# RKS: SUPERBUGS (IV) - The Real Reasons vs Perceived Causes

  

# RKS: SUPERBUGS (IV)

THE REAL REASONS vs PERCEIVED CAUSES

RKS / 2024-2025 / Ser 6 / Blog 6

1st March 2025

BUGS BECOME SUPERBUGS

THANKS TO DOCTORS & PATIENTS & DRUG REGULATORS

Dear Reader,

Antimicrobials have revolutionized patient cure prospects. On an average, 30-50% of patients visiting a general practitioner are prescribed an antibiotic. Why?

There are 3 reasons why someone, who is apparently healthy, thinks he / she is unwell enough to visit a doctor:

1. Headache
2. Cold and cough
3. Loose motions 

Two of the above 3 are caused by infections. Then how can antimicrobials be blamed for being unnecessarily prescribed by the medical professionals? And why would Drs prescribe antibiotics unnecessarily if their intent is to treat patients based on their clinical evaluation and diagnostic skills? If one suspects the abilities of their doctor to best treat their disease, the perception is subjective and there is every freedom for the patient to switch the expert as in any other profession - be it carpenter, car mechanic, gym trainer, etc.

The suspicion that doctors are overprescribing antimicrobials, especially fixed combination drugs (FDCs), is completely flawed. One of my friend and close buddy was not given a more effective antibiotic in combination timely and, hence, for a simple otherwise easily curable infection in an outpatient department (OPD), he landed up in Intensive Care Unit (ICU) in a critical condition with septicemia (bacteria in blood). Mind you, for the infection of the body part that he suffered, there is no published evidence of any even one single patient requiring hospitalization on account of septicemia across the globe!! If my friend were to have an adverse outcome I would have demolished that doctor for underprescribing antimicrobials for sure. A case to ponder indeed. 

Under the garb of creating resistant species of bacteria, the fact that antimicrobials are to be given with full dose or in combination, to overpower the culprit pathogens should not be overlooked.

ANTIMICROBIAL RESISTANCE - THE GENESIS

AntiMicrobial Resistance (AMR) was first reported in 1940s. (Koya SF et al. Lancet 2022; 4: 100025) It is a worldwide concern and the direct impact is because of more prescriptions / consumption of these antibiotics, albeit inappropriately. Why antimicrobials are being more used is likely because of: 

[Singh SK et al. J Hosp Infection 2019; 103(3): 280-283]

• Rising incomes leading to affordability of even the new more expensive antimicrobials.
• Health insurance indulgence by more and more of the population resulting in unrestrictive antibacterial consuming.
• Increasing burden of infections globally.

More than one-third increase in antimicrobial prescribing has been documented over a decade and one-third of this increased pattern has been reported in BRICS (Brazil, Russia, India, China and South Africa) countries. 

[Singh SK et al. J Hosp Infection 2019; 103(3): 280-283]

Graph: Export of antibiotics from India (1996-2019).

Data from Government of India (Soc Sci Med 2022; 312: 115386)

It is but apparent that infectious diseases are a concern globally and there is a dire need to combat these with antibiotics including combinations, if necessary, with no holds barred. 

RESISTANT BACTERIA

WHY BACTERIA BECOME RESISTANT?

The risk of bacterial resistance is always higher when the infection is polymicrobial wherein more than one bacterial species are implicated. The 3 most common bacterial infections in India include respiratory tract infection (RTI), diarrhea and urinary tract infection (UTI). 

1. RTI: In pneumonia, a type of Lower RTI (LRTI), there is always possibility of atypical pathogens complicating this Streptococci (Strep.) pneumonia - caused disease. 
2. DIARRHEA: The most frequently identified organisms causing bacterial diarrhea are Escherichia coli (E. coli) (most common worldwide), Shigella spp., Salmonella spp.,  Yersinia spp. and Clostridium spp. 
3. UTI: In UTI the most prevalent bacterial pathogen in India is E. coli but co-existing other common pathogens include Klebsiella pneumoniae (K. pneumoniae) Proteus mirabilis and Pseudomonas (P.) aeruginosa.

