Fungal infections during Neutropenia: The Role of Prophylaxis

Summary: Fungal infections are seen predominantly in patients with neoplastic diseases. Autopsy studies revealed that 30 to 50% of deceased patients with hematologic neoplasmas have histopathologically documented invasive fungal infections. The rationale for fungal chemoprophylaxis is the high incidence of fungal disease in these patients (3), the high mortality (29), the difficulty in diagnosing (28), and the severe side effects of systemic antifungal therapy with amphotericin B (3). Endogenous sources such as oropharyngeal and digestive mucous membranes and exogenous pathways such as air (e.g. aspergilli) or food have to be considered. Therefore, prophylaxis has to comprise both aspects: Prevention of acquisition through nonspecific hygiene measures (5), reduction of colonization (non-absorbable antifungals or systemic chemoprophylaxis) (20). Antifungal prophylaxis of candidosis with both non- and absorbable drugs has not been convincing in terms of reduction of proven fungal infections. Prevention of aspergillosis consists mainly of the control of room air.     

Risks Involved in Selective Decontamination in Immunocompromised Patients.

Summary: Selective oral and systemic decontamination are widely discussed when it comes to the prophylaxis of bacterial and fungal infections in immunocompromised patients. The number of such patients is clearly rising due to the aggressiveness of modern medicine. Host defence is based on a variety of factors including the barrier function of mucosal surfaces as well as the phagocytic system provided by the blood. It seems helpful to distinguish between three different stages of immunodeficiency: "Minor immunodeficiency", "immunodeficiency" (in a stricter sense), "major immunodeficiency". When it comes to the choice of measures to be taken to protect the host, it is not only needed to consider the microbes already present but also the present state of defence mechanisms. When invasive fungal infections in particular have to be prevented, several drugs have to be discussed, As conventional antifun-gals have not met all expectations there is clear need for new drugs such as itraconazole.     

Epidemiology of invasive fungal infections and rationale for antifungal therapy in patients with haematological malignancies

Invasive fungal infections (IFIs) in patients with haematological malignancies are difficult to diagnose and outcome is often fatal. Over the 7‐month study period, 117 cases with haematological malignancies receiving systemic antifungal treatment were included. Data regarding antifungal agents, dosage and reason for administration were recorded. Fungal infections in study patients were classified as possible, probable or proven according to recent European Organization for Research and Treatment of Cancer criteria. During the study period, 690 cases with haematological malignancies were admitted. A total of 117 cases received systemic antifungal therapy. Twenty‐four of 117 patients (21%) had possible, six (5.1%) had probable and four (3.4%) had proven IFI. Seven of 10 probable and proven infections were caused by Candida spp., 2 by Aspergillus spp. and 1 by a fungus belonging to Zygomycetes. Fifty‐two of 117 patients (44%) received antifungal prophylaxis, 81 of 117 (69%) received empirical (31/117; 26%) or pre‐emptive (50/117; 43%) antifungal therapy and four of 117 patients (3.4%) directed antifungal therapy. Mostly, systemic antifungal therapy was administered empirically or pre‐emptively. Twenty‐nine per cent of cases receiving systemic antifungal treatment met the international consensus criteria of mostly possible IFI, whereas 71% did not. Proven invasive fungal infections were rare.     

Prophylactic action of oral fluconazole against fungal infection in neutropenic patients. A meta-analysis of 16 randomized, controlled trials

