Prophylactic regimens with fluconazole for candidiasis in neonates under 1.500g: A retrospective chart review of two cohorts

Abstract

BACKGROUND:

The incidence rate of invasive candidiasis in newborns with birth weight below 1,500 g ranges from 2% to 8%, and fluconazole prophylaxis in neonatal units is recommended when the incidence of invasive candidiasis is higher than 5%. This study aimed to compare the effectiveness of targeted prophylaxis and universal prophylaxis with fluconazole in the prevention of invasive candidiasis.

METHODS:

This was a historical cohort comparing the targeted prophylaxis for newborns weighing less than 1,500 g and the universal prophylaxis for newborns weighing less than 1,000 g.

RESULTS:

The overall incidence rate of invasive candidiasis was 5.25% and was reduced from 7.1% to 3.72% with universal prophylaxis (p = 0.04). In a multivariate analysis, the significant factors associated with the development of candidiasis were birth weight less than 1,000 g, prolonged hospitalization, previous surgery, prolonged use of mechanical ventilation, prior exposure to antimicrobial treatments, and use of targeted prophylaxis.

CONCLUSIONS:

Universal prophylaxis had lower incidence of invasive candidiasis, and preventive measures considering the risk factors are mandatory to reduce the incidence of invasive candidiasis.

Keywords

Candidiasis invasive,fluconazole pre-exposure prophylaxis newborn infant very low birth weight

1. Introduction

Recent advances in healthcare assistance have enabled the survival of preterm newborns who experienced prolonged hospitalization and underwent invasive procedures such as mechanical ventilation (MV), central venous catheter (CVC), or indwelling urinary catheter (IUC) [1, 2]. Immaturity of the immunological system inherent to preterm neonates, the use of antimicrobial agents, and Candida sp colonization are also considered risk factors for invasive candidiasis (IC) [3 –5].

Candidemia is defined as bloodstream infection with isolation of Candida species in the blood samples. IC may affect organs, and/or the etiological agent can be isolated in sterile body fluids. It is the common cause of morbidity and mortality in newborns admitted in neonatal intensive care units (NICU) [1 , 6].

The incidence of IC ranges from 2% to 8% in very low birth weight (VLBW) infants (less than 1,500 g) and may reach 16% in extremely low birth weight (ELBW) infants (less than 1,000 g) [1 , 6–8]. Involvement of organs such as heart, kidneys, retina, liver, and central nervous system (CNS) is common [5, 9], and impairment of neuropsychomotor development can affect up to 60% of survivors [10, 11]. Mortality occurs in approximately 20% of newborns and can reach up to 40% [11 –13].

The use of antifungal prophylaxis with oral or intravenous fluconazole at a dose of 3 mg/kg/dose, two or three times a week, for 6 weeks has been recommended by international committees for the neonatal population [14 –17]. Indications of universal use of antifungal prophylaxis are: a) all ELBW infants admitted in NICU with a high incidence of IC (greater than 10%) (16), b) VLBW infants in NICU with an incidence rate of greater than 5% [14 , 17], and c) VLBW infants who are exposed to risk factors in NICU with an incidence rate of IC less than 5% [14 , 17]. Despite evidence in randomized studies comparing prophylaxis with placebo or comparing different doses of fluconazole, no study has compared targeted prophylaxis and universal prophylaxis [18].

Candida sp colonization is a risk factor for invasive fungal infection. We consider that the use of fluconazole for all neonates at risk, even before colonization is confirmed, reduces the incidence of invasive fungal infection. Thus, the present study aimed to compare two antifungal prophylaxis for newborns in a neonatal referral unit.

2. Methods

This is a retrospective chart review of two cohorts, conducted from January 2012 to December 2014 and approved by the Institutional Review Board. All VLBW infants admitted in the NICU from January 2012 to December 2014 was included in the study. Newborns who died before 72 hours and those who were re-admitted were excluded.

Systematic active surveillance was used to follow up the newborns admitted in the NICU. Standardized forms provided by the Hospital Infection Control Committee (HICC) were completed, prospectively and daily. Neonates included in the epidemiological surveillance system and the diagnostic criteria for healthcare-related infections, such as the diagnosis of laboratory-confirmed bloodstream infection (LCBI), were defined by the Brazilian Agency for Sanitary Surveillance (ANVISA) [19].

