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International Journal of Antimicrobial... Aug 2022Invasive candidiasis is the most common fungal infection in patients attending health services and is associated with high mortality rates and prolonged hospital stay.... (Meta-Analysis)
Meta-Analysis
AIM
Invasive candidiasis is the most common fungal infection in patients attending health services and is associated with high mortality rates and prolonged hospital stay. The aim of this review was to evaluate and compare efficacy and safety of antifungal agents for the treatment of candidemia.
METHODS
A systematic review with network meta-analysis (NMA), surface under the cumulative ranking analysis (SUCRA) and stochastic multicriteria acceptability analyses (SMAA) was performed (PROSPERO-CRD42020149264). Searches were conducted in PubMed and Scopus (Nov-2021). Randomised controlled trials evaluating the effect of oral antifungals (any dose or regimen) on mycological cure, discontinuation rates and adverse events were included.
RESULTS
Overall, 13 trials (n=3632) were analysed. There were no significant differences between therapies for the efficacy outcomes; however, caspofungin (50-150 mg), rezafungin (200-400 mg) and micafungin (100-150 mg) had higher rates of clinical and mycological responses (SUCRA overall response >60%) and were considered the most promising therapies. Fluconazole (400 mg) rated worst for overall response (17%). Rezafungin (200-400 mg) and micafungin (100 mg) were associated with lower discontinuation rates (<40%). Conventional amphotericin B (0.6-0.7 mg/kg) was more likely to be discontinued (odds ratio [OR] 0.08; 95% credibility interval [CrI] 0.00-0.95 vs. caspofungin 150 mg) and may impair liver function (87%).
CONCLUSION
Echinocandins are recommended as first-line treatments for invasive candidiasis following a priority order of caspofungin then micafungin. Rezafungin, an echinocandin under development, represents a potential option that should be further investigated. Azoles and liposomal amphotericin B can be used as second-line treatments in cases of fungal resistance or hypersensitivity.
Topics: Antifungal Agents; Candidemia; Candidiasis, Invasive; Caspofungin; Echinocandins; Humans; Lipopeptides; Micafungin; Network Meta-Analysis
PubMed: 35691603
DOI: 10.1016/j.ijantimicag.2022.106614 -
International Journal of Antimicrobial... Feb 2024The use of extracorporeal membrane oxygenation (ECMO) as a cardiocirculatory or respiratory support has tremendously increased in critically ill patients. In the setting...
BACKGROUND AND OBJECTIVE
The use of extracorporeal membrane oxygenation (ECMO) as a cardiocirculatory or respiratory support has tremendously increased in critically ill patients. In the setting of ECMO support, invasive fungal infections are a severe cause of morbidity and mortality. This vulnerable population is at risk of suboptimal antifungal exposure due to an increased volume of distribution (Vd), drug sequestration and decreased clearance. Here, we aimed to summarize ex-vivo and clinical studies on the potential impact of ECMO on the pharmacokinetics (PK) of antifungal agents and dosing requirements.
METHODS
A systematic search of the literature within electronic databases PubMed and EMBASE was conducted from database inception to 30 April 2023. Inclusion criteria were as follows: critically ill patients receiving ECMO regardless of age and reporting at least one PK parameter.
RESULTS
Thirty-six studies met inclusion criteria, including seven ex-vivo experiments and 29 clinical studies evaluating three classes of antifungals: polyenes, triazoles and echinocandins. Based on the available ex-vivo PK data, we found a significant sequestration of highly lipophilic and protein-bound antifungals within the ECMO circuit such as voriconazole, posaconazole and micafungin but the PK of several antifungals remains to be addressed such as amphotericin B, isavuconazole and anidulafungin. Most clinical studies have shown increased Vd of some antifungals like fluconazole and micafungin, particularly in the pediatric population. Conflicting data exist about caspofungin exposure.
CONCLUSIONS
The available literature on the antifungal PK changes in ECMO setting is scarce. Whenever possible, therapeutic drug monitoring is highly advised to personalize antifungal therapy.
