Sama seperti halnya dengan infeksi virus, diagnosis infeksi jamur sering terlambat ditegakkan karena gejala yang tidak spesifik. Diperlukan kejelian dalam identifikasi gejala yang berhubungan dengan infeksi jamur invasif.
Insidens infeksi jamur pada neonatus sangat rendah bila dibandingkan dengan infeksi bakteri. Sebanyak 2,5% infeksi aliran darah pada bayi dengan berat lahir rendah (BBLR) disebabkan oleh jamur.9 Akan tetapi, morbiditas dan
Tabel 2. Gejala infeksi virus.4
Virus Gejala Klinis
Enterovirus Kejang, miokarditis, Sepsis like disease
RSV Bronkiolitis, pneumonia
Rotavirus Diare, distensi abdomen
Adenovirus Gejala gastrointestinal dan saluran napas
CMV Hepatosplenomegali
Metapneumovirus Bronkiolitis
Parainfluenza Bronkiolitis
Tabel 3. Penggunaan antiviral pada infeksi virus.8
Virus Antivirus Dosis
CMV Gansiklovir
Foscarnet Cidofovir
5 mg/kg I.V (b.i.d) selama 12-21 hari 60 mg/kg I.V (ti.i.d) selama 14-21 hari*
5 mg/kg I.V + probensid 1 kali pemberian, kemudian 3 mg/kg setiap minggu*
Enterovirus non-polio Pleconaril 5 mg/kg p.o (t.i.d) minimal 7 hari*
Hepatitis B Lamivudin 3 mg/kg/hari p.o*
Hepatitis C Pegylated interferon Variatif*
HSV Asiklovir 20 mg/kg IV (t.i.d) selama 21 hari
HIV Zidovudin 160 mg/m2 setiap 8 jam
Influenza Amantadine
Rimantadin 2,5 mg/kg p.o (b.i.d) 2,5 mg/kg p.o (b.i.d)
RSV Ribavarin 20 mg/mL aerosol, 12-22 jam/hari
selama 3 hari atau hingga perbaikan*
*diperlukan pemantauan terhadap toksisitas
t.i.d: 3 kali sehari; b.i.d: 2 kali sehari; I.V: intravena; p.o: peroral
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mortalitas yang diakibatkan sama tinggi dengan infeksi bakteri, sehingga pemahaman mengenai infeksi jamur sangat penting. Infeksi jamur biasanya terjadi setelah lahir dan diperoleh melalu transmisi nosokomial. Adapun patogen yang sering ditemukan pada neonatus adalah Candida, Aspergillus, Malassezia, Cryptococcus, Balstomyces.spp.10
Jamur dapat masuk kedalam tubuh manusia melalui proses kolonisasi pada kulit atau mukosa, kemudian masuk ke dalam sirkulasi melalui kateter.
Di dalam tubuh manusia, jamur berproliferasi hingga akhirnya menginvasi jaringan host. Hal ini sangat mudah terjadi terutama pada bayi prematur dengan imaturitas sistem imun.11 Terdapat beberapa faktor risiko pada neonatus terinfeksi jamur yang terlampir pada Tabel 4.
Candida adalah penyebab terbanyak infeksi jamur pada neonatus.
