ABSTRACT
BACKGROUND: Candidaemia is associated with poor outcomes including high mortality rates. Controversy remains regarding whether fluconazole or an echinocandin is the optimal choice for initial candidaemia treatment, particularly among high-risk patients such as the immunocompromised or critically ill. OBJECTIVES: To understand optimal initial treatment of candidaemia. METHODS: We conducted a retrospective study of immunocompromised or ICU adult patients with candidaemia from 2010 to 2014. Patients who received ≥3 consecutive days of initial treatment with fluconazole or micafungin were included. The primary outcome was complete response at day 14, defined as clinical improvement and blood culture sterilization. Secondary outcomes included microbiological and clinical success, survival and recurrent candidaemia. RESULTS: A total of 197 patients were included; 76 received fluconazole and 121 received micafungin. There was no difference in complete response between the fluconazole and micafungin groups (ICU: 38% versus 40%, Pâ=â0.87; immunocompromised: 57% versus 59%, Pâ=â0.80). Secondary outcomes including survival were also similar. In multivariable analysis, among ICU patients, Pitt bacteraemia scoreâ<â4 (Pâ=â0.002) and time to antifungal (Pâ=â0.037) were associated with meeting the primary outcome; white blood cell countâ>â11â cellsâ×â103/µL on day 0 (Pâ<â0.001) and Candida isolated from a non-blood site (Pâ=â0.025) were associated with not meeting the primary outcome. Among immunocompromised patients, white blood cellsâ>â11â×â103/µL (Pâ=â0.003) and Candida isolated from a non-blood site (Pâ=â0.026) were associated with not meeting the primary outcome. CONCLUSIONS: These data suggest that among ICU or immunocompromised patients, severity of illness rather than initial antifungal choice drove clinical outcomes.
Subject(s)
Antifungal Agents , Candidemia , Critical Illness , Echinocandins , Fluconazole , Immunocompromised Host , Micafungin , Humans , Micafungin/therapeutic use , Micafungin/administration & dosage , Antifungal Agents/therapeutic use , Male , Retrospective Studies , Female , Middle Aged , Treatment Outcome , Candidemia/drug therapy , Candidemia/mortality , Aged , Fluconazole/therapeutic use , Fluconazole/administration & dosage , Echinocandins/therapeutic use , Echinocandins/administration & dosage , Adult , Lipopeptides/therapeutic use , Lipopeptides/administration & dosage , Survival AnalysisABSTRACT
OBJECTIVES: We assessed the efficacy of a 3-week primary or salvage caspofungin regimen in patients with chronic obstructive pulmonary disease (COPD) and concomitant proven or suspected invasive pulmonary aspergillosis (IPA). METHODS: Forty-four patients were treated with an initial loading caspofungin dose of 70 mg, followed by a daily dose of 50 mg for 20 days. The main efficacy endpoint was clinical effectiveness. Secondary endpoints included the clinical efficacy of caspofungin after 1 week, therapeutic efficacy based on the European Organization for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium (EORTC/MSG) criteria, the sensitivity of different Aspergillus strains to caspofungin in vitro, and the safety of caspofungin. RESULTS: An assessment of 42 patients in the intention-to-treat group revealed efficacy rates of 33.33% within 1 week and 38.10% within 3 weeks. According to the EORTC/MSG criteria, the treatment success rate was 38.10%. The success rate of first-line treatment was 54.76%, whereas salvage treatment had a success rate of 45.24%. No adverse events were reported among the participants. CONCLUSIONS: Caspofungin is effective and safe as an initial or salvage treatment for patients with IPA and COPD.
Subject(s)
Aspergillosis , Invasive Pulmonary Aspergillosis , Pulmonary Disease, Chronic Obstructive , Humans , Caspofungin/therapeutic use , Invasive Pulmonary Aspergillosis/complications , Invasive Pulmonary Aspergillosis/drug therapy , Invasive Pulmonary Aspergillosis/chemically induced , Antifungal Agents/adverse effects , Echinocandins/adverse effects , Lipopeptides/therapeutic use , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/drug therapyABSTRACT
Rezafungin is a long-acting, intravenously administered echinocandin for the treatment of candidemia and invasive candidiasis (IC). Non-inferiority of rezafungin vs caspofungin for the treatment of adults with candidemia and/or IC was demonstrated in the Phase 3 ReSTORE study based on the primary endpoints of day 14 global cure and 30-day all-cause mortality. Here, an analysis of ReSTORE data evaluating efficacy outcomes by baseline Candida species is described. Susceptibility testing was performed for Candida species using the Clinical and Laboratory Standards Institute reference broth microdilution method. There were 93 patients in the modified intent-to-treat population who received rezafungin; 94 received caspofungin. Baseline Candida species distribution was similar in the two treatment groups; C. albicans (occurring in 41.9% and 42.6% of patients in the rezafungin and caspofungin groups, respectively), C. glabrata (25.8% and 26.6%), and C. tropicalis (21.5% and 18.1%) were the most common pathogens. Rates of global cure and mycological eradication at day 14 and day 30 all-cause mortality by Candida species were comparable in the rezafungin and caspofungin treatment groups and did not appear to be impacted by minimal inhibitory concentration (MIC) values for either rezafungin or caspofungin. Two patients had baseline isolates with non-susceptible MIC values (both in the rezafungin group: one non-susceptible to rezafungin and one to caspofungin, classified as intermediate); both were candidemia-only patients in whom rezafungin treatment was successful based on the day 30 all-cause mortality endpoint. This analysis of ReSTORE demonstrated the efficacy of rezafungin for candidemia and IC in patients infected with a variety of Candida species.
