The Fleming Fund Stories

The pharmacy, covered in bright yellow paint, juts out towards the front of the Jinja hospital campus. Benches, covered by a zinc roof, shelter patients waiting to receive their prescriptions. And two pharmacy officers peer out from small windows at the building’s front, dispensing medicines to the waiting crowd.

William Olum’s office is at the back of the building. His desk is covered with stacks of documents, pharmacy manuals and a shiny new copy of the Ugandan AMR National Action Plan. He says his passion for helping others comes from his grandfather, a herbalist, who was revered in the community for his cures.

William is the Head of Pharmacy at the hospital and was hand-picked by the Ministry of Health to manage the drug supply for Jinja. Before he arrived, there was rampant theft of pharmacy drugs and patients weren’t accessing critical medicines. Since he’s been in post, he’s revolutionised the pharmacy and has also initiated a full infection prevention

William Olum

and control (or IPC) programme. “You can’t steward medicines well, without IPC,” he says.

In a back room, behind his office full of cabinets and papers, is a long thin room with what looks like a chemist’s bench. This room, where William has been manufacturing alcoholbased hand sanitizer, has been the key to much of the hospital’s success. In many public hospitals, water sources are not always reliable, resulting in abysmal hand-cleaning rates. However, by sourcing the raw ingredients to make an alcohol-based hand rub locally, William has made Jinja’s hand-cleaning rates the best in the country, 51%. He and Sofia, who leads the bacteriology unit at the hospital’s medical laboratory, both agree that to save more lives, these rates must improve. But supplying hand sanitizer is only half the battle, they also have to change behaviour.

To that end, William has been breathing new life into Jinja’s Medicines and Therapeutics Committee (MTC). MTCs bring together practitioners from all parts of the hospital –

OUR AIMS OUR ACTIVITIES

Encourage

Develop

physicians, nurses, surgeons, administrators, pharmacists – to review how drugs are used and prescribed. Their purpose is to reduce wastage, improve drug management and supply, review trends in antibiotic resistance and improve hospital infection control.

A few months ago, William took the MTC group to a hospital in the north of the country so they could benchmark their own activities against another facility’s. “The goal was really to improve their understanding and highlight the MTC’s importance. Since that visit people have been really engaged,” he says. “We are also trying to get a small budget from the hospital for our committee to supply tea and snacks during our meetings. Small things like this really help pass the time and encourage attendance.”

Despite William’s tenacity and focus in improving antibiotic use in hospital he says regulations and government intervention are vital to long-term success. “I’ve got a plan for this hospital, but really we need government to control access to antibiotics. If we don’t have a disciplined approach to antibiotic use and access as a country, much of the work we are doing here will not have an effect.”

As a Fleming Fund Fellow, William has big aspirations to improve the use antibiotics around the country. As part of the Fellowship, human and animal health professionals are collaborating (many for the first time) to understand how resistant bacteria move between animals and humans in Uganda. Over the next few months, William will be mentored by an antimicrobial pharmacist, which he hopes will take his initiatives in Jinja to a new level and help establish the type of cooperation needed to help clinicians and farmers use antibiotics better.

clinicians and farmers to use antibiotics better

On the shores of Lake Victoria, three hours from Kampala past bright green tea plantations and lush forests, is Jinja.

The city is most famous for being located at the source of the Nile River, where a giant white cable-stayed bridge connects the road from Kampala to the city.

The local hospital is large. It has some 600 beds, several surgical theatres, a medical laboratory and a tuberculous isolation ward. Hundreds of patients and their families are dotted throughout the campus. Relatives sit outside wards, bringing their family members food, clean water and items like blankets and clothes from home.

The laboratory sits toward the back of the campus where crowds of people gather out front to await sample collections from the technicians. Inside the lab, Sofia Kasuswa, who heads up the bacteriology unit, has started her daily staff meeting, where she and her team analyse samples and cultures from the day before.

She and her staff run through basic microbiology procedures on each sample including: culturing and incubating the bacteria, conducting gram stains to determine the classification of an organism, identifying the bacteria itself (often through a series of biochemical tests) and testing the bacteria’s susceptibility to a particular antibiotic (or its ability to be treated by a specific drug).

Microbiology is highly labour-intensive and for a laboratory with only a few automated machines, even more so. The sink in the corner is stained a deep purple from the gramstain testing and there are stacks of petri dishes in the incubator. The staff move from the sink to the microscope to an open bench where they plate bacteria onto an agar before incubation – sterilising the tools on an open flame.

