Antibiotic Resistance: Hidden Rates in Rural Areas of the Developing World

When the age of antibiotics commenced in the 1950s, diseases and infections that typically would lead to humans being stigmatized by society, a permanent stay at a sanatorium, and then ultimately death were suddenly able to be treated quickly and efficiently. Penicillin and Streptomycin, not only improved a patient’s quality of life and longevity, but reshaped the very nature of treating infectious diseases. Health care professionals now possessed a cure to end the spread of the ailment and to eliminate the actual microorganism that created the suffering. However, these agents brought with them negative consequences that the global health community is still combating today – antibiotic resistance being one of the most significant issues. Antibiotic resistance is the predator’s (bacteria, virus, other microorganism) ability to resist an antibiotic that once was able to eliminate it. Although antibiotic resistance can occur naturally due to the cleverness of bacteria, fungi, and protozoa, the misuse of antibiotics in humans has tremendously accelerated the rate and severity of resistance. This inappropriate use of medicine and skills has led to difficult to treat infections like Extended-spectrum beta-lactamase (ESBL) producing strains of Enterobacteriaceae and even untreatable infections with no known drug on the market able to help an infected patient. The concept of antibiotic resistance often differs within the medical community when comparing the developed world, particularly urban areas, and the developing world, particularly rural areas. The amount of research, minds, and technology mobilized to address this unruly behavior by microorganisms varies drastically between the two sets.

In the urban developed world where physicians are equipped with the most innovative antibiotics known to man like daptomycin or the “Crispr” agents, antibiotic resistance is frequently a topic of discussion along with funding, human resources, and technology available to address it. Also, common ideology is that antibiotic resistance arises from the direct misuse of antibiotics rather than of natural causes. Contrasting the rural developing world, the aforementioned necessities to deter antibiotic resistance are often lacking due to health inequalities that unfortunately are ubiquitous throughout this fragile planet. More interesting though, health care professionals have formed an impression that antibiotic resistance more commonly stems from the dissemination of resistant organisms. With this mindset ingrained in world health leaders, the agenda has been to focus on prevention through this venue in the rural developing world – often lacking a call of funding to determine actual causes of antibiotic resistance and their associated rates in the rural developing world. While the dissemination of strains of Escherichia coli through feces and Multi-drug resistance Tuberculosis through poor air quality certainly needs to be addressed, the Centers for Disease Control and Prevention (CDC) released a report in 1999 encouraging health care professions to consider a range of socioeconomic and behavioral factors including misuse of antibiotics by physicians, unskilled practitioners, the public, counterfeit medications, inadequate surveillance, and political factors. To follow up with this theoretical account, the World Health Organization (WHO) conducted a survey across twelve (12) low to middle income countries across the world in 2015 to interview the population about their beliefs towards antibiotics and resistance. Some of the results are presented below:

  • In lower income countries, it was reported that antibiotic use is higher (42%) than in higher income countries (29%).
  • Across the countries, the range of patients obtaining their antibiotics with a physician’s prescription ranges from 56% to 93%.
  • The percentage of individuals believing they can use the same antibiotic as a family member did to treat a similar illness is 25% while 43% believe it is acceptable to buy the same antibiotic from a local pharmacy.
  • When patient’s start to feel better, 32% of the those interviewed believe they can stop the antibiotics and not follow through with full course.
  • When treating colds and viruses, 62% of respondents believe antibiotics could be used to treat these ailments.
  • Finally, 44% of those interviewed believe antibiotic resistance is only a problem for those regularly taking antibiotics.

These specific social results from patients in the developing world directly conflict with the thought of the major distributor of antibiotic resistance being through dissemination of the disease. The beliefs presented through these percentages seem to lead to a whole host of factors being involved similar to the developed world. In addition to these social results, PLOS Biology released data in 2018 that Escherichia coli was resistant to commonly prescribed antibiotics like ampicillin (92%), ceftazidime (90%), cefoxitin (88%), streptomycin (40%) and tetracycline (36%) in the rural areas of Sikkim, India in pre-school and school-going children. The Journal of the Pediatric Infectious Diseases Society reported similar rates among children in 2015 with Klebsiella pneumoniae having a median resistance to ampicillin with a rate of 94% in Asia and 100% in Africa, and cephalosporins having a rate of 84% in Asia and 50% in Africa. Also, The World Health Organization informed the global community that in Malawi in 2018, nearly 100% of Neisseria gonorrheae genital isolates were non-susceptible to ceftriaxone and roughly 15% were non-susceptible to azithromycin. When analyzing both the social and technical results from above, a renewed emphasis and novel perspective needs to be created in order to properly address antibiotic resistance in the rural developing world.

