scholarly journals A Review of Clinical Experience with Newer Antifungals in Children

2008 ◽  
Vol 13 (3) ◽  
pp. 124-140
Author(s):  
Renee M. Fallon ◽  
Jennifer E. Girotto
Keyword(s):  
Children And Adolescents ◽  
21St Century ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Pediatric Population ◽  
Pharmacokinetic Data ◽  
Clinical Use ◽  
Clinical Experiences ◽  
Key Concepts ◽  
Pediatric Pharmacology

Fungal infections are a significant cause of morbidity and mortality in immunocompromised children. Since the beginning of the 21st century, many new antifungals including the echinocandins (i.e., caspofungin, micafungin, anidulafungin) and the newer generation triazoles (i.e., voriconazole and posaconazole) have received Food and Drug Administration approval. Unfortunately, despite making great strides in the adult arena, these agents are not currently approved in the pediatric population. However, pharmacokinetic data and clinical experiences with these agents in infants, children, and adolescents are mounting. As such, this review will discuss key concepts in pediatric pharmacology and clinical use of these newer antifungal agents.

Antifúngicos poliénicos. Mecanismo de acción y aplicaciones

2020 ◽  
Vol 63 (2) ◽  
pp. 7-17
Author(s):  
Evelyn Rivera-Toledo ◽  
Alan Uriel Jiménez-Delgadillo ◽  
Patricia Manzano-Gayosso
Keyword(s):  
Antifungal Activity ◽  
Key Words ◽  
Secondary Metabolism ◽  
Amphotericin B ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Variable Number ◽  
Therapeutic Failure ◽  
Morbidity And Mortality ◽  
Clinical Use

The first compounds with specific antifungal activity were identified in the middle of the last century as a product of the secondary metabolism of bacteria of the order Actinomycetales, and their clinical use significantly diminished the morbidity and mortality associated with severe fungal infections. Many of such biosynthetic compounds are characterized by a chemical polygenic structure, with a variable number of carbon-carbon double bonds. Currently, besides polygenic antimycotics, there are other antifungal agents, such as the azole compounds, that have less toxicity in patients; however, cases of therapeutic failure with such compounds have been documented, therefore, the use of polygenics is still the best alternative in such cases. This review presents data about the properties and applications of antifungal-polygenic compounds using amphotericin B as a model. Key words: Amphotericin B; antifungal polyenes; ergosterol

Safety and Tolerability of Fluconazole in Children

1999 ◽  
Vol 43 (8) ◽  
pp. 1955-1960 ◽  
Author(s):  
Vas Novelli ◽  
Helen Holzel
Keyword(s):  
Side Effects ◽  
Safety Profile ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Pediatric Population ◽  
Gastrointestinal Symptoms ◽  
Underlying Disease ◽  
Severe Underlying Disease ◽  
Excellent Safety Profile ◽  
Concomitant Medications

ABSTRACT The safety profile of fluconazole was assessed for 562 children (ages, 0 to 17 years) comprising 323 males and 239 females. The data are derived from 12 clinical studies of fluconazole as prophylaxis or treatment for a variety of fungal infections in predominantly immunocompromised patients. Most children received multiple doses of fluconazole in the range of 1 to 12 mg/kg of body weight; a few received single doses. Administration was mainly by oral suspension or intravenous injection. Overall, 58 (10.3%) children reported 80 treatment-related side effects. The most common side effects were associated with the gastrointestinal tract (7.7%) or skin (1.2%). Self-limiting, treatment-related side effects affecting the liver and biliary system were reported in three patients (0.5%). Overall, 18 patients (3.2%) discontinued treatment due to side effects, mainly gastrointestinal symptoms. Dose and age did not appear to influence the incidence and pattern of side effects. Treatment-related laboratory abnormalities were uncommon, the most frequent being transient elevated alanine aminotransferase (4.9%), aspartate aminotransferase (2.7%), and alkaline phosphatase (2.3%) levels. Although 98.6% of patients were taking concomitant medications, no clinical or laboratory interactions were observed. The safety profile of fluconazole was compared with those of other antifungal agents, mostly oral polyenes, by using a subset of data from five controlled studies. Side effects were reported by more patients treated with fluconazole (45 of 382; 11.8%) than by those patients treated with comparable agents (25 of 381; 6.6%); vomiting and diarrhea were the most common events in both groups. The incidence and type of treatment-related laboratory abnormalities were similar for the two groups. In conclusion, fluconazole was well tolerated by the pediatric population, many of whom were suffering from severe underlying disease and were taking a variety of concurrent medications. The safety profile of fluconazole in children mirrors the excellent safety profile seen in adults.

