Treatment of chronic rhinosinusitis and acute recurring rhinosinusitis with omadacycline: A case series

Abstract

Chronic rhinosinusitis (CRS), defined as persistent inflammation of the sinuses lasting longer than 12 weeks, and recurrent acute rhinosinusitis (RARS), characterized by multiple distinct episodes of acute bacterial sinusitis within a year, are among the most common chronic illnesses in the US. Several risk factors, including gastroesophageal reflux disease (GERD) are associated with CRS and RARS. For exacerbations of CRS and recurrent episodes of RARS, antibiotic therapy is the mainstay of treatment; however, a significant subpopulation of patients remain resistant to treatment, despite rigorous and prolonged treatment. Consequently, patients experience frequent recurrences and more complex infections involving multiple organisms. Multidrug resistant bacterial strains, such as methicillin-resistant Staphylococcus aureus (MRSA), are increasingly implicated in treatment failure. Thus, there is a need for new therapies to treat patients with CRS and RARS effectively. Omadacycline is a tetracycline derivative antibiotic approved by the FDA to treat adult patients with community-acquired bacterial pneumonia and acute skin and skin structure infections. Omadacycline has broad spectrum activity against select pathogens and was proven to be effective against select multidrug resistant bacteria, including MRSA. Presented here are three cases of patients with underlying GERD and polymicrobial chronic sinusitis involving MRSA, along with several gram-negative enteric organisms, who were successfully treated with omadacycline after many years of recurrent infections. Omadacycline was shown to be an oral option for patients with infectious exacerbations of CRS and RARS involving antibiotic resistance and was well tolerated. These findings suggest that further investigation of omadacycline in this setting is warranted.

Highlights

• •Chronic rhinosinusitis (CRS) and recurrent acute rhinosinusitis (RARS) are common chronic diseases in the US.
• •For treatment of CRS and RARS, antibiotic resistance is an increasing problem.
• •Omadacycline is an antibiotic effective against select multidrug resistant bacteria.
• •Here, omadacycline treated one CRS patient and two RARS patients with methicillin-resistant S. aureus.
• •Further investigation of omadacycline in this setting is warranted.

Introduction

Chronic rhinosinusitis (CRS) is defined as a persistent inflammation of the sinuses lasting longer than 12 weeks [1]. Recurrent acute rhinosinusitis (RARS) is defined as four or more distinct episodes of acute rhinosinusitis within a 12-month period, where each episode involves classic symptoms such as nasal blockage, discharge, and facial pain, lasts at least 10 days, and is followed by symptom-free intervals. This episodic pattern distinguishes RARS from CRS, where symptoms persist continuously. Rhinosinusitis affects approximately 12% of the US population and ranks as the fifth most common reason for prescribing antibiotics [2], [3]. Direct costs of CRS are estimated to be between US $10–13 billion annually in the US and indirect costs related to losses in work productivity are estimated to be more than $20 billion per year [4].

Potential etiologies of both CRS and RARS include bacteria, as well as viruses, fungi, and allergens [1], [5]. In CRS, additional factors such microbial biofilms also contribute to disease pathogenesis [5]. Physiological risk factors for rhinosinusitis include immunological deficiencies and gastroesophageal reflux disease (GERD) [6], [7]. GERD is thought to increase the risk of CRS via several proposed mechanisms, including triggering a chronic cough by stimulating an esophageal-bronchial cough reflex [8]. In addition, reflux has been proposed to cause damage to the sinonasal epithelium, allowing pathogens to flourish on the mucosal surface [6].

Management of CRS and RARS generally involves medical therapy, including intranasal corticosteroids and antibiotics when appropriate, with surgery reserved for refractory cases [1], [3], [9]. Without appropriate treatment patients experience frequent recurrences and more complex infections involving multiple organisms including antibiotic resistant pathogens. However, a significant subpopulation of patients with CRS and RARS remain resistant to treatment, despite rigorous and prolonged treatment [1], [10]. There are increasing reports that multidrug resistant bacterial strains, such as methicillin-resistant Staphylococcus aureus (MRSA) are causing treatment failure [1], [3], [10], [11]. In addition, studies have found that bacteria contributing to the persistence and severity of CRS can reside in biofilms in the sinus cavity, where they are not able to be eliminated with common antibiotic therapies at standard doses [10], [12]. Thus, there is a need for novel therapies to treat patients with both CRS and RARS effectively, in whom other treatments have failed.