Topics: Humans; Antifungal Agents; Caspofungin; Critical Illness; Extracorporeal Membrane Oxygenation; Micafungin
PubMed: 38161046
DOI: 10.1016/j.ijantimicag.2023.107078 -
BMC Infectious Diseases Nov 2020Candida auris is a new pathogen called "superbug fungus" which caused panic worldwide. There are no large-scale epidemiology studies by now, therefore a systematic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Candida auris is a new pathogen called "superbug fungus" which caused panic worldwide. There are no large-scale epidemiology studies by now, therefore a systematic review and meta-analysis was undertaken to determine the epidemic situation, drug resistance patterns and mortality of C. auris.
METHODS
We systematically searched studies on the clinical report of Candida auris in Pubmed, Embase and Cochrane databases until October 6, 2019. A standardized form was used for data collection, and then statics was performed with STATA11.0.
RESULTS
It showed that more than 4733 cases of C. auris were reported in over 33 countries, with more cases in South Africa, United States of America, India, Spain, United Kingdom, South Korea, Colombia and Pakistan. C. auirs exhibited a decrease in case count after 2016. Clade I and III were the most prevalent clades with more cases reported and wider geographical distribution. Blood stream infection was observed in 32% of the cases, which varied depending on the clades. Resistance to fluconazole, amphotericin B, caspofungin, micafungin and anidulafungin in C. auris were 91, 12, 12.1, 0.8 and 1.1%. The overall mortality of C. auris infection was 39%. Furthermore, subgroup analyses showed that mortality was higher in bloodstream infections (45%), and lower in Europe (20%).
CONCLUSIONS
Over 4000 cases of C. auris were reported in at least 33 countries, which showed high resistance to fluconazole, moderate resistance to amphotericin B and caspofungin, high sensitivity to micafungin and anidulafungin. The crude mortality for BSI of C. auris was 45% which was similar to some drug-resistant bacteria previously reported. In conclusion, C. auris displayed similar characteristics to some drug resistance organisms. This study depicts several issues of C. auris that are most concerned, and is of great significance for the clinical management.
Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Candida; Candidiasis; Caspofungin; Drug Resistance, Multiple, Fungal; Fluconazole; Humans; Micafungin; Prevalence
PubMed: 33176724
DOI: 10.1186/s12879-020-05543-0 -
Frontiers in Pharmacology 2021Invasive fungal infections (IFI) is an important contributing factor in morbidity and mortality of immunocompromised and critically ill patients. Although the... (Review)
Review
Invasive fungal infections (IFI) is an important contributing factor in morbidity and mortality of immunocompromised and critically ill patients. Although the therapeutic effects of these drugs on IFI have been well documented, the long-term use of antifungal agents has raised concerns about drug tolerability and treatment-related toxicity risks. We searched articles published before June 30, 2020 in four electronic databases: Web of Science, Cochrane Library, embase and PubMed. 66 trials were determined to meet our inclusion criteria, providing data on 18,230 participants. We sorted out 23 AEs by system organ classes and six laboratory AEs, 13 of these were used to construct 13 network meta-analyses. Compared with LAmB, anidulafungin, caspofungin, micafungin, fluconazole, and posaconazole had a significantly low incidence of discontinuation of therapy due to AEs (OR = 0.24 (0.09,0.65), 0.24 (0.13,0.43), 0.32 (0.19,0.52), 0.38 (0.23,0.62) and 0.35 (0.17,0.69), respectively). We found that echinocandins are the most tolerated antifungal agents with high safety. The AEs of triazole drugs are mainly concentrated on the increase in liver enzymes, nervous system disorders, especially visual disorders, gastrointestinal disorders, and cardiac diseases. LAmB is the least tolerated and has the most abundant AEs.
PubMed: 34776941
DOI: 10.3389/fphar.2021.697330 -
Mycoses Sep 2019Candida resistance to antifungals impaired invasive candidiasis outcome. In a context of echinocandin resistance development, we aimed to evaluate the association... (Meta-Analysis)
Meta-Analysis
Comparison of fks gene mutations and minimum inhibitory concentrations for the detection of Candida glabrata resistance to micafungin: A systematic review and meta-analysis.
