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Archives of Disease in Childhood 1994; 71: F130-F135 CURRENT TOPIC Systemic fungal infections in neonates PCNg Fungal infection in newborn babies can present as mild, superficial mucocutaneous infection or as life threatening and dissemi- nated sepsis. There are a number of ways in which fungal infection may be acquired. The infection may present at birth as congenital illness or later in life as nosocomial acquired infection. (I) Acquired systemic fungal infections Despite improvement in survival rates of very low birthweight (VLBW) infants, nosocomial infection remains an important contributing factor to neonatal morbidity and mortality. The emergence of fungi as important pathogens is likely to be the result of changes in the neonatal intensive care environment and their interaction with the host. INCIDENCE The incidence of disseminated fungal infection has not been systematically reported, due to problems in early recognition of the non-specific clinical symptoms and signs,' and difficulty in confirming the diagnosis by laboratory tests.2 Current serological tests are not entirely reliable2 and microbiological cultures from sterile body fluids may only be intermittently positive, and even positive results may be misinterpreted as colonisation or contamination.' A significant proportion of cases are only diagnosed at necropsy and those cases without postmortem examination would have been missed. Based on these limitations the incidence of acquired systemic fungal infections is estimated to be 2% to 5% among the VLBW infants,3-5 with species of candida being the most frequent invaders.4 6 Department of Paediatrics, Chinese University of Hong Kong Correspondence to: Dr P C Ng, Department of Paediatrics, Level 6, Clinical Sciences Building, Prince of Wales Hospital, Shatin, NT, Hong Kong. FACTORS PREDISPOSING TO SYSTEMIC FUNGAL INFECTION Factors responsible for emergence of fungal infections in modern neonatal intensive care unit include impaired host defence, aggressive neonatal intensive care procedures, and prolonged use of broad spectrum antimicrobial treatment. (a) Impaired host defence The preterm infants' fragile skin and mucous membranes are very susceptible to contact injury which frequently results in the invasion of micro-organisms into deeper tissues. Specific immunological defence systems are also underdeveloped and transplacentally acquired maternal IgG is low.7 T lymphocytes are reduced in number and are functionally incompetent with impaired cytotoxic activity. Both phagocytic and bactericidal activities of polymorphonuclear leucocytes are sub- normal.8 The monocyte-macrophage system is immature with greatly suppressed chemotactic activity8 and inadequate nutrition undoubtedly further compromises immune status. Immunocompetent term infants very rarely develop systemic fungal infections and they appear to have different risk factors from premature neonates. Most cases are associated with major congenital anomalies that include omphalocele, malrotation, sacrococcygeal teratoma, giant haemangioma, and congenital cyanotic heart disease. Infants who undergo complex surgery are also at a greater risk. (b) Intensive care procedures Invasive therapeutic and monitoring equipment has become an integral part of modern neonatal intensive care. Transcutaneous monitoring devices and adhesive tapes frequently cause superficial skin damage which facilitates the invasion of micro-organisms.9 Endotracheal tubes, urinary catheters, and indwelling vascular lines all bypass the skin barrier and enhance the suspectibility to systemic fungal infection by furnishing a portal of entry directly into the bloodstream.10 Although intravascular blood pressure monitoring devices and arterial can- nulas may cause disseminated sepsis, the central venous line used for total parenteral nutrition is by far the most important apparatus responsible for fungal septicaemia.' 4 6 9 11 The administra- tion of lipid emulsion may further increase the risk of fungaemia and narcotising pulmonary vasculitis due to lipophilic fungus.12-14 In addition, it has also been suggested that prolonged hospitalisationl5; prolonged stay in an incubator'5; extended period of endotracheal intubation6; the use of tracheostomies6; the requirement of an intraventricular shunt4; and the use of lamb's wool, sticking plaster, and transparent semipermeable dressing9 15 may increase the risk of fungal colonisation and subsequent systemic infection. Equipment such as blood pressure cuffs, thermometers, oxygen saturation probes, and other diagnostic devices that are shared between infants may also promote the incidence of cross infection. 13 F130 on 20 February 2019 by guest. Protected by copyright. http://fn.bmj.com/ Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/fn.71.2.F130 on 1 September 1994. Downloaded from

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Archives of Disease in Childhood 1994; 71: F130-F135

CURRENT TOPIC

Systemic fungal infections in neonates

PCNg

Fungal infection in newborn babies canpresent as mild, superficial mucocutaneousinfection or as life threatening and dissemi-nated sepsis. There are a number of ways inwhich fungal infection may be acquired. Theinfection may present at birth as congenitalillness or later in life as nosocomial acquiredinfection.

