Fungal infections of the CNS: treatment strategies for the immunocompromised patient

Infections with fungi cause significant morbidity in the immunocompromised host and invasion of the CNS may lead to devastating consequences. Vulnerable individuals include those with haematological malignancies, transplant recipients, and those infected with HIV. Potential pathogens include yeasts, Aspergillus spp., other moulds of an increasing variety, and a range of dimorphic fungi, often associated with particular geographical locations. Antifungal treatments include polyenes such as amphotericin B and its lipid formulations, azoles such as fluconazole and itraconazole, and the more recent voriconazole and posaconazole. The new antifungal class of echinocandins, such as caspofungin, micafungin and anidulafungin, typically lack CNS penetration. Amphotericin B and flucytosine are used to initiate treatment for CNS yeast infections caused by Candida and Cryptococcus neoformans. Voriconazole is preferred for aspergillus, although amphotericin B, particularly in lipid formulation, is also useful. Reliable treatment data are lacking for CNS infections with most of the non-aspergillus moulds; posaconazole holds promise for the zygomycetes and perhaps some of the rarer pigmented fungi, but amphotericin B preparations are still recommended. Oral fluconazole is effective for the CNS manifestations of coccidioides, while histoplasmosis and blastomycoses typically require amphotericin B therapy. Effective treatment requires a definitive diagnosis, which is often challenging in the population at risk of CNS fungal infections.     

Amphotericin B lipid complex in the management of invasive fungal infections in immunocompromised patients

Invasive fungal infections are associated with a poor outcome and their incidence is rising. Amphotericin B has for a long time been the gold standard for treatment of these infections, but the conventional formulation is associated with a high incidence of adverse events. Lipid formulations of amphotericin, developed to overcome these drawbacks, are now routinely used in clinical practice for the treatment of invasive fungal infections in immunocompromised patients. Amphotericin B lipid complex (ABLC) is prepared from amphotericin complexed to two phospholipids, a process that confers a number of important pharmacodynamic and pharmacokinetic properties compared with conventional amphotericin B. The results of retrospective observational studies and the analysis of databases, including the large Collaborative Exchange of Antifungal Research (CLEAR) database, have shown ABLC to be associated with response rates of up to about 80% in patients with confirmed fungal infections and around 60% in those treated empirically. Intranasal administration of ABLC for prophylaxis of invasive fungal infection in immunocompromised patients is safe and appears to be a promising treatment strategy for the future. ABLC is associated with a substantially lower incidence of nephrotoxicity than conventional amphotericin. Infusion-related reactions also occur less frequently than with conventional amphotericin and can be managed using premedication protocols. When direct and indirect costs are measured, ABLC appears to be less expensive than conventional amphotericin. The number of approved antifungal agents that are effective treatments for invasive fungal infections is increasing. However, lipid formulations of amphotericin, such as ABLC, are effective and well tolerated and remain the standard of care in the treatment of invasive fungal infections. Treatment strategies such as intranasal administration for prophylaxis and combination therapy with newer agents are future directions for these agents.     

Current strategies for the treatment of complicated intraabdominal infections

Introduction: Complicated intraabdominal infections (cIAIs) are a common cause of infection-related morbidity and mortality in hospitalized patients and present many challenges unique from other serious infections. cIAIs are generally polymicrobial in nature; however, controversy exists around the pathogenicity of some of the frequently identified microorganisms. Increasing antibiotic resistance among commonly isolated bacteria poses further challenges for clinicians managing patients with cIAIs.

Areas covered: This article highlights the microbiology and recent trends in antibiotic resistance most relevant to cIAIs, provides recommendations for treatment using currently available antimicrobials and introduces antibiotics in development with potential roles in managing cIAIs.

Expert opinion: Successful treatment of cIAI requires a combination of timely source control and thorough assessment of patient characteristics to guide selection of an appropriate empiric antimicrobial regimen. Specific considerations that should be made when choosing antibiotics include the origin of infection, presence of risk factors for potentially resistant pathogens and severity of disease. While it is encouraging that agents in development may prove helpful in the treatment of cIAIs with resistant pathogens, further identification of novel antibiotics is needed to address this growing concern. In addition, adherence to the principles of antimicrobial stewardship is needed if current antimicrobial resources are to be preserved for the treatment of cIAIs.     