Growing Resistance

Testing whether an antibiotic is effective against an infection, (also known as antimicrobial susceptibility testing, or AST)

is done through disk diffusion, a method in which several wafers containing different drugs are placed onto a petri dish full of the bacteria. The dish is then incubated, to give time for the antibiotic on the wafer to work and stop the growth of bacteria in its immediate area. If the antibiotic is effective, it will create a boundary around itself where no bacteria has been able to grow. The larger the circumference of the circle around the wafer, the more effective the antibiotic.

At this hospital, ineffective medicines are an everyday reality. “We don’t always set common antibiotics on the plate because we know they will come out resistant. For example, an antibiotic is resistant if the buffer around the wafer is 15mm, but here on this plate, the buffer is 6mm,” she said.

Many commonly used antibiotics are what clinicians refer to as “broad-spectrum”, meaning they treat a variety of classifications of bacterial infections. Doctors frequently prescribe these medications if their patient’s condition is quickly deteriorating or if they are unsure about the correct treatment approach. Many of these drugs are on the WHO’s List of Essential Medicines and can be purchased over the counter in the low-income countries for just a few pence. However, frequent and untargeted use creates resistance.

“Basically, all the samples we get are resistant to about four or five drugs – things like Ciprofloxacin, Cotrimoxazole, Ampicillin (used to treat variety of common infections). The drugs that are affordable are ineffective,” said Sofia. In some cases, the laboratory staff must plate 10-12 different drugs before finding one that is both affordable and effective. The staff say they’ve also found MRSA, better known as the ‘superbug’, in outpatients and in the community.

Evidence for a Healthier World

To curb the spread of resistance, more testing, more data and more awareness is needed, which is exactly what

“The drugs that are affordable are ineffective.”

Jinja Hospital

the Fleming Fund supports. In any environment, it can be difficult to encourage overstretched doctors to switch from syndromic treatment (based on symptoms) to ordering lab tests before prescriptions are made. But in Jinja, an active Medical Therapeutic Committee is hoping to change that. According to Sofia, a recent Global Point Prevalence Survey, (that analyses how and why medicines are prescribed in hospital) estimated that up to 77% of antimicrobial treatment in Uganda was based on empirical use - rather than laboratory testing. Jinja plans to reduce that number to 44%.

“There are three things we need to do to bring that number down,” says Sofia. “Make sure doctors have the microbiology request forms near them, improve our turnaround time and ensure that we provide doctors with preliminary laboratory results so they can start treating patients right after a gram stain test.”

In addition, their lab needs a steady supply of reagents and equipment. “At one point we only had 20 glass plates in the lab, meaning our turnaround time was over three days and doctors stopped requesting testing,” said Sofia. Support from the Fleming Fund will help to change this - ensuring there is a steady supply of reagents, procuring essential lab equipment and exploring possible renovations to the building, like sealing off windows.

Critically, more testing means more data – vital to understanding the patterns of resistance in the local community and for building an antibiogram. Antibiograms are a summary of all the antimicrobial susceptibility testing (AST) results in a particular area or hospital. In short, they provide empirical evidence that helps doctors treat patients better and reveal resistance trends in the community.

Dr. Asad Muhinda, the head of the Medical Therapeutic Committee in Jinja said: “At the moment, our sample size is

too small for a full antibiogram, but on the whole, what we are seeing is that patient [infections] are resistant to broad spectrum antibiotics. If people don’t stop misusing these drugs and prescribing them only when needed, we will have nothing.”

In Jinja, Dr. Asad and his colleagues have adopted the WHO’s AWaRe framework, which instructs doctors to access, watch or reserve certain medicines to reduce broad-spectrum resistance. The hospital’s supply chain use the framework and the resistance data to dictate their procurement listsso the most effective and appropriate drugs reach patients. Significant efforts have also been made to sensitise the community to the dangers of antibiotic misuse and staff say that patients are aware of the problem.

The final piece of the puzzle is ensuring that data from Jinja and other hospital laboratories reaches governments for policy making. The Fleming Fund’s focus on building national surveillance systems, by equipping countries to coordinate data collection and analysis will help. But

government action in Uganda and across other countries is needed to ensure antibiotics are properly used.

