0
D. K. BHAGWANI
1. Introduction
 1. premature infants are at risk of invasive fungal infections -their

relative immunodeficiency.

 2. ...
2. 1. fungal colonisation is seen in 10% of VLBW infants by the
 Candida colonisation

first week of life and this can in...
3. Candidiasis/candidaemia:
1. Infection/ isolation of candida species in the blood.
2.Invasive candidiasis is an importan...
4. Invasive/ Disseminated
candidiasis
 1. Isolation of candida from other normally sterile body fluids or a

persistent i...
5. Risk factors and transmission:
 Transmission of cabndida may be vertical ( from maternal to vaginal

infection/colonis...
Low period
Risk factors for IFI in neonatal age
gestational
or birth weight

Treatment with broadspectrum antibiotics
(par...
Neonatal candidiasis

 3rd most common cause of late-onset sepsis in NICU
(high risk)
 Bimodal frequency: early-onset (w...
6. Clinical manifestations:
 1. The clinical picture of systemic fungal infection in neonates is
 indistinguishable from...
7. DIAGNOSIS:
.

1. Isoaltion of candida from blood or other sterile body fluids is
diagnostic.

. 2. Always consider cand...
8. Management:
 1. When a blood culture is positive for candida.
 2.important investigations include: urine MC+S, LP, re...
9. Prophylaxis
 1. Oral Nystatin suspension 0.5ml OD is given to infants <27 weeks

gestation and/or <750gms from birth u...
Antifungals used in neonatal period & susceptibility of
fungus

Tezer H, et al. Expert Opin Pharmacother 2012; 13(2): 193-...
Mechanism of Action of Amphotericin B

• Irreversibly binds
to ergosterol
component of
fungal cell
membrane

Step 1

Step ...
LAmB: MOA Step 1 and 2
LAmB: MOA Step 3 and 4
Lipid-based deliveries of AmB Colloid
amphotericin B

AmB Lipid Complex

Occurred when AmB conc
increased > 3 mol %
Dimyri...
Advantages of LAmB over Conventional AmB
Increased daily dosage up to 10-fold
Mean duration of Rx with LAmB is shorter tha...
Nephrotoxicity with Amphotericin B
 Nephrotoxicity common


ARF rates: 49%-65%






Wingard study
Serum creatinine ...
How does amphotericin B cause nephrotoxicity?
Constriction of afferent
arterioles leading to
decreased glomerular
filtrati...
LAMBIN 10: ADR
 Transfusion Rxn, chills/rigors, abdominal pain, asthenia, back/chest pain
 Fever, phlebitis, sepsis, hyp...
10. Treatment
Dose
LIPOSOMAL
AMPHOTERCIN
1st line in systemic
fungal infection

Mode of action

Monitor

3mg/kg/day IV
Sta...
 Alternatives: caspofungin 2mg/kg/d is fungicidal, poor CSF

penetrance.
 Flucytosine can be used as adjunct to Amphoter...
DURATION OF ANTIFUNGAL
THERAPY
Condition

Duration of treatment

Catheter- related infection

Minimum of 7days after remov...
Management of systemic fungal infection in newborn
Management of systemic fungal infection in newborn
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Management of systemic fungal infection in newborn

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Transcript of "Management of systemic fungal infection in newborn"

