Choice Of Antifungal Agent Research Articles

Navigating fungal infections and antifungal stewardship: drug resistance, susceptibility testing, therapeutic drug monitoring and future directions.

Antifungal stewardship refers to the rational use of antifungal agents. Historically, in some instances, the misuse or overuse of antifungal agents has predisposed patients to an elevated risk of systemic side-effects and treatment resistance, as well as increased healthcare costs. Superficial mycoses, such as onychomycosis, are sometimes treated without any diagnostic testing and is associated with a high likelihood of self-diagnosis and self-treatment, potentially leading to the emergence of resistance against commonly used antifungals like terbinafine. Practitioners need to ensure that a proper clinical diagnosis is backed up by appropriate testing. This may include the traditional light microscopy and culture; additionally, molecular techniques (such as polymerase chain reaction, terbinafine gene mutational analysis) and antifungal susceptibility testing are considerations as appropriate. The choice of antifungal agent should be guided by what is the standard of care in the location where the clinician practices as well as more broadly state and national prescription patterns. Recently, reports of treatment resistance concerning both superficial and deep fungal infections have added another layer of difficulty to clinical practice. This review aims to explore the phenomenon of antifungal drug resistance, and highlights the importance of adopting antifungal stewardship programs. We provide an overview of treatment resistance and mechanisms of resistance reported thus far in dermatophytes. Challenges of performing antifungal susceptibility testing and therapeutic drug monitoring are discussed, as well as principles, recommendations and future directions of antifungal stewardship programs.

S1.4b Challenges in diagnosing and management of invasive fungal infections during the pandemic

S1.4 Fungal infections in Asia, bringing it out of the dark, September 21, 2022, 11:00 AM - 12:30 PMInvasive fungal diseases have been increasing in Asian countries. Recent advances in novel medical care such as solid organ and stem cell transplantations, chemotherapy for cancer treatment, and corticosteroid therapy, resulted in the increased prevalence of invasive mycoses. Invasive aspergillosis, mucormycosis, and endemic mycoses are among the most common mold infections in Asia. Non-classical and novel risk factors of invasive fungal diseases have been increasingly recognized in Asia. In contrast to the classical neutropenic patients, most of the patients with invasive mycoses who had non-classical risk factors are mostly non-neutropenic and may present with an atypical clinical manifestation. These novel risk factors include biologic agents or small molecule kinase inhibitors used for cancer treatment, and severe viral pneumonia such as influenza pneumonia or coronavirus disease 2019 (COVID-19) pneumonia. Recently, COVID-19-associated aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM) have been described. These particular mold infections had high mortality. Treatment of CAPA and CAM are similar to those who had mold infections without COVID-19. However, the interaction between triazole and drugs used for the treatment of COVID-19 must be taken into consideration. Timely and accurate diagnoses are crucial for the management of invasive fungal infections. Conventional fungal cultures from sterile clinical samples or blood are useful but they are time-consuming. Nevertheless, the diagnosis of invasive mold infections is challenging as the imaging is non-specific and the serological tests are not widely available in Asian countries. In some circumstances such as those with non-classical risk factors, serology revealed relatively low sensitivities. Molecular diagnostic tests are also the unmet needs among Asian countries for timely and accurate diagnosis of invasive fungal diseases. Several factors should be considered for the appropriate choice of antifungal agents, including antifungal coverage, adverse effects, underlying conditions, drug-drug interactions, and cost. Recently, novel antifungal agents such as novel triazoles or new classes of antifungal agents have been studied and may be a promising choice for the treatment of invasive fungal diseases.

Impact of Invasive Fungal Diseases on Survival under Veno-Venous Extracorporeal Membrane Oxygenation for ARDS.