BACKGROUND: Fluconazole is used widely for fungal prophylaxis. Although studies with bone marrow transplantation (BMT) recipients clearly showed the usefulness of oral fluconazole, results of the studies in neutropenic patients other than BMT recipients have been inconsistent. Therefore, the authors performed a meta-analysis to evaluate the efficacy of fluconazole prophylaxis during chemotherapy-induced neutropenia. METHODS: The authors identified reports that were not restricted to those in English and not restricted to published trials through MEDLINE, CANCERLIT, or the data base of the Pfizer company. The authors included prospective, randomized studies comparing oral fluconazole with placebo, no treatment, or oral polyenes as prophylaxis for fungal infections in neutropenic patients. Two independent authors extracted data from 16 trials with 3734 patients enrolled. The outcome measures were the development of fungal-related death, systemic and superficial fungal infections, the use of empiric intravenous amphotericin-B, and infections or colonization with fluconazole-resistant fungi. The summarized odds ratios (ORs) were calculated using the Mantel-Haenszel method and the DerSimonian-Laird method. RESULTS: Prophylactic fluconazole was not effective in reducing fungal-related death or in reducing proven, systemic fungal infections in non-BMT patients (OR, 0.91; 95% confidence interval [CI], 0.30-2.82 and OR, 0.85; 95% CI, 0.47-1.55, respectively). However, fluconazole was very effective in reducing superficial fungal infections (OR, 0.44; 95% CI, 0.24-0.80), even when it was given in lower doses (50-200 mg per day). There was no increase in proven, systemic infection of fluconazole-resistant fungi, although colonization of those fungi increased. When the results were combined in studies in which the incidence of systemic fungal infections was > 15%, fluconazole was effective in reducing such infections (OR, 0.23; 95% CI, 0.15-0.36). CONCLUSIONS: The current analyses failed to find an effect of fluconazole on both fatal fungal infection and systemic fungal infection in non-BMT patients. Further studies on severely neutropenic patients are warranted because prophylactic fluconazole seemed to be effective when the incidence of systemic fungal infection was expected to be > 15%.     

Invasive cutaneous fungal infections requiring radical resection in cancer patients undergoing chemotherapy

Invasive fungal infections have emerged as a significant problem in patients with cancer with the development of better systemic therapies for malignancy and more effective antibacterial agents. The currently available world published medical literature was reviewed on invasive fungal infections in cancer patients with specific attention devoted to the multidisciplinary role of surgery in refractory cutaneous cases. Infections can develop on the forearm where peripheral intravenous catheters had been inserted in cancer patients undergoing cytotoxic chemotherapy. Curative intent begins with systemic contemporary anti-fungal therapy. Following resolution of neutropenia, patients may require radical surgical debridement with negative margins of resection for complete eradication of the fungal infection. Although invasive fungal infections refractory to antifungal systemic therapy in immunocompromised patients undergoing chemotherapy are a rare event, it is critical for surgeons and other multidisciplinary clinicians to recognize these potentially life-threatening infections that may necessitate radical surgical resection for cure.     

Assessing risk factors for systemic fungal infections

The incidence of invasive fungal infection has increased in recent years. Most infections are caused by Candida albicans and Aspergillus spp. but the emergence of other fungal infections is changing the spectrum of disease. Immunosuppression and breakdown of anatomical barriers such as the skin are the major risk factors for fungal infections. Health care workers encounter at-risk patients in various settings, including AIDS clinics and intensive care, transplantation and oncology units. Patients with prolonged and deep neutropenia (haematological malignancy patients) are most at risk and are therefore most likely to receive prophylactic therapy. Practical measures can be taken to avoid exposing the patient to fungi (air filtration, regular hand washing, avoiding plants and flowers) and antifungal agents can be administered to prevent systemic fungal infection. Most fungal infections have non-specific symptoms; this makes recognition of the signs and symptoms of the disease important but also makes diagnosis difficult and empirical treatment necessary. Some antifungal agents have limitations but new formulations will improve therapy and play a key role in future antifungal strategies.     

Filamentous fungal infections of the cornea: a global overview of epidemiology and drug sensitivity

Fungal keratitis is a serious suppurative, usually ulcerative corneal infection which may result in blindness or reduced vision. Epidemiological studies indicate that the occurrence of fungal keratitis is higher in warm, humid regions with agricultural economy. The most frequent filamentous fungal genera among the causal agents are Fusarium, Aspergillus and Curvularia. A more successful therapy of fungal keratitis relies on precise identification of the pathogen to the species level using molecular tools. As the sequence analysis of the internal transcribed spacer (ITS) region of the ribosomal RNA gene cluster (rDNA) is not discriminative enough to reveal a species‐level diagnosis for several filamentous fungal species highly relevant in keratitis infections, analysis of other loci is also required for an exact diagnosis. Molecular identifications may also reveal the involvement of fungal species which were not previously reported from corneal infections. The routinely applied chemotherapy of fungal keratitis is based on the topical and systemic administration of polyenes and azole compounds. Antifungal susceptibility testing of the causal agents is of special importance due to the emergence and spread of resistance. Testing the applicability of further available antifungals and screening for new, potential compounds for the therapy of fungal keratitis are of highlighted interest.     

