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Healthcare use of antibiotics far outweighs the predicted incidence of bacterial causes of acute and chronic sinusitis. That’s the conclusion of a new study published in the March 2007 issue of Archives of Otolaryngology - Head and Neck Surgery.

Antibiotics are only effective against bacterial infection. Many sinus infections are due to viral infection, allergies or hormonal changes. Physicians try to avoid antibiotic use to reduce the emergence of dangerous resistant bacterial strains, such as methicillin-resistant Staphylococcus aureus. However, most patients with sinus congestion want immediate relief and, because more effective drugs for chronic sinusitis are lacking, demand antibiotics.

The four-year prospective study found Americans made on average 4.25 million visits to healthcare facilities per year for sinus infection between 1999 and 2002. At least one antibiotic was prescribed in nearly 83% of cases of acute sinusitis and 70% of cases of chronic sinusitis. Antibiotics were prescribed more often than antihistamines, nasal decongestants, corticosteroids, and antitussive, expectorant, and mucolytic agents (order reflects the frequency of recommended medication).

The penicillins amoxicillin and amoxicillin-clavulanate potassium (brand name Augmentin) were the most commonly used antibiotics for both chronic and acute bacterial sinusitis. According to the Sinus and Allergy Health Partnership, the next most frequently used antibiotics should be erythromycins, lincosamides, and macrolides. However, the authors found cephalosporins, sulfonamides, trimethoprim, and tetracyclines were more commonly used.

Corticosteroids are used to reduce or prevent inflammation of the sinus mucous membranes. They do this by altering the actions of various cells of the immune system. Corticosteroids may be applied topically as a nasal spray or orally. Oral corticosteroids are rarely used to treat sinusitis. Prolonged use of oral corticosteroid treatments can cause serious side effects, including thinning of the bones, diabetes and increased risk of infection. Corticosteroid nasal sprays generally don’t cause these side effects. In addition, discontinuing use of corticosteroids does not lead to rebound congestion like topical nasal decongestants, frequently used to reduce sinus inflammation and congestion.

The use of corticosteroids was found in 15 to 16 percent of visits for acute and chronic cases of sinusitis. The authors maintain the rate of corticosteroid use is higher than published studies imply is necessary for acute sinusitis, while the rate may actually be lower than indicated for chronic sinusitis. Several studies suggest that intranasal corticosteroid use in conjunction with antibiotics are effective for improving the symptoms of acute sinusitis compared with antibiotic therapy alone [1-3]. Recent promising results from a study in patients with acute, uncomplicated sinusitis found that mometasone furoate (brand name Nasonex) nasal spray used twice daily produced significant symptom improvements versus amoxicillin and placebo, without predisposing the patient to disease recurrence or bacterial infection [4]. However, further studies may be needed to better clarify the role and proper dosage of corticosteroids when used alone or in combination with antibiotic therapy in the management of acute and chronic sinusitis.

The authors of the study express concern regarding the problems surrounding antibiotic overuse and conclude:

“When two-thirds of patients with sinus symptoms expect or receive an antibiotic and as many as one-fifth of antibiotic prescriptions for adults are written for a drug to treat rhinosinusitis, these disorders hold special pertinence on the topic.”

Increasing antibiotic resistance
Children average six to eight colds per year. Of those, only 0.5 to 5 percent will develop a sinus infection [6]. Nevertheless, sinusitis is the fifth most common diagnosis for which an antibiotic is prescribed [5]. There are a number of methods to determine whether a sinus infection is bacterial, including:

• Nasal cytology - examining a swab from the lining of the nose.
• Nasal endoscopy - running a tube into the nose to obtain a sample of mucus from the sinus cavity.
• X-ray, computer tomography, magnetic resonance imaging (MRI) or ultrasound
• Sinus puncture and bacterial culture - usually only performed if a reasonable diagnosis cannot be made using noninvasive techniques.

Unfortunately, all these methods are expensive and time-consuming.

A recent study found that 28% of Haemophilus influenzae strains cultured from patients with an acute exacerbation of chronic or acute sinusitis were resistant to ampicllin; 79% of Streptococcus pneumoniae strains were found to be penicillin-intermediate resistant [7]. An earlier study in 2001 in children with sinusitis found that 44% of Haemophilus influenzae cultures isolated were ampicillin resistant (41% having high-grade resistance) and 64% of Streptococcus pneumoniae isolates were resistant to penicillin (24% having high-grade resistance) [8].

Antibiotic resistance is an emerging public health crisis. Today, virtually all important bacterial infections in the United States and throughout the world are becoming resistant. The Centers for Disease Control and Prevention calls antibiotic resistance one of the world’s most pressing public health problems.

Remember
Taking antibiotics for viral infections will increase the risk of antibiotic resistance. Millions of antibiotics prescribed in doctors’ offices each year are for viral infections, which cannot effectively be treated with antibiotics. An alternative therapy for sinus infection is nasal irrigation, which can relieve symptoms, reduce inflammation and remove stagnant mucus in the nasal passages, making it difficult for infections to develop. The spread of viral infections can be reduced through frequent hand washing and by avoiding close contact with others.