Objective: To assess the incidence and significance of invasive fungal diseases (IFD) during veno-venous (VV) ECMO support for acute respiratory distress syndrome (ARDS). Methods: Retrospective analysis from January 2013 to April 2021 of all ECMO cases for ARDS at a German University Hospital. In patients with IFD (IFD patients), type of IFD, time of IFD, choice of antifungal agent, duration, and success of therapy were investigated. For comparison, patients without IFD (non-IFD patients) were selected by propensity score matching using treatment-independent variables (age, gender, height, weight, and the Sequential Organ Failure Assessment (SOFA) score at ICU admission). Demographics, hospital and ICU length of stay, duration of ECMO therapy, days on mechanical ventilation, prognostic scores (Charlson Comorbidity Index (CCI), Therapeutic Intervention Scoring System (TISS), and length of survival were assessed. Results: A total of 646 patients received ECMO, 368 patients received VV ECMO. The incidence of IFD on VV ECMO was 5.98%, with 5.43% for Candida bloodstream infections (CBSI) and 0.54% for invasive aspergillosis (IA). In IFD patients, in-hospital mortality was 81.8% versus 40.9% in non-IFD patients. The hazard ratio for death was 2.5 (CI 1.1–5.4; p: 0.023) with IFD. Conclusions: In patients on VV ECMO for ARDS, about one in 17 contracts an IFD, with a detrimental impact on prognosis. Further studies are needed to address challenges in the diagnosis and treatment of IFD in this population.

Diagnosis and Management of Invasive Candida Infections in Critically Ill Patients.

Invasive candidiasis (IC) has become a serious problem in the intensive care unit patients with an attributable mortality rate that can reach up to 51%. Multiple global surveillance studies have shown an increasing incidence of candidemia. Despite their limited sensitivity (21-71%), cultures remain the gold standard for the diagnosis of IC associated with candidemia. Many adjunct laboratory tests exist to support or rule out the diagnosis, each with its indications and limitations, including procalcitonin, 1,3-β-D-glucan, mannan and anti-mannan antibodies, and Candida albicans germ tube antibody. In addition, polymerase chain reaction-based methods could expedite species identification in positive blood cultures, helping in guiding early empirical antifungal therapy. The management of IC in critically ill patients can be classified into prophylactic, preemptive, empiric, and directed/targeted therapy of a documented infection. There is no consensus concerning the benefit of prophylactic therapy in critically ill patients. While early initiation of appropriate therapy in confirmed IC is an important determinant of survival, the selection of candidates and drug of choice for empirical systemic antifungal therapy is more controversial. The choice of antifungal agents is determined by many factors, including the host, the site of infection, the species of the isolated Candida, and its susceptibility profile. Echinocandins are considered initial first-line therapy agents. Due to the conflicting results of the various studies on the benefit of preemptive therapy for critically ill patients and the lack of robust evidence, the Infectious Diseases Society of America (IDSA) omitted this category from its updated guidelines and the European Society of Intensive Care Medicine (ESICM) and the Critically Ill Patients Study Group of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) do not recommend it.

Fluconazole vs. voriconazole prophylaxis for prevention of invasive fungal infections post haploidentical stem cell transplant.

e19504 Background: IFIs are one of the most detrimental complications of profound and prolonged neutropenia post-allogeneic SCT. Prophylaxis with broad spectrum azole antifungals has become standard of care given favorable outcomes associated with their use in this setting. Nonetheless, the choice of antifungal agent varies between institutions due to absence of consensus guidelines in patients undergoing haploidentical SCT. Methods: Non-interventional retrospective study seeking to compare efficacy of fluconazole vs. voriconazole for prevention of IFI post haploidentical SCT for hematologic malignancies. SCT databases at two academic insitutions (one uses fluconazole and other uses voriconazole) were queried to identify patients who underwent allogeneic SCT from April 2012 until March 2018, and received prophlaxis with either voriconazole (group I) or fluconazole (group II). Patients with intent to start prophylaxis with fluconazole or voriconazole were included, even if antifungal agent was changed later. Primary endpoint was cumulative incidence of breakthrough IFIs (based on MSG criteria) on day +100 and +180. Fisher exact test was used to compare rates of breakthrough IFIs between two cohorts. Secondary endpoint was overal survival (OS). Kaplan Meiers analysis was performed to compare OS on day +180 and 1-year post SCT. Results: The cohort included 141 patients (group I: 75 and group II: 66). Percentage of patients who underwent transplant for leukemia was higher in group I compared to group II (77.3% vs. 56.1%, p < 0.001). A haploidentical SCT was performed in 62.7% of patients in group I compared to 100% in group II (p < 0.001). All patients received non-myeloablative conditioning. There was no statistically significant difference in rates of IFIs between two groups on day +100 (0% in I vs. 4.5% in II, p = 0.9) and +180 (1.4% vs. 4.6%, p = 0.2). A significant difference in OS was noted on day +180 and at 1-year in univariate analysis (Table). Conclusions: Our findings suggest that prophylactic use of either voriconazole or fluconazole after haploidentical SCT is associated with low rates of IFIs. However, survival data favored voriconazole over fluconazole. [Table: see text]

