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Home , Cryptococcosis, Invasive candidiasis

REVIEW

Fungal infections – An overview

Natalie Schellack, BCur, BPharm, PhD(Pharmacy); Jade du Toit, BPharm; Tumelo Mokoena, BPharm; Elmien Bronkhorst, BPharm, MSc(Med)

School of Pharmacy, Faculty of Health Sciences, Sefako Makgatho Health Sciences University

Correspondence to: Prof Natalie Schellack, [email protected]

Abstract Fungi normally originate from the environment that surrounds us, and appear to be harmless until inhaled or ingestion of spores occurs. A pathogenic may lead to infection. People who are at risk of acquiring fungal infection are those living with human immunodeficiency virus (HIV), cancer, receiving immunosuppressant therapy, neonates and those of advanced age.

The management of superficial fungal infections is mainly topical, with agents including terbinafine, miconazole and ketoconazole. Oral treatment includes griseofulvin and .

Invasive fungal infections are difficult to treat, and are managed with agents including the azoles, and . This paper provides a general overview of the management of fungus infections.

© Medpharm S Afr Pharm J 2019;86(1):33-40

Introduction more advanced biochemical or molecular testing.4 Fungi normally originate from the environment that surrounds Superficial fungal infections us, and appear to be harmless until inhaled or ingestion of spores Either or fungi can cause , or superficial occurs. Infection with fungi is also more likely when the body’s fungal infections.7 Fungi that infect the , , nails and mucosa becomes weakened. A may lead to infection. The number of fungus species ranges in the can cause a superficial fungal infection. are found millions and only a few species seem to be harmful to humans; the naturally in soil, and keratin-containing structures, 3 ones found mostly on the mucous membrane and the skin have which provide them with a source of nutrition. been noted to cause fatal infections.1 Table I. The classification of superficial fungal infections according People who are at risk of acquiring fungal infection are those to the site of infection8 living with human immunodeficiency virus (HIV), cancer, receiving Classification Common names immunosuppressant therapy, neonates and those of advanced Scalp Ringworm of the head age.2 In crowded living conditions and low income communities Beard – the prevalence of fungal infections is much higher.3 Face Tinea facie Ringworm of the face Skin (body) Ringworm Fungi are divided into yeasts and moulds, and some can be a – combination of both, which are called dimorphic. Some fungi Hands – 4 are also seen as atypical. Moulds are filamentous fungi that are Nails Tinea unguium – multicellular in structure. They grow best in warm and damp Groin Jock itch conditions. They can reproduce and survive in extreme conditions Feet Tinea pedis Athletes foot by producing spores.5 Yeasts are unicellular and mainly reproduce asexually by budding.6 Dimorphic fungi appear to be in a mould form between 25 °C to 30 °C, however, at body temperature (37 °C) Overview and management of superficial they appear as a or yeast-like structure.5 fungal infections

Identification of the genus is made by examining the colony under An overview of different fungi causing superficial fungal infections a microscope, whereas the identification of the species requires and the management thereof is set out in Table II.

