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p e d i a t r i c i n f e c t i o u s d i s e a s e 5 ( 2 0 1 3 ) 7 8e8 2

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journal homepage: www.elsevier .com/locate/p id

Antimicrobials in Clinical Practice

Newer antifungals

Tanu Singhal

Consultant, Pediatrics and Infectious Disease, Department of Pediatrics, Kokilaben Dhirubhai Ambani Hospital

and Medical Research Institute, Mumbai, Maharashtra 400053, India

a r t i c l e i n f o

Article history:

Received 2 June 2013

Accepted 12 June 2013

Available online 12 July 2013

Keywords

Voriconazole

Posaconazole

Echinocandins

Children

E-mail addresses: tanusinghal@yahoo.com2212-8328/$ e see front matter Copyright ªhttp://dx.doi.org/10.1016/j.pid.2013.06.004

a b s t r a c t

Azoles including voriconazole and posaconazole and the echinocandins including caspo-

fungin, micafungin and anidulafungin are the new antifungal drugs introduced in the past

decade. These drugs are at least equal and sometimes more efficacious, more convenient

to use and less toxic as compared to the earlier antifungals. Voriconazole is the drug of

choice for invasive aspergillosis, posaconazole is useful for antifungal prophylaxis and as a

salvage drug for zygomycosis and aspergillosis whereas the echinocandins have excellent

efficacy against invasive candidiasis. Limited pediatric data, lack of pediatric formulations

and high cost are the main limitations.

Copyright ª 2013, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights

reserved.

1. Introduction limitations to its use. It is notable that children especially

A lot of developments have happened in the antifungal drug

front in the past few years. These have been the result of an

increase incidence of fungal infections (due to rising

numbers of critically sick, oncology and immunocompro-

mised patients) as well as limitations with the previously

available antifungals. This article discusses the newly

available antifungal drugs including the newer azoles (vor-

iconazole and posaconazole) and the echinocandins in pe-

diatric perspective.

2. Limitations of older antifungals1

Amphotericin B deoxycholate is a cheap, broad-spectrum and

time tested antifungal drug. However infusion related toxicity,

nephrotoxicity and lack of oral switchover optionsweremajor

, tanu.singhal@reliance2013, Indian Academy of

neonates tolerate amphotericin B deoxycholate better than

adults. The lipid formulations of amphotericin B were devel-

oped to overcome problems of infusion related toxicity and

nephrotoxicity which they partially ameliorated but at very

high costs. Fluconazole is a cheap drug with an oral formu-

lation with predictable bioavailability. However rising inci-

dence of resistant candida and lack of activity against

filamentous fungi are its major limitations. Itraconazole

despite having anti Aspergillus activity is limited by erratic

oral bioavailability and restricted availability of the intrave-

nous formulation.

These unmet needs have led to the development of new

antifungal agents including the echinocandins and vor-

iconazole/posaconazole. Amajor limitation to the use of these

new antifungal agents is lack of pediatric formulations and

limited pediatric clinical trial data. Hence most of the infor-

mation is extrapolated from adult studies. Table 1

ada.com.Pediatrics, Infectious Disease Chapter. All rights reserved.

Table 1 e Salient features of currently availableantifungal drugs.

Flucon Itra Vori Posa AMB-D L AMB Echino

C. Albicans Yes Yes Yes Yes Yes Yes Yes

C. Species þ þþ þþþ þþþ þþþ þþþ þþþþAspergillus 0 þ þþþ þþþ þþ þþ þþMucor No No No Yes Yes Yes No

Cryptococcus Yes Yes Yes Yes Yes Yes No

Route

available

IV, PO PO IV,

PO

PO IV IV IV

Adverse

effects

þþ þþ þþ þ þþþþ þþ þ

Drug

interactions

þþþ þþþ þþþ þþ þ þ þ

Toxicity Hep Hep Hep Hep Renal Renal None

Cost/day þ þþ þþþ þþþ þ þþþþ þþþ

þ (Low), þþ (Moderate), þþþ (High), þþþþ (Very high).

p e d i a t r i c i n f e c t i o u s d i s e a s e 5 ( 2 0 1 3 ) 7 8e8 2 79

summarizes the salient features of currently available anti-

fungal drugs.