The efficacy of an antimicrobial is USUALLY assessed on basis of MIC90 meaning the minimum inhibitory concentration of the drug required at the site of infection to inhibit multiplication of 90% of a particular bacterial species. The challenges therefore are:

• First of all, no single antimicrobial can ever be effective against all the bacterial species and there is thus a constraint in treating common infections which by and large are polymicrobial in etiology.
• Any one antibiotic prescribed does not possess equivalent efficacy in curtailing all the bacterial species. Hence, the dose should be such that the concentrations achieved is higher than the highest known MIC90 from amongst the infecting bacteria in any infection.
• There are no tests available to correlate the susceptibility of the infecting bacteria AT INFECTION SITES with TISSUE CONCENTRATIONS of the antimicrobial. The Culture and Sensitivity (C&S) test merely correlates the ability of the antimicrobial to eliminate a pathogen based on BLOOD levels achieved!
• To add to the wove, there are two types of antimicrobials: one that kills the bacteria (bactericidal) and another that merely inhibits growth (bacteriostatic); bacteriostatic agents rely on the body's defences to eliminate the pathogen after they have been castrated. The bactericidal activity of bactericidal antibiotics is measured as MBC90 which means minimum bactericidal concentration required to kill 90% of the infecting bacteria. Sadly, no estimation of MIC90 / MBC90 possible of tissue levels in routine practice, and neither there is even consideration of MBC as an important parameter in C/S testing which is the basis of antimicrobial prescribing. 

Summarising, antimicrobials prescribed should ONLY be bactericidal since all bacteria at the infection site are then KILLED and not just stunned. Also, since most infections have a diverse pathogenic population, the antibiotic, or the FDC of the same, opted must ensure each and every bacteria are dealt the death blow. 

Since the bacteria are never mostly 100% killed, the survivors scheme mechanisms to develop resistance for defending themselves against future onslaught by the same antimicrobial/s.

(https://www.cdc.gov/antimicrobial-resistance/about/index.html)

FACTORS RESPONSIBLE FOR INCULCATING RESISTANCE IN PATHOGENS

Why does such a scenario of an 'incomplete' elimination of pathogens emerge?

Surprisingly, there are not only medical reasons for bacteria developing resistance but also the doctors (Dr.), patients and, now, even the regulators are to be blamed for having contributed to the same in equal measure. Some of these can be deduced as:

• Opting for a bacteriostatic rather than a bactericidal drug.
• One single antimicrobial is employed for a polymicrobial infection.
• Dr. writes less than therapeutic doses of an antibiotic which can kill (hopefully) maybe only 30% or 50% or 70% of the susceptible bacteria. 
• The prescription is not given for the full duration of antimicrobial needed to kill all the infecting pathogens.
• Patient in his / her ignorance / 'smartness' opts or decides unilaterally to consume the prescribed antibiotic for less than the duration required or defaults on the frequency of intake feigning forgetfulness or blaming the Dr. as giving too many doses.
• Patient's perception makes him / her take consume half the dose prescribed under the belief that the full 'amount' of the antibiotic is 'too strong' for the body.
• The regulators in India, with support from lesser-clinically oriented and academic-minded medical professionals, keep on questioning the use of FDC of antimicrobials and have been rampantly banning these time and again since the last decade.

It is but a compulsive need to clarify why regulators are to be blamed for banning FDCs of antimicrobials - the same being an unscientific exercise. Banning combination of 2 antibiotics for the same infection in a patient in meaningless since:

• The treating doctor can write the two antimicrobials as two separate pills for the same infection to the same patient in one prescription for which there are no curbs and there never could be.
• The chemist is free to dispense two antimicrobials for a single patient on a particular day in the same bill against his / her name.