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3,11 11 11 11 3,11 spores on patients and asymptomatic and asymptomatic on patients spores carriers. and household contacts patients All with ketoconazole, should be treated and povidone selenium sulphide, iodine. Griseofulvin, terbinafine, fluconazole, fluconazole, Griseofulvin, terbinafine, . and clotrimazole miconazole, Topical: terbinafine. griseofulvin, or terbinafine, Oral: itraconazole. and terbinafine miconazole, Topical: clotrimazole. and fluconazole terbinafine, Oral: itraconazole. Terbenafine, itraconazole. ineffective. are creams Topical 5% nail amorolfine treatment: Local lacquer. in ineffective are creams Topical inadequate nail infections due to in the nail. penetration (first-line), terbinafine Oral: and fluconazole. itraconazole or terbinafine miconazole, Topical: 1% and and clotrimazole clotrimazole is 1% 30 g (if there hydrocortisone inflammation). griseofulvin, or terbinafine, Oral: itraconazole. • • • • • • Management • • • • • • • Itching with no Scaly patches hair of hair Black dots on area loss Cervical and suboccipital lymphadenopathy within interdigital Occurs and soles of the spaces feet soggy or dryMaceration, Scaly of the and itching associated area, affected with burning Malodour Starts with one or more plaques with a circular border raised Itchy Erythematous scaly spots; plague size Ranges 1–5 cm from One or more flat circular circular flat One or more erythematous with patch borders raised Scaly and itchy Sometimes causes hair loss Thickened Brittle nails Discoloured Well-demarcated itching borders, Erythema Scaling of patches10 (Kaushik 2015) et al, • • • • • • • • • • • • Signs and symptions • • • • • • • • • 9,10 9,10 10,13 Appearance Microscopy Culture Microscopy Cultures acid– Periodic stain Schiff (PAS) Clinical examination Microscopic examination Cultures Clinical presentation history Patient Physical examination Microscopy Signs Microscopy Cultures Diagnosis • • • • • • • • • • • • • • • • verrucosum verrucosum Trichophyton Trichophyton mentagrophytes rubrum Trichophyton Trichophyton mentagrophytes rubrum Trichophyton (common) Trichophyton mentagrophytes rubrum Trichophyton Trichophyton mentagrophytes Epidermophyton floccosum tonsurans Trichophyton (common) rubrum Trichophyton Epidermophyton floccosum Trichophyton Microsporum canis Causative agents Causative • • • • • • • • • • • • • • • • Farm and domestic Farm it to animals can spread humans in warm and Occurs is moist climates, in athletes, prevalent people, overweight sweating excessive Person-to-person contact Direct contact Sharing of combs, and hats. hairbrushes, and dogs Cats Transmission • • • • • • Affects mostly males on the beard/ Affects moustache and neck areas. as to referred Also affects the nail (fungal infection that unit). and It adolescents children, affects adults. prevalent Infection is more of toenails than fingernails. takes about 3–6 Onychomycosis treat. to months adolescent seen in young Commonly males. females. than males more Affects moisture by is promoted growth Fungal and warmth. locker Risk infection from of acquiring athletic swimming pools floors, room shoes and sports equipment. than affects men more Commonly women. portion area, of the the groin Involves the affect upper thigh, usually doesn’t the buttocks. to but can spread scrotum the face and involves age, any at Occurs trunk, shoulders, legs (occasionally), and arms. Affects children between 3–9 years. 3–9 between children Affects usually asymptomatic are Adults carriers. and poverty- in crowded Prevalent stricken areas. Aetiology • • • • • • • • • • • • • • • Table II. Overview of superficial and management fungal infections Table barbae Tinea Tinea unguium pedis Tinea cruris Tinea corporis Tinea Tinea capitis Tinea

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15 15 17 15 15 -resistance -resistance C. glabrata 15 15 11 5 17

5 Topical: miconazole, terbinafine or terbinafine miconazole, Topical: 1% and and clotrimazole clotrimazole is 1% 30 g (if there hydrocortisone inflammation). griseofulvin, or terbinafine, Oral: itraconazole. See tinea pedis. 17 Lifelong azole-therapy considered in azole-therapy considered Lifelong • • Management • 17 5

10 5 (Kaushik 2015) et al, Dry, scaly, sometimes scaly, Dry, diffuse itchy hyperkeratosis Well-demarcated Well-demarcated itching borders, Erythema Scaling of patches Signs and symptions • • • • Itraconazole is second-line treatment for invasive . invasive for treatment is second-line Itraconazole patients with or without prosthetic valve- with or without prosthetic replacements. patients Voriconazole is choice of drug for fluconazole-resistant species such as C. krusei . of drug for is choice Voriconazole Fluconazole is first-line treatment of infections for those who candidiasis infections of invasive treatment is first-line Fluconazole azoles. to exposure not had previous and have not critically ill, are fluconazole. towards intrinsic resistance C. krusei displays C. krusei is reported resistant. previously and C. krusei infections, of C. glabrata treatment is used for B and azoles. amphotericin tolerate unable to patients or for with azoles treated Posaconazole is used if treatment failure occurs with voriconazole. with voriconazole. occurs failure is used if treatment Posaconazole imidazoles. to is reported be resistant to C. glabrata infections. C. krusei and C. glabrata of C. albicans, treatment is used for fungal infections. Amphortericin systemic B can be used for has been reported amphortercin to B. : caused by suggests high doses of Evidence B with or without . amphotericin in those recommended is replacement valve A also effective. echinocandins are least at for continued Treatment surgery. undergo stable enough to are that patients surgery. replacement after valve six weeks . with C. glabrata infected patients for with echinocandins is preferred Treatment echinocandins. with candidemia are patients non-neutropenic for First-line Continue B. echinocandins or amphotericin are patients neutropenic for Treatment culture. after negative weeks two for treating is used for treatment of any Candida species. Candida of any treatment is used for Anidulafungin Management • • • • • • • • • • • • • • See tinea pedis Clinical presentation • Diagnosis • 15 Culture from sterile sterile from Culture such as spinal fluid site or bone marrow taken from Cultures digestive respiratory, and urogenital to difficult tracts are as they are interpret part of the normal flora Diagnosis • • Trichophyton (common) Trichophyton mentagrophytes Epidermophyton floccosum Trichophyton rubrum Trichophyton Trichophyton mentagrophytes Epidermophyton floccosum 4 • • • Causative agents Causative • • • 19 The infection can infection The causing disseminate endocarditis, and Asymptomatic chills and , oxygenation reduced of sepsis Symptoms be present may such as hypotension and tachycardia. • • • Signs and symptions Direct contact with person, animal infected or soil Occurs in warm and Occurs is moist climates, in athletes, prevalent people, overweight sweating excessive 17 • Transmission • Candidia parapsilosis Candidia tropicalis Candida • • • • • • Causative agents Causative Candida species are species are Candida part of the normal breach thus any flora, in the superficial surface can lead to candidiasis. invasive Affects the palmar and interdigital areas areas the palmar and interdigital Affects the and can appear at of the hand/s, same time as tinea pedis. ‘one as the to It referred is commonly syndrome’. feet hand two Commonly affects men more than affects men more Commonly women. portion area, of the the groin Involves the affect upper thigh, usually doesn’t the buttocks. to but can spread scrotum • Aetiology • • Aetiology • • Tinea Tinea manuum Table II. Overview of superficial and management (Cont.) fungal infections Table cruris Tinea fungal infections III. Overview of invasive and management Table Infection Yeasts: Invasive candidiasis