At the beginning of this year (January 2018), the World Health Organization released its initial reports utilizing an innovative reporting system for antibiotic resistance christened Global Antimicrobial Surveillance System (GLASS). This system was developed in order to preserve human and animal health throughout the globe in relation to antibiotics and their resistance. Although GLASS was officially launched in 2015, it is still in its early implementation period with only 22 countries reporting on actual resistance within their nation states and 40 countries reporting on their national surveillance program. However, GLASS aims at a variety of measures that will ensure antibiotic resistance is more appropriately addressed in the rural developing world by providing a standardized approach to collection, analysis, and dissemination of information to participating countries. GLASS will strengthen nation states antibiotic resistance surveillance systems and modify the data being studied from solely laboratory data to epidemiological, clinical, and population-level data. The preliminary results that were released by WHO revealed that across the 22 reporting countries, there were 500,000 individuals suffering from an infectious disease with antibiotic resistance. Although this data varies with completeness and accuracy across countries, the outcomes highlight the global emergency antibiotic resistance posses from the urban developed world to the rural developing world and everywhere in between – these mutated organisms will fail to respect national borders.

The global health bodies throughout the world have initiated programs and offered advice to nations that will serve the battle against antibiotic resistance well. However, the concealed rates of resistance in the rural developing world will need to be undertaken medically and socially in order to properly end this global emergency. Pipeline innovative antibiotics like relebactam, a novel beta-lactamase inhibitor and an educational emphasis on behavior habits will aid these parts of the world – but the health community will fall short unless the world changes its perception of antibiotic resistance in the countryside of Cambodia, the rice terraces of Vietnam, the jungles of Belize, and areas with similar socioeconomic status.

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United Nations High-Level Meeting on Tuberculosis: Importance of drug quality

At the end of next month, the inaugural United Nations (UN) High-Level meeting on Tuberculosis (TB) will take place in New York to discuss the future of the bout against the devastating yet elusive disease. As TB remains the largest infectious disease torturer in today’s society taking the lives of 4500 humans each day, the theme of this occurrence is “United to end Tuberculosis: an urgent global response to a global panic”. This unparalleled step undertaken by governments throughout the world along with those allies engaged in ending Tuberculosis will address an assortment of issues at this meeting. Although the exact agenda has yet to be revealed, the resolution to host this single day meeting mentioned the following items could be discussed:

  • Adequate funding for novel diagnostic testing, medications, and vaccinations
  • Multi-Drug Resistant Tuberculosis (MDR-TB)
  • Responsibility for multisectoral collaboration within nation states, regions, and the globe
  • Universal health care coverage and ensuring tuberculosis coverage is included

Each of these items – ranging from the use of prophylactic low dose isoniazid therapy to equal distribution of the recently designed TB diagnostic test Xpert MTB/RIF – are crucial in accomplishing the END TB strategy laid out by the World Health Organization. However, after looking over these action items for the meeting, Tuberculosis drug quality seems to absent.

As health care professionals across the globe continue to treat TB on a patient specific basis, certain untreated cases occur that puzzle even those who have treated the disease for years. The reasoning behind treatment failure? Adherence to medication or drug resistance are often the first assumed thoughts those sharing their patient’s fate may have. Yet, the actual medicine with its various active and inactive ingredients is often not called into question.

Towards the end of last year, the World Health Organization released an alarming figure concerning drug quality in low to middle income countries. In the report released to the public, WHO stated that approximately 10% of medications are counterfeit in these areas of the world – which happen to be the areas where Tuberculosis and other infectious diseases take their largest toll. In addition, WHO added that this percentage is most likely only a small part of the number of humans truly affected by counterfeit medications. To provide clarification, WHO considers counterfeit medications to be unapproved by regulators, unable to meet quality standards, or purposefully misrepresented active or inactive ingredients in the medication. In addition to this report by WHO, the National Institutes of Health (NIH) published a report outlining in 2015 that 9% to 41% of anti-tuberculosis and other infectious disease medications failed to meet the standards sought in specific studies.

