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Starting this year 18-24 November will annually be observed as the World Antimicrobial Awareness Week, according to a joint decision by the Food and Agriculture Organization of the United Nations (FAO), the World Organisation for Animal Health (OIE) and the World Health Organization (WHO). These three agencies—FAO, OIE and WHO—on 20 November 2020 also launched the One Health Global Leaders Group on Antimicrobial Resistance where India also has representation.

To mark the first World Antimicrobial Awareness Week, we bring to you an article on antibiotic resistance, or bacteria becoming resistant to certain drugs. The danger of antibiotic resistance was apparent to scientists like Sir Alexander Fleming—who discovered Penicillin by a happy mistake in his lab—as early as the 1950s.

Read on to know all about antibiotic resistance:

  1. What is antibiotic resistance?
  2. How does antibiotic resistance develop?
  3. Major causes of antibiotic resistance
  4. Prevention of antibiotic resistance
  5. Common antibiotic-resistant bacteria
  6. Current strategies to treat antibiotic resistant infections
Doctors for What is antibiotic resistance?

Antibiotics are life-saving medicines that fight bacterial infections. They do not have any action against viruses, fungi or other disease-causing organisms. Based on their mechanism of action—that is, how they stop (bacteriostatic) or kill (bactericidal) bacteria—they are classified into different categories. Improper and excessive usage of antibiotics coupled with poor infection prevention practices have caused antibiotic-resistant bacteria to emerge.

How does antibiotic-resistance occur?

Antibiotic resistance can occur:

  • When you take the wrong antibiotics
  • When you take the wrong dosage of antibiotics
  • When you don't complete the antibiotic course
  • When you complete the course but don't see your doctor at the end of the prescription period, to check if the infection has cleared or if you need to take the medicines for a little while longer
  • When you don't need antibiotics but take them anyway (like for a viral infection)

In many of these situations, the drug-sensitive bacteria are neutralised but those bacteria that resist the drug's action persist, grow and multiply.

Furthermore, the bacteria that survive can transfer this resistant trait to other drug-sensitive bacteria, making them resistant too.

Why is antibiotic-resistance such a big problem?

Antibiotic-resistant bacteria cause infections that are difficult or nearly impossible to treat. Each year, nearly seven lakh people worldwide die of such infections and this number is estimated to reach 10 million by 2050. It is, therefore, important to understand how antibiotic-resistance can be prevented and controlled and what role individuals can play.

Before we go further into antibiotic-resistance and its implications, let's take a quick look through what are antibiotics:

Antimicrobial drugs are medicines that either stop the growth of or kill disease-causing organisms like bacteria, viruses, fungi among others. Antibiotics are that subset of antimicrobials that act specifically on bacteria. These drugs have no action on organisms other than bacteria (like flu causing viruses for which a separate kind of medicine, antivirals, are needed).

Since their discovery in the early twentieth century and first widespread use during the Second World War, antibiotics have revolutionised healthcare. With the advent of the antibiotic era, infectious diseases that earlier nearly always resulted in death have been reduced to few-day long illnesses.

Antibiotics often work by inhibiting the enzymes that bacteria need to grow (bacteriostatic) and survive (bactericidal). Whereas narrow-spectrum antibiotics work on a limited range of bacteria, broad-spectrum ones work on a larger selection of bacteria. Usually, broad-spectrum antibiotics are initiated on clinical suspicion of bacterial infection and are subsequently replaced with bacteria-specific drug after culture and sensitivity studies.

Based on their mechanism of action, antibiotics are grouped under the following classes:

Cell wall synthesis inhibition:

  • Beta-lactams: A substance called peptidoglycan which is present in the bacteria’s protective cell wall is prevented from forming adequate bonds (cross-linking) leaving the bacteria incapable of surviving. These bactericidal (bacteria-killing) drugs include penicillins (amoxicillin, ampicillin, piperacillin, etc.), cephalosporins (consists of five generations; ceftriaxone belongs to this sub-class), carbapenems (imipenem, meropenem, etc.) and monobactams (aztreonam). These drugs have a beta-lactam ring structure that confers strength and integrity on them.
  • Glycopeptides: Another bactericidal category of drugs that includes the commonly used vancomycin, it stops the synthesis of cell wall peptidoglycan altogether in bacteria.

Protein synthesis inhibition (30S ribosome subunit)

  • Aminoglycosides: Drugs like streptomycin, amikacin, gentamicin, neomycin and tobramycin block a portion of the ribosome, preventing bacterial protein production. This has a bactericidal action.
  • Tetracyclines: Tetracycline and doxycycline, amongst others, act on a bacterial enzyme and reduce protein manufacturing. These slow down bacterial growth (bacteriostatic).

Protein synthesis inhibition (50S ribosome subunit)

  • Macrolides: Erythromycin, clarithromycin and azithromycin bind with a specific site of the ribosome and reduce the creation of new bacterial protein, thereby hampering its growth (bacteriostatic).
  • Lincosamides: Clindamycin, by a similar process of protein synthesis inhibition, reduces bacterial proliferation (is bacteriostatic).

