A STUDY ON NEONATAL CANDIDA BLOOD STREAM INFECTION IN A TERTIARY CARE HOSPITAL
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THE TAMIL NADU DR.MGR MEDICAL UNIVERSITY CHENNAI – 600032
In partial fulfillment of the regulations for the awards of the degree of M.D. PAEDIATRICS BRANCH – VII
GOVERNMENT MOHAN KUMARAMANGALAM MEDICAL COLLEGE,
SALEM MAY 2021
GOVERNMENT MOHAN KUMARAMANGALAM MEDICAL COLLEGE, SALEM
DECLARATION BY THE CANDIDATE
I solemnly declare that this dissertation “A STUDY ON NEONATAL CANDIDA BLOOD STREAM INFECTION IN A TERTIARY CARE HOSPITAL” was prepared by me at Government Mohan Kumaramangalam Medical College and Hospital, Salem under the supervision of DR.P.
SAMPATH KUMAR, M.D, D.C.H., Professor of Paediatrics, Govt Mohan Kumaramangalam Medical College and Hospital, Salem. This dissertation is submitted to the Tamilnadu Dr. M.G.R Medical University, Chennai- 32 in fulfillment of the University regulations for the award of the degree of M.D.
Paediatrics (Branch VII).
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Signature of the candidate DR.C. BHAVYA
GOVERNMENT MOHAN KUMARAMANGALAM MEDICAL COLLEGE, SALEM
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This is to certify that this dissertation entitled “A STUDY ON NEONATALb CANDIDA BLOOD STREAM INFECTION IN A TERTIARY CARE HOSPITAL” is a work done by DR.C. BHAVYA under my guidance. This has been submitted to the partial fulfillment of the award of M.D. Degree in Paediatrics (Branch VII) examination to be held in May 2021 by Tamilnadu Dr. M.G.R Medical University, Chennai – 32
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This is to certify that this dissertation “A STUDY ON NEONATAL CANDIDA BLOOD STREAM INFECTION IN A TERTIARY CARE HOSPITAL” in Government Mohan Kumaramangalam Medical College Hospital, Salem is a bonafide work done by DR.C. BHAVYA under the guidance and supervision of Professor and Head, Department of Paediatrics, Government Mohan Kumaramangalam Medical College Hospital, in partial fulfillment of the requirement for the degree of M.D. in Paediatrics, examination to be held in 2021.
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ACKNOWLEDGEMENT
I am extremely thankful to Prof. Dr. R. BALAJINATHAN MD, Dean, Govt.
Mohan Kumaramangalam Medical College and Hospital, Salem for allowing me to utilize the hospital facilities for doing this work. I am also thankful to Prof. Dr. P.V. DHANAPAL Medical Superintendent, Govt. Mohan Kumaramangalam Medical College Hospital, Salem for his whole hearted support and encouragement for the completion of this dissertation. I express my deep sense of gratitude and indebtedness to Prof. DR.P. SAMPATH KUMAR, MD, D.C.H., Head of the Department of Paediatrics and Prof. Dr.
K.S. KUMARAVEL, M.D., Guide for giving me inspiration, valuable guidance and his unstinting help in completing the course and preparing this dissertation. I also thank my Associate Professor.
DR. GOBINATHAN, MD, DCH. for his advice and kind help. I also thank my Assistant Professor Dr. D. SATHEESH KUMAR, MD who helped and guided me in many aspects of this study. I also thank my assistant professors who supported me for thesis work. I take this opportunity to thank all my Post Graduate colleagues and friends who helped me a lot in completing this dissertation successfully. I cordially thank my parents who have always been there with me whenever I needed their help and cooperation. I am deeply obliged to my patients, without whose help the present study would not have been possible.
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LIST OF CONTENTS
SL.NO TITLE PAGE
NO.
1. INTRODUCTION 1
2 REVIEW OF LITERATURE 29
3. AIMS AND OBJECTIVES 42
4. MATERIALS AND METHODS 42
5. OBSERVATIONS AND RESULTS 45
6. DISCUSSION 87
7. CONCLUSION 92
8. RECOMMENDATIONS 93
9. ANNEXURES
BIBLIOGRAPHY PROFORMA MASTER CHART
ABBREVIATIONS USED
NICU - Neonatal intensive care unit BSI – Blood stream infections
ELBW – Extremely low birth weight VLBW – Very low birth weight.
LBW – Low birth weight
NDI – Neurodevelopmental impairment.
TPN –Total parenteral Nutrition LOS – Late onset sepsis
UTI –Urinary tract infection CSF – Cerebrospinal fluid
PCR – Polymerase chain reaction NAC – Non Albicans candida FBP – Focal bowel perforation NEC- Necrotizing enterocolitis HCW –Health care worker VS - Versus
ABCD – Amphotericin B colloidal dispersion ABLC – Amphotericin B lipid complex.
MODS – Multiorgan dysfunction syndrome.
PPN – Partial parenteral Nutrition.
HCA – High chrome Agar.
ANC – Absolute Neutrophil count.
CVC – Central venous catheter IVH – Intra ventricular hemorrhage
ABSTRACT Introduction:
Candidemia or Candida Blood Stream Infection (BSI) is associated with medical advancements. Though the Advances in neonatal management have led to considerable improvement in new-born survival, there is a surge of Candida BSI.
Aim: The aim of the study is to describe the clinical profile of Candida BSI in neonates including the risk factors, symptoms and signs, outcome associated with Candida BSI. Also the study aimed to isolate the predominant organisms, and to study the antifungal sensitivity patterns.
Materials and Methods: This is a prospective descriptive study conducted in NICU of Government Mohan Kumaramangalam Medical College, Salem.
Study participants included neonates presented or developed signs of sepsis in NICU. All these neonates underwent septic workup, which included complete hemogram, C-reactive protein and blood culture. Neonates tested positive for fungal cultures were analysed and their Speciation of Candida was performed using germ tubetest, observation of morphology in corn-meal agar and pigment production in HiChrome Candida differential agar. Further antifungal sensitivity was done for Amphotericin and fluconazole using disc diffusion method.
Results:
The incidence of Candida BSI is 1.27%. C. Albicans accounted for about 45%
and Non Albicans candida (NAC) species were responsible for 55% of neonatal candidemia. Among Non Albicans candida species, Candida Tropicalis (48%) was the most predominant species followed by C. Glabrata (7%). Among the risk factor observed for candidemia were low birth weight (83%), prematurity (81%,), prolonged antibiotic use and ventilator support more than 7 days and total parentral nutrition. Mean duration of hospital stay among candida blood stream infected neonates was 18 days. More than half of the neonates had clinical features of lethargy, apnoea, temperature instability, feeding intolerance, shock, thrombocytopenia and hypo/ hyperglycemia. About 41.1%
of neonates expired. Antifungal sensitivity results revealed that most of the candida isolates were susceptible to fluconazole and Amphoterician B.
Conclusion: Candida BSI is an important morbidity in NICU with a high mortality rates. The increase in neonatal fungal BSI necessitates the need to review use of strict infection control strategies. The initiation of prophylactic antifungals in high risk neonates , early therapeutic use of antifungals in cultue positive fungimia and a restrictive antibiotic use helps in reducing the incidence and the morbidity, mortality associated with candidemia.
