Fungal Infections
In the first month following transplantation, lung transplant recipients are prone to bacterial pneumonias, secondary to mechanical ventilation; infection harbored in the donor lung and other postoperative nosocomial sources. Opportunistic infections occurring in this early post-transplant period suggest excessive exposure, such as Aspergillus infection encountered during hospital construction, and should prompt environmental analysis. In the period 1 to 6 months following transplantation, infections primarily arise from modulating viruses such as cytomegalovirus and less frequently from Epstein-Barr virus. These viral agents are thought to contribute to the net state of immunosuppression and may play a role in opportunistic superinfection by other organisms such as fungi, Pneumocystis, Nocardia, and Legionella. In the late time period, ie, greater than 6 months following transplantation, the etiologic infectious pathogens relate to the degree of immunosuppression at that time point. Patients, who are free of acute and chronic graft rejection, and are maintained on relatively low levels of immunosuppressive medications are prone to typical community-acquired infections, while those patients experiencing recurrent acute or chronic rejection requiring augmented immunosuppression are prone to similar opportunistic infections as outlined above. In addition, patients with obliterative bronchiolitis are particularly susceptible to infection with Gram-negative bacterial organisms.
Fungal infections account for approximately 15% of infections encountered in lung transplant recipients, but carry the highest mortality of all infectious agents. In comparison to other solid-organ transplants, lung transplant recipients have a significantly higher incidence of fungal infection.5,6 In one study conducted at a single institution, the incidence of fungal infections in lung vs heart transplant recipients was 22% and 5%, respectively. In recipients of lung transplants the prevalence of fungal infections ranged from 10 to 35%, with mortality directly due to fungal infection reported to be 8.7%, and an overall associated mortality with fungal infection ranging from 40 to 70%.5,7 The reasons for the high mortality from fungal infections in solid-organ transplant recipients include difficulty in early diagnosis, lack of effective antifungal therapy, interactions of antifungal drugs with immunosuppressant agents, and unclear data on antifungal prophylaxis.
Both opportunistic and endemic fungal infections may be encountered following lung transplantation. The majority of fungal infections are caused by Aspergillus and Candida species, and the vast majority originate in the allograft. Aspergillus is perhaps the most devastating and one of the most common fungal infections in lung transplant recipients.
At least one study has attempted to analyze risk factors for acquiring Aspergillus infection in lung transplant patients. The authors analyzed rejection, degrees of immunosuppressive therapy, and cytomegalovirus pneumonia as potential risk factors for the development of aspergillosis. In this small study, only cytomegalovirus pneumonia emerged as a statistical risk factor for invasive aspergillosis.9 Neither rejection nor immunosuppression were found to be associated with the risk of invasive aspergillosis. Patients with CF are often colonized with bacterial and fungal organisms, particularly Aspergillus, in the bronchial tree and the sinuses.
Candidal infection is also frequently encountered in the lung transplant recipient primarily due to defects in cell immunity induced by immunosuppressive agents. Candida frequently colonizes the donor lung and can be transmitted at the time of transplantation. In addition, candidal infection is encountered frequently in patients with prolonged hospitalization subjected to antibiotic treatment and use of indwelling catheters, further compounded by immunosuppression.
Other opportunistic fungal infections including Cryptococcus, mucormycosis, infection with Scedosporium prolificans, and infection with Trichosporon bigelli have been described in lung transplant recipients. Cryptococcus has presented as localized pulmonary disease beginning in the allograft resulting in disseminated disease and was thought to be inhalationally acquired.Occasionally, infection with the endemic fungi such as coccidioidomycosis and histoplasmosis has been encountered. Despite the introduction of newer antifungal agents in recent years, amphotericin B remains the standard of treatment for all life-threatening fungal infections and the initial therapy for severe infections in immunocompromised patients.Amphotericin B is a polyene antifungal agent with action against a wide variety of fungal pathogens. The activity of the polyene antifungals depends on the inhibition of fungal cell wall synthesis because of its ability to bind to sterols, primarily ergosterol. Coincident binding to mammalian cell membranes is believed to be the basis of polyene toxicity in man, which has limited the intravenous dose to 1.0-1.5 g/kg/d. Amphotericin B should be considered the initial therapy of choice in the treatment of severe, invasive infections and in moderate-to-severe aspergillosis, coccidioidomycosis, cryptococcal meningitis (in combination with flucytosine), histoplasmosis, blastomycosis, paracoccidioidomycosis, and sporotrichosis infection. Despite the widespread use of fluconazole in patients with severe candidiasis or candidemia, there are few comparative trials proving its equivalence to amphotericin B. Fluconazole is less active against Candida glabrata and inactive against Candida krusei;24 therefore, we recommend the use of amphotericin in transplant patients with severe candidal infections until a germ-tube test is positive (Candida albicans). Although select Candida sp. (C lusitaniae and C guillermondii) demonstrate resistance to amphotericin B, most of these isolates have been from mucocutaneous sites or urine and have not been associated with deep-seated infection.25 Pseudallescheria boydii and phaeohyphomycosis (black molds) are rare opportunistic fungi that also demonstrate resistance to amphotericin B. Infection with these organisms may respond to itraconazole therapy in combination with surgery. (Source: By Stephanie M. Levine, MD, FCCP; and Jay I. Peters, MD, FCCP )