Omadacycline has broad-spectrum activity against certain gram-positive, gram-negative, anaerobic, and atypical pathogens [13]. Mechanistically, omadacycline exerts its antimicrobial effect by binding to the 30S subunit of the bacterial ribosome, thereby inhibiting bacterial protein synthesis. Its structural modifications to the tetracycline core enable it to overcome two key tetracycline-class resistance mechanisms: efflux pumps and ribosomal protection proteins [14], [15]. It is effective against a number of multidrug resistant bacteria, including MRSA [14], [15]. In addition, a mouse model study showed that omadacycline reduced biofilm-associated A. baumannii infection, with optimal efficacy observed at 10 mg/kg and 15 mg/kg dosing [16]. While not directly studied in CRS, this may be relevant given the presence of bacterial biofilms in the sinus cavity [10], [12]. Omadacycline is approved in the US as an oral and intravenous (IV) therapy for adult patients with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) [17]. For both CABP and ABSSSI, omadacycline may be initiated with IV loading doses (200 mg IV over 60 min or 100 mg IV over 30 min twice; with an alternative 450 mg oral loading dose once daily for ABSSSI) followed by either IV or oral maintenance therapy (300 mg orally once daily or 100 mg IV once daily) [17]. In Phase 3 clinical trials, omadacycline was generally well tolerated, with the most common adverse reactions (≥2%) being nausea, vomiting, infusion site reactions, elevations in hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase), hypertension, headache, diarrhea, insomnia, and constipation [17]. The following three case reports demonstrate successful use of omadacycline off label for the treatment of patients with infectious CRS or RARS, and underlying GERD and warrants further investigation.

Case discussion

Case 1)

This was a 73-year-old male who, at the time of examination, still worked in the field of fire and safety management. The patient was relatively healthy; however, he had an underlying medical condition of GERD and had been symptomatic with CRS for over ten years. The patient had a history of taking multiple courses of antibiotics for CRS, with minimal improvement and relapse within days or weeks of completing the antibiotic regimen.

For a particular exacerbation of CRS, the patient was treated with amoxicillin/clavulanic acid 875 mg twice daily (recommended dosing regimen is 500 or 875 mg every 12 h or 200 or 500 mg every 8 h) [18].Due to consistent growth of MRSA and Klebsiella pneumoniae in cultures from his sinus cavities, the patient was referred by his ENT clinic to the infectious disease clinic. The patient was treated with doxycycline 100 mg twice daily (recommended dosing regimen 100 mg orally twice daily or 200 mg orally daily), and cefdinir 300 mg twice daily (approved dosing 300 mg twice daily or 600 mg once daily) [19], [20]. The patient continued to show symptoms of purulent nasal discharge, postnasal drip cough and sinus pressure headaches, and was then prescribed trimethoprim/sulfamethoxazole (TMP/SMX), one double strength tablet twice a day for two weeks. Following this, physical examination identified swollen and erythematous turbinates bilaterally with purulent nasal secretions, and the oropharynx was erythematous. Due to the lack of improvement, the patient’s antibiotic regimen was changed to omadacycline 300 mg daily for four weeks, taken orally, along with addressing lifestyle changes for GERD. Specifically, a minimum of three hours was advised between dinner and bedtime, along with no late-night snacking, alcohol, or caffeine.

The infection demonstrated a favorable response to omadacycline, with no recurrent infections during the follow-up period. Clinical follow-up was conducted every two weeks for the first three months, followed by monthly assessments for the next four months. The patient continues to undergo active clinical monitoring at six-month intervals. Symptomatic improvement was notable and included resolution of purulent nasal discharge and reduction of the postnasal-drip-associated cough. Sinus pressure headaches also resolved. Additional constitutional symptoms that improved included fatigue and improvement in olfactory function. Lifestyle modifications allowed the patient to avoid use of proton pump inhibitors or histamine−2 blockers, both commonly used to treat GERD. However, their use is controversial due to their hinderance of the absorption of both minerals and medications and the proliferation of bacteria that may contribute to recurrent infections, including drug resistant infections. The patient has continued to stay free of infection, as demonstrated by endoscopic examination by an otolaryngologist one month after treatment.

Case 2)

This was a 78-year-old male who was retired from the military, had an active lifestyle and was an avid golfer. The patient had hypogammaglobulinemia which was managed with IV immune globulin (IVIg) therapy for 14 years, and for the prior three years was treated with 50 g IVIg every three weeks. The patient had a history of GERD-related RARS that he managed with lifestyle changes, including sinus saline rinses after outdoor activities. The patient reported that past episodes of RARS could be debilitating.