It is vital for the global health community to obtain an effective vaccine to prevent pulmonary tuberculosis, to have a rapid yet specific TB diagnostic test, to create a strategy for various sectors of a nation state to work together in ending TB, and novel agents to treat the most severe cases of MDR-TB. Individuals in rural Kampot, Cambodia, inmates in the Russian prison system, or those residing in the slums of Bangalore, India often can be restored to health through the means that have been available for the last half a century. The RIPE (rifampin, isoniazid, pyrazinamide, and ethambutol) regime has proven its success in treating non-resistant tuberculosis – so long as each of the medications are of appropriate quality. However, The Lancet released a report in January 2017 that found that 8.9% of Indian rifampicin products were of inadequate quality in a country that is burdened with the highest prevalence of tuberculosis across the globe. Moreover, WHO revealed that 28.3% of rifampicin containing medications found in the Russian Federation in 2011 failed to meet predetermined specifications for proper quality – a country known to have one of the highest MDR-TB burdens in the world. With the aforementioned statistics released by the WHO, The Lancet, and NIH, a renewed emphasis needs to be placed on ensuring the quality of each and every tuberculosis medication that reaches a human being. The possibility of one in ten (or more) TB medications being counterfeit will continue to lead to failed treatment regimes, inappropriate use of resources, and spread of MDR-TB even if innovative technology is developed.

In order to combat counterfeit medications on a global level, the World Health Organization developed a reporting system for the interconnectedness of the medication market. The Global Surveillance and Reporting System (GSRS), that all WHO members are eligible to contribute to, aims at collecting data on falsified medications, vaccines and other medical equipment to address real-time situations and prevent further harm. With this reporting arrangement in place, the WHO has reacted and thwarted mortality and morbidity associated with counterfeit medications – including the contaminated cough medication supply that led to 60 deaths in Pakistan and a number of individuals treated with an antidote in Paraguay in 2013. On top of the GSRS, WHO has implemented Good Manufacturing Practices (GMP) that each manufacturer should achieve in order to be certified by WHO; thus, providing a reliable source of medications that nation states can purchase from. Although these initiatives have brought about encouraging results along with halting global medication emergencies, there are still barriers that accompany these programs. The technical training, technology, and adequate staffing to properly identify and report through the GSRS is often difficult to obtain in the developing world while GMPs are often misapplied and have inadequate supervision. The root cause is the long-term development of countries’ public health systems – of which continuing problems with counterfeit medications remains deficiently addressed. A county’s public health care system is the vital organ to ensuring quality medications through these mechanisms that WHO has created and employed. An underutilized and under resourced public health care system leads a budding yet unregulated private market – unable to ensure proper treatment for those seeking it.

Since the United Nations declared this a high-level meeting, meaning all heads of member states are encouraged to participate in the highest level possible, this venue provides the ideal opportunity to recommit to guaranteeing TB drug quality. The sustained empowerment of the public health care systems for those countries tirelessly battling tuberculosis will be a step forward into truly ending this devastating disease. Each health care professional spanning the globe has a responsibility to accompany these governments, colleagues, and fellow humans by investing their time, resources, and talents to develop procedures and systems to ensure effective drug quality.

@MSF Video: Patents and the fight for #generics

Intellectual property protects those items that we can’t live without – think Netflix and the iPhone 7 – and those that we would surely die without, including life saving and extending medications.  Today’s video covers the latter and the barriers much of the developed world faces courtesy of patent laws that protect pharmaceutical companies.  This issue has come to recent attention as the UN’s Panel on Access to Medicines published its recommendations to Big Pharma’s chagrin.

At the crux of the UN Recommendations is a struggle that pits profits against people.  Enacted in 1995 by the World Trade Organization, the agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) introduced minimum standards for protecting intellectual property, including patents on medicine.  TRIPS proved a boon for international trade, but set a 20-year patent on novel medication.  Only after the patent lapses can generic alternatives hit the marketplace.  It is at this point when many lifesaving and extending drugs are first available to the developing world.  The price tag of a medication to treat HIV/AIDS can drop from $10,000 per year to $200 due to generics.

