News in Diagnosis and Treatment of Fungal Infections

Theoklis Zaoutis, MD, MSCEProfessor of Pediatrics and Epidemiology

Perelman School of Medicine at the University of PennsylvaniaAssociate Chief, Division of Infectious Diseases

The Children’s Hospital of Philadelphia

Pediatric Infectious Diseases Seminar, Thessaloniki 2014

Overview

• Changes in epidemiology – Do they change or treatment decisions?

• Challenges in diagnosis• What’s new in treatment• New considerations in neonatal candidiasis

Fridkin, S. K. et al. Pediatrics 2006;117:1680-1687

Neonatal Candidiasis: Incidence over Time

Fisher, et al CID 2013

Vital Signs: Central Line-Associated Bloodstream Infections-US, 2001 to 2008-2009

• Hospital ICUs: 58% reduction (2001 vs 2009)– 25,000 fewer CLABSIs– 3-6K lives saved (2009)– $414M saved (2009)– $1.8B cumulative savings, 27K lives (2001-2009)

• Candida spp. (46% reduction; RR = 0.54; CI = 0.487--0.606)

MMWR, March 4, 2011

Year C. albicans C. parapsilosis C. glabrata

1992-2000 49-63 19-45 0-7

1996-2001 (Italy) 66 17 6

1998-2008(GER) 45 17 14

2001-2004 (AUS) 42 38 4

2000-2006 (USA) 26 45 13

2004-2009 (DEN) 73 13 3

2000-2009 (USA) 44 24 7

1997-2009 (USA) 49 24 4

2005-2009 (GRE) 45 23 5

2000-2009 (UK) 55 22 4

2000-2010 (USA) 47 28 9

2007-2010 (PFN) 56 22 11

2009-2011 (ESP) 37 47 4

Pfaller MA, Diekema DJ. Clin Microbiol Rev. 2007;20:133-163. Manno G. Int J Antimicrob Agents. 2004; Tragiannidis A et al. Clin Microbiol Infect. 2012;18:e27-e30. Blyth CC et al. Pediatrics. 2009;123:1360-1368. Neu N et al. Pediatr Infect Dis J. 2009,28:806-809. Arendrup MC et al. J Clin Microbiol. 2011;49:3300-3308. Dutta A, Palazzi DL. Pediatr Infect Dis J. 2011;30:664-668. Dotis J et al. Pediatr Infect Dis J. 2012;31:557-560. Oeser C et al. Pediatr Infect Dis J. 2013;32:23-26. Steinbach WJ et al. Pediatr Infect Dis J. 2012;31:1252-1257. Klatte JM et al, ICHE 2013

Species Distribution in Children

Species Specific Risk Factors

• Independent risk factors for C. parapsilosis– 99 cases compared to 307 other Candida spp.– Urinary catheter within 1 week, OR 0.37 (95% CI: 0.19, 0.72)– Mech ventilation 48 hrs prior, OR 2.44 (95% CI: 1.44, 4.14)– No difference in outcomes

• 112 cases C. albicans vs 141 non-albicans Candida – No difference in risk factors or outcomes

• Independent risk factors for C. glabrata– 26 C. glabrata/C. krusei compared to 380 other Candida spp.– Fluconazole exposure in week prior, OR 2.96 (95% CI: 1.18,

7.42)– Age > 2 years, OR 3.52 (95% CI: 1.28, 9.66)

Dotis J et al. Pediatr Infect Dis J. 2012;31:557-560.Dutta A et al. Pediatr Infect Dis J. 2011;30:664-668.Prasad P et al. J Pediatr Infect Dis Soc. 2013;2:263-266.