Candida resistance to antifungals impaired invasive candidiasis outcome. In a context of echinocandin resistance development, we aimed to evaluate the association between phenotypic resistance to micafungin and fks mutations of Candida glabrata. For this systematic review and meta-analysis, we searched MEDLINE, Scopus and Web of Science for reports published up to December 2017. Studies of C glabrata candidiasis with minimum inhibitory concentrations (MIC) determination of micafungin and fks genotyping were included. Reviews, studies not using reference methods, non-glabrata Candida, experimental isolates and undetailed mutations were excluded. Two authors independently assessed the eligibility of articles and extracted data. The main outcome was the diagnostic accuracy of fks mutations compared to micafungin MIC for C glabrata, measured as fixed-effect odd ratio. Heterogeneity was calculated with the I statistic. This study is registered with PROSPERO (CRD42018082023). Twenty-four studies were included in the meta-analysis. Pooled analysis found that S663P (OR 7.25, 95% CI 3.50-15.00; P < 0.00001), S629P (OR 3.70, 1.64-8.33; P = 0.002) and F659del (OR 5.66, 1.22-26.18; P = 0.03) were associated with increased risk of having a resistant isolate according to authors' interpretation of MICs. In sensitivity analysis based on new CLSI clinical breakpoints, the ORs for S663P and S629P remained significant. Genotyping of isolates of C glabrata for S663P and S629P mutations is an effective alternative to micafungin susceptibility tests. Relevant molecular markers of drug resistance will significantly improve the management of C glabrata infections.
Topics: Antifungal Agents; Candida glabrata; Candidiasis; Drug Resistance, Fungal; Fungal Proteins; Genotype; Humans; Micafungin; Microbial Sensitivity Tests; Mutation
PubMed: 31077631
DOI: 10.1111/myc.12929 -
Journal of Clinical Pharmacy and... Dec 2020Anidulafungin, caspofungin and micafungin are three widely used echinocandin drugs licensed for the treatment of invasive fungal infections, and their clinical use is... (Comparative Study)
Comparative Study Meta-Analysis
WHAT IS KNOWN AND OBJECTIVE
Anidulafungin, caspofungin and micafungin are three widely used echinocandin drugs licensed for the treatment of invasive fungal infections, and their clinical use is widespread. To evaluate pharmacokinetic/pharmacodynamics variability of echinocandins in critically ill patients by comparing the differences in pharmacokinetic parameters between critically ill patients and healthy volunteers or general patients.
METHODS
MEDLINE, EMBASE, The Cochrane Library and Pubmed were searched from inception until 6 September 2018. Studies investigating the pharmacokinetic parameters of echinocandins in critically ill patients, healthy volunteers or general patients were included. Our primary outcomes included AUC , C and C (24 hours). Two reviewers independently reviewed all titles, abstracts and text, and extracted data. We applied R software (R 2017) to conduct meta-analysis.
RESULTS AND DISCUSSION
Of 3235 articles screened, 17 studies were included in the data synthesis. Descriptive data from single-arm studies show that critically ill patients who received caspofungin had more stable AUC than those who received anidulafungin and micafungin. The C of critically ill patients who received caspofungin and micafungin was similar to healthy volunteers. However, the C in critically ill patients who received anidulafungin was lower than in healthy volunteers. The C and T of critically ill patients who received caspofungin were larger than in healthy volunteers. The V and CL of critically ill patients receiving anidulafungin and micafungin were larger than in healthy volunteers.
WHAT IS NEW AND CONCLUSION
This systematic review provides an analysis of the pharmacokinetic/pharmacodynamics variability of echinocandins in critically ill patients. Based on the limited data available, caspofungin has less pharmacokinetic/pharmacodynamics variability than anidulafungin and micafungin.
