Madhukar Pai: How drug resistant TB can show the path to tackling antimicrobial resistance

Madhukar PaiAntimicrobial resistance (AMR) is a global health threat, and it is estimated that if we do not find solutions to tackle the rise of drug resistant pathogens, by 2050 10 million lives a year and a cumulative 100 trillion USD of economic output will be at risk.

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 gonorrhoea, 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 overuse of antibiotics, poor adherence to standard treatment protocols, overuse of antibiotics in livestock, poor infection control in health facilities, poor sanitation, and challenges with new antibiotic research and development.

According to the State of the World’s Antibiotics report (2015), antibiotic consumption is increasing globally, with 20-50% estimated to be inappropriate. Countries such as 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 of drug resistant TB is multidrug resistant TB (MDR-TB), which refers to TB that is resistant to two key first line antibiotics: isoniazid and rifampicin. Globally in 2014, the World Health Organization (WHO) estimated that 3.3% of new cases and 20% of previously treated cases had 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 has been previously understood.

Extensively drug resistant tuberculosis (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 (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, when TB patients were managed in sanatoriums and mortality rates were extremely high.

Why should we care about DR-TB? Drug resistant TB requires extensive treatment (for two 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 to treat it.

WHO has proposed five priority actions to tackle the global DR-TB crisis: 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, countries with a high TB burden have 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. The quality of TB care for even drug susceptible TB remains suboptimal in many countries, especially in countries with large numbers of private healthcare 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 countries with a high TB burden. 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 countries with a high TB burden 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 eight 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 the 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 programmes in high burden countries are seriously underfunded, 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. Policymakers and donor agencies have prioritised 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 that it receives adequate funding and support.

Madhukar Pai is director, Global Health Programs, McGill University, Montreal, Canada. Twitter: @paimadhu

Author’s competing interests: None declared.

This blog was first published on the Huffington Post‘s website.