DNA gyrase inhibition

  • Fluoroquinolones: drugs like ciprofloxacin, ofloxacin and other similar-sounding medicines block the action of a bacterial enzyme called DNA gyrase, which is needed to uncoil DNA before protein synthesis can occur.

Folic acid synthesis reduction/prevention

  • Sulphonamides: Trimethoprim and sulphamethoxazole are examples of such drugs and are often given together in combined form, called cotrimoxazole. These too interfere with DNA and affect bacterial survival and replication.

With continued use of antibiotics, bacteria, on which these drugs act, adapt and develop mutations (changes occur in their genetic material) that help them counter bacteriostatic and bactericidal action.

For example, many bacteria develop genetic changes that help them produce beta-lactamase enzymes which cause the ring structure of beta-lactams to disintegrate, rendering the drugs ineffective.

While mutations in any organism are natural and expected over the course of time, due to inappropriate and excessive use of antibiotics (a common example being the use of antibiotics in viral infections) has accelerated this process.

The production of newer antibiotics that can tackle the new antibiotic-resistant "superbugs", is a very difficult task which hasn't been keeping pace with the appearance of new resistant strains.

In this situation—with antibiotic-resistant bacteria growing and few new medicines to tackle them—a post-antibiotic era seems imminent. When this happens, this period could be a lot like the pre-antibiotic era when there was no cure for many infectious diseases and thousands died of conditions like the bubonic plague (which is currently curable with antibiotics, if it is detected early enough), but with the added danger of even more lethal bugs.

The biggest causes of antibiotic resistance are:

  • Inappropriate and excessive prescription and usage of antibiotics: Sometimes, due to shared symptoms of viral and bacterial infections (like cold, cough and fever), antibiotics are erroneously used. This unnecessary dosage of antibiotic kills the body’s good bacteria, allowing harmful resistant bacteria to grow unchecked.
  • Failure to complete antibiotic course: Many patients, upon the alleviation of symptoms, presume total recovery and abandon the antibiotic course midway. This leads to incomplete bactericidal action—drug-sensitive bacteria are killed but stronger bacteria persist, grow and proliferate. These antibiotic-resistant bacteria cause infections that are difficult to treat later.
  • Overuse of antibiotics in animal husbandry and fisheries: Antibiotics used to prevent infection in animals being housed in close quarters for the purpose of dairy and poultry farming can give rise to resistant strains of bacteria. Additionally, excessive antibiotics enter the food chain, giving rise to further resistance.
  • Improper infection control in healthcare setups: If proper sanitation measures are not taken in healthcare facilities, multidrug-resistant superbugs can develop and spread from one patient to the next.
  • Poor hygiene and sanitation: In areas with poor standards of sanitation, antibiotic resistance soon emerges due to the constant transmission of bacteria from one individual to another.
  • Lack of development of new antibiotics: It is an uphill task to create new antibiotics that work against resistant bugs. Due to lack of resources, funding and limited knowledge of potent compounds, newer drugs take a long time to develop and come to market.

Having said that, scientists are constantly working on newer medicines like synthetic antibiotics and therapies like gene therapy to get the better of bacterial infections once again.

Although work is being carried out on the creation of new antibiotics and strategies to utilise older ones, a cure for infections caused by antibiotic-resistant bacteria is not guaranteed. Sometimes, when even the most potent antibiotics fail, treating the infection is virtually impossible. Therefore, antibiotic resistance must be prevented from arising and spreading in the first place.

What patients can do:

  • Never use antibiotics without a prescription from a physician
  • Follow healthcare professionals' instructions on when, how and for how long to take antibiotics
  • Do not share or use leftover antibiotics
  • Prevent infections by maintaining proper hygiene, cooking food well and practising safe sex
  • Vaccinate against vaccine-preventable bacterial diseases like tuberculosis, whooping cough (pertussis), tetanus, etc.

What governments can do:

  • Initiate, and continually improve, antimicrobial resistance surveillance programmes
  • Regulate and make available quality antimicrobial drugs
  • Create a standardised protocol for antibiotic use
  • Draw public attention to and increase awareness about antimicrobial resistance by providing easy to understand and accurate information
  • Invest in the development of new antibiotics and diagnostic tools

What healthcare workers can do:

  • Prevent the spread of resistant bugs by properly sanitising hands, facilities and instruments to prevent hospital-acquired (nosocomial) infections
  • Judicious prescription of antibiotics on a case to case basis
  • Report emerging antibiotic-resistant infections to the surveillance programme
  • Explain to patients the importance of correct antibiotic use and good hygiene and sanitation practices

What animal husbandry sector can do:

  • Ensure good sanitation on animal-keeping premises
  • Not give antibiotics preemptively or unnecessarily to animals
  • Vaccinate animals to reduce the need for antibiotics instead

The following are the 10 most common antibiotic-resistant bacteria:

  • Methicillin-resistant Staphylococcus aureus (MRSA): Staphylococcus aureus can cause bone infection (osteomyelitis), lung infection (pneumonia), heart infection (carditis), brain infection (meningitis and encephalitis), skin infection (cellulitis) and urinary tract infections (UTI). Earlier, it was sensitive to beta-lactams like methicillin but has since developed resistance. Now vancomycin and linezolid may be used in complicated infections.
  • Vancomycin-resistant Staphylococcus aureus (VRSA): Vancomycin, which was once a last-line treatment option for staphylococcus infections, too faces bacterial resistance now. Such bacterial strains may be treated with more advanced antibiotics like linezolid or daptomycin.
  • Drug-resistant Streptococcus pneumoniae: While it causes seemingly benign throat and ear infections, it can also cause community-acquired pneumonia (CAP). High-dose beta-lactams (like co-amoxiclav and ceftriaxone) and select fluoroquinolones and macrolides may work.
  • Vancomycin-resistant Enterococcus (VRE): Enterococci bacteria are normally present in the human intestines and female genital tract. Vancomycin-resistant strains might be picked up in healthcare setups and cause urinary tract infections, bloodstream infections or catheter-related infections. Penicillins in combination or advanced drugs like linezolid and daptomycin are treatment options.
  • Multi-drug resistant Pseudomonas aeruginosa: Causes infections in immunocompromised patients. Beta-lactam-beta-lactamase inhibitor combinations (like ceftazidime-avibactam, etc) are effective.
  • Clostridioides difficile: Infection occurs in patients taking antibiotics or having recently completed a course in the hospital. Colonic infection and watery diarrhoea occur. Treatment options include vancomycin.
  • Carbapenem-resistant Enterobacteriaceae (CRE): These include resistant Klebsiella and E.coli. Generally acquired in healthcare settings and are near impossible to treat. Management is decided on a case-by-case basis.
  • Multi-drug resistant Mycobacterium tuberculosis (MDR-TB): Usually tuberculosis bacilli become resistant to rifampicin and isoniazid. Therefore, in place of them, a second-line injectable (amikacin, capreomycin, etc) and a fluoroquinolone (moxifloxacin, etc) are added to the prolonged regime
  • Multi-drug resistant Acinetobacter: Also causes infections in immune-deficient patients and may be treated with polymixin B.
  • Drug-resistant Neisseria gonorrhoea: This pathogen causes the sexually transmitted disease gonorrhoea. Is now treated with dual therapy: one-time injection of ceftriaxone along with oral azithromycin.

Prevention is better than cure. This holds true especially in the case of antimicrobial (and antibiotic) resistance. However, as antibiotic resistance is not a threat of the distant future but an existing and evolving problem, it is essential to combat it with the resources currently available by formulating new strategies. Before starting any antibiotic therapy, culture and antibiotic sensitivity studies must be carried out to prevent treatment failure and development of further resistance.

Antibiotic combination therapy for multi-drug resistant bacterial infections

Combination therapy with antimicrobial drugs is not new. It has been used to treat drug-resistant malaria (caused by a parasite called Falciparum) and also routinely to treat tuberculosis. Whereas a four-drug regimen (consisting of rifampicin, isoniazid, pyrazinamide and ethambutol) are used to treat drug-sensitive mycobacterium tuberculosis infection, in case of multi-drug resistant (MDR-TB) or extensively drug-resistant (XDR-TB) tuberculosis more drugs are added. Combination therapy in antibiotic-resistant infections can work by one of the following mechanisms by:

  • Inhibiting targets in different pathways of bacterial cell survival (as with tuberculosis treatment)
  • Inhibiting different targets in the same pathway of bacterial cell survival (as with sulphamethoxazole-trimethoprim; both blocking different aspects of colic acid synthesis)
  • Inhibiting the same target in different pathways of bacterial cell survival

Beta-lactamase inhibitor drug combination therapy

Beta-lactamase inhibitor drug combination therapy comprises:

  • Beta lactams (like penicillins, cephalosporins, carbapenems and monobactams) useful antibiotics which are routinely administered. Due to their excessive use, anaerobic and gram-negative bacteria, in which their action was once lethal, have developed defence mechanisms (resistance) by which they produce the enzyme beta-lactamase. Beta-lactamase breaks the beta-lactam-ring structure of these drugs leaving them ineffective. Drug compounds called beta-lactamase inhibitors have been produced which when given with beta-lactams, reinstate the efficacy of the latter. Augmentin (also known as co-amoxiclav) is the most popular of such combinations and consists of amoxicillin (beta-lactam penicillin) and clavulanate (beta-lactamase inhibitor).

Antibiotic hybrids

Research is being carried out on chemically bonding two antibiotics, with different mechanisms of action, to create new compounds that will target different pathways of the bacterial cell at the same time. Hybrids with fluoroquinolones, aminoglycosides and tetracyclines appear promising.

Dr. Arun R

Dr. Arun R

Infectious Disease
5 Years of Experience

Dr. Neha Gupta

Dr. Neha Gupta

Infectious Disease
16 Years of Experience

Dr. Lalit Shishara

Dr. Lalit Shishara

Infectious Disease
8 Years of Experience

Dr. Alok Mishra

Dr. Alok Mishra

Infectious Disease
5 Years of Experience

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