Frequency of Antifungal Resistance in Sentry 2008-2009

(% Resistant)

C. albicans C. glabrata C. parapsilosis C. tropicalis C. kruzei

Fluconazole 0 7.7 5.8 3.3 0

Voriconazole 0 6.4 0 2.2 0

Posaconazole 0 5.1 0 0 0

Caspofungin 0.5 5.1 0 0 8.7

Micafungin 0.25 3.2 0 0 0

Anidulafungin 0.25 3.8 0 0 0

Resistance defined as: >0.5 for cas, anid, mica for cab, ctrop, ckz and > 4 for Cpar; Cglab >.12 for mica, >.5 for anid and cas; flu > 4 for cab, ctrop, cpara and > 32 for pos and vori for all species

Pfaller, et al AAC 2011

Diagnosis

Diagnostic Considerations in Children

• Standard diagnostic procedures generally not different between children and adults– Blood cultures for yeasts and molds– Cultures, microscopy

• Different from adults (?)– Chest CT imaging– Usefulness of antigen markers– PCR

Day 3 Day 7 Day 14

“halo sign” 68% 22% 19%

“air crescent sign” 8% 28% 63%

Computerized tomography in adults with invasive aspergillosis

Caillot et al. JCO, 2001;19:253

CT Scan Characteristics: Less Specific in Children

• Prospective study of 139 cases of proven or probable IA in children– Nodules (35%), infiltrates (21%), cavity (14%)– Halo sign (11%) and air crescent sign (2%) uncommon

• Retrospective study proven/probable IA (14 cases)– Nodules, pleural effusion, segmental pneumonia– Halo sign in 2/14(14%) and air crescent sign in 3/14 (21%)

• Retrospective study of children with IA (8 cases with CT scans)– Multiple small nodules, no halo or air crescent sign– Bibasilar and segmental infiltrate

Burgos A et al. Pediatrics. 2008;121:e1286-e1294. Thomas KE et al. Pediatr Radiol. 2003;33:453-460. Allan BT et al. Pediatr Radiol. 1988;18:118-122.

Author Year Total # patients/ episodes in study

Testing Indication

IA Definitiona Proven or probable IA

Sens Spec TP FP TN FN False positive rateb

Rohrlich 1996 37 Neutropenia Guiot 1994 Criteria

10 100% 92.6% 10 2 25 0 7.4%

Sulaihan 2011 347 Neutropenia Locally defined

9 100% 89.9% 9 34 304 0 10.1%

Steinbach 2007 64 Neutropenia/ acute GVHD

EORTC/MSG 2002

1 0% 87% 0 8 55 1 12.7%d

Hovi 2007 117 Neutropenia EORTC/MSG 2002

1 100% 93% 1 11 105 0 9.5%

Armenian 2009 78 Neutropenia +/- fever/GVHD

EORTC/MSG 2008

3e 100% 98.7% 34 1 74 0 1.3%

Fisher 2012 195 Neutropenia EORTC/MSG 2002

1 0% 95% 0 10 184 1 5.2%

Prospective Studies Evaluating Galactomannan in Children

Table adapted with permission from Fisher BT et al. J Pediatr Infect Dis Soc. 2012;1:103-111.

Diagnosis of IFD Recommendations

Prospective monitoring of GM in serum every three to four days in children at high risk for IFD is reasonable for early diagnosis of invasive aspergillosis (AII)*

Although the optimal cut-off value of GM in the serum of children is not well defined, published data support the use of a threshold of an optical density index 0.5. (serum specimens) (BIII)

** uncertainty whether implementation of this strategy improves clinical outcome; unclear whether this strategy is cost effective

(modified)

Diagnosis of IFD Recommendations

The very limited published data support the value of GM in the diagnosis of pulmonary aspergillosis (GM in BAL; cut-off 1) and central nervous system aspergillosis (GM in CSF; cut-off 0.5) in children (BIII)

Systemic mold-active prophylaxis may decrease the performance of the test (BIII).

β-D-Glucan (BG)• Very limited data in children:

– Elevated levels of BG were reported in 4 children with IFD (3 patients with candidemia, 1 patient with probable aspergillosis)

– Mean BG levels are higher in immunocompetent uninfected children than adults: optimal cut-off children

• Cohort study of 130 pediatric patients– Malignancy (89 hematologic, 11 other)– Critically ill at high risk (30)– Twice-week sampling using GKT-5M assay– Sensitivity 82% and specificity 82%

Karageorgopoulos DE et al. Clin Infect Dis. 2011;52:750-770. Mularoni A et al. Clin Vaccine Immunol. 2010,17:882-883. Smith PB et al. Clin Vaccine Immunol. 2007;14:924-926. Zhao L et al. J Clin Pediatr. 2010;28:1-10.