Keywords - candida BSI, Candida Tropicalis , prematurity , outcome.
1
INTRODUCTION
The infection caused by Candida species is called candidiasis. Candida is a yeast like fungus[1]. Candida is a ubiquitous fungus and is one of the major cause of increasing fungal infections in intensive care unit patient [2]. Candida species are commensal organism that colonize skin and mucosal surface and cause opportunistic infections ranging from superficial to invasive in immuno- compromised patients [3]. Candidiasis is the fourth most cause of nosocomial bloodstream infections in US with estimated mortality of about 50% [4,5,6].
Candida belongs to one of the large order family Saccharomycetales [7]. Candida is a fungal genus consists of about 20 pathogenic species. Among them Candida Albicans accounts for most Human infections but Candida Parapsilosus, Candida Tropicalis , Candida Krusei, Candida Lusitaniae, Candida Glabrata and several other species commonly isolated from children[8]. Regarding its morphology candida exists in three morphological forms oval to round blastospores or yeast cells (3 to 6mm) in diameter, chlamydospore which is double walled (7 to17mm) in diameter, which are usually at the terminal end of a pseudohypae and pseudomycelium which is a mass of pseudohypae and represent the tissue phase of candida[8,9].
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FIGURE -1 Different morphology of Candida. (Courtesy Thompson et al., 2011)
Candida is a genus of heterogenous fungus which shows both yeast and hyphae form. In general, members of this genus do not exhibit sexual life cycle
(10). Based on global epidemiological reports the important sub species of this genus are Candida Albicans and Candida Glabrata. Candida Albicans with other similar species belong to the family Saccharomycetales incertaesedis (11). C.Albicans is dimorphic in nature as it can exist in yeast and filamentous form, and another is C Dubliniensis, a close relative of C. Albicans. C.Glabrata is non-dimorphic yeast and exist in environment inform of oval shaped blastoconidia in commensal and pathogenic form while C.Albicans is polymorphic fungi that grow either as oval shaped, unicellular budding yeast or in filamentous form as elongated ellipsoid cell with constriction at the site of septations (pseudohyphae) or as parallel-walls true hyphae (12).The size of blastoconidia of C.Albicans ranges from 4-16 μm while that of C. Glabrata is much smaller and ranges from 1-4 μm. C. Albicans form white to cream colored, smooth, glabrous colonies on sabouraud dextrose agar while C.
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Glabrata forms glistening, smooth cream-colored colonies [13].On chrom agar medium, C.Glabrata gives pink to purple colour colony while C.Albicans form green to blue-green colored colony. C. Albicans grow in hyphal form in various micro-environments and also in response to several morphogenetic regulators like serum, GlcNAc, 5%CO2, etc(14) . And Glabrata
form pseudohyphae only on solid nitrogen starvation medium (SLAD) (15).
BIOFILM STRUCTURE
Biofilm is a microbiome of pathogen where they grow safely without interference of antifungal agents and ensure their existence in host. Biofilm is multicellular structure or cluster of surface-associated cells enclosed in extracellular matrix.The process of biofilm development is a very systematic process and occurs in an organized fashion involving early, intermediate, and maturation phases of development (16).The adherence of cell to surface is an early step towards biofilm formation, mediated either as non-specific hydrophobic and electrostatic interactions or by adhesin molecules. Further adhered cells grow horizontally to form basal layer which grow as hyphae in case of C. Albicans or pseudo-hyphae in case of C. Glabrata and forms the upper layer. Finally, multilayer structure will form after matrix secretion (17, 18). This biofilm forming ability helps this pathogen to resist the effect of antifungal and support their persistence or survival (18). In addition to living tissues, Candida cells have a propensity to adhere to various non-living, biological, indwelling devices like: intravenous catheter, dental implants, heart valves, artificial joints, etc.[19] In rich medium, C. Glabrata forms a less biofilm,
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whereas on silicon surface in the presence of urine, C.Glabrata forms highest biofilm as compared to other NAC species [20].
FIGURE 2 – Percutaneous intravenous central catheter and Fungal biofilm formation.
COMPOSITION OF BIOFILM
Depending on the environmental conditions like oxygen, media and ph, the Biofilm composition and structure varies in different species. The extracellular matrix (ECM) of C. Albicans consist of mainly proteins and glycoproteins (55%), carbohydrates (25%), lipids (15%) and nucleic acid (10%) while ECM of C. Glabrata is known to have high amount of
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Carbohydrates and proteins. Carbohydrates are mainly consisting of complex of α-1, 2-linked and α-1, 6-linked mannan to β-1,6-glucan [21,22,23].
VIRULENCE ATTRIBUTES
Virulence attributes are those factors which plays an important role in the Pathogenicity of an organism in the host. Following are the virulence attribute of Candida:
(A). Yeast to hyphae transition: The switching of C. Albicans between yeast and hyphal form is also known as dimorphism and is important for pathogenicity. Hyphal form is associated with invasion and yeast form with dissemination. C. Albicans undergo morphological transition in response to several environmental signals like CO2, presence of serum and N-acetyl glucosamine, physiological temperature, and also by quorum sensing molecules (farnesol, trosol, dodecanol). Candida cells unable to form hyphae showed attenuated virulence. Hyphal formation is organized with expression of following genes like HWP1 (hyphal wall protein), SAP4, 5, 6 (secreted aspartic proteases), ALS3 (agglutinin-like sequence) and also other hyphal associated genes e. g. HYR1, ECE1[24,25,26].
(b). Cell surface hydrophobicity (CSH): CSH is an important factor of C.Albicans which increases their adherence to biotic and abiotic surfaces. CSH also protects pathogen from attack of host neutrophils. In C.Albicans , CSH plays a major role in enhancing the cellular adherence upon host buccal epithelial cells (BEC) and acrylic surfaces. CSH is not an exclusive factor in
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adhesion of C.Albicans but it is an important factor in irreversible attachment of cells to the surface [27, 28]
(c). Adhesion: It is an important feature of Candida to adhere on biotic and abiotic surfaces. Adhesion is an initial step in the course of development of biofilm which is executed by specific cell wall components, adhesins. C.
Albicans have three gene families of adhesins namely ALS, HWP and HYR while in C.Glabrata , EPA and PWP are two gene families which encodes adhesins .These gene families encode GPI-anchored cell wall proteins.[29]
(d) Biofilm formation: Biofilm formation is the major virulence factor which create a safer environment for survival of pathogen and acts as reservoir of infection. Candida species has the virulence trait that helps in biofilm formation on both biotic and abiotic. It includes a complex and sequential process of attachment, proliferation, accumulation of Extracellular matrix and dispersion of yeast cells. The Candida biofilm is clinically having major concern because itis resistant to antifungals and host immune factors [30, 31].
(e) Hydrolytic enzymes: Hydrolytic Enzymes helps in Invasion and colonization of host tissue by Candida species. Colonization is facilitated by secretion of numerous hydrolytic enzymes like secreted lipases; phospholipases (LIPs) and aspartyl proteases (Saps) and hemolysins [32]. These enzymes also enhance the ability of nutrient acquisition from host tissue and deeper penetration into tissue of Candida. In C. Albicans, Aspartyl proteases enzymes consist of ten members whereas C.Glabrata only presence of Saps is known.