It is Drs. prerogative to write for a particular patient 2 or more antimicrobials simultaneously depending upon his knowledge of the being treated infection's causative pathogens, past clinical experiences and patient profile / attributes. How could banning FDC prevent the same? In fact, one judge during the course of proceeding in Supreme Court (SC) of India even asked the regulator' legal counsel as to how would it be any different if one were to take FDC of 2 antibiotic in a single pill or pop the 2 antibiotics as two separate pills at the very same time and swallow? 

FDCs

FDCs are a hallmark of the Indian drug market since 40% of the value is because of combination products. India is the leader in introducing novel RATIONAL combinations of 2 or more drugs. The combination of antimicrobials is not a just a 'khichdi' as has been publicised or perceived but is scientific and legit and as per international guiding norms for combining any 2 or more drugs. The principles for the FDC formulating are:

• The 2 (or more) drugs are needed for a particular indication for which they are to be prescribed.
• The 2 (or more) drugs have differing actions so as a provide a synergistic end-effect.
• The 2 (or more) drugs are usually never from the same chemical class or sub-category.
• The 2 (or more) drugs do not interact in any pill when formulated (during the manufacturing process).
• The 2 (or more) drugs when simultaneously consumed do not interact inside the body as well.
• The non-interference of 2 (or more) drugs, when combined, with each other has been documented by means of blood level estimations (bioequivalence studies).
• That the 2 (or more) drugs do exert a greater patient benefit in terms of beneficial outcome for an illness is also proven by means of clinical trials conducted.
• Lastly, the 2 (or more) drugs have matching profiles such that their administration frequencies are the same and not out of sync - if 2 antibiotics combined BOTH individually are required to be given 2 times a day and the FDC is also indicated as twice daily. 

The regulators, by virtue of blindfolded banning of rationalized use of antimicrobial combination, is nothing but a futile effort to curb AMR and additionally subject the patient to more inconvenience since he / she has to take 2 or more pills instead of a single tablet / capsule at a time. Why the banning of a rational and already approved FDC, as per the above listed parameters, is even potentially harmful is because:

• Adherence to full course of antimicrobials can decline by 10% because of 2 tablets / capsules required to be consumed at a time instead of a single pill.
• Adherence to full course of antimicrobials can decline by a further 5% because of 3 tablets / capsules required to be consumed at a time instead of a single pill.

[Clin Therapeutics 2001; 23(8): 1296-1310]

FDCs of antibiotics can enhance compliance in patients to therapy by 1.3 times! (Front Pharmacol 2023; 14: 1-10; | https://doi.org/10.3389/fphar.2023.1156081) A meta-analysis of 9 studies (Am J Med 2007; 120: 713-719) considering over 20,000 patients cumulatively reported: “Fixed-dose combination regimens reduce the risk of non-compliance by 24%-26% compared to free-drug regimens.”

MINIMIZING ANTIMICROBIAL RESISTANCE

In 2017, the World Health Organization (WHO) developed the Access, Watch and Reserve (AWaRe) classification system of antimicrobials as part of AMR. This was a great milestone in the fight against AMR because a more objective, user-friendly tool became available to organize the antibiotics. The WHO AWaRe framework categorizes antimicrobials according to their spectrum of activity and potential to develop resistance. In India, the AWaRe classification when applied the antimicrobials consumed, the prescribing pattern has been captured as:

(Koya SF et al. Lancet 2022; 4: 100025)

• Access: SF, 17.7%; FDC, 45.1%
• Watch: SF, 80.7%; FDC, 4.6%
• Reserve: SF, 1.6%, FDC, 0.001%
• Discouraged: SF, 0%; FDC, 48.5%
• Not classified: SF, 0%; FDC, 1.7%

Of the antimicrobials evaluated as above, 54.3% are single formulations (SF) and 45.7% are FDCs marketed in India. The global goal is to have 60% of antimicrobials consumed in 'Access' group. In India, linezolid is only one of the few most widely advocated antibiotic from the 'Reserve' category of AWaRe classification. As far as rampant use of antibiotics from 'Watch' group is concerned, there should be a need to understand the need behind prescribing the same and not turn a Nelson's eye to the real life 'infection' situations being encountered by medical professionals in private and institutional practice in India.

