How Drug-Resistance TB Can Show The Path To Tackling Antimicrobial Resistance
Antimicrobial resistance (AMR) is a global health threat, and it is estimated that by 2050, 10 million lives a year and a cumulative 100 trillion USD of economic output are at risk due to the rise of drug-resistant infections, if we do not find solutions to tackle the rise of drug resistant pathogens.
Since the introduction of antibiotics, microbes have evolved a variety of methods to resist antibiotics. We are now dealing with ‘superbugs’ that are virtually untreatable, including colistin-resistant E. coli, drug-resistant gonorrhea, carbapenem-resistant enterobacteriaceae, methicillin-resistant Staphylococcus aureus, extensively drug-resistant tuberculosis, and extended-spectrum-beta-lactamase producing strains. The antibiotic pipeline is running dry, and AMR is threatening to undo major gains made in the control of infectious diseases.
AMR is driven by several factors, but major causes include over-use of antibiotics, poor adherence to standard treatment protocols, over-use of antibiotics in livestock, poor infection control in health facilities, poor sanitation, and challenges with new antibiotic R&D.
According to the State of the World’s Antibiotics report (2015), antibiotic consumption is increasing globally, with 20-50% estimated to be inappropriate. Countries like India and China are rapidly becoming the most important consumers of antibiotics.
Drug-resistant tuberculosis (DR-TB) is a prime example of the threat posed by AMR. The most common form drug-resistant TB is multi-drug resistant TB (MDR-TB), which refers to TB that is resistant to two key first-line antibiotics – isoniazid and rifampicin. Globally in 2014, WHO estimated 3.3% of new cases and 20% of previously treated cases to have MDR-TB. Drug resistance surveillance data show that an estimated 480 000 people developed MDR-TB in 2014 and 190 000 people died. Even children are impacted by DR-TB, with recent estimates suggesting that MDR-TB in children may be far more prevalent than previously understood.
Extensively drug-resistant (XDR-TB) strains are resistant to at least four of the core anti-TB drugs [i.e. isoniazid and rifampin, plus any fluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin)], and XDR-TB has been reported by 105 countries in 2014. About 10% of people with MDR-TB have XDR-TB. Some studies have also reported totally drug-resistant strains of TB, resistant to all antibiotics tested. This scary form of TB takes us back to the pre-antibiotic era, where TB patients were managed in sanatoria, and mortality rates were extremely high.
Why should we care about DR-TB? Drug-resistant TB requires extensive treatment (for 2 years or longer) with multiple, potentially toxic drugs and outcomes are poor. One in two patients with drug-resistant TB die because of it. Treatment of DR-TB is also very expensive because of the high cost of second-line TB drugs. Thus, it is much smarter and cheaper to prevent DR-TB than treat it.
1) prevent the development of drug-resistance through high quality treatment of drug-susceptible TB;
2) expand rapid testing and detection of DR-TB cases;
3) provide immediate access to effective treatment and proper care;
4) prevent transmission through infection control; and
5) increase political commitment with financing.
Unfortunately, high TB burden countries are yet to seriously address these priority actions to tackle DR-TB. In many countries, not even half of all patients with DR-TB are on second-line drug therapy. Quality of TB care for even drug-susceptible TB remains suboptimal in many countries, especially in countries with large numbers of private health care providers. In such settings, doctors prescribe irrational drug regimens, and adherence monitoring is poor.
Empirical antibiotic use is widespread in many countries with weak regulation, and healthcare providers tend to use antibiotics as diagnostic tools; this further increases the risk of AMR. Also, over-the-counter (OTC) antibiotic abuse is widespread in many high TB burden countries. OTC use of fluoroquinolones, a widely used antibiotic, can delay the diagnosis of TB, and also increase the risk of DR-TB. This is particularly relevant, since some of the emerging new TB drug regimens contain fluoroquinolones (i.e. Moxifloxacin).
While highly accurate and rapid molecular tests such as Xpert MTB/RIF are now available to quickly detect TB as well as drug-resistance, most high-burden countries are still reliant on sputum smear microscopy, a technology that is not only insensitive but also incapable of detecting drug-resistance. This means patients are often managed with no information on drug-susceptibility test results. This approach of treating TB ‘blindly’ is no longer tenable in places such as Mumbai, where DR-TB is a widespread problem.
A recent report called ‘Out of Step‘ by MSF and Stop TB Partnership surveyed 24 high TB burden countries, to see how already existing TB policies and interventions are being implemented. This survey found major gaps in how TB tools and policies are implemented. For example, only 8 countries included in the survey had revised their national policies to include Xpert MTB/RIF as the initial diagnostic test for all adults and children with presumptive TB, replacing smear microscopy. Six of 24 countries, including India, still recommended intermittent treatment for drug-sensitive TB (which is less effective than daily therapy). Even simple interventions such as fixed dose combination pills to improve treatment adherence are not routinely used in all countries. Such implementation gaps are most definitely generating DR-TB and have to be urgently addressed.
A major reason behind poor TB control is the fact that TB is a low priority for many developing countries, and current TB budgets are insufficient to make progress in addressing DR-TB. Most National TB Programs in high burden countries are seriously under-funded, and, sadly, even emerging economies such as India are not spending enough on TB.
In this context, it may be more impactful for DR-TB control to be seen as one component of a comprehensive strategy to address AMR. Unlike TB, AMR is increasingly seen as a global health emergency and a security threat. Policy makers and donor agencies have prioritized AMR as a key issue for the global health security agenda. The door is wide open for the TB community to leverage this interest, and advocate for a well-funded, comprehensive AMR initiative that includes DR-TB as a key component. In fact, DR-TB could well be a pathfinder for successfully tackling AMR in low and middle income countries, and help make the case for greater investments.
The End TB Strategy and the Global Plan to End TB offer excellent blueprints for ending the epidemic of TB, including DR-TB. It is time for the TB community to step up and make sure TB features prominently in the broader agenda to tackle AMR globally, and receives adequate funding and support.