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The Lancet. Haematology May 2022On the basis of improved overall survival, treatment guidelines strongly recommend antifungal prophylaxis during remission induction chemotherapy for patients with acute... (Review)
Review
Antifungal prophylaxis in adult patients with acute myeloid leukaemia treated with novel targeted therapies: a systematic review and expert consensus recommendation from the European Hematology Association.
On the basis of improved overall survival, treatment guidelines strongly recommend antifungal prophylaxis during remission induction chemotherapy for patients with acute myeloid leukaemia. Many novel targeted agents are metabolised by cytochrome P450, but potential drug-drug interactions (DDIs) and the resulting risk-benefit ratio have not been assessed in clinical trials, leading to uncertainty in clinical management. Consequently, the European Haematology Association commissioned experts in the field of infectious diseases, haematology, oncology, clinical pharmacology, and methodology to develop up-to-date recommendations on the role of antifungal prophylaxis and management of pharmacokinetic DDIs with triazole antifungals. A systematic literature review was performed according to Cochrane methods, and recommendations were developed by use of the Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision framework. We searched MEDLINE, Embase, and Cochrane Library, including Central Register of Controlled Trials, for randomised controlled trials and systematic reviews published from inception to March 10, 2020. We excluded studies that were not published in English. Evidence for any identified novel agent that is active against acute myeloid leukaemia was reviewed for the following outcomes: incidence of invasive fungal disease, prolongation of hospitalisation, days spent in intensive-care unit, mortality due to invasive fungal disease, quality of life, and potential DDIs. Recommendations and consensus statements were compiled for each targeted drug for patients with acute myeloid leukaemia and each specific setting. Evidence-based recommendations were developed for hypomethylating agents, midostaurin, and the venetoclax-hypomethylating agent combination. For all other agents, consensus statements were given for specific therapeutic settings, specifically for the management of patients with relapsed or refractory acute myeloid leukaemia, monotherapy, and combination with chemotherapy. Antifungal prophylaxis is recommended with moderate strength in most settings, and strongly recommended if the novel acute myeloid leukaemia agent is administered in combination with intensive induction chemotherapy. For ivosidenib, lestaurtinib, quizartinib, and venetoclax, we moderately recommend adjusting the dose of the antileukaemic agent during administration of triazoles. This is the first guidance supporting clinical decision making on antifungal prophylaxis in recipients of novel targeted drugs for acute myeloid leukaemia. Future studies including therapeutic drug monitoring will need to determine the role of dosage adjustment of novel antileukaemic drugs during concomitant administration of CYP3A4-inhibiting antifungals with respect to adverse effects and remission status.
Topics: Adult; Antifungal Agents; Hematology; Humans; Leukemia, Myeloid, Acute; Mycoses; Quality of Life; Triazoles
PubMed: 35483397
DOI: 10.1016/S2352-3026(22)00073-4 -
Clinical Reviews in Allergy & Immunology Aug 2023Vernal keratoconjunctivitis (VKC) is a chronic, bilateral corneal and conjunctival problem which typically presents in young individuals. VKC is characterized by... (Review)
Review
Vernal keratoconjunctivitis (VKC) is a chronic, bilateral corneal and conjunctival problem which typically presents in young individuals. VKC is characterized by itching, photophobia, white mucous discharge, lacrimation, foreign body sensation, and pain due to corneal involvement of shield ulcers. Vernal keratoconjunctivitis is categorized within ocular diseases. The diagnosis is clinical, as no sure biomarkers pathognomonic of the disease have yet been identified. The VKC therapy relies on different types of drugs, from antihistamines and topical steroids to cyclosporine or tacrolimus eye drops. In extremely rare cases, there is also the need for surgical treatment for the debridement of ulcers, as well as for advanced glaucoma and cataracts, caused by excessive prolonged use of steroid eye drops. We performed a systematic review of the literature, according to PRISMA guideline recommendations. We searched the PubMed database from January 2016 to June 2023. Search terms were Vernal, Vernal keratoconjunctivitis, and VKC. We initially identified 211 articles. After the screening process, 168 studies were eligible according to our criteria and were included in the review. In this study, we performed a systematic literature review to provide a comprehensive overview of currently available diagnostic methods, management of VKC, and its treatments.