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Sap1-8 is released in surrounding environment whereas Sap9and Sap10 remains confined to cell surface. Phospholipases hydrolyze the phospholipid present in cell membrane of host to fatty acids. In C. Albicans, phospholipases have four classes namely A, B, C and D, among class B five of phospholipases (PLB1-5) are extracellular and have been shown to be contributing towards virulence [33,34,35]. Lipases are enzymes that hydrolyze triacylglycerol and ten members of lipases (LIP1-10). Candida species also secrete hemolysin which degrades hemoglobin for release of elemental iron.
Both C. Albicans and C. glabrata have the ability to produce hemolytic factor which mediate lysis of erythrocytes and facilitate release of hemoglobin [36]
(f) Antifungal resistance: Currently, resistance to available antifungals by various candida species is increasing. Some Candida species are inherently resistant to drugs while other acquiring resistance to drugs over time due to excessive or improper use of broads-spectrum antibiotics [37]. In C. Albicans, one of the mechanisms of antifungal resistance involves over-expression of CDR1, CDR2 and MDR1which increases efflux of antifungal drugs. Mutation in lanosterol 14α-demethylase encoded by ERG11 is also responsible for azole resistance because this mutation results in accumulation of 14α-methylated sterol and decreases ergosterol level.C. Glabrata is inherently resistant or less susceptible to azoles. Inherent azole resistance in C. Glabrata is also associated with upregulation of expression of ERG11 and over-expression of CDR1 andPDH1.Recent data has shown that C. Glabrata strains are showing resistance to echinocandins. These strains have acquired mutation in FKS1 or
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FKS2 genes which encodes enzyme that degrades the echinocandin. Biofilm contributes a lot towards drug resistance, yet the biofilm development is clinically unexploited for development of antifungals. The β-1,3 glucan is crucial element of extracellular matrix and have role in sequestration of the antifungal molecules, which is largely responsible for drug resistance trait of Candida biofilm. The diffusion of antifungal molecule into biofilm is more retarded in Candida. The level of sterol decreases significantly in mature and intermediate biofilm as compared to early phase biofilm and this is related to the primary cause of resistance of biofilm to widely used antifungals because these antifungal targets sterol in Candida [38,39,40,41].
Candidiasis is broadly classified into two categories: superficial and systemic. The superficial infections are mainly confined to mucosal surface, characterized by the white patches in the oral cavity and are commonly called thrush. Also the site of superficial infections include gastrointestinal epithelial cells, oro-pharyngeal and vaginal mucosa. In some case superficial infection leads to life threatening systemic infection, that mainly occurs in immune- compromised patients [42, 43].
During the past 20 years , the incidence of Invasive fungal infections have been increasing in preterm infants, particularly when hospitalized in a Neonatal Intensive Care Unit (NICU).Thus, for the last years, it was estimated that 6.3 million children under the age of 5 died each year and more than 40% of these deaths occur in the neonatal period [44] .Also many studies
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suggests particularly the neonates are at high risk due to fungal infections, mainly by yeasts of the genus Candida [45,46].
EPIDEMIOLOGY
The incidences of fungal infections have increased significantly, contributing to high level of mortality and morbidity. Candida infections are increasing alarmingly in India. The incidence of Candida infection from various reports available from all parts of country shows different epidemiology. In a tertiary care center in North India, a total of 4651 samples were studied, out of which 27(5.79%) were of Candida species, isolated.
From ICU patients, the most common isolated was candida species namely C. Tropicalis (40.8%) followed by C.Albicans (29.6%), C. Glabrata (18.5%) and others (11.1%). Antifungal susceptibility testing of the isolates revealed a lower level of drug resistance to amphotericin B (18.5% of the isolates) versus 77.8% resistance to fluconazole [47]. Many studies observed the emergence of Non-Albicans Candida species in neonates with candidemia in recent years. [48, 49].
The third most common cause of blood stream infection in premature infants are candida infection. Its incidence was about <0.3% in Neonates with birth weight >2.5 kg. And 8% in Neonates with birth weight less than 750grams [8]. Incidence in ELBW babies vary from 2-20% . [50,51,52] Candidemia leads to significant mortality of 25-40% and 73% of end organ damage involving all organ tissues. Invasive candidiasis usually manifests as late-onset sepsis in newborns and is associated with increased mortality and increase
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Neuro-developmental impairment among survivors [53]. The Major risk factors that predict mortality in Candidemia include Birth weight and Gestational age.
Mortality rate higher in neonates with candida blood stream infection than compared to uninfected neonates [54]. Prompt diagnosis and early initiation of antifungal treatment is necessary to reduce the higher mortality rate and to reduce the risk of NDI. Initiation of Empirical antifungal therapy reduces the disseminated infection and reduce mortality [55]. In Recent times, Non-Albicans Candida were emerged as important opportunistic pathogen. The Non Candida Albicans species include C.Tropicalis, C. Parapsilosis, C.Glabrata and many others.[48,49,56]. Use of antifungal agents may pose a vital role in this epidemiological shift. It was also known that Non Candida Albicans species have shown resistance to antifungal agents like fluconazole (FLK) and also to newer triazoles.[57]
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RISK FACTORS
FIGURE 3 - Risk Factors for Candidemia. PICC – peripherally inserted central catheter.
Neonates particularly represent a highly vulnerable patient population.
Immaturity of immunological functions and altered cutaneous barriers play some role in increasing the vulnerability of neonates to infections [58]. Vertical transmission from maternal flora and also horizontal transmission from hands of healthcare workers (HCW) can lead to candida infections [59,60]. The potential risk factors for candidemia include Low birth weight and prematurity. [61,62,63,64] Number of factors that contribute to invasive fungal infections are low birth weight(LBW), prematurity, use of indwelling devices,
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on prolonged parenteral nutrition, use of broad spectrum antibiotics, any gastrointestinal surgery, prolonged invasive ventilation. Especially very low birth weight babies and extremely low birth weight preterms and critically ill neonates are at higher risk of acquiring invasive Candida Infections. Studies also shown that Broad spectrum antibiotics will contribute to Candida growth in neonates. The risk of Candida BSI increases to multiple times with more antibiotic usage. In many studies the use of third generation Cephalosporin was considered to be an important risk factor. Various studies have identified Mechanical ventilation and Ionotrope use also contributes to the risk factors for invasive candidiasis in term infants. It is also found that gastrointestinal pathology like NEC, gastrochisis, omphalocele, intestinal atresia, Hirschprung’s disease, intestinal perforation, CDH in infants impose a potential risk factors for invasive candidiasis.[ 65,66,67,68]
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PATHOGENESIS
FIGURE 4 – Pathogenesis of invasive fungal infection.
The pathological process of fungal infections in infants include adherence, colonization and dissemination. Candida colonize and disseminate into the bloodstream and body tissues through the process called adherence. Its slow growing nature also helps in dissemination before signs and symptoms occur.