The first episode of IC defined as the isolation of Candida sp in one blood culture was considered as the primary outcome. As a secondary event, mortality rate (number of deaths in the entire group) and lethality rate (number of deaths in the group of individuals affected by a particular disease) were also evaluated.

For the evaluation of the use of prophylaxis, institutional protocols were followed:

First cohort (January 1, 2012, to May 31, 2013): Targeted prophylaxis was prescribed when Candida sp colonization was confirmed from the perianal swab of all VLBW infants admitted in the NICU, collected at the 1st, 3rd, 7th, 14th, and 21st day of life. If the swab test was positive, the infants were given intravenous or oral fluconazole, 3 mg/kg/day daily, in case they undergo an invasive procedure (CVC, MV, or IUC). The administration of prophylaxis was suspended whenever invasive procedures were discontinued.

Second cohort (June 1, 2013, to December 31, 2014): The use of intravenous or oral fluconazole for all ELBW infants was initiated on the third day of life, with 3 mg/kg/dose, every 72 h, for 6 weeks or until invasive procedures were no longer needed, independent of colonization evidence. A routine perianal swab was performed to identify the presence of fungal colonization.

Data were collected by HICC active surveillance, which was performed according to the Brazilian legislation. Study variables included demographic characteristics, risk factors for IC, Candida sp colonization, antifungal prophylaxis with fluconazole, and mortality and lethality rate associated with IC.

Predictor variables were considered before the occurrence of the first episode of IC, until the end of the follow-up period, or once the infant who did not develop IC is discharged from the NICU.

A descriptive analysis of variables was performed, and the results were expressed as frequency, mean and standard deviation, and median and distribution. Chi-square test, Student’s t-test, and Mann-Whitney test were used to compare the risk factors of IC in ELBW and VLBW infants. In the multivariate analysis, binary logistic regression included all variables with a p-value of≤0.2. The quantitative variable was prioritized in the multivariate analysis, and one variable from each topic was chosen. However, weight was adjusted for categorical classification (ELBW infants weighing 1,000 g and 1,499 g), according to prophylaxis regimen. A p value of≤0.05 was considered significant. A chi-square test was used to compare the mortality rates of patients in each cohort and mid-test was used to compare the density of the IC events per 1,000 patients in each cohort. Data was analyzed using SPSS^®, version 19.0, IBM, New York, United States.

3. Results

During the study period, 2,712 newborns were admitted in the NICU, which correspond to 69,288 patient-days. Among them, 359 newborns (13.24%) were ELBW infants, and 629 (23.19%) weighed between 1,000 g and 1,499 g. A total of 95 neonates (3.5%) were excluded from the study due to death, re-admission, or incomplete data.

Of the 893 newborns included in the study, 47% were male newborns (2% not reported) and vaginal birth occurred in 41% (3% was ignored). With regard to birth weight, 309 (34.6%) were found to be ELBW infants and 584 (65.4%) weighed between 1,000 g and 1,499 g.

Table 1 presents a comparison of the demographic and clinical characteristics of the two cohorts. Only the days of CVC (p = 0.012) and days of prophylaxis (p < 0.02) were found to be different between the two groups.

Table 1
Descriptive analysis for continuous variables: Newborns weighing less than 1500 g

1st cohort 2nd cohort p OR (CI 95%)

Birth weight - grams 1112.5 1107.1 0.76¹ –– –

(Mean/standard deviation) (255.06) (256.26)

Weigh group - frequency (%)

<1.000g 136 (15.2) 173 (19.4) 0.44² 0,90 (0.68–1.18)

1.000 g and 1.499g 273 (30.6) 311 (34.8)

Gestational weight 29.54 29.50 0.82¹ –– –

Mean (standard deviation) (2.52) (2.62)

Days in NICU^* 44.96 44.74 0.20¹ –– –

Mean (standard deviation) (26.32) (25.53)

Apgar 1st minute 7 7 0.89³ –– –

Median (maximum-minimum) (0–10) (0–10)

