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Echinocandins – your weapon against fungal infections

Learning objectivesYou will learn:

• The mechanism of action and pharmacological parameters of echinocandins

• Clinical factors promoting antifungal resistance

• The recommended management of candidiasis in accordance with the principles of good antifungal stewardship.

IntroductionCandida species are the leading cause of invasive fungal disease in the intensive care unit (ICU) setting and are a major cause of morbidity and mortality; at least 15 distinct Candida spp. cause human disease; however, >90% of invasive disease is caused by the five most common pathogens: C. albicans, C. glabrata, C. tropicalis, C. parapsilosis and C. krusei. In many centres across the world, C. auris is increasingly more common than other Candida spp. Each has unique virulence potential and antifungal susceptibility, but taken as a whole, significant infections caused by these Candida spp. are generally referred to as invasive candidiasis.1,2

C. parapsilosis, followed by C. albicans, was the most common species isolated in cases of candidaemia in South Africa in 2017 (Figure 1), although azole-resistant strains of C. parapsilosis3 and C. auris now dominate in the private healthcare sector, and susceptibility of C. auris to amphotericin B needs to be monitored carefully.4.5 Two echinocandin-resistant C. glabrata FKS mutants have also been isolated in South Africa.6 The recent emergence of multidrug-resistant Candida spp. will complicate the selection of antifungal therapy in the immediate future.

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In many centres across the world, C. auris is increasingly more common than other Candida spp.

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Echinocandins – your weapon against fungal infections

None of the echinocandins requires dose adjustment for renal insufficiency or dialysis, and caspofungin is the only echinocandin for which dose adjustment is recommended for patients with moderate-to -severe hepatic dysfunction

This review focuses on the echinocandin class of antifungals and the reasons why these agents are the preferred first-line medicines for the management of invasive candidiasis in accordance with the principles of good antifungal stewardship. All of the echinocandins - caspofungin, micafungin and anidulafungin - are approved for the treatment of invasive candidiasis.1,7

What is the mechanism of action of echinocandins?Echinocandin drugs are lipopeptide mol-ecules that non-competitively inhibit β-1,3-D-glucan synthase. This fungal-specific enzyme, not found in humans, is responsible for the biosynthesis of β-1,3-D-glucan, a principal structural component of fungal cell walls. Depletion of β-1,3-D-glucan results

in thinning of the cellular wall, abnormal swelling, an irregular shape of the fungal cell and aberrant budding, all of which lead to cell lysis. The echinocandins have fungistatic activity against Aspergillus spp. and fungi-cidal activity against most Candida spp.8,9

Pharmacological parameters of echinocandins Echinocandins are available only as paren-teral preparations. Each has been studied for the treatment of oesophageal candidiasis and invasive candidiasis, and each has demon-strated efficacy in these situations. The mini-mum inhibitory concentrations (MICs) of the echinocandins are low for most Candida spp., including C. glabrata and C. krusei. C. parapsi-losis demonstrates innately higher MICs to the echinocandins and may be less responsive.1,2

In adults, the different echinocandins all have very similar pharmacological properties. Each is administered intravenously once daily, and

each achieves therapeutic concentrations in all infection sites with the exception of poor penetration into the urinary tract, the central nervous system and the eye. None of the echi-nocandins requires dose adjustment for renal insufficiency or dialysis, and caspofungin is the only echinocandin for which dose adjustment is recommended for patients with moderate-to-severe hepatic dysfunction. All echinocan-dins have minimal adverse effects. Side effects include nausea, vomiting, headache, phlebitis and histamine-mediated symptoms such as rash, urticaria, flushing, pruritus, dyspnoea and hypotension (Table 1).1,9

Figure 1. Species distribution for cases of candidaemia with a viable bloodstream isolate by health sector, South Africa, 2016-20174

Species of candidaemia

Public sector

Private sector

Candida albicans

Candida parapsilosis

Candida glabrata

Candida auris

Candida tropicalis

Candida krusel

Other Candida species

800

700

600

500

400

300

200

100

0

Dist

ribut

ion

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Echinocandins – your weapon against fungal infections