Surface glycoproteins helps in fungal adherence. It is found that Antibiotics treatment also led to increased candida colonization. Also steroid is added to antibiotics, it presumably amplify the inherent immune incompetence state leading to more colonization and dissemination of filamentous fungi. Candida Albicans is dimorphic and its filamentous form has increased virulence in host.
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In preterm Infants colonization of the skin, mucosal membranes and central venous catheters occurs through both vertical and horizontal transmission.
Patient factors such as gestational age, low birth weight, Invasive ventilation, central vascular access, on prolonged parenteral nutrition, GI diseases and abdominal surgery can contribute to fungal infection after its exposure. Also Fungal factors which contribute to infection include the size of inoculums.
Candia infection may lead to dissemination of many organ tissues causing end organ damage [69].
CANDIDA SPECIES
Neonates can be infected by any candida species. The most frequently isolated yeast species in infected neonates was candida Albicans followed by Non candida Albicans. Recent years have shown that Non-Albicans species becoming the emerging pathogen than C.Albicans.[55,56,70].
CANDIDA INFECTIONS
Congenital cutaneous candidiasis:
It is manifested immediately or few days after birth by pustules, vesicles, or an erythematous maculopapular rash. Scalp, face, trunk, perineal areas were most commonly affected. Occasionally these lesions cause desquamation. The treatment includes administration of systemic antifungals for period of 14 days. In term, treatment should be continued for 7 to 14 days.
Dissemination to other organs occur in both term and preterm neonates.
Although 20-25% of all pregnant women develop candida vulvo vaginitis, but only a small number of infants born to infected women develop
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congenital candidiasis. It is to be differentiated from staphylococcal infections, herpes simplex infection, erythema toxicum neonatorum, syphilis, transient neonatal pustular melanosis, drug eruptions and langerhan cell histiocytosis.
Congenital cutaneous candidiasis needs to be differentiated from cutaneous candidiasis which usually present after first week of life as oral thrush or diaper dermatitis [71]
FIGURE- 5 Congenital cutaneous candidiasis.
This condition is diagnosed by demonstration of budding yeast cells and pseudo hyphae on potassium hydroxide examination. Neonates with disseminated infection may have positive blood culture, urine and CSF cultures. The course of the disease is benign in full term infants. Topical antifungal is the treatment of choice. Systemic antifungals are indicated in disseminated infections. The first line treatment for systemic disease is Amphotericin B (0.5-1 mg/kg/day). Fluconazole (6-12 mg/kg/day) can be used
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as an alternative therapy if there is resistance or toxicity to amphotericin B develops. [71,72]
MUCOCUTANEOUS CANDIDIASIS
This usually characterized by an erythematous papulo pustular rash in neonates. ELBW infants with candida dermatitis are more prone to develop bloodstream dissemination. The treatment of mucocutaneous candidiasis include systemic antifungal therapy for a period of 14 days to prevent bloodstream dissemination. [73]
BLOODSREAM INFECTION
Candida bloodstream infection has similar clinical signs and symptoms as that of bacterial sepsis. The incidence of candidemia reported 2 to 6.8% among VLBW infantsand ranges from 4 to 16% among ELBW infants
[74,75].It was also found that the candida BSI incidence increases with decreasing gestational age.[76].Most of the candidemia often complicated by disseminated disease. So this necessitates for evaluvation of other systems like cardiac, renal, ophthalmologic and central nervous systems.
URINARY TRACT INFECTION:
Candida causing urinary tract infection is more common in neonates.
The screening for late onset sepsis should include a urine culture. The urine sample should be collected by sterile catheterization or by suprapubic bladder aspiration. And if the urine culture shows fungal growth, renal ultra- sonography should be done to detect fungus in the collecting system. Candida
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UTI is seen in 2.4% of Very low birth weight infants and in Neonates with birth weight less than 1000grams its incidence is up to 6%. Studies have shown mortality rate in infants with candida UTI is (26%) as compared to candida BSIs which is (28%) in ELBWs [77].
MENINGITIS:
Systemic candidiasis can be complicated by candida meningitis in premature neonate. A 10-year retrospective review of cases of systemic candidiasis in neonates has shown candida meningitis in 0.4% of admissions to the neonatal intensive care unit. In the study, the median gestational age was 26.2 weeks, the median birth weight was 820 g, and the median age at the onset of illness was 8 days. The Clinical severity of disease was commonly manifested by respiratory decompensation. Findings of cerebrospinal fluid (CSF) analyses showed varied findings: pleocytosis was inconsistent, hypoglycorrhachia was common, gram staining was uniformly negative and Candida was isolated from 17 neonates (74%) [78].
DISSEMINATED INFECTION:
Disseminated candida infection may present with several entities in neonates. These infections should be treated for longer period of 4 to 6weeks or longer until resolution. Endocarditis has been observed in 5-15% of candidemia cases. Whereas in 5% of patients with candidemia reported renal abscess. Fungal meningitis leading to brain abscess is reported in 4% of patients with candidemia [79]. Neonates with candidemia may suffer from
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Endophthalmitis. Candida endophthalmitis manifest as single or multiple, white raised or yellowish white raised lesion located in the posterior fundus or vitreous. It may be unilateral or bilateral eye involvement [80]. Liver abscess can occur in about 3% of patients with candidemia and Liver ultrasonography is recommended in neonates with persistent candidemia. Also Splenic ultrasonography to be performed in candidemia neonates if Splenomegaly occurs or with persistent candidemia. Candida spp. peritonitis typically occurs as a complication of bowel perforation. A study conducted by Coates et al has shown candida species in 44% and 15% of focal intestinal perforation and NEC cases, respectively [81].
CLINICAL FEATURES:
The classical clinical features of candidiasis BSI in neonates is
Similar to that of bacterial sepsis. The symptoms of candidemia include lethargy, hypotonia , Gastrointestinal aspirate, distention, bloody stools 30%, hypotension (15%), hyperglycemia (13%), increase in oxygen requirement (56%), increase in assisted ventilation (52%). Whereas signs of candidemia include leucocytosis, metabolic acidosis, thrombocytopenia with count less than 1 lakh (84%), immature to total neutrophil ratio of 0.2 or higher (77%), absolute neutrophil count less than <1500[82]. Thrombocytopenia is present in most cases of fungal sepsis.[83]
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DIAGNOSIS:
The investigation of fungal infections in newborns includes the blood culture, urine culture and cerebrospinal fluid (CSF) cultures. The blood culture is the gold standard for detection of candidiasis, although its sensitivity seems poor [84]. The small blood volume used for culture in infants makes isolation of Candida species in blood more difficult. Because it was found that four or more vital organs are typically involved even prior to documentation of candidemia. Any positive blood culture for Candida should almost never be considered as a contaminant and should be regarded as the infection. Even when blood culture is able to diagnose Candida, the time to detect the organism can be problematic - because the median time for detection of Candida species from blood culture in infants is 36 hours and increases to 42hours when the infant is receiving antifungal therapy [85]. Three or more Negative blood culture results indicate the clearance of candidemia BSI and each negative culture result must be taken at least 24 hours apart. It is difficult to diagnose candida meningitis as only 37% of infants with proven candidial meningitis also had positive blood cultures for Candida. In addition, cerebrospinal fluid (CSF) parameters appear normal in almost half of infants with candida meningitis [86].
