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Pakistan fights drug resistant typhoid on war-footing

After the first-ever outbreak of an extremely drug-resistant typhoid strain anywhere in the world, Pakistan has become the only country with a national action plan to contain antibiotic resistance.
by Ramsha Jahangir

In a densely populated mohalla of Qasimabad, Hyderabad —the second largest city of Sindh— the residents depend on a filtration plant established in 2008 for water consumption. Till a month ago, four-year-old Adil’s father who lives in the same vicinity was convinced that he was using ‘safe’ water.  But to his dismay, his son had to bear the cost of relying on the free ‘filtered’ water.

In Brief

  • Pakistan is the third highest consumer of antibiotics after India and China as per a study that covered 76 low and middle-income countries. Studies suggest that the country has witnessed a 65 percent increase in use of antibiotics over the last 16 years.
  • Typhoid fever is a life-threatening infection caused by the bacterium Salmonella Typhi. An estimated 11–20 million people get sick from typhoid and between 128,000 and 161,000 die from it every year. XDR typhoid — a bacterial strain that has never been detected in an outbreak before — is resistant to five antibiotics, responding only to azithromycin, which is considered the last line of defence against typhoid.
  • According to the record being maintained at Aga Khan University Hospital (AKUH), at least 1,000 cases of XDR typhoid have been laboratory-confirmed in 14 districts of Sindh, of which 800 patients were reported in Hyderabad alone in a 10-month period between 2016 and 2017.

Adil was rushed to the emergency department of a public hospital in Karachi with high-grade fever and severe drowsiness which had lasted for three weeks. Back in Hyderabad, a doctor who runs a local clinic had prescribed first-line antibiotics. However, the high temperature persisted. A week later, another general physician gave him oral antibiotics, but the fever did not subside.

“My son was in distress. He was extremely lethargic and had very high temperatures. A relative of ours in Karachi then advised us to bring Adil there,” Asghar recalls. Having suffered for weeks, the toddler was then admitted in the intensive care unit and started on intravenous antibiotics. After two days, a blood culture revealed that he had developed “extensively drug resistant” typhoid or XDR— meaning it would only respond to one powerful, broad-spectrum class of antibiotics: azithromycin, which is considered the last line of defence against typhoid.

Despite the intense treatment, Adil remained sick for another six days and regained complete strength over a span of months. “They told me the water was not safe for drinking. Why is it called filtered then?” asks Asghar, who now has an added expense on his pocket.

Unfortunately, his is not an isolated case of XDR typhoid in Pakistan. In November 2016, a major outbreak — first in the world — gripped areas of Sindh, mainly Hyderabad and Karachi.

Read more: Typhoid outbreak in Sindh caused by drug resistant strain

Typhoid fever is a life-threatening infection caused by the bacterium Salmonella Typhi. According to the World Health Organization (WHO), an estimated 11–20 million people get sick from typhoid and between 128,000 and 161,000 people die from it every year.

XDR typhoid, on the other hand, is resistant to five antibiotics in total—a bacterial strain that has never been detected in an outbreak before. Medical experts attribute the rise in infectious diseases in Pakistan to poor sanitation measures and a lack of food security policy.

AKU vaccination drive in Hyderabad

There are no official statistics on the total number of victims yet, but according to the record being maintained at Aga Khan University Hospital (AKUH), at least 1,000 cases have been laboratory-confirmed in 14 districts of Sindh, of which 800 patients were reported in Hyderabad alone in a 10-month period between 2016 and 2017. These figures though were collated from blood tests in only AKUH and Liaquat University of Medical and Health Sciences and do not include patients admitted in other hospitals.

‘Work in progress’

A quick check with leading infectious disease experts in Karachi reveals that indeed the figure is grossly underestimated with the superbug spreading across the country rapidly.

“A dozen of XDR patients have been admitted in the last [May] month only. The paediatrics department has witnessed many more. In fact, all cases of typhoid we have diagnosed recently are of XDR,” observes Dr Naseem Salahuddin, head of the division of infectious diseases at the Indus Hospital in Karachi.