scholarly journals Pharmacodynamics of the Orotomides against Aspergillus fumigatus : New Opportunities for Treatment of Multidrug-Resistant Fungal Disease

mBio ◽  
2017 ◽  
Vol 8 (4) ◽  
Author(s):  
William W. Hope ◽  
Laura McEntee ◽  
Joanne Livermore ◽  
Sarah Whalley ◽  
Adam Johnson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Mechanism Of Action ◽  
Drug Exposure ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Invasive Fungal Infections ◽  
Clinical Use ◽  
Drug Concentrations ◽  
Phase Ii And Iii

ABSTRACT F901318 is an antifungal agent with a novel mechanism of action and potent activity against Aspergillus spp. An understanding of the pharmacodynamics (PD) of F901318 is required for selection of effective regimens for study in phase II and III clinical trials. Neutropenic murine and rabbit models of invasive pulmonary aspergillosis were used. The primary PD endpoint was serum galactomannan. The relationships between drug exposure and the impacts of dose fractionation on galactomannan, survival, and histopathology were determined. The results were benchmarked against a clinically relevant exposure of posaconazole. In the murine model, administration of a total daily dose of 24 mg/kg of body weight produced consistently better responses with increasingly fractionated regimens. The ratio of the minimum total plasma concentration/MIC ( C min /MIC) was the PD index that best linked drug exposure with observed effect. An average C min (mg/liter) and C min /MIC of 0.3 and 9.1, respectively, resulted in antifungal effects equivalent to the effect of posaconazole at the upper boundary of its expected human exposures. This pattern was confirmed in a rabbit model, where C min and C min /MIC targets of 0.1 and 3.3, respectively, produced effects previously reported for expected human exposures of isavuconazole. These targets were independent of triazole susceptibility. The pattern of maximal effect evident with these drug exposure targets was also apparent when survival and histopathological clearance were used as study endpoints. F901318 exhibits time-dependent antifungal activity. The PD targets can now be used to select regimens for phase II and III clinical trials. IMPORTANCE Invasive fungal infections are common and often lethal. There are relatively few antifungal agents licensed for clinical use. Antifungal drug toxicity and the emergence of drug resistance make the treatment of these infections very challenging. F901318 is the first in a new class of antifungal agents called the orotomides. This class has a novel mechanism of action that involves the inhibition of the fungal enzyme dihydroorotate dehydrogenase. F901318 is being developed for clinical use. A deep understanding of the relationship between dosages, drug concentrations in the body, and the antifungal effect is fundamental to the identification of the regimens to administer to patients with invasive fungal infections. This study provides the necessary information to ensure that the right dose of F901318 is used the first time. Such an approach considerably reduces the risks in drug development programs and ensures that patients with few therapeutic options can receive potentially life-saving antifungal therapy at the earliest opportunity.

scholarly journals Dosing Recommendations for Vancomycin in Children and Adolescents with Varying Levels of Obesity and Renal Dysfunction: a Population Pharmacokinetic Study in 1892 Children Aged 1–18 Years

2021 ◽  
Vol 23 (3) ◽  
Author(s):  
Cornelis Smit ◽  
Sebastiaan C. Goulooze ◽  
Roger J. M. Brüggemann ◽  
Catherine M. Sherwin ◽  
Catherijne A. J. Knibbe
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Children And Adolescents ◽  
Pharmacokinetic Study ◽  
Pediatric Population ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Obese Children ◽  
Population Pharmacokinetic Study