Sedikitnya ada 15 spesies candida yang berhasil diidentifikasi, dan yang sering dijumpai pada manusia adalah C.albicans, C.glabrata, C.tropicalis, C.parapsilosis, dan C.krusei. Candidia albicans adalah spesies yang paling banyak ditemukan sebagai penyebab infeksi jamur invasif terutama pada BBLR.9,10,14
Gejala infeksi jamur pada neonatus berupa oral thrush, letargis, perdarahan, intoleransi minum, instabilitas suhu, peningkatan kebutuhan oksigen, dan keterlibatan multisistem organ lainnya (meningitis, kandidiasis renal, endocarditis, endoftalmitis).11,12 Kultur darah jamur merupakan metode yang digunakan dalam menegakkan diagnosis infeksi jamur invasif. Akan tetapi, pemeriksaan ini tidak sensitif disebabkan hasil kultur yang rentan dipengaruhi oleh waktu pengambilan dan jumlah sampel. Namun demikian, kultur darah jamur masih menjadi pemeriksaan baku emas hingga saat ini, karena metode ini adalah metode yang paling mudah dikerjakan. Pemeriksaan lain yang dapat dilakukan untuk mengidentifikasi infeksi jamur adalah dengan melakukan pemeriksaan antigen jamur (beta D glukan dan mannan, galaktomannan, (1,3)-beta-D glukan, persepsis), PCR (DNA jamur), rapid test (aglutinasi),
Tabel 4. Faktor risiko infeksi jamur invasif.11-3
Faktor intrinsik Faktor ekstrinsik
1. Prematur (32 minggu) atau berat lahir
rendah (<1500 g) 1. Penggunaan >2 antibiotik spektrum luas (sefalosporin generasi 3)
2. Gangguan imunitas 2. Penggunaan alat invasif - Akses sentral > 7 hari - Ventilasi mekanik > 5 hari 3. Pertumbuhan janin terhambat
4. Skor Apgar <5 pada menit ke-5
5. Perdarahan paru 3. Penundaan nutrisi enteral >5 hari
6. Syok 4. Mendapat kortikosteroid sistemik
5. Mendapat nutrisi parenteral > 7 hari (terutama emulsi lemak)
7. Koagulopati intravaskular diseminata
6. Pembedahan pada saluran cerna/enterokolitis nekrotikans 7. Penggunaan H2 blocker
8. Durasi rawat inap > 28 hari
Pendekatan Klinis Sepsis Neonatorum Akibat Jamur dan Virus
kadar C-reactive protein (CRP) dan interleukin (IL) 6, serta beberapa prosedur lain yang masih dalam penelitian seperti metabolomik.15,16
Pemberian antijamur sangat penting dalam mengeradikasi infeksi jamur invasif pada neonatus. Pilihan antijamur yang sering digunakan adalah amfoterisin B dan flukonazol. (Tabel 5)17 Pemilihan antijamur yang digunakan tentunya dengan mempertimbangkan efek terapeutik yang aman dengan efek samping yang minimal.12,13 Flukonazol merupakan pilihan antijamur yang paling sering digunakan pada neonatus baik sebagai terapeutik maupun profilaksis dengan durasi pemberian bervariasi sesuai dengan kondisi infeksi yang dialami.
(Tabel 6) Efektifitasnya cukup baik, mudah diberikan, dan memberikan sedikit efek samping pada ginjal dibandingkan dengan antijamur lainnya.
Tabel 5. Antijamur pada neonatus.17
Golongan Antijamur Dosis
Polyene Amfoterisin B
Deoksikolat
Liposomal 1 mg/kg/hari I.V
3-5 mg/kg/hari I.V
Azol Flukonazol 12 mg/kg/hari I.V/p.o
Ekiinokandins Mikafungin 10-12 mg/kg/hari*
*Dipertimbangkan penggunaan pada neonatus
t.i.d: 3 kali sehari; b.i.d: 2 kali sehari; I.V: intravena; p.o: peroral
Pada kasus infeksi jamur invasif persisten harus dipertimbangakan evaluasi multisistem untuk menghindari keterlibatan di berbagai organ. Pemeriksaan lumbal punksi, evaluasi retina, ultrasonografi saluran genitourinaria, hati, dan ginjal disarankan pada neonatus dengan hasil kultur jamur darah dan/atau urin positif yang menetap.18
Tabel 6. Durasi pemberian flukonazol.18
Kondisi Durasi
Infeksi berkaitan dengan kateter Minimal 7 hari setelah pencabutan kateter Kandidiasis kutaneus diseminata 14-21 hari hingga klinis perbaikan
Infeksi aliran darah 14-21 hari hingga klinis perbaikan dan hasil kultur negatif
Endokarditis Minimal 6 minggu
Endoftalmitis 6-12 minggu hingga vitrektomi
Meningitis Minimal 4 hari hingga klinis perbaikan
Pemberian flukonazol sebagai terapi profilaksis di unit perinatologi direkomendasikan bila terdapat insidens infeksi jamur invasif yang tinggi (>10%), terutama pada kelompok neonatus dengan berat lahir <1000 gram.
