I am against to TDM in critically ill patient

TDM

I am against to TDM in critically ill patient TDM of antifungals: where are we? Dr. Rafael Zaragoza Antifungal therapy in ICU; prophylaxis, pre-emptive and targeted

Conflicts of interest: Pfizer Astellas MSD Gilead Cephalon

A new scheme Antifungal agent in ICU. The case for TDM http://www.disfrutalograti s.com/coches/oporto2.jpg Introduction and definition. Following the guidelines Real needs of monitoring depending the type of antifungal drug. 5-fluorocytosine Azoles Amphotericin B Echinocandins. The same or different? Special clinical situations Obesity Renal and hepatic failure Interactions CRRT Take home messages

TDM Recommendations TDM: therapeutic drug monitoring

Are therapeutic drug monitoring (TDM) indicated for patient management?? 1 TDM must be used for patients treated with 5-fluorocytosine TDM is not normally required for drugs used in the treatment of Candida infections (ECMO (extra-corporeal membrane oxygenation) can reduce echinocandin concentration) TDM is recommended if voriconazole is prescribed (voriconazole TDM is highly recommended in unsatisfactory response to therapy, suspicion of toxicity or drug interaction(s), impaired liver or renal function an in patients on extracorporeal membrane oxygenation)

Are therapeutic drug monitoring (TDM) indicated for patient management? 1 TDM must be used for patients treated with 5-fluorocytosine TDM is not normally required for drugs used in the treatment of Candida infections (ECMO can reduce echinocandin concentration) TDM is recommended if voriconazole is prescribed (voriconazole TDM is highly recommended in unsatisfactory response to therapy, suspicion of toxicity or drug interaction(s), impaired liver or renal function an in patients on extracorporeal membrane oxygenation) References: 1) Trifilio et al. Cancer 2007;109:1532-5 2) Pascual et al. Clin Infect Dis 2008;46:201-11 3) Buchkowsky et al. Ther Dr Monit 2005; 27:322-33 4) CLSI M27-S3 (itraconazole) 5) Andes et al. Antimicrob Agents Chemother 2009;53:24-34

Thank you very much zaragoza_raf@gva.es

INTRODUCTION. When using a prophylactic, empiric, or preemptive therapeutic approach, clinicians must take into account the local epidemiology, spectrum of activity, pharmacokinetic and pharmacodynamic parameters, and safety profile of different antifungal agents, together with unique host-related factors that may affect antifungal efficacy or safety. Therapeutic drug monitoring provides a way to optimize the use of antifungal agents. Therapeutic drug monitoring is increasingly recognized as important or necessary when employing lipophilic triazoles (itraconazole, voriconazole, posaconazole) or flucytosine. Objetives of TDM: To optimize efficacy To avoid infradosification To ensure no toxicity Kontoyiannis DP. Am J Med. 2012 Jan;125(1 Suppl):S25-38.

Real needs of monitoring depending the type of antifungal drug. 5-fluorocytosine Azoles Echinocandins. Same or different? Amphotericin B

5-fluorocytosine Goodwin ML et al. JAC 2008 Flucytosine is one of the oldest antifungal medications. The clinical use of flucytosine is limited due to its toxicities (gastrointestinal, haematological and neurological),rapid development of resistance (when used as monotherapy)and lack of parenteral formulations. It is generally utilized in combination with other agents for the treatment of select IFIs,notably cryptococcal meningitis, severe or refractory candidiasis or aspergillosis.

5-fluorocytosine and ICU A retrospective, observational study of 53 intensive care unit patients reported that patients with flucytosine concentrations exceeding 100 mg/l exhibited significantly: higher incidence of thrombocytopenia (P< 0.05) and elevated liver enzymes (P <0.05) when compared with thetotal population Vermes A, van Der SH, Guchelaar HJ. Flucytosine: correlation between toxicity pharmacokinetic parameters. Chemotherapy 2000;46: 86 94.

5-fluorocytosine and TDM Final recomendations Goodwin ML et al. JAC 2008 Based on available data, a 2 h post-dose concentration of flucytosine should be obtained after 3 5 doses have been administered. A reasonable goal is to maintain such concentrations >25 mg/l while avoiding concentrations exceeding 100 mg/l. In all instances, adjustments of flucytosine dosing in patients with renal insufficiency, in addition to close monitoring of bothrenal function and blood counts, would be advised.