WHY ARE 'AWaRe' RESERVE / WATCH DRUGS USED FREQUENTLY IN INDIA?

India has been always under the firing squad for using higher antibiotics and hence being considered a culprit in fostering drug resistance. But the regulators, instead of probing into the reasons why Indian Drs. prefer the prescribed antibiotics, undeterred by the classification as per AWaRe, unrealistic curbs are being imposed and further being planned on the antimicrobial's advocacy by medical professionals.

WHY 'RESERVE' DRUG USED FREQUENTLY IN INDIA?

Linezolid, the most common 'Reserve' drug prescribed in India, is the antibiotic of choice for resistant Staphylococcus (S.) aureus infections. The prevalence of the latter in India is 37% according to the Indian Council of Medical Research (ICMR) and S. aureus can cause OPD as well as infections in hospitalized patients. On a yearly basis, 144 per 1,00,00 patients in India, vs 20-50 per 1,00,000 population globally, develop S. aureus bacteremia (pathogens enter blood in large numbers from an infected site) (SAB). [Int J Infect Dis 2013; 17(11): e1051-e1055; Clin Microbiol Rev 2012; 25(2): 362-386]

Since, there is a larger staphylococcal burden there is dire need to employ linezolid - one of the most effective antibiotic for S. aureus. It is the wide prescribing of this agent that has kept the mortality on account of SAB in India (27%) similar to global incidence (25%). [Infect Dis Res Treat 2020; 13: https://doi.org/10.1177/1178633720970569; Mol Med 2020; 117(4): 341-345; JAMA 2002; The Lancet 2022; 22: 100438]

WHY 'WATCH' DRUGS USED FREQUENTLY IN INDIA?

Azithromycin, ceftriaxone, amikacin, co-amoxiclav, doxycycline and cefixime are among the top ten antibiotics that have consumed across the ten hospital sites studied in the last five years in India. [Surveillance of Antimicrobial Consumption under  National Antimicrobial Consumption Network (NAC-NET). National Programme on AMR Containment; National Centre for Disease Control (NCDC), Directorate General of Health Services. July 2023 pp 26-28] Of these, the antibiotics classified under the 'Watch' category of WHO's AWaRe are: [WHO releases the 2019 AWaRe Classification Antibiotics. https://www.who.int/news/item/01-10-2019-whoreleases-the-2019-aware-classification-antibiotics. Accessed on 29th December 2024]

1. Azithromycin: Guidelines recommend macrolides (azithromycin) and penicillins as preferred antibiotics for the treatment of Group A streptococci-mediated upper RTIs (URTIs). (Infect Drug Resist 2025;18: 523-531)
2. Ceftriaxone: Infectious Diseases Society of America (IDSA) treatment guidelines for community-acquired pneumonia recommend ceftriaxone as a first-line empiric treatment option. [J Pharm Technol 2017; 33(6): 215-218]
3. Cefixime: Many authorities highly recommend cefixime as a first-line antibiotic in overcoming cases of resistance to URTI and LRTI, especially against the pathogens Strep. pneumoniae, Strep. pyogenes, Hemophilus influenza (H. influenzae) and Moraxella catarrhalis. (Sci Reports 2021; 11: 18461)

When the incidence of acute respiratory tract infections (both URTI and LRTI) is 50-60% and the population of India is more than 140 crores, how can one blame Drs. for the widespread prescribing of azithromycin, cefixime and ceftriaxone (the latter in hospitalized patients) in India and label the same as overuse of antibiotics? It defies sheer logic when these very 3 antibiotics have been recommended as first-line or preferred drugs by various guidelines itself! It needs to be emphasized here that 20-40% of patients hospitalized are because of acute RTI. Maybe the judicious and free choice to prescribe the recommended azithromycin, cefixime and other antimicrobials, even though from the 'Watch' category, has reined in the incidence of hospitalizations of RTI patients.

WHY NOT ADVOCATE MULTIPLE ANTIBIOTICS - FDCs FOR CURING INFECTIONS ASSUREDLY?

