Fungal infections in Neonates: How do I treat · fungal infections? Evaluation to assess the extent of dissemination urinary tract, CNS, eyes, heart valves, bone, or joints Removal

Dr Pankaj Garg

Senior Consultant, Department of Neonatology

Sir Ganga Ram Hospital, New Delhi

9810146581, [email protected]

13/12/2019: NEOCON 2019; HYDERABAD

Fungal infections in Neonates:

How do I treat

SGRH

PHOT

O

• MBBS, MD, DNB

• DNB PEDIATRICS, NEONATOLOGY and GYNAE & OBS TEACHER

• TAKES CARE OF 40 BEDDED NICU; 1200 ADMISSIONS FOR LAST 20

YEARS

• 32 INDEXED PUBLICATIONS

• PRESIDENT NORTH DELHI IAP BRANCH

• PAST NNF DELHI CHAPTER GENERAL SECRETARY

• SPEAKER INTEREST: NEONATAL INTENSIVE CARE, NEONATAL AND

PEDIATRIC NUTRITION, IMMUNIZATION

Which neonatal population gets

fungal infections?

Systemic infection: VLBW; ELBW even more

likely

Oral thrush/Fungal diaper dermatitis: Term babies;

preterm babies after discharge

Goals of management?

Adequate treatment

Supportive

Antifungal drugs

Prevention

General measures

Fluconazole prophylaxis in ELBW/VLBW

infants

Oral or diaper dermatitis: does it

always require treatment

No

In healthy term infants who lack symptoms, are feeding well,

and are at low risk of invasive candidiasis

National Institute for Health and Care Excellence guidelines

suggest treatment

the symptoms are causing pain to the woman or the baby or

feeding concerns to either

Nystatin/Miconazole (DAKTARIN oral gel) /Clotrimazole

If no response

Fluconazole

3mg/kg OD for 7 days

When is treatment always required??

Invasive fungal infections

Congenital cutaneous candidiasis

Retrospective case series of 21 infants with CCC (18

preterm and 3 term; mean birth weight 950 g)

20 treated within 48 hrs of rash; 1 not treated

1/20 got infection; 1/1 got disseminated infection

Kaufman DA, Coggins SA, Zanelli SA, Weitkamp JH. Congenital Cutaneous Candidiasis:

Prompt Systemic Treatment Is Associated With Improved Outcomes in Neonates. Clin

Infect Dis 2017; 64:1387

Management principles for invasive

fungal infections?

Evaluation to assess the extent of dissemination

urinary tract, CNS, eyes, heart valves, bone, or

joints

Removal of any source of infection (e.g, central

venous catheter [CVC], urinary catheter)

Drugs

Amphotericin B is the preferred drug for treatment

of most systemic neonatal candidal infections

Is removing central line evidence

based?

Yes

Retrospective study (104 neonates)

Early removal (within 3 days of the first positive blood

culture)

Associated with shorter duration of candidemia; 3vs 6

Lower mortality (0 versus 39 percent)

Karlowicz MG, Hashimoto LN, Kelly RE Jr, Buescher ES. Should central

venous catheters be removed as soon as candidemia is detected in

neonates? Pediatrics 2000; 106:E63.

How to choose antifungal drugs in

invasive fungal infections?

