MRSA Chronic Bacterial Laryngitis: A Growing Problem

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2 The Laryngoscope VC 2017 The American Laryngological, Rhinological and Otological Society, Inc. MRSA Chronic Bacterial Laryngitis: A Growing Problem Patrick S. Carpenter, MD ; Katherine A. Kendall, MD Objectives: Chronic bacterial infection of the larynx is characterized by long-standing hoarseness and exudative laryngitis. Prolonged antibiotic therapy is required to clear the infection, and methicillin-resistant staphylococcus aureus (MRSA) may be the responsible pathogen. The objective of this study was to describe the presentation, comorbidities, treatment response, and underlying etiology including the incidence of MRSA in our patient population with chronic bacterial laryngitis. Methods: A review of patients with a diagnosis of chronic bacterial laryngitis from 2012 to 2016 was performed. Diagnosis of chronic bacterial laryngitis was based on clinical history and findings on flexible laryngoscopy. In selected cases, the diagnosis of bacterial laryngitis was confirmed by operative biopsy. Information regarding clinical presentation and course was collected. Results: Twenty-eight patients were included in the study. Twenty-three were treated empirically with Amoxicillin-clavulonic acid for a minimum of 21 days. Twelve of the 23 (52%) had recurrence or nonresolution of infection. Seven of the 12 nonresponders (58%) were found to have MRSA by laryngeal tissue culture. Five patients were treated initially with Sulfamethoxazole and trimethoprim, and all resolved the infection without the need for further treatment. There was a nonstatistically significant increase in smoking and reflux in the MRSA population compared to the non-mrsa group. Conclusion: MRSA infection was documented in 30% of patients overall with chronic bacterial laryngitis. Based on the results of the study, a treatment algorithm for management of this unusual patient population is suggested. Key Words: Chronic, bacterial, laryngitis, methicillin, staph aureus, MSSA, MRSA. Level of Evidence: 4. Laryngoscope, 128: , 2018 INTRODUCTION Chronic laryngitis, or inflammation of the larynx lasting for greater than 3 weeks, is a complex but increasingly common problem. Bacterial infection remains an underrecognized but clinically significant etiology of chronic laryngitis. 1 Chronic bacterial laryngitis can be diagnosed in the setting of chronic dysphonia with or without dysphagia. Laryngoscopy reveals erythematous and edematous vocal cords and exudative crusting and purulence (Fig. 1). 2 Treatment usually requires extended targeted antibiotic therapy. 3 5 Like all open-ended passageways in the body, the larynx has been shown to have normal colonization with bacteria. It is a disruption of this homeostatic microbiome that is theorized to contribute strongly to the development of chronic invasive bacterial laryngitis. 6 8 Methicillin-resistant staphylococcus aureus (MRSA) has been increasingly identified as a pathogen responsible From the Department of Surgery Division of Otolaryngology Head and Neck Surgery, University of Utah Health System (P.C., K.K.), Salt Lake City, Utah, U.S.A. Editor s Note: This Manuscript was accepted for publication on September 10, Presented as a poster presentation at the 120th Annual Meeting of the Combined Sections Meeting of The Triological Society, San Diego, California, U.S.A., April 28 29, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Patrick S. Carpenter, MD, 50 North Medical Drive, SOM 3C120, Salt Lake City, Utah patrick.carpenter@hsc.utah.edu DOI: /lary for chronic bacterial laryngitis. 3,9 MRSA chronic laryngitis is difficult to distinguish from non-mrsa chronic bacterial laryngitis on physical examination 4 (Fig. (1 and 2)). Unlike typical nosocomial MRSA infections, it is unknown if laryngeal MRSA infections are linked to any specific patient risk factors. 4,5 Previous work has shown that the diagnosis of MRSA laryngitis can be confirmed with inoffice or operating room (OR) biopsy and culture of the true vocal fold tissue. 4,10 Currently, only eight cases of MRSA laryngitis have been reported in the literature, but evidence suggests an increasing incidence. 3,4,10,11 Our experience in the voice disorders clinic at a tertiary care hospital is that the symptoms of laryngeal MRSA infections are subtle in comparison to typical MRSA infections seen elsewhere in the body. 12 The objective of the study at hand was to assess the incidence in MRSA laryngitis in our patient population with chronic bacterial laryngitis, evaluate potential risk factors, and help create a treatment algorithm that may be used in the management of this growing problem. MATERIALS AND METHODS A retrospective review was conducted assessing adult patients associated with the diagnosis of chronic bacterial laryngitis (International Classification of Diseases, 10th Revision [ICD-10] J37.0, ICD ) seen in the voice disorders clinic from 2012 to The study protocol and parameters were approved by the University of Utah Institutional Review Board prior to analysis of any patient data. All patients included in the study had symptoms of dysphonia and persistent voice changes for a minimum of 3 weeks prior to being evaluated. 921