References

• Meltzer et al. Intranasal flunisolide spray as an adjunct to oral antibiotic therapy for sinusitis. J Allergy Clin Immunol. 1993 Dec;92(6):812-23.
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• Barlan et al. Intranasal budesonide spray as an adjunct to oral antibiotic therapy for acute sinusitis in children. Ann Allergy Asthma Immunol. 1997 Jun;78(6):598-601.
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• Dolor et al. Comparison of cefuroxime with or without intranasal fluticasone for the treatment of rhinosinusitis. The CAFFS Trial: a randomized controlled trial. JAMA. 2001 Dec 26;286(24):3097-105.
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• Meltzer et al. Treating acute rhinosinusitis: comparing efficacy and safety of mometasone furoate nasal spray, amoxicillin, and placebo. J Allergy Clin Immunol. 2005 Dec;116(6):1289-95. Epub 2005 Oct 24.
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• Anon et al. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg. 2004 Jan;130(1 Suppl):1-45.
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• Ramadan, HH. Pediatric sinusitis: update. J Otolaryngol. 2005 Jun;34 Suppl 1:S14-7.
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• Tellez et al. Microbiology of acute sinusitis in Mexican patients. Arch Med Res. 2006 Apr;37(3):395-8.
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• Slack et al. Antibiotic-resistant bacteria in pediatric chronic sinusitis. Pediatr Infect Dis J. 2001 Mar;20(3):247-50.
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A study published in The Journal of the American Medical Association (JAMA) made headlines recently. The review, “Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Systematic review and meta-analysis”, assessed the effect of antioxidant supplementation on mortality in randomized primary and secondary prevention trials and concluded that beta carotene, vitamin A and vitamin E supplementation are positively correlated with death and may increase mortality.

The Copenhagen University Hospital research group searched electronic databases and bibliographies published prior to November 2005 and included 68 randomized trials (385 publications) with 232,606 participants. The authors have published two other articles recently using a similar methodology and demonstrated similar results [1-2].

The study, not a clinical trial itself, but a study of studies (i.e. a meta-analysis), has a number of problems, notably flawed methodology and over-analysis of the data.

Flawed methodology
According to the article, the goal of the analysis was:

“… to analyze the effects of antioxidant supplements (beta carotene, vitamin A, vitamin E, vitamin C and selenium) on all-cause mortality of adults included in primary and secondary prevention trials.”

However, the researchers specifically excluded 405 studies that reported no deaths during a trial period or follow-up.

Did you get that?

The researchers are studying effects on mortality but failed to include any studies that were death-free. They excluded six times as many potentially eligible studies because no one died during a trial period or follow-up.

In addition, 47 of the 68 trials included in the meta-analysis were secondary prevention trials conducted on subjects that were diagnosed with disease. The goal of these trials was to establish whether intervention would slow disease progression or reduce the risk of death from disease. Only 21 were primary prevention trials conducted on healthy subjects (the goal of these trials was to establish a benefit to health). Thus, not only did all studies included in the meta-analysis report deaths during a trial period or follow-up, but over two thirds of the studies were trials on people that were already diagnosed with a disease.

I agree with Marc’s conclusion over at Marc Joseph Nutrition:

Bottom-line, as a meta-review analysis, this study is subject to selection bias* and the interpretation of the researchers.

* Selection bias is the error of distorting a statistical analysis by pre- or post-selecting the samples. Typically this causes measures of statistical significance to appear much stronger than they are, but it is also possible to cause completely illusory artifacts.

Over-analysis of the data
Trials were classified according to the risk of bias based on the quality of the methods used in the study, either low-bias risk (high methodological quality) or high-bias risk (low methodological quality). The abstract indicates that “randomization, blinding, and follow-up were considered markers of bias in the included trials”. Nevertheless, when all low- and high-bias risk trials of antioxidant supplements were pooled together, there was no significant association between supplement use and mortality.

Significant influences of dosage on mortality were found for beta-carotene, vitamin A, selenium and bias risk. Doses of vitamin A ranged from 1333 IU per day to 200,000 IU per day (mean value 20,219 IU), well above the upper tolerable limit. Notably, there was no increased risk for vitamin C or vitamin E in either single or combined regimen, duration of supplementation, or primary or secondary prevention. Selenium had a statistically significant protective effect by dose. However, when multiple variables were used in the meta-regression, dose of selenium for low-bias risk trials was associated with significantly higher mortality. Beta carotene and vitamin A, as well as the other antioxidants, failed to show increased risk.

On his Livejournal page, Phil explains the inverted-J-shaped response curve of vitamins. As with any medication, mortality will be observed if dosage exceeds toxic levels. In addition, he points out that all the antioxidants suggested to increase mortality (beta carotene, vitamin A and vitamin E) are fat soluble vitamins, which are stored in the body for long periods of time and can build up toxic levels when taken in high doses.