Subject(s)
Antifungal Agents , Candidemia , Candidiasis, Invasive , Caspofungin , Echinocandins , Microbial Sensitivity Tests , Adult , Aged , Female , Humans , Male , Middle Aged , Antifungal Agents/therapeutic use , Antifungal Agents/pharmacology , Candida/drug effects , Candida albicans/drug effects , Candida glabrata/drug effects , Candida tropicalis/drug effects , Candidemia/drug therapy , Candidemia/mortality , Candidemia/microbiology , Candidiasis, Invasive/drug therapy , Candidiasis, Invasive/microbiology , Candidiasis, Invasive/mortality , Caspofungin/therapeutic use , Caspofungin/pharmacology , Echinocandins/therapeutic use , Echinocandins/pharmacology , Lipopeptides/therapeutic use , Treatment OutcomeABSTRACT
OBJECTIVES: Lipopeptide Biosurfactant (LB) is a bacteria derived compound able to reduce surface tension between water and hydrophobic substances and exhibit antimicrobial and anti-biofilm properties. This study aimed to investigate the antimicrobial and anti-biofilm effect of a Lipopeptide Biosurfactant (LB) on Enterococcus faecalis, and its potential use in root canal treatment, either as a standalone irrigation solution or in conjunction with sodium hypochlorite (NaOCl). METHODS: LB was extracted from Bacillus clausii isolate and the dry extract was diluted in deionized water. The antimicrobial effect of LB against planktonic E. faecalis was evaluated by determining the Minimal Inhibitory Concentration (MIC50). The anti-biofilm effect was evaluated by Minimal Biofilm Inhibitory Concentration (MBIC50) and Minimal Biofilm Eradication Concentration (MBEC50) assays on biofilm grown on dentin specimen surface. To evaluate the effectiveness of LB as a single irrigation solution and as a pre-irrigation prior to NaOCl, live and dead bacterial cells were quantified using Confocal Laser Scanning Microscopy (CLSM), and cell biomass was assessed. RESULTS: LB exhibited an MIC50 and MBIC50 of 100 ppm, with an MBEC50 of 1000 ppm, resulting in 52.94 % biofilm inhibition and 60.95 % biofilm eradication on dentin specimens. The effectiveness was concentration-dependent, at 500 ppm, LB demonstrated comparable antimicrobial efficacy to 2.5 % NaOCl. Pre-irrigation with LB resulted in lower biofilm biomass compared to NaOCl alone. CONCLUSION: Pre-irrigation with LB enhanced the antimicrobial effect when followed by NaOCl irrigation. Consequently, LB shows promise as both a standalone root canal irrigation solution and as an adjunct to NaOCl in root canal treatment. CLINICAL SIGNIFICANCE: The study highlights the potential of Lipopeptide Biosurfactant (LB) as an environmentally friendly irrigation solution for root canal treatment, demonstrating potent antimicrobial and anti-biofilm properties against Enterococcus faecalis. LB exhibits concentration-dependent efficacy comparable to 2.5 % NaOCl and can be used as a standalone irrigation solution or in conjunction with NaOCl.
Subject(s)
Anti-Infective Agents , Lipopeptides , Root Canal Preparation , Surface-Active Agents , Surface-Active Agents/therapeutic use , Therapeutic Irrigation/methods , Anti-Infective Agents/therapeutic use , Biofilms/drug effects , Lipopeptides/therapeutic use , Hydrophobic and Hydrophilic Interactions , Humans , Bacillus clausii , Root Canal Therapy/methods , Biological Products/therapeutic useABSTRACT
Antifungal infections are becoming a major concern to human health due to antimicrobial resistance. Echinocandins have been promising agents against resistant fungal infections, primarily caspofungin, which has a more effective mechanism of action than azoles and polyenes. However, fungi such as Cryptococcus neoformans appear to be inheritably resistant to these drugs, which is concerning due to the high clinical importance of C. neoformans. In this review, we review the history of C. neoformans and the treatments used to treat antifungals over the years, focusing on caspofungin, while highlighting the C. neoformans problem and possible explanations for its inherent resistance.