AbstractVancomycin is an effective but potentially nephrotoxic antibiotic commonly used for severe infections. Dosing guidelines for vancomycin in obese children and adolescents with or without renal impairment are currently lacking. This study describes the pharmacokinetics of vancomycin in a large pediatric cohort with varying degrees of obesity and renal function to design practical dosing guidelines for this population. A multi-center retrospective population pharmacokinetic study was conducted using data from patients aged 1−18 years who received >1 dose of vancomycin and had ≥1 vancomycin concentration measured between January 2006 and December 2012. Besides pharmacokinetic data, age, gender, body weight, creatinine clearance (CLcr, bedside Schwartz equation), ward, race, and neutropenic status were collected. Population pharmacokinetic analysis and simulations were performed using NONMEM7.4. A total of 1892 patients (5524 samples) were included, with total body weight (TBW) ranging 6−188 kg (1344 normal weight, 247 overweight, and 301 obese patients) and CLcr down to 8.6 mL/min/1.73 m2. The two-compartment model, with clearance (CL) significantly increasing with TBW and CLcr, central and peripheral volume of distribution and inter-compartmental clearance increasing with TBW, performed well for all age, weight, and renal function ranges. A dosing guideline is proposed that integrates body weight and CLcr resulting in effective and safe exposures across all ages, body weight, and renal functions in the pediatric population. We have characterized the full pharmacokinetic profile of vancomycin in obese children and adolescents aged 1−18 years and propose a practical dosing guideline that integrates both body weight and renal function.

The Importance of Fluconazole in Treatment of Endogenous Endophtalmitis in Patients Prior Treated Using Negative Pressure Therapy for Wound Closure Contaminated with Meticillin-resistant Staphylococcus aureus

2017 ◽  
Vol 68 (7) ◽  
pp. 1598-1601 ◽  
Author(s):  
Anisia Iuliana Alexa ◽  
Roxana Ciuntu ◽  
Alina Cantemir ◽  
Nicoleta Anton ◽  
Ciprian Danielescu ◽  
...  
Keyword(s):  
Antifungal Agents ◽  
Fungal Infections ◽  
Prolonged Treatment ◽  
Endogenous Endophthalmitis ◽  
Pressure Therapy ◽  
First Case ◽  
Severe Infections ◽  
Pars Plana ◽  
Delay In Treatment ◽  
Vitreous Biopsy

Severe infections with C. albicans should be treated promptly with antifungal agents, any delay in treatment increases the risk of endophthalmitis. The systemic Amphotericin B therapy is the gold standard in the treatment of endophthalmitis, but in the case of fungal infections it has not yet been determined. Numerous studies have shown that the use of Fluconazole is effective in the treatment of fungal endophthalmitis. In this paper, we report two cases (3 eyes) that have been presented for the same accusations of significant decrease of AV (visual acuity), ocular pain and blepharospasm suddenly installed, both of which required urgent antibiotic and intravenous antifungal treatment. Both are diagnosed with endogenous endophthalmitis and vitreous biopsy + VPP (pars plana vitrectomy) are performed, with a negative result of the vitreous culture. In both situations the treatment was with antibiotic and systemic antifungals. Postoperatively, evolution was favorable in the first case and less favorable in the second one. The prognosis depends on the virulence of the microorganisms and the time elapsed until initiation of the treatment. Also, the presence of risk factors such as diabetes, sepsis, recent abdominal surgery (C. Albicans is part of the comesary flora of the digestive tract) have influenced the prognosis decisively. Severe infections with C. albicans should be promptly treated with antifungal agents, any delay in treatment increases the risk of endophthalmitis. Even when prolonged treatment of candidemia is instituted, 3% of patients can develop endogenous endophthalmitis, so ocular evaluation is particularly important for patients immobilized in anesthesia and intensive care units.

