Fungal Infections in the ICU

Global scenario

EPIC II STUDY

Gram negative: 62%

Gram positive:47%

Fungi:19% JAMA 2009;302(21);2323-2329

N=14,414 patients from 1,256 ICUs of 75 countries

Fungi

• The fungi are a group of eukaryotic microorganisms, some of which are capable of causing superficial, cutaneous, subcutaneous, or systemic disease

• There are more than a million spp. of fungi & about 400 spp. are pathogenic.

CLASSIFICATION OF FUNGIYeasts Dimorphic fungi Molds

Candida Blastomyces Aspergillus

Cryptococcus Coccidioides Fusarium

Trichosporon Histoplasma Rhizopus

Sporothrix Mucor

Absidia

= Zygomycetes

J Pharmacy and Bioallied Sciences 2010; 2: 314-320

Fungal cell - An overview

Myco = Fungi

High risk populations include• Use of broad spectrum antibiotics• Invasive devices• Hospitalization in ICU settings• Renal failure• Burns• GI/cardiac surgery• Parenteral nutrition• Neutropenic patients• Solid Organ Transplant patients • Diabetics• Immunocompromised patients• Premature infants • Surgical populations

Medical Microbiology. 4th edition: 1996

Medical Microbiology. 4th edition: 1996

Clinical manifestations

Fungal InfectionsMost common

Candidiasis

Aspergillosis

Zygomycosis / “Mucormycosis”

Cryptococcosis

Less common

• Blastomycosis

• Coccidioidomycosis

• Histoplasmosis

• Paracoccidiomycosis

• Sporotrichosis

Epidemiology of Fungal Infections

Candida and Aspergillus are the most common causes in invasive fungal infections, accounting for 70-90% and 10-20% of all invasive mycoses, respectively.

Mortality in candidemia cases can be as high as 70%

Swiss Med Wkly 2006;136:447-463

Jpn.J Med.Mycol 2008; 49:165-172

Why is India a favorable ground for fungal infections

• Tropical climate: hot and humid weather• HIV +ve: 3-6 million• >30 million diabetics• Systemic steroids available over the counter and

misused• IV drug users • Gross overuse of broad spectrum antibiotics• Inadequate infection control practices

Jpn.J Med.Mycol 2008; 49:165-172

Candida prevalence in ICUIndia

• Most common invasive mycotic infection across India

• Most common cause of bacteremia

Jpn.J Med.Mycol 2008; 49:165-172J. Hosp Inf 2009 71, 143-148

Risk factors for Invasive Candidiasis

• Use of broad spectrum antibiotics• Parenteral nutrition• Central catheters• Hospitalization in ICU settings• Renal failure• Burns• GI/cardiac surgery• Candida colonization

J Hosp Med 2009;4:102-110

Earlier……….

Non albicans candida

• C. albicans • C. glabrata • C. tropicalis • C. parapsilosis • C. krusei • C. guilliermondii • C. lusitaniae • C. kefyr • C. rugosa • C. famata • C. inconspicua • C. norvegensis • C. dubliniensis • C. lipolytica • C. zeylanoides • C. pelliculosa

Now…………

Steep rise in Non-albicans

24

46

74

1980s 1997-2000 2011

NA

C pr

eval

ence

(%

)

Year

Jpn.J Med.Mycol 2008; 49:165-172Ind J.Medical Microbiol 2011;29;3:309-311

1980s

C albicans—76%

Non-albicans—24%

1997–2000

C albicans—54%

Non-albicans—46%

C glabrata—16%

C parapsilosis—15%

C tropicalis—10%

C krusei—2%

Other—3%

Shift from albicans to

Non-albicans

Jpn.J Med.Mycol 2008; 49:165-172

AIIMS New Delhin=7297 patients with suspected candidemia over 5 yrs

Infection 2007; 35:256-259

80% of candidemia were caused due to non-albicans

Multi super-speciality care in S.IndiaN=68 candidemia episodes

Ind J.Medical Microbiol 2011;29;3:309-311

74% candidemia cases due to NACs

Fungal biofilms

• Biofilms can be defined as communities of microorganisms attached to a surface

• Majority of diseases caused by Candida are associated with biofilm formation

• Candida biofilms exhibit enhanced resistance against most antifungal agents

Antimicrob Agents Chemother 2009:4377–4384

ANTIFUNGALS

The armamentarium

Medical Mycology:The Last 50 Years

Nys

tatin

Am

phot

eric

in B

(195

8)

