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Rational use of antibiotics in respiratory tract infections

Leilani Johnston, BPharm Amayeza Info Services Correspondence to: Leilani Johnston, e-mail: leilani@amayeza-info.co.za Keywords: antibiotics, respiratory tract infections

Abstract Viruses account for most respiratory tract infections. However, antibiotics continue to be prescribed and utilised inappropriately. Indiscriminate prescribing and patient noncompliance contribute to the rising prevalence of antibiotic resistance. Only 15 (out of 167) new antibiotic agents are being developed that have a new mechanism of action. It is imperative that healthcare professionals adhere to the rational use of antibiotics, and advise their patients accordingly.
Medpharm S Afr Pharm J 2012;79(4):34-39

Introduction
Respiratory tract infections account for almost 10% of worldwide morbidity and mortality.1 The respiratory tract is the most common site of infection because it comes into direct contact with the environment and airborne microorganisms. The most common causative agents in respiratory tract infections are viral. However, the respiratory tract may be infected by a range of microorganisms, including bacteria, fungi and parasites.2 It is divided into the upper and lower respiratory tract. Infection of either of these areas may lead to inflammation, which may be categorised as follows (see Table I). Most respiratory tract infections are caused by viruses. As such, they are generally self-limiting, treated symptomatically, and have a high rate of spontaneous recovery. Despite this, respiratory tract infections account for the most frequent visits to the doctor. Most primary care consultations still result in a prescription for antibiotics (Table II).5,6 In the event that antibiotics are indicated for the treatment of bacterial respiratory infections, it is essential that they are used
Table I: Upper and lower respiratory tract infections Upper respiratory tract infections3

rationally. Injudicious use may lead to antibiotic resistance, adverse effects, and higher healthcare costs.

Antibiotic resistance
Antibiotic resistance is a global health problem, and a major cause for concern. It is associated with the inappropriate, as well as frequent, use of antibiotics.18 It occurs when bacteria transform in some way that makes them resistant to antibiotics. Resistant bacteria continue to multiply in the presence of therapeutic levels of an antibiotic.19 Some bacteria are innately resistant to certain antibiotics. However, others may acquire resistance by means of genetic mutation, or acquiring resistance from another bacterium through gene transfer from one microorganism to another.20 Antibiotic-resistant bacteria pose a huge problem as infections fail to respond to standard treatment, leading to prolonged illness, high treatment costs, extended hospitalisation, and possibly death. In addition, while patients fail to respond to standard therapy, they remain infectious, and have the potential to infect others, leading to possible outbreaks.20

Lower respiratory tract infections4 Bronchitis (inflammation of the trachea and bronchi) Bronchiolitis (inflammation of the bronchioles) Pneumonia (inflammation of the lungs)

Rhinitis (inflammation of the nasal mucosa) Rhinosinusitis or sinusitis (inflammation of the nares and paranasal sinuses) Nasopharyngitis (inflammation of the nares, pharynx, hypopharynx, uvula and tonsils) Pharyngitis (inflammation of the pharynx, hypopharynx, uvula and tonsils) Epiglottitis (inflammation of superior region of the larynx and subglottic area) Laryngitis (inflammation of the larynx) Laryngotracheitis (inflammation of the larynx, trachea and subglottic area) Tracheitis (inflammation of the trachea and subglottic area)

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Table II: Causes and treatment of upper and lower respiratory tract infections Upper respiratory Viral causes (viral infections are not Bacterial causes tract infection treated using antibiotics) Acute otitis media Most commonly caused by viruses. Resolves without antibiotics in 80% of cases.7 Examples: Respiratory syncytial virus Rhinovirus Adenovirus Parainfluenza virus Coronavirus Most commonly caused by viruses, such as:9 Rhinovirus Influenza virus Coronavirus Respiratory syncytial virus Adenovirus Enterovirus Parainfluenza virus Streptococcus pneumoniae Non-typeable Haemophilus influenzae Moraxella catarrhalis7 Antibiotics indicated for bacterial infection in adults

The treatment of choice is oral amoxicillin:8 Amoxicillin, 1 000 mg three times daily for 5 days In patients with -lactam allergy: Erythromycin estolate, 500 mg four times daily for 5-7 days Azithromycin, 500 mg once daily for 3 days Clarithromycin (modified release), 500 mg or 1 g once daily for 5-7 days

Acute paranasal sinusitis

Streptococcus pneumoniae9 Haemophilus influenzae Staphylococcus aureus Moraxella catarrhalis Anaerobes

