Antibiotic Resistance : Where does Bangladesh Stand?

[ This write-up is an effort to address the current problem of antibiotic resistance occurring in Bangladesh and how it is going to affect all of us. The information and statistical data have been collected from scientific papers, websites and daily news sources ]

Antibiotic resistance has become a global phenomenon nowadays, particularly affecting the developing nations where medical rules & regulations are not strictly followed. Countries like Bangladesh are witnessing some of the grave effects of this hard-nut-cracking problem. In recent times, the number of patients diagnosed with antibiotic resistance is increasing at an alarming rate. Not only is it posing a great challenge to the scientists to find a new cure but also putting the future of the world at stake. Superbugs like MRSA, Carbapenem-Resistant Enterobacteriaceae (CRE), Multidrug-Resistant Acinetobacter or Neisseria gonorrhoeae are giving us a red signal about our health sector in the coming days. The rapid pace of antibiotic resistance is occurring due to so many factors, however, needless to say, that a very large portion of it is happening owing to our lack of knowledge and understanding of microbes, antibiotics, and resistance.

This article is, therefore, going to tackle this issue by explaining the science behind it in a simple manner and provide the reader with a basic concept of what antibiotics are, how they become resistant and what are the possible solutions to go for. I begin this article by defining what microbes & antibiotics are, how they are connected and then move on to explaining how resistance occurs against antibiotics and later come its possible solutions.

What are microbes?

Microbe is a microscopic living organism, which may be single-celled or multicellular, and Antibiotic is a medicine (such as penicillin) that inhibits the growth of or kills microorganisms. Although the word ‘microorganism’ includes all bacteria, archaea and most protozoa, nonetheless, as a convention the term ‘antibiotic’ is generally used for treating diseases caused by bacteria. This means, viral diseases cannot be treated with antibiotics because viruses have no cellular structure. The history of antibiotics could be traced back to as far as the ancient times when Greeks and Indians used moulds and other plants to treat infections or the Babylonian doctors who healed the eyes using a mixture of frog bile and sour milk. But, the modern history of antibiotics will always remember Sir Alexander Fleming for his outstanding contribution to discovering enzyme lysozyme and the antibiotic substance penicillin from the fungus Penicillium notatum. Suffice it to say that, with the discovery of Penicillin, antibiotics had been proven to be magic bullets capable of healing bacterial infection until resistance came into play. Antibiotic resistance resulted when bacteria under attack (i.e. selective pressure), learnt to defend itself through various measures to render antibiotics futile.

Now the big question is, how does this happen? How do bacteria fight back and become resistant to antibiotics??

Mechanism of Antibiotic Resistance:

There are several ways bacteria shoot down antibiotics like a toy and scientists are working day and night to unearth the inner mechanisms of this phenomenon. Findings are being published in the journals and several possible ways have already been suggested. Here are some of the ways bacteria use to gain antibiotic resistance.

1. Intrinsic factor: Bacteria have innate ability to resist activity of antimicrobial agent through its inherent structural or functional characteristics. For example, the inability of antibiotics to cross the outer membrane automatically makes Gram-negative bacteria to be intrinsically resistant to many antibiotics (e.g. vancomycin). On top of being intrinsically resistant, bacteria can also acquire resistance to antibiotics via mutations in chromosomal genes and by horizontal gene transfer.

2. Antibiotic Efflux: Bacterial efflux pumps play a significant role in acquiring antibiotic resistance. Efflux pumps can throw antibiotics out of the cell and when overdosed, efflux pumps can confer high levels of resistance to previously clinically useful antibiotics.

3. Poor Penetration of Antibiotics: Gram-negative bacteria are less susceptible to many antibiotics due to their outer membrane structure. However, hydrophilic antibiotics can still cross the outer membrane by diffusing through porin proteins. If porin proteins are somehow replaced with more-selective channels causing poor penetration of agent, resistance can develop.

4. Genetic Mutation of antibiotic target: Most antibiotics specifically bind to their targets with high affinity. A single point mutation in the encoding gene of an antibiotic target can lead to the alteration in the target structure — resistance to antibiotics.

5. Uptake of DNA: Antibiotic resistance can occur by the uptake of DNA from the environment through target protein modification. A classic example of this is penicillin resistance in S. pneumoniae, which is conferred by mosaic penicillin-binding protein (pbp) genes encoding for penicillin-insensitive enzymes. These mosaic alleles have arisen by recombination with DNA from the closely related Streptococcus species.

6. Inactivation of antibiotics by hydrolysis: Enzymes can modify antibiotics. It has been proven to be a major mechanism of antibiotic resistance since the first use of antibiotics. Thousands of enzymes have since been identified that can degrade and modify antibiotics of different classes including β-lactams, aminoglycosides, phenicols, and macrolides. There are also subclasses of enzymes that can also degrade different antibiotics within the same class. For example, penicillins, cephalosporins, clavams, carbapenems, monobactams.