Topics: Humans; Conjunctivitis, Allergic; Ulcer; Cyclosporine; Tacrolimus; Ophthalmic Solutions
PubMed: 37658939
DOI: 10.1007/s12016-023-08970-4 -
Journal of Fungi (Basel, Switzerland) Oct 2022The alarming spread and impact of multidrug-resistant infections alongside the limited therapeutic options have prompted the development of new antifungals. These... (Review)
Review
The alarming spread and impact of multidrug-resistant infections alongside the limited therapeutic options have prompted the development of new antifungals. These promising agents are currently in different stages of development, offering novel dosing regimens and mechanisms of action. A systematic search in MEDLINE, EMBASE, Web of Science, and Scopus up to 27 June 2022 was conducted to find relevant articles reporting data of in vitro activity and in vivo efficacy of investigational antifungals against . These included new additions to existing antifungal classes (rezafungin and opelconazole), first-in-class drugs such as ibrexafungerp, manogepix/fosmanogepix, olorofim and tetrazoles (quilseconazole, oteseconazole and VT-1598), as well as other innovative agents like ATI-2307, MGCD290 and VL-2397. From 592 articles retrieved in the primary search, 27 met the eligibility criteria. The most studied agent was manogepix/fosmanogepix (overall MIC: 0.03 mg/L), followed by ibrexafungerp (overall MIC: 1 mg/L) and rezafungin (overall MIC mode: 0.25 mg/L), while VT-1598 and ATI-2307 were the least explored drugs against . All these compounds demonstrated significant improvements in survival and reduction in tissue fungal burden on neutropenic animal models of candidemia due to . Continual efforts towards the discovery of new treatments against this multidrug-resistant fungus are essential.
PubMed: 36354911
DOI: 10.3390/jof8111144 -
The Cochrane Database of Systematic... Jan 2022Recurrent vulvovaginal candidiasis (RVVC) affects up to 5% of women. No comprehensive systematic review of treatments for RVVC has been published. (Review)
Review
BACKGROUND
Recurrent vulvovaginal candidiasis (RVVC) affects up to 5% of women. No comprehensive systematic review of treatments for RVVC has been published.
OBJECTIVES
The primary objective was to assess the effectiveness and safety of pharmacological and non-pharmacological treatments for RVVC. The secondary objective was to assess patient preference of treatment options.
SEARCH METHODS
We conducted electronic searches of bibliographic databases, including CENTRAL, MEDLINE, Embase, and CINAHL (search date 6 October 2021). We also handsearched reference lists of identified trials and contacted authors of identified trials, experts in RVVC, and manufacturers of products for vulvovaginal candidiasis.
SELECTION CRITERIA
We considered all published and unpublished randomised controlled trials evaluating RVVC treatments for at least six months, in women with four or more symptomatic episodes of vulvovaginal candidiasis in the past year. We excluded women with immunosuppressive disorders or taking immunosuppressant medication. We included women with diabetes mellitus and pregnant women. Diagnosis of RVVC must have been confirmed by presence of symptoms and a positive culture and/or microscopy. We included all drug and non-drug therapies and partner treatment, assessing the following primary outcomes: • number of clinical recurrences per participant per year (recurrence defined as clinical signs and positive culture/microscopy); • proportion of participants with at least one clinical recurrence during the treatment and follow-up period; and • adverse events.
DATA COLLECTION AND ANALYSIS
Two authors independently reviewed titles and abstracts to identify eligible trials. Duplicate data extraction was completed independently by two authors. We assessed risk of bias as described in the Cochrane Handbook for Systematic Reviews of Interventions. We used the fixed-effects model for pooling and expressed the results as risk ratio (RR) with 95% confidence intervals (CI). Where important statistical heterogeneity was present we either did not pool data (I > 70%) or used a random-effects model (I 40-70%). We used the GRADE tool to assess overall certainty of the evidence for the pooled primary outcomes.
