The role of antibiotics in treating chronic rhinosinusitis.

Chronic rhinosinusitis (CRS) is an inflammatory disease of the paranasal sinuses that occurs in 1% to 5% of the U.S. It may significantly decrease quality of life. CRS is defined as an inflammatory condition of the paranasal sinuses that persists for 12 weeks or longer, despite medical management. Treatment is directed at enhancing mucociliary clearance, improving sinus drainage/outflow, eradicating local infection (with antibiotics) and inflammation (with steroids), and improving access for topical medications.

The microbiology of rhinosinusitis evolves through several stages. The early phase (acute) is generally caused by a virus that may be followed by an aerobic bacterial infection in 2% to 10% of patients. Aerobic (Staphylococcus aureus) and anaerobic (Prevotella and Fusobacteria) members of the oral flora emerge as predominant sinus cavity isolates.

Antimicrobials are one component of comprehensive medical and surgical management for this disorder. Antimicrobialtherapy of chronic rhinosinusitis should be adequate against the potential aerobic and anaerobic pathogens. Because most of these infections are polymicrobial and many include beta-lactamase producing aerobic and anaerobic organisms, amoxicillin-clavulanate is the first-line regimen for most patients. Clindamycin is adequate for penicillin-allergic individuals and is also generally appropriate for methicillin resistant Staphylococcus aureus treatment is administered for at least three weeks and may be extended for up to 10 weeks in refractory cases. Treatment can be guided by a culture preferably from the sinus cavity obtained from individuals who have not shown improvement or deteriorated despite therapy.

Chronic sinusitis is associated with higher risk of some head and neck cancers

Chronic rhino-sinusitis (CRS) may be involved in causing of certain head and neck cancers (HNCs), because of immunodeficiency or inflammation.

Several studies explored this issue. Tsou et al. who studied the Taiwan Longitudinal Health Insurance Database found a 3.55-fold increased risk of developing nasopharyngeal cancer (NPC) compared with individuals without rhinosinusitis associations between and CRS throughout a 3-year period. 

Riley et al. conducted a systematic review found a 2.7- fold increased risk of developing NPC in patients with CRS compared with patients without sinusitis.  

Beachler and Engels of the National Institutes of Health, Bethesda, Maryland evaluated the associations of chronic sinusitis with subsequent HNC, including NPC, human papillomavirus-related oropharyngeal cancer (HPV-OPC), and nasal cavity and paranasal sinus cancer (NCPSC), in an elderly US individuals. They evaluated 483 546 Medicare beneficiaries treated from 2004 through 2011. CRS was associated with increased risk of developing particularly NPC, HPV-OPC, and NCPSC within 1 year of the chronic sinusitis diagnosis. Overall, the risk of any HNC type was 8% higher in patients with CRS than individuals without chronic sinusitis.

Future studies are warranted to evaluate whether inflammation in patients with sinusitis contributes to emergence of cancer, especially in middle-aged adults.

Bacteriology of normal non-Inflamed sinuses and its significance

Attempts to recover organisms from non-inflamed tonsils were carried out for over seven decades. Some studies failed to find any microorganisms and others recovered them only in a portion of the cases. Only three studies identified bacteria in all sinus sample. 

Brook evaluated the microbiology of maxillary sinuses of 12 adults and found an average of 4 isolates/sinus  of aerobic and anaerobic bacteria. The predominant anaerobes were Prevotella  Fusobacterium ,and Peptostreptococcus spp., and Propionibactreium acnes. The most common aerobic bacteria were beta-hemolytic Streptococcoci, Staphylococcus aureus, Streptococcus pneumoniae, and Haemophillus parainfluenzae.

Ramakrishnanet al. collected middle meatus specimens from 28 individuals with no sinusitis. Bacterial colonization was assessed in these specimens using quantitative PCR and 16S rRNA pyrosequencing. All subjects were positive for bacterial colonization of the middle meatus. S. aureus, S. epidermidis and P. acnes were the most prevalent and abundant microorganisms detected. The authors found rich and diverse bacterial assemblages in all of the individuals, including opportunistic pathogens typically found in the nasopharynx.