FDCs have a definite curative role to play in infections:

• SINGLE PATHOGEN INFECTIONS: In infections wherein a single bacteria is the culprit combining 2 antibiotics with 2 different mechanisms of action will provide an assured killing of most bacteria at the infection site - much more than that could have been achieved with a single agent. The need for an FDC is especially in those cases wherein the bacteria are, or suspected to have become, resistant such that single drug can only partially cure (kill few unresistant bacteria but not the resistant species) thereby risking the surviving pathogens to develop resistance techniques to fight against future doses of the same antimicrobial.
• POLYMICROBIAL INFECTIONS: 30-50% of infections in India are because of attack by multiple species of bacteria simultaneously. No antibiotic, no matter how much broad spectrum, can claim equivalent high effective eliminative action against ALL pathogens. Thus, since different antimicrobial are more effective against a single or few particular species, judicious combinations of antibiotics (as FDCs) can be prescribed such that best possible complete destruction of pathogenic bacterial flora is realized in a polymicrobial infection.

Contrary, to widespread perceptions and (erroneous) reporting, FDCs of antibiotics, instead of contributing to development of AMR, actually will prevent the same since survival chances of bacteria will be close to zero and hence there is little risk, if any, of allowing resistance to be developed.

CONCLUSIONS

The out-of-patient (OOP) expenditure of an Indian is 36% for infectious diseases out of the total health spent. The prevalence of infectious diseases in India had slightly reduced between 2004 and 2014 but it still constitutes a public challenge. [Ram B & Thakur R. Frontiers in Public Health 2022; 10: Article 901276] it is on account of the incidence of infections in India, the country is the largest consumer of antibiotics globally in terms of absolute volume. [Koya SF et al. JAC-Antimicrobial Resistance 2022; 4(5): dlac112]

Along with widespread need and prescribing of antibiotics, accompany the risk of developing AMR.

Fig: Drug Resistance Index (DRI) global map.

The culprits for AMR are: [Mayo Clin Proc 2011; 86(4): 304-314]

1. Drs.
2. Patients
3. Healthcare regulators

The attempt by Drs. is to cure infections and save lives and the vision of regulators and the belief of patients is to minimize intake of antimicrobials for God knows what gains when the sufferer is having an infection and there is hesitancy to initiate measures to get rid of the same!!

DOCTORS by and large want to kill all the bacteria so he / she employs the best effective antimicrobial or a FDC of antibiotics. He can be guilty of contributing to AMR on few counts:

• Dr. knowingly or unknowingly prescribes lesser than the therapeutically required dose of an antibiotic.
• Dr. instructs the patient to take antimicrobial therapy for an insufficient period - for example 5-7 days is the treatment duration for most infections; for UTI it is 7-14 days and for bacteremia and certain other infections the same is 10-14 days. The caveat is to continue the antimicrobial/s for 48-72 hours more till after the fever has subsided. [J Assoc Med Microbiol Infect Dis Can. 2021; 6(3): 181-197]

PATIENTS defy Drs. by firstly avoiding taking an antibiotic (and thereby exposing themselves to the possibility of hospitalization). Even worse is the patient's ignorance directly encouraging the bugs to become resistant by:

• Taking the antibiotic less frequently than recommended.
• Stopping therapy before the course is completed sans any medical advice!

Both the above 'misdeeds' of the patient leads to:

• Allowing many bacteria to escape the arsenal unleashed upon them.
• Encourage the surviving bacteria to do research and development (R&D) and thereby empower themselves with power to resist the same antibiotic in future. 

Development of AMR is thus facilitated by patients themselves and yet there is questioning in lay press of the medical professionals practice habits, and blaming Drs. treating infections to have been responsible for the glaring AMR catastrophe prevalent in India!

REGULATORS, not to be left behind, lend fuel to the fire. They question FDCs of antibiotics and blame these for the high incidence of AMR! This is contrary to what is desirable in tackling an infection fully. If combinations are taboo then why would hospitalized patients receive 2-, 3- or even 4 (or more) antimicrobials simultaneously to cure them in an effort to ensure their surviving an episode of serious infection.