MAIN RESULTS
Studies: Twenty-three studies involving 2212 women aged 17 to 67 years met the inclusion criteria. Most studies excluded pregnant women and women with diabetes or immunosuppression. The predominant species found on culture at study entry was Candida albicans. Overall, the included studies were small (<100 participants). Six studies compared antifungal treatment with placebo (607 participants); four studies compared oral versus topical antifungals (543 participants); one study compared different oral antifungals (45 participants); two studies compared different dosing regimens for antifungals (100 participants); one study compared two different dosing regimens of the same topical agent (23 participants); one study compared short versus longer treatment duration (26 participants); two studies assessed the effect of partner treatment (98 participants); one study compared a complementary treatment (Lactobacillus vaginal tablets and probiotic oral tablets) with placebo (34 participants); three studies compared complementary medicine with antifungals (354 participants); two studies compared 'dermasilk' briefs with cotton briefs (130 participants); one study examined Lactobacillus vaccination versus heliotherapy versus ciclopyroxolamine (90 participants); one study compared CAM treatments to an antifungal treatment combined with CAM treatments (68 participants). We did not find any studies comparing different topical antifungals. Nine studies reported industry funding, three were funded by an independent source and eleven did not report their funding source. Risk of bias: Overall, the risk of bias was high or unclear due to insufficient blinding of allocation and participants and poor reporting. Primary outcomes: Meta-analyses comparing drug treatments (oral and topical) with placebo or no treatment showed there may be a clinically relevant reduction in clinical recurrence at 6 months (RR 0.36, 95% CI 0.21 to 0.63; number needed to treat for an additional beneficial outcome (NNTB) = 2; participants = 607; studies = 6; I² = 82%; low-certainty evidence) and 12 months (RR 0.80, 95% CI 0.72 to 0.89; NNTB = 6; participants = 585; studies = 6; I² = 21%; low-certainty evidence). No study reported on the number of clinical recurrences per participant per year. We are very uncertain whether oral drug treatment compared to topical treatment increases the risk of clinical recurrence at 6 months (RR 1.66, 95% CI 0.83 to 3.31; participants = 206; studies = 3; I² = 0%; very low-certainty evidence) and reduces the risk of clinical recurrence at 12 months (RR 0.95, 95% CI 0.71 to 1.27; participants = 206; studies = 3; I² = 10%; very low-certainty evidence). No study reported on the number of clinical recurrences per participant per year. Adverse events were scarce across both treatment and control groups in both comparisons. The reporting of adverse events varied amongst studies, was generally of very low quality and could not be pooled. Overall the adverse event rate was low for both placebo and treatment arms and ranged from less than 5% to no side effects or complications.
AUTHORS' CONCLUSIONS
In women with RVVC, treatment with oral or topical antifungals may reduce symptomatic clinical recurrences when compared to placebo or no treatment. We were unable to find clear differences between different treatment options (e.g. oral versus topical treatment, different doses and durations). These findings are not applicable to pregnant or immunocompromised women and women with diabetes as the studies did not include or report on them. More research is needed to determine the optimal medication, dose and frequency.
Topics: Antifungal Agents; Candidiasis, Oral; Candidiasis, Vulvovaginal; Female; Humans; Immunosuppressive Agents; Pregnancy
PubMed: 35005777
DOI: 10.1002/14651858.CD009151.pub2 -
Antimicrobial Agents and Chemotherapy May 2024The prevalence of obesity has increased considerably in the last few decades. Pathophysiological changes in obese patients lead to pharmacokinetic (PK) and...
The prevalence of obesity has increased considerably in the last few decades. Pathophysiological changes in obese patients lead to pharmacokinetic (PK) and pharmacodynamic (PD) alterations that can condition the correct exposure to antimicrobials if standard dosages are used. Inadequate dosing in obese patients can lead to toxicity or therapeutic failure. In recent years, additional antimicrobial PK/PD data, extended infusion strategies, and studies in critically ill patients have made it possible to obtain data to provide a better dosage in obese patients. Despite this, it is usually difficult to find information on drug dosing in this population, which is sometimes contradictory. This is a comprehensive review of the dosing of different types of antimicrobials (antibiotics, antifungals, antivirals, and antituberculosis drugs) in obese patients, where the literature on PK and possible dosing strategies in obese adults was critically assessed.
Topics: Humans; Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Antitubercular Agents; Antiviral Agents; Critical Illness; Obesity
PubMed: 38526051
DOI: 10.1128/aac.01719-23 -
Dermatologic Therapy Jan 2021There are a wide variety of treatments for plantar warts, but none has been shown to be effective in all patients. We aimed to perform a systematic review of the... (Review)
Review
There are a wide variety of treatments for plantar warts, but none has been shown to be effective in all patients. We aimed to perform a systematic review of the efficacy of different topical treatments on plantar warts. Systematic electronic searches (Pubmed, Cochrane Library, Embase, and Web of Science) were conducted in April 2020. Meta-analyses, systematic reviews, and retrospective or prospective clinical trials of the effects of topical and nonsurgical treatments of plantar warts were included. Two authors performed the study selection and data extraction. Any discrepancies between the two reviewers were discussed with a third reviewer. Forty-four studies were included. The average cure rates of the most frequent treatments were variable across the studies: cryotherapy (45.61%), salicylic acid (13.6%), cantharidin-podophyllin-salicylic acid formulation (97.82%), laser (79.36%), topical antivirals (72.45%), intralesional bleomycin (83.37%), and intralesional immunotherapy (68.14%). Twenty-two studies (50%) had a level of evidence 1b and grade of recommendation A, five studies (11.4%) had a level of evidence 2b and grade of recommendation B, two studies (4.5%) had a level of evidence 3b and grade of recommendation B, and 15 studies (34,1%) with a level of evidence 4 and grade of recommendation C. First-choice treatments for common warts, such as cryotherapy and salicylic acid, have low-cure rates for plantar warts. Other treatments, such as CPA formulation, immunotherapy, and intralesional bleomycin, which have compassionate use, have higher cure rates. This review should stimulate future high-quality research to evaluate these specialized treatments.