Aurora et al. compared the microbiome and immune response from 30 patients with chronic rhino-sinusitis (CRS) and 12 healthy controls. The microbiome was analyzed by deep sequencing of the bacterial 16S and fungal 18S ribosomal RNA genes. Although quantitative increase in most bacterial and fungal species was observed in patients with CRS relative to controls, the microbiomes of patients with CRS were qualitatively similar to the controls. The predominate aerobic organisms were Cyanobacterium , Curtobacterium, and  Pseudomonas spp., and staphylococcus aureus. The commonest anaerobes were Propionbacterium, and Prevottela spp.

Patients with CRS had increased levels of the following cytokines: IL-4, IL-5, IL-8, and IL-13, along with increased levels of eosinophils and basophils in the lavage. Furthermore, peripheral blood leukocytes obtained from some patients with CRS responded to control lavage samples (ie, to commensals) to produce IL-5. In contrast, the same lavage sample evoked no IL-5 production in leukocytes from healthy controls. These results may explain why systemic steroid treatment provides relief for some patients with CRS.

Colonization of non-inflamed “normal “ sinus is possible because there is direct communication between the sinuses nasal cavity through the ostia which could enable organisms that reside in the nasopharynx to spread into the sinus. The presence of bacteria in the sinus can explain why following closure of the ostium, these organisms may become involved in the emerging inflammatory process.

The study by Aurora et al. that the host response or lack of response to the normal sinus flora may be key to the development of sinus inflammation. Modulation the sinus flora by topical antimicrobial and/or probiotic organisms that may interfere with the growth of pathogens may be used to prevent and treat sinus inflammation. Future studies that would explore these modalities are warranted. 

                                                      

                                                       CT of normal sinuses

Clinical Practice Guidelines for Adult Sinusitis by the American Academy of Otolaryngology—Head and Neck Surgery Foundation

The American Academy of Otolaryngology—Head and Neck Surgery Foundation has published an updated “Clinical Practice Guideline: Adult Sinusitis” as a supplement to Otolaryngology–Head and Neck Surgery. The guideline recommendations address diagnostic accuracy for adult rhinosinusitis, the appropriate use of ancillary tests to confirm diagnosis and guide management (including radiography, nasal endoscopy, computed tomography, and testing for allergy and immune function), and the judicious use of systemic and topical therapy. Emphasis was also placed on identifying multiple chronic conditions that would modify management of rhinosinusitis, including asthma, cystic fibrosis, immunocompromised state, and ciliary dyskinesia.

The treatment recommendations include:

Symptoms of viral sinusitis can be treated symptomatically by relieving pain, and administration of nasal steroid sprays, and/or nasal saline rinse (irrigation).

Acute bacterial sinus can be watchful waited without antibiotics or be treated with an antibiotic. If a decision is made to treat acute bacterial sinus infection with an antibiotic, amoxicillin will likely be prescribed. A combination of amoxicillin with clavulanate for 5 to 10 days may also be prescribed as a different treatment. If after 7 days the patient feel worse or does not improve (whether receiving antibiotic treatment or not) he/she should see their healthcare provider. The healthcare provider will review the diagnosis and exclude other causes. The provider may also decide to start or change antibiotics. To relieve symptoms, the healthcare provider may recommend over-the-counter treatments. These include pain relievers, nasal steroid sprays, decongestants, mucus thinners, cough suppressants, and nasal saline rinse. 

Chronic sinusitis may be linked to an hyperactive immune system

A recent study in JAMA Otolaryngology--Head& Neck Surgery, in October 2013, suggested that chronic rhinosinusitis (CRS) may be caused by an overactive immune response to normal microbes, and not necessarily to bacterial infection. Investigators from Saint Louis University School of Medicine in Missouri lead by Dr. Rajeev Aurora found that patients and healthy controls tended to have qualitatively similar microorganisms in their sinus cavity. While control patients sinus lavage samples triggered interleukin (IL)-5 production in peripheral blood leukocytes from patients, this did not occur with leukocytes from controls.