Apgar 5th minute 9 9 0.74³ –– –

(Median/maximum-minimum) (1–10) (2–10)

Days of central venous catheter^* 23.22 20.14 0.012¹ –– –

Mean (standard deviation) (18.51) (18.80)

Days of mechanical ventilation^* 10.48 9.18 0.14¹ –– –

Mean (standard deviation) (12,87) (13,11)

Days of indwelling catheter^* 0.55 0.54 0.97¹ –– –

Mean (Standard deviation) (1.69) (3.13)

Number of LCBI prior IC^* 0 0 0.41³ –– –

Median (maximum-minimum) (0–3) (0–2)

Days of ATM^* 10 10 0.98³ –– –

Median (maximum-minimum)∼ (0–66) (0–75)

Number of ATM treatment^* 1 1 0.40³ –– –

Median (maximum-minimum) (0–4) (0–4)

Age at colonization^* (days of life) 9.39 11.16 0.40¹ –– –

Mean (standard deviation) (10,70) (10.77)

Days of prophylaxis^* 14.13 20.42 0.02¹ –– –

Mean (standard deviation) (10,94) ∼(14,61)

Previous surgery - frequency (%)

No 395 (44.2) 456 (51.1) 0.097² 1.73

Yes 14 (1.6) 28 (3.1) (0.90–3.34)

Previous use of antimicrobial-frequency (%)

No 221 (24.7) 263 (29.5) 0.93² 0.99 (0.76–1.29)

Yes 188 (21.1) 221 (24.7)

Candida sp colonization - frequency (%)

No 329 (36.8) 446 (49.9) <0.001² 0.35 (0.23–0.53)

Yes 80 (9) 38 (4.3)

Prophylaxis - frequency (%)

No 378 (42.3) 326 (36.5) <0,001² 5.91 (3.9–8.93)

Yes 31 (3.5) 158 (17.7)

	1st cohort	2nd cohort	p	OR (CI 95%)
Birth weight - grams	1112.5	1107.1	0.76¹	–– –
(Mean/standard deviation)	(255.06)	(256.26)
Weigh group - frequency (%)
<1.000g	136 (15.2)	173 (19.4)	0.44²	0,90 (0.68–1.18)
1.000 g and 1.499g	273 (30.6)	311 (34.8)
Gestational weight	29.54	29.50	0.82¹	–– –
Mean (standard deviation)	(2.52)	(2.62)
Days in NICU^*	44.96	44.74	0.20¹	–– –
Mean (standard deviation)	(26.32)	(25.53)
Apgar 1st minute	7	7	0.89³	–– –
Median (maximum-minimum)	(0–10)	(0–10)
Apgar 5th minute	9	9	0.74³	–– –
(Median/maximum-minimum)	(1–10)	(2–10)
Days of central venous catheter^*	23.22	20.14	0.012¹	–– –
Mean (standard deviation)	(18.51)	(18.80)
Days of mechanical ventilation^*	10.48	9.18	0.14¹	–– –
Mean (standard deviation)	(12,87)	(13,11)
Days of indwelling catheter^*	0.55	0.54	0.97¹	–– –
Mean (Standard deviation)	(1.69)	(3.13)
Number of LCBI prior IC^*	0	0	0.41³	–– –
Median (maximum-minimum)	(0–3)	(0–2)
Days of ATM^*	10	10	0.98³	–– –
Median (maximum-minimum)∼	(0–66)	(0–75)
Number of ATM treatment^*	1	1	0.40³	–– –
Median (maximum-minimum)	(0–4)	(0–4)
Age at colonization^* (days of life)	9.39	11.16	0.40¹	–– –
Mean (standard deviation)	(10,70)	(10.77)
Days of prophylaxis^*	14.13	20.42	0.02¹	–– –
Mean (standard deviation)	(10,94)	∼(14,61)
Previous surgery - frequency (%)
No	395 (44.2)	456 (51.1)	0.097²	1.73
Yes	14 (1.6)	28 (3.1)	(0.90–3.34)
Previous use of antimicrobial-frequency (%)
No	221 (24.7)	263 (29.5)	0.93²	0.99 (0.76–1.29)
Yes	188 (21.1)	221 (24.7)
Candida sp colonization - frequency (%)
No	329 (36.8)	446 (49.9)	<0.001²	0.35 (0.23–0.53)
Yes	80 (9)	38 (4.3)
Prophylaxis - frequency (%)
No	378 (42.3)	326 (36.5)	<0,001²	5.91 (3.9–8.93)
Yes	31 (3.5)	158 (17.7)