Treatment strategies for Aspergillus infections

Infections caused by Aspergillus species consist of many different disease presentations, ranging from relatively benign asthma in atopic disease to life-threatening systemic invasive infections. The spectrum of disease manifestations is determined by a combination of genetic predisposition, host immune system defects, and virulence of theAspergillus species. For the purposes of this discussion, we will address three principal entities: invasive aspergillosis, both primary and disseminated, pulmonary aspergilloma, and allergic bronchopulmonary aspergillosis. Amphotericin B is the standard of treatment for severe Aspergillus infections, despite the fact that mortality in these patients remains high. Alternative therapies such as combination regimens and itraconazole also have efficacy against Aspergillus infections. We discuss the role of current therapies, the potential role of drugs in development, and the results of ongoing research with combination and immunotherapies.     

Therapeutic strategies for invasive fungal infections in neonatal and pediatric patients

Invasive Candida and Aspergillus infections are the most commonly encountered fungal infections. They appear to be life threatening in the setting of profound immunosuppression, whereas cases that are resistant to antifungal therapy are occasionally encountered. Novel antifungal triazole and echinocandin agents appear to exhibit good activity as first-line or salvage therapy, whereas the use of amphotericin B formulations is particularly valuable in neonates. Significant differences in toxicity have been demonstrated among various antifungal agents with in vitro activity from available comparative data on fungal infections in children: however, no clear difference in treatment efficacy has been demonstrated. However, very little data are available about neonates. Host factors and responsible fungal species most frequently guide the choice of therapy.     

Treatment of invasive candidiasis in immunocompromised pediatric patients

In the last 3 decades, systemic candidiasis has become increasingly recognized as a major source of morbidity and mortality in immunocompromised pediatric patients. As the number of children receiving chemotherapy and bone marrow transplantations continue to increase, clinicians should expect that invasive infections from Candida spp. will also increase in these vulnerable hosts. Fortunately, in the past 15 years, the evolution of older antifungals coupled with the discovery of new classes of antifungal agents has equipped physicians with reasonable options for treating these otherwise life-threatening infections.This review aims to familiarize the reader with the evolving epidemiology of candidiasis in immunocompromised children as well as discuss therapeutic options from each class of antifungal agents. Mechanisms of action, pharmacokinetics, toxicities, resistance patterns, chemotherapy interactions, and clinical relevance in immunocompromised children are reviewed for polyenes, flucytosine (5-fluorocytosine), azoles, and echinocandins.     

Role of cidofovir in the treatment of DNA virus infections,other than CMV infections,in immunocompromised patients

Cidofovir is a nucleotide analog marketed for the treatment of human cytomegalovirus infections in immunocompromised patients. An increasing number of reports have appeared on the use of cidofovir for the treatment of other severe DNA virus infections in immunocompromised patients. The activity of cidofovir against herpes simplex viruses resistant to classic (acyclovir and/or foscavir) therapy has been widely documented. Cidofovir has also been used for the treatment of other herpesvirus infections, such as drug-resistant varicella-zoster virus, and Epstein-Barr virus-induced proliferative diseases. For papillomavirus infections, cidofovir represents a valuable alternative to the conventional therapies, which are mostly based on surgery, as in the treatment of laryngeal papillomatosis. The role of cidofovir in the treatment of polyomavirus infections is more controversial, but here too, cidofovir represents, to date, the only available efficacious therapeutic modality. Cidofovir has demonstrated activity against all poxviruses and represents a unique therapeutic modality for use against these viruses, particularly in the immunosuppressed host, should this prove necessary (eg, in a bioterrorism scenario).     

The Nationwide Austrian Aspergillus Registry: a prospective data collection on epidemiology, therapy and outcome of invasive mould infections in immunocompromised and/or immunosuppressed patients

A prospective, observational, multicentre study was performed to assess the incidence, diagnosis, epidemiology and outcome of invasive mould infections (IMIs) reported to the Nationwide Austrian Aspergillus Registry. In total, 186 cases were recorded, corresponding to an annual incidence of 42 cases/1000 patients at risk or 2.36 cases/100000 inhabitants. Patients with acute myelogenous leukaemia (34%) and lung transplant recipients (17%) are currently at highest risk for IMI, followed by a mixed population with impaired immunity (14%). In total, 34%, 30% and 36% were proven, probable and possible cases of IMI. Predominant pathogens were Aspergillus spp. (67%), followed by the zygomycetes (28%). Voriconazole was the most frequently administered agent (38%), followed by caspofungin (20%) and posaconazole (19%). Eighty patients (43%) received antifungal prophylaxis for ≥7 days, 30% of whom (24 patients) suffered from a breakthrough infection. The overall crude 12-week mortality was 34%. Multivariate analysis showed that outcome and survival did not correlate with the status of fungal disease, breakthrough infection, fungal species or age (P>0.05). Aspergillosis remains the most commonly identified IMI amongst immunocompromised and/or immunosuppressed patients, but other moulds constitute a significant problem. Survival from IMIs appears to have improved and the main challenge is to overcome breakthrough fungal infections.     