3 were obtained in the OR using microlaryngeal forceps. Tissue samples were sent for routine culture and sensitivities, gram stain, and pathologic analysis. Oral antibiotic therapy was initiated based on results of the culture and sensitivities. Follow-up was continued at 1-month intervals. Response to treatment was determined by both improvement of dysphonia and resolution of abnormality on flexible laryngoscopy. RESULTS Fig. 1. MRSA laryngitis flexible laryngoscopy findings before and after treatment. Pretreatment MRSA laryngitis with classic vocal fold irregularity and crusty purulence. Posttreatment resolution of laryngitis after 9 weeks of Bactrim. MRSA 5 methicillin-resistant staphylococcus aureus. Full head and neck evaluation in the clinic on each patient included a flexible laryngoscopy exam. Physical exam findings of vocal cord crusting, erythema of cords, and edema of cords were considered suggestive of chronic bacterial laryngitis, and patients were thus included in the study. All patients were followed for a minimum of 30 days. Items reviewed for each patient included documentation from history and physical examination, culture results, biopsy results, operative reports, and recorded flexible endoscopy exams. Patients were initially treated empirically with either amoxicillin/clavulanic acid (Augmentin) or trimethoprim/sulfa (Bactrim). Follow-up visits were scheduled 3 to 4 weeks after initiation of oral antibiotic therapy. Patients were judged to have improvement after treatment based on normalization of vocal fold characteristics on flexible endoscopic imaging, combined with subjective improvement per patient report. Individuals who improved after treatment with Augmentin were deemed to be MRSA-negative patients. If patients continued to be symptomatic and had little improvement in laryngeal findings after a 3-week course of empiric antibiotic therapy, biopsies Patient Demographics A total of 28 patients met the inclusion criteria for chronic bacterial laryngitis. Nine patients were female, and 21 were male. Ages ranged from 33 to 69 years old. Eight patients in the study had diabetes type 2 treated with either oral medications or insulin at the time of presentation. Twenty (71%) patients were being treated with a proton pump inhibitor (PPI) for reflux. Only one patient had a recent hospitalization. There were 17 patients actively smoking at first office visit, and 16 who drank alcohol regularly. Only nine patients had been treated with antibiotics prior to presentation to the laryngologist. The average duration of voice change prior to presentation in the voice clinic was 82 days (range days) (Table I). Diagnostic and Treatment Results Of the 28 patients who met criteria for chronic bacterial laryngitis, 23 of the patients were initially treated with amoxicillin/clavulanic acid (high dose typically Augmentin 875 mg/125 mg, one tab twice daily for 30 days). Five individuals were prescribed sulfamethaxazole/trimethoprim at the first clinic visit (high dose, typically Bactrim DS, 800 mg/160 mg two tabs twice daily for 30 days). Of the 23 patients treated with Augmentin, 11 individuals demonstrated significant improvement or complete resolution of symptoms and findings at their follow-up appointment 1 month later. In this cohort of patients, the median duration of treatment until complete resolution of laryngitis was 40 days (range: days). TABLE I. General Patient Characteristics, Demographics, and Common Comorbidities. Number of patients 28 Fig. 2. Comparison in flexible laryngoscopy exams between MRSA and non-mrsa chronic bacterial laryngitis. No significant physical exam differences between MRSA (A) and non-mrsa (B) bacterial chronic laryngitis. Both exams consistent with edematous vocal cords, crusting, and purulence. MRSA 5 methicillin-resistant staphylococcus aureus. Age (median) 46 years Sex (percent female) 61% Duration of dysphonia prior to ENT evaluation 82 days (range days) Diabetes 29% PPI Using 71% Smoking 61% Nasopharyngeal flexible laryngoscopy exam findings Erythema, irregular vocal fold margins, dry crusting PPI usage criteria was met only if patient currently taking medicine at time of exam. Smoking was defined as having > 10-pack year history and currently smoking in past 6 months. Nasopharyngeal flexible laryngoscopy exams were similar between groups ENT 5ear, nose, throat; PPI 5 proton pump inhibitor. 922