Amphotericin-B

As soon as fungal

growth positive

Monotherapy

1-1.5mg/kg/d

Very less side effects

Fluconazole

Only after sensitivity

documented

Feeding well, not toxic

Follow up therapy

Uncomplicated UTI

12 mg/kg/d

Very less side effects

Time to positivitySGRH Data

Gram negative organisms 0.5 days

CONS / Staph aureus 0.7 days

Candida 2.3 days

Flow

chart

for

Candida

UTI

Urine culture positive

Blood culture

Positive

Treat as systemic infection

Negative

No fungal mass on USG abdomen

Not toxic, feeding well

yes

Oral Fluconazole

no

Amphotericin B or IV fluconazole for 14 days or till resolution of mass

Flow chart

for

Candida

Meningitis

CSF culture positive or CSF cytology/bio positive with blood culture positive,

Monotherapy with Amphotericin-B

Removal of shunt if any

Clinical improvement

Continue for 21 days

Clinically unstable

Repeat CSF still positive

Add Oral Flucytosine 25mg/kg/dose every 6 hrly

MRI

Continue till all signs/MRI fungal shadows persist

Flow chart

for

Invasive

Candida

Infections

Blood culture positive; End organ evaluation normal

Monotherapy with Amphotericin-B; Removal of Central line if possible

Clinical improvement

Repeat blood culture after 7 days

Negative

2 weeks more or till resolution of imaging

findings

Positive

Add Fluconazole if sensitive; otherwise Caspofungin

Flow chart

for

Invasive

Candida

Infections

Blood culture positive; End organ evaluation abnormal

Monotherapy with Amphotericin-B; Removal of Central line if possible

Clinical improvement

Repeat blood culture after 7 days

Negative

3-5 weeks more or till resolution of imaging findings

Positive

Add Fluconazole if sensitive; otherwise Caspofungin

Surgical option may have to be exercised

When can a new PICC be inserted?

New PICC should ideally be inserted after documentation of

clearance of Candida from blood with at least 3 negative cultures

within first 3 days of therapy or

Two or more than 2 negative cultures after 4 days of antifungal

treatment

Amphotericin-B

Does the dose needs to be modified with pre-

existing renal disease

No

Does the dose needs to be modified with renal

disease appearing after start of drug

Yes (50%)

Any Candida strains resistant to it?

Candida lusitaniae

Side effects of Ampho-B in neonates more or

less compared to older children or adults?

Less

Hypokalemia, renal tubular dysfunction, bone

marrow toxicity, hypomagnesemia, liver enzymes

raised

Infrequent, dose dependent, and resolve with

cessation of the drug.

Plain vs Liposomal Ampho-B

Plain except

develop intolerant infusion-related reactions or

renal dysfunction during standard amphotericin

B administration.

The lipid formulations should not be used in

patients with Candida urinary tract infections

(UTIs).

Is it just the cost or evidence also

against liposomal ampho-B?

Multicenter retrospective review of 730 infants

Multivariate analysis showed higher mortality with

liposomal

[OR] 1.96, 95% CI 1.16-3.33)

Ascher SB, Smith PB, Watt K, et al. Antifungal therapy and outcomes in

infants with invasive Candida infections. Pediatr Infect Dis J 2012; 31:439.

Disadvantages of Fluconazole?

Certain species are resistant

Krusei, Glabrata

Resistance increasing esp after prophylaxis

Clinical trials using as first line drugs: few with

high mortality rates

Newer Antifungals

Reserved for difficult cases only

Voriconazole

Not many trials in neonates

Usual reported dose: 12 to 20 mg/kg/day divided

every 8 to 12 hours

Caspofungin

Very well tolerated

2 mg/kg/dose once daily

Any role of empirical ampho-B

????

Outcome

Guarded

Mortality: 20-40% in ELBW

Survivors of neonatal candidemia, especially in

those with central nervous system involvement,

are at risk of long-term neurodevelopmental

impairment

Antifungal prophylaxis

No routinely provide antifungal prophylaxis for all

preterm infants

Antifungal prophylaxis is reserved for ELBW

NICUs with a high baseline rate of systemic fungal

infection (ie, greater than 5 to 10 percent)

Consistent with American Academy of Pediatrics and

the Infectious Diseases Society of America

recommendation

Antifungal prophylaxis

Fluconazole

within the first 48 to 72 hours after birth

3 mg/kg per dose given intravenously twice a week

for four to six weeks or until the infant no longer

requires intravenous access

Evidence

2015 meta-analysis of 10 trials (including 1371 very

preterm or VLBW infants)

Reduced the incidence of invasive fungal infection

compared with placebo or no drug (6.2 versus 15.7

percent; RR 0.43, 95% CI 0.31-0.59)

Effect on mortality was not statistically significant

(12.7 versus 17.3 percent; RR 0.79, 95% CI 0.61-

1.02)

Take Home Messages

Disease of high morbidity and mortality

Fluconazole prophylaxis in ELBW

Ampho B (plain) drug of choice

Dose of fluconazole going up; 12mg/kg/day

PICC removal helps

Candida non albicans more common now

Prevention holds the key

Antibiotics are not with out harm

Dr Pankaj Garg

Senior Consultant, Department of Neonatology

Sir Ganga Ram Hospital, New Delhi

9810146581, [email protected]

13/12/2019: NEOCON 2019; HYDERABAD

Fungal infections in Neonates:

How do I treat

SGRH