(I) Acquired systemic fungal infectionsDespite improvement in survival rates of verylow birthweight (VLBW) infants, nosocomialinfection remains an important contributingfactor to neonatal morbidity and mortality.The emergence of fungi as importantpathogens is likely to be the result of changes inthe neonatal intensive care environment andtheir interaction with the host.

INCIDENCEThe incidence of disseminated fungal infectionhas not been systematically reported, dueto problems in early recognition of thenon-specific clinical symptoms and signs,' anddifficulty in confirming the diagnosis bylaboratory tests.2 Current serological tests arenot entirely reliable2 and microbiologicalcultures from sterile body fluids may only beintermittently positive, and even positiveresults may be misinterpreted as colonisationor contamination.' A significant proportion ofcases are only diagnosed at necropsy and thosecases without postmortem examination wouldhave been missed. Based on these limitationsthe incidence of acquired systemic fungalinfections is estimated to be 2% to 5% amongthe VLBW infants,3-5 with species of candidabeing the most frequent invaders.4 6

Department ofPaediatrics, ChineseUniversity ofHongKong

Correspondence to:Dr P C Ng, Department ofPaediatrics, Level 6, ClinicalSciences Building, Prince ofWales Hospital, Shatin, NT,Hong Kong.

FACTORS PREDISPOSING TO SYSTEMIC FUNGAL

INFECTIONFactors responsible for emergence of fungalinfections in modern neonatal intensive care

unit include impaired host defence, aggressiveneonatal intensive care procedures, andprolonged use ofbroad spectrum antimicrobialtreatment.

(a) Impaired host defenceThe preterm infants' fragile skin and mucous

membranes are very susceptible to contactinjury which frequently results in the invasion

of micro-organisms into deeper tissues.Specific immunological defence systems arealso underdeveloped and transplacentallyacquired maternal IgG is low.7 T lymphocytesare reduced in number and are functionallyincompetent with impaired cytotoxic activity.Both phagocytic and bactericidal activitiesof polymorphonuclear leucocytes are sub-normal.8 The monocyte-macrophage system isimmature with greatly suppressed chemotacticactivity8 and inadequate nutrition undoubtedlyfurther compromises immune status.Immunocompetent term infants very rarely

develop systemic fungal infections and theyappear to have different risk factors frompremature neonates. Most cases are associatedwith major congenital anomalies that includeomphalocele, malrotation, sacrococcygealteratoma, giant haemangioma, and congenitalcyanotic heart disease. Infants who undergocomplex surgery are also at a greater risk.

(b) Intensive care proceduresInvasive therapeutic and monitoring equipmenthas become an integral part of modern neonatalintensive care. Transcutaneous monitoringdevices and adhesive tapes frequently causesuperficial skin damage which facilitates theinvasion of micro-organisms.9 Endotrachealtubes, urinary catheters, and indwelling vascularlines all bypass the skin barrier and enhance thesuspectibility to systemic fungal infection byfurnishing a portal of entry directly into thebloodstream.10 Although intravascular bloodpressure monitoring devices and arterial can-nulas may cause disseminated sepsis, the centralvenous line used for total parenteral nutrition isby far the most important apparatus responsiblefor fungal septicaemia.' 4 6 9 11 The administra-tion of lipid emulsion may further increase therisk of fungaemia and narcotising pulmonaryvasculitis due to lipophilic fungus.12-14 Inaddition, it has also been suggested thatprolonged hospitalisationl5; prolonged stay inan incubator'5; extended period of endotrachealintubation6; the use of tracheostomies6; therequirement of an intraventricular shunt4;and the use of lamb's wool, sticking plaster, andtransparent semipermeable dressing9 15 mayincrease the risk of fungal colonisation andsubsequent systemic infection. Equipment suchas blood pressure cuffs, thermometers, oxygensaturation probes, and other diagnostic devicesthat are shared between infants may alsopromote the incidence of cross infection. 13

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(c) DrugsThe suppression of the normal bacterial floraby prolonged and extensive use of broadspectrum antibiotics in VLBW infants hasundoubtedly contributed to the increasedincidence of fungal sepsis in sick prematureinfants.' 4 6 13 Theophylline has been reportedto inhibit the candidicidal activity of humangranulocytes.16 The liberal use of dexametha-sone in bronchopulmonary dysplasia, however,is not associated with a significant increasein the incidence, or a change in the pattern,of infection.'0 It seems that the anti-inflammatory potency of a particular steroidhas little influence on its immunosuppressiveaction.