ID: 1046 Antifungal prophylaxis in hematopoietic stem cell transplantation recipients: drug use evaluation at Vietnam National Institute of Hemotology and Blood transfusion


 
 
 
 *For correspondence:
 tungson94@gmail.com
 
 Competing interests: The authors declare that no competing interests exist.
 Received: 2017-07-13 
 Accepted: 2017-08-04
 Published: 2017-09-05
 
 Copyright The Author(s) 2017. This article is published with open access by BioMedPress (BMP).
 This article is distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0) which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. 
 
 
 
 
 Background: Hematopoietic stem cell transplantation (HSCT) recipients were known to be in high risk of fungal infection. However, not all HSCT patients need antifungal prophylaxis. The aim of this study was to describe the characteristics of the use of antifungal prophylaxis in hematopoietic stem cell transplantation recipients and to evaluate the appropriateness of use.
 Methods: In this observational prospective study, adult hematopoietic stem cell transplantation recipients without using antifungal treatment were recruited from start of stem cell transfusion in Vietnam National Institute of Hematology and Blood Transfusion (from April to December 2016) to end of antifungal prophylaxis or start of antifungal treatment. Appropriateness was defined based on National Comprehensive Cancer Network (NCCN) guidelines. Clinically significant Drug-drug interactions related to antifungals were defined based on Hansten and Horn’s Drug interaction and management 2013.
 Results: 38 patients (mean age: 35.7 ± 12.0; 57.9% male) were admitted, included 21 autologous and 17 allogeneic HSCT recipients. After HSCT, 3 deaths, 1 to ICU, 1 IFI. Azoles prophylaxis was given to 100% of patients with median 17.5 days (13 - 47.5). Fluconazole was the most used antifungal agents, in 94.7% of patients and 74.5% of episodes. 10 patients had been changed antifungal agents. Indication was appropriate in 44.7%, 0% in autologous and 100% in allogeneic group. In patients with appropriate indication, choice of antifungal agents was 100% appropriate. 100% of patients used inappropriate dosage, mostly lower than recommeded dosage with azoles. 12.7% had appropriate prophylactic time. Potential drug-drug interactions were identified in 92.1% of patients. Most frequent interactions involved azoles-diazepam (80.4% of episodes) and azoles-immunosuppressive drugs (49% of episodes).
 Conclusion: Our evaluation revealed a high proportion of inappropriate of antifungal prophylaxis. An antifungal stewardship programme is needed to strengthen rational use of antifungal in this specific circumstance.

Current Algorithms in Fungal Diagnosis in the Immunocompromised Host.

Invasive fungal diseases (IFDs) are a major cause of morbidity and mortality in immunocompromised patients such as patients with hematological malignancies or allogeneic hematopoietic stem cell transplant recipients. Whereas the definite diagnosis of IFD requires invasive diagnostic procedures, imaging and noninvasive diagnostic assays may help in decision making with regard to the institution and the choice of antifungal agents, the duration of therapy, surgical intervention, and monitoring of fungal manifestations.Unfortunately, signs and symptoms of IFD are often nonspecific in the immunocompromised patient. Therefore, in immunocompromised patients with suspected IFD, all samples collected need to be cultured for fungi, and, in the case of specimens obtained by invasive diagnostic procedures, also microscopically examined. For high sensitivity of the cultural and microscopic approaches, specific media and stains, respectively, are crucial. Non-culture based method such as the detection of galactomannan or ß-d-glucan and molecular tools such as polymerase chain reaction may help in the early diagnosis of IFD. Imaging studies may be indicative for IFD, but invasive diagnostics such as bronchoalveolar lavage and/or biopsy should be pursued in order to identify the causative pathogen. This chapter summarizes the current knowledge on diagnosing IFD and proposes practical help in the use of diagnostic tools.