Dosis yang digunakan adalah 3-6 mg/kg, diberikan sebanyak dua kali dalam 1 minggu selama 6 minggu. Nistatin oral dapat menjadi pilihan alternatif
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terapi profilaksis pada neonatus dengan berat lahir <1500 gram dengan dosis pemberian 100.000 unit/8 jam selama 6 minggu.19
Keterlambatan diagnosis dan pemberian terapi berpengaruh terhadap luaran jangka panjang bayi sakit. Infeksi jamur invasif berhubungan dengan morbiditas dan mortalitas yang sangat tinggi. Hasil pemantauan jangka panjang menunjukkan adanya gangguan neurodevelopmental (palsi serebral, kebutaan, tuli, gangguan kognisi) yang dapat memengaruhi kualitas hidup di kemudian hari.19 Pencegahan infeksi dapat dilakukan yaitu dengan pencabutan akses sentral sejak dini bila tidak dibutuhkan dan menghindari transmisi nosokomial di rumah sakit.
Daftar pustaka
1. Pass RF. Viral Infections in the Fetus and Neonate. Long SS, penyunting. Dalam:
Principles and practice of pediatric infectious diseases. Edisi ke-4. Philadelphia:
Saunders; 2012. h. 544-8.
2. Tzialla C, Civardi E, Borghesi A, Sarasini A, Baldanti F, Stronati M. Emerging viral infections in neonatal intensive care unit. J Matern Fetal Neonatal Med.
2011;1:156-8.
3. Civardi E, Tzialla C, Baldanti F, Strocchio L, Manzoni P, Stronati M. Viral outbreaks in neonatal intensive care units: what we do not know. Am J Infect Control. 2013;41:854-6.
4. Agueda S. Viral Infections in a Neonatal Intensive Care Unit. Pediat Therapeut.
2013;3:147.
5. Morriss FH Jr, Lindower JB, Bartlett HL, Atkins DL, Kim JO, Klein JM. Neonatal Enterovirus Infection: Case Series of Clinical Sepsis and Positive Cerebrospinal FluidPolymerase Chain Reaction Test with Myocarditis and Cerebral White Matter Injury Complications. AJP Rep. 2016;6:344-51.
6. Shahroodi MJG, Ghazvini K, Sadeghi R, Sasan MS. Enteroviral Meningitis in Neonates and Children of Mashhad, Iran. Jundishapur J Microbiol. 2016;9:19955.
7. Naing Z, Rayner B, Killikulangara A, Vunnam K, Leach S, McIver CJ, et al.
Prevalence of viruses in stool of premature neonates at a neonatal intensive care unit. J Paediatr Child Health. 2013;49:221-6.
8. Barford G, Rentz AC, Faix RG. Viral infection and antiviral therapy in the neonatal intensive care unit. J Perinat Neonatal Nurs. 2004:259-74.
9. Kaufman DA. Challenging issues in neonatal candidiasis. Curr Med Res Opin.
2010;26:1769-78.
10. Kelly MS, Benjamin DK, Smith PB. The epidemiology and diagnosis of invasive candidiasis among premature infants. Clinics in perinatology. 2015;42:17–105.
11. Jahan S, et al. Epidemiology of candida infections among high risk neonates and infants from a tertiary care setting of north india. EC Microbiology. 2016: 585-596.
12. Basu S, Kumar R, Tilak R, Kumar A. Candida Blood Stream Infection in Neonates:
Experience from A Tertiary Care Teaching Hospital of Central India. Indian Pediatr. 2017;54:556-559.
Pendekatan Klinis Sepsis Neonatorum Akibat Jamur dan Virus
13. Agarwal RR, Agarwal RL, Chen X, Lua JL, Ang JY. Epidemiology of Invasive Fungal Infections at Two Tertiary Care Neonatal Intensive Care UnitsOver a 12-Year Period (2000-2011). Glob Pediatr Health. 2017;4.
14. Hundalani S, Pammi M. Invasive fungal infections in newborns and current management strategies. Expert Rev Anti Infect Ther. 2013;11:709-721.