Table 2 e Drug interactions of voriconazole.

Mechanism Comment

Increased metabolism of voriconazole

INH, rifampicin, rifabutin,

phenytoin, phenobarbital,

carbamazepine

Potential for therapy

failure, increased

potential for

hepatotoxicity

Increased concentration of coadministered drug through inhibition of its

metabolism by triazole

Terfenadine, astemizole,

cisapride, pimozide,

quinidine

Concomitant use

prohibited

Lovastatin, simvastatin,

atorvastatin

Concomitant use

prohibited

Phenytoin Monitor levels

Benzodiazepines Monitor closely

Ritonavir, NNRTI Monitor closely

Vinca alkaloids Avoid concomitant use

Cyclosporin A, tacrolimus Monitor serum levels

Sulfonyl urea drugs, warfarin,

prednisolone

Monitor closely

3. Voriconazole1e3

3.1. Mechanism of action and spectrum of activity

Voriconazole is a second generation triazole that exerts an

antifungal effect by inhibiting ergosterol synthesis through its

interaction with C-14 alpha demethylase a cytochrome 450

dependent enzyme. It is effective against a wide variety of

fungi including most Candida species (except Candida glabrata

and some Candida krusei), Trichosporon beigelii, Cryptococcus

neoformans, Aspergillus species (fungicidal), Fusarium species

and most dimorphic fungi. It is not effective against

zygomycetes.

3.2. Pharmacokinetics

Voriconazole is almost completely absorbed after oral

administration. It is distributedwell with tissue and CSF levels

several times the plasma levels. It is extensively metabolized

by the liver and is both an inhibitor and substrate of enzymes

CYP2C19, CYP2C4 and CYP2C4. As a result of pointmutation in

the genes encoding these enzymes, patients are either poor or

extensivemetabolizers of voriconazole. The levels can be upto

4 times higher in patients who are deficient in this gene as

compared to homozygous subjects. 20% non-Indian Asians

and 5% of whites are deficient. Owing to problems in vor-

iconazole metabolism, therapeutic drug monitoring of vor-

iconazole levels is recommended.4 Voriconazole metabolism

is nonlinear in adults with an approximately 3-fold increase in

its area under the concentrationetime curve after a 33% in-

crease in dosage. In contrast, in children the elimination of

voriconazole seems to be linear with doses of 3 mg/kg and

4 mg/kg every 12 h.

3.3. Dosage

The dosage in adults is 6 mg/kg/dose BD for 1 day followed by

maintenance of 4 mg/kg/dose BD. In children, drug

elimination is quicker and doses of 7 mg/kg twice daily with

no loading is recommended. In patients with renal insuffi-

ciency no dosing changes are required for the oral prepara-

tion; but because of renal clearance of the IV carrier,

individuals with creatinine clearances of less than 50 ml/min

should receive the oral preparation. Those with mild to

moderate hepatic dysfunction should receive half the main-

tenance dose.

3.4. Adverse effects

Well tolerated drug. Important side effects include transient

dose related visual disturbances such as altered enhanced

perception of light, blurred vision (25e45%), hallucinations or

confusion (10%), skin reactions (10%) and transient liver

enzyme abnormalities (10e20%).

3.5. Drug interactions

Drug interactions are plentiful and detailed in Table 2. It is

useful to do a formal drug interaction check before using

voriconazole, especially when the patient is on multiple

drugs. A free online drug interaction checker is available at

www.drugs.com.

3.6. Clinical use

Voriconazole is the drug of choice for invasive aspergillosis. A

landmark randomized control trial showed reduced mortality

with voriconazole as compared to conventional amphotericin

B in invasive aspergillosis.5 Treatment should be given for at

least 6e12 weeks till there is clinical and radiographic reso-

lution. In the immunocompromised, treatment has to

continue till duration of immunosuppression is over and

treatment resumed once immunosuppression is restarted.

p e d i a t r i c i n f e c t i o u s d i s e a s e 5 ( 2 0 1 3 ) 7 8e8 280

Voriconazole is approved for management of Candida in-

fections, but it does not offer any significant advantage over

the cheaper fluconazole. As per IDSA guidelines, treatment of

fluconazole resistant candida should be with echinocandins

or amphotericin instead of voriconazole.3 The only niche use

of voriconazole in Candida infections is in oral step down

therapy for C. krusei if the isolate demonstrates susceptibility

to voriconazole.