Terbinafine: broad new spectrum of indications in several subcutaneous and systemic and parasitic diseases

Immunocompromised patients are at risk of contracting serious fungal infections. The emergence of acquired resistance to azole treatment by opportunistic fungal organisms is increasing and poses a major therapeutic challenge. Treatment of some deep cutaneous and subcutaneous mycoses remains unresolved, relapses are frequent, lack of tolerability of the antifungal drugs becomes an obstacle, and, unfortunately, surgery is, in some cases, the last option. The development of allylamine antifungals, of which terbinafine is the most effective to date, may help to resolve this situation. In vitro, terbinafine is highly active against a broad spectrum of pathogenic fungi. Clinical studies have shown that terbinafine is effective in the treatment of both cutaneous and lymphocutaneous sporotrichosis, and in several patterns of disseminated and refractory aspergillosis. Patients with chromoblastomycosis, and other mycoses (phaeohyphomycosis, maduromycosis, and mucormycosis) have also been successfully treated with terbinafine. Old World cutaneous leishmaniasis, a parasitic disease, has also been treated with terbinafine. These results suggest that the therapeutic potential of terbinafine extends well beyond its currently licensed applications to include a range of serious and life-threatening subcutaneous and systemic mycoses.     

Itraconazole — a potent antifungal drug

Itraconazole is an orally active triazole antifungal drug which has demonstrated a broad spectrum of activity and a favourable pharmacokinetic profile. It is a potent inhibitor of most human fungal pathogens including Aspergillus species. In non comparable clinical trials, Itraconazole was shown to be extremely effective in a wide range of superficial and more serious deep fungal infections when administered once or twice daily. Preliminary findings also indicate that itraconazole, may hold promise for the prophylaxis of opportunistic fungal infections in patients at risk, i.e. women with recurrent vaginal candidiasis, AIDS patients and patients receiving immunosuppressant drugs.     

Candida infections in newborns: a review

Despite adequate treatment, nosocomial fungal infections have become an increasingly important cause of morbidity, extended hospitalization, and mortality in critically ill newborn babies. Furthermore, the high incidence of central nervous system involvement in septic newborns frequently results in serious neurological damage and psychomotorial sequelae. The prevention of fungal colonization in the population at risk, together with prompt diagnosis and treatment, are an efficient combination which lead to a better outcome of neonatal fungal infections. New drugs characterized by great efficacy and tolerance have recently been employed in clinical practice. This article summarizes certain aspects of Candida spp. infections in the neonatal period with regard to multisystemic presentation and involvement.     

Fungal infection models: Current progress of ex vivo methods

Experimental alternative ex vivo models that simulate infectious processes in vivo are of fundamental importance for the evaluation of new drugs, since in some cases, their execution does not depend on the approval of an ethics committee in research. Although studies using alternative infectious models to evaluate the efficacy of antifungal molecules have been increasingly described and reported, there is no critical consensus that establishes the most appropriate ones regarding the type of infection. Numerous studies contemplate ex vivo protocols of fungal infections on nails, corneas, dentinal tubules and skin and reveal counterpoints and concordances not yet finely confronted. In this minireview, we propose a critical analysis of the main ex vivo models of fungal infections for the evaluation of new antifungal candidates for both topical and systemic use, as opposed to the advantages and disadvantages of the traditional in vivo models employed in preclinical research.     

