Effect of Treating Parents Colonized With Staphylococcus aureus on Transmission to Neonates in the Intensive Care Unit: A Randomized Clinical Trial | Infectious Diseases | JAMA | JAMA Network
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Figure 1.  Flow of the Treating Parents to Reduce NICU Transmission of Staphylococcus aureus (TREAT PARENTS) Trial, November 2014 to October 2018
Flow of the Treating Parents to Reduce NICU Transmission of Staphylococcus aureus (TREAT PARENTS) Trial, November 2014 to October 2018

NICU indicates neonatal intensive care unit.

Figure 2.  Kaplan-Meier Curves for Staphylococcus aureus Acquisition
Kaplan-Meier Curves for Staphylococcus aureus Acquisition

A, Time to concordant S aureus acquisition (primary outcome). The confidence level for the primary outcome was 95.2%, which accounted for the 2 preplanned interim analyses. B, Time to any S aureus colonization. Time at risk is calculated the same way for panels A and B; namely, time from randomization to first of S aureus acquisition, collection of last culture, or 90 days. Median time at risk, 14 (interquartile range [IQR], 8-23) days for the intervention group and 9 (IQR, 8-20) days for the placebo group. X-axes truncated because a small number of neonates remained at risk after 40 days. Vertical ticks on curves indicate neonates censored at the time of last culture (surveillance or neonatal intensive care unit discharge). Most neonates had their first follow-up culture collected 1 week after randomization, illustrated by the few events occurring before day 7. The bias-corrected and accelerated bootstrap confidence interval accounts for bias and skewness in the bootstrap distribution. The bias correction is related to the proportion of bootstrap estimates that are less than the observed statistic; the acceleration parameter is proportional to the skewness of the bootstrap distribution and is estimated using a jackknife method.

Table 1.  Neonate and Parent Characteristicsa
Neonate and Parent Characteristicsa
Table 2.  Summary of Primary and Secondary Outcomes
Summary of Primary and Secondary Outcomes
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Gregory  ML, Eichenwald  EC, Puopolo  KM.  Seven-year experience with a surveillance program to reduce methicillin-resistant Staphylococcus aureus colonization in a neonatal intensive care unit.  Pediatrics. 2009;123(5):e790-e796. doi:10.1542/peds.2008-1526PubMedGoogle ScholarCrossref
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Maraqa  NF, Aigbivbalu  L, Masnita-Iusan  C,  et al.  Prevalence of and risk factors for methicillin-resistant Staphylococcus aureus colonization and infection among infants at a level III neonatal intensive care unit.  Am J Infect Control. 2011;39(1):35-41. doi:10.1016/j.ajic.2010.07.013PubMedGoogle ScholarCrossref
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Voskertchian  A, Akinboyo  IC, Colantuoni  E, Johnson  J, Milstone  AM.  Association of an active surveillance and decolonization program on incidence of clinical cultures growing Staphylococcus aureus in the neonatal intensive care unit.  Infect Control Hosp Epidemiol. 2018;39(7):882-884. doi:10.1017/ice.2018.81PubMedGoogle ScholarCrossref
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Preliminary Communication
December 30, 2019

Effect of Treating Parents Colonized With Staphylococcus aureus on Transmission to Neonates in the Intensive Care Unit: A Randomized Clinical Trial

Author Affiliations
  • 1Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 2Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
  • 3Department of Hospital Epidemiology and Infection Control, The Johns Hopkins Hospital, Baltimore, Maryland
  • 4Department of Pediatrics, Cooper University Health Care, Camden, New Jersey
  • 5Division of Medical Microbiology, Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland
  • 6Division of Neonatology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 7Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 8Division of Medical Microbiology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 9Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
JAMA. 2020;323(4):319-328. doi:10.1001/jama.2019.20785
Key Points

Question  Does treating parents with short-course intranasal mupirocin and topical chlorhexidine bathing compared with placebo reduce acquisition of Staphylococcus aureus colonization in neonates?

Findings  In this randomized clinical trial that included 190 neonates with parents colonized with S aureus, treating parents with intranasal mupirocin and chlorhexidine-impregnated cloths compared with placebo significantly reduced the hazard of acquiring colonization with a parental S aureus strain (hazard ratio, 0.43).

