Professor of Medicine Division of Infectious Diseases University of Alabama at Birmingham School of Medicine. Division of Infectious Diseases, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
David Rogers Pharm D., Ph.D
Division of Infectious Diseases, Wayne State University School of Medicine, Detroit Medical Center, Detroit, MI, USA [email protected]. Division of Infectious Diseases, Henry Ford Hospital, Wayne State University School of Medicine, Detroit, MI, USA.
Introduction
Over time, more than 100,000 species of fungi have been identified and described. However, less than 500 of these species are associated with human disease, and no more than 100 can cause infection in otherwise normal individuals.
What Are Fungi?
Laboratory Aspects of Medical Mycology
Classification of Fungi
Classification of Anamorphic Fungi
This class contains a large number of anamorphic fungi of medical importance, including the genera Aspergillus, Blastomyces, Cladophialophora, Fusarium, Histoplasma, Microsporum, Penicillium, Phialophora, Scedosporium and Trichophyton.
Nomenclature of Fungi and Fungal Diseases
Laboratory Procedures for the Diagnosis of Fungal Infection
Histopathological examination of tissue sections is one of the most reliable methods for establishing the diagnosis of subcutaneous and systemic fungal infections. Methenamine silver staining (Grocott or Gomori) and periodic acid Schiff (PAS) staining are among the most commonly used procedures for specific fungal cell wall staining.
Culture
A number of simple rapid tests have been devised for the presumptive identification of some of the most important human pathogens. The results can be expressed as individual sequences (genotypes) at each locus, or as diploid sequence types (DSTs), unique combinations of the genotypes in each isolate.
Molecular Diagnostics
The M27-A reference series has enabled much greater standardization of in vitro testing of antifungal agents. An advantage of the disc diffusion analysis is that the zone diameters are read after 24 hours.
Multicenter evaluation of the Etest method for antifungal drug susceptibility testing of Candida spp. Subcommittee on Antifungal Susceptibility Testing (AFST) of the ESCMID European Committee on Antimicrobial Susceptibility Testing (EUCAST).
Cycle of Disease Prevention
It will discuss principles of epidemiology, risk factors and prevention of infection using specific fungal diseases as examples of broader public health principles. Major public health issues will be discussed, including potential strategies to reduce morbidity and mortality associated with fungal diseases.
Surveillance
Advances in medical treatment have led to improved survival in the general population, but these advances have also led to a greater number of individuals (including those who have indwelling catheters, who are in intensive care, who have received various immunosuppressive treatments, and undergoing organ or stem cell transplantation) are at risk of fungal infection. While numbers have declined dramatically in developed countries [1–4], many countries in sub-Saharan Africa [5–7] and parts of Asia [8–10] remain heavily affected by these and other fungal diseases.
Epidemiology of Systemic Fungal Diseases: An Overview
Population-based surveillance programs identify all cases of the disease under control in the catchment area. In endemic states of the US Southwest, cases of coccidioidomycosis are reported to state health departments by practitioners or laboratories.
Reducing the Public Health Burden of Systemic Fungal Diseases
Systemic Antifungal Drugs
Although improvements in purification and fermentation over the past 30 years have improved tolerability, infusion-related reactions and renal dysfunction are still common when using the deoxycholate-soluble formulation. This may be attributed to delays in the diagnosis of invasive mycoses, the immunocompromised state of the patient being treated, the unique pharmacokinetic/pharmacodynamic properties of different formulations, and dose limitations associated with toxicity.
Amphotericin B Deoxycholate Chemistry
Amphotericin B
The immunomodulatory effects of AmB have been found to be variable, and research results are contradictory. For example, imidazole pretreatment before AmB-d administration has been reported to be antagonistic [68].
Administration
Topical preparations (3% lotion, cream or ointment, 10 mg tablets or oral suspension, 100 mg/. mL) can be combined as needed to treat superficial or skin yeast infections. However, few drugs penetrate the vitreous, and intravitreal injection of 5–10 mg/0.1 mL is often used for vitritis [81].