Abbreviations; NICU, neonatal intensive care unit; LCBI: laboratory-confirmed bloodstream infection; ATM, antimicrobials. ^*Variables evaluated until the occurrence of IC, until the end of the follow-up period, or until discharge of newborns without occurrence of the event. ¹T–test; ²X²; ³Mann-Whitney test.

A total of 409 newborns were included in the first cohort, of which 136 were ELBW infants (9,004 patient-days) and 273 weighed between 1,000 g and 1,499 g (11,880 patient-days). A total of 31 (7.6%) newborn received target prophylaxis, of which 12 (8.82%) were ELBW infants and 19 (6.96%) weighed between 1, 000 g and 1, 499 g. A total of 484 infants were included in the second cohort, of which 173 were ELBW infants (8,808 patient-days) and 311 weighed between 1,000 g and 1,499 g (11,975 patient-days). A total of 158 (91.32%) infants weighing less than 1,000 g received prophylaxis.

The incidence of IC within the 3-year period was 5.25% (47/893). During treatment with targeted prophylaxis, the incidence of IC was 7.1% (12.5% in ELBW infants and 4.4% in infants weighing between 1,000 g and 1,499 g), whereas during treatment with universal prophylaxis, the incidence of IC was 3.72% (6.9% in ELBW infants and 2% in infants weighing between 1000 g and 1499 g). Comparing the two incidence rates, a significant reduction was observed in the overall rate of IC in the second cohort (p = 0.04) (Table 2).

A total of 32 patients with IC were not colonized previously. They had a mean birth weight of 963 (SD 243) and 31 weeks (SD 2.3) of gestational age. A total of 18 of these patients were included in the first cohort while 14 in the second cohort. Eight patients from the second cohort and one from the first cohort received prophylaxis. Four of the patients from the first cohort died.

Table 2

Comparison of rate and density of Invasive Candidemia incidence in two different prophylaxis cohorts < 1500 g

		Incidence rate	p^*	OR (IC95%)	Incidence density	P valor ^**
<1000g	1st P	17/136	0,14	1.93 (0,84–4.49)	17/9.004	0.196
	2nd P	12/173			12/8.808
1000 g a	1st P	12/273	0.14	2.35 (0.80–7.07)	12/11.880	0.081
1499g	2nd P			6/311	6/11.975
Total	1st P	29/409	0.04	1.97 (1.04–3,75)	29/20.884	0.057
	2nd P	18/484			18/20.803

^*X²;^**Mid-test. 1st P, cohort with targeted prophylaxis 2nd P, cohort with universal prophylaxis.

The presence of CVC or the number of days of CVC use was not considered a relevant risk factors for IC (p = 0.96 and p = 0.49, respectively). Results of the univariate analysis on the risk factors for IC and variables with a p value of < 0.20 are shown in Table 3. Birth weight < 1000 g, length of stay in the NICU, previous LCBI, presence of colonization, and days of colonization were found to be associated with IC. As days of antimicrobials (ATM) did not show any statistical significance, it was categorized based on the number of days (≤5 days and > 5 days) that the ATM were used as treatment for neonatal sepsis (p = 0.043) (Table 3).

Table 3

Univariate analysis of risk factors for invasive candidiasis with statistical significance, newborns <1500 g

