Treatment Of Invasive Candidiasis Research Articles

Tratamiento con equinocandinas en un paciente crítico sometido a técnica continua de reemplazo renal

BackgroundCritically ill patients with invasive candidiasis (IC) often suffer renal failure, which sometimes requires continuous renal replacement techniques (CRRT). Echinocandins are the first line treatment for IC in critically ill patients with mild or severe illness. Their elimination during CRRT should be negligible due to their pharmacokinetic and pharmacodynamic (PK/PD) profile, and dose adjustment are not needed, as suggested by the few reported clinical studies. Clinical caseThis is the case of a 66 year old male who underwent surgery due to peritonitis secondary to intestinal suture dehiscence. The patient was admitted to ICU with septic shock symptoms and multiple organ dysfunction syndrome (MODS), and CRRT was started. Anidulafungin was prescribed at the usual dosage due to the IC risk factors present, and the observation of yeasts in the peritoneal fluid. Anidulafungin was selected due to the hepatic failure suffered by the patient. An isolate of Candida albicans susceptible to fluconazole was cultured from peritoneal fluid and rectal exudates. However, anidulafungin was maintained due to the MODS and observing the clearance of fluconazole during CRRT. The patient's condition improved favourably, being moved to the surgical ward 20 days after the surgery. ConclusionsEchinocandins, due to their PK/PD profile, could be safely given at usual doses to critically ill patients undergoing CRRT. However, new studies are required to strengthen this recommendation. Its extrahepatic metabolism makes anidulafungin a more attractive option among echinocandins and other antifungals when used in patients with different degrees of hepatic failure

Impact of Treatment Strategy on Outcomes in Patients with Candidemia and Other Forms of Invasive Candidiasis: A Patient-Level Quantitative Review of Randomized Trials

Invasive candidiasis (IC) is an important healthcare-related infection, with increasing incidence and a crude mortality exceeding 50%. Numerous treatment options are available yet comparative studies have not identified optimal therapy. We conducted an individual patient-level quantitative review of randomized trials for treatment of IC and to assess the impact of host-, organism-, and treatment-related factors on mortality and clinical cure. Studies were identified by searching computerized databases and queries of experts in the field for randomized trials comparing the effect of ≥2 antifungals for treatment of IC. Univariate and multivariable analyses were performed to determine factors associated with patient outcomes. Data from 1915 patients were obtained from 7 trials. Overall mortality among patients in the entire data set was 31.4%, and the rate of treatment success was 67.4%. Logistic regression analysis for the aggregate data set identified increasing age (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00-1.02; P = .02), the Acute Physiology and Chronic Health Evaluation II score (OR, 1.11; 95% CI, 1.08-1.14; P = .0001), use of immunosuppressive therapy (OR, 1.69; 95% CI, 1.18-2.44; P = .001), and infection with Candida tropicalis (OR, 1.64; 95% CI, 1.11-2.39; P = .01) as predictors of mortality. Conversely, removal of a central venous catheter (CVC) (OR, 0.50; 95% CI, .35-.72; P = .0001) and treatment with an echinocandin antifungal (OR, 0.65; 95% CI, .45-.94; P = .02) were associated with decreased mortality. Similar findings were observed for the clinical success end point. Two treatment-related factors were associated with improved survival and greater clinical success: use of an echinocandin and removal of the CVC.

Cost-effectiveness analysis of anidulafungin versus fluconazole for the treatment of invasive candidiasis

Cost-effectiveness analysis of anidulafungin versus fluconazole for the treatment of invasive candidiasis

Clinical efficacy and safety of intravenous itraconazole in the management of invasive candidiasis in patients of surgery and critical care

