Dear Editor,

As the spectre of antimicrobial resistance (AMR) looms, urgent measures are needed to safeguard the effectiveness of our antimicrobial arsenal. Recent data from the National Centre for Disease Control (NCDC) underscores the gravity of the situation, with rising resistance rates among Gram-negative organisms to critical antimicrobials like carbapenems and piperacillin-tazobactam. At the same time, colistin remains one of the few remaining options with relatively low resistance rates. The survey revealed colistin resistance to be 0.24 to 0.48 % in contrast to carbapenems and penicillins, where the resistance rate is over 40% for most Gram-negative organisms.1,2

However, even colistin, our last line of defense against certain drug-resistant infections, faces the risk of overuse and consequent development of resistance. Empiric and prophylactic combination therapies involving colistin have raised concerns regarding their potential futility and adverse outcomes, including increased nephrotoxicity and resistance emergence. Certain Indian guidelines such as the ISCCM (Indian Society of Critical Care Medicine) Guideline for Antimicrobial Prescription In Critically Ill Patients suggest the use of Colistin or Polymyxin B, prescribed empirically in patients with febrile neutropenia.3 The over-use of colistin empirically puts us at a high risk of encountering pathogens that are pan-resistant and thereby worsening patient outcomes. We are gradually losing the antimicrobial race, as soon as new drugs such as tigecycline, ceftazidime-avibactam and cefiderocol have entered the market, the pathogens have developed resistance to them, thereby putting us in a crisis scenario.  

To address these challenges, a multifaceted approach is imperative. The deliberations in the Lok Sabha in 2017 and the Central Drugs Standard Control Organization (CDSCO) advisory highlight ongoing efforts to curb the indiscriminate use of antimicrobials and underscores the importance of regulatory measures.4,5 Concurrently, initiatives such as formulary restriction have gained attraction as a promising strategy to preserve the effectiveness of last-resort antimicrobials. Formulary restriction, a strategic approach in antimicrobial stewardship, involves limiting specific antimicrobials to designated indications and necessitating approval from authorized committees before their administration. This method ensures that crucial antimicrobials are preserved for situations without alternative treatment, thereby mitigating the selective pressure contributing to antimicrobial resistance.6

Incorporating formulary restriction into legislative frameworks, supported by antimicrobial stewardship program (AMSP) committees, provides a robust mechanism for oversight and accountability. Reed et al. conducted a study demonstrating the effectiveness of this approach in appropriately guiding the use of selected antimicrobials, underscoring its value in antimicrobial stewardship efforts.6 A recent systematic review and meta-analysis on the effect of antibiotic restriction and prevalence of antimicrobial resistance by Schuts et al. concluded that there was a benefit on the development of resistance to fluoroquinolones and piperacillin-tazobactam by restricted access, however, no discernible benefit could be seen for the carbapenems or third generation cephalosporins.7 Similar findings were also reported by Chatzopoulou et al in their systematic review.8 However, it is important to note that there are no RCTs assessing this effect, thereby the quality of evidence is noted to be low. Formulary restriction is just one of the tricks in the bag of Antimicrobial Stewardship and forming an AMS committee at the hospital level is the first step. Within an effective AMS Program formulary restriction can be introduced first with the reserve group antibiotics and taken forward for adequate implementation.  

The advantages of a restricted formulary are two-fold. One, it decreases the opportunity for initiation of unnecessary and inappropriate antimicrobials, secondly, it will ensure prompt clinical and microbiological assessments prior to starting antimicrobial therapy.

In spite of being an attractive approach to antimicrobial stewardship, implementing formulary restrictions is challenging in itself.  It can lead to confusion as it limits clinicians’ freedom to choose antimicrobials, and obtaining approval from the relevant authority can be cumbersome, especially in emergency situations. It can lead to treatment delays, and limit the autonomy and decision-making skills of the treating physician.

Antimicrobials can be categorized into restricted, limited access, and unrestricted groups, adapting to the WHO AWaRe classification. All antimicrobial prescriptions must be co-signed in duplicate by consultants or unit faculty, not by post-graduate students or residents.

The pharmacy can retain one prescription for record-keeping and provide the second prescription to the Antimicrobial Stewardship (AMS) team. The AMS team can review the antibiotic prescription, offering a second opinion by co-signing it. Continued use of the antimicrobial will require approval from the AMS team, with the duration for obtaining approval varying based on the antimicrobial class.

