ROLE OF

ECHINOCANDINS
IN INVASIVE
FUNGAL
INFECTIONS
 CLASSIFICATION OF FUNGAL INFECTIONS

FUNGAL
INFECTIONS

SUPERFICIAL
INFECTIONS CUTANEOUS
SUB CUTANEOUS DEEP MYCOSAL
On the surface of INFECTIONS INFECTIONS
INFECTIONS
Dermatophytes OR
the skin SYSTEMIC
Ringworm infections MYCOSAL
All Tinea sps INFECTIONS

Candida sps
 Invasive fungal infections

 Invasive fungal infections are a significant

and often lethal problem in transplant
patients.

 They are at risk for these infections as a

result of their general health status,
technical complications of surgery, and
immunosuppression.
 FUNGAL INFECTIONS IN
TRANSPLANTATION

 The incidence of invasive fungal infections in solid organ transplant

recipients varies according to the type of transplant.

 Most of these infections are due to Candida spp., Aspergillus spp. or

Cryptococcus spp.

 Currently, overall mortality due to invasive fungal infections in solid

organ transplant recipients ranges between 25%-80% and half of
these deaths are directly related to the fungal infection.
 CANDIDIASIS/ ASPERGILLOSIS

 Candidiasis is the most common

invasive fungal infection in SOT
recipients and accounts for 50–60%
infections.

 Candida species, particularly Candida

albicans, are frequent colonizers of
the human gastrointestinal,
respiratory and reproductive tracts,
and the skin.
 CANDIDIASIS/ ASPERGILLOSIS

 The majority of invasive candidiasis is

from an endogenous source – usually
the skin or gut.

 Aspergillosis is the next most common

infection, accounting for 20–25% of
fungal infections.

 In lung transplant recipients,

aspergillosis is the most common
infection
 INVASIVE CANDIDA INFECTIONS
REPORTED IN VARIOUS TRANSPLANT
TYPES
60

50
Prevalence, %

42
40 38

30

20 17
12
10 8

0
Liver Kidney Pancreas Lung Heart

*Numbers reflect data collected by TRANSNET from 2001 to 2004. Andes D, et al. ICAAC 2004. Abstract M-1014.
 DISTRIBUTION OF FUNGAL PATHOGENS
CAUSING INVASIVE FUNGAL INFECTIONS IN
TRANSPLANT RECIPIENTS

Ther Adv Infect Dis (2013) 1(3) 85105

 INCIDENCE OF INVASIVE FUNGAL
INFECTIONS

 The Transplant-Associated Infection Surveillance Network conducted a 5-year

prospective study among 1,063 organ transplant recipients.
 1028 were diagnosed with IFI.
 The most common IFIs were:
 Invasive candidiasis (53%),
 Invasive aspergillosis (IA) (19%),
 Cryptococcosis (8%),
 Non-Aspergillus molds (8%),
 Endemic fungi (5%), and
 Zygomycosis (2%)

 IA is a life-threatening complication in patients who undergo solid organ

transplantation, having an incidence between 0.5% and 2.2% with a mortality rate of
> 70% and a high case-fatality rate of up to 88%
 INDIAN PROSPECTIVE

 Recipients of solid organ transplants have 6–10% incidence of

opportunistic fungal infections with a very high mortality of
70–100% in the Indian subcontinent.
 PATHOPHYSIOLOGY

 Infection may be due to  Donor-derived infections are

reactivation of a previously an increasingly recognized
quiescent process such as mode of transmission .
colonization or subclinical  Transplanted organs may act
infection, or from de
as reservoirs for potentially
novo infection following
pathogenic fungi.
inhalation of fungi after
transplantation.
 DIAGNOSIS OF FUNGAL INFECTIONS IN
RENAL TRANSPLANT RECIPIENTS

 Fungal infections in renal transplant recipients are diagnosed on the

basis of:

 Clinical and radiologic signs and symptoms that include:

 Tissue invasion

 Positive culture results from a deep tissue specimen such as

 Blood

 Cerebrospinal fluid

 Peritoneal fluid, or a biopsy specimen

GOALS OF THERAPY IN TRANSPLANT
RECIPIENT

 Prevention of fungal infections.