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Table 1. A comparison of the pharmacological parameters of echinocandins

Caspofungin Micafungin Anidulafungin

Steady state 2 weeks 4 days Loading plus 1 dose

Volume distribution (l/kg)

8-10 27 30-50

Half-life (hours) 10.6 11-17 24-26

Protein binding 96% 99% 99%

Urine, CSF, eye Very low Very low Very low

Excretion Faecal 35%Renal 41%

Faecal 40%Renal <15%

Faecal 30%Renal <1%

Metabolism Spontaneous degradation

Hepatic Not metabolised, bile elimination

Usual dose 70mg loading dose,then 50mg daily

No loading dose,100-150mg daily

200mg loading dose,then 100mg daily

Renal failure No dose adjustment No dose adjustment No dose adjustment

Liver dysfunction Dose reduction if moderate

Increased clearance if severe? Use high dose 150mg

No dose adjustment

Drug interactions CyclosporineTacrolimusRifampicinOther CYP inducers

Sirolimus Cyclosporine

Safety and side effects Similar Similar Similar

Spectrum SameBetter for C. glabrata?

SimilarBetter for C. glabrata?Higher MIC for C. parapsilosis

Same

Candidiasis, invasive candidiasis, neutropenic patients

Yes Yes Yes

Paediatric dose FDA approvedDoses exist

FDA approvedDoses exist

Not FDA approvedDoses exist

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Echinocandins – your weapon against fungal infections

The principles of good antifungal stewardship should always be considered when making treatment decisions

Resistance to antifungalsPre-exposure to antifungal prophylaxis, in particular with azoles and to a lesser extent with echinocandins, has been associated with the occurrence of breakthrough infections with resistant Candida spp., which in turn are associated with increased morbidity and mor-tality in both immunocompromised and criti-cally ill patients. Therapeutic failures rarely occur among common Candida spp.; failures are more frequent with organisms such as C. auris, C. glabrata, and C. krusei, which are more likely to be multidrug resistant.10,11

Echinocandin resistance in susceptible species is always acquired during therapy. Mutations

in the FKS genes encoding the catalytic sub-units of glucan synthase confer echinocandin resistance in otherwise susceptible Candida spp.; the mechanism of resistance involves amino acid changes in hot-spot regions of FKS subunits of glucan synthase, which decreases the sensitivity of the enzyme to the drug. Cellular stress response pathways lead to drug adaptation, which promotes the formation of resistant FKS strains. Clinical factors promoting echinocandin resistance include empirical therapy, prophylaxis, gas-trointestinal reservoirs and intra-abdominal infections.8,11

Managing candidiasis in accordance with the principles of good antifungal stewardship

The principles of good antifungal steward-ship should always be considered when mak-ing treatment decisions; of note:1

• Start antifungals rapidly in appropriate cases

• Ensure loading doses and therapeutic doses are correct

• Make the diagnosis quickly, using clini-cal risk or likelihood and inflammatory markers

• Confirm or exclude fungal sepsis with the help of biomarkers or culture

• De-escalate intravenous therapy if appro-priate and transition to oral therapy

• Adequate duration of treatment.

Echinocandins are recommended as first-line treatment for critically ill patientsThe echinocandins are, across many different guidelines, the recommended first-line agents for the treatment of candidaemia in neutro-penic patients and in patients with moderate

or severe disease.1,7 Advantages of using echi-nocandins for first-line treatment are summa-rised in Table 2.

Table 2. Advantages of using echinocandins as first-line antifungal treatment in critically ill patients

• Broad spectrum, except Zygomycetes, Fusarium, Trichosporon and Cryptococcus neoformans• Resistance rare• Biofilm activity• Fungicidal• Good safety profile• Fewer drug-drug interactions.