Cytomegalovirus treatment options in immunocompromised patients

Cytomegalovirus (CMV) infection was recognised in congenitally infected infants in the first half of the 20th century. Following the increased use of immunosuppressive regimens for bone marrow and solid organ transplantation, various manifestations of CMV disease were recognised. Milder symptoms included fever, anorexia and malaise but severe symptoms included pneumonitis, hepatitis, gastrointestinal ulceration, choreoretinitis and encephalopathy, all with a high morbidity or mortality. With the onset of the AIDS epidemic, manifestations of CMV became evident, predominantly retinitis. Ganciclovir used intravenously has been the principal anti-CMV agent investigated. However, ganciclovir has problems with suboptimal efficacy, toxicity, poor oral bioavailability and evolution of resistant strains. Additional studies have been performed on foscarnet and cidofovir, although the use of both have been limited by their nephrotoxicity. Combination therapy with ganciclovir and foscarnet for resistant strains has been used. There are promising newer drugs like the methylenecyclopropane nucleoside analogues and benzimidazole. The most novel compound is the antisense oligonucleotide fomivirsen that has been evaluated principally in CMV retinitis. The role of immunotherapy with either immunoglobulin prophylaxis or the novel adoptive immunotherapy needs further evaluation.     

Cytomegalovirus treatment options in immunocompromised patients

Cytomegalovirus (CMV) infection was recognised in congenitally infected infants in the first half of the 20th century. Following the increased use of immunosuppressive regimens for bone marrow and solid organ transplantation, various manifestations of CMV disease were recognised. Milder symptoms included fever, anorexia and malaise but severe symptoms included pneumonitis, hepatitis, gastrointestinal ulceration, choreoretinitis and encephalopathy, all with a high morbidity or mortality. With the onset of the AIDS epidemic, manifestations of CMV became evident, predominantly retinitis. Ganciclovir used intravenously has been the principal anti-CMV agent investigated. However, ganciclovir has problems with suboptimal efficacy, toxicity, poor oral bioavailability and evolution of resistant strains. Additional studies have been performed on foscarnet and cidofovir, although the use of both have been limited by their nephrotoxicity. Combination therapy with ganciclovir and foscarnet for resistant strains has been used. There are promising newer drugs like the methylenecyclopropane nucleoside analogues and benzimidazole. The most novel compound is the antisense oligonucleotide fomivirsen that has been evaluated principally in CMV retinitis. The role of immunotherapy with either immunoglobulin prophylaxis or the novel adoptive immunotherapy needs further evaluation.     

Respiratory infections in the immunocompromised patient

Damage to local and systemic defences of the lungs makes the immunocompromised host vulnerable to inhaled microorganisms. The type of underlying disease and its associated immunodeficiency allow a high degree of accurate pathogen prediction. Neutropenia is associated with Gram-negative bacilli pneumonia. Prolonged neutropenia increases the risk of aspergillosis and mucormycosis. Cellular immunodeficiency is associated with Pneumocystis carinii, Legionella spp. and intracellular parasites including Mycobacteria spp., Nocardia spp. Rhodococcus equi, cytomegalovirus, Strongylo?des stercoralis, Histoplasma capsulatum and Coccidioides immitis. Humoral immunodeficiency predisposes to infection with Streptococcus pneumoniae and Haemophilus influenzae. Chest computerized tomography scan and bronchoalveolar lavage are essential procedures for diagnosis. Successful therapy depends on the type of pathogen, status of host defence sand early adequate choice of antibiotics. Enhancement of host defences with growth factors, cytokines and interferons can ameliorate the outcome.     

Therapeutic strategies for invasive fungal infections in neonatal and pediatric patients: an update

Introduction: Invasive fungal infections (IFIs) in neonatal and pediatric patients are still associated with high morbidity and mortality, increased length of hospital stay and high healthcare cost. Two key components are prerequisite to combat pediatric IFIs; first, definition of the ‘at-risk’ populations that could benefit the most from prophylactic treatment and second, prompt initiation of effective antifungal therapy.

Areas covered: In this article, updated prevention and targeted therapeutic approaches for IFIs in neonates and immunocompromised children are reviewed. Furthermore, European and American guidelines concerning IFI treatment in neonates and children are compared.