PATHOGENSCandida and malassezia species are the twomost frequent groups of opportunistic organ-isms causing disseminated fungal infection inpremature neonates under 1500 g.4 6 Otheropportunistic fungi such as aspergillus, crypto-coccus, mucor, rhizopus, saccharomyces,Trichosporm beigelii, etc, are uncommon andusually occur sporadically. Pathogenic fungiwhich include coccidioides, paracoccidioides,and blastomyces very rarely give rise toneonatal infections outside their endemic areasand are not a major problem in most neonatalunits.

CANDIDA SPPCandida albicans is the most frequent cause offungaemia in premature VLBW infants. Otherspecies of candida such as Candida parapsilosis,Candida tropicalis, Candida glabrate, andCandida lusitaniae have been reported to give aclinical picture indistinguishable from thatcaused by C albicans.

In most preterm infants, colonisation of can-dida occurs in utero or during delivery17 eitherby swallowing and aspirating the contaminatedliquor, or by physical contact with the birthcanal. Skin colonisation is common and oftenprecedes the dissemination process.'8 Infantswith oropharyngeal and gastrointestinal tractcolonisation may rarely have invasion of thebowel mucosa with resultant fungaemia.19Candida pulmonitis secondary to aspiration isalso uncommon."1 In contrast, babiescolonised with candida after 2 weeks of ageusually acquired the fungus nosocomially fromcaretakers. 17

(a) Clinical presentationThe clinical features of systemic candidiasisin neonates are often non-specific and indis-tinguishable from bacterial sepsis. The onset isusually insidious and the mean age of infectionis 33 days.' The infant presents with tempera-ture instability, carbohydrate intolerance,hypotension, apnoea, bradycardia, and deteri-orating respiratory function which frequentlyrequires ventilatory support. Feed intolerance,guaiac positive stools and generalised abdomi-nal distension (without pneumatosis intesti-

nalis) may also occur. This spectrum ofsymptoms and signs may be intermittent andmay even be absent in some infants.' It seemsthat a septic VLBW infant who deterioratesdespite antibiotic treatment should always beconsidered to have systemic fungal infectionespecially when recognisable predisposingfactors are present. In contrast, those casesdiagnosed at necropsy tend to have had theirinitial presentation at a much earlier age, withfewer predisposing factors, and have followed afulminant downhill course.

(b) Deep organ involvementDeep organ involvement is commonlyassociated with systemic candidiasis. Candidaspp have a high affinity for the renal tract.Haematuria, proteinuria, and pyuria areusually present with candiduria. Acute oliguriais associated with candida pyelonephritis, renalpapillary necrosis, multiple parenchymalabscesses, and obstructing fungal balls.2022Secondary hypertension due to renal arteryobstruction is rare.21 Candida can infiltrate theeyes via the haematogenous route causingendophthalmitis.' 5 These lesions are white,cotton wool ball-like and rapidly progress toinvolve the vitreous humour. Early detection ofthese lesions is important because they cancause permanent blindness. Septic arthritis23 24and osteomyelitis25 are uncommon manifesta-tions. Such infants usually present with a red,warm, tender, swollen, and fluid filled jointwith the affected limb typically placed in anabnormal posture. The knee is the mostfrequent joint to be involved. It has beensuggested that catheterisation of the umbilicuscolonised with candida gives rise to fungaemiaand subsequent synovial infection.23 Intra-cardiac fungal masses and endocarditis are fre-quently associated with indwelling right atriallines.6 26 The fungal masses may obstruct thevenous return to the heart24 26 giving rise topersistent peripheral oedema, hepatospleno-megaly, and the superior vena cava syndrome.Multiple septic emboli can occur leading to awider dissemination of the infection. Pulmon-ary candidiasis is difficult to diagnose duringlife. Nodular infiltrates, focal cavitation, andprogressive air space consolidation are themost frequent but non-specific radiologicalabnormalities observed.27 Candida may alsogain entry into the bloodstream by invadingthe bowel mucosa.19 Fungal necrotising ente-rocolitis is usually severe and carries a poorprognosis. Central nervous system involve-ment is most commonly associated with intra-ventricular shunts.4 24 Meningitis, ventriculitis,and multiple cerebral abscesses have beendescribed.24 28