  1. 1. D. K. BHAGWANI
  2. 2. 1. Introduction  1. premature infants are at risk of invasive fungal infections -their relative immunodeficiency.  2. The overall incidence of fungal septicemia on neonatal units is increasing because of both increased survival of VLBW neonates and use of broad spectrum antibiotics.  3. Invasive fungal infections are caused by Candida species  4.C albicans is responsible for most neonatal infections (up to 80% ), whereas C parapsilosis and C tropicalis account for 14% and 6% of infections respectively.  4. Colonisation of healthcare workers with fungus (predominantly C parapsilosis ) is common and can be as high as 30%. This organism is usually responsible for NICU outbreaks.
  3. 3. 2. 1. fungal colonisation is seen in 10% of VLBW infants by the  Candida colonisation first week of life and this can increase more than 50%by the 4th week of life.  2. Intial site of colonisation is usually gastrointestinal tract.  3.Colonisation with fungal organisms is an independent risk factor for subsequent invasive fungal infection, particularly in VLBW infants and the rate of progression to invasive candidiasis can vary from 7 to 24%.  4.. Colonisation is the isolation of candida from high risk sites ( catheter urine, ETT).
  4. 4. 3. Candidiasis/candidaemia: 1. Infection/ isolation of candida species in the blood. 2.Invasive candidiasis is an important cause of neonatal sepsis in VLBW infants accounting for upto 12% of late onset infection and carries an overall mortality of up to 30%. 2. Candida species is the 3rd mo0st frequent organism isolated (after CONS and Staph. aureus).
  5. 5. 4. Invasive/ Disseminated candidiasis  1. Isolation of candida from other normally sterile body fluids or a persistent infection after removal of catheter.  2. Candida is capable of invading all vital organs and following candidaemia, end organ dissemination is more likely with persistent candidaemia of more than 7 days.  3. Disseminated candidiasis involving the CNS has a mortality rate of 30% and survivors have a high incidence (up to 50%) of neurodevelopmental including cerebral palsy, hearing and visual problems.  4. Usual CNS involment includes Meningitis (15%), and Ventriculitis (4%).  5. Candida also results in other end organ damage such as endopthalmitis (3%), endocarditis (4%) and renal fungal balls which may calcify (5%)
  6. 6. 5. Risk factors and transmission:  Transmission of cabndida may be vertical ( from maternal to vaginal infection/colonisation) or horizontal. 1. Low birth weight (<1500g) and low gestational age (<28 weeks) 2. use of broad spectrum antibiotics and/or multiple antibiotics 3.central venous catheters 4.parentral nutrition, being NBM 5. H2 receptor blockers 6. fungal colonisation in VLBW infants.
  7. 7. Low period Risk factors for IFI in neonatal age gestational or birth weight Treatment with broadspectrum antibiotics (particularly cephalosporins) Delayed enteral feeding Treatment with corticosteroids Tezer H, et al. Expert Opin Pharmacother 2012; 13(2): 193-205. Invasive devices & procedures (e.g., central venous catheters, mechanical ventilation) Prolonged use of parenteral nutrition GI pathology including congenital anomalies & necrotizing enterocolitis
  8. 8. Neonatal candidiasis  3rd most common cause of late-onset sepsis in NICU (high risk)  Bimodal frequency: early-onset (within 3 days of birth) & late-onset (7 – 60 days & later)  Median gestational age: 27.5 weeks  Mortality in neonatal patients: 25 – 60% Castagnola E, et al. Drugs 2009; 69 (1): 45 -50.
  9. 9. 6. Clinical manifestations:  1. The clinical picture of systemic fungal infection in neonates is  indistinguishable from bacterial sepsis.  2.Often signs and symptoms are generalised such as apnoea, worsening cardio respiratory function, abnormal renal function and/or seizures.  3.. Candidiasis can also present with GIT symptoms similar to NEC, where there may be paucity of classic radiological signs of NEC.
  10. 10. 7. DIAGNOSIS: . 1. Isoaltion of candida from blood or other sterile body fluids is diagnostic. . 2. Always consider candida in the differential diagnosis of neonatal sepsis. Particularly late onset sepsis.
  11. 11. 8. Management:  1. When a blood culture is positive for candida.  2.important investigations include: urine MC+S, LP, renal and cranial USS and ophthalmological examination (as candida may worsen ROP and causes endopthalmitis).  3. Fungal endocarditis may occur even with only one positive blood culture, so consider an Echocardiogram if there is clinical suspicion of endocarditis.  4. Consider taking out the long line as prompt removal of central catheters is associated with improved short and long term outcomes.  4. Commencing antifungal thetrapy has to be a Neonatal consultant decision often involving the microbiologists.