Voriconazole has been evaluated in management of febrile

neutropenia where it was compared with liposomal ampho-

tericin B in a randomized controlled trial.6 In this trial, vor-

iconazole did not meet the predetermined non inferiority

criteria and thus was not licensed by FDA for empirical ther-

apy in febrile neutropenia. However, the use of voriconazole

was associated with fewer breakthrough infections. In clinical

practice, this drug is commonly used in empirical therapy for

febrile neutropenia.

Other indications of voriconazole use include fusariosis,

scedosporiasis and as salvage therapy for invasive and re-

fractory fungal infections (excluding zygomycetes).

4. Posaconazole7

4.1. Introduction and spectrum of activity

Posaconazole is a new expanded spectrum triazole agent with

mechanism of action similar to voriconazole and a spectrum

as wide as amphotericin B. Posaconazole is active against all

Candida species, Aspergillus, zygomycetes and Cryptococci.

Additionally it is effective against less common fungal path-

ogens which are intrinsically resistant to other antifungal

agents including Fusarium, Chromoblastomycosis, Coccidioi-

domycosis and other fungi.

4.2. Pharmacokinetics

The drug is available as an oral suspension. It is absorbed well

especially if given along with food or nutritional supplements.

Dividing the daily oral dose increases total exposure to the

drug. The drug is extensively distributed in all body tissues

and has a long half life of 35 h. Age, race, gender, renal and

hepatic function do not affect its elimination and no dosage

adjustments are required.

4.3. Dosage

Posaconazole is approved in patients � 13 years of age where

the prophylactic dose is 200 mg thrice daily and the thera-

peutic dose is 400 mg twice daily. In patients who have poor

oral intake it should be given as 200 mg four times daily. No

dose adjustments are needed for patients with renal or he-

patic dysfunction; the drug is not removed by hemodialysis.

4.4. Adverse effects

Nausea, vomiting and diarrhea and mild elevation of liver

enzymes are common side effects. Rarely the drug can cause

severe hepatic dysfunction and liver failure.

4.5. Drug interactions

Posaconazole only inhibits the cytochrome P 450 3A4 enzyme

and none of the other cytochrome P450 enzymes and thus

has limited potential for drug interactions as compared to

other azoles. It’s use is contraindicated with certain

cytochrome P 450 3A4 substrates such as ergot alkaloids,

quinidine, astemizole, terfenadine, cisapride, halofantrine,

pimozide due to effect on prolongation of the QT interval. Use

of anti convulsants and rifampicin reduce posaconazole

exposure and hence their concomitant use should be

avoided.

4.6. Indications

Posaconazole has received approval for prevention of fungal

infections in neutropenic patients. In a trial in patients with

acute myeloid leukemia and myelodysplastic syndrome, pro-

phylaxis with posaconazole reduced incidence of fungal in-

fections and all cause mortality at 100 days compared to

fluconazole/itraconazole.8 In patients who have undergone

hematopoetic stem cell transplant and graft versus host dis-

ease, posaconazole was as effective as fluconazole in reducing

invasive fungal infections and also reduced the incidence of

probable and proven aspergillosis and mortality due to fungal

infections.9

Posaconazole has also demonstrated efficacy in treatment

of many invasive fungal infections including aspergillosis,

fusariosis, chromoblastomycosis, candida and coccidioido-

mycosis where previous antifungal agents had failed.7 The

mortality in patients with refractory aspergillosis treated with

posaconazole was 42% compared with 26% in an external

control group.10

Posaconazole has also demonstrated efficacy in manage-

ment of oropharyngeal candidiasis.

5. Echinocandins11

The echinocandins are a new class of antifungal lipopeptides.

Three echinocandin compounds including caspofungin,

micafungin and anidulafungin are now licensed for use and

commercially available.

5.1. Mechanism of action and spectrum of activity

Echinocandins inhibit the synthesis of 1,3-ß-D-glucan, a

polysaccharide in the cell wall of many pathogenic fungi.