(c) Diagnosis and investigationsThe isolation of Candida spp from bloodculture is the most important investigation forestablishing the diagnosis of disseminatedcandidiasis. Blood samples may be taken fromthe indwelling central line, peripheral vein orartery. Although a positive blood culture is

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nearly always significant, a negative culturedoes not exclude the diagnosis, as up to200/-50% may not grow the organism.6 It mustbe emphasised that fungus grows more slowlythan bacteria and antifungal treatment musttherefore not be withheld in the absence ofpositive culture when clinical evidence is over-whelming. Examination of a Gram stainedperipheral blood buffy coat preparation issometimes useful for rapid diagnosis.29 Thepresence of budding yeast and hyphae in asuprapubic urine sample is diagnostic of deepseated fungal infection. Culture from othersterile sites such as cerebrospinal fluid, ascitesfluid, pleura, and tissue biopsy together withculture of indwelling catheters and long linesshould be obtained when clinically indicated.Candida meningitis is difficult to diagnose.Despite an increase in the cerebrospinal fluidwhite cell count and protein concentration,microscopy is usually negative. Moreover, theseparameters may also be increased with periven-tricular haemorrhage without fungal infectionin the central nervous system. Surveillancecultures from ears, throat, umbilicus, and rec-tum may also be helpful in identifying thecolonisation pattern of the individual patient.

Detection of candida antigens usingvarious enzyme linked immunosorbent assaytechniques appeared to be promising with adiagnostic sensitivity of about 70%/ when serialspecimens are evaluated.2 30 31 However,serum levels of candida antigen can be raisedin individuals who are heavily colonised or beundetectable in those with proved systemiccandidiasis. The polymerase chain reactiontechnique, with its capability of detecting can-dida DNA fragments, may in future representan important breakthrough for the early detec-tion of candida sepsis. Measurement of can-dida metabolites such as D-arabinitol andbiochemical tests such as the API-20c yeasttest are of limited value and not routinely usedin laboratories.2White cell and platelet counts are often

abnormal in candida septicaemia. Serialmeasurements of C reactive protein are partic-ularly useful in monitoring the response totreatment.9 29 A chest radiograph may showpulmonary infiltrates and progressive air spaceconsolidation but these changes are rathernon-specific and not unique for candidapulmonitis.

Specific investigations are sometimes usedto locate the focus of infection. Retinal exami-nation may reveal fluffy white lesions on retinaor vitreous, interlesional and lesional strands,and diffuse vitreous haze.' Evidence of ventri-culitis with foci of cavitary destruction and anetwork of fungal strands in the ventriclesmay be apparent on cranial ultrasoundscan.32 Cardiac and renal ultrasound scansshould be routinely performed. Intracardiacfungal infection may present as thrombi in theheart chambers and vegetations on thevalves,24 26 whereas renal involvement maymanifest as enlarged kidneys with highlyechogenic parenchyma and fungal ballswithin the dilated pelvicalyceal systems.32Percutaneous needle aspiration of the synovial

cavity is indicated when neonatal fungalarthritis is suspected.23

(d) TreatmentThree main categories of antifungal drugs arecurrently used for the treatment of systemicfungal infections. They are the polyenemacrolide class compounds, the azoles, andinhibitors of RNA synthesis, the fluorinatedpyrimidines.

Amphotericin B belongs to the polyenemacrolide class of drugs and is the mainstay oftreatment for opportunistic fungal infection.It must be administered intravenously forsystemic effect as it is not absorbed enterally.The dosage could be increased in a stepwisefashion starting from 025 mg/kg/day up to amaximum of 1 mg/kg/day or administered as aconstant dose of 0-6 mg/kg/day throughout thetreatment period. The usual recommendedduration of treatment is between three to sixweeks. Combining amphotericin B treatmentwith flucytosine will permit the use of a lowerdose and this combination is particularlyeffective for the treatment of central nervoussystem candida infection.4 6 Although the sideeffects are better tolerated by infants, fever,renal toxicity, gastrointestinal upset, bonemarrow suppression, anaphylactic reaction,and severe electrolytes disturbances includinghypokalaemia and hypomagnesaemia havebeen well documented. Electrolytes and renaland hepatic function must be monitoredclosely during the treatment period.Preparation of amphotericin B with parenterallipid solution has been reported to reducenephrotoxicity, improves clinical tolerance andpermits a larger daily dose to be used.33A new formulation of amphotericin encap-