Antifungal Prophylaxis in Lung Transplant Recipients.

Invasive fungal infection remains a serious postoperative complication in lung transplant recipients and is associated with significant morbidity and mortality. Although most lung transplant centers use antifungal prophylaxis, consensus on the strategy, choice of antifungal agent(s), route of administration, and duration of prophylaxis have not been established. This review provides an overview of the epidemiology and risk factors for common fungal infections seen in lung transplant recipients, evaluates the clinical efficacy and toxicity of the various antifungal agents used to prevent infection, and offers recommendations and opportunities for future research. Currently available data evaluating the efficacy of antifungal prophylaxis strategies is limited by a lack of prospective, randomized clinical trial data and variability in patient populations, prophylactic and immunosuppressive strategies, dosing, durations of use of antifungal agents, and definitions of invasive infection. There is controversy regarding significant risk factors for invasive fungal infection, which has limited the development and validation of targeted prophylactic strategies. Inhaled formulations of amphotericin B remain the most widely studied option for universal prophylaxis and have been shown to be effective in reducing the incidence of invasive Aspergillosis as compared with no prophylaxis. Concern over early postoperative extrapulmonary infection may suggest a benefit of initial prophylaxis with a systemic azole. Long-term use of systemic antifungals is not optimal due to emerging evidence of long-term toxicities. Multicenter, randomized trials are needed to ascertain the optimal prophylactic strategy in lung transplant recipients. New agents and delivery mechanisms may offer additional opportunities for comparative research.

Postoperative fungal endophthalmitis due to Basidiobolus ranarum: Report of a rare case

Postoperative fungal endophthalmitis is a significant cause of visual loss due to the rapid progress and severe inflammation. Management is dictated by the precise identification of fungus subspecies, choice of antifungal agent, and associated systemic features. We report a rare case caused by Basidiobolusranarum, never known to have caused endophthalmitis or any form of ocular infection or inflammation. A 59-year-old, Asian, immunocompetent, agriculturist presented with endophthalmitis on the 3 rd postoperative day. Smear and culture from the aqueous and vitreous samples detected a species of fungus called Basidiobolusranarum. Fungal endophthalmitis should be suspected even in patients who present in the early postoperative period and rare species considered even in immunocompetent individuals. Early detection and aggressive treatment is necessary for preventing morbidity or mortality due to these infections.

Candida infective endocarditis: an observational cohort study with a focus on therapy.

Candida infective endocarditis is a rare disease with a high mortality rate. Our understanding of this infection is derived from case series, case reports, and small prospective cohorts. The purpose of this study was to evaluate the clinical features and use of different antifungal treatment regimens for Candida infective endocarditis. This prospective cohort study was based on 70 cases of Candida infective endocarditis from the International Collaboration on Endocarditis (ICE)-Prospective Cohort Study and ICE-Plus databases collected between 2000 and 2010. The majority of infections were acquired nosocomially (67%). Congestive heart failure (24%), prosthetic heart valve (46%), and previous infective endocarditis (26%) were common comorbidities. Overall mortality was high, with 36% mortality in the hospital and 59% at 1 year. On univariate analysis, older age, heart failure at baseline, persistent candidemia, nosocomial acquisition, heart failure as a complication, and intracardiac abscess were associated with higher mortality. Mortality was not affected by use of surgical therapy or choice of antifungal agent. A subgroup analysis was performed on 33 patients for whom specific antifungal therapy information was available. In this subgroup, 11 patients received amphotericin B-based therapy and 14 received echinocandin-based therapy. Despite a higher percentage of older patients and nosocomial infection in the echinocandin group, mortality rates were similar between the two groups. In conclusion, Candida infective endocarditis is associated with a high mortality rate that was not impacted by choice of antifungal therapy or by adjunctive surgical intervention. Additionally, echinocandin therapy was as effective as amphotericin B-based therapy in the small subgroup analysis.

Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2014.