4 TABLE II. MRSA-Positive Specific Patient Characteristics. Patient Age Gender Diabetes PPI-Positive Smoking Duration SX Nasopharyngeal Flexible Laryngoscopy Findings 1 59 M No Yes Yes 12 mo *Leukoplakia, erythema, VF crusting 2 50 F No Yes Yes 1 mo Irregular VF, crusting, erythema 3 38 F No Yes Yes 5 mo Irregular VF, crusting, erythema 4 45 M No Yes Yes 1 mo Edematous and irregular VF 5 58 M No Yes Yes 6 mo Irregular crusting VF, erythema 6 51 M No Yes Yes 3 mo VF edema, dried crusting 7 32 F No No No 1 mo VF erythema, crusting, irregular margins Characteristics of chronic bacterial laryngitis patients who tested positive for MRSA. *Patient had in-situ carcinoma, in addition to MRSA. F 5 female; M 5 male; mo 5 months; MRSA 5 methicillin-resistant staphylococcus aureus; SX 5 symptoms; VF 5 vocal fold. Twelve individuals initially treated with Augmentin did not show any evidence of improvement at follow-up appointment at 1 month (52%). Ten of those patients were then taken to the OR for microlaryngoscopy and biopsy of vocal folds. Seven of the biopsies were positive for MRSA; two biopsies showed methicillin-sensitive staph aureus (MSSA); and one biopsy showed inflammatory tissue with anaerobic bacteria. All patients who underwent biopsy were treated with high-dose oral Bactrim or doxycycline (one patient had end-stage renal disease, a contraindication for Bactrim treatment). The median duration of treatment until resolution of signs and symptoms was 69 days in this group (range days). Two individuals who failed Augmentin at 1 month declined to undergo a biopsy. These individuals were treated empirically with extended Bactrim therapy, as above, and both achieved resolution of laryngitis (42 and 60 days, respectively). The five patients who were treated initially with empiric Bactrim all responded to treatment and did not require operative biopsy. They achieved resolution of symptoms at a median of 42 days on antibiotics. The general comorbidities between MRSA-positive group and MRSA-negative group were examined. There was a higher prevalence of males in the MRSA-positive group when compared to MRSA-negative group. There was an increased odds ratio (6.85) of being a smoker in the MRSA-positive group; however, it was not statistically significant. Also, there was an increased odds ratio (3) of active PPI use in the MRSA-positive group; however, this also was not statistically significant (Table II and Table III). DISCUSSION It has been over 200 years since one of the first published descriptions of laryngitis and attempts at treatment. 13 Most clinical cases of infectious laryngitis are due to acute viral infection and run a relatively short clinical course without the need for medical intervention. Prolonged or chronic laryngitis (greater than 3 weeks duration) is most commonly attributed to gastroesophageal reflux disease. 14 Increasingly, however, prolonged dysphonia without response to treatment with antireflux medications may be recognized as due to invasive bacterial laryngitis. 3,4 The hallmarks of the condition are exudates, erythema, and swelling of the vocal folds and/or supraglottic larynx on physical examination (Fig. 1). There was little difference in the physical exam findings between MRSA-positive and MRSA-negative patients in our cohort (Fig. 2). This current study describes the clinical course of patients with chronic bacterial laryngitis seen at a tertiary care center and considers possible risk factors for MRSA as the infectious etiology. Although only eight prior reports of MRSA laryngitis exist in the literature, this study increases the number of described biopsyproven MRSA laryngitis cases by seven, for an overall incidence of biopsy-proven MRSA in this study of 30%. Furthermore, the actual incidence of MRSA in the study population may have been higher because eight of the 28 patients in the study (25%) were treated empirically with trimethoprim/sulfa, with complete response, and also may have had MRSA. At the outset of the study period, empiric treatment with Augmentin was prescribed given that the common sinus and ear pathogens are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. 15,16 Once it became clear that over half the patients did not respond to this empiric treatment, biopsy and culture were performed and demonstrated a 30% overall incidence of MRSA and a 70% incidence of MRSA in nonresponding patients. These results prompted a shift in the TABLE III. Comparison of Characteristics Between MRSA Chronic Laryngitis and Non-MRSA Chronic Laryngitis. MRSA- Positive Non- MRSA Patients 7 14 Age (median) Sex (% female) 43% 58% Odds Ratio Confidence Interval Smoking 6 (86%) 6 (42%) , 0.38 PPI Use 6 (86%) 8 (57%) , 0.55 Patients treated empirically with Bactrim (N 5 5) were excluded from both MRSA-positive and MRSA-negative groups. The individuals who failed initial treatment but declined operative biopsy were excluded from both groups (n 5 2). Confidence intervals were calculated using a P<0.05. MRSA 5 methicillin-resistant staphylococcus aureus. 923