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4 4 20

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4 For more severe infections such as meningitis in HIV-infected patients, amphotericin amphotericin patients, in HIV-infected infections such as meningitis severe more For for two (800 mg – 1200 mg) should be used with fluconazole B in combination weeks and then fluconazole for eight 400 mg alone fluconazole thereafter weeks, one year. up to be used for 200 mg to Duration of treatment depends on clinical response, immunocompromised immunocompromised depends on clinical response, of treatment Duration pulmonary invasive for Treatment species. and typecondition of is about 6–12 weeks. aspergillus resistance against itraconazole has been reported. against itraconazole A. niger resistance B. against amphotericin resistance inherent has been reported have to A. terreus Voriconazole is preferred in most cases of invasive . Suspectiblity aspergillosis. in most cases of invasive is preferred Voriconazole enzymes, hepatic elevated with significantly patients However, must be tested. should not use voriconazole dysfunctionhepatic to and a history of intolerance treatment. as first-line voriconazole cannot be used. if voriconazole B is an alternative, Amphotericin however and itraconazole, posaconazole Second-line drugs include caspofungin, susceptibility must be tested. species are intrinsically resistant to echinocandins. to intrinsically resistant Cryptococcus species are and miconazole. for ketoconazole except effective, are Most azoles of potential is a significant there agent as a prophylactic using fluconazole When developing. resistance to is likely resistance a long period, over if used however B is effective, Amphotericin occur. has resistant strains to itraconazole and cross-resistance to voriconazole voriconazole to and cross-resistance itraconazole to strains A.fumigatus has resistant is emerging. and posaconazole echinocandins occurs. to cases resistance In rare • • Management • • • • • • • • • • •

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18 Diagnosis is made on Diagnosis taken of the culture tissue or fluids such as cerebrospinal blood, fluids or . Cryptococcal test is a rapid test performed on blood or . Glucose in the Glucose fluid is cerebrospinal usually normal and negative. are cultures can be Blood culture performed. and CT scans X-rays also aid in diagnosis. A tissue of the can be done to establish the specific organism. Diagnosis • • • • • • 5 21 Infection starts in the lungs and spreads the blood, through the central normally to nervous system causing meningitis. Aspergillus can cause Aspergillus of a wide range diseases. Respiratory symptoms: and , fever, pleuritic haemoptysis, , . CNS: seizures. • • • • Signs and symptions 21 Aspergillus fumigatus Aspergillus flatus Aspergillus terreus Aspergillus niger (found C. neoformans (found worldwide) Cryptococcus gattii6 • • • • • • Causative agents Causative 5

6 which plays a role a role which plays the in protecting in extreme organism conditions. C. neoformans is a cause of common hospital-acquired in HIV- meningitis patients. infected C. gattii can cause infections in immunocompetent and immunocompromised and is mostly patients and in tropical found areas. subtropical High mortality rates in documented are such sub-areas due Africa, Saharan of the high burden to patients. HIV-infected Cryptococcus species encapsulated are Most Aspergillus Most Aspergillus found species are globally. It is a life-threatening in immunocompromised patients. Species A. fumigatus in found is commonly grasslands. A. niger is commonly in soil. found • • • • • • • • Aetiology Table III. Overview and management of invasive fungal infections (Cont.) III. Overview of invasive and management Table Infection Yeasts: Cryptococcus Moulds Aspergillus

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22 is susceptible to all except echinocandins. echinocandins. except all antifungals to is susceptible H. capsulatum resistance reported acquired co-infected with H. capsulatum patients HIV-infected against fluconazole. disease such as in the severe more for of treatment; is the choice itraconazole Oral CNS, amphortencin B is required. The cell walls of P. jirovecii consist of cholesterol, therefore most drugs are drugs are most antifungal therefore of cholesterol, consist jirovecii of P. walls cell The wall. cell in the work on the ergosterol as antifungals not effective, High (trimethoprim/sulphamethoxazole). doses of co-trimoxazole • • • Management • • 23