Use in Pregnancy
Topical ophthalmic application solution) or subconjunctival injection (100–200 mg/0.5 ml) is suitable for most superficial infections. Intraperitoneal administration for the treatment of peritoneal dialysis-associated Candida infections can be achieved by administering AmB-d within the dialysate or intraperitoneally, but this is extremely irritating and is no longer recommended [82].
Lipid Preparations of Amphotericin B
Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis.
Mechanism of Action
Human clinical studies began in the late 1960s for both cryptococcal meningitis and disseminated candidiasis [ 3 , 4 ]. Currently, flucytosine is used as single-agent therapy in only a limited number of settings, including urinary candidiasis and chromoblastomycosis [8].
Pharmacology
Flucytosine
Dosage and Administration
Clinical Indications
Adverse Effects
Although flucytosine-induced blood dyscrasias are usually reversible upon discontinuation of the drug, fatal bone marrow suppression has been reported. Therapeutic monitoring of serum flucytosine levels followed by adjustment of the flucytosine dose may reduce the frequency of serious bone marrow toxicity.
Precautions
Brouwer AE, Rajanuwong A, Chierakul W, et al. antifungal therapies for HIV-associated cryptococcal meningitis: a randomized trial. Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS: a randomized trial. de Gans J, Portegies P, Tiessens G, et al.
Chemistry
The introduction of the azole class of antifungal drugs with the licensing of miconazole in 1979 marked the beginning of a new era in the treatment of systemic fungal diseases. For many systemic mycoses, these drugs have been effective and safe alternatives to the older antifungal drugs – amphotericin B, a member of the polyene class and for years the so-called.
Azoles
A lower daily dose (3 mg/kg) can be administered in mucosal candidiasis, but an initial dose of 6 mg/kg should be given. For the treatment of cryptococcal meningitis in children, fluconazole can be administered as a 12 mg/kg IV loading dose followed by 6 mg/kg daily.
Pharmacokinetics
Therefore, the intravenous formulation of itraconazole is not recommended for patients with creatinine clearance. Dose adjustments are not required in patients with renal dysfunction and posaconazole is not removed by hemodialysis [78].
Therapeutic Drug Monitoring
The oral formulation does not contain the cyclodextrin vehicle and is safe in patients with renal failure. A third study demonstrated a survival benefit in patients with breakthrough fungal infections associated with higher (>0.5 compared to 0.12 mg/ml) itraconazole trough concentrations [96].
Drug Interactions
The most common interaction is due to a CYP450 interaction leading to an increase in the concentration of the co-administered medication [105, 114]. Drug interactions resulting in decreased concentrations of the azole occur via two primary mechanisms.
Spectrum of Activity
In vitro Susceptibility Testing
Moderate activity in vitro; ++, excellent in vitro activity, -, no clinically useful activity, -/+, minimal in vitro activity. When related to clinical outcome, isolates with MICs of >2 mg/mL were associated with lower clinical success than isolates with MICs.
Drug Resistance
Rare cases of severe and sometimes fatal liver failure associated with ketoconazole, fluconazole, itraconazole, and voriconazole suggest that physicians should be more vigilant in monitoring liver function in patients receiving these drugs [220]. In addition to these common common side effects, each of the commercially available azoles is associated with unique reactions that deserve the attention of the physician.
Clinical Indications Candidiasis
Echinocandins
Disturbances in the structure of the cell wall cause osmotic instability and can ultimately lead to lysis of the fungal cell. Echinocandins are antifungal agents whose action is directed against the main components of the cell wall of fungi.
Antifungal Activity and Resistance
Antimicrobial Interactions
Pharmacodynamics
However, the analysis of isolates from patients enrolled in four clinical trials of caspofungin for esophageal and invasive candidiasis revealed no association between MIC and outcome for the entire data set, the different types of candidiasis, or specific Candida spp. This observation may be explained by the high efficacy of the doses used in these studies and the absence of Candida isolates with elevated MICs in the clinical trial datasets.
In Vitro Susceptibility Testing
Anidulafungin
The clinical efficacy of anidulafungin against Candida infections has been demonstrated in phase II and phase III studies in immunocompromised patients with esophageal candidiasis and in patients with candidemia or other forms of invasive candidiasis [105–108]. In the dose-ranging trial in patients with invasive Candida infections, review of adverse events and laboratory data indicated no dose response for safety parameters.