15. Arendrup MC, Fisher BT, Zaoutis TE. Invasive fungal infections in the paediatric and neonatal population: diagnostics and management issues. Clin Microbiol Infect. 2009;15:613-24.
16. Dessi A. Neonatal fungal infections: new strategies in diagnosis. J Pediatr Neonat Individual Med. 2014;3.
17. Tezer H, Canpolat FE, Dilmen U. Invasive fungal infections during the neonatal period: diagnosis, treatment and prophylaxis. Expert Opin Pharmacother.
2012;13:193-205.
18. Devlin RK. Invasive fungal infections caused by Candida and Malassezia species in the neonatal intensive care unit. Adv Neonatal Care. 2006;6:68-77.
19. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the InfectiousDiseases Society of America. Clin Infect Dis. 2016;62:1-50.
20. Shane LA. Common viral infections in neonates. 2018 NeoPREP. Disampaikan pada kursus 2018 NeoPREP “An Intensive Review and Update of Neonatal/Perinatal Medicine” di Atlanta tanggal 24 Januari 2018.
Prosiding Simposium LxxiV A to Z about infections pediatric antibiotic stewardship
Lampiran.
20Lampiran.20
HSV (Herpes Simplex virus) CMV (Cytomegalovirus) EBV (Epstein Barr virus) Epidemiology • Ubiquitous; transmitted from
symptomatic or asymptomatic with primary or recurrent infection.
• Persists after a primary infection with intermittent shedding.
• 1/3000-1/20,000 live births
• Ubiquitous, transmitted horizontally, vertically, and via transfusions and transplants.
• Persists after primary infection with shedding.
• Reinfection with other strains can occur.
• Humans only known reservoir, 90% adults infected
• Close personal contact (saliva), blood transfusion, transplantation
• Incubation 30-50 days.
Intrauterine infection not documented.
Clinical
Presentation Disseminated (25%) CNS (30%) SEM (45%)
Spectrum - asymptomatic to 10% with IUGR, jaundice, purpura, microcephaly, intracerebral calcifications, retinitis, developmental delays sensorineural hearing loss.
Fever, exudative pharyngitis with petechiae, lymphadenopathy, hepatosplenomegaly.
EBV-associated lymphoproliferative disorders.
Diagnosis Cell culture, PCR assay of mucosal swab specimens obtained 12-24 hours after birth, CSF, whole blood.
Shell vial (days) or traditional culture (>28 days) or PCR assay of tissue and fluids (rapid). Detection ≠ infection.
Serological testing and PCR of immunocompromised Management parenteral acyclovir, 60mg/kg/day
divided q8 for 14 days (SEM) and minimum 21 days for CNS or disseminated infections.
symptomatic - parenteral ganciclovir or oral valganciclovir before 1 month of age for 6 months to improve
developmental/auditory outcomes
Symptomatic
Prevention oral acyclovir suppressive therapy 300mg/m2/dose q 8 hours for 6 months following treatment of acute disease improves
neurodevelopmental outcomes and decreases SEM outbreaks.
hand hygiene for all - standard
precautions hand hygiene for all - standard
precautions
Consideration Observe of skin infection (skin lesions, respiratory distress, seizures, signs of sepsis)
• If asymptomatic: no specimens and empiric acyclovir needed
• Educate parents signs and symptoms during 1st6 wks of life
VZV (Herpes Zoster virus) HAV (Hepatitis A virus) HBV (Hepatitis B virus) Epidemiology • Highly contagious; airborne
• In utero infection results from trans placental passage during maternal viremia with VZV.
• Establishes latency and reactivates = herpes zoster or shingles.
Person to person; fecal-oral;
vertical transmission rare • Transmitted via blood and body fluids.
• Up to 90% infected in the first year of life will develop chronic HBV.
• Immune tolerant phase for years, some with growth impairment.
Clinical
Presentation • Fetal infection after maternal varicella in 1st or early 2nd trimester (1-2%) may result in death, varicella embryopathy (limb hypoplasia, cutaneous scarring, eye and CNS abnormalities).
• Children infected with VZV in utero may develop zoster without extra uterine varicella.
• Maternal varicella 5 days before to 2 days after delivery has high case fatality rate due to disseminated varicella.
