New Delhi: In the second week of April, a 62-year-old patient was admitted to the intensive care unit (ICU) of a tertiary care hospital in Chennai with a slew of vague, generic complaints—ranging from “weakness" to “tiredness".

He was passing blood in his stool, and an investigation revealed that multiple blood transfusions he had undergone in previous hospitals had caused a reaction, which led to acute renal failure. After a few days, he developed a raging fever and, inexplicably, a chest infection.

Even as the doctors swiftly put him on systemic antibiotics for drug-resistant bacterial infection—a common suspicion in such cases—they sent off his samples to a lab. The blood cultures showed the growth of an unusual fungus, identified as Candida auris (C. auris), which showed resistance to the most commonly available antifungal drugs, including Fluconazole.

“We put him on the appropriate treatment, but his condition continued to deteriorate. Unfortunately, we lost him after two weeks," said one of the doctors on condition of anonymity.

Over the last few years, ICUs in hospitals across the globe have been silently battling the emergence of this mysterious, drug-resistant strain of fungus, which causes severe skin and invasive blood stream infections in patients, and raises the mortality risk of patients who are already battling another ailment. More than one in three patients with invasive C. auris infection die.

Even as hospitals maintain a studied silence over outbreaks in their facilities (since they don’t want panic-stricken patients to boycott their premises), the bug has silently travelled across the globe and spread to nearly 35 countries in a span of just 10 years. It is now a global public health threat and India is at the centre of it.

Fungus behaves like bacteria

The bug was first identified in the ear canal of a 70-year-old patient in Japan in 2009, and named Candida auris. Two years later, South Korea reported two more cases. The researchers sequenced the genome and put the information of the identified strains in a multinational database.

Ever since India reported its first outbreak in 2011, hospitals across the country have found sporadic cases of C. auris in their critical care units.

“It was a fungus that behaved like bacteria. That is, the pathogen was clonal (replicates fast) and extremely invasive too, which means ready transmission from one patient to another," said Dr Anuradha Chowdhary from Vallabhbhai Patel Chest Institute, the University of Delhi, whose team was one of the first to identify the pathogen among 12 patients in two Delhi hospitals between 2011 and 2013.

But crucially, unlike many bacteria, the fungus can stick on to surfaces and fester for a long time, waiting for a new victim to show up in the vicinity. “From bed linen, blankets, medical instruments, windows, walls, door knobs, clothes, skin of the patient, IV tubes, to ventilators, it has been found everywhere," Chowdhary said.

Six years after her paper about the Delhi outbreak was published, Chowdhary said, the multi-drug resistant fungus has been found in various public and private-care hospitals in the national capital and other states. A study of 27 ICUs across the country in 2011 found nearly 1,400 isolates (harmful pathogen), out of which 74 isolates, or 5.3%, were identified to be that of C. auris. As many as 19 ICUs were affected by the fungus at different times during the period of the study.

A 2017 paper published in the Journal of Antimicrobial Chemotherapy found that the number of C. auris infection cases was higher in public-sector hospitals in north India.

As medical care facilities face the onslaught of antibiotic resistant bacteria, due to the misuse and overuse of antibiotics, the relatively new fungus, which has begun to show multi-drug resistance, has doubled the magnitude of the public health challenge. How does one save critically-ill patients from hospital-acquired infections, which are caused not just by superbug bacteria, as previously thought, but also new variants of fungus which lay waiting in hospitals.

Essentially, the critical care units of many hospitals are emerging as the new frontline of a century old skirmish. Since the late-1800s, humanity invented a slew of new chemicals which allowed humans to grow more food, keep animals in crammed environments without getting diseases, and fight back against common infections that resulted in deaths. Now, enough organisms in nature are acquiring immunity against these long-used concoctions and fighting back. And ICUs filled with patients whose immunity is already low are becoming the battlegrounds. One origin story for C. auris is that it might have been a soil fungus whose gene structure changed due to fertilizer overuse. Now, the fungus can enter the blood stream and cause Candidemia, leading to septic shock.

Antifungal drug shortage

At present, there are only three classes of antifungal drugs available—first line Azoles (Fluconazole, Itraconazole, Voriconazole, Posaconazole, Isavuconazole, and Ketoconazole), second line Echinocandin (Anidulafungin, Caspofungin, and Micafungin), and Polyenes (Amphotericin, Nystatin, and Pimaricin).

C. auris shows highest resistance (nearly 90%) to first line of drugs, especially Flucanazole. The level of resistance to second line of drugs is around 5-7%.

“But when resistance to second-line drugs occurs, it occurs to all three drugs in the category uniformly. So, the only option available is Polyenes, which is given intravenously during systemic infections but is highly toxic and not all patients can tolerate it. The options are limited and no new antifungal drug has entered the market in the last 10 years," said Dr Chowdhary.

Unlike antibiotics, the antifungal drugs are also far more expensive, and thus, the cost burden of fungal infections is higher, especially in a country like India where surging healthcare expenses are unaffordable to a bulk of the country’s 1.3 billion people.

