Impact of empiric antibiotics for methicillin-resistant Staphylococcus aureus (MRSA) infection and associated Clostridioides difficile infection (CDI) risk: Secondary analysis of the CLEAR trial

ABSTRACT We performed secondary analyses of a postdischarge decolonization trial of MRSA carriers that reduced MRSA infection and hospitalization by 30%. Hospitalized MRSA infection was associated with 7.9 days of non-MRSA antibiotics and CDI in 3.9%. Preventing MRSA infection and associated hospitalization may reduce antibiotic use and CDI incidence.

Methicillin-resistant Staphylococcus aureus continues to produce considerable morbidity, mortality, and healthcare costs. 1 Although national implementation of infection prevention measures have led to a substantial decrease in hospital-onset MRSA infections, addressing community-onset and healthcare-associated community-onset MRSA infections requires additional efforts. 1 Approximately 10% of hospitalized adult MRSA carriers (colonized or infected) experience MRSA infection in the year following discharge. Of these infections, 85% require readmission. 2 Once hospitalized, patients with MRSA infections often receive empiric antibiotics beyond focused treatment of MRSA. We aimed to quantify the extent of non-MRSA empiric antibiotics attributable to MRSA infections and assess any risk of hospital-onset CDI as a result of this treatment. These estimates can quantify the added benefit to antibiotic stewardship and CDI from prevention of MRSA infection after hospital discharge.

Methods
We conducted a secondary analysis of the CLEAR (Changing Lives to Eradicate Antibiotic Resistance) Trial that found that postdischarge decolonization (5-day regimen of mupirocin plus chlorhexidine bathing and mouthwash, repeated twice monthly for 6 months) among MRSA infected or colonized adult inpatients reduced MRSA infections by 30% in the year following discharge. The study design and patient population has been reported elsewhere. 2 We identified adult participants who were rehospitalized due to a new MRSA infection following trial enrollment between March 2011 and April 2014 to quantify antibiotics given and any hospital-onset CDI risk.
In this secondary analysis, full-text medical records with detailed medication administration records and culture reports underwent review with a standardized data collection form. Based on culture results, hospitalizations were assigned to 2 groups: (1) MRSA infection only and (2) polymicrobial infection including MRSA. We quantified the duration of oral and intravenous non-MRSA antibacterial days of therapy (DOT) given before and after culture results. Any number of doses of a specific antibiotic given in 1 calendar day was counted as 1 DOT (https:// www.cdc.gov/nhsn/pdfs/pscmanual/11pscaurcurrent.pdf). If a nosocomial infection occurred during MRSA hospitalization in either group, attributable antibiotics were quantified. CDI cases were determined by both CDC laboratory criteria 3 and clinical judgment of infectious diseases physicians.

Discussion
Reduction of MRSA infection remains a national prevention priority. In recently hospitalized MRSA carriers, MRSA infection after hospital discharge is often severe enough to result in readmission. These hospitalizations due to MRSA infection were lengthy and often resulted in extensive exposure to non-MRSA antibiotics.
It has been reported that most empiric antibiotic regimens remain unchanged even after culture results were made available. 4,5 In our study, hospitalizations due to MRSA infection resulted in a week of non-MRSA antibiotics, more than half of which were given after culture results were available.
Notably, in 16% of our MRSA hospitalizations, patients received only MRSA-targeted therapy. Treating clinicians sometimes used focused anti-MRSA therapy when documentation of MRSA colonization or recent prior MRSA infection was available. When the clinical disease characteristics fit, data related to multidrug-resistant organism (MDRO) carriage and historical infection can substantially guide empiric therapy. 6 We further demonstrated an association between hospitalized MRSA infection and hospital-onset CDI. It is well known that cocolonization with multiple MDROs and C. difficile occurs. 7 Our observed 3.9% hospital-onset CDI incidence during MRSA-caused hospitalizations exceeds the national incidence of acquiring CDI during a hospitalization of 0.3% 8 by 12-fold, and exceeds the other estimates of overall CDI incidence in hospitalized patients by 5-fold or greater. 9,10 Similarly, we found that commonly administered antibiotics were broad-spectrum in nature, including fluoroquinolones, cephalosporins, and β-lactamase inhibitor combinations that are known to carry a high risk for CDI. 9,10 Our study has several limitations. First, even though its population was derived from a large clinical trial of >2,000 patients, the number of MRSA hospitalizations with complete medication administration records was <200. This low sample number limited the precision of hospital-onset CDI infection that were attributable to MRSA infection. Our reported CDI incidence may also be underestimated because we did not evaluate for postdischarge cases.
Despite these limitations, our study highlights the value of eradicating MDROs, such as MRSA, to prevent acquisition of or infection with another antibiotic-associated pathogen such as C. difficile. Effective prevention strategies, such as postdischarge decolonization in MRSA carriers, have been proven to prevent MRSA infections and hospitalizations in the CLEAR Trial. Therefore, these MRSA strategies will also likely reduce non-MRSA antibiotic use and CDI associated with hospitalization due to MRSA infection.
Financial support. This work was supported by the use of internal funding from the University of California Irvine School of Medicine.
Conflicts of interest. Raveena Singh reports conducting clinical studies in which participating nursing homes and hospitals received donated antiseptic products from Stryker (Sage Products), 3M, Clorox, Xttrium Laboratories, and Medline. James A. McKinnell reports receiving grant support and consulting fees from Achaogen and Theravance Biopharma, grant support, consulting fees, and lecture fees from Allergan, consulting fees from Cempra, Melinta Therapeutics, Menarini Group, and Thermo Fisher Scientific, and fees for serving as a research investigator from Science 37, conducting clinical studies in which participating nursing homes and hospitals received donated antiseptic products from Stryker (Sage Products), 3M, Clorox, Xttrium Laboratories and Medline, and serving as cofounder of Expert Stewardship. Loren G. Miller reports receiving grant support from Gilead Sciences, Merck, Abbott, Cepheid, Genentech, Atox Bio, and Paratek Pharmaceuticals, grant support and fees for serving on an advisory board from Achaogen and grant support, consulting fees, and fees for serving on an advisory board from Tetraphase and conducting clinical studies in which participating nursing homes and hospitals received donated antiseptic products from Stryker (Sage Products), 3M, Clorox, Xttrium Laboratories, and Medline. Susan S. Huang reports conducting clinical studies in which participating nursing homes and hospitals received donated antiseptic products from Stryker (Sage Products), Molnycke, 3M, Clorox, Xttrium Laboratories, and Medline. All other authors report no conflicts of interest relevant to this article.