The limitations of culture for the diagnosis of Candida infections, paved way for laboratory investigators to explore other methods.1,3-β-D-glucan is a fungal cell wall component that has been used to diagnose a variety of fungal infections, including Candida. Levels of this polysaccharide component can be detected spectro photometrically [87]. The Candida DNA in blood and serum
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samples can be detected using polymerase chain reaction. This method has promising results based on several small studies, with sensitivity to detect fungal disease equal to or higher than blood culture [88]. Enzyme and PCR assays still remain experimental methods and these tests have not been validated in infants, and further studies are needed to evaluate their usefulness in diagnosis. The laboratory investigation to be obtained on presentation Include complete hemogram with platelet count, liver Function tests, Renal function test include serum urea, serum creatinine levels should be measured.
Thrombocytopenia is extremely common finding in candidemia.
Liver and renal function test should be done at the time of diagnosis so that helps in identifying liver or renal dissemination at the earliest and the further need for ultrasonography. Close monitoring of serum electrolytes and the hematologic, hepatic, and renal parameters should be done during antifungal treatment.
The fungemia lasting more than 5 days were associated with increased dissemination [88]. Hence ,Echocardiography, Renal ultrasonography, cranial USG, indirect ophthalmoscopy, should be done to rule out any fungal dissemination. In Neonates with persistent candidemia, central catheters should be removed as early as possible. Central catheters should be removed immediately once the bloodstream infection is diagnosed. Persistent candidemia of longer than 5 days, should undergo further investigations like Echocardiography, renal and cranial ultrasonography, abdomen
21
ultrasonography to rule out any dissemination. Also Lumbar puncture is done if CNS involvement is suspected and Bone scan done if warranted.
Newer diagnostic technique like polymerase chain reaction and fungal markers like beta-glucan can help in the diagnosis of fungal infection and also its treatment response after antifungals. PCR is useful in detecting fungal infections in all body fluids even when standard fungal cultures show negative results. Beta-glucan can assess the treatment response to antifungal therapy.
Usually Beta-glucan levels drops over time with therapy. [89]
22 TREATMENT OF CANDIDA BSI
ANTIFUNGAL DRUGS
FIGURE 6 Mechanism of action of Antifungal therapy.
23
AMPHOTERICIN
Amphotericin B deoxycholate remains the first line antifungal medication for invasive fungal infection. This Mechanism of action include binding to the ergosterol layer of the cell membrane, leading to cell death by creating a pore in the cell membrane. Amphotericin can be started with a dose of 1 mg/kg/d [90].Test dose usually not required. Inappropriate antifungal dosing may cause poor treatment response in infants with candidemia. It should be given over 2 to 6 hours through intravenous route. Parenteral nutrition can be stopped while administering Amphotericin. Liposomal amphotericin, amphotericin B colloidal dispersion, and amphotericin B lipid complex are the lipid formulations of Amphotericin [91,92]. Candidemia neonates with urinary tract infection or renal abscess are treated with Amphotericin B deoxycholate as the drug has higher renal penetration.
AZOLES
Fluconazole, act by preventing the synthesis of ergosterol,a cell membrane component by inhibiting the enzyme C-14 lanosterol demethylase.
The drug has similar efficacy to amphotericin B deoxycholate. The tissue penetration by the fluconazole is quite higher. New studies suggest a dose of 12 mg/kg/day. Fluconazole is available as both oral and parenteral drug. The bioavailability of oral drug is similar to that of parenteral drug [ 93].
Antifungal sensitivity should be done prior administration as resistance to fluconazole can occur. The drug has potential interactions with cisapride,
24
cotrimoxazole, phenytoin or macrolides hence close monitoring is necessary when these drugs are given together.
Voriconazole is an azole with a broader spectrum of antifungal activity.
Voriconazole is 58% protein bound and it contains acyclodextrin carrier. The drug is excreted by the kidney. So it is used with caution in infants with renal insufficiency. Voriconazole administration is considered only in patients with aspergillosis. Its use in neonates with candidemia should be evaluvated further
[94].
ECHINOCANDINS
A new class of antifungals is the echinocandins, its mechanism of action is by inhibiting 1,3-beta-glucan synthesis . Caspofungin is give at a dose of 2.5mg/kg and it is found effective in treating persistent candidemia.
Micafungin can be given at a dose of 10 mg. [95]
CENTRAL CATHETER REMOVAL WITH CANDIDA BSI
Following the first positive culture for fungal infection, central catheter should be removed immediately to prevent further dissemination and complication. Early removal of catheter, with first positive blood culture results, is associated with reduced mortality rates and decreased end-organ dissemination, also associated with improved neuro-developmental outcomes
[53, 67].
25
EMPIRIC TREATMENT
Various studies suggested that starting empiric antifungal therapy may decrease the mortality rate and improve the outcome in VLBW infants with candidemia [55, 85]. The isolation of fungal species from cultures can be obtained within 48 hours [85]. Therefore, some experts recommend prompt initiation of antifungal treatment following the culture results. Also suggested early removal of any central venous catheters upon positive culture results. Empiric antifungal therapy may be administered in infants with negative blood culture results but still showing the signs and symptoms of sepsis. In addition, the infants may have any one of the following criteria:
Platelet count less than 1 lakh
Necrotizing Enterocolitis
Gestational age of less than 26 weeks or Weight of less than 750 g
PROPHYLAXIS
The high mortality rate and poor neuro-developmental outcome in VLBW infants associated with fungal sepsis can be prevented by administration of prophylactic antifungals in the highest-risk patients.
Fluconazole found to be an effective drug for prophylaxis. Fluconazole has high tissue concentration. The intravenous fluconazole prophylaxis can be initiated in high-risk infants like Extreme preterm less than 28 weeks and had an endo-tracheal tube or central vascular catheter,on prolonged antibiotic
26
therapy in order to prevent invasive candida infection [51,96]. Researchers also studied prophylaxis of 3 mg/kg of intravenous fluconazole every 72 hours on days 1-14 and every 2 days on days 15-28, and also daily administration on 29- 42 days totally for a period of 6 weeks has shown similar efficacy as that of dosing with 3 mg/kg twice a week [96]. If fluconazole is administered for antifungal prophylaxis, then the primary treatment of an invasive fungal infection should be treated using an alternative antifungal agent (eg, amphotericin B). This decreases the risk of antifungal resistance. Following the completion of fluconazole prophylaxis, surveillance cultures for fungal resistance are recommended.
ANTIFUNGAL PROPHYLAXIS IN HIGH RISK POPULATION
The neonates with neuro-developmental impairment and with significant mortality, and neonates with risk factors for fungal infection were considered to be high risk. Many Candida studies in neonates have consistently shown increased mortality and neuro-developmental sequelae in preterm infants with the birth weight less than 1000 grams. Prophylaxis if initiated in the first days of life in high risk patients possibly will reduce the incidence of candidemia[97]. Gestational age less than 28 weeks and neonates with the presence of risk factors for candida can be benefitted by antifungal prophylaxis [76, 98]
The AAP recommends prophylaxis in [1] Infants with a birth weight of less than 1000 grams [2] Preterm and full-term infants with GI disease, such as Necrotizing enterocolitis, focal bowel perforation ,etc , delayed enteral feedings
27
for >7 days, on prolonged invasive ventilation. The dosage of fluconazole prophylaxis given is 3 mg/kg twice weekly. Patients with documented fungal infection who receive prophylaxis with fluconazole, amphotericin B should be administered as the initial antifungal therapy for further treatment.[96,99,100].