Under TRIPS, each country has the right to a grant compulsory license, as stated in this excerpt:

Where the law of a Member allows for other use of the subject matter of a patent without the authorization of the right holder, including use by the government or third parties authorized by the government, the following provisions shall be respected:

(b)   such use may only be permitted if, prior to such use, the proposed user has made efforts to obtain authorization from the right holder on reasonable commercial terms and conditions and that such efforts have not been successful within a reasonable period of time. This requirement may be waived by a Member in the case of national emergency or other circumstances of extreme urgency or in cases of public non-commercial use. In situations of national emergency or other circumstances of extreme urgency, the right holder shall, nevertheless, be notified as soon as reasonably practicable. In the case of public non-commercial use, where the government or contractor, without making a patent search, knows or has demonstrable grounds to know that a valid patent is or will be used by or for the government, the right holder shall be informed promptly;

In layman’s terms, if it is in the public’s best interest, generic drugs can be pursued without the patent holder’s consent.

A few years after TRIPS, South Africa attempted to pass an act that would grant a compulsory license for antiretroviral therapy in response to a staggering HIV/AIDS epidemic. The act was met with a lawsuit by 40 multinational companies and the United States, citing South Africa in violation of the TRIPS agreement, though executed in the midst a public health crisis.  Despite controversy, President Nelson Mandela signed the act into law and the lawsuit was eventually dropped.  In response, the World Trade Organization signed the Doha Declaration in 2001 to further clarify the right to grant compulsory licenses.

Nearly 20 years after TRIPS and Doha, the developing world continues to suffer from catastrophic levels of health inequality.  Africa, among the hardest hit, is home to nearly half of all tuberculosis cases and 91% of HIV-positive children. Countries that attempt to circumvent TRIPS, even in the direst of public health crises, are subject to retaliation by termination of trade agreements that help keep their economies afloat.

Earlier this year, Colombian Health Minister Alejandro Gaviria, warned a large pharmaceutical company, Novartis, that a compulsory license to pursue a generic form of a popular cancer drug was imminent if Novartis didn’t lower its prices.  In a letter from the Colombian Embassy in Washington, Colombia’s government was threatened by the United States with withdrawal of support to join the Trans-Pacific Partnership trade zone and funding to facilitate a peace deal with a longstanding rebel group.

The exorbitant cost of pharmaceuticals can also threaten consumers in developed countries.  Recent outcry over the soaring price of the anaphylaxis drug, EpiPen, has many in the United States worried. The price of EpiPen has gone from $60 to over $600 in recent years and are now exclusively sold in two-packs, further increasing the cost for consumers.  A similar product, Adrenaclick, is not considered equally therapeutic to EpiPen and pharmacies are unable to fill prescriptions.  Another pharmaceutical company applied to make a generic version, but the application was rejected by the FDA.

This has led to repercussions such as children carrying expired EpiPens and EMTs dispensing epinephrine by syringe, which makes it much harder to administer the correct dose.  A recent article in the American Journal of Medicine suggests that EpiPens be added to a list of preventive medicines, effectively lowering the copay without lowering the overall price of the drug by the pharmaceutical company, Mylan Specialty.  The cost would likely be shifted to consumers in higher deductibles.

In light of the UN recommendations, what is the next step to guarantee medications are available to those who need them?  Dr. Bernard Pecoul of Drugs for Neglected Diseases Initiative urges action, not apathy:

“Governments mustn’t allow the report to become yet another exercise that describes the current failures of the medical innovation system without contributing concrete steps to address those failures. Responsibility now clearly falls on them at the highest political levels to act by putting in place innovative and practical solutions.”


Let’s Get Ethical: Giving Untested Experimental Drugs to Ebola Patients

West Africa is in the throes of the worst Ebola outbreak to date. Ebola virus disease, the hemorrhagic fever caused by the Ebola virus, has been seen in small but often deadly outbreaks in tropical sub-saharan Africa since its discovery in 1976. Though researchers are fairly certainly that it is transmitted through bush meat, and fruit bats are suspected, no animal species has been confirmed as a reservoir. Combined with the fact that the virus is highly contagious and so often deadly (usually because there is little to no medical infrastructure in areas where outbreaks occur), it is the source of international fascination and fear. It is the perfect plot device for outbreak movies and sensational media reports – a mysterious ailment from the heart of darkness that could rear its ugly head in our packed population centers at any moment.