Meaning  Treating colonized parents may reduce risk of S aureus transmission to neonates, but these findings are preliminary and require further research for replication and to assess generalizability.

Abstract

Importance  Staphylococcus aureus is a leading cause of health care–associated infections in the neonatal intensive care unit (NICU). Parents may expose neonates to S aureus colonization, a well-established predisposing factor to invasive S aureus disease.

Objective  To test whether treating parents with intranasal mupirocin and topical chlorhexidine compared with placebo would reduce transmission of S aureus from parents to neonates.

Design, Setting, and Participants  Double-blinded randomized clinical trial in 2 tertiary NICUs in Baltimore, Maryland. Neonates (n = 236) with S aureus–colonized parent(s) were enrolled. The study period was November 7, 2014, through December 13, 2018.

Interventions  Parents were assigned to intranasal mupirocin and 2% chlorhexidine–impregnated cloths (active treatment, n = 117) or petrolatum intranasal ointment and nonmedicated soap cloths (placebo, n = 119) for 5 days.

Main Outcomes and Measures  The primary end point was concordant S aureus colonization by 90 days, defined as neonatal acquisition of an S aureus strain that was the same strain as a parental strain at time of screening. Secondary outcomes included neonatal acquisition of any S aureus strain and neonatal S aureus infections.

Results  Among 236 randomized neonates, 208 were included in the analytic sample (55% male; 76% singleton births; mean birth weight, 1985 g [SD, 958 g]; 76% vaginal birth; mean parent age, 31 [SD, 7] years), of whom 18 were lost to follow-up. Among 190 neonates included in the analysis, 74 (38.9%) acquired S aureus colonization by 90 days, of which 42 (56.8%) had a strain concordant with a parental baseline strain. In the intervention and placebo groups, 13 of 89 neonates (14.6%) and 29 of 101 neonates (28.7%), respectively, acquired concordant S aureus colonization (risk difference, –14.1% [95% CI, –30.8% to –3.9%]; hazard ratio [HR], 0.43 [95.2% CI, 0.16 to 0.79]). A total of 28 of 89 neonates (31.4%) in the intervention group and 46 of 101 (45.5%) in the control group acquired any S aureus strain (HR, 0.57 [95% CI, 0.31 to 0.88]), and 1 neonate (1.1%) in the intervention group and 1 neonate (1.0%) in the control group developed an S aureus infection before colonization. Skin reactions in parents were common (4.8% intervention, 6.2% placebo).

Conclusions and Relevance  In this preliminary trial of parents colonized with S aureus, treatment with intranasal mupirocin and chlorhexidine-impregnated cloths compared with placebo significantly reduced neonatal colonization with an S aureus strain concordant with a parental baseline strain. However, further research is needed to replicate these findings and to assess their generalizability.

Trial Registration  ClinicalTrials.gov Identifier: NCT02223520

Introduction

Staphylococcus aureus is a leading cause of health care–associated infections in neonatal intensive care units (NICUs).1 Data from 1997 to 2012 suggested that up to 3.7% of very low-birth-weight infants in US NICUs developed S aureus bacteremia or meningitis, with an overall mortality of 10% to 25%.2,3 In spite of appropriate therapy, neonatal infections can have long-term sequelae including poor neurodevelopmental and growth outcomes.4

During delivery or after birth, S aureus can transfer from people or objects in the environment and asymptomatically colonize neonates. Vertical transmission of S aureus from mother to infant during delivery is rare, but postnatal transmission from mother to infant is common in the first few months of life.5,6 In the NICU, many infection prevention strategies focus on health care workers and the physical environment as reservoirs for neonatal exposure to S aureus, but parents may also be an important reservoir for S aureus transmission.7-9

S aureus colonization is a well-established predisposing factor to invasive, life-threatening infection.10,11 Up to 34% of neonates colonized with S aureus in the NICU develop an S aureus infection.11-14 Identifying and treating S aureus carriers can decrease colonization and reduce S aureus infections.15 However, antibiotics and antiseptics applied topically for decolonization have inadequate safety data in neonates. The Treating Parents to Reduce Neonatal Transmission of Staphylococcus aureus (TREAT PARENTS) trial was designed to test the hypotheses that parents are a primary reservoir from which neonates acquire S aureus colonization and that treating S aureus–colonized parents with intranasal mupirocin and topical chlorhexidine gluconate antisepsis would reduce the spread of S aureus from parents to their neonates.

