Growth of Klebsiella pneumoniae CRE (Carbapenem-resistant enterobacteriaceae) from positive blood culture on MacConkey agar. Photo: Chiara.marraccini/Wikimedia Commons, CC BY 4.0.
Found among the top three ranks in WHO’s priority list for pathogens, Klebsiella pneumoniae is one of those bacteria against which medical and scientific institutions around the world have struggled over the last few decades. In this time, it has evolved into one of the most virulent and antibiotic-resistant microbes that infect humans. Some of these versions of K. pneumoniae, also called strains or genotypes, have been responsible for multinational disease outbreaks across the globe. Scientists and doctors around the world are also worried that microbes like K. pneumoniae might pose a greater risk to human health after our struggles against COVID-19.
When the passenger starts to create trouble
In 1882, German microbiologist Carl Friedlander discovered K. pneumoniae. He identified this microorganism in the lungs of patients who had succumbed to pneumonia. Eventually, the medical term for lung infections – pneumonia – became a part of this microbe’s scientific name. Later studies unveiled other aspects of this microbe, including the fact that it can colonise the mouth and other regions in the human gut or gastrointestinal tract.
While it does not seem to be directly harmful in the gut, K. pneumoniae can cause havoc if it reaches other parts of the human body. People whose health is compromised due to pre-existing illness, are hospitalised and on long term medication with immunosuppressants or antibiotics, are particularly prone to such K. pneumoniae infections. These infections can happen in various organs such as the lungs, blood, liver, eyes and brain. This microbe can also initiate infections after colonising medical devices, such as catheters and endotracheal tubes.
Prolonged sickness can weaken the immune system, preventing the human body from fighting off attacks by opportunistic microbes like K. pneumoniae. Making a bad situation worse, such microorganisms can then goad the impaired immune system into making counterproductive responses, like sustained inflammation. Other preexisting, chronic disease conditions like diabetes and alcoholism also allow K. pneumoniae to spread easily from the gut to other organs, such as the liver or lungs, and cause infections.
Along with spreading inside a person, there are two ways in which this bacterium can be spread between people: through hospitals and through the ‘community’. Hospital facilities that don’t adequately clean or inappropriately reuse medical equipment, and maintain poor hygiene standards for personnel, can act as long-lasting sources of infection. Community-acquired infection happens if we come in contact with an already infected individual in public places like the subway or a market.
But regardless of how this microbe spreads, the outcomes of infection have become worse because of antibiotic resistance.
Antibiotic resistance raises the stakes
When used excessively, antibiotics can have two types of side effects. First, they can cause collateral damage by killing many kinds of beneficial microbes that live in the human body. Opportunistic pathogens like K. pneumoniae can become dangerous when they are not kept in check by competing beneficial microbes. Second, the overuse of antibiotics can increase the populations of antibiotic-resistant bacteria. Such bacteria can no longer be killed or destroyed by certain kinds of antibiotics. Acting at the individual and community level, these two side effects make K. pneumoniae extremely dangerous.
While some strains of K. pneumoniae have become resistant to single antibiotics, others have become resistant to multiple antibiotics and are said to be multi-drug resistant. Infections caused by such strains are very hard to cure and K. pneumoniae is a textbook example of the dangers of indiscriminate use of antibiotics.
Quite often, we see antibiotics as just another kind of medicine and don’t consider their origins. Actually, every kind of antibiotic is derived from molecules that are naturally produced by some microbes to kill or stop the growth of other microbes. Scientists have extracted such antibiotic molecules, tweaked their chemical structures, and produced them in large quantities. Humanity has used these antibiotics to defend itself against disease-causing bacteria.
But if antibiotic molecules are weapons, then resistance mechanisms are the defence, and all microbes can evolve resistance to antibiotics. They develop resistance mechanisms over time and share them with other microbes in their vicinity. When antibiotics are used, the susceptible bacteria are killed and the resistant bacteria survive and increase in numbers. If used too frequently, no antibiotic can remain useful for very long. Seen from this perspective, antibiotics are a natural resource. We need to use them sparingly, to prolong their usefulness in combating disease.