Caspofungin
The clinical efficacy of caspofungin, 50 mg daily after a loading dose of 70 mg, against invasive aspergillosis was studied in a multicenter, open-label, non-comparative phase II trial in patients with definite or probable, refractory or intolerant invasive aspergillosis. standard therapies. [130]. In patients with mild hepatic insufficiency (Child-Pugh category A), no adjustments are necessary; in patients with moderate hepatic insufficiency (Child-Pugh category B), it is recommended to reduce the maintenance dose to 35 mg/day after a loading dose of 70 mg.
Micafungin
Pharmacodynamics Mechanism of Action
Terbinafine
In vitro activity against other dimorphic fungi, such as Blastomyces dermatitidis, Histoplasma capsulatum and Coccidioides species is good [10, 16]. In conclusion, terbinafine combined with amphotericin B, caspofungin and selected azoles shows modest additive or synergistic in vitro activity against Pythium insidiosum [29-31].
Pharmacokinetics Oral
Due to terbinafine's unique affinity for keratin tissue, therapeutic levels can be found in the stratum corneum, hair and nails for up to 12 weeks after cessation of therapy. In addition, measurable concentrations of terbinafine can be found in nail clippings up to 10 months after stopping a limited course (1-4 weeks) of terbinafine [35, 36].
Dosing and Administration
Approximately 80-85% of terbinafine metabolites are excreted in the urine and 15-20% in the bile. It is not absorbed systemically in any measurable amount, but significant levels are reached in the stratum.
Clinical Uses Onychomycosis
One possible use of terbinafine is in combination therapy with other approved antifungal agents for patients with cryptococcosis and invasive fungal infections. Up to 2000 mg of terbinafine per day has been successfully administered with stable clinical outcome and was well tolerated by patients [15, 70].
Summary
Comparative evaluation of the efficacy and safety of two doses of terbinafine (500 and 1000 mg day-1) in the treatment of cutaneous or lymphocutaneous sporotrichosis. Double-blind, parallel-group comparison of terbinafine and griseofulvin in the treatment of toenail onychomycosis.
Pharmacokinetic Concepts
Numerous in vitro, animal and clinical studies have been instrumental in characterizing the pharmacodynamic activity of the clinically available antifungal drug classes, including triazoles, polyenes, flucytosine and echinocandins [6–18]. The following chapter outlines the pharmacodynamic characteristics of antifungal agents and presents evidence for the clinical relevance of these concepts.
Antifungal Pharmacokinetics and Pharmacodynamics
Knowledge of the pharmacokinetic/pharmacodynamic index and magnitude associated with efficacy may be useful for clinicians to predict therapeutic success/failure, guide optimal dosing levels and intervals, assist in susceptibility breakpoint development, guide therapeutic drug monitoring, and limit potential adverse effects . outcomes, including toxicity and the development of resistance [5-8]. Accumulating clinical data have also become available with several antifungal agents allowing pharmacodynamic data analyzes [19–25] .
Pharmacodynamic Concepts
- Impact of Antifungal Concentration on Activity over Time
- Impact of Dosing Interval Variation or Fractionation
- Pharmacodynamic Target
- Clinical Pharmacodynamics
This knowledge may also be useful in designing studies to determine the amount of drug or index size associated with treatment efficacy. The results of these studies have shown that the magnitude of a pharmacodynamic index associated with efficacy is similar for drugs within the same class, provided that free drug levels are taken into account.
Polyenes
Conversely, amphotericin B lipid complex (ABLC) and amphotericin B colloid dispersion (ABCD) achieve higher concentrations in the intracellular space and in organs of the reticuloendothelial system. Consideration of each of the pharmacodynamic indices further shows that %T > MIC is most closely associated with efficacy.
Triazoles
Second, the AUC/MIC exposure associated with survival was nearly identical for both triazoles when free drug concentrations were considered. Recent studies have begun to investigate the magnitude of the Cmax/MIC and AUC/MIC indices required for treatment efficacy.
