Treatment Of Invasive Candidiasis Research Articles

The Role of Echinocandins in the Treatment of Invasive Candidiasis

The Role of Echinocandins in the Treatment of Invasive Candidiasis

Micafungin in the treatment of invasive candidiasis and invasive aspergillosis

Micafungin is an echinocandin antifungal agent available for clinical use in Japan, Europe, and the United States. Through inhibition of β-1,3-glucan production, an essential component of the fungal cell wall, micafungin exhibits potent antifungal activity against key pathogenic fungi, including Candida and Aspergillus species, while contributing minimal toxicity to mammalian cells. This activity is maintained against polyene and azole-resistant isolates. Pharmacokinetic and pharmacodynamic studies have demonstrated linear kinetics both in adults and children with concentration-dependent activity observed both in vitro and in vivo. Dosage escalation studies have also demonstrated that doses much higher than those currently recommended may be administered without serious adverse effects. Clinically, micafungin has been shown to be efficacious for the treatment of invasive candidiasis and invasive aspergillosis. Furthermore, the clinical effectiveness of micafungin against these infections occurs without the drug interactions that occur with the azoles and the nephrotoxicity observed with amphotericin B formulations. This review will focus on the pharmacology, clinical microbiology, mechanisms of resistance, safety, and clinical efficacy of micafungin in the treatment of invasive candidiasis and invasive aspergillosis.

Impact of early catheter removal during treatment of invasive candidiasis: analysis from two phase 3 micafungin trials

Prompt central venous catheter (CVC) removal is often recommended in candidemic patients [1,2]. To investigate further, we evaluated relationships between CVC status and 28-day and 42-day survival post-treatment initiation, overall treatment success, and time to mycological eradication.

Anidulafungin in the treatment of patients with invasive candidiasis

Echinocandins have emerged as important agents for the treatment of invasive candidiasis. Forthcoming guidelines are expected to recommend an echinocandin agent as initial primary therapy in patients who are severely ill and/or have risk factors for azole resistance. Amphotericin B deoxycholate and fluconazole should be considered for initial therapy in specific populations. The echinocandin, anidulafungin, has been shown to have higher response rates compared with fluconazole in patients with invasive candidiasis. Additionally, patients treated with anidulafungin compared with patients receiving fluconazole have exhibited a trend toward improved survival. The three echinocandins (anidulafungin, caspofungin and micafungin) offer proven efficacy along with excellent side-effect profiles. While these three drugs have important differences, the empirical selection of an echinocandin should be based on the specific patient population, including clinical status, the suspected pathogen, and the susceptibility pattern at the institution. Once the Candida species is identified and its susceptibility is determined, clinicians should consider step-down therapy to either fluconazole or voriconazole, with possible conversion from intravenous to oral therapy.

Anidulafungin: a drug evaluation of a new echinocandin

Background: Over the past two decades, the frequency and type of invasive fungal infections have increased greatly and thus have driven the need for new antifungal agents. Anidulafungin is the newest addition to the echinocandin armamentarium. Objective: The intention of this review is to provide a drug evaluation of anidulafungin, including its spectrum of activity, pharmacokinetics, pharmacodynamics, clinical efficacy, adverse event profile, and its role in the treatment of invasive candidiasis. Methods: A PubMed search was performed to gather the most current and pertinent articles. Conclusions: Clinical trials have demonstrated anidulafungin's efficacy and tolerability in invasive candidiasis. Anidulafungin is not associated with any drug–drug interactions and does not require dosage adjustment in patients with renal and/or hepatic impairment.

Echinocandins: a wealth of choice – how clinically different are they?

The recent decade has been a 'golden age' for antifungal therapy. The introduction of a novel class of antifungals, the echinocandins, has revolutionized the therapy for invasive candidiasis, provided increasing options for antifungal prophylaxis in high-risk patients and energized the debate regarding combination antifungal therapy for invasive mycoses. Randomized, controlled data exist for each echinocandin in the treatment of invasive candidiasis, and experts largely believe the agents to be equivalent in this setting. Future trials of combined echinocandin-triazole therapy for invasive aspergillosis are desired. Additionally, maximal dosing limitations are being pursued. The echinocandins as a class offer an advance in the treatment of invasive candidiasis, an additional option for prophylaxis and an attractive choice for the study of combination antifungal therapy. Particularly for the major indication (treatment of invasive candidiasis), major clinical differences between agents have not been noted.