Along with chitin, rope like glucan fibrils are responsible for

the cell wall’s strength and shape; are essential inmaintaining

osmotic integrity of the fungal cell and play an important role

in cell division and cell growth. As 1,3-ß-D-glucan is a selec-

tive target present only in fungal cell walls and not in

mammalian cells, echinocandins have few adverse effects.

These agents have similar spectrum of activity. They

possess potent, broad-spectrum, fungicidal in vitro activity

against all Candida sp including those that are inherently

resistant to amphotericin B (Candida haemulonii and Candida

lusitaniae). The MIC’s to Candida parapsilosis are relatively

higher but are still within the sensitive range. The

p e d i a t r i c i n f e c t i o u s d i s e a s e 5 ( 2 0 1 3 ) 7 8e8 2 81

echinocandins demonstrate potent inhibitory activity against

Aspergillus sp (fungistatic). Echinocandins are inactive against

zygomycetes, Fusarium and Cryptoccocci.

5.2. Pharmacokinetics

Echinocandins are available only in parenteral form, have

favorable pharmacokinetic properties and are targeted for

once-daily dosing. They are distributed well into all tissues

including the brain but not in CSF and urine. The pharmaco-

kinetics of the echinocandins are compared in Table 3.

5.3. Dosage and administration

See Table 3.

5.4. Adverse reactions

Well tolerated drugs with side effects serious enough to cause

discontinuation seen only in 5%. The most frequently re-

ported side effects include elevated transaminases, GI upset,

headaches and occasionally histamine mediated symptoms.

Injection site reactions may be seen and are more common

with caspofungin. Micafungin can cause benign liver tumors

in rats.

5.5. Drug interactions

Caspofungin levels are decreased by carbamazepine, dexa-

methasone, efavirenz, nevirapine, phenytoin and rifampicin

(initially increased and then reduced). Hence consider

increasing the dose of caspofungin. The plasma concentration

of caspofungin is increased by cyclosporin. Micafungin and

anidulafungin have fewer drug interactions as compared to

caspofungin. Cyclosporin increases anidulafungin levels but

the significance of this is not known. Micafungin can increase

nifedipine and cyclosporine levels.

Table 3 e Pharmacokinetics and dosage of the echinocandins.

Caspo

T ½ in hours 9e11

Protein binding 96e97

Metabolism Metabolised, spontaneous degradation

Dose change in liver disease

Mild

Moderate

Severe

None

Dec dose

No data

Loading dose Required

Infusion times 60 min

Storage after reconstitution 48 h

Protection from light Not required

Volume of diluent 250 ml

Adult dose 70 mg loading and then 50 mg OD

Pediatric dose 70 mg/m2 loading and then 50 mg/m2

Neonatal dose 25 mg/m2 (some have used upto 5 mg/kg)

5.6. Clinical use3

All echinocandins have been approved for management of

invasive candidiasis. In studies comparing caspofungin with

liposomal amphotericin B for candidemia, caspofungin was as

efficacious with lower toxicity. In a comparative trial with

fluconazole in invasive candidiasis in mainly non neu-

tropenic, anidulafungin was superior to fluconazole. Mica-

fungin in comparative trials with liposomal amphotericin B

and caspofungin was non inferior. Hence in candidemia in

adults in both neutropenic/non neutropenic patients, echi-

nocandins have supplanted amphotericin B as drugs of choice

due to similar efficacy and lower toxicity.3 All the echino-

candins are similar in efficacy in management of candidemia.