The patient developed an acute episode of RARS after developing COVID−19. The patient was symptomatic for two weeks with purulent nasal discharge and a postnasal-drip-associated cough. Physical examination revealed edematous and erythematous turbinates with purulent nasal secretions. The patient’s oropharynx was only mildly erythematous. The patient was treated with three empiric two‑week courses of cefdinir prescribed by his ENT, with relapse occurring 2–3 weeks after each course. Following the third relapse, he was referred to the infectious diseases clinic. Next generation sequencing of sinus secretions demonstrated methicillin-resistant Staphylococcus epidermidis, Klebsiella oxytoca and Streptococcus mitis, all of which were resistant to TMP/SMX. The patient was placed on a course of omadacycline 300 mg daily for two weeks, taken orally.

The patient’s nasal secretions resolved and the patient reported improvement in symptoms during monthly follow-ups over the course of two years. Improvement in symptoms included elimination of purulent nasal discharge and improvement of the postnasal-drip-associated cough.

Case 3)

This was a 32-year-old male patient with an active lifestyle, who exercised regularly and worked in the entertainment industry. The patient had underlying hypogammaglobulinemia, RARS, GERD, migraines requiring multiple medications, and obstructive sleep apnea which had exacerbated both his GERD and RARS.

The patient experienced multiple episodes of RARS that no longer responded to amoxicillin/clavulanic acid or oral cephalosporins due to antibiotic resistance. The patient was unable to take a fluoroquinolone due to an interaction with nortriptyline. Prior cultures had grown Klebsiella and Enterobacter species with resistance to most oral antibiotic therapies and therefore, the patient was treated previously with ertapenem 1 g daily, infused intravenously.

For a particular RARS episode, the patient experienced purulent nasal discharge and upon examination, his turbinates were edematous and erythematous. The patient was symptomatic for nearly two weeks before being seen by the infectious disease clinic. He was started on omadacycline 300 mg daily, taken orally for 21 days. The patient also improved the management of GERD with lifestyle changes and adherence to his continuous positive airway pressure regimen.

The patient reported improvement in symptoms during follow-up visits conducted every two weeks over a period of 10 weeks, after which the schedule was reduced to monthly follow-up appointments. Symptom resolution included the elimination of purulent nasal discharge and marked improvement in postnasal drip-associated cough. Sinus pressure headaches also resolved completely. Additional constitutional symptoms that improved included fatigue and improvement in olfactory function.

The patient remains under active clinical monitoring with monthly follow-up, as they continue to receive IVIg therapy through the infectious diseases clinic.

Discussion

GERD is associated with rhinosinusitis [6]; however, in many instances it is overlooked when it comes to the medical management of these chronic illnesses. For many patients, if this underlying risk factor is not addressed, recurrent infections will likely occur, requiring multiple courses of antibiotics, increasing the risk of antibiotic resistance. As such, many patients who suffer with CRS or recurrent episodes of RARS have polymicrobial infection involving gram negative enteric organisms often involving resistant strains, such as MRSA [3], [10], [11]. While GERD featured in all three patient cases, primary immunodeficiency disorders, such as hypogammaglobulinemia present in Cases 2 and 3, are also recognized risk factors for both RARS and CRS [7].

In the US, Guidelines from the Sinus Allergy Health Partnership describe that bacterial resistance in patients with sinusitis in the US is increasing – in particular, S. pneumoniae and H. influenzae are commonly resistant to ß-lactams and TMP/SMX [3]. Similarly, elsewhere, in Iran a cross-sectional study of patients with chronic sinusitis found that among staphylococcus strains the rate of MRSA was up to 60% and up to 37% of enterobacteriaceae produced extended-spectrum beta-lactamase [21]. Antimicrobial resistance is one of the greatest threats to modern medicine and in the most extreme cases there is resistance to last line antibiotics, such as carbapenems, for which multiple new IV antibiotics have been recently approved for use in the US. Unfortunately, for many patients, long-term IV antibiotic therapy is not a viable option for any number of reasons, most importantly the time required for the daily administration of IV antibiotics. Other concerns include care and maintenance of IV access either a peripherally-inserted central catheter line, mid-line, or peripheral venous line, which most homecare companies do not recommend if treatment is greater than two weeks.

To address a polymicrobial infection involving both MRSA and gram negative enterics, two antibiotics have to be used in most cases. Ceftaroline is a fifth-generation cephalosporin that covers both MRSA and most gram negative enterics, but twice a day administration makes this option extremely time consuming [22]. Until 2018 there had not been a new oral antibiotic in decades, despite rising resistance to the most prescribed oral antibiotics, i.e., amoxicillin-clavulanic acid, oral third-generation cephalosporins (e.g., cefdinir and cefpodoxime), azithromycin, and clindamycin.