Caspofungin is a drug used to treat several types of fungal infections. Resistance to caspofungin is a huge problem, especially in those that are immunocompromised. It is important to understand the history of caspofungin discovery, its clinical applications and its mechanism of action, as well as if a new drug target could be used overcome resistance. This review may perform guide new studies combining caspofungin with other drugs and indicate new potential targets for caspofungin.
Subject(s)
Antifungal Agents , Caspofungin , Cryptococcosis , Cryptococcus neoformans , Drug Resistance, Fungal , Caspofungin/therapeutic use , Caspofungin/pharmacology , Cryptococcus neoformans/drug effects , Antifungal Agents/therapeutic use , Antifungal Agents/pharmacology , Humans , Cryptococcosis/drug therapy , Cryptococcosis/microbiology , Echinocandins/therapeutic use , Echinocandins/pharmacology , Animals , Microbial Sensitivity Tests , Lipopeptides/therapeutic use , Lipopeptides/pharmacologyABSTRACT
BACKGROUND: Pediatric living-donor liver transplantation (LDLT) candidates often receive long-term antibiotic treatment. Micafungin has been used as an antifungal agent after LDLT, but the adequate dose after pediatric LDLT was unknown. Here, we report micafungin blood concentrations after pediatric LDLT and discuss its safety and adequate dosing. METHODS: Pediatric patients with data on micafungin concentrations after LDLT were identified. Those with surgical complications were excluded. All patients received standard tacrolimus-based immunosuppression. A micafungin dose of 1 mg/kg was administered once daily for 10 days starting on postoperative day (POD) 1. The trough and peak micafungin blood concentrations were evaluated on PODs 1, 4, 7, and 10. Beta D glucan levels and liver function tests were assessed to determine micafungin effectiveness and safety. RESULTS: Ten patients were enrolled, with a median age of 1.2 years. The median graft vs body weight ratio was 2.7%. The primary diseases were biliary atresia (n = 7), Alagille syndrome (n = 2), and progressive familial intrahepatic cholestasis type 2 (n = 1). Mean peak micafungin levels were 4.47, 6.27, 5.47, and 5.47 µg/mL on PODs 1, 4, 7, and 10, respectively. Mean trough levels were 2.03, 1.88, and 2.66 µg/mL on PODs 4, 7, and 10, respectively. The micafungin half-lives were 13.7, 14.7, and 14.0 hours on PODs 4, 7, and 10, respectively. Beta D glucan levels were 4.4 pg/mL and 3.7 pg/mL before and after transplantation, respectively, indicating no significant difference (P = .3). No clinical fungal infections were observed. CONCLUSION: Micafungin administration is safe and effective after pediatric LDLT.
Subject(s)
Antifungal Agents , Liver Transplantation , Living Donors , Micafungin , Humans , Micafungin/therapeutic use , Micafungin/administration & dosage , Antifungal Agents/therapeutic use , Antifungal Agents/blood , Male , Female , Infant , Child, Preschool , Child , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/blood , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/administration & dosage , Lipopeptides/pharmacokinetics , Lipopeptides/therapeutic use , Lipopeptides/administration & dosageABSTRACT
The rising prevalence of global antibiotic resistance evokes the urgent need for novel antimicrobial candidates. Cationic lipopeptides have attracted much attention due to their strong antimicrobial activity, broad-spectrum and low resistance tendency. Herein, a library of fluoro-lipopeptide amphiphiles was synthesized by tagging a series of cationic oligopeptides with a fluoroalkyl tail via a disulfide spacer. Among the lipopeptide candidates, R6F bearing six arginine moieties and a fluorous tag shows the highest antibacterial activity, and it exhibits an interesting fluorine effect as compared to the non-fluorinated lipopeptides. The high antibacterial activity of R6F is attributed to its excellent bacterial membrane permeability, which further disrupts the respiratory chain redox stress and cell wall biosynthesis of the bacteria. By co-assembling with lipid nanoparticles, R6F showed high therapeutic efficacy and minimal adverse effects in the treatment of MRSA-induced sepsis and chronic wound infection. This work provides a novel strategy to design highly potent antibacterial peptide amphiphiles for the treatment of drug-resistant bacterial infections.
