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A persistently positive culture >24 h after starting antibiotic therapy has been correlated with adverse outcome in several invasive bacterial infections, but few reports address persistent positivity and outcome in infections caused by fungi and other pathogens that replicate more slowly and therefore may succumb less quickly to therapy.To assess whether positive culture >24 h after achieving target doses (amphotericin ≥0.5 mg/kg/day or fluconazole ≥6 mg/kg/day) of systemic antifungal therapy predicts focal infectious complication(s) or death from infection, we compared neonatal intensive care unit infants who had persistent (P+) or nonpersistent (P−) positive cultures with invasive candidiasis (clinical signs of infection and recovery of Candida from a normally sterile site) at this center from January 1, 1981, through June 30, 1999. Infants who died ≤ 24 h after attaining target dosing, recovered without therapy, had a focal infectious complication already present at the time target dosing was achieved or were diagnosed with invasive candidiasis only postmortem were excluded.We identified 58 P+ (29, 12 and 7 had positive cultures for >7, >14 and ≥21 days, respectively) and 38 P− infants. No differences were found between P+ and P− for birth weight; gestational age; gender; onset age; central vascular catheters; necrotizing enterocolitis, surgery or bacterial sepsis; or duration of parenteral nutrition, antibiotics, tracheal intubation or postnatal steroids. P+ were more likely to have blood or cerebrospinal fluid involvement (68 vs. 45%, P = 0.03). Distribution of Candida species was similar (albicans in 53 vs. 63% for P+vs. P−). P+ were significantly more likely to develop later “fungus ball” uropathy (16 of 56 vs. 2 of 32, P = 0.01), to develop renal infiltration (11 of 56 vs. 1 of 32, P = 0.03) and to die from invasive candidiasis (11 of 58 vs. 0 of 38, P = 0.003) than P−. P+ were also more likely to develop endocarditis, abscess, ventriculitis and invasive dermatitis, although P > 0.05. Focal complication increased as duration of P+ increased (48, 55, 67 and 71% at >1, >7, >14 and ≥21 days, P = 0.06). When comparing only those with positive blood and/or cerebrospinal fluid culture, similar patterns were observed, although only death and focal complication or death from invasive candidiasis attained significance.These observations suggest that in neonatal invasive candidiasis: (1) cultures usually remain positive >24 h after attaining target antifungal doses; (2) aggressive imaging for focal complications may be reserved for infants with persistently positive cultures after several days of antifungal therapy at target doses or have signs strongly suggestive of focal complication; (3) focal complications and/or death from candidiasis increase with persistence; (4) focal complications increase with duration of persistence; (5) serial culture of infected site(s) helps predict outcome and the need for aggressive surveillance and intervention for focal complications.