Coagulase-neg staph indicates coagulase-negative Staphylococci; Spp species.
Carr TF, Hill JL, Chiu A, Chang EH. Alteration in Bacterial Culture After Treatment With Topical Mupirocin for Recalcitrant Chronic Rhinosinusitis. JAMA Otolaryngol Head Neck Surg. 2016;142(2):138-142. doi:10.1001/jamaoto.2015.3059
Topical mupirocin therapy is used to treat symptomatic chronic sinusitis (CRS). However, the potential adverse impact of this therapy on the sinus microbiota has not been well quantified.
To determine changes in microbiologic culture results before and after topical mupirocin therapy in patients with CRS with medically and surgically refractory disease.
Design, Setting, and Participants
We performed a retrospective medical chart review for 22 consecutive adults evaluated and treated between January 1, 2012, and January 1, 2014, at an otolaryngology-rhinology clinic at a regional academic medical center. The patients were 14 men and 8 women, who had undergone functional endoscopic sinus surgery for CRS, and in whom sinus aspirate cultures were performed before and after topical mupirocin therapy for symptomatic disease. Analyses were performed in April 2014.
Patients underwent treatment with saline sinus rinse, with the addition of mupirocin, for at least 1 week.
Main Outcomes and Measures
Bacterial isolates from sinus aspirate culture.
The patients included 14 men and 8 women, 18 to 75 years old, who underwent a mean of 1.9 functional endoscopic sinus surgical procedures. The mean (range) duration of mupirocin therapy was 6 (2-12) weeks. Before mupirocin therapy, cultures from symptomatic patients (14 men and 8 women, ages 18-75 years) revealed common bacteria implicated in CRS, which are characteristically gram-positive. After mupirocin therapy, cultures from symptomatic patients shifted significantly: 19 were gram-positive vs 3 gram-negative before treatment; 9 were gram-positive vs 13 gram-negative after treatment (P = .004), with increased growth of pathogenic gram-negative bacteria and Corynebacterium.
Conclusions and Relevance
These data present evidence supporting the distinct abrogation of culturable sinus bacteria after mupirocin rinses, identifying a shift toward increased pathogenic bacteria. Consideration of healthy host microbiome and immune dysfunction should guide future treatment considerations.
Chronic rhinosinusitis (CRS) is highly prevalent, affecting approximately 12% to 15% of the adult population1,2 and contributing to annual direct health care costs of $11 billion.3 The heterogeneous etiology of CRS makes a common successful therapy difficult. Current treatment algorithms recommend medical therapy with intranasal and/or systemic corticosteroids, prolonged courses of culture-directed systemic antibiotics, and, for those who remain symptomatic, surgical therapy.4 Despite adequate medical and surgical interventions, some patients experience persistent, recalcitrant CRS. Several primary factors could contribute to recalcitrant disease, such as genetic background, anatomic complexity of the sinuses, and impaired physiologic and immunologic response to infection.5,6 Furthermore, iatrogenic factors, such as prolonged antibiotic therapy, could lead to the reduction of normal flora, development of resistant pathogens, as well as alteration of the normal physiologic and immune defense mechanisms of the paranasal sinus.7- 9
Staphylococcus aureus is the most commonly identified bacteria cultured in recalcitrant CRS populations, and the emergence of methicillin-resistant S aureus (MRSA) has led to controversies in the potential overuse of oral antibiotics.10S aureus can be particularly difficult to eradicate in the sinus cavity, owing to the propensity of this bacterium to develop biofilms, reside intracellularly, and produce superantigen.11- 13 Topical antibiotic therapies in CRS deliver a high concentration of antibiotics directly to the diseased sinonasal mucosa, thereby increasing efficacy and decreasing systemic absorption and associated adverse effects. Mupirocin is an antibiotic ointment that, when used in saline nasal irrigations, has been shown to improve clinical outcomes and eradicate S aureus in several studies.10,14 However, the optimal duration of usage is unknown, and the use of any antibiotic may result in unintended consequences to the native microbial environment. We hypothesize that mupirocin therapy can alter the microbial composition from a gram-positive to gram-negative environment in postsurgical patients with recalcitrant CRS. Therefore, we investigated patients who failed medical and surgical therapy for CRS to determine changes in microbiologic culture results before and after topical mupirocin therapy.