Update in infectious disease treatment

Studies published during the past year on the treatment of several infectious diseases provide valuable information that should enable us to treat our patients more effectively. Among those findings: Oral vancomycin (Vancocin) is superior to oral metronidazole (Flagyl) for treating patients with severe Clostridium difficile-associated disease. The risk of death from any cause may be higher with the use of cefepime (Maxipime) than with other beta-lactam antibiotics. In patients presenting to primary care physicians with symptoms of acute maxillary sinusitis, antibiotics and topical nasal steroids do not seem to be effective, either alone or in combination. For patients with Bell palsy, early treatment with prednisolone improves the chance of complete recovery; antiviral therapy may be indicated for patients with complete facial nerve paralysis. In patients undergoing chemotherapy for acute myelogenous leukemia or myelodysplasia, posaconazole (Noxafil) prevented fungal infections more effectively than fluconazole (Diflucan) or itraconazole (Sporanox) and improved overall survival. Anidulafungin (Eraxis) was not inferior to fluconazole in the treatment of invasive candidiasis.

Anidulafungin: advantage for the newcomer?

Anidulafungin is the most recently approved compound of the echinocandin antifungal class. Its mode of action is the noncompetitive inhibition of β–(1,3)-D-glucan synthesis. Potent fungicidal activity has been demonstrated against many Candida spp., including non-albicansCandida spp. and fluconazole-resistant strains, as well as fungistatic activity against Aspergillus spp. Owing to low oral bioavailability, it can only be administered intravenously. Anidulafungin is not metabolized by the liver and renal clearance is negligible, thus rendering dosage adjustments in patients with impaired hepatic or renal function unnecessary. Due to lack of interference with the cytochrome P450 pathway, it displays minimal drug–drug interaction. Anidulafungin has been approved by the US FDA for the treatment of esophageal and invasive candidiasis after clinical trials demonstrated its noninferiority to fluconazole. In September 2007, anidulafungin gained EMEA approval for the treatment of invasive candidiasis in adult non-neutropenic patients. For those with invasive or noninvasive candidiasis with resistance or intolerance to fluconazole in particular, as well as those requiring antifungal medication, that anidulafungin does not interact with concomitant medication means it may be regarded as a safe and efficacious treatment option. Promising results from animal models and experience with the other echinocandins indicate several potential lines of investigation: invasive aspergillosis, prophylaxis and treatment of transplant patients, and empirical treatment in patients with febrile neutropenia. Significant differences in clinical efficacy or safety favoring anidulafungin over the other echinocandins are yet to be discovered.

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.

Emergence of Candida tropicalis resistant to caspofungin

Sir, Candida species is the fourth leading cause of nosocomial bloodstream infection in the USA. The incidence and mortality of invasive candidiasis (IC) remain high despite new antifungal agents. Although Candida albicans remains the most common isolated species causing IC, the incidence of IC caused by non-albicans species is increasing. 1 Caspofungin, an echinocandin, is approved for treatment of IC. 2 Resistance to caspofungin has been rarely reported. We admitted a 28-year-old female with acute myelogenous leukaemia (AML) for fever and otitis media. She was started on caspofungin [70 mg intravenous (iv) loading dose followed by 50 mg iv daily] on her fifth hospital day due to persistent fever despite iv broad-spectrum antibiotics. Defervescence was noted and she was started on induction chemotherapy for AML on the sixth hospital day. She again developed fever with symptoms of oesophagitis on her 21st hospital day. Oesophagogastroduodenoscopy with oesophageal biopsy was performed and showed invasive candidal oesophagitis. Caspofungin was switched to liposomal amphotericin B. Her repeat blood cultures grew Candida tropicalis susceptible to fluconazole. Amphotericin B was switched to fluconazole and the patient improved slowly. She completed 4 weeks of fluconazole treatment. We subsequently performed additional in vitro MIC testing for echinocandins on the isolated C. tropicalis using the CLSI (formerly NCCLS) M27-A2 standard methods. 3 This method has been proven to be reproducible and reliable in the study of MIC trends and patterns of antifungal medications. 4 MICs of