The investigators obtained sinus cavity samples from thirty patients with CRS and 12 controls. They used deep sequencing to characterize the patients' microbiomes and search for pathogens that may potentially trigger an immune response. They also identified the immune cells and cytokines in the specimens. Almost all the recovered fungal and bacterial species were non pathogenic . Although there were higher numbers of these organisms in patients than in controls, the microbiomes in the two groups were qualitatively similar. The fact that only leukocytes from patients with CRS reacted to nasal samples from controls, suggests that CRS patients have an abnormal immune response to normal microorganisms.

The researchers postulated in an interview with Reuters Health that these results indicate that immune cells from a patient with CRS are getting activated by the microbes found in the normal sinus. These non-virulent organisms are most likely picked up from the air the patients breath, and therefore antibiotics cannot eliminate them in the sinus as they re-colonize the sinus with each breath. The authors also believe that these organisms may leads to a persistent inflammation in people whose immune system is aberrantly sensitive to these common organisms.

In an interview with Reuters Health  Dr. Itzhak Brook, a pediatrician at Georgetown University in Washington, D.C., who specializes in sinus infections, called the study "innovative and provocative." However, he noted that 16 of 30 patients in the CRS group were asthma suffers and prone to allergies. "They therefore do not represent the average patient with CRS, but a subgroup in whom the immune system is hyperactive," Dr. Brook added that the findings shouldn't change how doctors treat patients. The fact that the sinus cavity in normal individuals harbors the same bacteria (albeit in greater numbers) as infected sinuses is not new and was describe in study done by Dr. Brook in 1981.  

Patient’s outcome in acute invasive fungal sinusitis

Acute invasive fungal sinusitis (AIFS) is an aggressive and often fatal infection. Despite improvements in medical and surgical therapy, survival remains limited and the factors that contribute to patient outcomes remain poorly understood. Turner et al from the Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee performeda  systematically reviews of  the literature to characterize prognostic factors associated with survival after AIFS..

The authors reviewed 52 studies comprising a total of 807 patients, and analyzed the prognostic factors as they related to the treatment, presentation, and outcomes. Univariate and multivariate logistic regression was used to identify prognostic factors.

The most common presenting symptoms of patients with AIFS were facial swelling (64.5%), fever (62.9%), and nasal congestion (52.2%). Most patients were treated with a combination of intravenous antifungal medication and surgery. The overall survival rate was 49.7%. Poor prognosis was associated with renal/liver failure, altered mental status, and intracranial extension. Patients who were diabetic, had surgery, or received liposomal amphotericin B had an improved chance of survival. Advanced age and intracranial involvement were identified as independent negative prognostic factors. Positive prognostic factors again included diabetes and surgical resection.

The conclusion of the analysis was that the overall mortality of patients with AIFS remains high, with only half of the patients surviving. Diabetic patients appear to have a better overall survival than patients with other comorbidities. Patients who have intracranial involvement, or who do not receive surgery as part of their therapy, have a poor prognosis.

                             

CT scan of acute invasive fungal sinusitis caused by zygomycosis. There is increased attenuation in the ethmoid air cells with destruction of the median wall of the left orbit (arrow).

US FDA issues guidelines for developing drugs for acute bacterial sinusitis

The US Food and Drug Administration (FDA) has issued guidelines for the pharmaceutical  industry for developing antimicrobials for the treatment of acute bacterial sinusitis (ABS). The FDA stated that any new drug being studied for ABS should have documenting in-vitro antibacterial activity against the most commonly pathogens associated with ABS. These include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Even though animal models of ABS has been developed, particularly for S. pneumoniae infection, they cannot substitute for clinical trials in patients that must be conducted to evaluate drug safety and efficacy. The FDA recommend that two adequate and well-controlled human trials establishing safety and efficacy be conducted for that indication.  However, a single trial for an ABS indication may be appropriate if there is data from other clinical trials demonstrating effectiveness in other respiratory tract diseases such as community acquired bacterial pneumonia. Additional supportive information like pharmacokinetic and pharmacodynamic studies demonstrating concentration of the antibacterial drug in the sinuses at a level expected to be active against the common pathogens causing ABS would be required. Because direct assessment of ABS symptoms to support a conclusion of treatment benefit in response to antibacterial drug therapies is readily measured no surrogate markers of success of therapy are needed. Antimicrobials with clinically significant toxicity would not be considered appropriate for study of ABS unless treatment of a more seriously ill patient population is being considered.