Gris

eofu

lvin

5-FCMiconazole

KetoconazoleFluconazole

Itraconazole

L-AmB ABCD ABLC

Terbinafine

Voriconazole

Posaconazole

XM

P

Cas

po

fun

gin

MicafunginRavucon

Ani

du

lafu

ngi

n

CLASSIFICATION

Cell wallEchinocandins:CaspofunginMicafunginAnidulafungin

CytoplasmAzoles: FluconazoleKetoconazoleItraconazoleVoriconazolePosaconazole

Cell membranePolyenes:Amphotericin BLipid AmB formulations*

Nystatin

DNAAntimetabolites:5-fluorocytosine

Site of action of Antifungal classes

Polyenes

Examples Conventional Amphotericin B (AmB-d) Liposomal Amphotericin B (LAmB) Colloidal Amphotericin B (ABCD) Lipid complex Amphotericin B (ABLC)

Mechanism Binds directly to ergosterol to alter cell membrane activity

Adverse effects Fever, chills, phlebitis, anaphylaxis ,increased creatinine, hypokalemia, renal tubular

acidosis.

• Examples Fluconazole, Itraconazole, Ketoconazole, Voriconazole,

Posaconazole. • Mechanism

Inhibits ergosterol biosynthesis by inhibition of 14-a-demethylase.

• Adverse effects Nausea; diarrhoea; abdominal pain; rash; edema; CHF*;

pulmonary edema, visual disturbances

*Cardiac heart failure

Azoles

Echinocandins Examples:

Caspofungin,Micafungin,Anidulafungin

Mechanism Inhibitor of fungal beta-(1,3)-D-glucan synthesis

Adverse effects Chills,GI disorders, hives, itching, difficulty in breathing,swelling

of the mouth, face, lips, or tongue, coughing,rapid breathing, or wheezing, fainting, fast heartbeat, high fever, pain, swelling, or redness at the infusion site or in the infused limb.

Amphotericin B

Caspofungin

Antifungal Spectrum

FungistaticFungicidal 10-50 %Fungicidal >90 %

InactiveC. a

lbicans

C. glabrata

C. tropica

lis

C. parapsilo

sis

C. kruse

i

Cryptoco

ccus

A. fumigatus

A. flavu

s

A. terre

us

Mucorales

Scedosp

orium

Itraconazole

Fluconazole

Ketoconazole

Voriconazole

At a glance

Ind Pediatr 2008;45:905-910

Need for Caspofungin

• Shifting trends of fungal infections – – Rise in NAC– Emergence of antifungal resistance against

candidal isolates

• Greater potential of drug-drug interactions with existing antifungals

EchinocandinsComparison

Similiar spectrum Similiar safety profile

But....Drugs 2011; 71; 1: 11-41

US FDA approved Indications

Caspofungin Micafungin AnidulafunginEmpiric in FN Yes No NoCandidemia Yes No Yes

Candidal abscesses Yes No YesCandida peritonitis Yes No Yes

Esophageal candidiasis Yes Yes YesInvasive aspergillosis Yes No NoCandida prophylaxis No Yes No