Acute, self-limited fever, malaise,
anorexia, and jaundice • Subacute (nonspecific) to clinical and fulminant hepatitis.
• Extrahepatic manifestations.
Diagnosis VZV PCR of lesion Serology Serology
Management VariZIG or IVIG considered for exposed, asymptomatic neonates at risk.
Supportive care No therapy for acute HBV; screened periodically; goal to prevent progression to hepatocellular carcinoma Prevention Airborne and contact Contact precautions for 1 week
following symptom onset.
Hand hygiene and immunization including post exposure prophylaxis for up to 40yr; immune globulin (0.02mL/kg) to infant if maternal symptoms began between 2 weeks before and 1 week after delivery.
Efficacy has not been established.
• HBIG and hepatitis B vaccine for infants born to HBsAg + women.
• Contact precautions if visible blood.
Pendekatan Klinis Sepsis Neonatorum Akibat Jamur dan Virus
HCV (Hepatitis C virus) Measles Rubella
Epidemiology • Maternal-fetal transmission
• Risk of perinatal transmission 5-6%;
10-20% if HIV co-infected, occurring only from women who are HCV RNA + at delivery.
Humans only host; transmitted by droplets or airborne spread; one of most highly communicable of all infectious diseases.
Humans only source; transmitted through direct or droplet contact with nasopharyngeal secretions.
Communicability few days before to 7 days after rash onset.
Infants may shed and transmit for 1 year following infection.
Clinical
Presentation Mild and insidious; jaundice < 20%,
less hepatitis than hepatitis B • Acute fever, cough, coryza, and conjunctivitis maculopapular rash spreads cephalo-caudally and centrifugally.
• Complications include otitis media, bronchopneumonia, croup, diarrhea, acute encephalitis.
• Post- infectious: SSPE
Many subclinical; generalized erythematous maculopapular rash, lymphadenopathy, mild fever.
Encephalitis and thrombocytopenia are complications.
Congenital rubella syndrome:
more severe Diagnosis • Hepatitis C IgG serology and
NAATS to detect HCV RNA – may be performed at 1-2 months of age.
• Passively acquired maternal antibody may persist in infants for up to 18 months.
• Serology
• Measles PCR from throat, nasopharyngeal, urine, blood.
Recommend both serologic and virologic testing.
Rubella IgM from birth to 3 months of age (false positives occur) and stable or increasing rubella IgG first 7-11 months of life. Isolation of virus from throat, NP, or urine in cell culture Management Antivirals aimed at inhibiting HCV
replication and eradicating infection. Supportive; vitamin A
supplementation daily x 2 days Supportive Prevention Standard precautions • Airborne precautions until day 4
after rash onset.
• Administer IGIV within 6 days after exposure to measles-susceptible pregnant women.
• Measles in pregnancy associated with severe maternal; infection and prematurity.
• Droplet precautions until 7 days after onset of rash.
• Contact precautions for known/suspected CRS until 1 year of age or cultures obtained 1 month apart after 3 months of age are negative.
• MMR immunization.
Influenza Non Polio Enterovirus RSV
Epidemiology • Epidemics attributed to influenza A & B. Antigenic drift results in new strains and seasonal epidemics.
• Antigenic shift only with influenza A strains pandemic.
• Person to person via droplets.
• Infectious 24 hours before symptoms; shedding correlated with fever.
• Fecal-oral and respiratory routes, mother to infant in prenatal period and via breastfeeding.
• Usual incubation 3-6 days
• >100 distinct serotypes (group A and B coxsackieviruses, echoviruses, and numbered enteroviruses.
• NP enteroviruses also grouped into 4 species EV A,B,C,D with polioviruses = EV-C.
• Echoviruses 22 and 23 = human parechoviruses 1 and 2.
• Acute respiratory tract infection.
• Most RSV hospitalizations within the first 3 months of life.
• Predisposed are premature, cyanotic or complex cardiac disease, pulmonary hypertension, premature lung disease, immunodeficiency.
• Occurs in annual epidemics in during winter and early spring.
• Viral shedding 3-8 days up to 3-4 weeks.
Incubation period is 2-8 days.