Methods
Trial Design

This study was designed as a double-blinded randomized clinical trial that enrolled at The Johns Hopkins Hospital NICU, a 45-bed level IV NICU in a quaternary care center, and The Johns Hopkins Bayview Medical Center NICU, a 25-bed, level III unit. The study period was November 2014 through December 2018. All parents or legal guardians provided written informed consent. The trial was conducted in the setting of an S aureus infection prevention program that includes weekly active surveillance cultures with decolonization of all S aureus–colonized neonates in the 2 study NICUs as previously described.16 The study was approved by the Johns Hopkins Medicine institutional review board. The protocol has been published,17 and the final protocol, amendments, and statistical analysis plan are available in Supplement 1.

Participants

Neonates admitted to the 2 study NICUs and their parent(s) were prescreened for eligibility. Eligible neonates had never had a prior culture positive for S aureus, had an estimated NICU length of stay of at least 5 days, were no more than 7 days old if admitted to the NICU from an outside location, and had at least 1 parent who tested positive for S aureus at screening. Parents were defined as the biological mother and father. If only 1 parent was available, the parent could identify a primary visitor to be included. Only 2 parents (or 1 parent, 1 primary visitor, or both) were enrolled for each neonate. Eligible parents were able to visit the child at the bedside, were willing to be randomized, and had no documented or reported allergies to any agent used in either treatment regimen.

Treatment Allocation and Masking

After providing written informed consent, parents underwent a prerandomization screening for eligibility and samples were collected from multiple anatomical sites (nares, throat, groin, perianal). If either parent screened positive for S aureus, then both parents as a pair were eligible for randomization. The neonate-parent “grouping” was the unit of randomization, such that neonates of multiple gestations and each parent were allocated to the same group. A study team member (E.C.) performed stratified permuted-block randomization via computer-generated random numbers with block sizes of 4 and 6 to balance allocation by study sites and strata of birth weight (<1500 g or ≥1500 g). Intervention and placebo products were manufactured using identical packaging. The Johns Hopkins Hospital Investigational Drug Pharmacy prepared study kits and dispensed kits in sequence based on study site and birth weight and used lot numbers to track intervention and placebo products. Investigators, participants, and treating clinicians were blinded to treatment assignment.

Intervention

Parents in the intervention group received 2% intranasal mupirocin ointment (McKesson Co) and 2% chlorhexidine gluconate–impregnated cloths (Sage Products Inc), and parents in the placebo group received 2% petrolatum intranasal ointment (McKesson Co) and nonmedicated soap cloths (Comfort Bath; Sage Products Inc). Parents in both groups were provided standardized instructions for use. Participants self-administered the ointment twice daily for 5 days and used packaged cloths for daily skin cleaning of designated body areas, including arms, legs, chest and neck, and back and perineum for 5 days.

Study Outcomes

The primary outcome was neonatal acquisition of an S aureus strain that was concordant with an S aureus strain that parent(s) were colonized with at the time of prerandomization screening (baseline S aureus strain). Secondary outcomes included acquisition of any S aureus strain (concordant and discordant) and neonatal S aureus infection as defined by the Centers for Disease Control and Prevention National Healthcare Safety Network criteria.18 Additional secondary outcomes, including effect of decolonization on parent S aureus colonization, and parent attitudes regarding knowledge and feasibility, will be presented in future publications.