As with all medicines, doctors prefer using antibiotics that are effective against microbes and safe for humans. But their ability to make such clear cut choices has started to crumble over time, when faced with antibiotic resistance. This sad transition is apparent in humanity’s struggle against K. pneumoniae.
Many strains and many abilities
In the 1980s, some K. pneumoniae strains were found to be resistant to many beta-lactam antibiotics. This set of antibiotics, counted among the most commonly prescribed classes of medication, includes penicillin and its derivatives. By producing enzymes called beta-lactamases, these K. pneumoniae strains can chemically inactivate these antibiotics. This phenomenon heralded the first wave of antibiotic resistance observed in this microbe.
To cure infections from such resistant bacteria, doctors began to use a group of modified beta-lactam antibiotics called carbapenems. For a while, these modified antibiotics were effective. But this victory did not last long. Resistance to carbapenems was first observed in the US in 1996, with the bacteria producing another enzyme called carbapenemase that triumphed over these antibiotics.
With regard to India, antibiotic resistance was brought into sharp focus with the discovery of New Delhi Metallo-β-lactamase, a new antibiotic resistance mechanism in K. pneumoniae in 2009. The resistant bacteria were found in a diabetic patient who had had surgery and a course of multiple antibiotics from a hospital in New Delhi. The scientists who discovered this also found a strain of Escherichia coli, from the same patient, harbouring the same resistance mechanism. Genetic clues showed that the antibiotic resistance originated in K. pneumoniae and was then passed on to E. coli.
Such exchanges of resistance between different bacteria cause scientists and policymakers to worry about a post-antibiotic future. This scenario is only a step ahead of what’s happening right now, where doctors are forced to compromise on the kind of antibiotics that they have to use for their patients. The increased resistance of K. pneumoniae to common medications has led doctors to start using last-resort antibiotics that were previously abandoned.
Despite the toxicity that it produces in the human nervous system and kidneys, an antibiotic called colistin gained a second life as a drug to treat beta-lactam- or carbapenem-resistant K. pneumoniae. But, as early as 2010, some K. pneumoniae strains were also found to be resistant to colistin. And just like that, another antibiotic bit the dust. With multi-drug resistance showing up in many bacteria, we seem to be quickly heading towards a time when most of the antibiotics we use right now might become useless.
While antibiotic resistance certainly makes K. pneumoniae hard to deal with, certain strains of the bacterium have developed other dangerous capabilities. Hypervirulence is another emerging problem associated with this microbe.
It began around the year 1986, when cases of extremely severe K. pneumoniae infections were reported in Taiwan. Later, the same strains were also found in Asia, followed by cases popping up in Australia, North America and Europe. They can infect young and otherwise healthy individuals. Once established in a patient, they can spread from the primary site of infection to other parts of the body. In this way, the bacteria attack various bodily tissues and cause severe infections in skin, bones and liver. These hypervirulent K. pneumoniae bacterial strains are also able to withstand attacks from the human immune system. They manage this by producing a protective outer layer or covering for themselves, which is also effective against antibiotics.
Over the last fifty years, the threat that K. pneumoniae posed to humanity has grown by leaps and bounds. Initially, this bacteria could only cause a problem in already weakened patients and could be killed with many antibiotics. But as of today, there are strains of this bacteria that have become both hypervirulent and multi-drug-resistant. This combination of abilities means that they are no longer limited to attacking only people who are already weakened by other diseases. They can attack otherwise healthy people and, when they do this, they cannot be controlled with many commonly used antibiotics.
Meet the challenge with policy and research
We are dealing with the problems posed by K. pneumoniae and other bacteria like it in two ways: policy initiatives and new research. Policy initiatives that are widely implemented across national and private-public divisions can have the fastest effects. The focus would be towards two results: control the spread of disease causing bacteria and slow down their development of resistance to antibiotics.
Global policy changes have been driven by lessons learnt in the past. Following a nationwide outbreak of carbapenem-resistant K. pneumoniae in its hospitals in 2006, Israel successfully managed to contain the spread of the microbe. Israel’s strategic infection control measures contributed to WHO’s global guidelines in 2017 for combating similarly resistant microbes.