7. Inactivation of antibiotic by transfer of a chemical group: Bacterial enzymes can cause force addition of chemical groups to vulnerable sites on the antibiotic molecule. This phenomenon prevents the antibiotics from binding to its target protein as a result of steric hindrance. Various different chemical groups can be transferred, including acyl, phosphate, and groups.

The Current Scenario of Bangladesh:

The very first problem we face is that there is not enough statistical data available on the systematic drug sensitivity reports against microorganisms, especially on the use of antibiotics. Public health research is emerging, nevertheless, the effort is still not close enough to tackle such a huge problem. An ICDDR,B report reveals that children under two years of age in Dhaka have been found to have taken over 10 antibiotic courses per year on average– an alarmingly high rate compared to global standards. A study conducted by the environmentalist group Poribesh Bachao Andolon showed that about 55.6% of antibiotics prescribed for patients in the capital does not work against the pathogens.

Viewing the issue of AR from the perspective of Bangladesh reveals a desperate situation of dual problems. First, we couldn’t fight off the diseases & infectious pathogens to render them ineffective. Second, we are, at the same time facing drug-resistant microorganisms. Dr. Sanya Tahmina, the director of Disease Control said that antibiotic resistance will be the leading cause of death by 2050. A research conducted by the Pharmaceutical Technology department at the University of Dhaka revealed that the most heavily victimized age group are children between one and four. The result of the misuse of these antibiotics led to longer hospital stays, more physical complications, and higher death rates.

Antibiotics are frequently prescribed for acute respiratory tract infections, acute watery diarrhea, acute trauma, and gastrointestinal symptoms. The most prescribed of them are: 1. ceftriaxone (30.19%) 2. cefixime (18.87%) and 3. amoxycillin (16.98%)

A study report from Dhaka Shishu Hospital revealed that the principal organisms for neonatal sepsis are Klebsiella, Acinatobactor, E coli, coagulase negative staphylococci and Staphylococcus aureus. Over the years, Vibrio cholerae has acquired resistance to a number of antimicrobials including tetracycline. Pseudomonas aeruginosa responsible for wound, urine, ear, throat and other infections were more than 50% resistant to commonly-used antibiotics in Bangladesh, including ciprofloxacin, gentamicin, ceftriaxone, cefixime, and azithromycin.

However, a study published in Biomed Central shows that among the isolated blood-borne bacterial pathogens in Bangladesh, S. Typhi was the most frequent, accounting for 36.9% of the total isolates (14,015 samples). Other frequently isolated pathogens included coagulase-negative Staphylococcus species (21.5%), Pseudomonas species (12.5%), S. Paratyphi A, B (8.9%) and Acinetobacter species (5.1%).

Bloodstream infection (BSI) commonly associated with S. pneumonia is a big threat to preschool children in Bangladesh. About 75% of the BSI cases from S. pneumoniae occurs among children less than five years of age. The pathogen continues to show its resistance against macrolides and β-lactams and a high level of resistance against ciprofloxacin.

Another big public health concern in Bangladesh comes from S.Typhi infection. High level of resistance against the first line of antibiotics poses a major problem in Typhoid treatment. Again, ciprofloxacin shows reduced susceptibility which is probably due to the presence of a mutation in the quinolone resistance-determining region (QRDR) of the gyrA gene.

The worst news perhaps is the presence of a very high level of antibiotic resistance and Multi Drug Resistance (MDR) level among E.coli isolates from environmental samples. In the study conducted by ICDDRB, a much higher level of antibiotic resistance and MDR level (36% MDR in environment samples vs. 62.38% MDR in clinical samples) among BSI causing E. coli strains were identified. Another study also reports that Escherichia coli was resistant in 40% of cases to commonly used antibiotics ceftriaxone, levofloxacin, ciprofloxacin, amoxicillin and ampicillin and 95% resistant to azithromycin.

Factors that contribute to AR:

There are many factors that contribute to AR, however, the main catalysts in my view are (i) ignorance and (ii) laxity in the application of law. Pharmacies and Medicine corners are selling antibiotics without realizing the impact that it can bring to the society. This scenery is clearly reflected in the study showing about 92% medications dispensed by pharmacies were without a prescription. People are to be blamed too for taking no heed as to what they are consuming. There is also a serious tendency in patients to self-medicate based on their experience, not on the basis of scientific knowledge. Poverty-stricken patients tend to forgo the cost of visiting a physician and hence take antibiotics without a prescription.