• 40% of hospitalized patients in India required 2 antibiotics.
• 15% of hospitalized patients in India required 3 antibiotics.
• 3% of hospitalized patients in India required 4 or more antibiotics.

[Infect Prev Pract 2022; 4(4): 100253]

The 2024 WHO Bacterial Priority Pathogens List (WHO BPPL) categorized the pathogens into critical, high and medium priority groups to inform R&D and public health interventions. The list includes 24 pathogens belonging to 15 families: 

1. CRITICAL PRIORITY: Acinetobacter baumannii (A. baumannii), Enterobacteriaceae species (spp.), Mycobacterium (Myco.) tuberculosis
2. HIGH PRIORITY: P. aeruginosa), S. aureus, Enterococcus fecium, Neisseria gonorrhea (N. gonorrhea), Salmonella spp., Shigella spp.
3. MEDIUM PRIORITY:  Group A & B streptococci, Strep. pneumoniae, H. influenzae  

(https://www.who.int/news/item/17-05-2024-who-updates-list-of-drug-resistant-bacteria-most-threatening-to-human-health)

Although India has a very large pool of drug-resistant bacteria including WHO BPPL, the mortality rate with respect to AMR is 60th in rank compared with 204 countries. With respect to age-standardized mortality rates, India ranks 3rd lowest amongst the South Asian countries (Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, Sri Lanka, Afghanistan) and 145th in global ranking (204 countries). This is on account of not over use but aggressive employing of antimicrobials, including FDCs, for even suspected bacterial pathogens in any disease.

Bearing in mind that hospitalized patients require multiple antimicrobials simultaneously, how can the regulators question FDCs of antibiotics being prescribed by doctors in day-to-day practice. Are we to foster increased risk of hospitalization by imposing prescribing of less than effective therapies for infections. Also there is a glaring concern of AMR before the country just because the bacteria were not completely wiped out during an infection and survivors were encouraged. The 'minorities' populace of escaped bacteria then progressed to become lethal SUPERBUGS and scientists across the globe are running helter-skelter to synthesize and develop more and more effective antimicrobials. If the otherwise never-ending race with the devil (superbugs) is to be brought to a screeching halt, the following Good Antimicrobial Prescribing Practice (GAPP) must be introduced and adhered and even policed (by regulators):

• Antimicrobials prescribed must be bactericidal.
• Full dose of antimicrobial must be prescribed by Dr.
• The antimicrobial frequency recommended must be according to prescribing information and not on whims and fancies of Dr.
• Full therapy duration according to the infection must be advocated.
• Patients must be educated via social media, on similar lines as expiry date awareness being propagated, to take the antimicrobial as per frequency and duration such as been prescribed by the treating Dr. or to face risk of admission in hospitals.
• There are recommendations being mooted that General Practitioners in India should curb antimicrobial prescriptions to less than 27% of the drugs advocated vs 57% as in current practice. [J Comprehensive Health 2023; 12(1): 44-49; J Hosp Infect 2019; 103(3): 280-283]
• Regulators must be guided by practising Drs. such that they do not rampantly ban FDCs of antibiotics. Instead the regulators must ensure that 'matching & synergistic' combos are encouraged especially for infections that could be challenging and possibly life-threatening if not quick-enough eliminated.

Dr. Rohini Kelkar, Head - Microbiology Department of TATA Memorial Hospital (Mumbai, India) has stated [Times Of India (Times City) Mumbai; Friday, May 2, 2014; pp 16]: "Appropriate drug combinations hold the key to beat drug resistance. It is preferred to a single antibiotic regimen." 

The mission of treating infections is to cure infections ('completely') and the mission should be to prevent development of AMR and create SUPERBUGS. If both these objectives are met, then only ...

 “न रहेगा बांस न बजेगी बाँसुरी”.

DR R K SANGHAVI

Prophesied Enabler

Experience & Expertise: Clinician & Healthcare Industry Adviser

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