With a risk of mortality ranging from 10% to 42%, it is important not to overlook invasive candidiasis. Candidaemia that develops in neutropenic patients is a life-threatening infection associated with acute disseminated candidiasis, a sepsis-like syndrome,

multiorgan failure and death. Outcomes are particularly poor for people with protracted neutropenia; in those patients who have septic shock caused by Candida spp. and who do not start antifungal therapy within 24 hours, mortality approaches 100%.1,7,12

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The golden period within which to initiate antifungal treatment is 12 hours; earlier therapy is associated with better outcomes, with as much as a 50% reduction in mortality

The golden period within which to initi-ate antifungal treatment is 12 hours; earlier therapy is associated with better outcomes, with as much as a 50% reduction in mortality (Figure 2). If there is a high level of suspi-cion (Table 3), do not wait for laboratory results before initiating treatment but rather start early, based on the risk of candidiasis

if there are clinical signs of septic shock and there is no other known cause of fever.1,10,12 The Candida score (Table 4), relevant for the non-neutropenic patient in ICU for ≥7 days, is useful for guiding this decision-making and it is recommended that antifungal therapy be initiated immediately if the score is ≥3.13

Table 3. Risk factors associated with the development of invasive candidiasis10

• Colonisation of several body sites• Broad-spectrum antibiotics• Immunosuppression• Neutropenia• Burns (>50%)• Disruption of physiological barriers in the digestive tract• Major abdominal surgery• Surgery of the urinary tract in the presence of candiduria• Major trauma (ISS >20)• Parenteral nutrition• Haemodialysis• APACHE score II >20• Central venous catheter• Candiduria >105cfu/ml• Young and old ages• Diabetes• Renal failure• Recent surgery• Urinary catheter• Vascular catheters• Prolonged ICU stay (>7 days)• Multiple transfusions.

Figure 2. Relationship between hospital mortality and the timing of antifungal treatment12

The timing of antifungal therapy was determined to be from the time when the first blood sample for culture, positive for fungi, was drawn to the time when antifungal treatment was first administered to the patient.

Delay in start of antifungal treatment (hours)

<12 12–24 24–48 >48

35

30

25

20

15

10

5

0

Hosp

ital m

orta

lity

(%)

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Echinocandins – your weapon against fungal infections

If used and interpreted judiciously, nonculture diagnostic tests can identify more patients with invasive candidiasis and better direct antifungal therapy

Table 4. The Candida score13

Start antifungal therapy immediately if the total score is ≥3

Total parenteral nutrition 1

Surgery 1

• Multifocal Candida colonisation 1

Severe sepsis 2

Diagnosis of candidiasis

Adjunctive to the gold standard of blood cultures or cultures of other samples for the diagnosis of invasive candidiasis, nonculture diagnostic tests increasingly used in clinical practice include polymerase chain reaction

and antigen and β-D-glucan detection assays. If used and interpreted judiciously, nonculture diagnostic tests can identify more patients with invasive candidiasis and better direct antifungal therapy.1,2

De-escalation from an echinocandinDe-escalation from an echinocandin to intra-venous/oral fluconazole is encouraged when the patient is clinically stable and the isolated strain is susceptible to fluconazole. Exact

timing for shifting to fluconazole is unknown and may vary from patient to patient, depending on patient- and pathogen-related factors.

Management and follow-upThe IDSA recommendation is that in patients who have no clinical response to empirical antifungal therapy at 4-5 days and who do not have subsequent evidence of candidiasis after the start of empirical therapy, or have

a negative nonculture-based diagnostic assay with a high negative predictive value, consid-eration should be given to stopping antifun-gal therapy.1

Key learnings

• Most cases of invasive candidiasis are caused by five common Candida spp.

• Multidrug-resistant Candida spp. have recently emerged in South Africa

• The different echinocandins have very similar pharmacological parameters and are the recommended first-line agents for the treatment of candidaemia and invasive candidiasis

• It is important not to undertreat invasive candidiasis; delayed treatment leads to significantly poorer outcomes.

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DisclaimerThe views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities.

Echinocandins – your weapon against fungal infections

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© 2021 deNovo MedicaReg: 2012/216456/07

This summary report was compiled for deNovo Medica byGlenda HardyBSc(Hons) Medical Cell BiologyReviewed by Dr Justyna WojnoPathologist (Medical Microbiology), Lancet Laboratories

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