MORBIDITY AND MORTALITY IN CANDIDA SEPSIS
Neonates with Candidemia is associated with higher morbidity and with significant Neuro developmental impairment than the neonates not affected.
The infants with fungal sepsis who weigh less than 1000 grams suffer from significant morbidity and with significant Neuro developmental impairment.
The adverse neuro-developmental outcomes in infants with fungal sepsis include psychomotor impairment, cerebral palsy, visual impairment and hearing impairment [53].
MORTALITY
In multicentric studies, candidemia is associated with a mortality rate of 21-32% in very low birth weight infants [50,52,54]. Gestational age less than 26 weeks' and ELBW babies were associated with increased mortality. Some centers have shown high Mortality rates of about 40 t0 50% and several other studies have reported no mortality thus survival of affected neonates depends on intensive care management of affected neonates and also other factors.
28
FOLLOW UP
Neuro-developmental follow-up should be done in all Preterms with
Candidemia in the first few years of life and to receive early intervention services, if needed.
29
REVIEW OF LITERATURE
1. A study conducted by ASIFANAZIR et al, dept of microbiology, Srinagar, India found that candida isolation rate was about 18.86%
among neonatal sepsis cases. The most common candida species isolated in this study is Candida tropicalis (13.8%) among the Non- Albicans Candida. The study also revealed both C.Albicans and Non Albicans candida shows increase in antifungal drug to Azole group of drugs. The study also noted sensitivity to other drugs like micafungin, and caspofungin. The present study highlights the mycological shift towards Non-Albicans Candida species in recent times[49].
2. A prospective study conducted by DANIEL K BENJAMIN et al regarding neonatal candidiasis among ELBW Showed the candidemia incidence rate was about 7%. The study also observed birth weight, cephalosporins, gender, and lack of enteral feeding were associated with development of candidiasis. It is also found 73% of extremely low birth weight infants with candidiasis had shown significant mortality and impaired Neurodevelopmental outcome. Study also suggested that early removal or change of catheter is associated with decreased mortality and NDI [53]
3. SHILPA PUTTA et al studied invasive candida outbreak in a NICU, R.C.M.S. Govt medical college, Maharashtra found that candidemia incidence in current outbreak was 7.71%. The most common species involved was C.Glabrata in 43(81.13%) followed by C.Tropicalis
30
10(18.87%).The study also analyzed the environmental samples and among environmental samples candida species were isolated from in use Total Parenteral Nutrition (TPN) and Dextrose solution used in NICU. The study also identified different possible factors associated with outbreaks were increased use of intra medical devices, colonization of animate and inanimate objects, cross-infection via the hands of health care workers or total parenteral nutrition solutions that may be contaminated during preparation or intravenous administration. The study also suggested strict aseptic precautions during IV set preparation and strict adherence to hand hygiene practice before and after administration of fluid [60].
4. KUMARAVEL K S, ANUREKHA V et al, conducted a retrospective study in NICU, dept of paediatrics in Govt Mohan Kumaramangalam medical college, salem from jan2017 to march 2018 and found that the incidence of Candida BSI is 1.43%. About 86% of the neonates weighed less than 2.5kgs and 84% were preterm. It is also found that the risk of Candida BSI increase with more use of antibiotic usage. The study also observed the clinical features of lethargy, apnea, temperature instability, abdominal distention, feeding intolerance, shock, thrombocytopenia and hypo/hyperglycemia in candidemia group. Also the study observed the Mortality rate was about 39% [61].
5. In 2017 NEERUL PANDITA et al observed that Fungal sepsis accounted for about 13.6% of cases in his study. The study also stated
31
that Non Albicans candida (NAC)species were responsible for 88% of cases with Candida Glabrata (54%) as the most predominant species.
Antifungal sensitivity results revealed that most of the Non Albicans Candida isolates especially candida Glabrata, were resistant to flucanazole, than Candida Albicans. Amphoterician B had greater sensitivity than fluconozole over NAC species. The risk factors observed for candidemia in the present study include low birth weight (62%), prematurity (60%,), broad spectrum antibiotic use (60%), ventilator support (56%) and total parenteral nutrition (50%). The initiation of prophylactic antifungals in high risk neonates, early therapeutic use of antifungals in culture positive fungemia and a restrictive antibiotic use helps in reducing the incidence and the morbidity, mortality associated with candidemia [63].
6. In India, study conducted by SRIPARNA BASU et al 2017 in dept of paediatric Banaras university, observed that incidence of Candida BSI was 0.9% among total deliveries and 3.6% of total admissions. C.
Tropicalis was the common Candida species isolated, followed by C.
Albicans and C. Parapsilosis . Susceptibility for fluconazole and amphotericin B was 86.6% and 68.3% It was also found that Central line
>7 days and hospital stay >28 days were independent risk factors for Non Albicans candida infection. C. parapsilosis and C. Tropicalis demonstrated higher resistance to fluconazole and amphotericin B [64].
32
7. A prospective study conducted by AGARWAL et al observed candida isolation rate was about 13.6%. Majority of species isolated were Non- Albicans Candida. Low birth weight was found in 73.3%. Crude mortality was about 52.6% the study also emphasized that Non Albicans Candida are emerging as important pathogens for neonatal septicaemia
[101].
8. R RANI et al studied the changing trends of candida species in neonatal septicaemia found that candida isolation rate was about 11% among neonatal septicaemia. C. Tropicalis was the most predominant species isolated. The study also suggested that wide use of broad spectrum antibiotics, loss of mucosal immunity, colonization, umbilical vessel catheterization, prolonged length of hospital stay and very importantly low birth weight plays a potential risk factor for neonatal candidemia [102].
9. A study conducted by DINA M HASSAN et al, dept of paediatrics and neonatology, Cairo university, Egypt 2018 stated that Out of 214 neonates with BSI, candidemia afflicted 32 neonates (15%). The predominant isolate was C. Tropicalis (43.8%), followed by C.
Albicans (25%). The study also revealed that antibiotic use and antifungal prophylaxis were contributing factors (P values of 0.02 and <
0.01, respectively). Susceptibility testing revealed that 87.5% of the retrieved Candida isolates were sensitive to amphotericin B, 81.25% to fluconazole, 75% to voriconazole, and 62.5% to itraconazole while 48.75% were sensitive to caspofungin. The study also explained the
33
worldwide progressive shift towards Non-Albicans candidemia which necessitates regular surveillance. On the other hand, the study showed neonates subjected to invasive ventilation, prolonged venous catheterization, TPN, prolonged antibiotic use, very low birth weight, and prematurity were significant risk factors for candida blood stream infection [103].