Expert opinion: IFIs in neonates and children present substantial differences from adults in respect to their epidemiology, pharmacokinetics of antifungal agents and dosing as well as absence of interventional Phase III and IV clinical trials for guidance of evidence-based decisions. In the therapeutic armamentarium of these age groups, although amphotericin B formulations remain widely indicated, azoles with broader spectrum activity as well as echinocandins have been added in the updated antifungal treatment algorithm. Recent European guidelines (ESCMID and ECIL) contain specific recommendations for pediatric patients with IFIs. In both age groups, definitive updated guidance for prophylaxis and more importantly targeted treatment need to be further evaluated by large, multicenter, randomized controlled trials.     

Anthelmintics. Current concepts in the treatment of helminthic infections

This article discusses the anthelmintics now in common use and describes their mode of action and toxic side effects. The drugs reviewed include: pyrantel pamoate, mebendazole, piperazine, thiabendazole, niclosamide, praziquantel, niridazole, oxamniquine and diethylcarbamazine. Most of the common roundworm intestinal infections respond to treatment with pyrantel pamoate, which has the advantage of single-dose therapy. Trichuriasis requires therapy with mebendazole, while the filariases are treated with diethylcarbamazine. There is no specific therapy for trichinellosis, but its symptoms can be alleviated. Intestinal cestode infections respond to treatment with niclosamide and cerebral cysticercosis to praziquantel, but echinococcal hydatid disease still requires surgical intervention in certain cases, although prolonged treatment with mebendazole shows promise. The greatest recent advance in the therapy of helminthiases is the development of praziquantel which effectively treats the most severe of these infections.     

Laboratory diagnosis of infections in febrile neutropenic or immunocompromised patients

Laboratory diagnosis of infections in febrile neutropenic or immunocompromised patients is particularly challenging, and covers the most frequent clinical presentations such as bloodstream infections, lung, CNS and skin infections, as well as invasive fungal infections. Classic methods such as direct examination, culture and tests for susceptibility are being more complemented by molecular detection of microorganisms (PCR in particular) and antigen detection in various body fluids or tissues; two promising methods which offer the advantage of speed and high sensitivity even after starting antimicrobial therapy.     

Prophylaxis of herpesvirus infections in immunocompetent and immunocompromised older patients

In older patients, prophylaxis of herpesvirus infections mainly involves preventing the recurrence of herpes simplex virus (HSV) and complications of herpes zoster in immunocompetent patients, while in immunocompromised patients it is more concerned with the prevention of opportunistic virus reactivation. HSV ocular infection is the most frequent cause of corneal blindness in the US. The effectiveness of aciclovir 400mg twice daily in preventing the recurrence of HSV eye disease in immunocompetent patients has been well demonstrated. The issue of treatment duration for patients with highly recurrent ocular herpes remains unresolved. Post-herpetic neuralgia (PHN) is one of the most common neuralgic illnesses worldwide. Some progress in prevention of PHN has been made with a combination of antiviral therapy (famciclovir or valaciclovir), started within 72 hours of onset of the rash, and analgesic treatment. However, the best prevention of PHN is the prevention of herpes zoster disease, and the varicella vaccine is an option which over the next few years will be tested in clinical trials. For immunocompromised patients of any age, restoring immunity prevents herpesvirus disease, as demonstrated for cytomegalovirus (CMV) in AIDS patients receiving highly active antiretroviral therapy. Specific antiviral therapy during the initial period after transplantation could prevent reactivation of HSV or CMV in seropositive recipients. Whether pre-emptive therapy or prophylaxis with ganciclovir is the optimal approach against CMV remains controversial, and the relative merits and limitations of each approach may guide the choice. In stem cell transplantation, pre-emptive therapy with foscarnet avoids the neutropenia and related complications associated with ganciclovir. In renal transplant recipients, universal prophylaxis of CMV infection with valaciclovir has the same efficacy as ganciclovir. Although it is relatively toxic, cidofovir should be further evaluated because of its in vitro activity against most DNA viruses.     