	Invasive candidiasis		p	OR	IC 95%
	Yes	No
Birth weight n (%)
<1000 g	29 (3.25)	280 (31.36)	<0.001^*	0.31	0.17 – 0.56
≥1000g	18 (2.02)	566 (63.38)
Gestational age in weeks	28.33	29.58	0.001^**	–– –	–– –
Mean (SD)	(2.13)	(2.58)
Days in NICU	67.66	42.43	<0.001^**	–– –	–– –
Mean (SD)	(28,82)	(25,09)
Apgar 5 minute	8	9	0.046^***	–– –	–– –
Median (variation)	(4–10)	(1–10)
Indwelling catheter n (%)
Yes	15 (1.68)	118 (16.21)	0.001^*	2.89	1.52 – 5.50
No	32 (3.58)	728 (81,52)
Mechanical ventilation n (%)
Yes	42 (4.70)	693 (77.60)	0.193^*	1.86	0.72 – 4.77
No	5 (0.56)	153 (17.13)
Days of mechanical ventilation	13.79	9.55	0.030^**	–– –	–– –
Mean (SD)	(15.59)	(12.82)
Previous surgery n (%)
Yes No	7 (0.78) 40 (4.45)	35 (3.92) 811 (90.82)	0.001^*	4.06	1.70–9.69
Previous LCBI n (%)
Yes	19 (2.13)	0	<0.001^*	1.68	1.33–2.12
No	28 (3.14)	846 (94.74)
Number of LCBI prior IC	0	0	<0.001^*	–– –	–– –
Median (variation)	(0–3)	(– – –)
Number of ATM treatments	2	1.69	0.063^**	–– –	–– –
Median (SD)	(1.18)	(1.12)
Days of ATM
≤5days	8 (0.90)	262 (29.34)	0.043^*	2.19	1.01–4.75
>5days	39 (4.37)	584 (65.40)
Previous colonization n (%)
Yes	15 (1.68)	103 (11.53)	<0.001^*	3.38	1.77–6.46
No	32 (3.58)	743 (83.20)
Days of colonization	0	0	<0.001^***	–– –	–– –
Median (variation)	(0–35)	(0–77)
Prophylaxis n(%)
1°Períod	29 (3.25)	380 (42.55)	0.025^*	0.51	0.28 – 0.93
2° Períod	18 (2.02)	466 (52.18)

Abbreviations: LCBI, laboratory-confirmed bloodstream infection; ATM, antimicrobial; IC, invasive candidiasis. ^* X²; ^** t-test; ^***Mann-Whitney test.

The multivariate analysis revealed that the following factors were associated with the occurrence of IC: birth weight less than 1000 g (risk: 3.2 times higher), length of hospital stay (risk: 1.05 times higher each day), previous surgery (risk: 2.02 times higher), duration of MV (89% reduction in days of MV can lead to 9% lower risk of infection), exposure to antimicrobial treatments (a reduction in 33% of ATM treatments can lead to a 49% decreased risk of IC), and use of targeted prophylaxis (risk: 2.62 times higher) (adjusted model: 97.5%) (Table 4).

Table 4

Multivariate analysis of risk factors for invasive candidiasis, newborns < 1.500 g

Risk factors	B	p	OR	95% CI Exp B
Birth weight < 1.000g	1,16	0.012	3.19	1.28 – 7.92
Days of NICU	0.05	<0.001	1.05	1.03 – 1.07
Previous surgery	2.02	0.012	7.55	1.57–36,36
Days of mechanical ventilation	–0.09	0.007	0.92	0.86 – 0.98
Number of ATM treatments	–0.68	0.015	0.51	0.30 – 0.88
1st cohort	0.96	0.04	2.59	2.62–6.56

Abbreviations: NICU, neonatal intensive care unit; ATM, antimicrobial.

Considering death as a secondary outcome, 40 deaths were associated with both LCBI and IC. The lethality rate of patients with other LCBI was 13.73% (35/255) and that of patients with IC was 10.6% (5/47). A higher risk of death was associated with IC (odds ratio (OR): 1.143; 95% confidence interval (CI): 1.017–1.285; p < 0.001). All deaths associated with IC occurred in the first cohort; which were associated to the non-use of universal prophylaxis (OR: 0.988; 95% CI 0.977–0.998; p = 0.015; data not shown).

4. Discussion

4.1. Incidence rate and density

The incidence rate of IC found in the study (5.25%) is comparable with those of published literature, as well as the incidence rates by weight range throughout the period, that is, 9.35% for newborns with birth weight < 1,000 g and 3.1 % for newborns with birth weight between 1,000 g and 1,499 g [1 , 6–8].