For Dr Asad and many of his patients in hospital, he knows without government intervention, his actions won’t lead to lasting change. He said, “One of our biggest challenges is that people can get antibiotics over the counter, without any prescription. There is also rampant drug misuse in small local clinics. But what happens outside the hospital affects us. If patients come in with resistant infections, it spills over. We are a community; we all move in the same bus.”

Microbiology

How does the laboratory process work?

Microbiology is complex. Understanding the quagmire of information around how to test, when to test, how long to incubate samples and how to decide how to treat patients requires 4-8 years of advanced post-graduate study, which is beyond the scope of a two-page spread.

However, in bacteriology, there are a few key steps that most of the laboratory technicians will follow to test samples. The Fleming Fund supports laboratories and technicians to with equipment and training to ensure facilities can carry out these basic functions.

Sample collection. There are several types of sample in human health, including blood, cerebrospinal fluid, stool, urine and genital samples. Each sample type requires a different type of process and preparation.

Incubation. Blood cultures are usually collected directly into a special culture bottle. Other samples must be plated out on to solid agar in a petri dish so that individual bacterial colonies can grow. This takes between 12-48 hours.

Separate colonies. Sometimes there are more than one bacteria type in a sample. If that is the case, the different colonies must be plated on to separate, fresh agar plates, so each can be identified independently.

4 5

Gram Stain Test. Gram-stain testing differentiates bacteria into two main categories based upon the contents of their cell wall, Gram-positive and Gramnegative. This is important because based on the type of bacteria, doctors can start to tailor treatment of patients based on the likely infection.

1 2 3 6

Bacterial Identification. This can be done through a series of biochemical tests, or, in large, modern laboratories, by MALDI TOF mass spectrometry (more on that later).

OUR AIMS OUR ACTIVITIES

Equip countries to collect and use data on drug resistance

Establish laboratory capacity and surveillance systems.

MALDI-TOF

Uganda’s national reference laboratory sits on a hill with a stunning view of green hills and the city in the distance. The building is clean and new, built a few years ago with support from the US Centers for Disease Control and Prevention. The laboratory spans several floors and the bacteriology unit is well equipped, except for the absence of a MALDI TOF mass spectrometer.

The acronym for MALDI-TOF is intimidating: it stands for matrix-assisted laser desorption/ionization-time of flight. But in short, it works by vaporising bacterial samples into small, charged particles that then “fly” into a vacuum tube. The speed at which the particles fly through the tube allows scientists to instantly identify the organism with high accuracy because every organism has its own “flight pattern”. To run the machine the laboratory staff pipe a microlitre (that’s onemillionth of a litre) onto a sterile metal plate which is loaded into the machine. They press a button and results pop up on a computer screen within a few minutes.

The Fleming Fund is providing MALDI TOF mass spectrometers in reference laboratories around the world, because they provide extra fast results (in two minutes rather than 18-48 hours), can test 96 samples at a time, and cost only 50 cents a test versus 5-10 USD for standard testing. They are also highly accurate and use far fewer chemicals and disposables.

For national surveillance systems to mature, laboratory results must be regularly quality assured for correctness. And because microbiology is a highly manual process, samples can easily become contaminated, skewing results.

The MALDI-TOF will provide a national benchmark for laboratories. Hospitals can regularly quality assure their results at the national reference laboratory, which now has the equipment to ensure testing is accurate.

My interest in AMR stems from personal experiences with ineffective drugs. I have seen the health of relatives significantly deteriorate because they could not get drugs effective against their ailment. The Fleming Fund is equipping me with the needed skills for AMR surveillance and data management to help inform policy in the right direction.

Charles Emejuru, Nigeria Fellow

Eme Enkeng

different bacteria should be tested against different drugs, depending on their natural resistance.

Intrinsic resistance means that bacteria are naturally resistant to certain antibiotics. This happens because some antibiotics target specific components of a bacteria’s structure. For example, bacteria that have no cell wall have intrinsic resistance to an antibiotic that destroys bacterial cell walls. “I’ve learned how to do antimicrobial susceptibility testing (AST) completely differently. Our visit to our Host Institution [academic mentor] blew our minds. There is so much we need to correct,” said Eme.

She has also become acutely aware of her new position as a leader in the microbiology community in Nigeria. The level of training she has received is unique and

many of her colleagues have high hopes for how she can use her new skills. “The Fellowship has given me a big sense of responsibility, because working at this reference laboratory means we are affecting the whole population when we get it wrong. Doctors can injure patients when we make errors.”