Subject(s)
Anti-Bacterial Agents , Methicillin-Resistant Staphylococcus aureus , Microbial Sensitivity Tests , Sepsis , Methicillin-Resistant Staphylococcus aureus/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Sepsis/drug therapy , Sepsis/microbiology , Wound Infection/drug therapy , Wound Infection/microbiology , Animals , Mice , Staphylococcal Infections/drug therapy , Surface-Active Agents/chemistry , Surface-Active Agents/pharmacology , Surface-Active Agents/chemical synthesis , Lipopeptides/pharmacology , Lipopeptides/chemistry , Lipopeptides/therapeutic useABSTRACT
The continued emergence of highly pathogenic viruses, which either thwart immune- and small molecule-based therapies or lack interventions entirely, mandates alternative approaches, particularly for prompt and facile pre- and post-exposure prophylaxis. Many highly pathogenic viruses, including coronaviruses, employ the six-helix bundle heptad repeat membrane fusion mechanism to achieve infection. Although heptad-repeat-2 decoys can inhibit viral entry by blocking six-helix bundle assembly, the biophysical and pharmacologic liabilities of peptides have hindered their clinical development. Here, we develop a chemically stapled lipopeptide inhibitor of SARS-CoV-2 as proof-of-concept for the platform. We show that our lead compound blocks infection by a spectrum of SARS-CoV-2 variants, exhibits mucosal persistence upon nasal administration, demonstrates enhanced stability compared to prior analogs, and mitigates infection in hamsters. We further demonstrate that our stapled lipopeptide platform yields nanomolar inhibitors of respiratory syncytial, Ebola, and Nipah viruses by targeting heptad-repeat-1 domains, which exhibit strikingly low mutation rates, enabling on-demand therapeutic intervention to combat viral outbreaks.
Subject(s)
Coronavirus Infections , Lipopeptides , Humans , Lipopeptides/pharmacology , Lipopeptides/therapeutic use , Lipopeptides/chemistry , Pandemics/prevention & controlABSTRACT
OBJECTIVES: Invasive Aspergillus infections during the early phase of childhood acute lymphoblastic leukemia (ALL) treatment come with morbidity and mortality. The interaction with vincristine hampers first-line azole prophylaxis. We describe the efficacy of an alternative twice-a-week micafungin regimen for Aspergillus prophylaxis. METHODS: Newly diagnosed paediatric patients with ALL treated according to the ALL-11 protocol received micafungin twice-a-week (9 mg/kg/dose [max. 300 mg]) during the induction course (first 35 days of treatment) as part of routine care. A historical control cohort without Aspergillus prophylaxis was used. During the first consolidation course (day 36-79), standard itraconazole prophylaxis was used in both groups. The percentage of proven/probable Aspergillus infections during the induction/first consolidation course was compared between the cohorts. The cumulative incidence of proven/probable Aspergillus infections was estimated using a competing risk model. For safety evaluation, liver laboratory chemistry values were analysed. RESULTS: A total of 169 and 643 paediatric patients with ALL were treated in the micafungin cohort (median age: 4 years [range 1-17]) and historical cohort (median age: 5 years [range 1-17]). The percentage of proven/probable Aspergillus infections was 1·2% (2/169) in the micafungin cohort versus 5·8% (37/643) in the historical cohort (p=0.013; Fisher's exact test). The differences in estimated cumulative incidence were assessed (p=0·014; Gray's test). Although significantly higher ALT/AST values were reported in the micafungin cohort, no clinically relevant side effects were observed. CONCLUSIONS: Twice-a-week micafungin prophylaxis during the induction course significantly reduced the occurrence of proven/probable Aspergillus infections in the early phase of childhood ALL treatment.
Subject(s)
Aspergillosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Child , Infant , Child, Preschool , Adolescent , Micafungin/therapeutic use , Antifungal Agents/pharmacology , Echinocandins/adverse effects , Cohort Studies , Lipopeptides/therapeutic use , Lipopeptides/pharmacology , Aspergillosis/drug therapy , Aspergillosis/prevention & control , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/chemically inducedABSTRACT
Interaction between Middle East respiratory syndrome coronavirus (MERS-CoV) spike (S) protein heptad repeat-1 domain (HR1) and heptad repeat-2 domain (HR2) is critical for the MERS-CoV fusion process. This interaction is mediated by the α-helical region from HR2 and the hydrophobic groove in a central HR1 trimeric coiled coil. We sought to develop a short peptidomimetic to act as a MERS-CoV fusion inhibitor by reproducing the key recognition features of HR2 helix. This was achieved by the use of helix-stabilizing strategies, including substitution with unnatural helix-favoring amino acids, introduction of ion pair interactions, and conjugation of palmitic acid. The resulting 23-mer lipopeptide, termed AEEA-C16, inhibits MERS-CoV S protein-mediated cell-cell fusion at a low micromolar level comparable to that of the 36-mer HR2 peptide HR2P-M2. Collectively, our studies provide new insights into developing short peptide-based antiviral agents to treat MERS-CoV infection.
