The Antimicrobial Susceptibility of NTM MAC
The antibiotic resistance emergency
Antibiotics are the only weapon in a clinician’s arsenal when it comes to fighting bacterial infections. Resistance to antibiotics is one of the biggest threats to global health leading to longer hospital stays, higher medical costs and increased mortality.1 Frequent non-compliance and misuse of these precious antimicrobials has led to the current emergency we face. Multi-antibiotic-resistant infections.
Where did it all begin?
Contrary to the common belief that exposure to antibiotics is confined to the modern “antibiotic era”, exposure has been shown to date back as far 350-550 CE. The excavation of human skeletal remains from ancient Sudanese Nubia in this period contained traces of tetracycline, an antibiotic used today to treat acne, chlamydia and other susceptible infections.2 3 Other examples of exposure to antimicrobials in the pre-antibiotic era include the discovery of artemisinin, a potent anti-malarial drug found in Artemisia plants used in Chinese herbal medicines for thousands of years, which also has antimicrobial properties.2 4
Perhaps one of the most notable names of the modern antibiotic era is Alexander Fleming, with his discovery of Penicillin. Researchers before him had observed the antimicrobial activity of Penicillium. It was, however, Fleming’s persistence and his belief that Penicillium could act as a successful medicine for bacterial infections, that made the difference. For 12 years after his initial observation in September 1928, Fleming was persistent in requesting the assistance of chemists to resolve issues surrounding purification and stability of the active substance but was largely unsuccessful. It wasn’t until 1940 that an Oxford team, led by Howard Florey and Ernest Chain, published a paper describing the purification of penicillin quantities sufficient for clinical testing. Their protocol eventually led to penicillin mass production and distribution in 1945.2
What is causing antibiotic resistance?
Antibiotic resistance is a frightening concept that has been anticipated for quite some time. Fleming himself was among the first who cautioned about the potential resistance to penicillin if used too little or for too short a period during treatment.2 Bacteria reproduce by cell division which allows them to evolve rapidly and adapt to new environmental conditions. During replication, mutations arise, some of which may help an individual bacterium survive exposure to an antimicrobial. Drug resistant bacteria multiply, thrive and quickly become the dominant type throughout the microbial population resulting in antibiotic resistance. The overuse of antibiotics in agriculture and hospitals and the community, has been highlighted as a cause for the accelerated evolution of antibiotic resistant bacteria. Other causes include the inappropriate use of antibiotics and the ‘just-in-case’ attitude, relating to prescribing without an adequate diagnosis.5 It is estimated that approximately 33,000 people die each year as a direct consequence of an antibiotic resistant bacterial infection, with the burden of these infections comparable to that of influenza, tuberculosis and HIV/AIDS combined.6
How is NTM-PD and antibiotic resistance linked?
LRTIs in general are thought to be a key player in driving antibiotic resistance. LRTI’s are one of the leading reasons for consultations in primary care and for antibiotic prescriptions.7 Macrolide antibiotics such as clarithromycin and azithromycin, are key drugs for treating non-tuberculous mycobacteria pulmonary disease (NTM-PD). Both display good activity against these pathogens, they are easy to administer and have good tolerability in long-term use.8 The inappropriate prescription of antibiotics for NTM-PD patients is contributing to the antibiotic resistance crisis. Macrolide monotherapy is a risk factor in the development of macrolide resistance, a situation which is associated with worse treatment outcomes.8 9 10 11 Studies of patients with macrolide resistant Mycobacterium avium complex (MAC) pulmonary disease, have showed that the most common regimen before identification of macrolide resistance was clarithromycin monotherapy.8 A study conducted in 2017 demonstrated that only 17.8% of patients in the UK with MAC pulmonary disease received at least 6 months of treatment with the suggested rifamycin-ethambutol-macrolide regimen.12
A three-drug combination including macrolides is recommended by the 2017 British Thoracic Society (BTS) and the 2007 American Thoracic Society/Infectious Diseases Society of America guidelines.9 10 Macrolide-containing regimens have shown better outcomes compared to those without macrolides. However, patients with macrolide-resistant MAC pulmonary disease have very poor culture conversion rates and high five-year mortality rates. Therefore, development of macrolide resistance has great clinical significance for both the response to antibiotic treatment and long-term patient outcomes.8
What can we do to reduce antibiotic resistance?
Public understanding of antibiotics has, in general, not improved substantially in over a decade. Surveys carried out in 2017 showed that 35% of the general public thought that antibiotics kill viruses. Among respondents who had an infection or antibiotics within the past year, 43% stated they did not receive any advice or information about the medication. Others admitted having “leftovers” from previously prescribed courses of antibiotics, with the intention to use them again in the future.13 Active provision of advice and information during primary and secondary care consultations should be increased to help counteract the widespread misunderstanding amongst the general public. Education and increased awareness around antibiotic use and the causes of antibiotic resistance should be made a priority. Campaigns such as the recent Public Health England ‘Keep Antibiotics Working’, will help to achieve this important goal.14
In direct relation to NTM MAC pulmonary disease, it is incredibly important that patients receive the recommended multidrug therapy the first time they are treated.9 BTS guidelines state that susceptibility to macrolides should be tested on isolates prior to treatment initiation for MAC due to the potential for macrolide resistance.10 Given the possibility of macrolide resistance developing, even in patients that have been given guideline-based therapy, clinicians should focus on carefully monitoring patients with persistently positive sputum cultures. Clarithromycin susceptibility testing should be performed after six months of treatment, for patients who fail sputum culture conversion.8 10