In the coming months, Eme hopes the knowledge from the Fellowship will help her support the laboratory to get accreditation and improve the quality management system, nationally and locally. “When we are up to standard, doctors and laboratories across the country will believe in us.”

Nigeria’s public health reference laboratory sits just outside the city centre in Abuja. That’s where Eme Enkeng, a medical laboratory scientist for the Nigerian Centre of Disease Control, works. Growing up in Lagos, Eme was fascinated by biology, even as a child. “I love biology. I love the colours, the colour changes and seeing how bacteria grows over time. It was also always easy for me to understand.”

She went on to study medical bacteriology because it was a hands-on profession. She could read about a disease or pathogen and then go use a microscope and run tests on in the laboratory. “I prefer seeing, prefer practical application - bacteriology gave me that picture,” she said.

After working in Lagos for several years, her managers saw potential in her and asked if she would move to Abuja, Nigeria’s capital, to help set up a National Reference

Laboratory. Only the best scientists were chosen for the move, a decision aimed at improving the whole country’s microbiology capacity.

From the beginning, working in Abuja was a learning experience, she learned new testing methods and laboratory skills and was recently awarded a Fleming Fund Fellowship. The Fellowship programme provided her with bespoke scientific and leadership training and expanded her perspective on microbiology.

“The Fellowship programme has completely changed the way think on the job,” she said. In the past, she used to run a standard panel of susceptibility tests to determine whether a specific drug could be used to fight a particular organism. But through the Fellowship, she has learned about the intrinsic or natural resistance of certain bacteria, meaning

Surveillance

How do you set up an AMR surveillance system?

1 2 3

Antimicrobial resistance surveillance systems involve ongoing data collection and analysis of the type of bacteria, resistance patterns and use of antimicrobial drugs in humans and animals. Surveillance is important because understanding the patterns and trends of diseases is vital for guiding local treatment practices, monitoring and controlling outbreaks and for making public health policy.

Fully functioning systems should also share data with a national coordinating centre so that a central body can develop a national picture of resistance. The Fleming Fund provides funds to countries to support each step of the process.

Get Governance in Order

Develop National Action Plan: Countries develop a National Action Plan for AMR that outlines the objectives and strategy for tackling drug resistance. A national AMR committee is also formed that can spearhead discussions and take policy recommendations forward.

Develop a Surveillance Strategy: The committee then drafts a surveillance strategy for human, animal and environmental surveillance of AMR. Reference laboratories, responsible for supporting surveillance site laboratories across the country, are selected for each sector.

Set up Surveillance Sites

Choose Surveillance Sites: The national AMR committee selects surveillance sites which will collect and process samples and supporting information. For surveillance in humans, these are usually government hospitals and samples are collected as part of routine hospital care. AMR Surveillance in animals, is usually done on farms or food production centres, like markets, abattoirs or processing plants and is managed by the national Veterinary Services, with the support from their network of laboratories.

4 5 6

Surveillance sites are responsible for processing samples, identifying the bacteria, performing antimicrobial susceptibility testing and sending data to the national data coordination body (often a technical working group, national focal point for AMR, or government epidemiology department).

Deliver Equipment & Training: Some surveillance sites and reference laboratories aren’t well-equipped and require renovations and/or new equipment. Staff must also be trained to ensure they can perform core laboratory functions, including safe and reliable testing on specimens, identification of important bacteria, antimicrobial susceptibility testing and collection of basic information of patients, animal herds or farms.

Implement Protocols & Standard Procedures: Every laboratory must adhere to and implement biosafety & security guidelines, protocols for carrying out specific tests and general laboratory procedures for data storage, etc. These documents need to be written and implemented for each site.

Gather & Use Data

Gather & Report Data: After protocols have been established, bacteriology testing results from surveillance sites are entered into a national database, shared with the national data coordinating body (e.g. a technical working group, the national AMR focal point, or a government epidemiology unit.)

This body compiles and analyses data to discover national trends. Data should be shared and used locally, nationally and internationally.

Analyse and Use Data Locally: Testing results should be shared locally with clinicians to help them treat patients better and understand local resistance patterns.