Cytomegalovirus infections in non-immunocompromised and immunocompromised patients in the intensive care unit

Infection, inflammatory response, activation of coagulation cascade and sepsis are tightly interconnected. In the initial phase, sepsis is characterized by a pro-inflammatory state, while in the late phase, by an anti-inflammatory state which favors cytomegalovirus reactivation. Cytomegalovirus infection would accentuate the sepsis-induced immunologic effects increasing the risk for other infections. The rate of CMV infection is 17% in critically ill nonimmunocompromised patients, up to 30% in hematopoietic stem cell transplant and up to 60% in solid organ transplant recipients. Cytomegalovirus infection in critically ill patients is associated with prolonged ventilator support, nosocomial infections, prolonged hospital and/or ICU stay and increased mortality. In immunocompromised patients, cytomegalovirus causes direct effects (viral syndrome, pneumonia, meningo-encephalitis, and gastro-intestinal tract involvement) and indirect (immunomodulatory) effects. These indirect effects would predispose the patients to secondary infections, delay immune recovery after hematopoietic stem cell transplant, and increase the risk of EBV-related B-cell lymphoproliferative disease and allograft rejection. Cytomegalovirus serology is not useful for the diagnosis of active infections. Cytomegalovirus culture is impractical for clinical purposes. The shell vial assay has low sensitivity. pp65 antigen is a sensitive and specific diagnostic method. Real-time PCR is more sensitive and specific (earlier detection) than pp65 antigen test and it is a more reliable marker to monitor the clearance of viremia. Ganciclovir and valganciclovir are the first-line antiviral therapies for the treatment of immunocompromised patients, while foscarnet and cidofovir are reserved mainly for treatment of ganciclovir-resistant cytomegalovirus infections.     

Delivery strategies of amphotericin B for invasive fungal infections

Invasive fungal infections (IFIs) represent a growing public concern for clinicians to manage in many medical settings, with substantial associated morbidities and mortalities. Among many current therapeutic options for the treatment of IFIs, amphotericin B (AmB) is the most frequently used drug. AmB is considered as a first-line drug in the clinic that has strong antifungal activity and less resistance. In this review, we summarized the most promising research efforts on nanocarriers for AmB delivery and highlighted their efficacy and safety for treating IFIs. We have also discussed the mechanism of actions of AmB, rationale for treating IFIs, and recent advances in formulating AmB for clinical use. Finally, this review discusses some practical considerations and provides recommendations for future studies in applying AmB for combating IFIs.     

Prevention of fungal infections in the immunocompromised host

The incidence and severity of invasive fungal infections have significantly increased among immunocompromised hosts leading to excessive morbidity and mortality. Several preventative antifungal strategies (prophylaxis, empirical and pre-emptive) have been developed to improve the outcome of these infections. Although effective, these strategies are associated with toxicity, high cost and potential emergence of resistance. An alternative strategy, in the attempt to optimize the use of antifungal agents in preventing fungal infections, is a risk-adjusted approach based on the risk for, and severity of, infection in a given patient. This strategy has the potential to provide patients likely to suffer severe fungal infection the benefits of antifungal agents while avoiding the negative aspects (toxicity, cost and risk of resistance) in patients at low risk for these infections. In this review we focus on this strategy in cancer patients but it may also be applied to other immunocompromised hosts.     

Recent progress in the diagnosis of fungal infections in the immunocompromised host.

The management of invasive fungal infections has been hampered by the inability to diagnose the infection at an early stage of disease. Although proving the presence of infection by histology and culture remains the cornerstone of the diagnosis, non-culture based methods are becoming available that enable early detection. Molecular diagnosis by PCR appears very promising since fungal DNA can be detected in the blood of infected patients before conventional methods. Furthermore, a broad range of yeasts and molds can be identified to species level. Automation of sample preparation and use of real-time PCR systems will help standardize the procedure and reduce false positive results due to contamination. Promising assays for the detection of fungal antigens in serum have been commercialized, including detection systems for mannan (Candida) and galactomannan (Aspergillus). Circulating antigens can be detected at an early stage of infection, often before the onset of clinical symptoms. Antigen detection is limited to detecting only one genus and not enabling speciation. Furthermore, both PCR and antigen detection can be used to monitor the response of patients to treatment with anti-fungal agents. Although prospective screening of high-risk patients for the presence of circulating markers of fungal infection appears to be an appropriate strategy, studies are needed to help to establish the optimal approach to managing invasive fungal infections that incorporates the benefits of non-culture based methods.     

Selecting antifungal agents for the treatment of invasive fungal infections in patients with renal failure

The use of antifungal agents in patients with renal insufficiency requires careful consideration of not only the degree of renal insufficiency, but also other factors such as the fungal organism involved, site of infection and antifungal pharmacokinetics. Given the increase in the antifungal armamentarium, it is essential to have a comprehensive understanding of these agents to enable tailored therapy in this unique, but not uncommon patient population. This review will focus on the currently available data on this subject, providing guidelines for the use of antifungals in patients with renal failure.