 Individual risk assessment

 Initiated early in patients with a suspected fungal infection.

 Optimize the pharmacokinetics of antifungal drugs.

 Assess for potential side effects.

NANTIFUNGALS

ERGOSTEROL SYNTHESIS
INHIBITORS

Voriconazole
Itraconazole
Posaconazole
Fluconazole
 ECHINOCANDINS

 Newer antifungal agents that inhibit the fungal cell wall

synthesis

 During fermentation process, some metabolites were found

to inhibit Candida sp., and they were named Echinocandins

 The echinocandins have potent activity against Aspergillus

and most Candida species, including those species resistant
to azoles. However, they have minimal activity against other
fungi.
 ECHINOCANDINS

 Caspofungin, micafungin, and anidulafungin are semisynthetic

echinocandin derivatives with clinical use due to their solubility,
antifungal spectrum, and pharmacokinetic properties.
 All these preparations so far have low oral bioavailability, so
must be given intravenously only.
 MECHANISM OF
ACTION

Inhibits the synthesis of β 1,3 – D- glucan via noncompetitive inhibition of

the enzyme 1,3-β glucan synthase and are thus called "penicillin of

antifungals“ resulting in the inhibition of cell wall, leading to lysis and

death.
 FUNGICIDAL AND
FUNGISTATIC ACTION

 Echinocandins exhibit fungicidal activity against Candida species,

including triazole-resistant isolates, and fungistatic activity against
Aspergillus species.
 PHARMACOKINETICS

 Due to the large molecular weight of echinocandins, they have poor

oral bioavailability and are administered by intravenous infusion.
 In addition, their large structures limit penetration into cerebrospinal
fluid, urine, and eyes.
 In plasma, echinocandins have a high affinity to serum proteins.
 Echinocandins do not have primary interactions with CYP450 or P-
glycoprotein pumps.
 Caspofungin has triphasic nonlinear pharmacokinetics.

 Micafungin and anidulafungin have linear elimination.

 ADVANTAGES OF
ECHINOCANDINS

• Broad range (especially against all Candida), thus can be given

empirically in febrile neutropenia and stem cell transplant.
• Can be used in case of azole-resistant Candida or use as a second-
agent for refractory aspergillosis
• Long half-life
 Not an inhibitor, inducer, or substrate of the cytochrome P450 system,
or P-glycoprotein, thus minimal drug interactions
 No dose adjustment is necessary based on age, gender, race
 ADVANTAGES OF
ECHINOCANDINS
• IV administration
• CNS penetration: poor
• Dose: once daily
• Little infusion related toxicity
• Little or no renal and hepatic toxicity
• Drug-drug interaction limited
• Potential combination with other antifungals (AMB or azoles)
• Animal data suggest synergistic effect
• Echinocandins: Caspofungin Anidulafungin Micafungin
 1
Echinocandins : In vitro activity

Minimum inhibitory concentrations of the echinocandins against Candida species

Anidulafungin Micafungin* Caspofungin

Candida species MIC50 MIC90 MIC50 MIC90 MIC50 MIC90

(µg/ml) (µg/ml) (µg/ml) (µg/ml) (µg/ml) (µg/ml)

albicans 0.03 0.03 0.015-0.03 0.03 0.03-0.5 0.06-1

glabrata 0.03 0.13 0.015-0.03 0.015-0.06 0.03-1 0.06-2

tropicalis 0.03 0.13 0.03 0.06 0.12-0.5 0.25-1

dubliniensis 0.03 0.06 0.03 0.033 0.25-0.5 0.5

krusei 0.06 0.13 0.06-0.13 0.06-0.25 0.12-2 0.25-2

lusitaniae 0.06 0.25 0.06 2 0.5-1 1-2

parapsilosis 2 2 1 2 1-2 1-4

guilliermondii ND 1 ND 0.5 2 -> 8 2 -> 8

MIC50 or MIC90 = minimum inhibitory concentration for 50% or 90%, respectively, of tested strains; ND = not done.
1- Cappelletty D. et al. Reviews of therapeutics : the echinocandins Pharmacotherapy 2007, 27(3):369-388.

