Zygomycosis Disease Diagnosis

Mucormycosis

• Caused by fungi Mucor, Rhizopus, Absidia, and Cunninghamella
• Infection occurs through inhalation of fungal spores or direct penetration through the skin
• Presents as palatal necrosis or ulcerations, which can extend to adjacent structures, causing tissue necrosis and invasion of the brain
• Risk factors include organ transplant, uncontrolled diabetes, high-dose glucocorticoids, malnutrition, and poor wound care

Diagnosis and Therapy of Deep-Seated Oral Fungal Infections

• Diagnosis involves biopsy, with patient's medical history provided to the pathologist
• Patients with deep oral fungal infections must be referred to medical specialists for further evaluation
• Different diagnostic methods are used for different fungal infections, including:
  • Blastomycosis: smear/culture, direct immunostaining, DNA probes
  • Cryptococcosis: microscopy/staining, serology
  • Histoplasmosis: microscopy/staining, serology, skin tests
  • Mucormycosis: microscopy/histology, smear/culture

Systemic Mycoses

• Caused by opportunistic pathogens, which invade via the respiratory tract, alimentary tract, or intravascular devices
• Can be life-threatening, especially in immunocompromised hosts
• Include infections such as candidiasis, aspergillosis, cryptococcosis, histoplasmosis, blastomycosis, zygomycosis, coccidioidomycosis, paracoccidioidomycosis, and penicilliosis

Oral Fungal Infections

• Include candidiasis, aspergillosis, cryptococcosis, histoplasmosis, blastomycosis, zygomycosis, coccidioidomycosis, paracoccidioidomycosis, and penicilliosis
• Most solitary or primary oral fungal infections are rare, with the exception of oral candidiasis
• Candidiasis is the leading infection that most dental practitioners will see in clinical practice

Candida Species

• Normal residents of the oral microflora
• Dimorphic yeast with over 200 different species, only a few of which are implicated in human infection
• C. albicans accounts for over 80% of oral cavity isolates

Opportunistic Pathogens

• Microorganisms that do not cause disease in a healthy host, but take advantage of a host with a weakened immune system
• Include some bacteria, viruses, fungi, and protozoa
• Opportunistic pathogens can cause disease in hosts with a weakened immune system due to various factors, such as physiological, local, medication, nutritional, systemic, immune, and malignancy-related factors

Fungal Infections (Mycoses)

• Classified into four types: superficial, cutaneous, subcutaneous, and systemic
• Superficial mycoses infect the skin and hair, while cutaneous mycoses infect keratinized tissue, such as skin, hair, and nails
• Subcutaneous mycoses are usually introduced by trauma or breach of dermal tissue, infecting the subcutaneous fascia, muscle, and deeper epidermal layers
• Systemic mycoses are caused by primary pathogens and can be life-threatening, especially in immunocompromised hosts

Candida - Morphology

• Ability to grow in several morphological states, including budding yeast cells, pseudohyphae, and true filamentous hyphae
• Yeast cells are essential for dissemination, while hyphal forms are essential for invading mucosal surfaces
• Morphology switch between budding yeast and hyphal growth is triggered by host environmental cues, such as temperature, pH, serum, and CO2

Oral Candidiasis

• Host-related factors, such as compromised immune system, breakdown of the normal skin or mucosal barrier, and disturbance of the host by external factors, are important in the development of oral candidiasis
• Risk factors include diabetes, HIV infection, AIDS, and long-term use of corticosteroids, antipsychotics, antibiotics, and steroid inhalers

Types of Oral Candidiasis

• Pseudomembranous candidiasis (oral thrush)
• Acute erythematous candidiasis
• Chronic hyperplastic candidiasis
• Chronic erythematous candidiasis
• Other secondary forms of oral candidiasis, including angular cheilitis, median rhomboid glossitis, and chronic mucocutaneous candidiasis

Uncommon Oral Fungal Infections

• Aspergillosis: caused by Aspergillus species, second most common opportunistic fungal infection, and commonly associated with high-dose corticosteroid use, organ and marrow transplantation, and increased use of immunosuppression
• Cryptococcosis: caused by Cryptococcus species, most common fungal pathogen responsible for meningitis, and usually affects immunocompromised patients, especially those with advanced AIDS

New Drug Development

• Levels of testing:
  • Biochemical testing
  • Isolated tissue experiments
  • Whole animal experiments

Animal Models of Efficacy

• Existing normal behaviors/effects
• Creating behaviors (e.g. fat rats, hypertensive rats, anxious rats, epileptic rats)
• Finding unrelated behaviors affected by existing drugs

Predictivity of Models

• Exact replica = 100% predictor
• Mechanism same = good predictor
• Mechanisms different = poor predictor

Chemical and Biological Characterisation

• Chemical: structure, synthesis, solubility, etc.
• Biological: acute pharmacological profile, binding data for many receptors, dose-effect relationships

Safety and Toxicity in Animals

• Acute toxicity profile
• Chronic toxicity profile
• 14-day toxicity test in one rodent and one non-rodent species before use in humans
• 3-month study read out at 28 days
• Longer studies (12 & 24 months)
• Three dose levels (below, about, and well above human dose)

Pharmacotherapeutics

• Drug names: generic, chemical, and trade names
• Risk-benefit ratio and analysis

Sources of Drugs

• Many drugs originate as natural products (plants, animals, minerals, bacteria, fungi)
• Synthesis also produces drugs
• Recombinant DNA technology

Clinical Trials

• Drug action depends on:
  • Pharmacodynamics
  • Pharmacokinetics and dose regimen
  • Drug interactions
  • Receptor sensitivity of patient
  • Mood/personality of patient and doctor
  • Patient expectations and past experience
  • Social environment of patient
  • Clinical state of patient
• Clinical trials control these variables and examine the action of the drug in defined circumstances

Safety and Efficacy

• Safety is the number and type of adverse effects associated with the drug
• Adverse reactions may require immediate action
• Be alert to patient complaints after starting a new drug

Drug Discovery/Development Process

• Discovery: finding new active structures
• Development: converting active structures to useful drugs
• Refinement: chemical and biological characterization
• Safety and toxicity in animals
• Formulation development
• Volunteer studies
• Patient studies
• Regulatory process
• Lessons and post-registration monitoring
• Marketing

Pharmacokinetics

• The study of what a drug does to the body

Clinical Testing

• Phase 0: non-clinical testing
• Phase 1: volunteer studies (15-30 people)
• Phase 2: patient studies (150-350 people)
• Phase 3: large-scale multi-center trials (1500-3500 people)
• Phase 4: post-registration monitoring

Volunteer Studies (Phase 1 Trials)

• Objectives:
  • Metabolic and excretory pathways
  • Variability between individuals
  • Effect of route
  • Bioavailability
  • Tolerated dose range
  • Indication of therapeutic effects
  • Indication of side effects

Patient Studies (Phase 2 Trials)

• Objectives:
  • Indication for use
  • Type of patient
  • Severity of disease
  • Dose range
  • Nature of side effects and severity
  • Effects in special groups

Patient Studies (Phase 3 Trials)

• Objectives:
  • Confirmation of efficacy
  • Further evaluation of safety
  • Comparison with existing treatments

Drug Metabolism

• Close relationship between drug metabolism and normal biochemical processes
• Many enzymes involved in drug metabolism are designed for the metabolism of endogenous compounds
• Lipid-soluble drugs are poorly excreted in the urine and tend to store in fat or circulate until converted to more water-soluble metabolites
• Water-soluble drugs are more readily excreted in the urine and may be metabolized but not by the CYP enzyme systems