There is a strong argument for the use of antifungal prophylaxis in high-risk patients given the significant mortality associated with invasive fungal disease, the late identification of these infections, and the availability of safe and well-tolerated prophylactic medications. Clinical decisions about which patients should receive prophylaxis and choice of antifungal agent should be guided by risk stratification, knowledge of local fungal epidemiology, the efficacy and tolerability profile of available agents, and estimates such as number needed to treat and number needed to harm. There have been substantial changes in practice since the 2008 guidelines were published. These include the availability of new medications and/or formulations, and a focus on refining and simplifying patient risk stratification. Used in context, these guidelines aim to assist clinicians in providing optimal preventive care to this vulnerable patient demographic.

Invasive Fungal Infections in the ICU: How to Approach, How to Treat

Invasive fungal infections are a growing problem in critically ill patients and are associated with increased morbidity and mortality. Most of them are due to Candida species, especially Candida albicans. Invasive candidiasis includes candidaemia, disseminated candidiasis with deep organ involvement and chronic disseminated candidiasis. During the last decades rare pathogenic fungi, such as Aspergillus species, Zygomycetes, Fusarium speciesand Scedosporium have also emerged. Timely diagnosis and proper treatment are of paramount importance for a favorable outcome. Besides blood cultures, several laboratory tests have been developed in the hope of facilitating an earlier detection of infection. The antifungal armamentarium has also been expanded allowing a treatment choice tailored to individual patients’ needs. The physician can choose among the old class of polyenes, the older and newer azoles and the echinocandins. Factors related to patient’s clinical situation and present co-morbidities, local epidemiology data and purpose of treatment (prophylactic, pre-emptive, empiric or definitive) should be taken into account for the appropriate choice of antifungal agent.

Chemoprophylaxis of neonatal fungal infections in very low birthweight infants: efficacy and safety of fluconazole and nystatin

To review the use of antifungal chemoprophylaxis to prevent neonatal invasive fungal infections (IFI) in very low birthweight infants (VLBW <1500 g). Systematic review of randomised controlled trials. Nine trials were identified (2029 infants), with six comparing fluconazole with placebo/no treatment (840 infants), three comparing nystatin with placebo/no treatment (1200 infants) and two comparing fluconazole and nystatin (257 infants). Prophylactic fluconazole reduced the incidence of IFI in VLBW infants <1500 g to 5.1% compared with 16.0% in infants receiving placebo, relative risk (RR) = 0.36 (95% confidence interval 0.15-0.89). The mortality was 10.9% and 16.7%, respectively (RR 0.76, 0.54-1.08). Oral nystatin reduced the incidence of IFI in VLBW infants to 5.3% compared with 28.0% in infants receiving placebo (RR 0.16, 0.11-0.23). Mortality was 7.5% with nystatin and 10.9% with placebo (RR 0.86, 0.59-1.26). The incidence of IFI in studies comparing fluconazole and nystatin was 3.6% and 8.0%, respectively (RR 0.54, 0.19-1.56), and mortality was not significantly different: 4.6% versus 9.8% (RR 0.43, 0-4.31) Prophylactic fluconazole and oral nystatin are both highly effective in preventing IFI in VLBW infants. Both agents are safe without significant toxicities. Antifungal prophylaxis should therefore be used in all VLBW infants. Given the paucity of data comparing fluconazole with nystatin, the choice of antifungal agent should be influenced by the incidence of IFI, local epidemiology and relative cost.

Candida Urinary Tract Infections—Treatment

In many instances a report from the clinical laboratory indicating candiduria represents colonization or procurement contamination of the specimen and not invasive candidiasis. Even if infection of the urinary tract by Candida species can be confirmed, antifungal therapy is not always warranted. Further investigation may reveal predisposing factors, which if corrected or treated, result in the resolution of the infection. For those with symptomatic urinary tract infections (UTIs), the choice of antifungal agent will depend upon the clinical status of the patient, the site of infection, and the pharmacokinetics and pharmacodynamics of the agent. Because of its safety, achievement of high concentrations in the urine, and availability in both an oral and intravenous formulation, fluconazole is preferred for the treatment of Candida UTIs. Flucytosine is concentrated in urine and has broad activity against Candida spp, but its use requires caution because of toxicity. Low-dose amphotericin B may be useful for Candida UTIs in selected patients. The role of echinocandins and azoles that do not achieve measurable concentrations in the urine is not clear. Small case series note some success, but failures have also occurred. Irrigation of the bladder with antifungal agents has limited utility. However, with fungus balls, irrigation of the renal pelvis through a nephrostomy tube can be useful in combination with systemic antifungal agents.