Topics: Cryotherapy; Humans; Prospective Studies; Retrospective Studies; Salicylic Acid; Warts
PubMed: 33263934
DOI: 10.1111/dth.14621 -
Chest Feb 2022Current guidelines recommend empirical antifungal therapy in patients with sepsis with high risk of invasive Candida infection. However, many different risk factors have... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Current guidelines recommend empirical antifungal therapy in patients with sepsis with high risk of invasive Candida infection. However, many different risk factors have been derived from multiple studies. These risk factors lack specificity, and broad application would render most ICU patients eligible for empirical antifungal therapy.
RESEARCH QUESTION
What risk factors for invasive Candida infection can be identified by a systematic review and meta-analysis?
STUDY DESIGN AND METHODS
We searched PubMed, Web of Science, ScienceDirect, Biomed Central, and Cochrane and extracted the raw and adjusted OR for each risk factor associated with invasive Candida infection. We calculated pooled ORs for risk factors present in more than one study.
RESULTS
We included 34 studies in our meta-analysis resulting in the assessment of 29 possible risk factors. Risk factors for invasive Candida infection included demographic factors, comorbid conditions, and medical interventions. Although demographic factors do not play a role for the development of invasive Candida infection, comorbid conditions (eg, HIV, Candida colonization) and medical interventions have a significant impact. The risk factors associated with the highest risk for invasive Candida infection were broad-spectrum antibiotics (OR, 5.6; 95% CI, 3.6-8.8), blood transfusion (OR, 4.9; 95% CI, 1.5-16.3), Candida colonization (OR, 4.7; 95% CI, 1.6-14.3), central venous catheter (OR, 4.7; 95% CI, 2.7-8.1), and total parenteral nutrition (OR, 4.6; 95% CI, 3.3-6.3). However, dependence between the various risk factors is probably high.
INTERPRETATION
Our systematic review and meta-analysis identified patient- and treatment-related factors that were associated with the risk for the development of invasive Candida infection in the ICU. Most of the factors identified were either related to medical interventions during intensive care or to comorbid conditions.
Topics: Anti-Bacterial Agents; Blood Component Transfusion; Candidiasis, Invasive; Catheterization, Central Venous; Comorbidity; Critical Illness; Humans; Parenteral Nutrition, Total; Risk Factors
PubMed: 34673022
DOI: 10.1016/j.chest.2021.08.081 -
Journal of Wound Care Dec 2021Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and severe skin and mucosal reactions that are associated with high mortality. Despite the... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and severe skin and mucosal reactions that are associated with high mortality. Despite the severity, an evidence-based treatment protocol for SJS/TEN is still lacking.
METHOD
In this systematic review and meta-analysis, the PubMed database was searched using the following terms: [Stevens-Johnson syndrome] OR [toxic epidermal necrolysis] AND [therapy] OR [treatment] over a 20-year period (1999-2019) in the German and English language. All clinical studies reporting on the treatment of SJS/TEN were included, and epidemiological and diagnostic aspects of treatment were analysed. A meta-analysis was conducted on all comparative clinical studies that met the inclusion criteria.
RESULTS
A total of 88 studies met the inclusion criteria, reporting outcomes in 2647 patients. Treatment was either supportive or used systemic corticosteroid, intravenous immunoglobulin, plasmapheresis, cyclosporine, thalidomide or cyclophosphamide therapy. The meta-analysis included 16 (18%) studies, reporting outcomes in 976 (37%) patients. Systemic glucocorticoids showed a survival benefit for SJS/TEN patients in all analyses compared with other forms of treatment. Cyclosporine treatment also showed promising results, despite being used in a small cohort of patients. No beneficial effects on mortality could be demonstrated for intravenous immunoglobulins.
CONCLUSION
Glucocorticoids and cyclosporine may be tentatively recommended as the most promising immunomodulatory therapies for SJS/TEN, but these results should be investigated in future prospective controlled trials.