sulated in liposomes is commercially available.The resultant liposomal preparation isdesigned to maximise the delivery of ampho-tericin to deep seated sites of infection. Theuptake by macrophages and the transport ofliposomal amphotericin to the infective areasappear to play a major part in increasingefficacy and diminishing toxicity.34 35 Tworeports indicate that liposomal amphotericin iseffective in the treatment of disseminatedfungal infections in VLBW infants.36 37 Astarting dose of 1-5 mg/kg/day was used andthis was increased progressively over a week toa maximum of 5 mg/kg/day.36 Side effectsassociated with conventional amphotericinsuch as fever, bronchospastic reactions, andrenal toxicity were significantly less,36 37 butneonatal cholestasis with raised hepaticenzymes values and conjugated hyperbili-rubinaemia has been observed.37 High doseliposomal amphotericin should be tried whenthe fungal infection is refractory or the baby isunable to tolerate conventional treatment.The azole group of antifungals include the

imidazoles such as miconazole, ketoconazole,and the newer triazoles such as fluconazole,itraconazole, and saperconazole. They arefungalstatic agents. All triazoles show promiseas broad spectrum, orally active, systemicantifungal drugs with less toxicity than the

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imidazoles. Fluconazole has been successfullyused with minimal adverse effects4 for thetreatment of neonatal candida septicaemia,38pneumonia,39 osteomyelitis,25 central nervoussystem shunt infection,40 and pelviuretericcandidal bezoars.22 A dose of 6 mg/kg/day iscommonly used. A recent study suggested thatan adequate drug concentration in the bloodcould be achieved using a regimen of 6 mg/kgevery three days in the first week followed by6 mg/kg every two days or even daily in subse-quent weeks, as the half life of fluconazolevaries from 55 to 89 hours in VLBW babies.4'Despite good evidences of its therapeuticefficacy,22 25 38-40 treatment failure in thepresence of adequate minimum inhibitory con-centrations has been reported.42 This group ofdrugs should, therefore, be considered assecond line treatment for infants who do notrespond to the standard treatment or whosecondition does not permit the use of toxicantifungal agents.

Flucytosine is a synthetic compound and hasthe advantages of excretion via the urinarytract and good absorption when given orally.Synergy has been demonstrated with ampho-tericin B.43 Flucytosine is not recommended tobe used as a single agent because resistance is acommon problem and can develop duringtreatment. Flucytosine is given in a dose of 100mg/kg/day44 and serum drug concentrationsand blood counts must be monitored at leastonce a week because it can induce severe bonemarrow suppression. Other side effects aremild and include gastrointestinal, hepatic, andrenal impairment.

Acute resuscitation with plasma expander,inotropic agents, and mechanical ventilatorysupport are often required in the acute phase ofsystemic fungal illness. Removal of the infectedindwelling lines9 and intraventricular shunt aremandatory. Surgical drainage of subcutaneousfungal abscess can be carried out at the bedsideunder local anaesthesia.9 Consultation withthe orthopaedic team will help to define thesituation when surgical drainage of the septicjoint and convalescent immobilisation in aplaster cast is necessary. Urinary diversion,local irrigation with amphotericin B, andguidewire fragmentation of renal fungal ballshave been attempted.45 The indications forsurgical removal of intracardiac fungal masseswill depend on the response to antifungaltreatment, the size and mobility of the mass,the likelihood of embolisation and its haemo-dynamic significance on the patient. Forinfants under 2000 g in weight, cardio-pulmonary bypass is technically difficult andrisky. The removal of intracardiac masseshas been successful with the use of an inflowocclusion technique.26

(e) PrognosisDisseminated candida infections are associatedwith high morbidity and mortality in neonateswith a significant proportion of cases beingdiagnosed at necropsy. Although centralnervous system involvement usually has a poorprognosis and frequent neurological sequelae,

intact survivors are occasionally seen.46Current mortality rates range from 18%46 to500/o,l 28 but with a trend towards prompt andaggressive antifungal treatment, outcomeshould improve.