Analyse and Use Data Nationally: Results are shared with the national AMR Coordinating Committee and relevant technical working groups to compare patterns across human and animal health. Analysis should then be provided to policy makers to guide national regulations around antibiotics.

Report Internationally: Ideally, all data is also reported to relevant international organisations (WHO, OIE) so that patterns and trends can be analysed at the regional and global level. For surveillance in humans, countries should be participating in the WHO Global AMR Surveillance System (GLASS).

Michael Omodo

decision in life there is always a driving factor behind that choice,” he says, explaining that his uncle was the impetus behind his study. “My uncle lives in our village and he owns cattle, goats and chickens. The first time one of his animals fell sick, he consulted a veterinary doctor. They told him what to do and he bought the drugs. But the second time, because he thought he knew everything, he treated his animals without consulting a veterinarian. A little while back went to see him, and saw him injecting his animals with stronger drugs – but they didn’t work, and he lost some of his animals. I told him I’d take samples for him and test them in the lab, and I found the pathogens in the animals were resistant to the drugs.”

and resistance (starting in chickens) and highlighting the importance of reducing drug misuse. Investments in training and laboratory equipment will allow staff to gather samples and analyse data, to develop a national picture of drug resistance in chickens.

Uganda’s National Animal Health Laboratory sits right next to Entebbe airport, facing Lake Victoria. Mango trees, wild monkeys and the occasional bird are randomly peppered around the laboratory’s campus which is getting a huge face-lift, thanks to investment from the Fleming Fund. The buildings are being renovated, new state-of-the-art equipment is being installed and some of the staff are receiving on-going mentorship and training from global animal health experts as part of the Fleming Fund Fellowship programme.

In one of the rooms, Michael Omodo, is busy with a team of researchers preparing for an influx of samples from his Fellowship project. Michael is a laboratory scientist with a background in animal health and has been working for the Ministry of Agriculture for nearly 10 years. He and his colleagues from the Fellowship programme are being mentored by experts from the University of Edinburgh, in the UK and are starting work on their final collaborative project.

The Fellows, comprised of human and animal health specialists, are planning to gather some 9000 samples from livestock and people across Uganda to demonstrate how resistant bacteria transfers between humans and animals.

The ultimate goal, he explains, is to ensure the data is of sufficient quality for policy making as it is only through regulation that the country can curb misuse of antibiotics which leads to resistance.

Throughout the world, a larger quantity of antibiotics is used in animal rearing than in human health, which means curbing drug misuse and overuse in animals is critical to tackling resistance. For example, according to the UK’s AMR Review, published in 2016, 70% of all antibiotics in the US are sold for animal use.

Michael’s interest in studying antibiotic resistance comes from direct experience of drug misuse in animals. “For every

Unfortunately, this is a common story for many farmers in Uganda. According to the country’s situational analysis on antibiotic resistance, antibiotics are frequently used as prophylaxis and as additives in animal feed. Tetracycline and penicillin are the most common antibiotics used, but farmers rarely consult veterinary services and few laboratories are available to analyse samples from sick animals.

A lack of veterinarians and laboratory analysis services mean that AMR surveillance in animals is also rare. Across the country there is less investment in supporting animal health services than human health services. And surveillance efforts in animals are primarily targeted at zoonotic viruses or diseases which cause the most harm in animals. For example, foot and mouth disease in livestock, can cause lameness, a significant reduction in milk production and occasionally death in animals, but does not easily transfer to humans. In contrast, animals carrying E. coli bacteria may show no signs of illness, yet dairy and meat products, contaminated by faeces from that animal could cause sickness in humans.

The Fleming Fund’s investment in Uganda aims to tackle those issues by boosting surveillance of antibiotic use

An automated susceptibility testing machine and a MALDITOF (an instrument that can identify bacteria within two minutes, rather than the normal 18-48-hour process) have been delivered and installed at the site. Michael says these investments will make a huge difference and will give the laboratory and resulting surveillance data enormous credibility. The challenge now, for both Michael and others in the laboratory, is to convince policy makers to turn their hard-earned evidence into action and enact regulations to curb misuse of antibiotics in farming.

My passion for AMR arose when I lost my beloved father to multi-drug resistant tuberculosis. As a veterinarian and an epidemiologist with great passion for public health, I have always believed bridging gaps and understanding major health problems such as AMR is a task bothering the academia, public health institutions and the world at large.

Oluwadamilola Abiodun-Adewusi, Nigeria Fellow