Antifubgals and FUNGAL INFECTIONS IN NICU.pptx

Fungal infection in nicu

1. FUNGAL INFECTIONS IN NICU BY LOKESH PARAMITHA CHILDRENS HOSPITAL

2. INTRODUCTION 3 rd most common cause of LOS Patient popuations : a)More common in ELBW & VLBW neonates b)Neonates with gastroschisis, SIP,NEC 7 times more mortality than staph.epidermidis Slow growing – EOS & LOS (vertical & horizontal transmission respectively)

3. INCIDENCE & DEMOGRAPHICS 15% of LOS 25% - colonization in ELBW 30% - mortality in ELBW due to sepsis 50%- LP is positive with blood c/s is negative GA > BW (25 times risk in <28WK neonates) Linear relation with GA

4. Pathogenic strains C.albicans,C.paraspsilolis,C.glabarta,C.kreusi,C.tropicalis C.albicans more pathogenic C.glabarta – fluconazole resistant Forms bio films Changes morphology – resistance Production of hydrolytic/proteolytic enzymes

5. PATHOGENESIS ADHESION – most important step.(adhesins ,INT gene on cell surface) COLONIZATION BLOOD STREAM DISSEMINATON TISSUE SPREAD CLINICAL FEATURES

6. FACTORS INFLUENCING INFECTION

7. Risk factors

8. WHY PRETERMS ARE AT HIGH RISK? Immature immunity – immature neutrophil, macrophage, complement function Immature barrier function – skin,lungs (immature lung macrophages),GIT Immature skin – increased transepidermal loss of water , glucose Relative asphyxia @ birth and intermittent desaturation – decreased immunity. Decreased phagocytosis.

9. CLINICAL SPECTRUM

10. BLOOD STREAM INFECTIONS CLINICAL FEATURES: indolent course. Dull activity ,lethargy , altered aspirates , bloody stools , abdominal distension, recurrent apnea - MV , hypotension, high FIO2,metabolic acidosis. LABORATORY FINDINGS: High CRP , thrombocytopenia , leukopenia/ leukocytosis , hyperglycemia , increased beta D glucan & i /t ratio.

11. Invasive candida infections SKIN: CONGENITAL CUTANEOUS CANDIDIASIS PRESENTATION: <1 week of life (MC <3 days) RASH: maculopapular/pustular/scaly/dry/desquamating lesions All exposed surface area except genitalia Umbilicus & placenta - white plaques CRITERIA: 1) 2 SKIN EXPOSED AREAS OR 2) 1 SKIN EXPOSED AREA + UMBILICUS/ PLACENTAL PATHOLOGY

12. Invasive candida infections DIAGNOSIS: isolating fungus from >2 skin areas Silver staining of umbilical cord /placenta. Positive blood/CSF/urine culture & sensitivity TREATMENT: topical alone not sufficient Systemic for >14 days is required

13. d/ d:cutaneous candidiasis DIAPER DERMATITIS: >7 days of life Involves perianal area Erythematous leisons ,erosive dermatitis , satellite lesions In TERM – topical anti fungal In PRE TERM- both topical and systemic for 14 days High risk of invasive disease

14. Fungal uti Risk factors: PRE TERM, urinary catheter insitu Ascending infection > hematogenous Cortical – renal abcess Collecting tubule – fungal balls

15. Fungal uti C/f : fever , dull activity LABORATORY: raised creatinine & BUN C&S : urine bag – 10 5 CFU Supra pubic aspiration – 10 3 CFU,<10 3 CFU- colonization. Blood C&S f/b USG KUB. End organ dissemination.

16. Fungal uti Antifungal prophylaxis prevents incidence. Systemic antifungal for 14 days. Low dosage or duration increases invasion & NDI. Upper UT- fluconazole Lower UT- ampho –B > lipoid formulation.

17. Cns infection Rule of 50- A)50% fungal sepsis – CNS infection B)50% LP is positive with negative blood culture. C)50% mortality in CNS infection. Neuroimaging –must NSG – not useful

18. Cns infection COMPLICATION: PVL both in Term & PT neonates. LP – sometimes inconclusive. LP is + ve – dissemination screening. TREATMENT: systemic antifungals for 14 days/4-6 weeks.

19. GIT INFECTION Common culprit of peritonitis in focal bowel perforation and NEC. Systemic signs of sepsis with probable NEC- fungal colonization screen : A)positive – add antifungal along with antibacterial B)negative – add prophylactic till NEC resolves and full feeds.

20. END ORGAN DISSEMINATION Clinical features after dissemination. 3% - endophthalmitis 4% - CNS abscess 5% - endocarditis & renal involvement Persistent infection – 10% increase in EOD. Early catheter removal – decreases EOD ,Mortality & NDI.

21. ASSOCIATION BETWEEN CENTRAL LINE & CANDIDIEMIA Early removal of central line. Removal vs non removal – 2 days earlier clearance Median duration of clearance – 3 days. NICHD data – mortality 34% to 21%. Improved neurological outcome

22. ASSOCIATION BETWEEN CENTRAL LINE & CANDIDIEMIA Early removal and replacement at different site Repeat blood culture – confirmation Continuation of antifungals 14 days more after negative culture Persistent candidemia- check EOD & add 2 nd antifungal

23. Laboratory methods CBP – leukocytosis /leukopenia , thrombocytopenia , hyperglycemia , metabolic acidosis CRP Culture of sterile fluids like blood, CSF, urine, peritoneal fluid Mean duration of positive value by 3 days

24. End organ DISSEMINATION

25. MOLECULAR METHODS Fungal PCR 1-3 beta D GLUCAN (BDG) Mannan Useful in negative blood culture. Less invasive and prevention of iatrogenic blood loss in PT