Subject(s)
Antiviral Agents , Middle East Respiratory Syndrome Coronavirus , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Middle East Respiratory Syndrome Coronavirus/drug effects , Peptides/chemistry , Protein Conformation, alpha-Helical , Lipopeptides/pharmacology , Lipopeptides/therapeutic useABSTRACT
Recently, opportunistic pathogens like Acinetobacter baumannii and Pseudomonas aeruginosa have caused concern due to their ability to cause antibiotic resistance in weakened immune systems. As a result, researchers are always seeking efficient antimicrobial agents to tackle this issue. The hypothesis of the recent study was that probiotic products derived from bacteria would be effective in reducing drug resistance in other bacteria. This research aimed to investigate the antimicrobial properties of probiotic products from various bacterial strains, including Lactobacillus rhamnosus, Pediococcus acidilactisi, Bacillus coagulans, Bacillus subtilis, and Bacillus licheniformis. These were tested against multi-drug-resistant (MDR) standard strains A. baumannii and P. aeruginosa. B. licheniformis was found to be the most effective probiotic strain, possessing the LanA and LanM lantibiotic genes. The lipopeptide nature of the probiotic product was confirmed through high-performance liquid chromatography (HPLC) and Fourier-transform infrared spectroscopy (FTIR) techniques. The anti-biofilm and antimicrobial properties of this probiotic were measured using an SEM electron microscope and minimum inhibitory concentration (MIC) test. Real-time PCR (qPCR) was used to compare the expression of bap and luxI genes, which are considered virulence factors of drug-resistant bacteria, before and after treatment with antimicrobial agents. The MIC results showed that the probiotic product prevented the growth of bacteria at lower concentrations compared to antibiotics. In addition, the ΔΔCqs indicated that gene expression was significantly down-regulated following treatment with the obtained probiotic product. It was found that B. licheniformis probiotic products could reduce drug resistance in other bacteria, making it a potential solution to antibiotic resistance.
Subject(s)
Acinetobacter baumannii , Anti-Infective Agents , Bacillus licheniformis , Pseudomonas Infections , Humans , Pseudomonas aeruginosa/genetics , Bacillus licheniformis/genetics , Acinetobacter baumannii/genetics , Lipopeptides/pharmacology , Lipopeptides/therapeutic use , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Anti-Infective Agents/pharmacology , Bacillus subtilis , Microbial Sensitivity TestsABSTRACT
INTRODUCTION: Hepatitis delta virus (HDV) causes acute and chronic liver disease that requires the co-infection of the Hepatitis B virus and can lead to significant morbidity and mortality. Bulevirtide is a recently introduced entry inhibitor drug that acts on the sodium taurocholate cotransporting peptide, thereby preventing viral entry to target cells in chronic HDV infection. The mainstay of chronic HDV therapy prior to bulevirtide was interferon alpha, which has an undesirable side effect profile. AREAS COVERED: We review bulevirtide data from recent clinical trials in Europe and the United States. Challenges to development and implementation of bulevirtide are discussed. Additionally, we review ongoing trials of emerging drugs for HDV, such as pegylated interferon lambda and lonafarnib. EXPERT OPINION: Bulevirtide represents a major shift in treatment for chronic HDV, for which there is significant unmet need. Trials that compared bulevirtide in combination with interferon alpha vs interferon alpha monotherapy demonstrated significant increase in virologic response. Overall, treatment with different doses of bulevirtide were comparable. Bulevirtide was generally well tolerated, and no serious adverse events occurred. Understanding the true prevalence of HDV, as well as continued studies of emerging drugs will prove valuable to the larger goal of eradication of Hepatitis D.
Subject(s)
Hepatitis D , Humans , Hepatitis D/drug therapy , Lipopeptides/pharmacology , Lipopeptides/therapeutic use , Interferon-alpha/adverse effects , Hepatitis Delta Virus/physiology , Hepatitis B virus , Antiviral Agents/adverse effectsABSTRACT
INTRODUCTION: Recurrent aphthous stomatitis is a common lesion of the oral cavity, and many treatments have been introduced by researchers. OBJECTIVE: This study aims to determine the effect of biosurfactant lipopeptide (Acinetobacter baumannii and Pseudomonas aeruginosa) adhesive mucus paste on the healing process of oral wounds. MATERIALS AND METHODS: The studied population included 36 people (age range, 20-41 years). The volunteers had a history of oral ulcers and were randomly assigned to 3 groups: positive control (mouthwash chlorhexidine 0.2%), biosurfactant lipopeptide mucoadhesive (A baumannii and P aeruginosa), and base groups. In this analysis, the 2-paired sample t test, ANOVA, and Kruskal-Wallis test (Wilcoxon signed-rank test) were used. RESULTS: On the second day of treatment, the efficacy index of the positive control group was higher than that of the mucoadhesive and the base groups (P = .04) and there was a significant difference between the mucoadhesive group and the positive control group compared with the base group (P = .001). On the sixth day of treatment, the positive control group was significantly different from the mucoadhesive and base groups in terms of wound size (P < .05). CONCLUSIONS: This study showed that the use of mucoadhesive gel formation containing lipopeptide biosurfactant reduces pain and wound size compared to mucoadhesive without biosurfactant lipopeptide treatment, but it has less effect than routine treatment. Therefore, other studies should be done.