Diagnosis of IFD Recommendations

Although BG testing has been shown to be useful in diagnosing IFD in adult patients, data are too limited to make any recommendations on BG testing in children

Polymerase Chain Reaction-Based Assays for the Detection of Candida Species in Blood Samples From

Patients With Invasive Candidiasis

Reference (Date)

Design Population Characteristics

No. ofCenters

PCR Amplification

and Identification

Method

Type of Blood

Sample

Maximum Sens of Assay

(cfu/mL)

Volume of Blood

Used (mL)

Gene(s) Sens/Spec/PPV/NPV

Wellinghausen et al (2009)

P, D Adults and children: 329 adults and 55 children with HM and immuno-deficiency and/or ICU stay

3 Real-time PCR WB 3 5 (adults), 2.5 or 1.4 (children)

18S 88/93/21.8/99.7

Khlif et al (2009)

P, D Adults and children: 110 at risk for invasive fungal infection

1 Real-time PCR WB 100 0.2 18S, ITS1, ITS2

81/96/90.6/91

Tirodker et al (2003)

P, D Children: 70 in neonatal ICU or pediatric ICU with suspicion of sepsis

1 PCR Se 200 0.2-0.5 18S 100/88/45.5/100

Dendis et al (2003)

P, D Children: 24 with cancer and FN

1 PCR followed by APLP/RFLP and sequencing

WB 3 0.5 ITS2 100/75/44.5/100

True-positive findings are defined as blood cultures positive for Candida species, whereas true-negative findings are defined as the absence of European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria for invasive candidiasis.Abbreviations: APLP, amplification product length polymorphism; D, diagnostic; ED, emergency department; FN, febrile neutropenia; HM, hematological malignancy; ICU, intensive care unit; ITS, internal transcribed spacer, NPV, negative predictive value; P, prospective; PCR, polymerase chain reaction; PPV, positive predictive value; RFLP, restriction fragment length polymorphism; S, Svedberg; Scr, screening; Se, serum; Sens, sensitivity; Spec, specificity; WB, whole blood.

ECIL 4 Recommendations: 1st line Therapy of Invasive Aspergillosis

Antifungal therapy: *

ABLC B II1

Liposomal AmB B I 1

Voriconazole i.v. +TDM A I 1

Combination therapy C III

1 voriconazole should be preferred in CNS infection. 2 oral voriconazole should be used in presence of renal failure because of potential for accumulation of the cyclodextrin excipient

* in alphabetical order

Initial Treatment Algorithm in Pediatric Patients

Voriconazole susceptible strain

likely

LiposomalAmphotericin

Modification guidedby species, response

and tolerance

yes

Voriconazole

no

VCZ exposedPCZ exposed

high incidenceof zygomycosis

orno TDM available

age < 2 yearscontraindications

references in Groll AH, EHD 2011

© The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Soler-Palacín P et al. J. Antimicrob. Chemother. 2012;67:700-706

Voriconazole doses in patients <5 years old and ≥5 years old achieving trough therapeutic

plasma levels of voriconazole (1–5.5 mg/L).

© The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Soler-Palacín P et al. J. Antimicrob. Chemother. 2012;67:700-706

Relationship between voriconazole trough therapeutic plasma levels until week 4

(yeasts)/week 6 (moulds) and Outcome 1.