Although itraconazole exhibits potent activity against Candida species, there have been few studies examining the use of intravenous itraconazole in the treatment of invasive candidiasis. A nationwide multicenter clinical study was conducted to evaluate the efficacy and safety of intravenous itraconazole in the management of invasive candidiasis, including non-albicans Candida species, in non-neutropenic patients undergoing surgery and critical care. Between September 2007 and August 2009, patients with proven and presumed candidiasis were enrolled at 22 participating institutions. Patients with presumed candidiasis had a deep-body temperature of 37.8°C or higher and were positive for serum β-D: -glucan or two or more colonization sites of Candida species. The main exclusion criterion was severe renal impairment (creatinine clearance <30 ml/min). The primary efficacy analysis was based on clinical and microbiological responses 5-10 days after the end of treatment, assessed by an independent data review committee. Of the 60 patients enrolled, 49 were included in the modified intention-to-treat population; 31 patients received a definitive diagnosis and 18 patients a presumed diagnosis. Intravenous itraconazole was used as first-line therapy to treat 39 patients and as second-line therapy for 10 patients. The isolated species included Candida albicans (25 strains with definitive diagnosis and 17 with presumed diagnosis) and non-albicans species (16 and 10, respectively). Treatment was successful in 61.5% patients (65.5% in first-line and 50.0% in second-line therapy); 60% of proven invasive candidiasis (IC) patients were judged as successful compared with 63.2% of presumed candidiasis patients. Eradication rate was 63.6% for C. albicans and 71.4% for C. glabrata. Adverse effects occurred in 9 of 60 patients (15.0%), commonly impaired liver function. The clinical efficacy and safety of intravenous itraconazole were suggested in the management of proven and presumed candidiasis including C. glabrata in non-neutropenic patients. The status of intravenous itraconazole in the Japanese guideline warrants reconsideration.

Cost-effectiveness analysis of anidulafungin versus fluconazole for the treatment of invasive candidiasis

Anidulafungin was found to be non-inferior to and possibly more efficacious than fluconazole for treatment of invasive candidiasis (IC) in a major randomized clinical trial (RCT). There are no data comparing the cost-effectiveness between azoles and echinocandins in treating IC. This economic analysis investigated the cost-effectiveness of anidulafungin compared with fluconazole for treatment of IC in an Australian setting. A decision analytic model was constructed to capture downstream consequences of using either agent for treatment of IC. The main outcomes analysed in the model were treatment success and treatment failure (observed and indeterminate). Outcome probabilities and treatment pathways were derived from a published RCT. Resources used were estimated by an expert panel and cost inputs were derived from the latest Australian resources. The analysis was based on an Australian hospital perspective. Sensitivity analyses were conducted using Monte Carlo simulation. Anidulafungin (AU$74,587) had a higher total cost than fluconazole (AU$60,945) per successfully treated patient, primarily due to its higher acquisition cost. Hospitalization was the main cost driver for both comparators. However, when the rates of mortality in both treatment arms were considered, treatment with anidulafungin was expected to save an additional 0.53 life-years, with an incremental cost-effectiveness ratio (ICER) of AU$25 740 per life-years saved, which was below the implicit ICER threshold value for Australia. The results were robust over a wide range of variables. This is the first economic evaluation of anidulafungin versus fluconazole in the treatment of IC in Australia. Anidulafungin appears to be a cost-effective option.

Recomendaciones sobre el tratamiento de la candidiasis invasiva y otras infecciones por levaduras de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC). Actualización 2011

These guidelines are an update of the recommendations of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) that were issued in 2004 (Enferm Infecc Microbiol Clin. 2004, 22:32-9) on the treatment of Invasive Candidiasis and infections produced by other yeasts. This 2010 update includes a comprehensive review of the new drugs that have appeared in recent years, as well as the levels of evidence for recommending them. These guidelines have been developed following the rules of the SEIMC by a working group composed of specialists in infectious diseases, clinical microbiology, critical care medicine, paediatrics and oncology-haematology. It provides a series of general recommendations regarding the management of invasive candidiasis and other yeast infections, as well as specific guidelines for prophylaxis and treatment, which have been divided into four sections: oncology-haematology, solid organ transplantation recipients, critical patients, and paediatric patients.