Subject(s)
Adhesives , Stomatitis, Aphthous , Humans , Young Adult , Adult , Adhesives/pharmacology , Lipopeptides/pharmacology , Lipopeptides/therapeutic use , Wound HealingABSTRACT
The objective of this study was to evaluate the efficacy of various micafungin dosing regimens against Candida spp. in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Monte Carlo simulations were conducted using pharmacokinetic (PK) parameters and pharmacodynamic (PD) data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration targets of micafungin. Current standard clinical micafungin dosing regimens of 1 and 2 mg/kg/day were appropriate for the prevention and treatment of Candida glabrata infection in pediatric patients undergoing HSCT, respectively. Moreover, the high-dose prophylactic dosage (2 mg/kg/day) and therapeutic dosage (4 mg/kg/day) should be the preferred option to optimize efficacy against Candida albicans. However, none of the simulated regimens was effective against Candida parapsilosis in pediatric HSCT patients. These PK/PD-based simulations rationalize and optimize the micafungin dosing regimens against Candida spp. in pediatric patients undergoing HSCT.
Subject(s)
Candidiasis , Hematopoietic Stem Cell Transplantation , Humans , Child , Micafungin/pharmacology , Candida , Antifungal Agents/therapeutic use , Echinocandins/therapeutic use , Monte Carlo Method , Candidiasis/drug therapy , Microbial Sensitivity Tests , Lipopeptides/therapeutic useABSTRACT
STUDY OBJECTIVE: Echinocandins are guideline-preferred therapies for invasive candidiasis (IC). Fixed dosing of echinocandins is commonly used despite variations in body mass index and echinocandin susceptibility. The purpose of this study was to evaluate clinical outcomes of micafungin based on population-predicted pharmacokinetic/pharmacodynamic (PK/PD) factors and susceptibility. DESIGN AND SETTING: Candida isolate results were screened from bloodstream or intraabdominal cultures of hospitalized patients admitted to a quaternary-care teaching hospital. Patients with a first episode of IC who received micafungin for at least 48 h were included. Patients with mixed cultures or Candida species with no minimum inhibitory concentration (MIC) differences were excluded. Breakpoints for micafungin MIC and area under the curve (AUC)/MIC ratio were calculated using classification and regression tree (CART) analysis and related to clinical outcomes. Primary efficacy outcome was candida-contributable mortality, defined as mortality within 28 days of positive culture with concomitant micafungin treatment failure; secondary outcome was micafungin treatment failure within 28 days, MAIN RESULTS: Seventy-two patients were included of whom 15 (21%) had Candida-contributable mortality and 34 (47%) experienced micafungin treatment failure. C. albicans and C. tropicalis did not have differing MICs and these patients were excluded from the study. Mortality using a CART-derived MIC breakpoint of ≥1.0 mg/L was 38% compared to 9% in patients infected with lower MIC strains (p = 0.003). Patients with a CART-derived AUC/MIC value >138.5 had a mortality rate of 9% compared to 41% for patients with AUC/MIC values below the breakpoint (p = 0.0013). Results were similar for treatment failure rates, and both were confirmed using multivariable models. CONCLUSIONS: CART-derived micafungin MIC and AUC/MIC breakpoints predicted patient mortality and treatment failure for certain Candida species. These results support the need for further PK/PD studies to optimize echinocandin dosing and improve patient outcomes.
Subject(s)
Candida , Candidemia , Humans , Micafungin/therapeutic use , Candidemia/drug therapy , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Lipopeptides/pharmacology , Lipopeptides/therapeutic use , Echinocandins/pharmacology , Echinocandins/therapeutic useABSTRACT
PURPOSE: Echinocandins are favored drugs for the treatment of fungal infections. There is growing evidence that obese patients treated with echinocandins have lower exposures due to pharmacokinetic (PK) alterations. We conducted a scoping review to characterize, evaluate, and summarize the available evidence on echinocandins exposures in obese patients. SUMMARY: A comprehensive search of PubMed, Embase, and Cochrane Library for studies on echinocandins published from database inception to October 28, 2022, was conducted using PRISMA-ScR methodology. A total of 25 studies comprising more than 3,174 subjects (8 micafungin studies, 7 caspofungin studies, 9 anidulafungin studies, and 1 rezafungin study) were included in this review. Seventeen studies reported lower echinocandins exposures in overweight and obese individuals compared with normal-weight individuals; the authors of these studies recommended dose adjustments. Conversely, 8 studies did not find significant differences in echinocandin exposure among subjects in varying body weight categories. Clinicians may consider dose adjustments of echinocandins in obese patients; however, there is limited evidence on the ideal dose adjustment strategy to overcome the low echinocandins exposures in obese patients. CONCLUSION: This scoping review shed light on a growing body of evidence indicating that obese patients have lower echinocandin exposures relative to targeted PK indices, which may lead to negative therapeutic implications. Currently, a lack of high-quality evidence impedes reaching consensus on recommendations for echinocandin dosing adjustment in obese patients. Future research evaluating the optimal echinocandin dosing strategy for obese patients is needed.