Regina over at Weight of Evidence did an extensive review of the study and summarizes the results for each antioxidant as follows:

• Beta carotene by itself, bad; combined, nothing; exlude some study data and again it’s bad.
• Vitamin A alone or in combination, nothing; exclude some study data, bad.
• Vitamin E alone, in combination, in high dose - nothing; exclude some study data, it’s bad.
• Vitamin C alone, in combination and when excluding some study data, nothing.
• Selenium alone or in combination, nothing; data analyzed together singly or in combination, benefit; exclude some data, nothing.

The meta-analysis did not investigate causes of death, but it’s likely given that 69% of the trials analyzed were secondary prevention that the deaths occurring were principally due to previously diagnosed disease and not antioxidant supplementation. The authors also failed to analyze for potential outcome differences between primary and secondary prevention trials.

Thus, there are many problems with this meta-analysis. Unfortunately, the media has focused only on the results of the low risk bias group, which showed a 16% increase in mortality rate. Here’s the rest of the story:

1. Intervention effect of antioxidant supplements vs placebo on mortality in trials with low risk of bias
   Antioxidants: 15,366 out of 99,095 participants (15.5%)
   Control: 9,131 out of 81,843 participants (11.1%)
   Relative to control: 15.5% - 11.1% = 4.4% (Not 16% as reported by the media)
   Relative risk: 1.05, mortality significantly increased
2. Intervention effect of antioxidant supplements vs placebo or no intervention on mortality in trials with high risk of bias
   Antioxidants: 2,532 out of 36,940 participants (6.9%)
   Control: 1,027 out of 14,728 participants (7.0%)
   Relative to control: 6.9% - 7.0% = -0.1%
   Relative risk: 0.91, mortality significantly decreased
3. Pooled low- and high-risk bias
   Antioxidants: 17,898 out of 136,035 (13.2%)
   Control: 10,158 out of 96,571 (10.5%)
   Relative to control: 13.2% - 10.5% = 2.7%
   Relative risk: 1.02, no significant effect on mortality

Note that there was a significant decrease in mortality in trials with high risk of bias.

Rebuttal
The Council for Responsible Nutrition (CRN) has rebuked the meta-analysis review, noting several problems including:

• The meta-analysis combined studies that differ vastly from each other in a number of important ways that compromise the results, including dosage, duration, study population and nutrients tested.
• Many of the clinical trials included in the meta-analysis tested nutrients beyond those that were the focus of the article including lutein and zinc, making it difficult to appropriately evaluate the contribution of those trials to the overall meta-analysis.
• The overwhelming majority of the clinical trials included in the meta-analysis tested for secondary prevention.
• Many of the treatment trials had limitations, including the expectation that a simple antioxidant vitamin could be expected to overturn serious illness, such as cancer or heart disease.

Andrew Shao, vice president for science and regulatory affairs at CRN, said:

“The study authors concluded that overall there was no effect of antioxidant supplements on all-cause mortality. It was only after the researchers divided the chosen clinical trials into ‘high risk bias’ and ‘low risk bias’ groups, using their own criteria, that they observed a statistically significant effect on mortality. This meta-analysis appears to be a predetermined conclusion in search of a method to support it.”

On a final note, the study authors acknowledge that their results are in conflict with observational studies that have shown beneficial effects of supplemental antioxidants, even in secondary prevention trials [3-5].

References

1. Bjelakovic et al. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet. 2004 Oct 2-8;364(9441):1219-28.
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2. Bjelakovic et al. Meta-analysis: antioxidant supplements for primary and secondary prevention of colorectal adenoma. Aliment Pharmacol Ther. 2006 Jul 15;24(2):281-91.
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3. Fleischauer et al. Antioxidant supplements and risk of breast cancer recurrence and breast cancer-related mortality among postmenopausal women. Nutr Cancer. 2003;46(1):15-22.
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4. Baron et al. Neoplastic and antineoplastic effects of beta-carotene on colorectal adenoma recurrence: results of a randomized trial. J Natl Cancer Inst. 2003 May 21;95(10):717-22.
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5. Whelan et al. Vitamin and calcium supplement use is associated with decreased adenoma recurrence in patients with a previous history of neoplasia. Dis Colon Rectum. 1999 Feb;42(2):212-7.
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A clinical trial, also called a clinical study, is a research study designed to answer specific questions about new medical approaches (e.g. drugs, therapies) or new ways of using existing approaches. These studies can test screening methods as well as prevention, diagnosis or treatment of a condition or disease. A clinical trial is one of the final steps in the research process. Health professionals run clinical studies according to strict guidelines set by the Food and Drug Administration (FDA) to ensure that people who agree to be in the studies are treated as safely as possible. Clinical trials are usually conducted in four phases with patients to evaluate the effectiveness of new medical approaches. The FDA requires strict testing of all drugs and vaccines prior to their approval for use as therapeutic agents in the general population.