Clinical
Presentation Influenza infection in neonates associated with a sepsis-like syndrome, apnea, pneumonia, and morbidity.
• Significant and frequent illnesses with numerous manifestations.
• Nonspecific febrile illness, respiratory, skin, neurologic, GI, ocular, cardiac, muscular.
• Neonates without maternal immunity at risk for severe viral sepsis, meningoencephalitis, myocarditis, hepatitis, coagulopathy, and pneumonitis.
• Rhinitis, cough, wheezing, tachypnea.
• Preterm infants may not manifest respiratory symptoms – lethargy, anorexia, apnea.
Diagnosis RT-PCR, rapid influenza
molecular assays, viral culture RT-PCR from stool, nasopharynx, conjunctival swabs, CSF, tissue, blood, urine.
Antigen detection assays, RT-PCR (30%
coinfected), rapid molecular assays.
Management • 2 classes of antivirals – neuraminidase inhibitors (NI) and adamantanes.
• Oseltamivir (NI) licensed for
>2 weeks; may be used in neonates.
Supportive; IGIV or convalescent maternal plasma used for life- threatening neonatal infections
• Supportive – hydration and ventilation if indicated.
• Ribavirin not recommended for routine use;
consider for severe infections.
• Corticosteroids, antimicrobials, and bronchodilators not recommended.
Prevention • Droplet precautions: hand hygiene.
• Infants born to influenza- immunized mother have better outcomes and reduce chance of preterm/SGA.
Contact precautions for infants for duration
of illness; cohorting • Palivizumab (humanized mouse immunoglobulin (Ig) G1 monoclonal antibody may reduce the risk of RSV.
Administered IM q 30 days for 5 months during RSV season. Not effective in treatment of RSV disease or in controlling outbreaks.
• Infants in a neonatal unit who qualify because of CLD, CHD, or prematurity may receive the first dose 48-72 hours before discharge.
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Rotavirus Perinatal HIV Metapneumovirus (hMPV)
Epidemiology • Most common etiology of acute gastroenteritis in community and healthcare settings prior to universal immunization.
• Transmission by fecal-oral route and possibly via fomites.
• Incubation 1-3 days.
Blood, semen, cervicovaginal secretions, and human milk implicated in transmission.
Mother to child transmission (MTC) in utero, at labor and delivery and via breastfeeding.
Mild disease in immunocompetent;
severe in immunocompromised.
Similar to and overlaps with RSV season.
Clinical
Presentation Acute onset of fever and vomiting followed by watery diarrhea for 3-8 days. Dehydration, electrolyte abnormalities, and persistent diarrhea.
Unexplained fevers, generalized lymphadenopathy, hepatomegaly, splenomegaly, failure to thrive, persistent candidiasis, recurrent diarrhea, parotitis, hepatitis, CNS disease, opportunistic infections.
• Acute respiratory tract illness, including bronchiolitis, pneumonia, asthma, croup, acute otitis media.
• Preterm birth and cardiopulmonary disease at risk for more severe disease.
Diagnosis Enzyme immunoassays (EIAs) RT-
PCR to detect viral RNA HIV DNA PCRpositive result by 48 hours. In utero transmission; 93% HIV DNA PCR+ by 2 weeks of age and 95% DNA PCR+ by 4 weeks of age.
RT-PCR
Management Supportive – hydration. Antiretroviral
Zidovudine prophylaxis • Supportive – hydration, respiratory support.
• Ribavirin has activity with hMPV but clinical benefit not demonstrated.
• Antimicrobial agents not indicated unless bacterial infection.
Prevention • Contact precautions bleach (1:2 with water) and 70% ethanol inactivates rotavirus on environmental surfaces.
• Consumption of human milk is associated with milder risk
• Immunization requireddebatable administration in NICU.
• Preterm infants may be immunized when > 6 weeks postnatal age and clinically stable.
• Standard precautions for care of HIV infected infant (all infants).
• Decreased MTC due to antenatal testing, antiretroviral (ARV) prophylaxis ante-, intra-, and post- partum, cesarean section before labor and ROM, and avoidance of breastfeeding.
Contact precautions with hand hygiene.