Data Collection and Laboratory Analysis

To ascertain the primary outcome, neonates’ S aureus colonization status at the time of study randomization (day 0), weekly (day 7, 14, etc), and at discharge was determined using study surveillance swabs collected from multiple anatomical sites (nares, umbilicus, groin, and perineum). Results of cultures from weekly surveillance swabs (Tuesdays) collected as part of the NICU’s S aureus infection prevention program and results of cultures collected during clinical care (eg, blood cultures, respiratory cultures) were also used to identify S aureus acquisition. S aureus strains were analyzed and considered concordant if pulsed-field gel electrophoresis (PFGE) patterns had 3 or fewer band differences.19 If PFGE did not produce an interpretable fingerprint, strains were analyzed by multilocus sequence typing using whole-genome sequencing. Strains were considered concordant when all 7 genes compared had identical alleles. To identify S aureus infections, 2 study team members (A.M.M., D.F.K.) blinded to treatment assignment reviewed all cultures sent during routine clinical care and applied criteria established by the National Healthcare Safety Network.18 To monitor for safety and treatment adherence (Supplement 1, Final statistical analysis plan sections 9.e and 10), the research team contacted parents daily. As described in the protocol, neonates were monitored for bloodstream infections attributable to any organism or for death. Clinical and demographic data were collected via manual review of electronic medical records and through participant interviews. Prior studies of risk factors for S aureus colonization have suggested an association with race20,21; therefore, race and ethnicity were collected based on fixed categories via manual review of electronic medical records and through participant interviews. If parents left the question blank on the paper self-completed data collection form, information from the electronic medical record, if available, was used.

Sample Size and Power Calculation

The primary outcome, concordant S aureus colonization, was analyzed using a time-to-event survival analysis. After accounting for 2 preplanned interim analyses and possible clustering of the primary outcome among nonsingleton neonates, 40 events were required to detect a 60% reduction in the hazard of concordant S aureus colonization in the intervention group, with 80% power and a 5% type I error rate. Given that no data were available to inform the potential size of the treatment effect, the 60% reduction was derived using the following rationale: under ideal conditions, parent decolonization would reduce parent-to-neonate transmission by 100%; however, it was anticipated that adherence would be less than 100% and that some parents would become recolonized after treatment. The study was not powered to assess S aureus infections, which are rare events in the study setting of an S aureus infection prevention program that includes weekly active surveillance cultures with decolonization of all S aureus–colonized neonates.

Statistical Analyses

Interim analyses were completed after 20 and 30 neonates achieved the primary outcome. The data and safety monitoring board reviewed results of the interim analysis to determine if the trial met preplanned minimum criteria to stop for efficacy based on an approximation to the O’Brien-Fleming alpha spending function for survival analysis. The preplanned approach for calculating the type I error rate for the final analysis used a linear search to identify the final critical value such that the overall type I error rate, ie, the probability of rejecting the null hypothesis for at least 1 of the 3 analyses, was 5%. The linear search required the preplanned critical values for the 2 interim analyses as well as the covariance of the test statistics for the log hazard ratio from the Cox proportional hazards model obtained at each analysis, estimated via bootstrap. A full description of the interim analyses can be found in the protocol and statistical analysis plan in Supplement 1.

On the day parents were randomized, the neonate underwent testing to determine baseline S aureus colonization status. Neonates who tested positive for S aureus colonization at the time of randomization did not satisfy the inclusion criteria and were not included in the analytic sample. For the primary analysis, time at risk for the primary outcome, concordant S aureus colonization, was defined as randomization to the first of S aureus acquisition, collection of last culture, or 90 days. This primary analysis is referred to as concordant acquisition within 90 days. The treatment effect was defined as the hazard ratio (HR) of concordant S aureus colonization comparing the intervention and placebo groups and estimated using a Cox proportional hazards model that included only a main term for treatment assignment. Post hoc, the Schoenfeld residual plot and complementary log-log survival plot were visually inspected and the Grambsch and Therneau test for proportional hazards was conducted.22