Topics: Anidulafungin; Antifungal Agents; Area Under Curve; Caspofungin; Critical Illness; Echinocandins; Humans; Invasive Fungal Infections; Micafungin
PubMed: 32672361
DOI: 10.1111/jcpt.13211 -
Open Forum Infectious Diseases Jun 2024is a World Health Organization critical priority fungal pathogen. We conducted a systematic review to describe its epidemiology in Africa. PubMed and Google scholar... (Review)
Review
is a World Health Organization critical priority fungal pathogen. We conducted a systematic review to describe its epidemiology in Africa. PubMed and Google scholar databases were searched between January 2009 and September 2023 for clinical studies on cases and/or isolates from Africa. Reviews were excluded. We included 19 studies, involving at least 2529 cases from 6 African countries with the most, 2372 (93.8%), reported from South Africa. Whole-genome sequencing of 127 isolates identified 100 (78.7%) as clade III. Among 527 isolates, 481 (91.3%) were resistant to fluconazole, 108 (20.5%) to amphotericin B, and 9 (1.7%) to micafungin. Ninety of 211 (42.7%) patients with clinical outcomes died. is associated with high mortality and antifungal resistance, yet this critical pathogen remains underreported in Africa. Collaborative surveillance, fungal diagnostics, antifungals, and sustainable infection control practices are urgently needed for containment.
PubMed: 38887473
DOI: 10.1093/ofid/ofad681 -
Journal de Mycologie Medicale May 2023Systemic candidiasis is caused by Candida invading the bloodstream. The efficacy and safety of echinocandins in monotherapy and combination therapy regimes have not been... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Systemic candidiasis is caused by Candida invading the bloodstream. The efficacy and safety of echinocandins in monotherapy and combination therapy regimes have not been adequately compared in immunocompromised patients with Candidiasis, and thus this systematic review aims to do so.
METHODS
A protocol was prepared a priori. PubMed, Embase and Cochrane Library databases were searched systematically (from inception of each database to September 2022) to identify randomized controlled trials. Two reviewers performed screening, quality assessment of trials, and extracted data independently. Pairwise meta-analysis was performed using random-effects model to compare echinocandin monotherapy versus other antifungals. The primary outcomes of interest were treatment success and treatment-related adverse events.
RESULTS
547 records (PubMed=310, EMBASE=210 and Cochrane Library=27) were reviewed. Following our screening criteria, six trials involving 177 patients were included. Risk of bias of four included studies had some concerns due to lack of a pre-specified analysis plan. Meta-analysis shows that echinocandin monotherapy does not have significantly higher rates of "treatment success" compared to other classes of antifungals (RR 1.12, 95%CI 0.80-1.56). However, echinocandins appeared to be significantly safer than other forms of antifungal therapy (RR 0.79, 95%CI 0.73-0.86).
CONCLUSION
Our findings have shown that echinocandin monotherapy (micafungin, caspofungin) given intravenously are just as effective as other antifungals (amphotericin B, itraconazole) in the treatment of systemic candidiasis in immunocompromised patients. There appears to be similar benefits when using echinocandins compared to amphotericin B which has also been used as a broad-spectrum antifungal, while avoiding the severe adverse effects that amphotericin B causes, such as nephrotoxicity.
Topics: Humans; Antifungal Agents; Echinocandins; Amphotericin B; Candidiasis; Immunocompromised Host; Lipopeptides
PubMed: 36867970
DOI: 10.1016/j.mycmed.2023.101362 -
Frontiers in Pediatrics 2020This study aimed to identify alterations in pharmacokinetics in children on extracorporeal membrane oxygenation (ECMO), identify knowledge gaps, and inform future...