New guideline for the treatment of sinusitis released by the Infectious Diseases Society of America (IDSA).

The new guideline emphasize that the vast majority of sinus infections are caused by viruses and should not be treated with antibiotics. In those cases the new guidelines call for shorter treatment time than older guidance, which suggested a 10 to 14 days weeks of antibiotic treatment for a bacterial infection. The IDSA guideline suggests that five to seven days is long enough to treat  most bacterial infection without encouraging resistance in adults, though children should still receive the longer course.

Because of increasing resistance to amoxicillin (the current standard of care) the guideline recommends amoxicillin-clavulanate as the treatment of choice for acute sinusitis.  Amoxicillin-clavulanate is a combination that helps to overcome antimicrobial resistance by inhibiting an enzyme that breaks down the antibiotic.

The guidelines also recommend against other commonly used antibiotics, including azithromycin, clarithromycin and trimethoprim/sulfamethoxazole, because of growing drug resistance.

Whether the sinus infection is bacterial or viral, the use of decongestants and

antihistamines is not recommended as they may make symptoms worse. Nasal steroids can help ease symptoms as may nasal irrigation using a sterile solution, including sprays, drops or liquid. It is also recommended to use acetaminophen for sinus pain and drink plenty of fluids.

The symptoms of a bacterial sinus infection that does warrant prompt attention and possibly antibiotics are:

1. Symptoms that last for 10 or more days and are not improving, or severe symptoms accompanied by a fever of 102 degrees Fahrenheit or higher

2. Facial pain and green nasal discharge that lasts for 3 or 4 days

3. Symptoms that initially improve after 5 to 7 days, but then return and worsen.

Is amoxacillin an adequate agent for the treatment of sinusitis?

A recent study by Garbutt and associates evaluated the effect of amoxicillin treatment over symptomatic treatments for adults with clinically diagnosed acute sinusitis.

They performed a randomized, placebo-controlled trial of 166 adults with uncomplicated, acute sinusitis between 2006 and 2009. Patients were randomized to receive a 10 days course of either amoxicillin ( 85 patients) or placebo (81 patients). All received a supply of symptomatic treatments for pain, fever, cough, and nasal congestion to use as needed. On day 3 of treatment, there was no difference in improvement between placebo-takers and those prescribed antibiotics. On day 7, the antibiotic group reported a slight improvement that the researchers said was unlikely to represent a noticeable relief in symptoms, but that edge disappeared by day 10, when 80 percent of patients in both groups reported they felt better or cured.

The main problem in this study is that many of the patients included in it may have not suffered from bacterial sinusitis but a viral one rendering amoxicillin useless. Furthermore, amoxicillin is no longer a reliable antimicrobial for the treatment of bacterial sinusitis. This is because many of the pathogens causing bacterial sinusitis have become resistant to it. These include Streptococcus pneumoniae (5-10% highly resistant), haemophillus influenzae (30-40%), Moraxella catarrhalis (>95%) and Staphylococcus aureus (>80%).

The implementation of the 7-valent pneumococcal conjugate vaccine has created a shift in the isolation rate of pathogens causing sinusitis. The proportion of H. influenzae in relation to S. pneumoniae has increased over the years such that currently they are approximately equal ( about 40%). This shift contributes to the therapeutic inefficacy of amoxicillin.

The reduced efficacy of amoxicillin lead a multidisciplinary expert panel of the Infectious Diseases Society of America to generate new guidelines for the treatment of acute rhinosinusits. These guidelines recommend that amoxicillin-clavulanate is preferred over amoxicillin as empiric antimicrobial therapy in adults and children with acute bacterial rhinosinusitis.

Are systemic corticosteroids effective in relieving symptoms of acute sinusitis?

Systemic corticosteroids are frequently used to treat acute sinusitis. A recent analysis of the Cochrane Central Register of Controlled Trials (CENTRAL) assess the effectiveness of systemic corticosteroids in relieving symptoms of acute sinusitis.