(G) PreventionSince the colonisation of the newborn withsubsequent mucocutaneous candidiasis maypredispose to systemic candida infection,attempts have been made to eradicate theorganism from the skin and gastrointestinaltract of at risk infants. Clotrimazole vaginaltablets and cream given to pregnant womenwith vaginal candidiasis have significantlyreduced the number of fungal contaminatednewborns.47 Breast feeding has no impact onthe incidence of oral thrush nor has chlorhexi-dine alcohol spray applied to the nipples ofbreast feeding women. The most promisingprophylactic measure is perhaps the use of oralantifungal drugs, namely nystatin and mico-nazole oral gel, which have been shownto be effective in reducing the incidence ofpostnatally acquired gastrointestinal fungalcolonisation.4849 Nevertheless, the success oforal antifungal prophylaxis has not been trans-lated into prevention of systemic candidainfection in the newborns. As disseminatedfungal infection is becoming more frequentamong preterm neonates, there must be strin-gent control in the selection and usage of anti-biotics, judicious use of indwelling lines andexpedient weaning from mechanical ventila-tion. These must be combined with strictimplementation of infection control surveil-lance measures in the intensive care nurseryand especially careful handwashing.50

MALASSEZLA SPPMalassezia furfur is a lipophilic yeast. It is afrequent skin commensal and may colonise upto 64% to 84% of babies in a neonatalunit.15 51 Bronchopneumonia with necrotisingpulmonary vasculitis and fungaemia in infantsreceiving parenteral lipid therapy have beenreported.'2-14 M furfur cannot be recoveredfrom routine culture medium because it has anabsolute nutritional requirement for mediumchain fatty acids (C12-C24).4 6 13 Lipidenriched medium (such as Sabourand's dex-trose agar with olive oil and 0.2% Tween 80) isrequired for its culture.4 As most cases resolvequickly after parenteral lipid is stopped andindwelling venous catheter is removed, only ashort course of amphotericin B is required.The prognosis is usually good if the diagnosis ismade early and appropriate measures promptlyimplemented.

(2) Congenital fungal infectionsIn the United States 5% to 1 0% of fetal deathseach year are due to intrauterine infections.2Diagnosis of fetal infection is often difficultand requires elaborate laboratory tests forisolation of the organism or demonstration ofits specific nucleic acids. Congenital fungal

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infection is extremely rare but has beenreported with candida, blastomyces, cocci-dioides, and cryptococcus.The syndrome of congenital systemic

candida infection is very different from themore common acquired infection viahaematogenous dissemination. Predisposingfactors such as previous exposure to broadspectrum antibiotics, total parenteral nutrition,and central venous catheterisation are typicallyabsent. The presence of a foreign body in themother's genital tract such as an intrauterinecontraceptive device or a cervical suture con-tributes to colonisation of Candida spp.52-54Although severe candidal sepsis with pneumo-nia,52 septicaemia, and meningitis3 have beenreported, the pattern of organ involvementusually suggests a slow, locally invasiveinfection with little evidence ofhaematogenousdissemination, even in cases with deep tissueinfection.53 Congenital candidiasis typicallypresents in the first week of life and maysimulate congenital infection of bacterial originor other conditions such as respiratory distresssyndrome or idiopathic persistent pulmonaryhypertension of the newborn. In most cases,candida can be recovered from surface swabs,endotracheal or gastric aspirates. Histologicalexamination and culture of the placentaand umbilical cord may provide importantevidences for the diagnosis.2 Blood andcerebrospinal fluid specimens, however, fre-quently fail to demonstrate the infectiondespite the presence of serious generalisedcandidiasis.53 Antifungal treatments are similarto postnatally acquired systemic candidiasis.Congenitally infected infants have a highmortality.53

SummarySystemic fungal infections, previously consid-ered to be a rare complication, are nowfrequently diagnosed in VLBW infantsreceiving intensive care. Confirming thediagnosis by laboratory tests is difficult and ahigh index of suspicion is required. Promptand aggressive use of antifungal treatmentis justified in a clinically septic neonate,especially those with a raised serum concentra-tion of C reactive protein, who do not show asatisfactory response to antibiotics. The newergeneration of liposomal amphotericin andazole antifungal drugs appear to be safe,effective, and well tolerated. With increasingawareness, prompt treatment, and betterneonatal intensive care, the outcome ofsystemic fungal infection in preterm infantsshould improve.

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