Emprirical Antifungal Therapy of Persistent Neutropenic Fever After Allogeneic Hematopoietic Stem Cell Transplantation With Caspofungin or Liposomal Amphotericin B

Caspofungin and liposomal amphotericin B (L-ampho B) have shown similar efficacy for the treatment of persistent febrile neutropenia (PFN). Although patients undergoing allogeneic stem cell transplantation (allo-SCT) are at high risk of life-threatening invasive fungal infections (IFI), specific data on the best choice of antifungal agent in this setting are scarce.

Deep Skin Infection of Scedosporium apiospermum in a Patient with Refractory Idiopathic Thrombocytopenic Purpura

Infection of Scedosporium apiospermum is very rare but is now emerging as an important cause of both localized and disseminated infections in immunocompromised patients. A 62-year-old woman, who had undergone steroid therapy for refractory idiopathic thrombocytopenic purpura and had a history of diffuse large B cell lymphoma, developed a deep skin ulcer complicated with lymphangitis. After culture study demonstrated the presence of S. apiospermum, voriconazole (VRCZ) was administered and prompt improvement was observed. Because it is difficult to distinguish S. apiospermum from Aspergillus by histopathology and S. apiospermum is resistant to amphotericin B, VRCZ should be selected as the first choice of antifungal agent when mold is considered to be the causative organism.

In Vitro Interactions Between Antifungals and Methotrexate Against Aspergillus spp.

Methotrexate has been widely used in the treatment of osteosarcoma, intracranial lymphomas and leukemia. However, patients are also at high risk of opportunist pathogens such as Aspergillus spp. infection for their deeply depressed immunity. The optimal choice of antifungal agents during the infection of Aspergillus for these patients is necessary to be explored. In this study, we investigated the interactions between antifungals and methotrexate against Aspergillus in vitro. A total of 23 clinical isolates of Aspergillus spp. were studied. Microdilution checkerboard technique was performed to evaluate the interaction of methotrexate with voriconazole, itraconazole, terbinafine and amphotericin B. The highest rate of synergy was obtained for the combination of terbinafine and methotrexate, which exhibited synergy against 60.9% (14/23) of strains. No interaction was detected for the combinations of methotrexate plus itraconazole or amphotericin B against 95.7% (22/23) or 100% of strains, respectively. Although voriconazole exhibited indifferent against 87% (20/23) of strains when combined with methotrexate, antagonism effect was found against 13% (3/23) of strains. The positive interactions of terbinafine and methotrexate were also certified by disk diffusion assay. In addition, we observed the morphological changes for the interaction of methotrexate with terbinafine against Aspergillus. Further inhibition and distortion of growth were found after the combination of terbinafine and methotrexate compared with the drugs treated alone. Clinical studies are warranted to further elucidate optimal treatments for the immunocompromised patients with Aspergillus infection.