Anidulafungin versus Fluconazole for Invasive Candidiasis

Anidulafungin, a new echinocandin, has potent activity against candida species. We compared anidulafungin with fluconazole in a randomized, double-blind, noninferiority trial of treatment for invasive candidiasis. Adults with invasive candidiasis were randomly assigned to receive either intravenous anidulafungin or intravenous fluconazole. All patients could receive oral fluconazole after 10 days of intravenous therapy. The primary efficacy analysis assessed the global response (clinical and microbiologic) at the end of intravenous therapy in patients who had a positive baseline culture. Efficacy was also assessed at other time points. Eighty-nine percent of the 245 patients in the primary analysis had candidemia only. Candida albicans was isolated in 62% of the 245 patients. In vitro fluconazole resistance was infrequent. Most of the patients (97%) did not have neutropenia. At the end of intravenous therapy, treatment was successful in 75.6% of patients treated with anidulafungin, as compared with 60.2% of those treated with fluconazole (difference, 15.4 percentage points; 95% confidence interval [CI], 3.9 to 27.0). The results were similar for other efficacy end points. The statistical analyses failed to show a "center effect"; when data from the site enrolling the largest number of patients were removed, success rates at the end of intravenous therapy were 73.2% in the anidulafungin group and 61.1% in the fluconazole group (difference, 12.1 percentage points; 95% CI, -1.1 to 25.3). The frequency and types of adverse events were similar in the two groups. The rate of death from all causes was 31% in the fluconazole group and 23% in the anidulafungin group (P=0.13). Anidulafungin was shown to be noninferior to fluconazole in the treatment of invasive candidiasis. (ClinicalTrials.gov number, NCT00056368 [ClinicalTrials.gov]).

Could Risk Assessment for Non-albicans Candida Improve Empiric Treatment for Invasive Candidiasis?

The changing epidemiology of invasive candidiasis, along with concerns for the emergence of drug resistance, necessitates the identification of patients at increased risk of non-albicans Candida (NAC) to optimize selection of antifungal therapy. The major findings of a study regarding the demographic characteristics, costs, and outcomes of nonneutropenic patients with candidemia due to NAC are discussed. Given available treatment options, such risk assessment is most relevant to initial empiric therapy in stable patients without neutropenia who might be candidates for initial therapy with an azole (eg, fluconazole). The study's investigators reinforce the need for timely antifungal therapy for patients with candidemia.

Treatment of bilateral candidal endophthalmitis with intravenous caspofungin.

Fungal resistances to drugs are increasing. Caspofungin is a new antifungal agent effective in the treatment of invasive candidiasis. We report a case of candidal endophthalmitis that responded adequately to caspofungin. A 24-year-old man with acute myeloid leukemia presented with vision loss in both eyes. Visual acuity was 20/50 in the right eye and counting fingers in the left eye. Fundus examination revealed multiple, premacular, vitreous, pearl stringshaped condensations in the right eye and a subretinal abscess in the left eye. Treatment with 50 mg of intravenous caspofungin once daily was started. After 1 month, inflammation in both eyes had decreased, although the left eye developed macular scarring. Medication at discharge was intravenous caspofungin once daily for another 6 weeks. Nine months after presentation, the patient had residual vitreous condensations in the premacular region of the right eye with visual acuity of 20/25 and severe macular scarring in the left eye with visual acuity of 20/100. This case adds support for the use of caspofungin as monotherapy for candidal endophthalmitis. Further studies are necessary to determine treatment options for the new antifungal agents.

Adjunctive immunotherapy in combination with lipid-associated amphotericin B for the treatment of invasive candidiasis

Introduction: Nosocomial bloodstream infections caused by Candida spp result in increased morbidity and mortality in hospitalized patients, especially those in the intensive care unit [1]. Despite the availability of the less toxic lipidassociated amphotericin B formulations, as well as the newer triazoles and echinocandins, the outcome of therapy remains poor. Crude mortality rates for patients with candidemia range from 30% to 60%; and mortality rates directly attributable to candidemia range between 10% and 30% [2,3]. In order to improve clinical outcome, combination therapy with conventional antifungal agents for the treatment of candidemic patients has recently been evaluated [4]. Because patients with serious candidal infections are frequently immunocompromised, combining adjunctive immunotherapy with conventional antifungal agents is also under study [5].