In Vitro Effects of Ampicillin,Ciprofloxacin and Ofloxacin on Salmonella typhi within Human Monocyte-Derived Macrophages

Abstract

The incidence of invasive fungal infections (IFIs) caused by both common and uncommon opportunistic fungi is increasing along with emerging fungal resistance. Since traditional agents (amphotericin B, fluconazole, itraconazole) are limited by an inade-quate spectrum of activity, drug resistance or toxicity, there is a great interest in the development of new antifungal agents for treatment of IFIs in high-risk populations. In recent years a number of systemic antifungal drugs have become available and options for treatment of IFIs have expanded. A new generation of triazole agents (voriconazole, posaconazole, isavuconazole, ravuconazole and albaconazole), with a broad spectrum of activity and sufficient improvements in potency to overcome resistance have emerged and represent an alternative to conventional antifungals for the prevention and treatment of IFIs. This article focuses on the microbiology, pharmacology, clinical efficacy and safety of the new antifungal triazole generation.     

Intra-abdominal mycoses

The incidence of invasive mycoses in patients undergoing abdominal surgery amounts to approximately 8% and shows an upward trend in epidemiological studies. The lethality of these systemic mycoses, which are mostly based on Candida infections constitutes up to 60%. The development of a sytemic mycosis is marked by exogenic, endogenic and iatrogenic risk factors and typically displays tissue invasion after an initial fungal contamination or systemic dissemination via fungal sepsis. Fungal peritonitis is generally a monoinfection with Candida spp., where Candida albicans outweighs in 70% of cases. Aspergillus spp. are only detected abdominally in rare cases. The histological verification of a fungal invasion is regarded as proof of the existence of an invasive mycosis, but typical macroscopic findings with corresponding cultural findings can also confirm the diagnosis. Systemic mycosis requires an early initiation of a consistent antimycotic therapy as well as definitive surgical eradication of the focus in order to reduce high lethal rate. Resistances or incorrect dosages can be validated objectively by means of histological monitoring of the antimycotic therapy, thus affording early recognition of the need to change the substance class.     

Susceptibility to Melaleuca alternifolia (tea tree) oil of yeasts isolated from the mouths of patients with advanced cancer

Yeasts that are resistant to azole antifungal drugs are increasingly isolated from the mouths of cancer patients suffering from oral fungal infections. Tea tree oil is an agent possessing antimicrobial properties that may prove useful in the prevention and management of infections caused by these organisms. In this study, 301 yeasts isolated from the mouths of 199 patients suffering from advanced cancer were examined by an in vitro agar dilution assay for susceptibility to tea tree oil. All of the isolates tested were susceptible, including 41 that were known to be resistant to both fluconazole and itraconazole. Clinical studies of tea tree oil as an agent for the prevention and treatment of oral fungal infections in immunocompromised patients merit consideration.     

Candida Infections in Newborns: a Review

Abstract

Despite adequate treatment, nosocomial fungal infections have become an increasingly important cause of morbidity, extended hospitalization, and mortality in critically ill newborn babies. Furthermore, the high incidence of central nervous system involvement in septic newborns frequently results in serious neurological damage and psychomotorial sequelae.

The prevention of fungal colonization in the population at risk, together with prompt diagnosis and treatment, are an efficient combination which lead to a better outcome of neonatal fungal infections.

New drugs characterized by great efficacy and tolerance have recently been employed in clinical practice.

This article summarizes certain aspects of Candida spp. infections in the neonatal period with regard to multisystemic presentation and involvement.     

A randomized trial comparing ketoconazole and nystatin prophylactic therapy in neutropenic patients

A randomized trial was conducted comparing ketoconazole and nystatin in the prevention of oral candidiasis and appearance of invasive fungal infections in 51 neutropenic leukemic patients undergoing induction chemotherapy. Ketoconazole was administered in a 200 mg dose twice daily. Nystatin oral suspension was given in doses of 500,000 units four times daily. Surveillance cultures of the throat and urine were obtained prior to treatment and conducted weekly. Patients were enrolled in the study if the absolute granulocyte count was less than 1500/microliter, if physical examination revealed no evidence of oral candidiasis, no evidence of urinary tract infection, and there was no pulmonary infiltrate on chest x-ray. Patients were continued on study until the absolute granulocyte count reached 1500/microliter, evidence of oral candidiasis appeared, or presumed or proven invasive fungal infections appeared. Of the 46 evaluable patients, 22 received ketoconazole, 3 (14%) developed oral candidiasis, and 5 developed suspected systemic fungal infections (23%). Of 24 patients who received nystatin, 4 (17%) developed oral candidiasis and 8 (33%) developed systemic fungal infections, 4 proven and 4 suspected. Significantly more patients on the nystatin arm progressed to invasive fungal infections. Ketoconazole was not superior to nystatin in reducing the frequency of oral candidiasis but possibly reduced the frequency of invasive fungal infections.     