5 Fig. 3. Proposed treatment algorithm for chronic bacterial laryngitis patients. Flex scope flexible nasopharyngeal laryngoscopy findings are 5 vocal fold crusting, irregular vocal fold margins, erythema of vocal fold, and edema of vocal fold. Abx 5 antibiotics; CBL 5 chronic bacterial laryngitis; PPI 5 proton pump inhibitor; RF 5 risk factor; Tx 5 treatment. [Color figure can be viewed in the online issue, which is available at empiric approach to treatment at the outset prescribing trimethoprim/sulfa, resulting in an improved overall initial response rate to empiric therapy (100% of 7 patients) (Fig. 3). Other studies of chronic bacterial laryngitis have shown that responsible pathogens may be similar to deep neck space infections, with Staphylococcus aureus predominating. 4,10,17 Our data confirms this finding; however, in contrast to those previous studies, this study found an increased prevalence of MRSA in the patient population. Seventy percent of patients who underwent biopsy (n 5 10) for refractory chronic laryngitis were positive for MRSA. Patients with MRSA were more likely to be male, smokers, and actively taking reflux medication, although these factors were not statistically significant. It is possible that other geographical and environmental differences play a role in increasing the incidence of MRSA in this outpatient population. In addition, all patients with biopsy-proven MRSA had undergone prior empiric antibiotic treatment that likely impacted the makeup of the infectious flora at the time of culture. 5 Otherwise, the study patient population did not have any of the previously established risk factors for MRSA infection. 12 In particular, Shah et. al. suggested that a history of diabetes may predispose to MRSA laryngitis. Although eight of our chronic laryngitis patients had type 2 diabetes, none of our MRSA-positive patients had a history of diabetes. 4 Thus, our study was unable to identify specific patient factors leading to the conditions necessary for disruption of the normal laryngeal homeostasis and allowing for invasive infection, especially MRSA infection. 924 Based on the results of this study, a protocol for treatment of exudative laryngitis due to bacterial infection is proposed (Fig. 3). Clinical differentiation of patients with MRSA-positive laryngitis from those infected with other organisms is difficult. Other authors have advocated for in-office laryngeal swabs for culture prior to initiation of antibiotic treatment. 4 Further study is needed to determine accuracy of this technique relative to tissue biopsy in the OR. 18 Our treatment regimen allows for 1 month of empiric treatment with trimethoprim/sulfa as the initial antibiotic choice, and if failed, operative biopsy for tissue culture and antibiotic sensitivities. Trimethoprim/sulfa is generally well tolerated and inexpensive. In our subsequent experience, initial treatment of the condition with antibiotics effective against MRSA has had a 100% success rate without the need for biopsy. Prolonged treatment is generally needed to clear the infection. 3 5 Patients are counseled at the initiation of therapy that they will likely require 6 to 9 weeks of treatment. Reasons for this prolonged treatment requirement are not well established. Possible factors include a relatively low vascularity of the laryngeal tissues, especially the lamina propria, patient factors predisposing to infection, and increased virulence of involved organisms. Limitations with our study should not be overlooked. Although this is the largest study population described to date, the retrospective nature of the review and the small study population limit the ability to interpret risk factors with much significance. Assumptions regarding infectious organisms were also made, and not all patients had confirmation with operative biopsy leading to a possible underestimation of the incidence of MRSA in the population. Further research should continue to expand upon risk factors and other clinical features that may help guide the otolaryngologist to diagnosis and treatment of this disease. CONCLUSION MRSA chronic laryngitis may be more common than previously thought. 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