Four randomized controlled trials with a total of 1008 adult participants met the inclusion criteria. All participants received oral antibiotics and were assigned to either oral corticosteroids (prednisone 24 mg to 80 mg daily or betamethasone 1 mg daily) or the control treatment (placebo in three trials and non-steroidal anti-inflammatory drugs in one trial). In all trials, participants treated with oral corticosteroids were more likely to have short-term resolution or improvement of symptoms than those receiving the control treatment: at Days 3 to 7. An analysis of the three trials with placebo as a control treatment showed similar results but with a lesser effect size: No data on the long-term effects of oral corticosteroids on this condition, such as effects on relapse or recurrence rates was identified. Reported side effects of oral corticosteroids were limited and mild.

It was concluded that that oral corticosteroids as an adjunctive therapy to oral antibiotics are effective for short-term relief of symptoms in acute sinusitis. However, data are limited and there is a significant risk of bias. High quality trials assessing the efficacy of systemic corticosteroids both as an adjuvant and a monotherapy in primary care patients with acute sinusitis should be initiated.

Is there a link between acid reflux and chronic sinusitis?

Acid reflux into the oesophagus, larynx, pharynx or nasopharynx has been suggested as a causal factor in chronic rhino-sinusitis (CRS), which can then be refractory to nasal treatments. A recent review by Flook  & Kumar  (Rhinology 2011)  evaluated the strength of the link between acid reflux and nasal symptoms and CRS.

The authors evaluated 19 studies including those of proton pump inhibitors therapy. Four adult case-controlled studies showed more acid reflux events/symptoms in refractory CRS patients. Paediatric cohort studies showed more reflux events in rhinosinusitis patients than the general paediatric population, but they are not conclusive. Many of the papers did not use robust CRS diagnostic criteria for inclusion into studies and take no confounding factors into consideration.

The authors concluded that the evidence of a link between acid reflux with chronic sinusitis or any nasal symptoms is poor with no good randomised controlled trials available. The few adult studies that show any link between acid reflux and nasal symptoms were small case-controlled studies with moderate levels of potential bias. They found that there is not enough evidence to consider anti-reflux therapy for adult refractory CRS and there is no evidence that acid reflux is a significant causal factor in CRS.

Increase in the Frequency of Recovery of Methicillin Resistant Staphylococcus aureus (MRSA) in Acute and Chronic Maxillary Sinusitis

An increase in the recovery of MRSA was recently noted in various infectious sites including sinusitis. The presence  of MRSA in the infected sinus may not only lead to failure of antimicrobial therapy but can also serve as a potential source for the spread of these organisms to other body sites as well as an origin for dissemination to other individuals.

A recent study of 458 patients with maxillary sinusitis illustrated a significant increase in the recovery rate of MRSA in these patients. S. aureus was isolates from 8% of acute sinusitis patients between 2001-2003; and 30% were MRSA. The organism  was recovered from 10% of patients with acute sinusitis between 2004-2006; and 69% were MRSA ( p< .01). S. aureus was found in 16% of chronic sinusitis patients between 2001-2003; and 27% were MRSA. It was recovered from 20% of chronic sinusitis patients between 2004-2006; and 61% were MRSA ( p< .05). MRSA was isolated more often from patients who received previous antimicrobial therapy.

These findings suggest the need to suspect the presence of MRSA in sinusitis patients who had received previous antimicrobial therapy or do not or fail to improve after 48 hours of therapy.  

Sinusitis after radiation is caused by resistant bacteria

Plain x-ray showing opacification of right maxillary sinus

Patients who undergo radiotherapy for nasopharyngeal carcinoma tend to suffer from sinusitis because irradiation causes damage to sinonasal tissue. There is very little information about the organisms causing sinusitis after radiation therapy. Two recent studies from China provided important information about the unique microbiology of sinusitis in these patients.

Huang et al (Am J Rhinol. 2007) endoscopically obtained specimens from 25 patients with acute sinusitis that developed sinusitis after irradiation therapy. Staphylococcus aureus comprised 42% and Gram-negative bacilli 36% of all aerobic isolates. The main anaerobic isolates were Peptostreptococcus and Veillonella spp. Polymicrobial infections and beta-lactamase-producing pathogens were highly prevalent.

