Fungal Infections in the ICU

Global scenario

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

Gram negative: 62% Gram positive:47% Fungi:19% JAMA 2009;302(21);2323-2329

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 FUNGI
Yeasts
Candida Cryptococcus Trichosporon

Dimorphic fungi
Blastomyces Coccidioides Histoplasma Sporothrix

Molds
Aspergillus Fusarium Rhizopus 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

Clinical manifestations

Medical Microbiology. 4th edition: 1996

Fungal Infections
Most 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 1020% 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 ICU India

Most common invasive mycotic infection across India Most common cause of bacteremia

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

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

Now

Non albicans candida

Steep rise in Non-albicans

2 2

4 4

2 2

) % ( c n l a v e r p C A N

22s 22

2 2 -2 2 22 22

22 22

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

1980s

Shift from albicans to Non-albicans

19972000

C albicans76% Non-albicans24%

C albicans54% Non-albicans46%
C glabrata16% C parapsilosis15% C tropicalis10% C krusei2% Other3%
Jpn.J Med.Mycol 2008; 49:165-172

AIIMS New Delhi

n=7297 patients with suspected candidemia over 5 yrs

80% of candidemia were caused due to non-albicans

Infection 2007; 35:256-259

N=68 candidemia episodes

Multi super-speciality care in S.India

74% candidemia cases due to NACs

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

Diagnosis
Apparent from symptoms alone. Microscopic examination of the sample. Samples of blood /infected tissues are sent for lab culture testing.

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

Antimicrob Agents Chemother 2009:43774384

ANTIFUNGALS
The armamentarium

XMP Anidulafungin Casp ofun gi n

Medical Mycology: The Last 50 Years

ter Gr icin ise B ofu (19 58 lv i n )

sta t Amin ph o

5-FC

Ra Micafungin L-AmB V Po oric ABCD sa ona zol co ABLC e na Terbinafine z ole Itraconazole Fluconazole Ketoconazole Miconazole

n co vu

Ny

CLASSIFICATION

Site of action of Antifungal classes

Cell membrane Polyenes: Amphotericin B Lipid AmB formulations* Nystatin Cytoplasm Azoles: Fluconazole Ketoconazole Itraconazole Voriconazole Posaconazole Cell wall Echinocandins: Caspofungin Micafungin Anidulafungin

DNA Antimetabolites: 5-fluorocytosine

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.

Azoles
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

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.

Fluconazole

Caspofungin

Ketoconazole

Amphotericin B

Itraconazole

C. al C. bi c gl a n s C. abr tr ata C. opi pa ca l ra is C. p kr silo Cr us s yp ei is t A. oc fu occ A. mig us fla at A. vu us te s M rre uc u or s Sc a ed les os po riu m

Fungicidal >90 % Fungicidal 10-50 % Fungistatic Inactive

Voriconazole

Antifungal Spectrum

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

Echinocandins
Comparison
Similiar spectrum Similiar safety profile But....
Drugs 2011; 71; 1: 11-41

US FDA approved Indications

Caspofungi Micafungi Anidulafungi n n n Empiric in FN Yes No No Candidemia Yes No Yes Candidal abscesses Yes No Yes Candida peritonitis Esophageal candidiasis Invasive aspergillosis Candida Yes Yes Yes No No Yes No
Drugs 2011; 71; 1: 11-41

Yes Yes No No

Yes

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

Novel mechanism of action

Blocks beta-(1,3)-dglucan synthesis Acts on cell wall:a unique target not encountered in mammalian cells Lower human related toxicity Lack of crossresistance

Drugs 2005; 65; 14:20492068

Spectrum
Fungicidal agent against Candida Fungistatic against Aspergillius

Drugs 2005; 65; 14:20492068

 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: 2049-2068 2. Int J of Antimicrob Agents 2007; 29:136143 3. Proc Am Thorac Soc 2010; 7: 222228

Pharmacokinetics
Cmax (mg/L) 50 mg single dose 70 mg single dose Protein binding (%) t (h) Distribution 7.6 12.3 90 911 Distributes well into tissues including lung, liver and spleen 35% in faeces, 41% in urine, 1.4% as unchanged drug Low
Drugs 2011; 71; 1:1141

Elimination CSF & eye penetration

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 candidiasis
N=212 patients with proven IC

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

Favourable response at the end of therapy

Antimicrob Agents Chemother 2010:18641871

1,095 patients oup 1 (N=556): Caspofungin I.V. 50 mg OD . , following a 70 mg loading dose on d oup 2 (N=539): Liposomal amphotericin B I.V. 3 mg/kg OD

Empirical treatment for persistent febrile neutropenia

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; 351:1391402

Invasive aspergillosis in patients refractory /intolerant of standard therapy N=90; immunocompromised patients with proven or probable invasive aspergillosis
Well tolerated in 97.8% patients, with the most common infusion-related events being fever, nausea and vomiting.

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; 39:156371

Oesophageal and oropharyngeal candidiasis

N=128; patients with symptomatically and microbiologically documented Candida oesophagitis

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

Clin. Infect. Dis. 2001; 33:152935

WELL TOLERATED WITH MINIMAL ADVERSE EVENTS

Clinical adverse events Laboratory related adverse events findings

Drugs 2005; 65; 14:20492068

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
Adults (above 18 years of age) Empirical therapy in febrile neutropenia, Single 70 mg loading dose candidaemia and other on day 1, followed by 50 mg Candida infections; once daily invasive aspergillosis Oesophageal and Single 50 mg dose once a oropharyngeal day for 7-14 days candidiasis

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 Dose adjustment in geriatric patients

No No

Dose in pregnancy & Use only if the potential benefit justifies the potential lactation
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 crossresistance and a better tolerability profile Highly active against most Candida spp., including azole-resistant strains andbiofilms Effective first-line agent for invasive candidiasis caused by non-albicans

 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 Candidiasis o Invasive aspergillosis in patients intolerant of or refractory to other therapies o Empirical treatment of presumed invasive fungal infections in febrile neutropenic patients. o Fungal infections in paediatric patients, 3

Candidemia Moderate to severe candidal infection or recent azole exposure Culture result shows presence of C.glabrata.C.krusei

Clin Inf Dis 2009; 48:50335

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

Clin Inf Dis 2009; 48:50335

Oropharyngeal candidiasis: Caspofungin is recommended as alternative therapy to nystatin, clotrimazole or fluconazole.

Clin Inf Dis 2009; 48:50335

Invasive Aspergillosis

Clin Inf Dis 2008; 46:32760

y k n a h T

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