Although it’s not quite as scary as movies like “Outbreak” would have you believe, the havoc that it is currently wreaking in West Africa is most definitely real. The most recent update from WHO puts the death count at 932 and the number of cases (both suspected and confirmed) at over 1,700. Guinea, Liberia, and Sierra Leone have been battling the virus since the spring, and last week it made its way to Nigeria and there was even a suspected death in Saudi Arabia. We all know that international air travel means that these types of illnesses are only a plane ride, which raises the question of why we haven’t made more progress in developing a vaccine or treatment for such a devastating disease.

Frankly, most global health and development professionals know the answer – if the only market for potential drugs is among the poor in central Africa, commercial drug companies won’t exactly be lining up to put money into the research:

The factor preventing such trials in humans, though, has been cost, said Dr. Daniel Bausch, an associate professor of tropical medicine at the Tulane University School of Public Health who is currently stationed at the U.S. Naval Medical Research Unit 6 in Lima, Peru.

That’s because, while the National Institutes of Health and the U.S. government often fund the early animal safety and efficacy testing of a vaccine, pharmaceutical companies typically fund the human clinical trials to take a drug or vaccine to market.

“When you have a population or situation with Ebola where it only sporadically occurs, and it occurs really in the world’s poorest populations, it’s not exactly an attractive candidate for the pharmaceutical industry on the economic side,” Bausch said.

That all changed, however, when two American aid workers who were treating Ebola patients in Liberia fell ill with the virus themselves. Dr. Kent Brantly, a doctor working with Samaritan’s Purse, and Nancy Writebol, a nurse employed by Service in Mission, are now all over U.S. and global headlines as the first Westerners to contract the virus – and, because of their privileged status, as the first people to receive an experimental treatment in the early stages of development before being flown back to Emory for medical care (despite objections from Donald Trump and Ann Coulter).

Though several people have raised objections to bringing Americans back stateside for treatment (particularly at what it probably cost), Emory is probably the safest and best-equipped facility to treat and contain the patients. Samaritan’s Purse is footing the bill for transporting them, so no government funds are being used. Bringing them back to the states for treatment is not so much of an issue, in my opinion – but using an experimental drug which is untested in humans is another matter.

At first glance, an outbreak of a disease with a high fatality rate (usually 40-70%) and no cure seems like the perfect situation to bypass the standard drug testing and approval process, which can take several years. However, it is the recklessness generated by precisely this type of desperate situation that raises ethical dilemmas. Does informed consent really count when patients are panicked at the prospect of imminent death? What if the drug is administered to the afflicted on a large scale and turns out to be toxic, or causes long-term disability? Who determines which patients to prioritize and how to protect those most vulnerable – such as children or pregnant women – who may react very differently to the drug?

Additionally, the fact that the drug has only been given to the two Westerners raises a very different, but equally important, problem. The international community has struggled for years to bring critical medicines to populations with the greatest need, who are simultaneously the least able to afford them. The fact that this experimental treatment was given to two aid workers – who, unlike their patients, have the support of large and wealthy organizations and will be more able to access the needed high-quality supportive care than their own patients – raises some disturbing questions.

The WHO has announced that it will convene a panel of medical ethicists to discuss and provide guidance on the issue. The pharmaceutical companies that develop and manufacture the drug are, naturally, chomping at the bit to get a large production run funded in order to provide ZMapp, the experimental serum, to a large number of Ebola patients. It is unclear how the global health community will move forward. But perhaps it can serve as a lesson to the pharmaceutical industry to take a more active interest in developing therapies for diseases that may not seem lucrative at first glance. Perhaps then we’ll be prepared for an unexpected multi-country outbreak – instead of having to scale up an untested drug developed by a tiny biopharmaceutical.

Vaccine Ping-Pong: GAVI and MSF’s Advocacy Campaign for Vaccine Access

MSF (Médecins Sans Frontières, also known as Doctors Without Borders) recently posted a set of three animated videos about child vaccines as part of their latest advocacy campaign. The first one, titled “We Need Better Tools to Save Lives” is pretty straightforward – it’s a basic explanation of what is needed to vaccinate children, how MSF struggles to fill that need, and a quirky analogy about what it is like to not have that need filled. Simple enough.