To control the emergence of antibiotic resistance, we need to ramp up stewardship of treatment plans against all medically significant disease-causing bacteria. Since 2013, the Indian Council of Medical Research (ICMR) has been running the Antimicrobial Resistance Surveillance and Research Network to guide the use of antibiotics against many disease-causing bacteria. India’s relatively recent inclusion into WHO’s Global Antimicrobial Resistance Surveillance System serves to increase the nation’s level of engagement and allow the international cooperation and information exchange needed to effectively deal with this problem.
So in recent years, India has been moving forward with some of the changes needed to help identify and control outbreaks of antibiotic-resistant bacteria like K. pneumoniae.
Ultimately, lowering the rate of human contact with disease causing microbes is probably the best way to limit antibiotic use. Improving community hygiene and sanitation can definitely help reach this goal. To complement this preventative approach, we need to invest in more research on vaccines that can help our immune system to fight off such microbes. But neither sanitation or vaccination are easy targets to coordinate, especially at the national or global levels. In this situation, it might be best to develop and use several therapeutic and diagnostic tools to fight such microbes.
Researchers have identified viruses known as bacteriophages that specifically target and destroy certain bacteria, including K. pneumoniae. Popularly known just as phages, these viruses are strictly host-specific – i.e., they tend to infect specific bacterial species, leaving human cells unharmed. Phage therapy has a long history and possibly a bright future in helping combat antibiotic resistant bacteria. Even developing resistance to phages might make bacteria more susceptible to antibiotics or alter them in other ways that make them easier to control.
Combination therapies that include antibiotics and phages might form a resilient defence against bacterial diseases in the future. Gene sequencing techniques that can quickly identify the genetic make-up of bacteria, and their associated capabilities, can support the best implementation of such next generation combination therapeutics.
In order to future-proof India’s healthcare, we need to continue making fundamental and interacting improvements in infection surveillance, treatment methodologies, auditing procedures and community hygiene in a fine-grained manner across the whole country. Better enforcement to prevent unregulated sales and over the counter usage of antibiotics can also help to keep preferred antibiotics useful for longer. The need for such efforts to be integrated at the national level acquires even more significance in the midst of other crises such as the ongoing novel coronavirus pandemic
Various strains of K. pneumoniae have been spreading around the globe for many years and are responsible for multinational disease outbreaks. They do not become less harmful simply because we now have COVID-19 to deal with. On the contrary, K. pneumoniae infections could even complicate the treatment and prognosis of COVID-19 patients, by producing ventilator-associated pneumonia and infections.
In our haste to declare victory against COVID-19, we must not allow other diseases to flourish. Whatever the disease, it is still human lives that are lost or saved. Dr Kamini Walia, the programme officer for antimicrobial resistance at ICMR, recently advised against actions during COVID-19 that could jeopardise India’s ability to fight bacterial diseases in the future, such as overprescribing antibiotics.
In our world, as it is today, we cannot afford to underestimate the impact of disease causing microbes like K. pneumoniae. If we do not marshal our forces and coordinate our efforts, even one bug can lead many microbial lives and end many human ones. Looking beyond governmental efforts and expert interventions, every concerned member of the public can help in this situation. Even as a patient or a caregiver there are important things you can do, such as taking care to fully complete prescribed courses of antibiotics. Not completing the full course of prescribed antibiotics is just as bad as taking such medicines without a prescription.
Other beneficial choices you can make are not sharing your leftover antibiotics with others, as well as maintaining personal and interpersonal hygiene. Coming together at the societal and global level, even these seemingly minor individual actions can have significant positive effects. Against microbial diseases, as with many other problems, we must all fight together to secure a better future for humanity.
While the original sources for all the information in this article are present as hyperlinks within the body of the text, the authors would like to acknowledge that Wikipedia was useful in tracing the sources for some of the points referred to in this article and for background information.
This article was edited by Abhishek Chari.
Ashwin Uday and Koyel Ray are undergraduate students at Acharya Narendra Dev College (ANDC), New Delhi, studying in the Department of Biomedical Sciences (BMS). This article was written as part of online training in science writing provided by IndSciComm.