This study aimed to identify alterations in pharmacokinetics in children on extracorporeal membrane oxygenation (ECMO), identify knowledge gaps, and inform future pharmacology studies. We systematically searched the databases MEDLINE, CINAHL, and Embase from earliest publication until November 2018 using a controlled vocabulary and keywords related to "ECMO" and "pharmacokinetics," "pharmacology," "drug disposition," "dosing," and "pediatrics." Inclusion criteria were as follows: study population aged <18 years, supported on ECMO for any indications, received any medications while on ECMO, and reported pharmacokinetic data. Clearance and/or volume of distribution values were extracted from included studies. Forty-one studies (total patients = 574) evaluating 23 drugs met the inclusion criteria. The most common drugs studied were antimicrobials ( = 13) and anticonvulsants ( = 3). Twenty-eight studies (68%) were conducted in children <1 year of age. Thirty-three studies (80%) were conducted without intra-study comparisons to non-ECMO controls. Increase in volume of distribution attributable to ECMO was demonstrated for nine (56%) drugs: cefotaxime, gentamicin, piperacillin/tazobactam, fluconazole, micafungin, levetiracetam, clonidine, midazolam, and sildenafil (range: 23-345% increase relative to non-ECMO controls), which may suggest the need for higher initial dosing. Decreased volume of distribution was reported for two drugs: acyclovir and ribavirin (50 and 69%, respectively). Decreased clearance was reported for gentamicin, ticarcillin/clavulanate, bumetanide, and ranitidine (range: 26-95% decrease relative to non-ECMO controls). Increased clearance was reported for caspofungin, micafungin, clonidine, midazolam, morphine, and sildenafil (range: 25-455% increase relative to non-ECMO controls). There were substantial pharmacokinetic alterations in 70% of drugs studied in children on ECMO. However, studies evaluating pharmacokinetic changes of many drug classes and those that allow direct comparisons between ECMO and non-ECMO patients are still lacking. Systematic evaluations of pharmacokinetic alterations of drugs on ECMO that incorporate multidrug opportunistic trials, physiologically based pharmacokinetic modeling, and other methods are necessary for definitive dose recommendations. : CRD42019114881.
PubMed: 32670992
DOI: 10.3389/fped.2020.00260 -
Mycoses Sep 2020Chronic pulmonary aspergillosis (CPA) is a potentially life-threatening debilitating lung disease necessitating long-term oral antifungal treatment. However, development... (Meta-Analysis)
Meta-Analysis
Chronic pulmonary aspergillosis (CPA) is a potentially life-threatening debilitating lung disease necessitating long-term oral antifungal treatment. However, development of antifungal-resistant isolates of Aspergillus and major toxicities requiring discontinuation of treatment limits their use. Intravenous (IV) antifungals are an option in this group of patients. We comprehensively evaluate the response rates to IV antifungals in the management of CPA. We searched Medline and Embase databases to select clinical studies providing information about IV amphotericin B or an echinocandin for the treatment of CPA from inception to May 2020. Reviews, single-case reports and case series reporting <10 patients were excluded. We evaluated 12 eligible studies. A total of 380 patients received amphotericin B (n = 143) or an echinocandin (n = 237) and were included in the meta-analysis. In a pooled analysis, overall response to IV antifungals was 61% ((95% confidence interval (CI): 52%-70%; I = 73.3%; P < .001), to amphotericin B was 58% (95% CI: 36%-80%; I = 86.6%; P < .001) and to echinocandins was 62% (95% CI: 53%-72%; I = 63.6%; P < .001). Amphotericin B courses were usually doses at slightly <1 mg/Kg (deoxycholate) or 3 mg/Kg (liposomal) for 2-3 weeks. Micafungin doses varied from 12.5 to 300 mg (frequently, 150 mg) daily for at least 3 weeks, and sometimes much longer. Liposomal amphotericin B was well tolerated, but led to renal function loss in 25% of patients. Adverse events were observed in 5-35.3% of patients receiving echinocandins, none of which was considered major. Intravenous antifungals have a place in the management of CPA. A head-to-head comparison of amphotericin B and echinocandins is lacking, and future studies should look at evaluating short- and longer-term outcomes of these agents.
Topics: Administration, Intravenous; Antifungal Agents; Chronic Disease; Disease Management; Echinocandins; Humans; Pulmonary Aspergillosis
PubMed: 32542771
DOI: 10.1111/myc.13131