5 Biopsy specimen for is essential diagnosis. pathologic Blood and bone culture marrow in positive are disseminated . the from Fluid respiratory tract, and can assist CT or X-rays in diagnosis. Sputum sample or biopsy can be investigated under a microscope. chain Polymerase reaction can also detectbe used to pneumocystis. Diagnosis • • • • 22 3 Dyspnoea, fever, chills, chills, Dyspnoea, fever, cough hypoxaemia, and wheezing2 It is mostly acquired the lungs and through include symptoms cough, chills, fever, chest pains , and body aches. • • Signs and symptions 5 Histoplasma Histoplasma var. capsulatum capsulatum Histoplasma var. capsulatum duboisii • • • Causative agents Causative 4

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5 It is classified as dimorphic as it grows 25 °C as a mould at 37 °C. at and as a yeast is found H. capsulatum and can worldwide as the to be referred disease as it is cave and bat in bird found soil and droppings, dust. It is an important cause of chronic . of Prevalence Histoplasma is in HIV- increasing in patients infected Africa. Pneumocystis jirovecii called (formerly ) Pneumocystis carinii isolated is commonly the human lung from via and can be spread coughing. also is known as PCP, seen in commonly or other HIV patients immunocompromised patients. • • • • • • Aetiology Table III. Overview and management of invasive fungal infections (Cont.) III. Overview of invasive and management Table Infection Dimorphic Histoplasma Atypical Pneumocystis

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Figure 1. Prevalent superficial fungal infections: 1. Tinea capitis 2. Tinea barbae 3. Tinea corporis 4. Tinea manuum 5. Tinea unguium 6. Tinea cruris 7. Tinea versicolor and 8. Tinea pedis

Table IV. Drugs used for the treatment of invasive fungal infections Drug class Drugs Mechanism of action Side-effects Monitoring parameters Imidazoles • Fluconazole • Imidazoles have a fungistatic effect with dose- • General side-effects: • Liver function • Voriconazole dependent inhibition of CYP 14α-demethylase. ◦◦ • QT-interval24 • Itraconazole This enzyme is responsible for the conversion ◦◦ diarrhoea of lanosterol to ergosterol, which plays an • Pasoconazole ◦◦ dyspepsia important role in the stability of the fungal • Isavuconazole ◦ abdominal pain cell membrane. This can lead to compromised ◦ membrane integrity.25 ◦◦ ◦◦ photosensitivity ◦◦ dermatological symptoms such as rash ◦◦ QT-elevation24 Echinocandins • Caspufungin • Mechanism of action of echinocandins • Hepatic dysfunction • Liver function24 • Micafungin includes the inhibition of glucan synthase, the • Rash • Anidulafungin enzyme responsible for the synthesis of β1–3 • Photosensitivity linked glucan, which is a major component of • Bronchospasm the polysaccharide, better known as the cell • Pruritus24 wall.26 Polyenes • Amphotericin B • Polyenes form aggregates in the cell • Chills and fever • Monitor magnesium membrane with ergosterol, leading to pores • Liver toxicity levels twice a week that cause leakage of cellular contents. This • Bronchospasm • Monitor creatinine, leads to cell lysis.27 • Renal toxicity complete blood count and metabolic panel19 • Hypokalaemia • Infusion-related reactions24

Invasive fungal infections Overview and management of invasive fungal infections Invasive fungal infections are usually uncommon, except when in immunocompromised and neutropenic patients.5 Treating An overview of fungi causing invasive infections and the invasive fungal infections can be challenging due to limited management thereof is set out in Table III. antifungal agents available and considering factors such as Conclusion toxicity, drug interactions and emerging resistance.15 Variations in species occur due to different geographical areas, hospital- Yeast, moulds or atypical fungi may cause fungal infections. The associated factors and the antifungal agents that are used to treat infection may be superficial or invasive. Superficial infections patients.15 will mostly infect the skin, nails and hair of the patient, while invasive infections may cause blood stream infection, or infect Risk factors for invasive fungal infection include a history of organ systems like the central nervous system, lungs or heart. prior exposure to antifungals or broad spectrum antibiotics, Management of superficial infections can be topical with agents immunocompromised conditions such as in organ transplants or like miconazole and ketoconazole, or systemic with agents like HIV-infected patients,15 exposure to intravenous lines, catheters fluconazole or griseofulvin. Invasive infections need susceptibility and dialysis,6 poorly controlled diabetes, cancer chemotherapy16 testing and close monitoring and must be treated systemically and neutropenic patients.5 with agents like the azoles, echinochandins or amphotericin B.

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