Besides the frequency in typhoid morbidity, Dr Salahuddin points toward the greater problem of dealing with cases. According to her, misdiagnosis or delayed diagnosis cause far more complications than the infection itself. “One of the most consistent trends witnessed is that patients come in after weeks of illness. Either they have been prescribed antibiotics to no avail or they have been on self-medication. The longer it takes for correct diagnosis, the lower the chances of recovery.”

Citing an example of a patient, the ID specialist explained how delayed treatment can lead to severe complications. “One of our patients has been sick for weeks before she came to Indus Hospital. She developed severe swelling in her right bicep during IV treatment. The infection had spread to her body and damaged her liver,” shares Dr Salahuddin.

Deploring the dismal state of health affairs in Pakistan, she notes that the treatment of XDR typhoid is “extremely challenging”.  “We [ID specialists] have still not developed consensus on what is the right treatment, what will work. Sometimes, patients don’t respond to third-line antibiotics during the first few days of treatment. Others, they respond to oral antibiotics. This is still a work in progress.”

Fighting resistance on war-footing

Antibiotic resistance is a growing trend across the world and poses a serious threat to modern medicine. In Pakistan, however, having witnessed the first known epidemic of an extensively drug-resistant bug, infectious disease experts are anxious to find a solution to the menace.

The country is the third highest consumer of antibiotics after India and China as per a study that covered 76 low and middle-income countries. Pakistan has witnessed an increase by a whopping 65 percent in use of antibiotic over the last 16 years, the study found.

According to a report published in Proceedings of the National Academy of Sciences scientific journal, antibiotic consumption in Pakistan between 2000 and 2015 increased from 800 million defined daily doses (DDD) to 1.3 billion DDD.

Read more: The Miracle Drug for Pakistan’s Medicine Cabinet

“A huge credit for overuse of antibiotics goes to medical practitioners themselves. Influenced by pharmaceutical companies or to convince patients of their credibility by fast recovery, they prescribe antibiotics in large quantities,” says Dr Asma Nasim, an assistant professor in the Department of Infectious Diseases, Sindh Institute of Urology and Transplantation (SIUT).

According to the Pakistan Medical Association, there are over 600,000 non-registered medical practitioners in the country. Realizing what this means for the future of national health, Dr Nasim calls for action to restrict antibiotic use on war-footing.

A child get vaccinated by the AKU team in Hyderabad

It is alarming that the bacterial strain has spread to district South in Karachi, she points out. “There is an urgent need to address food and water contamination in both rural and urban areas. One case is reported every day in SUIT. This is an emergency,” she asserts, adding that areas in the periphery of the Civil Hospital sharing the same sewerage line are the most affected.

Heavy on the pocket

On April 12, Karachi was sweltering under an intense heat spell. With scores of heat stroke patients coming to hospitals, it was perhaps the first thing that came to Dr Tehreem’s mind when she caught fever.

“I came home feeling low on energy and with pain in the neck. Mistaking it for a heat stroke, I had a tablet of Panadol. But the fever returned after five hours, this time accompanied with shivering,” she recalls the “most terrible experience” of her life.

For the next two days, Dr Tehreem tried antimalarial drugs, but to no avail. She describes feeling her body burning, shaking with frequent bouts of chills in high fever. Despite having treated patients of XDR herself, the ID specialist had never realised how excruciating the ordeal could be.

After her blood tests confirmed the infection, she was admitted in the hospital. Initially and to her relief, the fever reduced from five to three times a day. But the relief was short-lived. The high-grade fever returned after three days, leaving her with no option but to take double doses of IV injections.

Her treatment lasted for over three weeks, costing over Rs 100,000.

“One third-line antibiotic costs Rs3,000. During XDR treatment, a patient is prescribed with multiple doses. For a procedure ranging from a week to 14 days or sometimes more with the expense of IV drips and hospital charges, it is very difficult for people to afford the treatment,” she explains.