10. In a study conducted by M.S. SRINIVASAN ROA et al, dept of microbiology Apollo institute of medical science and research, Hyderabad 2014 had showed that Non Albicans candida was the common isolate & they showed decreased resistance to Fluconazole. The study had isolation rate of about 20.39% of all neonatal septicemia cases over a period of one year. C.Tropicalis was the most common organism isolated followed by C.Albicans. The study also revealed the potential risk factors for candidemia was prolonged antibiotic, low birth weight, prematurity prolonged central venous access, prolonged ventilator support, corticosteroid therapy [104]
11. GIUSEPPINA CAGGIANO et al, dept of Neonatalogy and Biomedical science studied the incidence of candidemia was 3.0 per 100 NICU admissions (range, 2.2–3.0). Male and female ratio was about 1.6: 1. The candidemia incidence in very low birth weight infants (56.1%). The study demonstrated Neonates with candidemia had prolonged hospital stay with a mean of about 8 to 14 days. All Candida infections were classified as LOS. Candida parapsilosis was the common species isolated
34
with the highest frequency (58.5%), followed by C.albicans, C.glabrata and others. The study also revealed that prematurity less than 32 wks, low birth weight, prolonged mechanical ventilation, prolonged antibiotic therapy, prolonged central venous lines, are the potential risk factor for candidemia [105].
12. A prospective observational study conducted by Dr. SURESH KUMAR CHAVHAN et al, SMS Medical college, Jaipur showed that candida isolation rate was about 20 (11.97%) among 167 NICU patients. Candida Albicans (35%) was the most common species isolated followed by Candida Parapsilosis, Candida Tropicalis , and others. It was also found that there is increased resistance to fluconozole among candida isolate.
The study also suggested increased incidences of candidemia along with emergence of Non-Albicans Candida species are become an important healthcare issue worldwide. Therefore, the early and accurate identification of Candida species along with susceptibility testing is very important [106].
13. ELIZABETH CAPARO INGRAM studied Candida parapsilosis had the highest associated lethality rate in neonates. The study also suggested Prolonged intra-hospital stay longer than seven days and thoracic and/or abdominal surgery were the most significant risk factors in this study for the development of neonatal candidemia [107].
14. S KUMAR et al 2011, in his present study observed candida isolation rate was about 14.9% among neonatal sepsis. Candida Albicans was
35
predominant isolate (66.3%), followed by Candida Glabrata (19.69%), Candida Parapsilosis (10.66%) and Candida Tropicalis (6.06%). The study also observed Persistent pneumonia (45.45%), failure to thrive (100%), lethargy (100%), and tachycardia (100%) were common clinical manifestations. The study highlights the underlying predisposing factors were antibiotic therapy, low birth weight, respiratory distress syndrome and mechanical ventilation. Candida Albicans was predominant isolate (66.3%), followed by Candida Glabrata (19.69%), Candida Parapsilosis (10.66%) and Candida Tropicalis (6.06%). The study suggested Candida Albicans is still the commonest cause of neonatal septicemia and Candida Glabrata is an emerging pathogen .[108]
15. Dr. RANJIT SINGH, dept of paediatrics ,Govt medical college, Amritsar conducted a study in NICU showing that Incidence of Candida infection was 42.30% for <1000g , 23.07% for 1001 - 1500g and 28.57% in overall population. The study also found oral thrush, poor perfusion, hypotension, abdominal distension, tachycardia and temperature instability as clinical manifestations of Candidiasis. The study also revealed Non-Albicans Candida species (61%) were predominant out of which 48% were Candida followed by Candida Albicans (39%). Most of the Candida species were sensitive to Amphotericin B (95%), Itraconazole (95%) and Voriconazole (95%) followed by Nystatin (82%), Fluconazole (74%). The study stated that Mortality related to Candida infection was 23%. The study suggested a
36
restrictive policy of antibiotic use, avoiding indiscriminate use of antifungal drugs and minimum possible duration of invasive procedures and IV fluids to reduce Candida infection rates [109].
16. A retrospective study conducted by DEEPAK JUYAL et al 2014 showed that Candida species manifests as late onset sepsis in intensive care unit (NICU). C. Parapsilosis was the most common species isolated in his study. The common clinical features observed in the study were abdominal distention,feeding intolerence. The potential risk factors were broad spectrum antibiotics (81.40%), TPN (79.07%) and usage of indwelling catheters (79.07%). Also additional risk factors include prematurity (72.09%) and low birth weight (65.12%). The study described early mortality accounted for 20.93%, whereas late mortality accounted for 11.63% [110].
17. A case control study done by MINGYUE LIEU China 2015 studied the imoortant risk factors for candidemia were prolonged application of antibiotics,secondary gastrointestinal surgery. In addition, maternal vaginal candidiasis pose arisk factor for candidemia in neonates . Incidence of shock, gastrointestinal and pulmonary hemorrhage and MODS are higher in neonatal candida BSI [111].
18. A prospective study conducted by BASHIR AHMED CHAROO in NICU, Srinagar, India, observed candida isolation rate of about 2% of total admissions and 11.6% of total VLBW and ELBW admissions.
C.Albicans was the most commonly isolated species in the
37
study followed by C. tropicalis, C. parapsilosis, and C. krusei the study also described the clinical spectrum of candidemia as worsening of respiratory distress (64%), shock (46.4%), DIC (31%), and NEC in addition the study suggested nearly 7.8% had cerebrospinal fluid culture positive for Candida. The mortality rate in the study group was about 55%. End-organ damage was noticed in 14% of patients. It was also found thatthrombocytopenia was the most common laboratory finding in babies with candidemia and was seen in 89% of patients. Hence the study had suggested thrombocytopenia can be taken as a surrogate marker for invasive fungal sepsis in high-risk low-birth weight population [112]
19. JICHENG CHEN et al observed the incidence rate of candidemia was about 13.6 per 1000 admissions. The study also suggested prolonged duration of antibiotic therapy, presence of total parenteral nutrition and neuro-developmental impairment were the major risk factors associated with neonatal candidemia. This study highlights the importance of the early detection, diagnosis and treatment of neonatal candidemia. The overall mortality rate was 7.2% in the candidemia group [113].
20. KAVITHA BANSIWAL 2016 studied Candidemia was 11.1% in neonates of NICU. Candida Albicans was the most common species causing colonization and candidemia. All candida species were susceptible to all antifungal agents except Candida krusei & Candida glabrata which were highly resistant to Fluconazole. I.V. antibiotics, preterm neonates, low birth weight, RDS, Ventilation therapy and prior
38
Candida colonization were identified as significant risk factors. The study also suggested Candida Parapsilosis is an emerging fungal pathogen and incidence of infection caused by it may continue to rise
[114].
21. LATHA G.S. et al in her present study showed the incidence of candidiasis in neonates revealed 13.8% of babies admitted in NICU.
Male babies outnumbered the female babies in incidence of candidiasis in neonates. Males formed 69% and females 31% of positive cases. The study also found most of neonates admitted in NICU were low birth weight between 1.5kg to 2.5 kg. The present study revealed that low birth weight, birth asphyxia and mechanical ventilation were significant risk factors for candidiasis in neonates. Blood cultures were positive in babies without mucosal lesions suggesting the importance of diagnosing fungal sepsis [115].