After approval from the University of Arizona institutional review board and waiver of consent, a retrospective medical chart review was conducted in April 2014 for consecutive patients with CRS after functional endoscopic sinus surgery, treated by physicians in the department of otolaryngology at the University of Arizona, in whom sinus aspirate cultures were performed before and after mupirocin therapy from January 1, 2012, to January 1, 2014. Fourteen men and 8 women ages 18 to 75 years, who received at least 1 week of treatment with mupirocin sinus washes and who were symptomatic before and after mupirocin therapy, were included in this study. At this institution, patients are usually instructed to emulsify a small amount of mupirocin into the buffered saline solution of a large-volume nasal rinse and use twice daily. Patients who were treated with oral antibiotics or corticosteroids in the 6 weeks prior to mupirocin therapy and those with immunodeficiency syndromes were excluded. Patient demographics, comorbidities, and medications were identified. Atopy was defined as at least 1 positive skin prick test (≥3-mm wheal with surrounding flare) or serum-specific IgE to a panel of local seasonal and perennial aeroallergens. Asthma was defined by physician diagnosis, per guideline recommendations.15
Culture specimens were obtained by direct aspiration of the affected sinus. Fluids were collected into a sterile container and immediately sent to the microbiology laboratory for plating. Specimens were plated to blood agar, MacKonkey agar, chocolate agar, Brucella agar, Thioglycollate broth, and Brucella Laked blood agar with kanamycin and vancomycin. Extended culture time and susceptibility testing were included in this protocol: aerobes were held for 3 days and anaerobe plates for 5 days. All organisms are identified.
Analyses comparing categorical variables were performed using Fisher exact test.
Twenty-two patients met inclusion and exclusion criteria. Demographic characteristics are presented in the Table. Patients had a mean age of 66 years and underwent a mean of 1.9 functional endoscopic sinus surgical procedures. The mean duration of mupirocin therapy was 6 weeks. All patients were symptomatic at the time of culture. Endoscopic evidence of infection at the time of culture was present in 18 cases (81.8%).
The sinus aspirate culture isolates prior to mupirocin therapy were reported as, in order of frequency, “mixed respiratory flora,” coagulase-negative staphylococci, S aureus, Pseudomonas aeruginosa, Propionibacterium acnes, Streptococcus pneumoniae, and Klebsiella pneumonia. Following mupirocin therapy, Corynebacterium was the most frequently cultured bacterium, followed by P aeruginosa, S aureus, Achromobacter xylosoxidans, Stenotrophomonas maltophilia, Eikenella corrodens, Acinetobacter baumannii, Enterobacter aerogenes, K pneumoniae, and Haemophilus influenza (Figure). Cultures positive for gram-positive bacteria vs gram negatives were significantly different before and after therapy (19 were gram-positive vs 3 gram-negative before treatment; 9 were gram-positive vs 13 gram-negative after treatment; P = .004). There were no differences in sinus culture results, either before or after mupirocin therapy, when adjusting for clinical characteristics.
Mupirocin, an antibiotic of the monoxycarbolic acid class, confers dose-dependent bactericidal effects against many gram-positive bacteria, including MRSA. However, it is known that Corynebacterium spp are insensitive to mupirocin.16 We present evidence herein that while topical mupirocin therapy is effective against many gram-positive bacteria, this may result in the overgrowth of both Corynebacterium and gram-negative bacteria at the exposure site. Indeed, in our cohort, pre–mupirocin treatment sinus cultures most commonly isolated gram-positive bacterial species of streptococci, staphylococci, P acnes, and the gram-negative P aeruginosa, similar to findings in previously published studies.8,17- 21
Importantly, in samples collected after mupirocin treatment, sinus cultures identified a high frequency of Corynebacterium spp, increased frequency of P aeruginosa, and 6 additional gram-negative bacterial isolates. Corynebacterium spp have been associated with mucosal inflammation and implicated in the development of CRS.8 Moreover, all of the gram-negative bacteria cultured only after therapy are associated with nosocomial or opportunistic infections, suggesting an altered host-defense immune response.22- 25
The standard therapy for purulent secretions in recalcitrant CRS has been “culture-directed antibiotic therapy” to eradicate disease. However, in-depth, non–culture-based investigations of the sinonasal epithelia, including the use of 16S rRNA sequencing, have identified that the sinuses are not “sterile” and the end goal of microbial eradication is impossible and may actually be harmful. Previous studies8,9,18 have supported the importance of a diverse microbiome for sinus health. Indeed, using culture-based and non–culture-based methods, significant abnormalities of the sinus microbiome have been associated with CRS, including enrichment of Staphylococcus or Corynebacterium species.18,26