The treatment of choice is oral amoxicillin:8 Amoxicillin, 1 g three times daily for 10 days For patients with severe -lactam allergy: Macrolides: - Erythromycin, 500 mg four times daily for 10 days - Clarithromycin (modified release), 1 000 mg once daily for 10 days - Azithromycin, 500 mg once daily for 3 days - Telithromycin, 800 mg once daily for 5-10 days Fluoroquinolones: - Gemifloxacin, 320 mg daily for 5-10 days - Levofloxacin, 500 mg bd or 750 mg once daily for 5-10 days - Moxifloxacin, 400 mg once daily for 5-10 days - Clindamycin, 450 mg three times daily for 10 days The treatment of choice is penicillin for strep throat:8 Penicillin VK, 500 mg bd for 10 days Benzathine penicillin (intramuscular injection) 1.2 MU For patients with severe -lactam allergy: Erythromycin estolate, 500 mg bd for 10 days Azithromycin, 500 mg once daily for 3 days Clarithromycin (modified release), 500 mg once daily for 5 days Telithromycin, 800 mg once daily for 5 days Antibiotics indicated for bacterial infection in adults Most guidelines do not recommend the use of antibiotics in acute bronchitis. Acute exacerbations of chronic bronchitis: Amoxicillin or doxycycline (co-amoxyclav or quinolones may be requested in special circumstances).14

Sore throat

The majority of sore throats are viral: Influenza virus Adenovirus Parainfluenzavirus Coronavirus Respiratory syncytial virus10

An important cause of bacterial pharyngitis is Streptococcus pyogenes.11,12 Other bacterial causes include: Haemophilus influenzae Staphylococcus aureus Chlamydia pneumonia

Lower respiratory Viral causes tract infection Bronchitis Approximately 90% of acute bronchitis is caused by viruses, such as: Influenza Parainfluenza virus Adenovirus Rhinovirus13 Viral pneumonia:15 Influenza virus Respiratory syncytial virus Adenovirus Parainfluenza virus (The relative importance of other viruses such as rhinoviruses, coronaviruses and human metapneumovirus, is likely to increase as diagnostic tests become more widely available).

Bacterial causes Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Mycoplasma pneumoniae Bordetella pertussis13

Pneumonia

Community-acquired pneumonia:16 Treatment of community-acquired pneumonia is Streptococcus pneumoniae (leading complex. Please refer to South African treatment guidelines.17 cause of CAP) Haemophilus influenzae Moraxella catarrhalis (Together, these three pathogens account for account for 85% of community-acquired pneumonia).

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In Europe, five drug-resistant organisms lead to the deaths of approximately 25 000 people annually. These infections result in added healthcare costs and loss of productivity amounting to 1.5 billion each year.21 In the USA, the estimated annual cost of antibiotic resistance in US hospitals is in excess of $20 billion.22 South African statistics are not known, but the country is recognised as a world leader in the prevalence of Gramnegative organisms with resistance to -lactam antibiotics.23 In South Africa, antibiotic-resistant bacteria that are of major concern include the following:20 Approximately 40% of bloodstream infections that are caused by Staphylococcus aureus in the major academic hospitals are resistant to first-line treatment with cloxacillin. This resistant bacterium is referred to as methiclllin-resistant Straphylococcus aureus. Approximately 60% of Klebsiella pneumoniae that cause bloodstream infections in the major academic hospitals contain an enzyme called extended spectrum beta-lactamase (ESBL) that causes them to be resistant to broad-spectrum antibiotics. K. pneumoniae causes life-threatening infections in hospitalised patients, and has been the cause of several hospital outbreaks in South Africa. Treatment options for these infections are limited. With the increasing incidence of antibiotic resistance, and a decline in the research and development of new antibiotics, all healthcare practitioners have an obligation and a responsibility to ensure the appropriate prescribing and use of antibiotics. Healthcare professionals have an instrumental role in educating patients about the aetiology of respiratory infections, as well as the correct use of antibiotics when indicated. Methods that may be effective include:18,25 Acknowledging the patients symptoms and discomfort. Promoting active management of the symptoms with nonpharmacological treatment, or the appropriate use of cold and flu preparations (decongestants and antipyretics). Giving a realistic time for resolution. The use of delayed prescriptions, whereby the prescriber gives a patient a prescription, with the instruction to only use it if symptoms do not improve within a given time frame.