Planned secondary analyses included (1) removing the censoring at 90 days when defining the time at risk (ie, randomization to the first of S aureus acquisition or collection of last culture [referred to as concordant acquisition by NICU discharge]), (2) defining the treatment effect as the difference in the proportion of neonates acquiring concordant S aureus by 4 and 8 weeks after randomization, (3) estimating the treatment effect (both HR and risk difference) on the acquisition of S aureus (regardless of concordant status), and (4) estimating the treatment effect (both HR and risk difference) on neonatal S aureus infection. To account for the possibility of clustering within multiple-gestation neonate-parent groupings, bootstrap confidence intervals for the treatment effects were generated via 10 000 bootstrap samples in which neonate-parent groupings were sampled with replacement, based on the bias-corrected and accelerated method (accounting for possible bias and skew in the bootstrap distribution).23 Additional planned exploratory secondary analyses included prespecified subgroup analyses, baseline covariate–adjusted treatment effect estimates, and a per-protocol analysis to account for parental adherence to treatment (see final statistical analysis plan in Supplement 1). Two post hoc subgroup analyses were performed to estimate the treatment effect by stratifying neonates based on birth weight and parent methicillin-resistant S aureus (MRSA) status. Analyses were conducted according to the allocated treatment assignment.

Neonates with a culture only on the day of randomization, ie, neonates discharged before either a day 7 or a discharge culture was obtained, were considered lost to follow-up and excluded from analyses of concordant and any S aureus colonization. Thus, preplanned primary and secondary analyses were conducted, assuming completely at random loss to follow-up. A preplanned sensitivity analysis censored these neonates at the time of discharge. A post hoc multiple imputation procedure for the primary outcome was conducted by creating 10 imputed data sets (eAppendix Section 1 in Supplement 2). Concordant colonization status was imputed by resampling from matched sets of neonates with known colonization status, based on treatment assignment, singleton vs nonsingleton birth, mode of delivery, gestational age, and birth weight.

After accounting for the conducted interim analyses, statistical significance for the primary outcome was based on the 95.2% bias-corrected and accelerated confidence interval excluding the null effect (ie, HR of 1). Statistical significance of secondary analyses, of the primary and secondary outcomes, was based on the 95% bias-corrected and accelerated confidence intervals (ie, P < .05) excluding the null for the given treatment effect (ie, 1 for HRs and 0 for differences in proportions). There was no plan for adjustment for multiple comparisons of secondary outcomes or planned secondary analyses. Because of the potential for type 1 error due to multiple comparisons, findings for analyses of secondary end points should be interpreted as exploratory. Data were analyzed using R version 3.6.1 (R Foundation for Statistical Computing).

Results
Study Participants

Of the 3215 neonates assessed for eligibility, 236 (7.3%) underwent randomization (119 to placebo and 117 to intervention) (Figure 1). The analytic sample excluded neonates who did not satisfy the inclusion criteria of the study: neonates who were colonized with S aureus at time of randomization (n = 25), had a culture obtained before randomization that was positive for S aureus after randomization (n = 2), and whose parents did not have confirmed S aureus colonization after being randomized (n = 1). Of the 208 neonates in the analytic sample, 55% were male, 76% were singleton births, the mean birth weight was 1985 g (SD, 958 g), 76% were vaginal birth, and the mean parent age was 31 (SD. 7) years. There were 101 and 107 neonates in the intervention and placebo groups, respectively (Table 1). Adherence to assignment was similar in the intervention and placebo groups (71% and 76%, respectively; P = .57). Seventy-six of 208 neonates (36.5%) had a culture positive for S aureus, of which 44 (57.9%) had an S aureus strain concordant with a parental baseline strain (eAppendix Section 2, eFigure 1 in Supplement 2); 42 neonates acquired S aureus within 90 days of randomization (primary outcome), and 2 neonates acquired S aureus more than 90 days after randomization but before NICU discharge. Of the 76 S aureus strains, 6 (7.9%) were MRSA and 70 (92.1%) were methicillin-susceptible S aureus (MSSA). Forty of 70 MSSA isolates (57.1%) and 4 of 6 MRSA isolates (66.7%) were concordant with a parent strain.

Primary Outcome

Among the 208 neonates in the analytic sample, 12 in the intervention group and 6 in the placebo group were discharged before the day-7 surveillance culture and did not have a discharge surveillance culture. These neonates were excluded from the primary analysis. Forty-two neonates (22.1%) acquired an S aureus strain concordant with a parental baseline strain within 90 days of randomization (13/89 [14.6%] in the intervention group vs 29/101 [28.7%] in the placebo group). Figure 2A shows the Kaplan-Meier survival estimates for acquisition of concordant S aureus colonization for each treatment group. Treating parents with intranasal mupirocin and 2% chlorhexidine–impregnated cloths compared with placebo reduced the hazard of concordant S aureus colonization within 90 days of randomization (HR, 0.43 [95.2% CI, 0.16 to 0.79]; P = .03) (Table 2). After accounting for the 2 interim analyses conducted, this result met the preplanned threshold for statistical significance. The proportional hazards assumption was supported by the data (P = .79). The post hoc multiple imputation yielded similar findings (HR, 0.45 [95.2% bias-corrected and accelerated CI, 0.18 to 0.87]) as the primary analysis.