Evidencias científicas que respaldan el uso de micafungina en el tratamiento de la candidiasis invasora

Micafungin is a semisynthetic lipopeptide developed from Coleophoma empetri, which blocks the synthesis of β-1,3-D-glucan, an essential component of the fungal wall, though non-competitive inhibition of β-1,3-D-glucan synthetase. Micafungin is a dose-dependent candidacidal agent with excellent in vitro efficacy against most Candida spp. including species resistant to amphotericin B, such as Candida lusitaniae, several azoles, such as C. glabrata or C. krusei, and isolates not susceptible to other echinocandins. Moreover, this drug is active against Candida biofilms. Micafungin is a first-line drug for the treatment of candidemias and invasive candidiasis in adults and children (including neonates). This drug is approved for use in the treatment of invasive candidiasis and Candida esophagitis, as well as in the prophylaxis of Candida infections in hematopoietic stem cell transplant recipients or those at risk of prolonged neutropenia. Micafungin can be used both in the treatment and prevention of candidiasis in neonates, children, adolescents, adults, and the elderly, making it highly useful in patient groups in which the use of other antifungal drugs has not been authorized.

Caspofungin therapy in immunocompromised children and neonates

The prevalence of invasive fungal infections is increasing and the infections are becoming a major problem in immunocompromised children and neonates. Fortunately, there has been a recent surge in the development of new antifungal agents. Caspofungin, the first licensed echinocandin, is a novel class of antifungal and is approved for use in children 3 months of age or older for the treatment of invasive candidiasis, salvage therapy for invasive aspergillosis and as empirical therapy for febrile neutropenia. This article reviews the published data on the use of caspofungin in immunocompromised children and neonates with invasive fungal infections.

Niveau de preuve du suivi thérapeutique pharmacologique du fluconazole

Fluconazole is a recommended treatment option for the treatment of invasive candidiasis. Fluconazole is active against most pathogenic Candida spp. except C. kruzei and C. glabrata. Fluconazole is orally well absorbed. Its volume of distribution is reported to be 0.7-1.0 L/kg and it is weakly bound to plasma proteins. The majority of fluconazole dose is excreted via the kidneys. Usually, fluconazole pharmacokinetics display moderate inter-individual variability. However, in presence of renal dysfunction or in pediatrics patients, fluconazole pharmacokinetics might be difficult to predict. Concentration-efficacy relationships are demonstrated whereas concentration-toxicity relationships are sparse. As a consequence, therapeutic drug monitoring is not routinely recommended but can be useful in certain situations.

Treatment and prophylaxis of invasive candidiasis with anidulafungin, caspofungin and micafungin and its impact on use and costs - review of the literature

Invasive fungal infections are on the rise. Echinocandins are a relatively new class of antifungal drugs that act by inhibition of a key enzyme necessary for integrity of the fungal cell wall. Currently there are three available agents: caspofungin, micafungin and anidulafungin.While the individual echinocandin antifungals have a different spectrum of licensed indications, basically all of them are available for the treatment of candidemia and invasive candidiasis. Antifungal treatment modalities basically include in therapy for suspected or proven infection and prophylaxis. All three drugs are comparatively expensive. Therefore a systematic review of the literature was performed to investigate the following aspects:• General aspects of cost-effectiveness in the treatment of invasive fungal infections• Cost-effectiveness of the treatment with the above-mentioned antifungals• Cost-effectiveness in two settings: therapy and prophylaxisEarly initiation of antifungal therapy, adjustment after availability of microbiological results, duration of therapy, success and occurrence of severe complications (e.g renal failure) are the most important cost drivers in antifungal therapy.Considering the specific antifungals, for caspofungin the best evidence for cost-effectiveness is found in treatment of invasive candidiasis and in empiric therapy of suspected infections. Favourable economic data are available for micafungin as a cost-effective alternative to LAmB for prophylaxis in patients with hematopoietic stem cell transplantation (HSCT). For anidulafungin, cost-effectiveness was demostrated in a pharmacoeconomic model. Net savings - yet not significant - were observed in a retrospective chart review of 234 patients. Generally, however, most analyses are still based on pharmacoeconomic modelling rather than direct analysis of trial data or real-life clinical populations.As an overall conclusion, using caspofungin, micafungin, or anidulafungin is not more expensive than using other established therapies. Micafungin has proven to be cost-effective in prophylaxis if the local fungal epidemiology indicates a high level of resistance to fluconazole. Switch strategies involving early initiation of broadly active therapy with switch to cheaper alternatives according to microbiology results and clinical status and early initiation of an appropriate therapy have been proven to be cost-efficient independent of the antifungal agent.