Patient education and improving compliance

Community pharmacists are often the first port of call when patients require medical information and advice, and are indispensable as educators. Pharmacists may help to address misconceptions about the cause of a patients illness, as well as the inappropriate use of antibiotics when prescribed. Pharmacists need to be aware of, and warn against, the following patient behaviours that constitute noncompliance, and which may lead to antibiotic resistance.

Omission of doses
One of the most common mistakes that patients make is forgetting to take a single dose. Often this is associated with frequent dosing intervals which may be inconvenient while at school or work. In general, more frequent dosing is associated with poorer compliance. For example, one study showed that during a fiveday treatment for respiratory tract infections, 34% of patients on a twice-daily regimen missed one dose, in comparison to 76.5% of patients on a three-times-a-day regimen. In contrast, oncedaily antibiotic dosing is associated with compliance rates close to 100%.26 Improved compliance has been shown with shorter courses of antibiotic therapy for respiratory tract infections. Better compliance was reported for regimens shorter than seven days, as opposed to longer treatment regimens. Some patients also stop taking their medication before the required treatment period is over. Generally, this occurs when their symptoms have been relieved, and once their health has improved. Patients may also stop treatment due to adverse effects.26 Other characteristic behaviours of noncompliance include:26,27 Taking additional doses at the start of treatment, to get better quickly. Reducing dosage frequency, e.g. from three times a day to twice a day, to fit in with a patients lifestyle and daily activities. Keeping leftover antibiotics for future use.

Avoid unnecessary prescribing

Research has shown that healthcare professionals are partly responsible for the development of bacterial resistance. Doctors sometimes prescribe antibiotics inappropriately, e.g. for viral infections such as colds and flu. They are often pressurised by patients who insist on antibiotics, through a lack of understanding of the cause of their respiratory tract infection. Unfortunately, doctors who have time constraints often oblige, in order to save time.18 However, research has shown that effective patient-doctor communication provides more patient satisfaction than providing a prescription for an antibiotic.24 Other prescribing errors include:18 Incorrect dosage Incorrect duration of treatment Prescribing broad-spectrum antibiotics in instances where narrow-spectrum antibiotics would have been effective. It is imperative that pharmacists and prescribers work together to ensure the correct, proper, and appropriate use of antibiotics, to curb rising antibiotic resistance. Pharmacists should confirm dosages and duration of treatment.