Potential of Nanoparticles in Combating Candida Infections

2019 ◽  
Vol 16 (5) ◽  
pp. 478-491 ◽  
Author(s):  
Faizan Abul Qais ◽  
Mohd Sajjad Ahmad Khan ◽  
Iqbal Ahmad ◽  
Abdullah Safar Althubiani
Keyword(s):  
Targeted Delivery ◽  
Recent Progress ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Fold Increase ◽  
Antifungal Drugs ◽  
Low Toxicity ◽  
Candida Infections ◽  
Made In

Aims: The aim of this review is to survey the recent progress made in developing the nanoparticles as antifungal agents especially the nano-based formulations being exploited for the management of Candida infections. Discussion: In the last few decades, there has been many-fold increase in fungal infections including candidiasis due to the increased number of immunocompromised patients worldwide. The efficacy of available antifungal drugs is limited due to its associated toxicity and drug resistance in clinical strains. The recent advancements in nanobiotechnology have opened a new hope for the development of novel formulations with enhanced therapeutic efficacy, improved drug delivery and low toxicity. Conclusion: Metal nanoparticles have shown to possess promising in vitro antifungal activities and could be effectively used for enhanced and targeted delivery of conventionally used drugs. The synergistic interaction between nanoparticles and various antifungal agents have also been reported with enhanced antifungal activity.

Firearm Injuries Affecting the Pediatric Population

PEDIATRICS ◽  
1992 ◽  
Vol 89 (4) ◽  
pp. 788-790
Author(s):  
Keyword(s):  
United States ◽  
Children And Adolescents ◽  
Pediatric Population ◽  
Age Groups ◽  
Unintentional Injury ◽  
The United States ◽  
Male Adolescents ◽  
Firearm Injuries ◽  
Group 2 ◽  
Developed Nations

In the United States approximately 30 000 people die from firearm injuries each year. Many more are wounded. In the mid 1980s, more than 3000 of the dead were children and adolescents aged 1 to 19 years.1 In 1989 nearly 4000 firearm deaths were among children 1 to 19 years of age, accounting for 12% of all deaths in that age group.2 All of these deaths or injuries affect other children because the victims who are killed or wounded are frequently relatives, neighbors, or friends. Comparison data for childhood age groups demonstrate that in 1987, 203 children aged 1 to 9 years, 484 children aged 10 to 14 years, and 2705 adolescents aged 15 to 19 years died as a result of firearm injuries.1 Firearm deaths include unintentional injuries, homicides, and suicides. Among the 1- to 9-year-olds, half of the deaths were homicides and half were unintentional. Among the 10- to 14-year-olds, one third of the deaths were homicides, one third were suicides, and one third were unintentional. Among the 15- to 19-year-olds, 48% were homicides, 42% were suicides, and 8% were unintentional.1 Firearm homicides are the leading cause of death for some US subpopulations, such as urban black male adolescents and young adults.3 Table 1 indicates how firearms contributed to the deaths of children and adolescents (homicides, suicides, and all causes) in 1987. Table 2 illustrates the unusual scale of firearm violence affecting young people in the United States compared with other developed nations.4 Firearm injuries are the fourth leading cause of unintentional injury deaths to children younger than 15 years of age in the US.5

scholarly journals Distribution and antifungal susceptibility of Candida species in patients with increased risk for fungal infections

2016 ◽  
Vol 62 (1) ◽  
pp. 65-76
Author(s):  
Gordana Mirchevska ◽  
Maja Jurhar Pavlova ◽  
Elena Trajkovska-Dokic ◽  
Zaklina Cekovska ◽  
Gordana Jankoska ◽  
...  
Keyword(s):  
Blood Culture ◽  
Amphotericin B ◽  
Critically Ill Patients ◽  
Candida Species ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Antifungal Susceptibility ◽  
Clinical Specimens ◽  
Fourth Group ◽  
Increased Risk