Anidulafungin: Review of its Role in the Treatment of Invasive Candidiasis

In 2006 a third echinocandin, anidulafungin, was approved in the USA for the treatment of candida esophagitis, candidemia, and invasive candida infections such as intra-abdominal abscesses and peritonitis in the non-neutropenic patient. Two years later it was approved in the EU for invasive candidiasis in non-neutropenic patients. Like other echinocandins, it is fungicidal against Candida species and fungistatic against Aspergillus species. It does not need adjustment for renal or hepatic insufficiency, and has no known drug interactions. Its administration is by the intravenous route only, and it is well tolerated. A steady state concentration can be achieved on day two by giving twice the maintenance dose on day one.

Invasive Candidiasis in the Neutropenic Cancer Patient

Invasive candidiasis (IC) is an important complication among cancer patients with neutropenia, as it is associated with significant mortality. Despite the introduction of the new antifungals in clinical practice and their widespread use as treatment or prophylaxis, the incidence of IC and the predominance of non-albicans Candida species remain unchanged, and mortality rates remain as high as in previous periods. New techniques have been developed to decrease the time to Candida species identification from blood cultures. Nonculture diagnostic methods and molecular diagnostic tests for detection of Candida are promising but have not been validated in neutropenic patients. Recently, voriconazole was proved to be as effective as fluconazole for prophylaxis in neutropenic recipients of hematopoietic stem cell transplants and in patients with graft-versus-host disease. Despite the lack of randomized studies of the treatment of IC among neutropenic patients, it seems that the success rates of antifungal therapy do not differ from those in non-neutropenic patients.

Echinocandin Antifungal Drug Resistance in Candida Species: A Cause for Concern?

The echinocandins, the newest generation of antifungal agents, are inhibitors of β-1,3-D-glucan synthesis, an action that damages fungal cell walls. Despite a relatively broad spectrum of activity, these drugs are rapidly fungicidal against most Candida spp and have established noninferiority over existing antifungal drugs in the treatment of invasive candidiasis. Clinical resistance to this class of agent is rare, although point mutations in the target Fksp have been shown to confer in vitro resistance to echinocandins in a range of Candida spp, which can result in clinical failures. In addition, the echinocandin treatment can induce a salvage mechanism involving the compensatory upregulation of chitin synthesis in the cell wall. Further elucidation of the echinocandin resistance mechanisms could be exploited to envisage new therapeutic strategies for the treatment of life-threatening Candida infections.

Caspofungin Use in Patients with Invasive Candidiasis Caused by Common Non- albicans Candida Species: Review of the Caspofungin Database