First-line use of voriconazole yields better outcomes and cost savings for life-threatening fungal infection
San Antonio (Sept. 16, 2003) Data presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) showed that the antifungal treatment voriconazole, a second-generation triazole, is more effective and less costly than the standard of care for invasive aspergillosis when used as first-line therapy (Posters M-964 and A-1359). Results from global studies were presented by The University of Texas Health Science Center at San Antonio (UTHSCSA) researchers, Thomas F. Patterson, M.D., professor of medicine, and James Lewis, Pharm.D., infectious diseases pharmacy specialist. "For patients whose immune systems are compromised by cancer chemotherapy or organ and bone marrow transplants, invasive aspergillosis can be fatal," said Dr. Patterson. "Physicians need to understand that the type of therapy selected for first line impacts the patient's chance of survival. These studies showed that patients initially treated with voriconazole had better outcomes and incurred fewer antifungal drug costs than patients treated initially with the prior 'gold standard therapy' amphotericin B." Enhancing Patient OutcomeDr. Patterson and other investigators assessed how initial therapy with voriconazole impacts ultimate outcomes compared to amphotericin B. This analysis was done with data from a previously published clinical trial (Herbrecht, NEJM, 2002) that compared voriconazole to standard therapy with amphotericin B. The study (Poster M-964) assessed 277 patients who were randomized to either voriconazole or amphotericin B and treated for up to 12 weeks. The results showed that initial treatment with voriconazole led to significantly better outcomes for patients compared to those treated initially with amphotericin B. Overall, voriconazole patients had a 53 percent success rate as compared to success in 32 percent of patients on amphotericin B. Notably success occurred in only 23 percent who were switched from amphotericin B for intolerance or progressive infection, suggesting the importance of effective initial antifungal therapy. In addition, significantly fewer voriconazole patients required other licensed antifungal therapy (OLAT). Thirty-six percent of voriconazole patients received OLAT following initial treatment compared to 80 percent taking amphotericin B. Seventy percent of amphotericin B patients switched therapies due to intolerance or insufficient response while only 24 percent of patients on voriconazole switched therapies. Healthcare Cost SavingsAs the treatment of invasive aspergillosis requires prolonged therapy and can be expensive, Dr. Lewis and other investigators analyzed data from the Herbrecht trial to evaluate "real-life" antifungal costs for aspergillosis therapy. The study (Poster A-1359) accounted for current drug acquisition costs of primary therapy, intravenous to oral switch in primary therapy, and the types and duration of OLAT. The data showed that initial therapy with voriconazole resulted in significantly reduced drug costs when compared to the treatment with conventional amphotericin B. Overall per patient cost was $722 less for patients receiving voriconazole than those randomized to initial therapy with amphotericin B due to the fact that patients initially receiving amphotericin B required other licensed antifungal therapy. At the end of 12 weeks, total drug costs for patients randomized to voriconazole were $783,184 compared to $826,005 for patients initially treated with amphotericin B. Total drug cost per positive outcome (treatment success) was $10,305 for voriconazole and $19,667 for amphotericin B. "The cost of antifungal therapy must include both the total drug costs as well as the potential for a positive outcome," said Dr. Lewis. "The reduced drug cost seen in the study is influenced by the improved efficacy and tolerability of voriconazole when compared to other therapies." About Invasive AspergillosisInvasive aspergillosis is a severe pulmonary infection usually accompanied by chest pain, fever and coughing. The infection can spread throughout the body and can settle in numerous organs, including the brain. If left untreated, invasive aspergillosis can kill within a matter of days. Invasive aspergillosis is caused by the fungus Aspergillus fumigatus, a ubiquitous fungus found in everything from water to dust to dirt. For healthy patients, aspergillosis has little effect, but for those whose immune system is compromised, the fungus could be deadly. The overall mortality rate for invasive aspergillosis in immunocompromised patients is estimated to be 58 percent, but approaches 90-100 percent in patients with disseminated infection. About VoriconazoleVoriconazole is a treatment for progressive, potentially life-threatening and serious fungal infections marketed by Pfizer Inc. Vfend is indicated for the primary treatment of invasive aspergillosis and for infections caused by Fusarium and Scedosporium apiospermum in patients who are intolerant of or don't respond to other therapy. Voriconazole is available in both IV and oral formulations. (Source: UTHSCSA The University of Texas Health Science Center at San Antonio)