Posaconazole Therapeutic Drug Monitoring: a Reference Laboratory Experience

We read with great interest the review by Andes et al. (1) describing antifungal therapeutic drug monitoring (TDM). We agree that there are limited data suggesting serum posaconazole concentrations predict the efficacy of prophylaxis or treatment with this agent. Prior studies have reported only mean serum drug levels by patient group (those with breakthrough invasive fungal infections versus those who remained uninfected) or by quartile with an average response rate to therapy (2, 5, 7-9). Serum posaconazole levels have also been repeatedly shown to have a large degree of interpatient variability (4-7). However, it is our experience that undetectable posaconazole levels are commonly encountered despite attempts to maximize absorption. One of two early posaconazole prophylaxis studies reported mean serum posaconazole levels of 1.470 μg/ml in patients with chronic graft-versus-host disease (GVHD) and 0.958 μg/ml in those with acute GVHD (8) However, the average posaconazole levels were 0.611 μg/ml in patients who developed breakthrough infection and 0.922 μg/ml in those who remained uninfected (5). The other and concurrently published prophylaxis study reported a mean serum posaconazole level of 0.583 ± 381 μg/ml—a mean value below the average of those who experienced breakthrough infection in the aforementioned GVHD prophylaxis study (2). A study evaluating posaconazole as salvage therapy for invasive aspergillosis correlated therapeutic response to serum drug concentrations by quartiles and found those with a mean serum drug level of 0.134 μg/ml had only a 24% response rate (9). Additionally, the FDA briefing document recommends a goal posaconazole average serum drug concentration of >0.700 μg/ml (3). We retrospectively reviewed 202 consecutive serum posaconazole concentrations obtained between 26 December 2007 and 30 December 2008 by The Fungus Testing Laboratory, San Antonio, TX, a reference laboratory specializing in fungal identification, susceptibility testing, and antifungal drug concentrations. Drug levels were obtained with a validated high-performance liquid chromatography assay (range, 0.125 to 5.0 μg/ml [equipment manufactured by Beckman Coulter, Fullerton, CA]). Levels less than 0.125 μg/ml were reported as undetectable, and levels greater than 5.0 μg/ml were diluted 1:2, reextracted, and reanalyzed. Our review confirmed the infrequent obtainment of levels suggestive of efficacy as described above. In our series, 158/202 (78.2%) posaconazole levels were <0.92 μg/ml and 135/202 (66.8%) were <0.611 μg/ml, a value that may represent patients at increased risk of breakthrough infection while receiving posaconazole prophylaxis. Although the exact value known to be therapeutic in the treatment of invasive mycoses has not been determined, it is noteworthy that 33/202 (16.3%) in our series were undetectable (<0.125), 35/202 (17.3%) were <0.134 μg/ml (the value associated with only a 24% response rate in posaconazole use as salvage therapy for invasive aspergillosis), and 142/202 (70.3%) were <0.700 μg/ml (the value cited by the FDA to place patients at increased risk) (Fig. ​(Fig.11). FIG. 1. Distribution of serum posaconazole levels obtained by the Fungus Testing Laboratory, San Antonio, TX, from 26 December 2007 through 30 December 2008. When drug concentrations thought to be subtherapeutic are observed, attempts at maximizing drug availability/absorption should be undertaken. Strategies proven to maximize posaconazole exposure include administration with or after a high-fat meal, with any meal or nutritional supplement, with an acidic beverage, or in divided doses and with the avoidance of acid suppression drugs (6). However, it is common for low serum posaconzole levels to be found despite these maneuvers, and these differences observed between serum drug levels within clinical trials and “real-world” use may have an important clinical impact on the frequency of TDM and choice of antifungal agent. We thus recommend repeat testing of serum posaconazole levels after the above attempts to maximize absorption. Although previous reports have questioned the need for TDM with posaconazole pending outcome studies based on levels, our data suggest that testing should be performed to ensure that measurable drug is present and therefore has the potential for efficacy.

Treatment of critically ill patients with candidemia

Early initiation of effective antimicrobial therapy is crucial for the prognosis of any infection, especially in the critically ill patient. This is particularly true in the case of candidemia. However, the earlier an empirical antimicrobial regimen is started, the greater the probability of diagnostic error and the possibility of side-effects. Recent experience of the clinical efficacy and good tolerance of echinocandins in the treatment of candidemia obliges us to review the indications for empirical antifungal treatment and the choice of antifungal agent in the critically ill patient.

Management of candidiasis in the intensive care unit

In the last two decades, Candida has emerged as an important opportunistic pathogen. Patients admitted to the intensive care unit (ICU) are particularly susceptible to this infection because of the severity of their underlying illness and the excess use of medical and surgical interventions. The frequent use of antibiotics, central venous catheters and other intravascular devices as well as poor gut motility or abdominal surgery place these patients at high risk of infection, which contributes to the morbidity and mortality of the already critically ill patient. Early recognition and appropriate management of invasive candidiasis are therefore important. This article addresses important management issues such as the role of screening for Candida colonization, the use of prophylaxis and the choice of antifungal agents for the treatment of presumed and proven invasive candidiasis in the adult ICU setting.