Subject(s)
Antifungal Agents , Echinocandins , Humans , Antifungal Agents/therapeutic use , Body Weight , Echinocandins/adverse effects , Echinocandins/pharmacokinetics , Lipopeptides/pharmacokinetics , Lipopeptides/therapeutic use , Microbial Sensitivity Tests , Obesity/drug therapy , OverweightABSTRACT
In recent years, clinicians and doctors have become increasingly interested in fungal infections, including those affecting the mucous membranes. Vulvovaginal candidiasis (VVC) is no exception. The etiology of this infection remains unexplained to this day, as well as the role and significance of asymptomatic vaginal Candida colonization. There are also indications that in the case of VVC, standard methods of determining drug susceptibility to antifungal drugs may not have a real impact on their clinical effectiveness-which would explain, among other things, treatment failures and relapse rates. The aim of the study was to verify the promising results obtained previously in vitro using standard methods, in a newly developed ex vivo model, using tissue fragments of the mouse vagina. The main goal of the study was to determine whether the selected ultrashort cyclic lipopeptides (USCLs) and their combinations with fluconazole at specific concentrations are equally effective against Candida forming a biofilm directly on the surface of the vaginal epithelium. In addition, the verification was also performed with the use of another model for the study of microorganisms (biofilms) in vitro-the BioFlux system, under microfluidic conditions. The obtained results indicate the ineffectiveness of the tested substances ex vivo at concentrations eradicating biofilm in vitro. Nevertheless, the relatively most favorable and promising results were still obtained in the case of combination therapy-a combination of low concentrations of lipopeptides (mainly linear analogs) with mycostatic fluconazole. Additionally, using BioFlux, it was not possible to confirm the previously obtained results. However, an inhibiting effect of the tested lipopeptides on the development of biofilm under microfluidic conditions was demonstrated. There is an incompatibility between the classic in vitro methods, the newer BioFlux method of biofilm testing, offering many advantages postulated elsewhere, and the ex vivo method. This incompatibility is another argument for the need, on the one hand, to intensify research on the pathomechanism of VVC, and, on the other hand, to verify and maybe modify the standard methods used in the determination of Candida susceptibility.
Subject(s)
Candidiasis, Vulvovaginal , Mice , Humans , Female , Animals , Candidiasis, Vulvovaginal/drug therapy , Candidiasis, Vulvovaginal/microbiology , Candida albicans , Pilot Projects , Fluconazole/pharmacology , Biofilms , Candida , Vagina/microbiology , Disease Models, Animal , Anti-Bacterial Agents/pharmacology , Lipopeptides/pharmacology , Lipopeptides/therapeutic useABSTRACT
BACKGROUND: Invasive candidiasis and/or candidemia (IC/C) is a common fungal infection leading to significant health and economic losses worldwide. Caspofungin was shown to be more effective than fluconazole in treating inpatients with IC/C. However, cost-effectiveness of caspofungin for treating IC/C in Ethiopia remains unknown. We aimed to assess the cost-utility of caspofungin compared to fluconazole-initiated therapies as primary treatment of IC/C in Ethiopia. METHODS: A Markov cohort model was developed to compare the cost-utility of caspofungin versus fluconazole antifungal agents as first-line treatment for adult inpatients with IC/C from the Ethiopian health system perspective. Treatment outcome was categorized as either a clinical success or failure, with clinical failure being switched to a different antifungal medication. Liposomal amphotericin B (L-AmB) was used as a rescue agent for patients who had failed caspofungin treatment, while caspofungin or L-AmB were used for patients who had failed fluconazole treatment. Primary outcomes were expected quality-adjusted life years (QALYs), costs (US$2021), and the incremental cost-utility ratio (ICUR). These QALYs and costs were discounted at 3% annually. Cost data was obtained from Addis Ababa hospitals while locally unavailable data were derived from the literature. Cost-effectiveness was assessed against the recommended threshold of 50% of Ethiopia's gross domestic product/capita (i.e.,US$476). Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the findings. RESULTS: In the base-case analysis, treatment of IC/C with caspofungin as first-line treatment resulted in better health outcomes (12.86 QALYs) but higher costs (US$7,714) compared to fluconazole-initiated treatment followed by caspofungin (12.30 QALYs; US$3,217) or L-AmB (10.92 QALYs; US$2,781) as second-line treatment. Caspofungin as primary treatment for IC/C was not cost-effective when compared to fluconazole-initiated therapies. Fluconazole-initiated treatment followed by caspofungin was cost-effective for the treatment of IC/C compared to fluconazole with L-AmB as second-line treatment, at US$316/QALY gained. Our findings were sensitive to medication costs, drug effectiveness, infection recurrence, and infection-related mortality rates. At a cost-effectiveness threshold of US$476/QALY, treating IC/C patient with fluconazole-initiated treatment followed by caspofungin was more likely to be cost-effective in 67.2% of simulations. CONCLUSION: Our study showed that the use of caspofungin as primary treatment for IC/C in Ethiopia was not cost-effective when compared with fluconazole-initiated treatment alternatives. The findings supported the use of fluconazole-initiated therapy with caspofungin as a second-line treatment for patients with IC/C in Ethiopia.