24
 ANIDULAFUNGIN

 Semi-synthetic lipopeptide
synthesized from a fermentation
product of Aspergillus nidulans.
MIC against candida species
 INDICATIONS

Anidulafungin is indicated in adults for the treatment of:

 Candidemia and other forms of Candida infections (intra-abdominal

abscess and peritonitis)

 Esophageal candidiasis
 DOSAGE IN CANDIDA
INFECTIONS

 200 mg loading dose on Day 1,

followed by 100 mg daily dose
thereafter for at least 14 days
after the last positive culture
 DOSAGE IN OES0PHAGEAL
CANDIDIASIS

 100 mg loading dose on Day 1,

followed by 50 mg daily dose
thereafter for a minimum of 14
days and for at least 7 days
following resolution of
symptoms

The rate of infusion should not exceed 1.1 mg/minute [equivalent to 1.4 mL/minute or 84
mL/hour when reconstituted and diluted per instructions]
 RECONSTITUTION

 Anidulafungin for Injection must

be reconstituted with sterile Water
for Injection and subsequently
diluted only with 5% Dextrose
Injection, USP or 0.9% Sodium
Chloride Injection, USP (normal
saline).
 HOW TO ADMINISTER

Dose No. of vials Total Infusion Total Rate of Minimum

required reconstituted volume infusion infusion duration
volume volume of
required infusion
100 1 30 ml 100 ml 130 ml 1.4 ml/min 90 min.
mg or 84 ml/hr
200 2 60 ml 200 ml 260 ml 1.4 ml/min 180 min.
mg or 84 ml/hr
 CONTRAINDICATION

 ANIDULAFUNGIN is
contraindicated in persons
with known hypersensitivity
to anidulafungin, any
component of ANICORD, or
other echinocandins.
 SUMMARY

 Wider spectrum of action and lower toxicity than caspofungin.

 Good in vitro antifungal activity against Candida and Aspergillus spp.

 One of the most interesting features of anidulafungin in solid organ

transplant recipients is that this drug is not metabolized by or eliminated

through the kidney so that dosage adjustments are not required in these

patients, who frequently show renal function alterations.

 SUMMARY

 Moreover, anidulafungin is not metabolized in the liver and is consequently

free of interactions with other drugs metabolized in this organ.

 Equally, dosage adjustments are not required in patients with severe liver
disease or in those administered immunosuppressive agents such as
prednisone, cyclosporine A, tacrolimus, mofetil mycophenolate or sirolimus.

 Hence anidulafungin will be highly useful in the clinical management of

solid organ transplant recipients.
 Anidulafungin

Clinical data

Anidulafungin vs Fluconazole
Reboli A.C. et al.

Anidulafungin versus Fluconazole for Invasive Candidiasis.

N Engl J Med 2007;356:2472-82.

35
 1
Primary endpoint

Global success at the end of IV therapy

ECALTA® demonstrated
superiority vs fluconazole:
• Significantly greater response rate
in the anidulafungin group
• Difference: 15.4%
(95% CI: 3.9% to 27.0%)

Mean (median) duration of IV therapy:

 fluconazole: 12.1 (11) days

 anidulafungin: 13.5 (14) days

1- Reboli A.C., Rotstein C., Pappas P.G. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis.
N Engl J Med 2007;356:2472-82.
36
MICAFUNGIN

Micafungin is a water-soluble antifungal agent that is

derived from Coleoptioma empedri.
MIC AGAINST CANDIDA SPECIES
 INDICATIONS

Micafungin is indicated for adults and paediatric patients of 4 months or

older for:

 Treatment of Patients with Candidemia, Acute Disseminated

Candidiasis, Candida Peritonitis and Abscesses

 Treatment of Patients with Esophageal Candidiasis

 Prophylaxis of Candida Infections in Patients Undergoing

Hematopoietic Stem Cell Transplantation (HSCT)
 ADVERSE EFFECTS

 Most common adverse reactions include diarrhoea, nausea,

vomiting, pyrexia, thrombocytopenia, and headache.