Sir Alexander Flemming, the discoverer of Penicillin, warned us in his Nobel Speech about the rise of antibiotic resistant organisms that could lead man to death. He said:

“The thoughtless person playing with Penicillin treatment is Morally Responsible for the death of the man who finally succumbs to infections with the Penicillin-resistant organism.“

It is a matter of regret that patients in our country often put Doctors under psychological pressure to prescribe drugs that can make the ‘quickest’ healing. This often results in unnecessary medications and side effects. There is evidence for people taking antibiotics in viral fevers, and in clean post-operative cases.

The prescription procedure in Bangladesh is also not ideal. Antibiotics are readily prescribed prior to identification of the pathogens; its sensitivity to the drug is rarely determined. When antibiotics are prescribed without aiming at the proper target, it generally misfires and then backfires. That is to say, if you screw with nature, nature will screw with you.

Application of unnecessary broad-spectrum antibiotics severely hamper the natural gut microbiota, and a study shows that about 50% of children from rural areas have enteric flora resistant to ampicillin, cotrimoxazole, and streptomycin throughout the year. The deputy project coordinator at icddr,b Dr.Mustafa Mahfuz said: “Using antibiotics in cases where it is not required can apparently cure the children but causes lifelong harm that cannot be reverted.”

There is another huge problem that has nothing to do with the Doctors or patients, but to do with the companies that manufacture these antibiotics. An assay involving 15 brands of ciprofloxacin showed that 47% of samples contained less than the specified amounts of the active ingredient. [United States Pharmacopeia (USP). Drug quality and information program. A review of drug quality in Asia with focus on anti-infective February 2004. (www.uspdqi.org/pubs/other/ANEReview.pdf -accessed 6 January 2011)]

As regrettable as it could be, the poultry and industries are using antibiotics as growth-promoting agents. The prevalence of rampant use of antibiotics in livestock means some bacteria are eventually winning the fight and getting exposed to environmental stresses such as chemical fertilizers, pesticides, other antimicrobial agents. These things are putting bacteria under selective pressure to become resistant to various kinds of bactericidal agents.

What can we do?

The government can actually do many things and we sincerely hope & pray that they do, but let us discuss here the things that we, the ordinary people, can do to mitigate the problem. Perhaps, the most effective measure to be taken is to make people aware of the danger of superbugs. There are nicely represented guidelines and infographics available on WHO website [http://www.who.int/antimicrobial-resistance/en/] that can be used to make campaigns, ads, and posters.

Doctors, Teachers, Medical students, Life Science students and health workers are the people who need to take the lead in the awareness program since it is they who can actually realize the magnitude of the AMR conundrum.

Another thing that we must do is to improve our lifestyle and also reduce the overuse of antibiotics that have become fallible in treatment. Doing so will eventually restore its capability of destroying microbes again. There is substantial proof that this method works. The ICDDR,B study exemplifies the phenomenon through observing an overall decrease in Salmonella species isolation rate and a steady decrease in resistance against ampicillin and cotrimoxazole over the ten year study period. This decrease may be attributed to the improved urban water management system and sanitation practices in Dhaka city in the past few years. If this trend continues, then using the cheaper, first line antibiotics could be used to treat S. Typhi and other infections again.

The bottom line:

The situation is difficult and the bar of antibiotic resistance is skyrocketing. The rise of the superbugs that are multidrug resistant is now a big headache for the scientists who are constantly battling to find out a new cure. Every now and then, new types of mechanisms of resistance are emerging and putting our life & future at stake. Provided that we continue to misuse antibiotics, the world will be severely affected by 2050 when a large number of people will die out of bacterial infections.

Bangladesh, as a model example of developing nations, is facing AMR enigma. But let us not forget that anything that happens here, will also affect other parties. In a world so termed as a global village, one of the crucial problems that strikes us is how quickly pathogens can spread from one part of the world to the other. This rapid dispersion of pathogens can dramatically change the public health status in a country.

So as a concerned citizen, you and I have got to carry some responsibilities on our shoulders. Our effort and actions will not only impact upon the lives of the people of Bangladesh but also the people of the world. We are right now, in the nick time, to revert the situation back to its old days where Antibiotics were successful. Let’s spread the message of awareness and contribute to healing the wounds.

Reference Link:
1. http://apps.who.int/iris/handle/10665/66672
2. https://www.ncbi.nlm.nih.gov/pubmed/25435309
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1610082/
4. https://pdfs.semanticscholar.org/7ebd/071a34156b6558130154918f76aa607f42ea.pdf
5. https://aricjournal.biomedcentral.com/articles/10.1186/s13756-016-0162-z
6. http://www.daily-sun.com/printversion/details/121050/56pc-antibiotics-used-by-city-patients-not-working:-Study
7. http://www.icddrb.org/news-and-events/features?id=20