Combination Therapy
Characterization and quantification of fluconazole pharmacodynamics in a neutropenic murine model of disseminated candidiasis infection. In vivo characterization of flucytosine pharmacodynamics in a mouse model of neutropenic disseminated candidiasis.
Polyene Resistance
Not only are a limited number of antifungal drugs available to treat these infections, but resistance to antifungal treatment can also occur. These variations are attributed to differences between the two agencies in the patient populations analyzed and in a number of parameters related to the activity and pharmacodynamics of antifungal agents.
Resistance to Antifungal Drugs
The agreement in determining minimum inhibitory concentration (MIC) values between both methods is more than 90% and is therefore considered acceptable [2]. This interaction is believed to result in the production of aqueous pores composed of polyene molecules linked to the membrane.
Flucytosine (5-Fluorocytosine)
Conversely, the removal of the NRE leads to an increase in CDR1 basal expression. Distribution of the GOF mutations (black bars) identified in the transcription factors Tac1p, Mrr1p and CgPdr1p.
Current Situation with Antifungal Drug Resistance
Rapid, transient fluconazole resistance in Candida albicans is associated with increased mRNA levels of CDR. Contribution of mutations in cytochrome P450 14a-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans.
Rationale for Combination Antifungal Therapy
Advances in modern treatment have led to an increase in the population at risk of fungal infections [3]. It seems clear that combinations will continue to be pursued intensively in the hope of improving patient outcomes and determining the optimal therapy for these serious infections.
Combination Antifungal Therapy
Polypharmacy, resulting from the use of agents in combination, may result in an increased risk of drug interactions, toxicity, or both. The combined use of these drugs has been shown to increase the risk of kidney failure in bone marrow transplant recipients [26].
Limitations of Available Studies of Combination Antifungal Therapy
Once the clinical role of combination antifungal therapy is more definitively established, pharmacoeconomic studies will be needed. Many of these drug-drug interactions will need to be considered as newer alternative agents are used as part of combination antifungal regimens.
Combination Antifungal Therapy for Yeast Infections
Interestingly, the combination of amphotericin B and flucytosine was associated with the greatest reduction in CFU compared to the other three regimens. Another randomized trial recently compared initial monotherapy with amphotericin B with combinations of amphotericin B plus low-dose (400 mg daily) or high-dose (800 mg daily) fluconazole for HIV-associated cryptococcal meningitis [ 42 ].
Combination Antifungal Therapy for Mould Infections
Caspofungin has been studied in combination with other antifungal agents in the treatment of invasive aspergillosis [67, 69]. Combination therapy was associated with improved survival compared with a historical cohort of patients receiving voriconazole alone.
Future Targets
Lopez-Ciudad V, Castro-Orjales MJ, Leon C, et al. Successful treatment of Candida parapsilosis mural endocarditis with combined caspofungin and voriconazole. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis.
Mycoses Caused by Yeasts
Within a few decades, Candida species have evolved from rare pathogens largely thought of as nuisance contaminants to important and common human pathogens that cause a broad spectrum of superficial and deep disease. The pathogenesis and risk factors for superficial and deep candidiasis, although overlapping, are distinctly different; hence superficial infection sometimes leads to systemic disease.
Organism
Candidiasis
The increased incidence of Candida infections is comparable to the availability of successive generations of antifungal drugs over the past 2 decades. Candida lusitaniae is uncommon (1–2%) but clinically important due to intrinsic or secondary resistance to amphotericin B [16].
Pathogenesis
Several studies have confirmed the importance of secreted aspartyl proteinases in the pathogenesis of tissue invasion by C. Candida colonization and biofilm formation play an important role in the pathogenesis of superficial and invasive infections due to increased resistance to antifungal therapy and the ability of yeast cells within biofilms to resist host immune defenses [41].
Epidemiology
The ability of Candida species to overcome the suppressive effect of antifungal chemotherapy is considered a virulence attribute. However, except in outbreak settings, the source of Candida species causing infection is usually from the host's endogenous flora.
Clinical Manifestations Oropharyngeal Candidiasis
The fungal ball is usually found in dilated areas of the urinary tract, especially in the bladder in the presence of obstruction. The finding of Candida organisms in the urine may indicate contamination, colonization of the drainage system or infection.