According to the latest National Sample Survey Office health survey, 36 million households incurred health expenses that exceeded the annual per capita consumption of those households.

Since the needle of suspicion for in-hospital infection has mostly fallen on bacteria, antibiotic resistance due to fungal infections has gone largely unnoticed, said microbiologists.

Most developing countries also do not have well-equipped and well-functioning mycology laboratories for research on fungal infections. The fungus, till date, is largely misidentified in several cases.

Invasive, Transmits Fast

What concerns health practitioners is the high transmissibility of the bug. “We studied the fungus in January, 2017, when we found it had colonized the skin of a patient who was referred to the Trauma Care ICU from another hospital. But within four days, it (bug) had spread to all the other patients admitted in the unit. All nine of them," said professor Arunaloke Chakrabarti from Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh.

Once the bug was identified to be C. auris, the nursing staff did Chlorhexidine body wash of all the nine patients to remove it and stepped up infection control practices, including strict hand-wash practices and aggressive use of disinfectants. The bug usually colonizes the armpits, groin and rectum.

All the medical instruments, bed linen, blankets were wiped clean, and some disposed-off completely to prevent a major outbreak. The filters of one of the ventilators which was found contaminated had to be destroyed to get the ventilator working again.

The patient recovered, and so did all the other nine patients, but as professor Chakrabarti said it’s not likely to be the case, most of the times.

“The mortality rate in such infections is nearly 70%. We were able to save the patients because the bug had just colonized the skin of the patient. We did not let it enter the body or cause any invasive infection because of strict infection control practices," he said.

In the last two years, at least 200 cases of C. auris infections have been reported in hospitals across the country, he said.

Chakrabarti said the experience with an outbreak within an ICU helped doctors understand the bug better. If identified early enough, transmission can be prevented as long as strict hygiene and infection control practices are adhered to within the hospital. “The use of disinfectants including phenols and simple alcohol scrubbing is sufficient to get rid of C. auris, if done properly," he said.

What makes C. auris different and deadlier than other anti-resistant species of fungi is its enigmatic nature. It cannot be identified by commercial methods of identifying a yeast.

Despite a decade of its existence in the critical care units of hospitals across the globe, the major question confounding researchers is where does it originate from? Its reservoir is not yet known.

“We have looked into food and water samples in the hospital, but we have not found the isolate. We looked into the community set-up, but it is not present there. What we know is that it originates and transmits in the hospital, but how and from where, we do not know yet. This question is bothering us," said Dr Chakrabarti.

Over-Crowded Hospitals

While there are high-risk factors associated with ICUs in hospitals, the problem in India is compounded by over-admission in over-capacity public and private sector hospitals.

Usually, C. auris infection occurs in patients who are on antibiotics for a long term or long ICU stays. Patients admitted in ICUs are on various broad-spectrum antibiotics which kill the entire normal flora in the gut. In such a scenario, the resistant C. auris begins to multiply because it is not affected by antibiotics.

Usually, a patient recovers and gets discharged. But if he keeps getting complications like fever, redness on skin, or any urinary or abdominal tract infection, then, in such cases, the samples are sent for testing. C. auris can cause any infection from head to toe. One can confirm C. auris only if it grows in the blood culture, and it is identified using suitable molecular techniques. The risk is higher for neo-natal units, where the newborns face a constant mortality risk.

“The more a patient stays in an ICU, more are the chances of him/her picking up drug resistant organisms from the hospital environment. The sooner you get out of the hospital, the better. That’s what we suggest post any surgery or deliveries, including caesarean. It’s better to go home," said Dr Joy Sarojini Michael of Christian Medical College (CMC), Vellore.

The fungus can form biofilms within the intravenous (IV) lines, which is like a cocoon that serves as a safe nesting place for the bug to escape the effects of antifungal drugs. Its thermo tolerant and salt tolerant properties allow it to persist in the hospital environment for a long time.

Research has shown that the strain grows well at 40 degrees Celsius, which explains why tropical countries like India tend to offer a better place for such germs to spread.

The Indian Council of Medical Research (ICMR) notified the fungus in 2017 and issued an advisory while mandating all hospitals to report its occurrence. However, the major challenge is that not many centres and laboratories in the country can correctly identify the fungus.

The pathogen requires a specialized method of identification, as commonly used automated phenotypic systems can label it wrong. There are only two methods which can be used to identify the strain. A definite confirmation can be done by either mass spectrometry technique called MALDI-TOF with upgraded database or DNA sequencing, both of which are not frequently available in diagnostic laboratories.

“This is the reason not many people have been reporting it in India. Majority of the laboratories do not have access to higher-end identification systems," said Dr Michael.

While hospitals in many other countries have shut down their premises after an outbreak, it is a massive exercise and financially unviable in a country like India. The practice requires that the patient, once identified to be infected with C. auris, is quarantined. Under the limitations under which India’s tenuous healthcare system functions, locally viable solutions may be required. And fast.

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