Introduction

Neonates are at high risk of devastating outcomes from Staphylococcus aureus (SA) infection. Methicillin-resistant Staphylococcus aureus (MRSA) infections in neonates increases length of stay, morbidity, mortality, and healthcare cost.^{Reference Song, Perencevich, Campos, Short and Singh1,Reference Ericson, Popoola and Smith2} Infection prevention practices in neonatal intensive care units (NICUs) must address unique challenges associated with this vulnerable patient population, such as extreme prematurity, low birthweight, prolonged hospital courses, use of numerous medical devices, procedures, shared areas or bed spaces, and family visitation practices. One study, published by the Chicago-Area Neonatal MRSA Working Group, describes the epidemiology of MRSA in NICUs with a consensus statement that provides guidance on preventing MRSA infections in NICUs.^{Reference Gerber, Jones and Scott3} The experiences of MRSA colonization and infection in various NICUs in the last two decades have contributed to our understanding of risk factors for MRSA colonization, infection, and outcomes in infants in NICUs.^{Reference Reich, Boyle and Hogan4–Reference Schuetz, Hogan and Reich7}

The first published case of MRSA infection in a NICU^{Reference Weeks, Garcia-Prats and Baker8} dates back to the early 1980s. Since the emergence of community-acquired MRSA in the late 1990s, both healthcare associated (HA) and community acquired (CA) strains can be transmitted to hospitalized neonates.^{Reference Healy, Hulten, Palazzi, Campbell and Baker9,Reference Lessa, Edwards, Fridkin, Tenover, Horan and Gorwitz10} Reich et al found a higher risk of infection associated with HA-MRSA colonization.^{Reference Reich, Boyle and Hogan4} In a large meta-analysis, Zervou et al. found that the relative risk of MRSA-colonized patients developing an MRSA infection during the hospitalization was 24.2 among patients admitted to NICUs and pediatric intensive care units, with the MRSA colonization rate among NICU patients being as high as 6.1%.^{Reference Zervou, Zacharioudakis, Ziakas and Mylonakis11} Healthcare providers and families are both sources of possible transmission of MRSA to the neonate.^{Reference Geva, Wright, Baldini, Smallcomb, Safran and Gray12–Reference Jimenez-Truque, Tedeschi, Saye, McKenna, Langdon, Wright, Alsentzer, Arnold, Saville, Wang, Thomsen and Creech14}Additionally, vertical transmission from the vaginal canal during delivery is reported to occur.^{Reference Ogura, Inayama and Sasamoto15} Risk factors associated with MRSA colonization among NICU patients include very low birth weight, extreme prematurity, prolonged mechanical ventilation, repeated peripheral intravenous line placements, visitors sharing rooming/toileting and a high point prevalence of colonization in the unit.^{Reference Galuszka, Thomsen, Knudsen, Stenkjaer, Nielsen, Nielsen, Petersen, Holzknecht, Damkjaer Bartels, Breindahl and Aunsholt5,Reference Balamohan, Beachy, Kohn and Rubin6,Reference Lessa, Edwards, Fridkin, Tenover, Horan and Gorwitz10} Some authors reported that infants with MRSA infection became colonized earlier in the hospitalization, had a longer length of stay, and were less likely to have received mupirocin compared to the neonates who did not develop an infection.^{Reference Schuetz, Hogan and Reich7,Reference Zervou, Zacharioudakis, Ziakas and Mylonakis11}

Infection control practices form the foundation for preventing transmission of MRSA within NICUs. These include hand hygiene, isolation of positive patients, cohorting, and the use of contact precautions (gown and gloves) when handling positive patients.^{Reference Gerber, Jones and Scott3} Some centers also employ surveillance and decolonization. Topical antimicrobials such as chlorhexidine (disrupts bacterial cell membrane)^{Reference Jenkins, Addy and Wade16} and mupirocin (inhibits bacterial protein and RNA synthesis)^{Reference Parenti, Hatfield and Leyden17} are utilized against SA. Decolonization practices vary by institution. A multi-center retrospective cohort study of tertiary care NICUs found that the adjusted hazard of gram-positive cocci infection was 64% lower among neonates who received mupirocin compared to neonates who did not, without increasing the risk of subsequent infections with gram-negative organisms.^{Reference Pierce, Bryant, Elward, Lessler and Milstone18} Nelson et al. conducted a randomized placebo-controlled study comparing mupirocin and placebo, revealing that up to 80% of neonates treated with mupirocin were successfully decolonized within two weeks with a significant reduction in the rate of invasive SA infections.^{Reference Nelson, Shaw and Gross19}

Despite improved outcomes with decolonization, some infants develop infection despite negative surveillance cultures. This is likely multifactorial in that MRSA may colonize body sites not sampled, infections can occur without prior colonization and that colonization can occur in between surveillance testing dates.^{Reference Gollerkeri, Oliver and Maria20} Goldstein et al. studied the frequency of surveillance by culture methods and found that increasing monitoring from every four weeks to weekly decreased the mean number of MRSA-colonized neonates from 2.9 to 0.6, respectively, thus supporting the use of weekly monitoring.^{Reference Goldstein, Jenness, Tuttle, Power, Paul and Eppes21}

Recolonization with MRSA after decolonization is more likely to occur in neonates with prolonged hospitalizations and those colonized with mupirocin-resistant strains.^{Reference Akinboyo, Voskertchian and Gorfu22} Resistance to mupirocin is a growing concern and is an area under study, particularly in cases of MRSA outbreaks in NICUs that employ decolonization with mupirocin. Balamohan et al. found that decolonization by mupirocin during their study period reduced rates of Methicillin-susceptible Staphylococcus aureus (MSSA) infection but did not impact MRSA infection rates, and that the MRSA strain circulating through the NICU was mupirocin resistant.^{Reference Balamohan, Beachy, Kohn and Rubin6} In contrast, Arora et al. did not observe higher MICs to mupirocin over a year-long study period of universal decolonization,^{Reference Arora, Khan, Ailumerab, Natarajan, Meert, Salimnia, Valentini, Thomas, Semproch, Asmar and McGrath23} suggesting that the widespread use of the topical antimicrobial may not necessarily lead to the emergence of more resistant strains.

The Centers for Disease Control and Prevention Recommendations for Prevention and Control of Infections in Neonatal Intensive Care Unit Patients (2020) include guidelines on screening and decolonization practices.²⁴ Consistent with these available guidelines, most NICUs screen for MRSA colonization during an outbreak, however there is variability in decolonization practices. The guidelines currently have a conditional recommendation to consider targeted decolonization for SA-colonized neonates, but no recommendation for the optimal decolonization agent or combination of agents. Thus, we sought to evaluate this in our study.