Update in the epidemiology, prophylaxis, and treatment of fungal infections in patients with hematologic disorders

Invasive fungal infections contribute to the morbidity and mortality of immunosuppressed patients treated for hematologic malignancy and those undergoing hematopoietic cell transplantation. After years of limited advances, the management of fungal infections in these patients is now rapidly evolving. In this update, we will outline changes in the epidemiology of invasive fungal infections, discuss current issues in diagnosis and susceptibility testing, and review the current classes of antifungal drugs, focusing on newly licensed therapies. Data on antifungal prophylaxis, empiric therapy, and treatment of documented invasive fungal infections including single agents and combinations with newly licensed agents will be reviewed with emphasis on their impact on patients with hematologic malignancies.     

Our 2014 approach to breakthrough invasive fungal infections

Evidence‐based clinical pathways to direct antifungal treatment options in patients with breakthrough fungal infections during current systemic antifungal therapy are not available. Nonetheless, for defined settings of such breakthrough infections approaches to management can be recommended based on clinical, epidemiological, pharmacological and in vitro susceptibility data.     

Supportive care in marrow transplantation.

Marrow transplantation is now an accepted form of therapy for patients with aplastic anemia, genetic diseases, and a variety of malignant diseases. Intensive chemotherapy and radiotherapy regimens are necessary to eradicate cancer cells and allow engraftment of the transplanted marrow. Patients undergoing such treatment suffer prolonged marrow aplasia and immunosuppression and experience significant nonmarrow toxicities. This requires maximum supportive care including hyperalimentation, fluid and blood transfusions, antibacterial and antiviral prophylaxis, and measures to reduce organ toxicities and accelerate engraftment. The use of drugs to suppress the production of antitumor necrosis factor-alpha has shown promise in reducing the nonmarrow toxicities of the conditioning regimen. Prophylactic antibiotics that reduce gastrointestinal colonization with aerobic bacteria yet preserve anaerobic flora may more effectively reduce not only systemic bacteria but fungal infections as well. The impact of infections due to cytomegalovirus has been reduced by more effective prevention in patients who are cytomegalovirus negative and reactivation in patients who are cytomegalovirus positive. The use of recombinant growth factors will significantly reduce morbidity after transplantation by reducing the period of marrow aplasia.     

Complement and fungal pathogens: an update

Fungal infections are a serious complication in immunocompromised patients such as human immunodeficiency virus-infected individuals, patients with organ transplantations or with haematological neoplasia. The lethality of opportunistic fungal infection is high despite a growing arsenal of antimycotic drugs, implying the urgent need for supportive immunological therapies to strengthen the current inefficient antimicrobial defences of the immunocompromised host. Therefore, increasing effort has been directed to investigating the interplay between fungi and the host immunity and thus to find starting points for additional therapeutic approaches. In this article, we review the actual state of the art concerning the role of complement in the pathogenesis of fungal infections. Important aspects include the activation of the complement system by the fungal pathogen, the efficiency of the complement-associated antimicrobial functions and the arsenal of immune evasion strategies applied by the fungi. The twin functions of complement as an interactive player of the innate immunity and at the same time as a modulator of the adaptive immunity make this defence weapon a particularly interesting therapeutic candidate to mobilise a more effective immune response and to strengthen in one fell swoop a broad spectrum of different immune reactions. However, we also mention the 'Yin-Yang' nature of the complement system in fungal infections, as growing evidence assigns to complement a contributory part in the pathogenesis of fungus-induced allergic manifestations.