A significant reduction in the incidence of IC was observed in the cohort who were treated with universal prophylaxis (p = 0.04). Other studies compared the incidence of IC between periods of universal prophylaxis and periods without prophylaxis, and they also showed a reduction in the incidence of IC, favoring the universal prophylaxis [20 –23]. Other clinical trials also reported a reduction in incidence of IC in the groups who received prophylactic fluconazole compared with placebo-controlled groups [24 –26].

Thus, literature suggest that prophylactic fluconazole reduces the rate of Candida sp colonization, a widely recognized risk factor for IC, as reported in historical studies and clinical trials [21 , 26]. Therefore, IC reduction was observed in the second cohort probably because the administration of targeted prophylaxis in the first cohort was delayed due to necessity of obtaining swab results.

4.2. Risk factors associated with IC

Several risk factors are described in the literature, and CVC is a highlighted risk factor for fungal infection. One of the recommendations for the treatment of IC is the withdrawal of CVC when a patient is diagnosed with fungemia [1 , 7–9]. In the present study, the device use and days of CVC were not significant factors for the occurrence of IC, although days of CVC were even higher in the first cohort and 98% of infants used CVC. With regard to the use of invasive devices, the multivariate analysis revealed that prolonged use of MV remained the only significant factor associated with IC.

The number of days of prophylaxis was even higher in the second cohort, as it was indicated for all ELBW infants (p = 0.02). By contrast, it was only used in the first cohort after confirmation of colonization. Moreover, the univariate analysis showed that previous colonization and age of colonization (days) were considered as significant factors, and universal prophylaxis was a protective factor for IC, as described in the literature [1 , 27]. In the multivariate analysis, these factors were not found to be associated with IC, probably because this study only compared the two types of prophylaxis using fluconazole.

Previous LCBI and the number of LCBI prior to IC were found to be significant based on the results of the univariate analysis, as well as number of antimicrobial treatments used. These factors are closely associated and support the importance of antimicrobial use as a predisposing factor for IC, as described in literature [3 , 28–30].

The risk factors that remained statistically significant in the logistic regression analysis were comparable with the risk factors found in the published literature. Furthermore, the cohort studies conducted in the United States and Spain showed that ELBW infants were a significant factor [1 , 32]. Lower gestational age and birth weight are associated with longer hospital stay, which favors colonization and, consequently, fungal infection [1 –3]. This association was also observed in infants with a birth weight of less than 1,000 g, while those who stayed longer in the NICU were independently associated with IC.

The duration of MV use was identified as an independent risk factor in this study. Tracheal tubes favor contamination of the lower airway with Candida sp, impairing the mucociliary clearance and allowing the invasiveness and subsequent dissemination of the fungi. Moreover, aspiration procedure allows colonization of the respiratory and digestive tracts, as previously reported [1 , 33].

Surgery prior to the IC was identified as a predictive factor for IC. In the present study, the type of surgery performed was not described. In previous studies, digestive tract surgery was also indicated as a risk factor for invasive fungal disease due to Candida colonization [7 , 31].

The number of antimicrobial treatments was an independent risk factor for IC. Previous studies showed that ATM modifies microbiome, which may lead to bacterial selection and may favor fungal growth [3 , 29]. Exposure to broad spectrum antimicrobials is also related to an increased risk of IC, especially for LBW infants [34].

4.3. Lethality and mortality associated with invasive candidiasis

Lethality rate found in the study (10.6%) was lower than those reported in literature, ranging from 20% to 40% [11 –13]. There was a statistical reduction associated with IC deaths (p = 0.015) when universal prophylaxis was used. Studies comparing non-prophylaxis group with prophylactic fluconazole groups found no significant difference in this outcome [20 , 26].

Reduction of mortality rate with the use of universal prophylaxis was not reported in the abovementioned studies. Hence, this issue should be evaluated further. Besides, the present study is a single center trial, and this restricts the generalization of results.

In conclusion, this was the first study to compare two different recommended prophylaxis using fluconazole for treatment of IC in patients admitted in the NICU. Results showed that a significant reduction in the incidence and lethality associated with IC during universal antifungal prophylaxis with fluconazole was achieved. Presence of risk factors such as used invasive devices and ATM also suggest the need for preventive measures that may reduce the incidence of IC.

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