Subject(s)
Candidemia , Candidiasis, Invasive , Adult , Humans , Caspofungin/therapeutic use , Fluconazole/therapeutic use , Candidemia/drug therapy , Cost-Benefit Analysis , Echinocandins/therapeutic use , Ethiopia , Lipopeptides/therapeutic use , Candidiasis, Invasive/drug therapy , Antifungal Agents/therapeutic useABSTRACT
BACKGROUND: Anthrax is endemic to many countries, including the United States. The causative agent, Bacillus anthracis, poses a global bioterrorism threat. Without effective antimicrobial postexposure prophylaxis (PEPAbx) and treatment, the mortality of systemic anthrax is high. To inform clinical guidelines for PEPAbx and treatment of B. anthracis infections in humans, we systematically evaluated animal anthrax treatment model studies. METHODS: We searched for survival outcome data in 9 scientific search engines for articles describing antimicrobial PEPAbx or treatment of anthrax in animals in any language through February 2019. We performed meta-analyses of efficacy of antimicrobial PEPAbx and treatment for each drug or drug combination using random-effects models. Pharmacokinetic/pharmacodynamic relationships were developed for 5 antimicrobials with available pharmacokinetic data. Monte Carlo simulations were used to predict unbound drug exposures in humans. RESULTS: We synthesized data from 34 peer-reviewed studies with 3262 animals. For PEPAbx and treatment of infection by susceptible B. anthracis, effective monotherapy can be accomplished with fluoroquinolones, tetracyclines, ß-lactams (including penicillin, amoxicillin-clavulanate, and imipenem-cilastatin), and lipopeptides or glycopeptides. For naturally occurring strains, unbound drug exposures in humans were predicted to adequately cover the minimal inhibitory concentrations (MICs; those required to inhibit the growth of 50% or 90% of organisms [MIC50 or MIC90]) for ciprofloxacin, levofloxacin, and doxycycline for both the PEPAbx and treatment targets. Dalbavancin covered its MIC50 for PEPAbx. CONCLUSIONS: These animal studies show many reviewed antimicrobials are good choices for PEPAbx or treatment of susceptible B. anthracis strains, and some are also promising options for combating resistant strains. Monte Carlo simulations suggest that oral ciprofloxacin, levofloxacin, and doxycycline are particularly robust choices for PEPAbx or treatment.
Subject(s)
Anthrax , Anti-Infective Agents , Bacillus anthracis , Amoxicillin-Potassium Clavulanate Combination/therapeutic use , Animals , Anthrax/drug therapy , Anthrax/prevention & control , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/therapeutic use , Cilastatin, Imipenem Drug Combination/pharmacology , Cilastatin, Imipenem Drug Combination/therapeutic use , Ciprofloxacin/therapeutic use , Doxycycline/therapeutic use , Glycopeptides/pharmacology , Glycopeptides/therapeutic use , Humans , Levofloxacin/therapeutic use , Lipopeptides/pharmacology , Lipopeptides/therapeutic use , Models, Animal , Tetracyclines/therapeutic use , United States , beta-Lactams/therapeutic useABSTRACT
Scarcity of effective treatments against sepsis is daunting, especially under the contemporary standpoints on antibiotics resistance, entailing the development of alternative treatment strategies. Here, we describe the design and antibiotic adjuvant properties of a new lipopeptide-like pentamer, decanoyl-bis.diaminobutyrate-aminododecanoyl-diaminobutyrate-amide (C10BBc12B), whose sub-maximal tolerated doses combinations with inefficient antibiotics demonstrated systemic efficacies in murine models of peritonitis-sepsis and urinary-tract infections. Attempts to shed light into the mechanism of action using membrane-active fluorescent probes, suggest outer-membrane interactions to dominate the pentamer's adjuvant properties, which were not associated with typical inner-membrane damages or with delayed bacterial growth. Yet, checkerboard titrations with low micromolar concentrations of C10BBc12B exhibited unprecedented capacities in potentiation of hydrophobic antibiotics towards Gram-negative ESKAPE pathogens, with an apparent low propensity for prompting resistance to the antibiotics. Assessment of the pentamer's potentiating activities upon efflux inhibition incites submission of a hitherto unreported, probable action mechanism implicating the pentamer's de-facto capacity to hijack bacterial efflux pumps for boosting its adjuvant activity through repetitive steps including outer-membrane adhesion, translocation and subsequent expulsion.