Planned secondary analyses of concordant S aureus colonization demonstrated that compared with neonates in the placebo group, neonates in the intervention group had a lower hazard of acquiring concordant S aureus colonization by NICU discharge (15/89 [16.9%] in the intervention group vs 29/101 [28.7%] in the placebo group; HR, 0.50 [95% bias-corrected and accelerated CI, 0.20 to 0.92]) and lower risk for acquiring a concordant strain within 4 weeks (risk difference, –14% [95% bias-corrected and accelerated CI, –31% to –4.7%]) and 8 weeks of randomization (risk difference, –14% [95% bias-corrected and accelerated CI, –31% to –3.9%]) (Table 2).

Secondary Outcomes

Among the 190 neonates in the analytic sample, 76 (40.0%) acquired S aureus colonization within 90 days of randomization (30/89 [33.7%] in the intervention group vs 46/101 [45.5%] in the placebo group). Figure 2B shows the time to acquisition of any S aureus colonization when comparing the intervention and placebo groups. Treating parents with intranasal mupirocin and 2% chlorhexidine–impregnated cloths compared with placebo reduced the hazard of a neonate acquiring S aureus within 90 days of randomization (HR, 0.57 [95% bias-corrected and accelerated CI, 0.31 to 0.88]). In addition, compared with neonates in the placebo group, neonates in the intervention group had a lower hazard of acquiring S aureus colonization by NICU discharge (32/89 [36.0%] in the intervention group vs 46/101 [45.5%] in the placebo group; HR, 0.62 [95% bias-corrected and accelerated CI, 0.34 to 0.95]) and lower risk for acquiring S aureus colonization within 4 weeks (risk difference, –13% [95% bias-corrected and accelerated CI, –30% to –1.3%]) and 8 weeks of randomization (risk difference, –13% [95% bias-corrected and accelerated CI, –31% to –0.3%]). Two S aureus bloodstream infections occurred before a neonate was identified as S aureus colonized (1/89 [1.1%] in the intervention group vs 1/101 [1.0%] in the placebo group; HR not calculated because there was not a sufficient number of events to warrant a statistical comparison).

Preplanned Exploratory Analyses

The results of the preplanned exploratory secondary analyses are presented in the eAppendix in Supplement 2. The findings for the primary and secondary outcomes were not sensitive to preplanned sensitivity analyses (eAppendix Sections 3 and 4 in Supplement 2). In preplanned adjusted analysis, adjusting for neonate birth weight, inborn/outborn status (inborn include those neonates born at The Johns Hopkins Hospital and outborn include those born at an outside hospital and transferred to the 2 Johns Hopkins study NICUs) and study site (eAppendix Section 5 in Supplement 2) resulted in no precision gain for estimating the treatment effect for the primary outcome; however, the width of the confidence intervals for treatment effects for secondary outcomes decreased by at most 13% compared with the unadjusted analyses. The estimated treatment effect for the primary outcome was not sensitive to the preplanned per-protocol analyses (eAppendix Section 6 in Supplement 2). Among the preplanned subgroup analyses (eAppendix Section 7 in Supplement 2), the intervention appeared most effective in the subgroup of parents who had nares-only colonization (eAppendix Section 7.2, eFigure 2 in Supplement 2). Other preplanned outcomes included infections and mortality. In addition to the 2 S aureus bloodstream infections that occurred before a neonate was identified as S aureus colonized (secondary outcome), there were 3 nonbloodstream S aureus infections before discharge, 1 in the intervention group and 2 in the placebo group. Additionally, there were 4 bloodstream infections caused by other organisms in the studied neonates, 3 in the intervention group and 1 in the placebo group. There were 3 deaths in the studied neonates (1 instance of multiorgan failure and 2 occurrences of respiratory failure), all in the placebo group; none were related to the study protocol. The study was not powered to detect differences in S aureus infections, all-cause bloodstream infections, or mortality.