Association of Fluconazole AUC/MIC and Dose/MIC Ratios with Mortality in Non-neutropenic Patients with Candidemia Although the weightnormalized dose/mic ratio (after 24 h) was significantly higher for the survivors [13.3+10.5 (mean+sd)] as compared with the nonsurvivors (7.0+8.0) (P. 0.03), the AUC/MIC ratio only showed a trend towards survival. 14 12 10 8 6 4 2 0 Survivors p = 0.03 Non Survivors Dose/MIC Pai M et al. Antimicrob Agents Chemother 2007; 51: 35

p=0.009 Baddley

Propiedades farmacodinámicas

Overall Response at EOT [MITT] N (%) Favorable Overall Response at EOT AmBi-3mg N=107 AmBi-10mg N=94 53 (50) 43 (46) CR 1 (1) 2 (2) PR 52 (49) 41 (44) Unfavorable Response Cornely O et al. Ambiload trial. Clin Infect Dis. 2007 Stable 8 (7) 5 (5) Failure 36 (34) 36 (38) Not evaluable 10 (9) 10 (11) p= 0.65

Cornely O et al. Ambiload trial. Clin Infect Dis. 2007 Favorable Overall Response: All Patients and Subsets 60% 50% 40% 50% 46% 50% 46% 42% 39% 56% 48% 50% 47% 53% 54% 48% 44% 43%42% 3 mg/kg/d 10 mg/kg/d 30% 20% 10% 0% All Patients N= 107 94 103 92 41 36 62 56 17 18 36 26 63 59 76 71 Aspergillosis (all cases) Micro Confirmed Halo only dx Allo-SCT Heme Malig-Controlled Neutropenia at Baseline Heme Malig-Uncontrolled No differences are statistically significant

Survival [MITT] 100 90 80 70 60 50 40 30 20 10 0 % Day 14 94 91 93 EOT 88 4 wks post-eot 76 69 12 weeks 72 59 3 mg/kg/d (n=107) 10 mg/kg/d (n=94) No differences are statistically significant Cornely O et al. Ambiload trial. Clin Infect Dis. 2007

Micafungin vs. Caspofungin: Clinical success Micafungin Micafungin Pappas PG y col. Clin Infect Dis 2007; 45:883 93.

Micafungin vs caspofungin: Cinical and microbiological success (población mitt) Micafungina Micafungina Micafungina Micafungina Pappas PG y col. Clin Infect Dis 2007; 45:883 93. 8 August 2003

PK Y ANTIFÚNGICOS Vd (l/kg) Media-vida Unión prot % Anfo B deox 4 24-34 >90 Albecet 2,3 173-235 >90 Ambisome 0,56 10-23 >90 Fluconazol 0,8 24 11 Voriconazol 4,6 6 58 Caspofungin 1 11 97 Anidulafung 26 99 Micafungin 0,39 14-17 99

ANTIFUNGAL DRUGS: INTERACTIONS Glöckner. Mycoses, 2008

Penetration

Pharmacokinetics and Tissue Distribution of Anidulafungin 1 in Rats Bharat Damle, Martin Stogniew, and James Dowell. Antimicrob. Agents Chemother 2008

Let s go.

No differences were found?

Obesity is important

EQUINOCANDINS: INTERACTIONS Mazzei T, et al. Drugs 2009;69 (Suppl 1):79-90 Equinocandin Coadministration Consequences Anidulafungin Ciclosporin 22% AUC* anidulafungin Caspofungin Ciclosporina 35% AUC caspofungina Caspofungin Tacrolimus 25% AUC tacrolimus Caspofungin Enzymatic inductors Possible caspofungin (30% if rifampicin) Micafungin Sirolimus 21% AUC sirolimus Micafungin Nifedipine 18 % and 42 % AUC and C max de nifedipine, respectively Micafungin Ciclosporin Inhibición ciclosporin metabolism

CRRT are one of the main causes of infradosification Dosage adjustement depends on: Molecular weigth Protein binding Clearance

8 August 2003

To loose or not to loose Micafungin Anidulafungin

Furthermore.. Anidulafungin Micafungin

I am against to TDM in acute critically ill patient, specially: treating Invasive Candidiasis Using echinocandins. Be careful with Obesity and interactions If you have some doubts,please choose the most adequate antifungal drug in each patient TDM of antifungals: where are we? Dr. Rafael Zaragoza Antifungal therapy in ICU; prophylaxis, pre-emptive and targeted