26. MOLECULAR METHODS In a meta-analysis of 14 studies, the sensitivity/specificity for the diagnosis of invasive candidiasis of mannan and anti mannan IgG individually  58%/93% and 59%/83%, respectively The pooled sensitivity and specificity of PCR for suspected invasive candidiasis in a recent meta analysis  95% and 92%, respectively

27. MOLECULAR METHODS In probable invasive candidiasis, sensitivity of PCR and blood cultures  85% and 38%, respectively A major limitation of PCR studies is the lack of standardized methodologies and multicenter validation of assay performance

28. MOLECULAR METHODS In meta-analyses of β-D-glucan studies, the pooled sensitivity and specificity for diagnosing invasive candidiasis  75%and 80 %, respectively β-D-glucan is a cell wall constituent of Candida species, Aspergillus species, Pneumocystis jiroveci and several other fungi Cut off values >125pg/ml

29. CANDINEO STUDY : Sensitivity Specificity PPV NPV PCR 87.5% 81.6% 26.9% 98.8% BDG 75% 64.6% 14%

30. Other markers Fluorescent buffy coat test – detects hyphae & spores Fungal chitin synthase Anti candida antibodies D- arabinitol –candida metabolite

31. treatment

32. Anti fungal prophylaxis High mortality & morbidity (NDI) in ELBW Only proven evidence in RCT trial Reduced colonization Increases phagocytic capacity of neutrophils Reduces 80% - ICI, 90% of mortality

33. Anti fungal prophylaxis <28 weeks &/ or <1kg. <72 hrs >10% fungal incidence in NICU >1kg- a)maternal HIV b)gastroschisis ,NEC,SIP

34. Anti fungal prophylaxis 3mg/kg vs 6 mg/kg a)no change in mortality or morbidity. b) increased resistance of non candida albicans sps with later. Twice weekly for 6 weeks Reduces NICU mortality

35. Anti fungal prophylaxis No change in bacterial infection No change in NEC incidence No change in cholestasis No change in NDI Improved QUALY Improved cognition @ 18 months

36. EmpIrical treatment In VLBW & non VLBW sick neonates Of NICU Suspect clinical signs of sepsis with back ground prolonged antibiotic usage,H2 #,post natal steroids, skin & oral rash Non azole antifungals usage Reduces mortality from 60% to 0 %

37. EmpIrical treatment An observational study of 136 extremely low birth weight (ELBW) infants with invasive candidiasis who were cared for at the NICHD suggested that empiric antifungal therapy for invasive candidiasis increased survival without neurologic impairment ( OR – 0.27, CI 0.08-0.86)

38. Pre emptive treatMEnt In <28 wk / <1kg Fungal colonization from respiratory tract by culture or mannan ag detection Reduces mortality from 75% to 0 %

39. TARGETED TREATMENT

40. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America AmB deoxycholate, 1 mg/kg daily, is recommended for neonates with disseminated candidiasis (strong recommendation; moderate-quality evidence). Fluconazole, 12 mg/kg intravenous or oral daily, is a reasonable alternative in patients who have not been on fluconazole prophylaxis (strong recommendation; moderate-quality evidence).

41. CONT. Lipoid formulation AmB , 3–5 mg/kg daily, is an alternative, but should be used with caution, particularly in the presence of urinary tract involvement (weak recommendation; lowquality evidence). Better renal penetration with D-AMPH > L-AMPH.

42. CONT. Echinocandins should be used with caution and generally limited to salvage therapy or to situations in which resistance or toxicity preclude the use of AmB deoxycholate or fluconazole (weak recommendation; low-quality evidence). CVC removal is strongly recommended (strong recommendation; moderate-quality evidence).

43. The recommended duration of therapy for candidemia without obvious metastatic complications is for 2 weeks after documented clearance of Candida species from the bloodstream and resolution of signs attributable to candidemia (strong recommendation; low-quality evidence) For 4- 6 weeks in EOD.

44. OTHER PREVENTIVE STRATEGIES In 2020 meta-analysis of six trials (3266 infants), enteral lactoferrin supplementation decreased invasive fungal infection compared with placebo (0.4 versus 1.7 percent; relative risk [RR] 0.23, 95% CI 0.10-0.54) Oral probiotics mainly L. rhamnosus & reuterii . Reduced colonization than placebo group by 50%.

45. Anti fungals action & monitoring POLYENES: Binds to ergosterol Makes pores of fungal cell wall Fungicidal. D-AMPH & L- AMPH.

46. CONT MONITORING OF AMPHOTERICIN B Serum electrolytes - every other day Serum creatinine daily or every other day initially and if stable, testing can be spaced to twice weekly Complete blood count twice a week initially and, if stable, testing can be spaced to once a week Liver enzymes twice a week initially and, if stable, testing can be spaced to once a week

47. cont AZOLES: Fungistatic – # cytochrome 450 & inhibiting 14- demethylase – decreased synthesis of ergosterol. Fluconazole,voriconazole & miconazole. RFT & LFT monitoing QT prolongation.

48. Cont. ECHINOCANDINS: Inhibits 1-3 beta glucan synthase, Candida- fungicidal Aspergillus – fungistatic No action – cryptococcus neoformans,zygomyces . LFT,RFT,GGT,Thrombophlebitis .

49. Other fungal infections. Commonly encountered in NICU rare Candida , Aspergillus, Malassezia. Less common are Zygomyces , Cryptococcus, Histoplasma, Coccidomyces .

50. Strategies to reduce nicu infection Early prophylaxis. Prompt dosing & schedule of antifungals. Restrict antibiotic ,steroid,H2#,PPI usage. Use bundle approach for invasive procedure. Early enteral nutrtition . Probiotic supplementation.