Post Hoc Subgroup Analyses

In post hoc subgroup analysis of neonate birth weight (eAppendix Section 8.2 in Supplement 2), 20 of 71 neonates (28.2%) with birth weight less than 1500 g acquired S aureus colonization, compared with 22 of 119 (18.5%) with birth weight 1500 g or greater.

Adverse Events

There were 26 adverse events reported by the study parents (10/147 parents in the intervention group and 16/160 parents in the placebo group), of which 88% were mild skin irritation or nasal congestion (eAppendix Section 9 in Supplement 2).

Discussion

Treating parents of neonates in the NICU with intranasal mupirocin and 2% chlorhexidine–impregnated cloths compared with placebo reduced the risk of a neonate acquiring S aureus colonization with strains that were the same as S aureus strains identified from the parent(s) at time of study enrollment. In neonates S aureus is a predominant pathogen causing health care–associated infections, including central line–associated bloodstream infections, surgical site infections, and late-onset sepsis.1,24 Rates of invasive S aureus disease in neonates are among the highest of any age group.3,21,25S aureus colonization is a predisposing factor to invasive S aureus disease.2,11-14 These findings provide early evidence that treating S aureus–colonized parents may provide a novel intervention to reduce the risk of S aureus transmission to neonates in the NICU, a period of high risk of invasive S aureus disease. Further research is needed to replicate these findings and assess their generalizability.

This trial suggests that parents are a major reservoir from which neonates acquire S aureus in the NICU. Neonates are unique in that they have an immature microbiome at time of admission to the NICU and rarely have preexisting S aureus colonization. Rather, neonates acquire S aureus colonization in the NICU from exposure to people and objects in the environment. In this trial, more than half of neonates who acquired S aureus had the same strain as their parent(s). Two primary strategies protect hospitalized patients from S aureus disease: the interruption of transmission to patients and the eradication of colonization.26 Standard hospital-based infection prevention strategies, such as hand hygiene and environmental cleaning programs, target health care workers, and less commonly parents, to prevent S aureus transmission to neonates. Yet parents are a major reservoir. Similar to studies in adults, identifying and treating S aureus–colonized neonates reduces infections, but S aureus remains a leading cause of infections in this population.27 This study suggests that treating S aureus–colonized parents may reduce a key reservoir and prevent or delay neonatal acquisition of S aureus.

Prior parent-directed interventions have shown success in reducing infections in neonates. Providing intrapartum chemoprophylaxis to mothers colonized with group B Streptococcus reduces neonatal invasive group B Streptococcus disease.28 Vaccinating pregnant women against influenza and pertussis prevents neonatal infections.29,30 Expanding the armamentarium of parent-directed infection prevention strategies may help decrease S aureus disease in neonates, given that other available strategies have proven ineffective at adequately reducing S aureus disease in this high-risk population.

Sixty-seven percent of neonates in the analytic sample (n = 4) who had NICU-onset MRSA colonization in this study had a strain that was concordant with a parental baseline strain. Reports exist of neonates acquiring MRSA infections in the NICU, and subsequent investigations identify the parents as a source of the infection.5-9 The trial data demonstrate that parents may import MRSA into the NICU. Neonates colonized with undetected MRSA are also reservoirs for ongoing MRSA transmission within the NICU. Whether investigation of MRSA transmission in NICUs should include parent screening requires further study.