Candida species are opportunistic yeasts that can be a serious threat for immunocompromised and critically ill patients, and a cause for increased morbidity and mortality in hospitalized patients. The aim of this study was to determine the frequency and distribution of different Candida species in clinical specimens in patients with increased risk for fungal infections, and to determine the antifungal susceptibility profile of invasive Candida species to antifungal agents. During a two year period, clinical specimens from 120 patients divided into 4 groups were analysed at the Institute of microbiology and parasitology, Faculty of Medicine, Skopje, Republic of Macedonia. Each of these 4 groups consisted of specimens from 30 patients, with primary immune deficiency, critically ill patients treated in the intensive care units (ICU), patients with mucosal candidiasis only, and patients with cystic fibrosis. All specimens were investigated with conventional mycological methods. Identification of Candida species was performed with VITEK-2 system (bioMérieux, France). E-test strips of fluconazole, voriconazole, amphotericin B and caspofungin (AB bioMerieux, France) were used for determination of the antifungal susceptibility profile. In this study, a total of 115 isolates of Candida species were confirmed in different clinical specimens (91 isolates from mucosal surfaces and 24 isolates from blood culture). Colonisation of mucosal membranes of gastrointestinal, respiratory and/or urinary tracts was registered in 56.67% (17/30), 56.67% (17/30), 90% (27/30) and 100% (30/30) of the specimens in the first, second, third and fourth group respectively. In all four groups of patients, the following Candida species were confirmed: C. albicans - 55%, C. glabrata - 17.6%, C. parapsilosis - 7.7%, C. tropicalis - 6.6%, unidentified Candida species - 4.4%, C. dubliniensis - 3.3%, C. kefyr - 2.2%, and one isolate of C. rugosa, C. pelliculosa and C. krusei each. Positive blood culture was registered in 23.33% specimens from the first group, 43.33% in the second group, 23.08% of the third group, and in one specimen of the fourth group. The most frequent isolates from blood culture were C. tropicalis and C. krusei, followed by C. albicans, C. parapsilosis and C. tropicalis, and in the second group C. albicans and C. pelliculosa were equally distributed, followed by C. parapsilosis and C. glabrata. All invasive isolates of Candida species were susceptible to amphotericin B, voriconazole and caspofungin. Resistance to fluconazole was registered in 8.3% (2/24) of all confirmed Candida species. Dose-dependent susceptibility to fluconazole was confirmed in 46% (11/24) of the isolates. Our study confirms high prevalence of colonisation and candidemia with non-albicans Candida species. Resistance to antifungal agents was registered only in two isolates of C. krusei. An epidemiological study is necessary for surveillance of dynamics of candidemia and antifungal susceptibility profile of invasive isolates of Candida species in our patients.

scholarly journals Physical activity versus metformin for increasing insulin sensitivity in children and adolescents at-risk for type 2 diabetes

2016 ◽  
Vol 85 (2) ◽  
pp. 26-28
Author(s):  
Andrew D Hanna ◽  
Natalie V Scime
Keyword(s):  
Physical Activity ◽  
Type 2 Diabetes ◽  
At Risk ◽  
Insulin Sensitivity ◽  
Children And Adolescents ◽  
Pediatric Population ◽  
Current Evidence ◽  
Beneficial Effects ◽  
Pediatric Populations

Global rates of type 2 diabetes (T2D) among children and adolescents are steadily rising. As such, an increasing amount of attention and research has begun to focus on strategies to prevent this chronic and burdensome disease in pediatric populations. The purpose of this article is to briefly review current evidence pertaining to the effectiveness of physical activity versus metformin in improving insulin sensitivity of children at-risk (ie, obese and/or insulin resistant) for developing T2D. Potential barriers to each preventative intervention will also be discussed. Physical activity, both aerobic and resistance, has demonstrated effectiveness in a moderate number of demographically diverse pediatric studies. However, the pediatric population is already alarmingly sedentary with barriers such as lack of motivation, social stigma and discomfort presenting a challenge. A small number of studies have demonstrated the beneficial effects of metformin in children and adolescents for improved insulin sensitivity. However, longer and larger studies are required to confirm these findings and elucidate upon the long-term safety and efficacy of this pharmaceutical in pediatric populations. While no head-to-head studies examining physical activity and metformin exist in pediatric populations and more research is needed, current evidence seems to favour the use of physical activity given the larger quantity of studies and generalizability of its beneficial effects. Thus, physical activity should be emphasized in clinical and public health practice when targeting at-risk children and adolescents to prevent a T2D diagnosis.

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