 Histamine-mediated symptoms including rash, pruritus, facial

swelling, and vasodilatation

 The drug has no significant effect on renal function.

 DOSAGE

Indication Dose
Adult Paediatrics 30 kg Paediatrics greater
or less than 30 kg

Candidemia, Acute 100 mg daily* 2 mg/kg/day

Disseminated Candidiasis, (maximum 100 mg daily)
Candida Peritonitis and
Abscesses
150 mg daily 3 mg/kg/day 2.5 mg/kg/day
Esophageal Candidiasis
(maximum 150 mg
daily)
 DOSAGE

Indication Dose
Adult Paediatrics 30 kg Paediatrics greater
or less than 30 kg

Prophylaxis of Candida 50 mg daily** 1 mg/kg/day

Infections in HSCT (maximum 50 mg daily)
Recipients

*100 mg micafungin is equivalent to 101.73 mg micafungin sodium.

**50 mg micafungin is equivalent to 50.86 mg micafungin sodium
 SPECIAL POPULATION

 Micafungin is administered intravenously as a 1-h infusion

once daily.

 Dose adjustments are not required for elderly persons or for

patients with renal dysfunction.

 Likewise, mild to moderate hepatic impairment does not

warrant changes in dose.
 SPECIAL POPULATION

 Pregnancy - No human data. Adverse effects in animals. Use if

potential benefits of treatment outweigh potential fetal risk

 Nursing Mothers - Caution should be exercised if administered to

a nursing woman

 Safety and effectiveness in paediatric patients less than 4 months

of age have not been established
 CONTRAINDICATION

 Micacord is contraindicated
in persons with known
hypersensitivity to micafungin
sodium, any component of
micafungin, or other
echinocandins.
MOLECULAR COMPARISON

Therapeutics and Clinical Risk Management 2007:3(1)

PHARMCOKINETICS COMPARISON

Therapeutics and Clinical Risk Management 2007:3(1)

COMPARATIVE PHARMACOKINETICS

• Caspofungin has triphasic nonlinear pharmacokinetics.

• Micafungin and anidulafungin have linear elimination.

 COMPARISON OF INDICATIONS
Indication Caspofungin Micafungin
Invasive candidiasis Yes Yes
Neutropenic patients Yes Yes
Pediatric patients 12 months or Yes
above
Neonates No Yes
Prophylaxis in HSCT patients or expected
neutropenic patients
Adults No Yes
Pediatric patients No Yes
Neonates No Yes
Oesophageal candidiasis No Yes
Invasive aspergillosis
Salvage Yes No
Empiric therapy in febrile neutropenia Yes No
 DOSAGE COMPARISON IN
DIFFERENT INDICATIONS

 LD=loading dose. MD=maintenance dose

Therapeutics and Clinical Risk Management 2007:3(1)
 COMPARISON OF DRUG
INTERACTIONS

Micafungin has less drug drug interaction as compared to caspofungin

ADVERSE EFFECT COMPARISON

Therapeutics and Clinical Risk Management 2007:3(1)

 Phase III study micafungin vs.
caspofungin Study design

Patients were stratified by Randomisation

region and APACHE II score (1:1:1)
(≤ 20 or > 20)

Micafungin Micafungin CAS

100 mg/day 150 50 mg/day*
mg/day
Treatment
period† Max 4 weeks†

Post-treatment
6 weeks‡
period
*70 mg loading dose on Day 1
†8 weeks in chronic disseminated candidiasis or Candida endophthalmitis; switch to oral

fluconazole permitted after 10 days in patients meeting protocol-specified criteria