Voriconazole: Current Dosage Recommendation

Children 2 to 11 years and adolescents 12-14 years and <50 kg

- 2x8 mg/kg IV (day 1: 2x9 mg/kg)- 2x9 mg/kg PO (max: 2x350mg)

Adolescents ≥12 to 14 years and > 50 kg and those 15 years and beyond:

- 2x4 mg/kg IV (2x6 mg day 1) - 2x200 mg PO (2x400 mg day 1) (adult dose)

New considerations for neonatal candidiasis

Outcomes Following Candiduria in Extremely Low Birth Weight Infants

CharacteristicNo Proven Infection

(n = 744)Candiduria

(n = 34)aCandidemia

(n = 69)bAdjusted ORc

(95% CI)e

Death by dischargec 85/744 (11%) 9/34 (26%) 19/69 (28%) 2.69 (1.18 – 6.13)

Death by 18 monthsc 94/725 (13%) 10/33 (30%) 22/61 (36%) 2.77 (1.25 – 6.14)

NDI by 18 monthsd 130/159 (22%) 6/22 (27%) 15/39 (38%) 1.62 (.57 – 4.59)

Death or NDI by 18 monthsd 224/693 (32%) 16/32 (50%) 37/61 (61%) 2.49 (1.16 – 5.33)

Reasons NDI could be missing: child died, child was not present at the 18-month follow-up, or not enough information was available to determine NDI. Number of children with complete NDI data: no infection (Bayley II [n = 290], Bayley III [n = 309]), candiduria (Bayley II [n = 9], Bayley III [n = 13]), candidemia (Bayley II [n = 26], Bayley III [n = 13]).Abbreviations: CI, confidence interval; CSF, cerebrospinal fluid; NDI, neurodevelopmental impairment; OR, odds ratio.a At least 1 urine culture positive during hospitalization. Infants who had multiple episodes of infection from the same organism are included. Infants who also had Candida in blood/CSF/other sterile source at any time during hospitalization are excluded.b At least 1 blood culture positive during hospitalization. Infants who had multiple episodes of infection from the same organism are included. Infants who also had Candida in urine/CSF/other sterile source at any time during hospitalization are excluded.c Analysis of death by discharge and death by 18 months are adjusted for clustering of children within center.d Analysis of NDI by 18 months or death/NDI by 18 month are adjusted to clustering of children within center and Bayley cohort.e OR (95% CI) is for no proven infection versus candiduria.

Guidelines for the Treatment of Neonatal Candidiasis

• IDSA– AmB deoxycholate 1 mg/kg (A-II)– Test dose not required; may contribute to delayed clearance– Tolerated well with limited effect on creatinine– Lipid formulations at 3- 5 mg/kg (B-II) if urinary tract involvement is excluded

• Fluconazole 12/mg/kg (B-II)• Echinocandins should be used with caution• ESCMID

– fluconazole, AmB, Lipid Ampho B, micafungin (B-II)– Caspofungin, ABLC (C-2)

Pappas P, CID 2009; Wade KC, et al. Antimicrob Agents Chemother. 2008; Linder N, et al. J.Antimicrob.Chemother. 2003; Saez-Llorens AAC 2008. 5. Heresi G PIDJ 2006; Hope WW, et al Clin Micro Infect 2012

© 2012 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

Antifungal Therapy and Outcomes in Infants With Invasive Candida Infections.Ascher, Simon; Smith, P; Brian MD, MPH; Watt, Kevin; Benjamin, Daniel; Cohen-Wolkowiez, Michael; Clark, Reese; Benjamin, Daniel; MD, PhD; Moran, Cassandra

Pediatric Infectious Disease Journal. 31(5):439-443, May 2012.DOI: 10.1097/INF.0b013e3182467a72

FIGURE 1 . Kaplan-Meier curve for mortality by antifungal therapy. HRs from Cox regression controlling for: gestational age groups (33 weeks), day of life at onset of infection groups (0-7, 8-30, >30 days), delay in therapy (days), and site of infection groups (any blood, any urine, and any CSF positive cultures).

Fisher et al. CID 2013

Summary

• Incidence of candidemia is decreasing in United

• Species distribution relatively stable• Resistance does not seem to big problem at

this time• More evidence being accumulated on

improved diagnostics and treatments• Mortality maybe decreasing?