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Improving patient compliance
The prescribing doctor and pharmacist should always communicate the importance of completing a course of antibiotics according to the recommended dosing, with regard to treatment failure, reducing total treatment costs, as well as the development of resistance. Dosing instructions should be simple, concise, and easy for the patient to understand. Whenever possible, a suitable antibiotic, with the shortest duration of treatment and most convenient dosing schedule, should be selected.26 Key points are as follows: Most respiratory tract infections are caused by viruses, in which case antibiotics are rarely indicated. In the event of bacterial infection, an antibiotic that is effective against the causative agent, or the most likely causative agent, should be selected. Wherever possible, an antibiotic with a narrow spectrum should be used. If an antibiotic has been taken in the previous three months, one that is in a different class should be selected.18 Antibiotics with the shortest treatment course, and least frequent dosing intervals, are associated with the best compliance.26 The prevention of respiratory tract infections should be encouraged with annual influenza vaccinations, conjugated pneumococcal vaccinations in children aged six weeks to five years, polysaccharide pneumococcal vaccines in adults > 65 years, and up-to-date childhood vaccinations against Haemophilus influenzae, while the importance of hand washing, and good coughing and sneezing etiquette, should be emphasised.
5. Peters S, Rowbotham S, Chisolm A, et al. Managing self-limiting respiratory tract infections: a qualitative study of the usefulness of the delayed prescribing strategy. Br J Gen Pract. 2011; 6(590):e579-589. 6. West JV. Acute upper airway infections. B Med Bull. 2002;61:215-230. 7. Massa HM, Cripps AW, Lehmann D. Otitis media: viruses, bacteria and vaccines. Med J Aust. 2009;191(9):S44-S49. 8. Updated guideline for the management of upper respiratory tract infections in South Africa: 2008. S Afr Fam Pract. 2010;52(4):312. 9. Brunton SA. Managing acute maxillary sinusitis in the family practice. The Journal of Family Practice 2003;45(9):S4-S11. 10. Fried MP. Sore throat. The Merck Manual for Health Care Professionals [homepage on the Internet]. 2008. 2012. Available from: http://www.merckmanuals.com/professional/ ear_nose_and_throat_disorders/approach_to_the_patient_with_nasal_and_pharyngeal_ symptoms/sore_throat.html 11. Halsey ES, Cunha BA. Bacterial pharyngitis. Medscape [homepage on the Internet]. 2012. c2012. Available from: http://emedicine.medscape.com/article/225243-overview 12. Bannister B, Gillespie S, Jones J. Microbiology and management. 3rd ed. Massachusetts: Blackwell Publishing; 2006. 13. Worrall G. Acute bronchitis. Can Fam Physician. 2008;54(2):238-239. 14. Western Cape academic hospitals antimicrobial recommendations and wound care management. National Health Laboratory Service, 2011 [homepage on the Internet]. c2012. Available from: http://www.medmicro.uct.ac.za/documents/antimicrobial2011.pdf 15. Mosenifar Z. Viral pneumonia. Medscape [homepage on the Internet]. 2011. c2012. Available from: http://emedicine.medscape.com/article/300455-overview 16. Cunha BA, Bronze MS. Community-acquired pneumonia. Medscape [homepage on the Internet]. 2012. c2012. Available from: http://emedicine.medscape.com/article/234240overview 17. Black AD. Community-acquired pneumonia: a clinical approach to assessment and management. S Afr Fam Pract. 2008;50(3):15-23. 18. Arnold SR, Straus SE. Improving how antibiotics are prescribed by physicians working in the community. Cochrane Summaries [homepage on the Internet]. 2009. c2012. Available from: http://summaries.cochrane.org/CD003539/improving-how-antibiotics-are-prescribed-byphysicians-working-in-the-community 19. General background: about antibiotic resistance. Alliance for the Prudent use of Antibiotics (APUA) [homepage on the Internet]. c2012. Available from: http://www.tufts.edu/med/ apua/about_issue/about_antibioticres.shtml 20. Combat antimicrobial resistance. South African Society for Clinical Microbiology; 2011. 21. The bacterial challenge: time to react. A call to narrow the gap between multidrug-resistant bacteria in the EU and the development of new antibacterial agents. ECDC/EMEA joint technical report. European Medicines Agency [homepage on the Internet]. c2012. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2009/11/ WC500008770.pdf 22. Antibiotics should be assigned to a special drug class to preserve their power, says Alliance for the Prudent Use of Antibiotics. Alliance for the Prudent Use of Antibiotics (APUA) [homepage on the Internet]. c2012. Available from: http://www.tufts.edu/med/apua/news/ press_release_7-13-10.shtml 23. Best care antibiotic stewardship: FAQ. Best Care Always! [homepage on the Internet]. c2012. Available from: http://www.bestcare.org.za/Antibiotic+Stewardship 24. European Antibiotic Awareness Day: key messages for primary care prescribers. The European Centre for Disease Prevention and Control [homepage on the Internet]. c2012. Available from: http://ecdc.europa.eu/en/eaad/antibiotics/Pages/messagesForPrescribers.aspx 25. Careful antibiotic use. Centers for Disease Control and Prevention [homepage on the Internet]. c2012. Available from: http://www.cdc.gov/getsmart/campaign-materials/infosheets/child-cough-illness.pdf 26. Kardas P. Patient compliance with antibiotic treatment for respiratory tract infections. J Antimicrob Chemother. 2002;49(6):897-903. 27. McNulty CAM, Boyle P, Nichols T, et al. The publics attitudes to and compliance with antibiotics. J Antimicrob Chemother. 2007;60 Suppl 1: i63-i68.

Conclusion
Antibiotic-resistance levels are increasing globally. It is crucial that antibiotics should only be prescribed for respiratory tract infections where indicated. Improved patient understanding of the aetiology of these infections, and improved compliance where antibiotic therapy is indicated, are of paramount importance.

References
1. Ball P, Baquero F, Cars O, et al. Antibiotic therapy of community respiratory tract infections: strategies for optimal outcomes and minimized resistance emergence. J Antimicrob Chemother. 2002;49 (1):31-40. 2. Chamberlain NR. Introduction to respiratory tract diseases. Computerised teaching materials for the infectious diseases course at AT Still University/Kirksville College of Osteopathic Medicine [homepage on the Internet]. 2010. c2012.Available from: http://www.atsu.edu/ faculty/chamberlain/Website/lectures/lecture/introurt.htm 3. Meneghetti A, Mosenifar Z. Upper respiratory tract infection. Medscape [homepage on the Internet]. 2011. c2012. Available from: http://emedicine.medscape.com/article/302460overview 4. Dasaraju PV, Liu C. Infections of the respiratory system. In Baron S, editor. Medical microbiology. 4th ed. Galveston: University of Texas Medical Branch;1996.

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