  12. 12. 9. Prophylaxis  1. Oral Nystatin suspension 0.5ml OD is given to infants <27 weeks gestation and/or <750gms from birth until removal of central venous catheters and whilst on broad spectrum antibiotics.  2.This is shown to reduce both colonisation of gastrointestinal tract and the rate of invasive candidiasis.  3. Fluconazole prophylaxis is effective in reducing the rate of colonisation and progression to systemic infection in neonatal units with a high rate of fungal infection (>10%).  4. Oral nystatin used in unit the incidence of systemic fungal infection is very low (1%), hence Fluconazole prophylaxis is currently not indicated (the NNT to prevent one case on the unit is around 200).
  13. 13. Antifungals used in neonatal period & susceptibility of fungus Tezer H, et al. Expert Opin Pharmacother 2012; 13(2): 193-205.
  14. 14. Mechanism of Action of Amphotericin B • Irreversibly binds to ergosterol component of fungal cell membrane Step 1 Step 2 • Damages cell membrane Step 4 • Cellular contents leak out • Fungal cell death Step 3 Fungicidal activity is believed to be caused by leakage of essential nutrients from the fungal cell
  15. 15. LAmB: MOA Step 1 and 2
  16. 16. LAmB: MOA Step 3 and 4
  17. 17. Lipid-based deliveries of AmB Colloid amphotericin B AmB Lipid Complex Occurred when AmB conc increased > 3 mol % Dimyristoyl phosphatidylcholine DMPC Dimyristoyl phosphatidylglycerol DMPG Ratio 7:3 Size: 1600-11,000 nm Ribbon-like structure ABELCET, 1981 Dispersion Complexed with non-PL carrier 1:1 molar ratio of AmB plus cholesteryl sulfate 2 molecules of AmB and 2 molecules of CS forming a tetramer that has hydrophilic and hydrophobic portion Aggregates into disc-like structure Not a liposome Size: 120-140 nm AMPHOCIL, 1995 AmB Liposomes True liposomal structure Sterol component and PL component Hydrogenated soy PC Cholesterol DMPG Ratio 10:5:4 Size: < 80 nm AMBISOME, 1997
  18. 18. Advantages of LAmB over Conventional AmB Increased daily dosage up to 10-fold Mean duration of Rx with LAmB is shorter than Amb but has similar efficacy High tissue concentrations in lungs, liver & spleen Higher dose administered with LAmB than AmB, but has 1.  infusion related side effects 2.  renal toxicity & hepatotoxicity Jeon GW, et al. Yonsei Med J, 2007; 48 (4): 621-626 Extent of tissue distribution may be an important determinant of treatment outcomes
  19. 19. Nephrotoxicity with Amphotericin B  Nephrotoxicity common  ARF rates: 49%-65%     Wingard study Serum creatinine x 2 in 53% cases Represents ↓ renal function by 70% 15% patients reqd dialysis    Pathophysiology Glomerular vasoconstriction Direct damage to tubular cells   How Soon? 45 min after infusion
  20. 20. How does amphotericin B cause nephrotoxicity? Constriction of afferent arterioles leading to decreased glomerular filtration Direct damage of distal tubular membranes leading to wasting of Na+, K+ and Mg++ Tubular-glomerular feedback: Further constriction of arterioles
  21. 21. LAMBIN 10: ADR  Transfusion Rxn, chills/rigors, abdominal pain, asthenia, back/chest pain  Fever, phlebitis, sepsis, hypertension, hypotension, tachycardia, hyperventilation, diarrhea, gastrointestinal hemorrhage, nausea, vomiting  ↑ Alk P, ↑ALT, ↑ AST, bilirubinemia, ↑ BUN, ↑ creatinine, edema  Hyperglycemia, hypernatremia, hypervolemia, hypocalcemia, hypokalemia, hypomagnesemia  Peripheral edema, anxiety, confusion, headache, insomnia, increased cough, dyspnea, epistaxis, hypoxia, lung disorder, rhinitis, pruritus, rash, sweating, hematuria, pleural effusion
  22. 22. 10. Treatment Dose LIPOSOMAL AMPHOTERCIN 1st line in systemic fungal infection Mode of action Monitor 3mg/kg/day IV Start at 1mg and increase dose every 24h. Doses upto 5mg/kg have been used. Fungicidal- binds to ergosterol imn fungal cell membrane and cause leakage of cations- cell death Renal function serum K and Mg Fungistaticinhibits fungal cytochrome P-450 – Enzyme inducer Urinary concentration 10* that in plasma. Transaminases weekly FLUCONAZOLE 12mg/kg/day 1st Line in fungal IV/PO UTI, 2nd line in systemic fungal infections
  23. 23.  Alternatives: caspofungin 2mg/kg/d is fungicidal, poor CSF penetrance.  Flucytosine can be used as adjunct to Amphotercin, only available PO.
  24. 24. DURATION OF ANTIFUNGAL THERAPY Condition Duration of treatment Catheter- related infection Minimum of 7days after removal of catheter Fungaemia 14-21 days after clinical improvement and negative blood culture Endocarditis Minimum of 6 weeks, surgery often require for cure Endopthalmitis 6- 12 weeks after vitrectomy Meningitis Minimum of 4 weeks after resolution of signs and sympotms Simple UTI 2 weeks
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