Drugs 2011; 71; 1: 11-41

Caspofungin The only echinocandin that is US FDA approved for

the broadest range of indications4

– Invasive Candidiasis– Invasive aspergillosis in patients intolerant of or

refractory to other therapies– Empirical treatment of presumed invasive fungal

infections in febrile neutropenic patients.– Fungal infections in paediatric patients, 3 months of age

and older

Novel mechanism of action

• Blocks beta-(1,3)-d-glucan synthesis

• Acts on cell wall:a unique target not encountered in mammalian cells

• Lower human related toxicity

• Lack of cross-resistance

Drugs 2005; 65; 14:2049–2068

Spectrum

Fungicidal agent against Candida Fungistatic against Aspergillius

Drugs 2005; 65; 14:2049–2068

• Fungicidal against C. albicans and NAC spp1

High susceptibility of >99% against non-albicans Candida species 1

• Kills >99% of Candidal biofilm cells at therapeutically achievable concentrations 2

• Fungistatic against A. fumigatus, A. flavus, A. niger, A. versicolor and A. terreus 1

High susceptibility of >98% against Aspergillus spp 1

• Echinocandins are inactive against Fusarium spp., Zygomycetes, Trichosporon spp., or C. neoformans 3

1. Drugs 2005; 65; 14: 2049-20682. Int J of Antimicrob Agents 2007; 29:136–1433. Proc Am Thorac Soc 2010; 7: 222–228

Pharmacokinetics

Cmax (mg/L) 50 mg single dose70 mg single dose

7.612.3

Protein binding (%) 90

t½ (h) 9–11

Distribution Distributes well into tissues including lung, liver and spleen

Elimination 35% in faeces, 41% in urine, 1.4% as unchanged drug

CSF & eye penetration Low

Drugs 2011; 71; 1:11–41

INDICATIONS

• Empirical therapy for presumed fungal infections in febrile, neutropenic patients

• Treatment of candidaemia and the following Candida infections.

• Treatment of oesophageal and oropharyngeal candidiasis.

• Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies

EFFICACY STUDIES

Invasive candidiasisN=212 patients with proven IC

Favourable response at the end of therapy

Effective first-line therapy for invasive candidiasis caused by Candida & NAC

Antimicrob Agents Chemother 2010:1864–1871

The time to negative blood culture was similar for all the species

Site of Infection:Abscess(Intra abd),Blood,Bone & joint space,peritoneal fluid,pleural fluid

Empirical treatment for persistent febrile neutropeniaN=1,095 patientsGroup 1 (N=556): Caspofungin I.V. 50 mg OD . , following a 70 mg loading dose on day 1Group 2 (N=539): Liposomal amphotericin B I.V. 3 mg/kg OD

Caspofungin recipients had better outcomes than LAmB recipeints w.r.t.: •Successful treatment of fungal infections•Better survival rates•Absence of premature discontinuation as a result of lack of efficacy or toxicity

N Engl J Med 2004; 351:1391–402

Invasive aspergillosis in patients refractory /intolerant of standard therapy

N=90; immunocompromised patients with proven or probable invasive aspergillosis

Primary: Patients receiving at least one dose of the study drug and having sufficient information to permit evaluation. Secondary: Evaluable patients who received at least 7 days of caspofungin therapy.

Clin. Infect. Dis. 2004; 39:1563–71

Well tolerated in 97.8% patients, with the most common infusion-related events being fever, nausea and vomiting.

Oesophageal and oropharyngeal candidiasisN=128; patients with symptomatically and microbiologically documented Candida oesophagitis

Clin. Infect. Dis. 2001; 33:1529–35

Equally effective but safer and, hence, is an alternative treatment option to conventional amphotericin B therapy

WELL TOLERATED WITH MINIMAL ADVERSE EVENTS

Drugs 2005; 65; 14:2049–2068

Clinical adverse events Laboratory related adverse events findings

Safety & Efficacy in paediatric population N=49; patients aged 3 mths-17 yrs of age with proven or probable invasive

aspergillosis, proven invasive candidiasis or proven oesophageal candidiasis

Effective, well-tolerated alternative for the treatment of Candida and Aspergillus infections in paediatric patients

DOSAGE

Empirical therapy in febrile neutropenia, candidaemia and other Candida infections; invasive aspergillosis

Single 70 mg loading dose on day 1, followed by 50 mg once daily

Oesophageal and oropharyngeal candidiasis

Single 50 mg dose once a day for 7-14 days

Adults (above 18 years of age)

Paediatric Patients (3 months to 17 years of age)

• Single 70 mg/m2 loading dose on day 1, followed by 50 mg/m2 once daily.