The WHO Expert Committee on Selection and Use of Essential Medicines 2017 developed the AWaRe classification of antibiotics in 2017. It was targeted to function as a tool for AMS at the global as well as national and local levels. This classification of antimicrobials into the Access, Watch and Reserve groups emphasizes the importance of their appropriate usage. The AWaRe classification is designed to aid in consumption monitoring, optimizing appropriate utilization and combating resistance. Any hospital planning to initiate a formulary restriction practice under the AMS can draw on the WHO AWaRe classification, combining it with the local antibiogram, and providing a list of antimicrobials that can be prescribed unrestricted along with a list of the reserve drugs.9  

As per the NCDC survey on antimicrobial use (NAC-NET), Indian tertiary care hospitals revealed 56 to 64% use of the WHO “Watch” category of drugs, and the trend of using the “reserve ” group is on the rise. Here comes the role of formulary restriction.2 Another study from North India highlighted the prescription of Access Group of antibiotics was only 29% which was worrying in the presence of a systematic review which summarized a prescribing rate of 60% or higher from the Access group.10 The more the reserve group of antibiotics are prescribed, the more is the risk for selection pressure for resistant strains, risk of adverse reactions, rising health care costs, and a challenge to public health. Keeping all this in mind, the formation of a hospital formulary and placing of watch and reserve groups on the restricted list would be imperative in ensuring a successful implementation of AMS programs. 

In conclusion, addressing the complex challenge of Antimicrobial Resistance (AMR) requires a comprehensive approach encompassing formulary restriction, antimicrobial stewardship, and stringent regulatory measures. By implementing these strategies collaboratively, we can safeguard the effectiveness of our antimicrobial arsenal and mitigate the threat of AMR, ensuring better patient outcomes and public health.

CONFLICT OF INTERESTS STATEMENT

The authors declare no conflict of interest.

SOURCE OF FUNDING 

None

AUTHORS’ CONTRIBUTIONS

SB: Writing the draft; Resources
SV: Conceptualization; Supervision; Review & Editing

REFERENCES

1. National Centre for Disease Control (NCDC). National AMR Surveillance Network (NARS-Net) Annual Report 2023. Accessed March 24, 2024. https://ncdc.gov.in/showfile.php?lid=1004

2. National Centre for Disease Control (NCDC). Surveillance of Antimicrobial Consumption under National Antimicrobial Consumption Network (NAC-NET) 2023. Accessed March 24, 2024. https://ncdc.gov.in/WriteReadData/l892s/7810983521691140244.pdf

3. Kulkarni AP, Sengar M, Chinnaswamy G, et al. Indian Antimicrobial Prescription Guidelines in Critically Ill Immunocompromised Patients. Indian J Crit Care Med. 2019;23(Suppl 1):S64-S96. 

4. Ministry of Health and Family Welfare (MoHFW). Government of India. Use of Antibiotics. Accessed March 24, 2024. https://pib.gov.in/PressReleaseIframePage.aspx?PRID=1524806

5. Central Drugs Standard Control Organization (CDSCO). Rational Use of Antibiotics for Limiting Antimicrobial Resistance. Accessed March 24, 2024. https://cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadCircularFile/AMRMiscircular.pdf

6. Reed EE, Stevenson KB, West JE, Bauer KA, Goff DA. Impact of formulary restriction with prior authorization by an antimicrobial stewardship program. Virulence. 2013;4(2):158-62.

7. Schuts EC, Boyd A, Muller AE, Mouton JW, Prins JM. The Effect of Antibiotic Restriction Programs on Prevalence of Antimicrobial Resistance: A Systematic Review and Meta-Analysis. Open Forum Infect Dis. 2021;8(4):ofab070.

8. Chatzopoulou M, Reynolds L. Role of antimicrobial restrictions in bacterial resistance control: a systematic literature review. J Hosp Infect. 2020;104(2):125-36.

9. Mudenda S, Daka V, Matafwali SK. World Health Organization AWaRe framework for antibiotic stewardship: Where are we now and where do we need to go? An expert viewpoint. Antimicrob Steward Healthc Epidemiol. 2023;3(1):e84. 

10. Dixit D, Ranka R, Panda PK. Compliance with the 4Ds of antimicrobial stewardship practice in a tertiary care centre. JAC Antimicrob Resist. 2021;3(3):dlab135.