxis: a correlation with cytochrome b5 reductase (Cb5R) enzyme levels.

Dapsone is commonly used for pneumocystis carinii pneumonia (PCP) prophylaxis in immunocompromised patients. Methemoglobinemia is a known complication of dapsone, but its true frequency and pathogenesis in childhood cancer patients are unknown. Additionally, practice guidelines for evaluation and management of dapsone-induced methemoglobinemia are not available. We studied 15 children with acute lymphoblastic leukemia (ALL) receiving dapsone for PCP prophylaxis to determine the frequency of methemoglobinemia, and correlate its occurrence with cytochrome b5 reductase (Cb5R) enzyme levels. Ten children with ALL receiving trimethoprim-sulfamethaxazole (TMP-SMX) were studied as controls. All patients underwent physical examination, pulse oximetry, and methemoglobin (metHb) estimation. Commercially available assay was used to measure Cb5R levels. Three (20%) patients receiving dapsone developed symptomatic methemoglobinemia. Average duration of dapsone prophylaxis prior to diagnosis was 6.6 weeks (range 3.5-10 weeks). Mean metHb level in symptomatic patients was 11.67%; 95% confidence interval (CI) 0-25.79 (range 7-18%), and 1.37%; 95% CI 0.6-2.14 (range 0.02-3%) in asymptomatic patients (P = 0.09), whereas the mean metHb level in the control group was 0.54%; 95% CI 0.35-0.73 (range 0.1-0.8%) (asymptomatic vs control P < 0.0001). Mean Cb5R level in symptomatic patients was 8.6 IU/g Hb; 95% CI 3.4-13.7 (range 6.9-10.9) compared to 12.5 IU/g Hb; 95% CI 11.1-13.9 (range 10.8-14.6) in asymptomatic patients (P = 0.06). Two symptomatic patients had Cb5R levels at or below 50% of normal, consistent with heterozygosity. Parental studies for Cb5R levels were suggestive of a carrier state in one of each patient's parents. Heterozygosity for Cb5R deficiency may pre-dispose to methemoglobinemia even on a thrice-weekly regimen of dapsone. Such individuals should avoid subsequent exposure to oxidant agents, if possible. Children with ALL tend to be symptomatic at low levels of metHb and may have delayed detection of methemoglobinemia. Hence, frequent monitoring of patients receiving dapsone is recommended. Monitoring guidelines for dapsone prophylaxis are proposed.

Discovery of novel antifungal (1,3)-beta-D-glucan synthase inhibitors.

The increasing incidence of life-threatening fungal infections has driven the search for new, broad-spectrum fungicidal agents that can be used for treatment and prophylaxis in immunocompromised patients. Natural-product inhibitors of cell wall (1,3)-beta-D-glucan synthase such as lipopeptide pneumocandins and echinocandins as well as the glycolipid papulacandins have been evaluated as potential therapeutics for the last two decades. As a result, MK-0991 (caspofungin acetate; Cancidas), a semisynthetic analogue of pneumocandin B(o), is being developed as a broad-spectrum parenteral agent for the treatment of aspergillosis and candidiasis. This and other lipopeptide antifungal agents have limited oral bioavailability. Thus, we have sought new chemical structures with the mode of action of lipopeptide antifungal agents but with the potential for oral absorption. Results of natural-product screening by a series of newly developed methods has led to the identification of four acidic terpenoid (1,3)-beta-D-glucan synthase inhibitors. Of the four compounds, the in vitro antifungal activity of one, enfumafungin, is comparable to that of L-733560, a close analogue of MK-0991. Like the lipopeptides, enfumafungin specifically inhibits glucan synthesis in whole cells and in (1,3)-beta-D-glucan synthase assays, alters the morphologies of yeasts and molds, and produces a unique response in Saccharomyces cerevisiae strains with point mutations in FKS1, the gene which encodes the large subunit of glucan synthase.

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.

Antifungal prophylaxis in immunocompromised hosts.

To review the literature on the efficacy and safety of antifungal agents for prophylaxis of fungal infections in populations of immunocompromised hosts (key words: hematology-oncology, surgical, solid organ transplant, HIV infection), and to develop guidelines and recommendations regarding safe and effective drug regimens for antifungal prophylaxis in this patient population. Comprehensive review of clinical trials of antifungal prophylaxis published in the English literature, with an emphasis on controlled trials, and discussion of key clinical trials illustrating efficacy and safety of agents for antifungal prophylaxis in immunocompromised patients. Much of the clinical data evaluating the efficacy and safety of antifungal prophylaxis has been generated in cancer patients. The choice of antifungal agent for prophylaxis in this population remains controversial. However, azole compounds such as clotrimazole, ketoconazole and fluconazole appear to be more effective and better tolerated than nystatin suspension. Although ketoconazole has been shown to reduce fungal colonization in surgical patients, current data do not support the routine use of antifungal prophylaxis in this population. In renal transplant recipients, clotrimazole troches have been shown to be more effective than placebo or nystatin suspension. Selective bowel decontamination with nonabsorbable antibiotics and nystatin may be useful in reducing Candida colonization in liver transplant patients but no definitive recommendations may be made at this time regarding optimal antifungal prophylaxis in these patients. In patients with advanced HIV disease or history of prior fungal disease prophylaxis for oropharyngeal candidiasis is indicated, although the agent of choice remains controversial. Fluconazole is the drug of choice for prevention of relapse of cryptococcal meningitis in patients with AIDS. Finally, only limited data exist assessing the relationship between local colonization and systemic fungal infection. Adverse effects associated with antifungal prophylaxis, generally limited to nausea and vomiting and transient elevations in hepatic transaminases, occur with similar frequency among available oral or topical agents. However, the incidence of nausea and vomiting with resultant poor patient tolerance and compliance is usually higher with nystatin. Based on available data from controlled clinical trials, azole agents are currently the most effective and best-tolerated drugs for antifungal prophylaxis in immunocompromised hosts. Choice of one agent in this group over another may be dictated by cost. As new antifungal treatments are released onto the market, these drugs should be compared with existing agents in controlled clinical trials. Future studies should be designed to evaluate the relationship between local colonization and disseminated infection.

Colonization pattern of the digestive tract by potentially pathogenic microorganisms: colonization-controlling mechanisms and consequences for antibiotic treatment.

An outline is given of the various host-related and flora-related parts of the colonization resistance of the digestive tract. The host-related part of the colonization resistance has been found to be somewhat decreased by sublethal irradiation and leukemia (or chemotherapy), while treatment with antibiotics active against gram-positive flora may severely decrease the colonization resistance (depending on the antibiotic concentration established within the digestive tract during antibiotic therapy). The flora-related part of the colonization resistance, which controls colonization by potentially pathogenic microorganisms, differs greatly from one individual to the next. This observation appears to be important for the host-related part of the colonization resistance. Finally, it is concluded that in the clinical situation preference should be given to antibiotics which do not affect the part of the flora constituting colonization resistance for two reasons: 1) to limit the spread of (multi-) resistant potentially pathogenic microorganisms and 2) for infection prophylaxis in immunocompromised patients. In the latter situation, the potentially pathogenic microorganisms in the flora are selectively eliminated from the digestive tract, provided the antimicrobial drugs used for selective decontamination are active against the endogenous potentially pathogenic microorganisms and given in sufficient (oral) doses.