The second video is a lot more direct. The show how the number of vaccines in the standard childhood vaccination battery, as well as the cost of those vaccines, have increased in the last decade. The video then takes a direct shot at pharmaceutical companies for keeping vaccine prices high in order to prioritize profits over saving lives. The debate on drug prices is a heated one, and everyone seems to have their own opinion on what “fair prices” for drugs are, but it is clear where MSF stands.

The last video was the one I personally found to be the most interesting. “Dear GAVI, Please Let Us Access Your Discounted Vaccine Prices” talks about how qualified governments are allowed to access GAVI’s low vaccine prices, but NGOs are not given access to them. MSF provides a more detailed description of their perspective on the issue in this press release:

MSF is also troubled by the fact that non-governmental organizations and humanitarian actors are excluded from accessing the GAVI-negotiated price discounts. MSF is often in a position to vaccinate vulnerable groups, such as refugee children, HIV-positive children, and older unvaccinated children who fall outside of the typical age range for standard vaccination programs. However, MSF has not been able to systematically access the lowest prices negotiated by GAVI, having to resort to lengthy negotiations with Pfizer and GSK over the last four years to access the pneumococcal vaccine. While the companies have offered MSF donations, this is not a sustainable, long-term solution for MSF as we work to respond quickly to needs in the field, and wish to expand vaccination of vulnerable groups in an increasing number of countries.

GAVI responded to the MSF campaign in this statement:

First, we agree with MSF – we do all want the same things. We want all children everywhere to be protected by immunisation. In fact, GAVI is proud to include MSF as a member of the GAVI Alliance. They are an active member of the steering committee of the GAVI Board’s Civil Society Organisation Constituency.

MSF first formally raised the issue of access to the same prices GAVI pays for vaccines at the GAVI Board meeting in December 2012. This issue is currently being discussed through the Alliance’s Governance channels. We find it disappointing that MSF, which knows and is engaged in the GAVI Governance process, has chosen to take on this issue as a public campaign.

MSF then offered this statement in response:

Thank you GAVI for publicly acknowledging our request for access to your vaccine prices. MSF has been frustrated by bilateral discussions, which have been ongoing for a few years now, with vaccine manufacturers and the GAVI Alliance on finding a solution for humanitarian actors to access pneumococcal conjugate vaccine at the GAVI price, and we anticipate that accessing GAVI prices for other new vaccines (for rotavirus, HPV) will also be a challenge. We ask GAVI to fast-track this process so that MSF can vaccinate more kids as soon as possible.

We often talk about issues of coordination (or lack thereof) and collaboration between different aid groups and funding organizations in the wake of natural disasters and humanitarian crises. It is interesting to see this kind of friction between different groups who are trying to do exactly that because of how complicated it can actually be.



To protect children right now, we have to use vaccines that aren’t well suited to the job they have to do. Vaccines can’t take the heat — they have to be kept at between 35 and 46 degrees at all times. But we need to use them in some of the hottest places on earth. For this and other reasons, we need better-adapted vaccines to protect children from life-saving illnesses.



Children are now protected with 11 vaccines; up from six vaccines a decade ago. The price of vaccinating a child has sky-rocketed. It cost $1.37 to vaccinate a child 10 years ago, now it’s $38.80. That’s a whopping 2,700 percent increase. So how do we decide how many vaccines children need? Is it based on how much money you can make, or on how many children’s lives can be saved?



The price to vaccinate a child has risen by 2,700 percent over the last decade. Countries where Doctors Without Borders/Médecins Sans Frontières (MSF) works will lose their donor support to pay for vaccines soon, and will have to decide which killer diseases they can and can’t afford to protect their children against. MSF is asking the GAVI Alliance to open up their discounted vaccine pricing to humanitarian actors that are often best placed to respond to vaccinating people in crisis.

The GAVI Alliance is an international public-private partnership whose stated mission is to increase access to immunization for children in poor countries. GAVI co-finances the cost of vaccines with qualifying countries. Participants include governments of developing and donor countries, the World Health Organization, UNICEF, the World Bank, the vaccine industry, research and technical agencies, the Bill & Melinda Gates Foundation and other philanthropic organizations.