Dr Nasim raises similar concerns while estimating that the total treatment for 14 days on average costs over Rs 50,000 while the required blood culture to diagnose typhoid in public hospitals costs around Rs 1,500-1,800. “This is the reason why vaccination is the solution. People in low-income areas cannot afford to pay for such hefty amounts,” she says.

Read more: Pakistani researchers get patents for nano-antibiotics

Last line of defence

A team of scientists from AKU and the Wellcome Sanger Institute in England studied samples of the typhoid-causing bacterium and found that the cause of the outbreak was likely to be contamination of the water supply with sewage due to damaged lines.

As the outbreak spread, an emergency response campaign was launched in January this year to vaccinate 250,000 children in Hyderabad using a new typhoid conjugate vaccine — Typbar-TCV — which was prequalified by the WHO in March. The drive was supported by a Bill and Melinda Gates Foundation grant which provided vials for vaccination in collaboration with the US Agency for International Development (USAID) that provided syringes.

The vaccine lasts at least five years and can be given to children as young as six-months old and up to 10 years, says Dr Tahir Yousafzai, a lead organiser of the vaccination drive.

“Typhoid is a notifiable illness in Sindh province, but the antibiotic resistance profile is not considered. We alerted the provincial health department on this new extensively resistant typhoid bug and contacted the government several times to update them by sending weekly notifications of new cases,” says Sadia Shakoor, an AKU microbiology professor and co-author of the study.

The government though, she adds, is now completely on board.

“The country now has a National Action Plan for containment of antibiotic resistance, which is in early stages of implementation. We cannot expect changes to come about soon, but the plan is in motion and we are hopeful,” Dr Shakoor maintains.

Experts attribute 40 percent of Pakistan’s infections to be caused due to unhygienic water. The Supreme Court of Pakistan (SCP) was recently apprised by a judicial commission on water quality and drainage in Sindh that not a single treatment plant was working in the province, and all sedimentation-based water supply schemes were dysfunctional with faulty design while untreated sewage continued to flow in irrigation water/canals at 750 points.

It was further noted that hospitals lacked medical waste disposal systems as well as clean drinking water, and because of choked drainage systems, wards remained surrounded by sewage dumps. Given that the leading cause of infectious diseases— which are almost unheard of in the developed world— is water and food contamination, time is running out for the authorities to curb further outbreaks.

In a bid to implement water purification, the government distributed 40-50,000 chlorine tablets in low-income areas across Sindh. “Chlorinate it or boil it”, reads a flyer part of the awareness campaign.

Despite the various challenges, the country is moving forward: Pakistan is the first country in the world to approve of a vaccine against typhoid.

“So far 65,000 doses have been administered in the largest-hit areas: Lateefabad and Qasimabad. We have support from the Ministry of Health, District Commissioner Hyderabad and Lady Health Worker Program which helps us reach sensitive areas,” Dr Yousafzai shares.

But, in a country where vaccination drives are prone to stir controversy, the challenge to face resistance continues.

Earlier in March, rumors were afloat on social media warning people against public inoculations after the death of three children who were administered expired measles vaccines in Nawabshah district of Sindh.

“Our campaign suffered at that time as a large fraction of people from both urban and rural areas refused to administer vaccines fearing death,” Dr Yousafzai admits.

In addition to the drive, GAVI, the Vaccine Alliance— a public–private global health partnership working to increase access to immunization— has pledged $85 million to ensure that typhoid vaccines reach developing countries.

“Since we have ‘limited options’, Pakistan has requested GAVI to expedite the process—but it will still take at least 1-1.5 years for the process to complete,” he points out.

The vaccine will be made available in the government’s Expanded Program for Immunization (EPI) for children (who are also the most affected by typhoid), bypassing any affordability issues, adds Dr Yousafzai.

“If vaccination is not widely implemented, we might become resistant to third-line antibiotics as well. What then?” he asks, warning that the future of medicine is at risk.

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