Caspogin Medical FINAL
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Transcript of Caspogin Medical FINAL
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!!