Dr Yeung Koon Sing
Consultant Respiratory Physician
St. Teresa’s Hospital
Hong Kong

Macrolides play a key role in the empiric treatment of community-acquired respiratory tract infections, which are commonly caused by Streptococcus pneumoniae.^1–3 Evidence of a dramatic increase in macrolide resistance over the past decade creates a need to review the risk factors influencing selection of antibiotics, the specifics of macrolide resistance, and strategies to minimise the impact.

Dr Yeung Koon Sing – consultant in respiratory medicine at the St. Teresa’s Hospital – shares his experience in the management of macrolide resistance in respiratory tract infections.

Q1. Please describe the aetiology and epidemiology profile of upper and lower respiratory tract infections (RTIs) in Hong Kong.

In Hong Kong, the majority of upper RTIs are self-limiting and  with no identified pathogens. While viral infections  account for the majority of RTIs, a proportion of infections are also linked to atypical bacteria, such as Mycoplasma pneumoniae and Chlamydophila pneumoniae. Upper RTIs caused by viruses include influenza virus, parainfluenza viruses, adenovirus, rhinovirus and respiratory syncytial virus. For lower RTIs caused by bacteria, more than 70% of cases are associated with S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis.  Patients with particular risk factors, such as illicit drug use and recent antibiotics exposure, are often associated with Staphylococcus aureus infections. Tuberculosis constitutes 10% of community-acquired pneumonia (CAP) in Hong Kong.

Q2. What are the current guideline recommendations for antibiotic selections for RTIs?

In Hong Kong, the Interhospital Multi-disciplinary Programme on Antimicrobial ChemoTherapy (IMPACT) guidelines provide recommendations to reduce antimicrobial resistance in both private and public hospitals.⁴ The guidelines released by the American Thoracic Society (ATS) in 2019 can also be used to guide the treatment of CAP, other than cases related to tuberculosis.⁵

Q3. What is the prevalence of macrolide-resistance among respiratory pathogens in Hong Kong? How has the emergence of macrolide-resistant pathogens affected the way clinicians approach patients with RTIs?

While macrolides have been used as a first-line treatment for CAP in the last decade, the increasing prevalence of macrolide resistance among patients with CAP creates a need for alternative antibiotic treatment. The rate of macrolide resistance in S. pneumoniae is around  70% to 90% in different age groups in Hong Kong and up to 40% in Mycoplasma pneumoniae. The presence of the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19 imposes a negative impact on patients with RTIs  similar to that of  the influenza virus, which worsens the clinical outcome for patients infected with both RTIs and COVID-19.

Clinicians no longer rely on macrolides as sole agents due to the emergence of macrolide-resistant pathogens. Instead, clinicians now use doxycycline, and high-dose penicillin [amoxicillin or ampicillin (3 g/day) ± beta-lactamase inhibitors] for the empirical treatment of CAP in the presence of atypical pathogens. S. pneumoniae strains with intermediate resistance to macrolides are susceptible to high-dose amoxicillin.

Q4. What is your opinion on the use of levofloxacin in respiratory tract infections? What are the common indications for high-dose and conventional dose in Hong Kong?

Levofloxacin should be used with caution when treating CAP patients due to its masking of tuberculosis – which may result in false negative test results, thus delaying the timely and accurate diagnosis of tuberculosis. Levofloxacin and other respiratory quinolones can be used as a second-line treatment if the patient: 1) is allergic to beta-lactams, 2) is unlikely to have tuberculosis, or 3) has failed to respond to first-line treatment, i.e. high-dose amoxicillin and/or beta-lactam.

High doses of levofloxacin typically range from 500–750 mg/day, which may reduce the development of antibiotic-resistant bacteria compared with low levofloxacin dosages of 250 mg/day or 250 mg twice daily. As an antibiotic, levofloxacin exhibits concentration-dependent killing. Its key PK/PD parameter is AUC/MIC and hence, once daily dosing is needed in patients with normal renal function. Some doctors use low-dose levofloxacin for the treatment of RTIs or urinary tract infections which may be inappropriate as it might increase the growth of quinolone-resistant bacteria.

Q5. Besides levofloxacin, are other respiratory quinolones being prescribed? What are the differences between using respiratory quinolones versus other antibiotics?

Moxifloxacin can be administered for the treatment of non-pseudomonal aspiration pneumonia as it is also active against anaerobes, while prulifloxacin can be administered for the treatment of infections caused by Pseudomonas aeruginosa. Quinolones are the only oral treatment active against P. aeruginosa. All respiratory quinolones are effective against tuberculosis and mycobacterium other than tuberculosis (MOTT). Clinicians should use quinolones with caution to reduce the development of drug resistance.

Q6. The U.S. Food and Drug Administration updated its drug safety information for fluoroquinolones to include the rare but serious risk of aortic ruptures or tears in certain patients.⁶ Considering this, should levofloxacin be avoided altogether?  

While there is low, or no cases of such adverse events being reported in Hong Kong, clinicians should avoid administering quinolones for high-risk patients, i.e. those who are: 1) experiencing connective tissue disease – due to their susceptibility to aortic regurgitation or rupture, and 2) diagnosed  with aortic aneurysms. However, quinolones can still be prescribed with caution in these high-risk patients if they have contraindication with first-line treatment (e.g. allergic reactions), especially if there is no other good alternative.

Q7. Fluoroquinolone use is also associated with disabling and potentially permanent serious adverse effects that can occur to the tendons, muscles, joints, nerves, and central nervous system.⁷ How can these adverse events be managed?

These adverse events are rarely reported in Hong Kong, with only four cases of quinolone-related tendinitis, none involving tendon rupture, and one case of neuropathic pain being reported over the last 10 years. To mitigate these adverse events, clinicians should proceed with greater caution when treating high-risk patients. Clinicians can also refer to international data for greater insights into this issue, as recent studies revealed that patients above 60 years of age receiving concomitant high-dose steroids are more prone to quinolone-related complications, including chronic renal failure.

Q8. Do you have any final comments or advice to other physicians on using quinolones?

Clinicians should work towards promoting patient education on appropriate antibiotic usage to reduce the chances of overusing quinolones and the subsequent development of antibiotic resistance.

References

1. Wierzbowski AK, et al. Curr Allergy Asthma Rep 2006;6:171-81.
2. Hoban DJ, Zhanel GG. Expert Rev Anti Infect Ther 2006;4:973-80.
3. Klugman KP. Int J Antimicrob Agents 2007;29(Suppl 1):S6-10.
4. Ho PL, Wu TC. Reducing bacterial resistance with IMPACT. 5^th ed. Hong Kong: 2017.
5. Metlay JP, et al. Am J Respir Crit Care Med 2019;200:e45-e67.
6. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics#:~:text=Health%20care%20professionals%20should%20avoid,syndrome%20and%20Ehlers%2DDanlos%20syndrome%2C. Accessed 6 April 2021.
7. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-advises-restricting-fluoroquinolone-antibiotic-use-certain#:~:text=An%20FDA%20safety%20review%20has,nerves%2C%20and%20central%20nervous%20system. Accessed 6 April 2021.