Successful Treatment of Invasive Candidiasis With Caspofungin in a Child With Acute Lymphoblastic Leukemia

Successful Treatment of Invasive Candidiasis With Caspofungin in a Child With Acute Lymphoblastic Leukemia

Evaluation of the usefulness of anti-glyceraldehyde-3-phosphate dehydrogenase antibodies as a treatment for invasive candidiasis in a murine model

We have evaluated the effect of antibodies against the Candida albicans glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a potential immunotherapeutic treatment for acute invasive candidiasis in a murine model of infection. Three different approaches were assayed: (i) active immunization of mice using recombinant His-tagged GAPDH, (ii) treatment of fungal yeast cells with anti-GAPDH antibodies prior to infection, and (iii) passive transfer of polyclonal anti-GAPDH antibodies. Results showed that all three approaches, although tending to show a slight beneficial effect in some instances, fail to have a relevant and statistically significant effect on the infection course, determined by survival curves and fungal burden in kidneys. This suggests that the cell wall-associated GAPDH of C. albicans, despite its potential role in virulence, does not appear to be a suitable target protein for the development of immunotherapeutic strategies against candidiasis, although further studies may be required to confirm this observation.

Echinocandins — An Advance in the Primary Treatment of Invasive Candidiasis

Echinocandins — An Advance in the Primary Treatment of Invasive Candidiasis

Pharmacological advances in the treatment of invasive candidiasis

Invasive candidiasis is a common nosocomial infection, especially among the critically ill and immunocompromised patient populations. The recent standardization and increasing availability of antifungal susceptibility testing has the potential to optimize the selection of antifungal therapy. Treatment has been revolutionized in recent years with the marketing of several antifungal agents with excellent activity against Candida spp. These agents include the triazoles, fluconazole and voriconazole, and the echinocandin antifungals. While more expensive by acquisition cost, these newer agents are less toxic than the previously used drugs, and the triazoles offer the additional benefit of oral administration. The availability of new agents, future adoption of diagnostic tests for candidiasis, and susceptibility testing will have a major impact in the management of invasive candidiasis.

Caspofungin

Caspofungin (Cancidas) is the first of a new class of antifungal agents, the echinocandins, that inhibit the synthesis of the fungal cell wall component beta-(1,3)-D-glucan. Caspofungin is administered once daily by slow intravenous infusion and is used to treat infections caused by Candida spp. and Aspergillus spp. Caspofungin is a valuable new antifungal agent with a novel mechanism of action. In comparative clinical trials, caspofungin was no less effective than liposomal amphotericin B in the empirical treatment of neutropenic patients with persistent fever, amphotericin B deoxycholate in the treatment of invasive candidiasis or fluconazole in the treatment of oesophageal candidiasis. Caspofungin also displayed broadly similar efficacy to amphotericin B deoxycholate in oesophageal or oropharyngeal candidiasis and was effective as salvage therapy in patients with invasive aspergillosis who were refractory to or intolerant of standard therapy. The tolerability profile of caspofungin was similar to that of fluconazole and superior to that of amphotericin B deoxycholate and liposomal amphotericin B. Therefore, in the appropriate indications, caspofungin is a viable alternative to amphotericin B deoxycholate, liposomal amphotericin B or fluconazole.

Combination Therapy for Invasive Mycoses: Evaluation of Past Clinical Trial Designs

Despite the availability of new antifungals, single-agent therapy frequently falls short of high cure rates. Combination therapy offers potentially higher cure rates, especially for resistant organisms. In vitro studies and experimental animal models have provided conflicting data. Retrospective, randomized, controlled clinical studies were reviewed. Results indicate a clear advantage for polyene and flucytosine combination therapy in cryptococcal meningitis and a possible advantage for combination amphotericin B and fluconazole for candidemia. Unfortunately, the few studies published have been flawed by design problems that have compromised the determination of outcome. Study review allows investigators the opportunity to design future studies to ensure optimal evaluation of efficacy. Combination antifungal therapy is advantageous in cryptococcal diseases and may have a role in the treatment of invasive candidiasis. The greatest potential exists for combination therapy against aspergillosis and resistant fungi in patients with refractory mycotic disease who experience failure of monotherapy.