The utility of mupirocin in topical sinus irrigations has been studied previously, showing improvements in short-term posttherapy microbiologic culture and clinical outcomes. However, long-term studies10,14 found a high failure rate of mupirocin in eradicating S aureus and the development of mupirocin-resistant S aureus. In our small cohort, S aureus was detected in sinus cultures both before and after mupirocin treatment. Because staphylococcus endotoxins are implicated in disease pathogenesis, failure to eradicate these bacteria may contribute to refractory disease.11,27
There are potential mechanisms beyond bactericidal effects through which mupirocin may alter the local microbiota of the sinus. Mupirocin was originally isolated from Pseudomonas fluorescens in 1971 and is composed of pseudomonic acids.28 Mupirocin strongly inhibits bacterial protein and RNA synthesis. However, mupirocin could potentially alter the microenvironment of the sinus through changing the airway surface liquid pH, thereby contributing to the effectiveness of antimicrobial agents in the airway. Furthermore, the reduction of normal gram-positive flora colonization by mupirocin could alter the microbial community by allowing overgrowth of harmful bacteria.29
The retrospective nature of this study, strict inclusion and exclusion criteria, and performance at a regional tertiary care center serve to limit this study’s generalizability to the general population of patients with chronic sinusitis. The strict inclusion and exclusion criteria could arguably have biased toward both a less severe cohort, through exclusion of those requiring systemic antibiotics, or to a more severe cohort, requiring patients to be symptomatic when the culture specimen is obtained. However, these criteria also support the study design through eliminating a confounding effect of other antimicrobial therapies and anticipating culture results to be clinically significant. While the number of individuals included in this study population is limited by the aforementioned criteria, the demographic characteristics of these individuals are consistent with that seen in chronic sinusitis. Ideally, a study assessing the impact of a therapy in chronic sinusitis would report changes in quality-of-life measures; these scores were not available to us at the time of this study.
The relationship between culture-based and RNA-sequencing-based microbiological testing of chronic sinusitis is still unclear. Further work is needed to correlate standard culture results and limited or shotgun microbiome sequencing of sinus aspirates, to determine the relative value of each modality toward identifying pathogenic bacteria or abnormal mucosal microbiological states.
In this study, we present evidence supporting the distinct abrogation of culturable sinus bacteria after mupirocin rinses, identifying a shift toward increased pathogenic bacteria. Our increased understanding of microbial communities and treatment-induced alterations therein suggest we may need to alter our mindset of “culture-directed antibiotic therapy” and move toward therapies that alter the host immune response or replete protective, healthy bacteria. Understanding the microbiome of CRS requires not only the identification of healthy and abnormal bacteria but also understanding their significance in health, disease, and interactions with others among the microbial community. With this information we could potentially target and modulate the host-microbiome interaction in CRS to improve outcomes in patients with recalcitrant disease.
Corresponding Author: Tara F. Carr, MD, Department of Internal Medicine and Otolaryngology, University of Arizona Medical Center, 1501 N Campbell Ave, Room 2342C, Tucson, AZ 85724-5030 (firstname.lastname@example.org).
Submitted for Publication: September 9, 2015; final revision received October 15, 2015; accepted October 27, 2015.
Published Online: December 23, 2015. doi:10.1001/jamaoto.2015.3059.
Author Contributions: Drs Carr and Hill 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.
Study concept and design: Carr, Chiu, Chang.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: Chiu, Chang.
Statistical analysis: Carr, Hill, Chang.
Administrative, technical, or material support: Carr, Chiu, Chang.
Study supervision: Carr, Chiu.
Conflict of Interest Disclosures: None reported.
Funding/Support: Dr Hill received support for this work from the Office of Graduate Medical Education, University of Arizona College of Medicine.
Role of the Funder/Sponsor: The funding source 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.
Previous Presentation: Preliminary data were presented during the Annual American Academy of Allergy, Asthma, and Immunology meeting; February 21, 2015; Houston, Texas, as Poster 172: Changes in Sinus Bacterial Culture Following Mupirocin Treatment in Surgically Recalcitrant Chronic Rhinosinusitis.