Anidulafungin has the lowest MIC’s, however the clinical

benefit of this phenomenon is still to be demonstrated.11

Theechinocandinshave revolutionized themanagementof

invasive candidiasis. Invasive candidiasis is the most

commonly encountered invasive fungal infection in clinical

practice. Candida is nowamong the topfivepathogens causing

nosocomial blood stream infection in patients admitted in

adult or pediatric intensive care units worldwide.12 Prominent

risk factors for candida blood stream infections are prolonged

antimicrobial use, central lines, immunosuppression, hemo-

dialysis, gut surgery, neutropenia, use of intralipids, diabetes,

highAPACHEscores,multipleblood transfusions, diabetes and

colonizationwithCandida atmultiple sterile sites. Candida is a

common blood stream infection in neonates where prematu-

rity, use of intralipids, necrotizing enterocolitis and antimi-

crobial use are prominent risk factors.13 In neonates

dissemination to the brain, eye, bones and joints and heart

valves frequently occurs. The symptoms and signs of invasive

candidiasis are indistinguishable from bacterial sepsis and

other causes of systemic inflammatory response syndrome

(SIRS). The sensitivity of blood cultures to detect candida is

only about 50%.14 Attributable mortality rates associated with

invasive candidiasis are high, ranging from 30 to 50% and rise

exponentially with delay in initiation of therapy.15 Owing to

Mica Anidula

11e17 24e26

99.8 84

Via COMP Slow degradation

None

None

No data

None

None

None

Not required Required

60 min 91e182 min

Can be used upto 48 (96) h Used within 24 h

required Not required

100 ml 115 (100 þ 15) for 50 mg

280(250 þ 30) ml for 100 mg

560 (500 þ 60) ml for 200 mg

100 mg OD 200 mg loading and then 100 mg OD

2e4 mg/kg OD Not approved, but 1.5 mg/kg

10e12 mg/kg Not approved

p e d i a t r i c i n f e c t i o u s d i s e a s e 5 ( 2 0 1 3 ) 7 8e8 282

these reasons, empirical therapy for suspected candidemia is

gaining prominence. As per current guidelines, patients with

sepsis who are at high risk for candida infections should be

initiated on antifungal therapy without waiting for results of

blood cultures.3 The choice of antifungal therapy depends on

several factors including the severity of disease, prior azole

exposure, existing renal or hepatic comorbidities and the

species distribution of candida isolated in the particular

intensive care unit. International guidelines now recommend

echinocandins as drugs of first choice as empirical therapy for

invasive candidiasis in adults who are extremely sick or who

have history of prior azole exposure; in others fluconazole can

be used as first line drug.3

There are some caveats in extrapolating these guidelines to

the Indiansettingand toneonatesandchildren. In Indian ICU’s

including pediatric intensive care units, Candida tropicalis and

Candida albicans are the most commonly isolated Candida

species of whichmajority are still susceptible to fluconazole.16

Also, echinocandins are fairly expensive with treatment costs

in adult’s amount to about Rs 10,000 per day. Hence each unit

must formulate its own policy on the basis of its own fungal

epidemiology. The data on echinocandins in neonates and

children is limited; anidulafungin has not yet been approved

for pediatric use. Echinocandins have poor CNS penetration;

CNS involvement is fairly common in neonates with invasive

candidiasis. Hence in neonates and children especially those

with CNS involvement, amphotericin B is still the drug of

choice. It should be noted that neonates and children tolerate

conventionalamphotericinBbetter thanadults. Fluconazole in

a dose of 12 mg/kg/day may be used as first line drug in chil-

dren/neonates with suspected invasive candidiasis who have

not received azole prophylaxis and in units where the epide-

miology of the fungal species is favorable.

Echinocandins have been demonstrated as non inferior to

fluconazole in management of oropharyngeal candidiasis.

However, anidulafungin has been seen to be associated with

higher relapse rates as compared to fluconazole.

Caspofungin is approved for salvage treatment of Asper-

gillus infections either alone or in combination with other

agents like amphotericin B and voriconazole. Caspofungin has

also been approved for empirical therapy of febrile neu-

tropenia. A randomized controlled trial of caspofungin with

liposomal amphotericin B, demonstrated it to be non inferior

with lower side effects as compared to amphotericin B.17

Studies with micafungin and anidulafungin for these two in-

dications are underway. Micafungin has also been approved

as prophylaxis for fungal infections in patients who have

undergone stem cell transplant.

6. Conclusions

The newer azoles and the echinocandins are valuable addition

in the armamentarium of antifungal drugs due to their

excellent efficacy, and lower toxicity compared to the older

antifungal agents. More pediatric data and formulations are

awaited. Cost of these drugs is also a major impediment

against for their use.

Conflicts of interest

The author has none to declare.

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