Topics: Cohort Studies; Cyclosporine; Humans; Immunoglobulins, Intravenous; Retrospective Studies; Skin; Stevens-Johnson Syndrome
PubMed: 34881995
DOI: 10.12968/jowc.2021.30.12.1012 -
Clinical Microbiology and Infection :... Jul 2022Pulmonary aspergillosis may complicate coronavirus disease 2019 (COVID-19) and contribute to excess mortality in intensive care unit (ICU) patients. The disease is... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Pulmonary aspergillosis may complicate coronavirus disease 2019 (COVID-19) and contribute to excess mortality in intensive care unit (ICU) patients. The disease is poorly understood, in part due to discordant definitions across studies.
OBJECTIVES
We sought to review the prevalence, diagnosis, treatment, and outcomes of COVID-19-associated pulmonary aspergillosis (CAPA) and compare research definitions.
DATA SOURCES
PubMed, Embase, Web of Science, and MedRxiv were searched from inception to October 12, 2021.
STUDY ELIGIBILITY CRITERIA
ICU cohort studies and CAPA case series including ≥3 patients were included.
PARTICIPANTS
Adult patients in ICUs with COVID-19.
INTERVENTIONS
Patients were reclassified according to four research definitions. We assessed risk of bias with an adaptation of the Joanna Briggs Institute cohort checklist tool for systematic reviews.
METHODS
We calculated CAPA prevalence using the Freeman-Tukey random effects method. Correlations between definitions were assessed with Spearman's rank test. Associations between antifungals and outcome were assessed with random effects meta-analysis.
RESULTS
Fifty-one studies were included. Among 3297 COVID-19 patients in ICU cohort studies, 313 were diagnosed with CAPA (prevalence 10%; 95% CI 8%-13%). Two hundred seventy-seven patients had patient-level data allowing reclassification. Definitions had limited correlation with one another (ρ = 0.268-0.447; p < 0.001), with the exception of Koehler and Verweij (ρ = 0.893; p < 0.001); 33.9% of patients reported to have CAPA did not fulfill any research definitions. Patients were diagnosed after a median of 8 days (interquartile range 5-14) in ICUs. Tracheobronchitis occurred in 3% of patients examined with bronchoscopy. The mortality rate was high (59.2%). Applying CAPA research definitions did not strengthen the association between mould-active antifungals and survival.
CONCLUSIONS
The reported prevalence of CAPA is significant but may be exaggerated by nonstandard definitions.
Topics: Adult; Antifungal Agents; COVID-19; Critical Care; Humans; Intensive Care Units; Pulmonary Aspergillosis
PubMed: 35150878
DOI: 10.1016/j.cmi.2022.01.027 -
Mycoses Sep 2023Isavuconazole is a novel triazole antifungal agent. However, the previous outcomes were highlighted by statistical heterogeneity. This meta-analysis aimed to validate... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Isavuconazole is a novel triazole antifungal agent. However, the previous outcomes were highlighted by statistical heterogeneity. This meta-analysis aimed to validate the efficacy and safety of isavuconazole for the treatment and prophylaxis of invasive fungal infections (IFIs) compared with other antifungal agents (amphotericin B, voriconazole and posaconazole).
METHODS
Scopus, EMBASE, PubMed, CINAHL and Ichushi databases were searched for relevant articles that met the inclusion criteria through February 2023. Mortality, IFI rate, discontinuation rate of antifungal therapy and incidence of abnormal hepatic function were evaluated. The discontinuation rate was defined as the percentage of therapy discontinuations due to adverse events. The control group included patients who received other antifungal agents.
RESULTS
Of the 1784 citations identified for screening, 10 studies with an overall total of 3037 patients enrolled. Isavuconazole was comparable with the control group in mortality and IFI rate in the treatment and prophylaxis of IFIs, respectively (mortality, odds rate (OR) 1.11, 95% confidential interval (CI) 0.82-1.51; IFI rate, OR 1.02, 95% CI 0.49-2.12). Isavuconazole significantly reduced the discontinuation rate in the treatment (OR 1.96, 95% CI 1.26-3.07) and incidence of hepatic function abnormalities in the treatment and prophylaxis, compared with the control group (treatment, OR 2.31, 95% CI 1.41-3.78; prophylaxis, OR 3.63, 95% CI 1.31-10.05).
CONCLUSIONS
Our meta-analysis revealed that isavuconazole was not inferior to other antifungal agents for the treatment and prophylaxis of IFIs, with substantially fewer drug-associated adverse events and discontinuations. Our findings support the use of isavuconazole as the primary treatment and prophylaxis for IFIs.
Topics: Humans; Antifungal Agents; Invasive Fungal Infections; Voriconazole; Triazoles
PubMed: 37300337
DOI: 10.1111/myc.13622