39
SUMMARY OF REVIEW OF LITERATURE NOSL. AUTHOUR
SAMPLE SIZE
INCIDEN
CE MORTAL
ITY COMMENTS
1 AsifaNazir
et al 424 18.86% a
mong neonatal sepsis
- 1.Predominant species – C. Tropicalis.
2. This study highlights the mycological shift from Albicans to NAC.
2 Daniel K Benjamin et al
178 7.7%
Among ELBW
40% 1. Risk factors for candidemia – low birth weight, cephalosporins, gender, and lack of enteral feeding.
2.Most of extremely low birth weight infants who developed candidiasis have significant mortality and higher NDI.
3 Shilpaputta
et al 687 7.7% - 1. Increased use of intramedical devices, colonization of animate and inanimate objects, and cross-infection via the hands of HCW results in outbreak.
2. C.Glabrata most common isolated subspecies.
4 Kumaravel
et al 51 1.43% 39% 1.Risk factors – LBW, Preterm,
Prolonged use of antibiotics, mechanical ventilation.
2. Clinical features in candidemia include lethargy, apnoea, temperature instability, feeding intolerance, shock, thrombocytopenia and hypo or hyperglycemia.
5 Nerulpandita
et al 360 13.6% - 1. NAC was resistant to fluconazole than Candida albicans. Amphoterician B had greater sensitivity than fluconozole over NAC species
2. Risk factors observed for candidemia were low birth weight (62%), prematurity (60 %,), broad spectrum antibiotic use (60%), ventilater support (56%) and total parentral nutrition (50%).
40
6 Sriparna Basu
et al 3128 3.6% 17% 1. Common species isolated – C.Tropicalis.
2. Central line >7 days and hospital stay >28 days were independent risk factors for Non Albicans candida infection.
7 Agarwal et al 660 13.6% 52.6% 1. Non albicans Candida are emerging as important pathogens for neonatal septicaemia.
8 Rani et al 454 11.1% - 1. Most predominant species isolated – C.Tropicalis.
2. Risk factors - wide use of broad spectrum antibiotics, loss of mucosal immunity, colonization, umbilical vessel catheterization, prolonged length of hospital stay and LBW.
9 Dina
M Hassan et al
214 15% 56.2% 1.The study explained the worldwide progressive shift towards NAC which necessitates regular surveillance
10 Srinivasan
roa et al 255 20.39% - 1. Most common isolate – C. Tropicalis.
2. Corticosteroid therapy as a risk factor for candidiasis.
11 Giuseppina Caggiana et al
41 3% 30% 1. Candida Parapsilosis was the common species isolated followed by C.Albicans .
12 Dr.suresh kumar
chavhan et al
167 11.97% - 1.Candida Albicans was the most common isolate followed by Candida Parapsilosis, Candida Tropicalis.
13 Elizabeth caparoingram et al
836 31.5% 62% 1. Prolonged intrahospital stay longer than seven days and thoracic and/or abdominal surgery were the most significant risk factors for the development of neonatal candidemia.
14 S Kumar et al 442 14.9% 1.5% 1. C.Albicans most commonly isolated.
2. The study also observed Persistent pneumonia (45.45%), failure to thrive (100%), lethargy (100%), and tachycardia (100%) were common clinical manifestations.
41
15 RanjithSighn
et al 131 28.5% 23% 1. The study suggested a restrictive policy of antibiotic use, avoiding indiscriminate use of antifungal drugs and minimum possible duration of invasive procedures and IV fluids to reduce Candida infection rates.
16 Deepak Juyal
et al 163 Early
Mortality- 20.93%.
late mortality- 11.63%
1. C. Parapsilosis was the most common species isolated.
2. The study also revealed Failure to thrive , abdominal distention , and feed intolerance were the most common clinical presentations of Candidemia.
17 Mingyue lieu
et al 40 26 % 1. Prolonged antibiotic usageand secondary gastrointestinal surgery appeared are potential risk factor for candidemia.
2. Maternal vaginal candidiasis also lead to neonatal candida infection.
3. Incidence of shock, gastrointestinal and pulmonary hemorrhage and MODS is more with candida infection.
18 Basheer Ahmed Charoo et al
304 11.6% 55% 1. End-organ damage was noticed in 14% of patients.
2. The Study suggested thrombocytopenia can be taken as a surrogate marker for invasive fungal sepsis in high-risk low-birth weight population.
19. Jichang cheu
et al 69 13.6/1000
Admission. 7.2% 1. Neurodevelopmental impairment commonly associated with neonatal candidemia.
20 Kavitha et al 153 11.1% - 1. The study also suggested Candida Parapsilosis is an emerging fungal pathogen and incidence of infection caused by it may continue to rise.
2. Preterm neonates, low birth weight, RDS, Ventilation therapy and prior Candida colonization were identified as significant risk factors.
21 Latha et al 296 13.8% - 1. The present study revealed that low birth weight, birth asphyxia and mechanical ventilation were significant risk factors for candidiasis in neonates.
42
AIMS AND OBJECTIVES
1. To estimate the incidence of candida BSI in NICU of our hospital
2. To study the clinical profile including the risk factors, clinical symptoms, signs and outcome associated with candida BSI in neonates admitted in NICU of our hospital.
3. To identify the candida subspecies in blood culture and its antifungal sensitivity.
INCLUSION CRITERIA
Newborn admitted in NICU,Government Mohan Kumaramangalam Medical College, Salem who had candida BSI or bacterial culture positive sepsis were recruited into the study. The study participants were divided into two groups. Group 1 had candida BSI and Group2 had non candida bacterial sepsis.
EXCLUSION CRITERIA
Parents who were not willing and neonates who went AMA.
METHODOLOGY:
This was a prospective cross sectional study performed in a NICU of a tertiary care hospital of South India, Govt Mohan Kumaramangalam Medical College. The study was conducted over 1 year from June 2018 to May 2019.The study is cleared by the Institutional ethical committee. Study participants included neonates presented or developed signs of sepsis in NICU.
All these neonates underwent septic workup, which included complete
43
hemogram, C-reactive protein and blood culture. Patients were treated as per unit protocol and were followed till discharged from hospital or death.
Complications if appeared such as respiratory distress, necrotizing enterocolitis (NEC), shock, disseminated intravascular coagulation(DIC), and apnea were noted. Neonates tested positive for fungal cultures were analyzed and their Speciation of Candida was performed using germ tube test, observation of morphology in corn-meal agar and pigment production in HiChrome Candida differential agar. Further antifungal sensitivity was done for Amphotericin and fluconazole using disc diffusion method.
Data entry has been made in the predesigned format which included variables such as gestational age, place of delivery (outborn /inborn), gender, duration of hospitalization, maternal risk factors for sepsis, history of prior antibiotics, relevant symptoms, and anthropometry studied. All relevant investigations were documented in studied patients who included complete blood count, blood culture, fungal culture, chest X-ray etc.
Statistical analysis was done using the SPSS version 20. Normality of data, and continuous data was checked by the Chi-square test. Parametric data are expressed as mean ± standard deviation. Discrete data are expressed as a percentage. odds ratio were calculated.