Increasing rates of invasive candidiasis caused by non-albicans Candida species have been reported worldwide. Particular concerns have been raised for C. parapsilosis because of reduced in vitro susceptibility to echinocandins. We identified 212 patients with invasive candidiasis due to non-albicans Candida species (>or=5 cases per species) in 5 clinical trials of caspofungin monotherapy from the pharmaceutical sponsor's (Merck and Co., Inc.) database: 71 cases were caused by C. parapsilosis, 65 by C. tropicalis, 54 by C. glabrata, 10 by C. krusei, 9 by C. guilliermondii, and 5 by C. lusitaniae. One hundred sixty-seven cases caused by C. albicans were also identified. Efficacy was assessed at the end of caspofungin therapy. Success (favorable overall response) required favorable clinical and microbiological responses. The mean APACHE II scores were 16.5 in the non-albicans group and 15.7 in the C. albicans group. Neutropenia at study entry was more common in the non-albicans group (12%) than in the C. albicans group (5%). The median duration of caspofungin therapy was 14 days in both groups. The success rates were 77% in both groups and at least 70% for each non-albicans species: 74% for C. parapsilosis, 71% for C. tropicalis, 85% for C. glabrata, 70% for C. krusei, 89% for C. guilliermondii, and 100% for C. lusitaniae. The times to negative blood culture were similar for the various species. The overall mortality rates were 26% in the non-albicans group and 29% in the C. albicans group. Drug-related serious adverse events and discontinuations due to caspofungin toxicity were uncommon. Although the sample sizes were limited, caspofungin demonstrated favorable efficacy and safety profiles in the treatment of invasive candidiasis caused by the following non-albicans Candida species: C. parapsilosis, C. tropicalis, C. glabrata, C. krusei, C. guilliermondii, and C. lusitaniae.

Clinical Aspects of Invasive Candidiasis in Paediatric Patients

Candida infections in paediatric patients are an important issue. They are associated with significant mortality, particularly in newborns and those with congenital immunodeficiencies. At present, there is limited knowledge regarding factors associated with an increased risk of developing invasive candidiasis in newborns and those with congenital immunodeficiencies, although there have been a number of studies conducted to characterize these risk factors. These studies have suggested that, in neonates, the most important of these factors is colonization, whereas in paediatric patients with congenital immunodeficiencies, risk factors may differ according to the specific deficiency present. Regarding treatment of invasive candidiasis in paediatric patients, fluconazole is considered an appropriate choice, although the method for determining treatment strategies for each patient should be the same as that used for such decisions in adult patients.

Treatment of invasive candidiasis with echinocandins

Blood stream infections by Candida spp. represent the majority of invasive fungal infections in intensive care patients. The high crude mortality of invasive candidiasis remained essentially unchanged during the last two decades despite new treatment options that became available. The echinocandins, the latest class of antifungals introduced since 2001, exhibit potent activity against clinically relevant fungi including most Candida spp. In several randomised multicentre phase III trials, anidulafungin, caspofungin and micafungin showed convincing efficacy when compared with standard treatment regimens. In all trials, echinocandins were at least non-inferior to standard treatments. Anidulafungin was shown to be superior to fluconazole. Echinocandins have a favourable tolerability profile and exhibit a minimal potential for drug interactions since their pharmacokinetics is independent of renal and--largely--hepatic function. As a result of these properties, echinocandins are appropriate drugs of choice for invasive candidiasis in intensive care where many patients experience organ failure and receive multiple drugs with complex interactions.

Efungumab: A Novel Agent in the Treatment of Invasive Candidiasis

To review the use of efungumab as an adjunctive agent in the treatment of invasive candidiasis (IC) and to provide guidance on formulary placement. Searches of MEDLINE (1966-June 2009) and EMBASE (1974-June 2009) were conducted using the terms efungumab, Mycograb, heat shock protein 90, and invasive candidiasis. Other resources included www.clinicaltrials.gov and article bibliographies. All studies and case reports evaluating efungumab use in IC were included. Literature review was limited to the English language. Efungumab is a monoclonal antibody targeted against heat shock protein 90 (HSP 90). It binds to HSP 90, preventing a conformational change needed for fungal viability. In vitro data show that HSP 90 inhibition may decrease resistance against antifungal agents and increase antifungal activity. Efungumab shows activity against Candida spp. when used alone and synergism when combined with fluconazole, caspofungin, and amphotericin B. A randomized controlled trial evaluated combination therapy of efungumab 1 mg/kg twice daily and liposomal amphotericin B versus amphotericin B therapy alone. At day 10, a favorable response was seen in 84% of patients in the efungumab group compared with 48% of patients in the placebo group (OR 5.76; 95% CI 2.4 to 13.8). Mortality at day 33 was also lower in the efungumab group, 4% versus 18%, respectively (OR 0.168; 95% CI 0.036 to 0.797). Although adverse effects were similar in this trial (10% vs 7%), case reports revealed an increased incidence of blood pressure fluctuations. Cytokine release syndrome has also been linked to efungumab use, warranting further exploration of its safety. Efungumab is a new antifungal agent with a novel mechanism of action. Available clinical data and synergy studies support the use of efungumab in combination with other antifungal agents for the treatment of IC. Further safety data are needed before formulary recommendations can be made.