Limitations

This study has several limitations. First, this trial enrolled at centers that have comprehensive S aureus surveillance and decolonization programs, so the effect of the intervention on overall S aureus acquisition in centers without such programs requires further investigation. Second, the definition of adherence to the intervention could have overestimated true adherence. Yet even with incomplete adherence in the analytic sample the intervention was highly effective. Third, the primary outcome was S aureus colonization, and the study was not powered to assess S aureus infections. Because all neonates colonized with S aureus in the 2 study units were treated with mupirocin and chlorhexidine gluconate as part of the active surveillance culture and decolonization programs at both hospitals, the observed rate of infections and effect of treating parents on preventing overall infection rates are not generalizable. Fourth, measuring parent hand hygiene or parent-neonate contact (eg, kangaroo care, breast feeding) was not possible, so adjusting for the degree of interaction between parents and neonates was not possible. Fifth, PFGE was used to distinguish strain types, as PFGE was considered the standard when the trial began. Sixth, there were missing outcome data for 18 neonates. Two sensitivity analyses that allowed inclusion of these neonates in the treatment comparison of the primary outcome, ie, that assigned all the neonates to no concordant colonization and a multiple imputation procedure matching these neonates to otherwise similar neonates with additional cultures after baseline, yielded similar estimated treatment effects.

Conclusions

In this preliminary trial of parents colonized with S aureus, treatment with intranasal mupirocin and chlorhexidine-impregnated cloths compared with placebo significantly reduced neonatal colonization with an S aureus strain concordant with a parental baseline strain. However, further research is needed to replicate these findings and to assess their generalizability.

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Article Information

Corresponding Author: Aaron M. Milstone, MD, MHS, Johns Hopkins Hospital, Johns Hopkins University, 200 N Wolfe St, Rubenstein 3141, Baltimore, MD 21287 (amilsto1@jhmi.edu).

Accepted for Publication: December 5, 2019.

Published Online: December 30, 2019. doi:10.1001/jama.2019.20785

Author Contributions: Drs Milstone and Colantuoni had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Milstone, Aucott, Carroll, Colantuoni.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Milstone, Voskertchian, Koontz, Khamash, Colantuoni.

Critical revision of the manuscript for important intellectual content: Milstone, Voskertchian, Khamash, Ross, Aucott, Gilmore, Cosgrove, Carroll, Colantuoni.

Statistical analysis: Colantuoni.

Obtained funding: Milstone, Colantuoni.

Administrative, technical, or material support: Voskertchian, Koontz, Ross, Aucott, Carroll.

Supervision: Milstone, Voskertchian, Aucott, Gilmore, Carroll.

Conflict of Interest Disclosures: Dr Milstone reported receiving grants from the Centers for Disease Control and Prevention, the National Institutes of Health (NIH), and Sage Products Inc and receiving personal fees from Becton Dickinson. Dr Cosgrove reported receiving personal fees from Novartis, Theravance, and Basilea. Dr Carroll reported receiving grants from NIH, Singulex Inc, Curetis Inc, Accelerate Inc, and GenMark and receiving personal fees from Pattern Diagnostics, GenMark, and Becton Dickinson. No other disclosures were reported.

Funding/Support: This project was supported by grant R01HS022872 from the Agency for Healthcare Research and Quality.

Role of the Funder/Sponsor: The Agency for Healthcare Research and Quality had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality.

Additional Contributions: We thank Josh Betz, MS (Johns Hopkins University School of Public Health), Yunfan Fan, BS (Johns Hopkins University), and Winston Timp, PhD (Johns Hopkins University), for statistical support; Avinash Gadala, MS (Johns Hopkins Hospital), for developing the trial database; other study team members (Johns Hopkins University) for their help in study coordination, patient recruitment, and data collection, including Victor O. Popoola, MBBS, Blessing Enobun, MD, Kathleen Harrelson, RNC-OB, Anne King, BSN, Tinuade Okoro, MD, Sean Thompson, BS, Marissa Totten, BS, and Lena Warrak, BS; Laura Wachter, PharmD (Johns Hopkins Hospital), for preparing and dispensing study treatment; the data and safety monitoring board (DSMB) members, including Neal Halsey, MD (Johns Hopkins University), Anthony D. Harris, MD (University of Maryland), Mary L. Leppert, MD (Kennedy Krieger Institute), Michael Rosenblum, PhD (Johns Hopkins University School of Public Health), and the Johns Hopkins Hospital neonatal intensive care unit nursing staff and microbiology laboratory staff for their support of this study. DSMB members received financial compensation for their contribution to the study. All other individuals involved in the study provided their assistance without any compensation beyond their usual salary.

Data Sharing Statement: See Supplement 3.

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