It should also be pointed out that treating complex polymicrobial infections such as MRSA in association with gram negative enterics just with oral antibiotics offers challenges, because patients will be required to take different oral antibiotics simultaneously. It is known that increasing the number of medications on a daily basis decreases the rate of compliance [23].

Together, these points mean that antibiotic management for patients with antibiotic resistant infections can be challenging for the physician and frustrating for the patient. Until recently, treatment options were limited for patients with both GERD-related sinusitis and history of antimicrobial resistance, particularly MRSA. In recent years, omadacycline has been shown to be active against a number of multidrug-resistant bacteria, including MRSA, macrolide and doxycycline-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus, some enteric gram-negative bacilli, and also many nontuberculous mycobacterium species [14]. In addition, as mentioned earlier, omadacycline may reduce biofilm formation [16], which may be beneficial for treating both CRS and RARS [10], [12]. As such, omadacycline may be an important option for patients with CRS or RARS who have developed resistance to other oral therapies and those with polymicrobial infections [14], [17].

For all three reported cases of patients with CRS or RARS, and GERD, the patients responded well to omadacycline, which was well tolerated. Treatment duration varied among cases due to differences in clinical severity, duration of symptoms prior to presentation, and the presence of underlying chronic conditions. These factors informed individualized therapeutic decisions rather than application of a uniform treatment duration across all cases. In Case 1, the patient had experienced persistent symptoms for several months and had been treated with multiple other regimens without clinical improvement, after which a longer course of omadacycline was initiated. In Case 2, the patient was treated for an acute exacerbation of underlying CRS and after no improvement was observed following treatment with cefdinir, the patient was treated with a shorter course of omadacycline given the acute nature of the infection. In Case 3, the patient had underlying comorbidities, including Ehlers-Danlos syndrome and IgG deficiency, which could influence the time required to respond to treatment. Prior cultures had demonstrated resistant organisms, and treatment with ertapenem was unsuccessful; therefore, a 21‑day course of omadacycline was subsequently administered.

In considering treatment options, all three individuals had at least one chronic condition in addition to chronic/recurrent sinusitis, most notably GERD, which can alter sinonasal microbiology and contribute to both delayed recovery and recurrence [5]. Management of patients with multiple chronic conditions has its own sets of challenges, including the need to be aware of potential severe drug interactions whenever adding a new medication to the regimen [24]. This was especially evident in Case 3, where the patient was unable to take fluroquinolone due to potentially serious drug-drug interactions. Omadacycline has limited drug-drug interactions, making it a potential option to treat patients who are on other medications [15] and also those with allergies to other antibiotics. In addition, each patient had already undergone standard therapeutic approaches, either without clinical improvement or with organisms demonstrating antimicrobial resistance. This combination of underlying conditions and prior treatment failure would usually exclude such individuals from controlled studies, leaving limited evidence to guide management. These factors collectively informed the decision to use omadacycline in this subset of patients and warrants further investigation.

Limitations

Limitations of this report include the small number of patients. Based on the success seen in these cases, combined with the clinical need for treatments for recalcitrant CRS, further studies are warranted.

Conclusion

The management of both CRS and RARS is challenging, especially in patients with multiple chronic conditions and those whose risk factors are not addressed. Repeated courses of antibiotics can lead to antimicrobial resistance, making antibiotic treatment options limited. Some patients may be on other medications which may eliminate certain antibiotic choices due to drug-drug interactions. Omadacycline, which has a broad antimicrobial spectrum and limited drug–drug interactions, was administered to three patients with infectious exacerbations of CRS or RARS, including cases involving resistant pathogens. All three patients tolerated the treatment, and in all three cases, omadacycline was associated with symptom improvement. These observations warrant further investigation of omadacycline in this treatment setting.

Abbreviations

ABSSSI, acute bacterial skin and skin structure infections; CABP, community-acquired bacterial pneumonia; COVID−19, Coronavirus disease 2019; CRS, chronic recurrent sinusitis; ENT, ear, nose, and throat; FDA, Food and Drug Administration; GERD, gastroesophageal reflux disease; IVIg, IV immune globulin; IV, intravenous; MRSA, methicillin-resistant Staphylococcus aureus; RARS, recurrent acute rhinosinusitis; TMP/SMX, trimethoprim/sulfamethoxazole;

Author statement

The manuscript was written, reviewed and approved by A.P. ahead of submission.

Funding sources

Support for medical writing assistance from Bioscript Group was funded by Paratek Pharmaceutical, Inc., according to GPP.

CRediT authorship contribution statement

Andrew Pugliese: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper" should be included.