Head-to-head comparison of micafungin versus caspofungin in the treatment of invasive candidiasis

Introduction: Invasive candidiasis is an important cause of morbidity and mortality among patients with health care–associated infection. The echinocandin class of antifungal agents has demonstrated consistent effi cacy and a favorable safety profi le in the treatment of candidemia and other forms of invasive candidiasis. The in vitro antifungal activity, pharmacokinetics, and toxicity profi les are slightly different for each echinocandin; however, the relevance of this fi nding is unclear. There are no clinical trials comparing the safety and effi cacy of different echinocandins in the treatment of invasive candidiasis.

Fluconazole Dosing for the Prevention or Treatment of Invasive Candidiasis in Young Infants

Young infants are susceptible to developmental factors influencing the pharmacokinetics of drugs. Fluconazole is increasingly used to prevent and treat invasive candidiasis in infants. Dosing guidance remains empiric and variable because limited pharmacokinetic data exist. Our population pharmacokinetic model derived from 357 fluconazole plasma concentrations from 55 infants (23-40 week gestation) illustrates expected changes in fluconazole clearance based upon gestational age, postnatal age, weight, and creatinine. We used a Monte Carlo simulation approach based on parametric description of a patient population's pharmacokinetic response to fluconazole to predict fluconazole exposure (median: 10th and 90th percentile population variability range) after 3, 6, and 12 mg/kg dosing. For the treatment of invasive candidiasis, a dose of at least 12 mg/kg/d in the first 90 days after birth is needed to achieve an area under the concentration curve (AUC) of >400 mg*h/L and an AUC/minimum inhibitory concentration (MIC) >50 for Candida species with MIC <8 microg/mL in > or =90% of <30 week gestation infants and 80% of 30 to 40 week gestation infants. The more preterm infants achieve a higher median AUC (682 mg*hr/L) compared with more mature infants (520 mg*hr/L). For early prevention of candidiasis in 23 to 29 week infants, a dose of 3 or 6 mg/kg twice weekly during the first 42 days of life is equivalent to an AUC of 50 and 100 mg*hr/L, respectively, and maintains fluconazole concentrations > or =2 or 4 microg/mL, respectively, for half of the dosing interval. For late prevention, the 6 mg/kg dose every 72 hours provides similar exposure to 3 mg/kg daily dose. Infants with serum creatinine > or =1.3 mg/dL have delayed drug clearance and dose adjustment is indicated if creatinine does not improve within 96 hours. A therapeutic concentration of fluconazole in premature infants with invasive candidiasis requires dosing substantially greater than commonly recommended in most reference texts. To prevent invasive candidiasis, twice weekly prophylaxis regimens can provide adequate exposure when unit specific MICs are taken into account.

Invasive candidiasis and candidemia: from current opinions to future perspectives

Candida spp. are the fourth most common cause of nosocomial bloodstream infections in the United States, as well as the single most important cause of opportunistic fungal infections worldwide. A delayed diagnosis of invasive candidiasis and/or inadequate treatment choice is associated with high mortality rates and prolonged hospital stays. Even though the antifungal armamentarium has been broadened significantly over the last years, the best options for diagnosing and treating invasive candidiasis still remain a matter of discussion. In this article we present and analyze current evidence on the epidemiology, diagnostic methods and treatment options of invasive candidiasis, with a focus on results from randomized clinical trials. Finally, the reader is provided with a brief overview on promising clinical trial designs and antifungals that might shape the treatment of invasive candidiasis in the years to come.