• Loading dose is calculated as BSA (m2) ×70 mg/m2.

• Maintenance dose is calculated as BSA (m2) × 50 mg/m2

• BSA(m2) = √ Height (Cm) X Weight(Kg)3600

Dosing in hepatic impairment

• No dose adjustment in mild hepatic impairment

• 70-mg loading dose, followed by 35 mg O.D. in moderate hepatic impairment

• No clinical experience in severe hepatic impairment and paediatric patients with any degree of hepatic impairment.

Dosage in special conditions

Higher dosage of caspofungin (70 mg/OD)• Is required when co-administered with drugs

like ciclosporins, tacrolimus, rifampicin, dexamethazone, carbamazapine, phenytoin and other inducers of drug clearance

Dose adjustment in renal impairment No

Dose adjustment in geriatric patients No

Dose in pregnancy & lactation

Use only if the potential benefit justifies the potential risk to the foetus

Women receiving caspofungin should not breast-feed

METHOD OF PREPARATION AND ADMINISTRATION

STORAGE AND HANDLING INSTRUCTIONS

Warnings & Precautions

Concomitant use with cyclosporine Do not use cyclosporine concomitantly in patients for

whom the potential benefit outweighs the potential risk.

Patients who develop abnormal liver function tests during concomitant therapy should be monitored and the risks/benefits of continuing therapy should be evaluated.

Hepatic effects• Laboratory abnormalities in liver function tests have been

seen in healthy volunteers and in adult and paediatric patients treated with caspofungin acetate.

• Patients who develop abnormal liver function tests during caspofungin acetate therapy should be monitored for evidence of worsening hepatic function and evaluated for the risk/benefit of continuing caspofungin acetate therapy.

Drug-drug interactions• Cyclosporine: Transient increases in liver ALT and AST when

caspofungin acetate and cyclosporine were co-administered.

• Tacrolimus: For patients receiving both therapies, both standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended.

• Rifampin: Decrease in caspofungin trough concentrations. Adult patients on rifampin should receive 70 mg of CASPOGIN I.V. daily.

Contraindications

Contraindicated in patients with a hypersensitivity to any component of this

product.

HIGHLIGHTS• Novel mechanism of action ensures low

potential to develop cross-resistance and a better tolerability profile

• Highly active against most Candida spp., including azole-resistant strains and biofilms

• Effective first-line agent for invasive candidiasis caused by non-albicans Candida species

• Favourable efficacy and safety profiles against infections caused by clinically relevant Candida and Aspergillus spps

• The only echinocandin that is US FDA approved for the broadest range of indications

o Invasive Candidiasiso Invasive aspergillosis in patients intolerant of or refractory to

other therapieso Empirical treatment of presumed invasive fungal infections in

febrile neutropenic patients.o Fungal infections in paediatric patients, 3 months of age and

older

Candidemia• Moderate to severe candidal infection or

recent azole exposure• Culture result shows presence of

C.glabrata.C.krusei

Clin Inf Dis 2009; 48:503–35

Oesophageal candidiasisCaspofungin is recommended is oesophageal candidiasis when patient is unable to tolerate oral therapy

Clin Inf Dis 2009; 48:503–35

Oropharyngeal candidiasis:• Caspofungin is recommended as alternative

therapy to nystatin, clotrimazole or fluconazole.

Clin Inf Dis 2009; 48:503–35

Invasive Aspergillosis

Clin Inf Dis 2008; 46:327–60

Thank you!!