A study by Deng and Tang ( Eur. Arch.Otolaryngolog, 2009) compared the bacteriology of chronic maxillary sinusitis that developed after radiation therapy to chronic sinusitis in non irradiated individuals. Thirty people with each condition were evaluated using cultures for aerobic bacteria.

The most common isolates in the post irradiation chronic sinusitis group was S. aureus while those in the other group were Haemophilus influenzae, and Pseudomonas aeruginosa. The isolation rate of gram-positive cocci in the post irradiation group was higher than in the non irradiated patients. (62.5% compared with 30%, respectively; P < 0.05). In contrast the isolation rate of gram-negative bacilli in the irradiated patients was lower than in non-irradiated patients (31% compared with 70%, respectively; P < 0.05).

The findings of both studies illustrate the high rate of recovery of S. aureus from sinus aspirates of individual who were irradiated for head and neck cancer. Because of the high prevalence of methicillin resistant S. aureus (MRSA) these individuals may need to be treated with antimicrobials effective against these organisms.

These studies underscore the need to obtain appropriate cultures from patients with chronic sinusitis who were irradiated so that proper antimicrobials can be administered to them.

Are Topical Antibiotic Effective in Treating Chronic Sinusitis?

Many different treatment options for chronic sinusitis (CS) exist but questions remain regarding the best options. While oral and intravenous antimicrobial therapies have traditionally been prescribed to manage CS, topical administration of these agents has gained increasing popularity over the past few years. Topical antimicrobials have the advantage of local delivery to the sinonasal mucosa and minimize the systemic effects seen with systemic agents. This is especially important in treatment of biofilms where higher concentrations of antibiotics are usually required.

Topical antibiotic delivery devices to date have included nasal sprays, irrigations, and nebulizers. Nasal spraying of topical antibiotics are not believed to be very effective. This is supported by studies that have shown that the majority of deposition occurs only in the anterior part of the nasal cavity. In addition, the nasal sprays rely on mucociliary clearance to transport the drug from the anterior to the posterior nasal cavity, and in patients with CS, their mucociliary clearance may be impaired. There are, however, other studies that found nebulization and irrigation to be effective.


Fungi can play a role in the pathogenesis of CS both in an allergic and inflammatory manner. Several recent studies that evaluated the efficacy of topical amphotericin B showed trends that were promising. However, most of the placebo-controlled studies showed no statistical difference between the treated patients and untreated controls.

Recent animal studies found that mupirocin was effective in reducing Staphylococcus biofilm mass by over 90%. Staphylococcus aureus-related acute exacerbations of chronic sinusitis in patients was also treated effectively with topical mupiricin. No success was, however, achieved with aminoglycosides in reducing Pseudomonas aeruginosa biofilm.

Since most of the initial clinical work done with topical antibiotics in CS was retrospective, prospective studies are warranted to further evaluate the utility of this approach. These should evaluate the efficacy of antimicrobials, antifungals and steroids alone and in combinations.

Smoking and sinusitis

Smoking is one of the most important causes of head and neck cancer. Another important untoward result of active and second hand smoke exposure is the increased risk of respiratory bacterial infecion.  These include acute and chronic sinusitis, ear infections, bronchitis and pneumonia. Recent studies we and others did show that smokers harbor more pathogenic bacteria that are also resistant to antibiotics, can be a source of spread of these bacteria to others (including their children), and when smokers get respiratory infections treating them may be more difficult than treating non-smokers.

In a recent study we evaluated the microbiology of sinus aspirates of smokers and nonsmokers with acute (244 patients, 87 smokers and 157 nonsmokers ) and chronic (214 patients, 84 smokers and 130 nonsmokers) maxillary sinusitis. We found that sinusitis in smokers is more often caused by antibiotic resistant bacteria including methicillin resistant Staphylococcus aureus (MRSA) than in non smokers.

Oropharyngeal ccolonization with potential bacterial pathogens is higher in smokers than non smokers. Cesation of smoking reverses the increased colonozation by pathogens.