‡Time from last dose day of protocol-defined antifungal therapy to final evaluation

Pappas PG, et al. Clin Infect Dis 2007; 45:883–93 CAS = caspofungin
Phase III study micafungin vs.
caspofungin: treatment success
80
76.4
Treatment success rate (%)

71.4 72.3
60

40

20

n = 191 n = 199 n = 188

0
n= 191 199 188
Micafungin Micafungin Caspofungin
100 mg/day 150 mg/day 50 mg/day*

Pappas PG, et al. Clin Infect Dis 2007; 45:883–93 *Loading dose 70 mg; mITT population
 Phase III study micafungin vs.
caspofungin: treatment success by
Candida species
Micafungin 100 mg/day Micafungin 150 mg/day Caspofungin 50 mg/day*
(n = 191) (n = 199) (n = 188)

100 p = 0.07 (NS)

Treatment success rate (%)

90 p = NS p = NS p = NS p = NS p = NS
85.7 88.2
80
77.2 75.9
70 69.6
73.5 75.0
71.6 71.1
75.0
71.4
75.0 75.0
66.7 67.7
60 60.6
64.3 62.5

50
40
30
20
10
0
n = 92 102 83 104 102 114 28 34 33 31 33 32 29 21 42 8 8 4
C. albicans Any non- C. glabrata C. tropicalis C. parapsilosis C. krusei
albicans
Non-albicans Candida spp.
Pappas PG, et al. Clin Infect Dis 2007; 45:883–93 *Loading dose 70 mg; mITT population
Phase III study micafungin vs.
caspofungin: treatment success by
neutropenic status
Overall Non-neutropenic Neutropenic
Treatment success rate (%)

100

80 81.8
76.4 75.7
71.4 73.1 72.3 72.9
60 63.6
52.9
40

20

0
n = 191 169 22 199 182 17 188 177 11

Micafungin Micafungin Caspofungin

100 mg/day 150 mg/day 50 mg/day*

Pappas PG, et al. Clin Infect Dis 2007; 45:883-93 *Loading dose 70 mg; mITT population
Safe and effective agent for the treatment of
newly diagnosed and refractory cases of
candidemia.
 GUIDELINES
RECOMMENDATIONS
Infectious Diseases Candidemia in Non-neutropenic Patients
Society of America  Micafungin: 100 mg daily is recommended as initial therapy for most adult
(IDSA) patients
Candidemia in Neutropenic Patients
 Micafungin: 100 mg daily is recommended for most patients
Empirical Treatment for Suspected Invasive Candidiasis in
Non-neutropenic Patients
 Micafungin (100 mg daily) is recommended as initial therapy
Stem cell transplant recipients with neutropenia,
 Micafungin (50 mg daily) is recommended during the period of risk of
neutropenia

European Society of Micafungin

 recommended in the treatment of candidaemia
Clinical Microbiology
 recommended in neutropenic patients
and Infectious Disease  recommended in the treatment of mucosal oropharyngeal or oesophageal
(ESCMID) candidiasis

European Conference Recommends micafungin as an alternative for empirical antifungal treatment in

on Infections in febrile neutropenic patients
Leukemia (ECIL)
 SUMMARY

 US FDA approved since 2005

 Fungicidal as well as fungistatic property

 Effective in solid organ transplant recipients

 Convenient dosing, no loading dose needed

 Excellent safety profile

 Recommended by IDSA, ESCMID and ECIL in the management of invasive

fungal infections.

 Remarkably few drug interactions

 SUMMARY

 Equally effective as fluconazole for the treatment of esophageal candidiasis

 Effective for the treatment of newly diagnosed or refractory candidemia

 Better tolerated compared to Amphotericin B

 Effective and safe antifungal drug in treating Invasive Aspergillosis

 Equally Safe and Effective as Caspofungin