The potential of 4D’s approach in curbing antimicrobial resistance among bacterial pathogens

ABSTRACT

Introduction

Antibiotics are life-saving drugs but irrational/inappropriate use leads to the emergence of antibiotic-resistant bacterial superbugs, making their treatment extremely challenging. Increasing antimicrobial resistance (AMR) among bacterial pathogens is becoming a serious public health concern globally. If ignorance persists, there would not be any antibiotics available to treat even a common bacterial infection in future.

Area covered

This article intends to collate and discuss the potential of 4D’s (right Drug, Dose, Duration, and De-escalation of therapy) approach to tackle the emerging problem of AMR. For this, we searched PubMed, Google Scholar, Medline, and clinicaltrials.gov databases primarily using keywords ‘optimal antibiotic therapy,’ ‘antimicrobial resistance,’ ‘higher versus lower dose antibiotic treatment,’ ‘shorter versus longer duration antibiotic treatment,’ ‘de-escalation study’, and ‘antimicrobial stewardship measures’ and based on the findings, form and expressed our opinion.

Expert opinion

More efforts are needed for developing diagnostics for rapid, accurate, point-of-care, and cost-effective pathogen identification and antimicrobial susceptibility testing (AST) to facilitate rational use of antibiotics. Current dosing and duration of therapies also need to be redefined to maximize their impact. Furthermore, de-escalation approaches should be developed and encouraged in the clinic. This altogether will minimize selection pressure on the pathogens and reduce emergence of AMR.

Graphical Abstract

KEYWORDS:

• Microbial drug resistance
• antimicrobial stewardship
• optimal antibiotic therapy
• right drug
• dose
• duration and de-escalation
• antimicrobial susceptibility testing

Article highlights

• Rapidly emerging antibiotic-resistant bacterial superbugs are becoming a global threat; whereas the rate of new antibiotic development is very slow. Hence, the world may soon enter into the post-antibiotic era where even a common infection may be life threatening.

• To save the existing last resort of antibiotics, rational drug use (RDU), which requires 1) accurate diagnosis, 2) regulated antimicrobial dispensing, and 3) right 4D’s (Drug, Dose, Duration and De-escalation of therapy), may be an optimal approach.

• Rapid, accurate, non/minimally-invasive, point-of-care and cost-effective diagnostics for pathogen identification and AST may help in choosing the right drug. However, no such diagnostic is currently available and this contributes to the inappropriate use of antibiotics.

• Clinical studies have demonstrated that an optimal dose for a shorter duration can also be similarly efficacious as a higher dose for a longer duration. However, such limited studies have merely been able to impact the current treatment practices. More clinical trials and united efforts are required to redefine the treatment approaches for current clinical scenarios.

• Antibiotic de-escalation (i.e. use of narrow-spectrum antibiotics, promoting monotherapy and using antibiotic cycling) may help in reducing the selection pressure on bacterial pathogens and hence the emergence of AMR. However, more clinical evidence is required for the development of such approaches.

• Awareness, educational programs, and a worldwide policy may be developed and implemented to maximize the benefits of the 4D approach to combat the problem of AMR.

Acknowledgments

We are grateful to Prof. Pramod Kumar Garg (Executive Director), Mr. M.V. Santo (Head Administration), Shrikant Kumar (Technical officer-MCTR), Shailesh Kumar and Manoj Kumar (Lab Technicians-MCTR) of Translational Health Science and Technology Institute Faridabad, India for their support.

Abbreviations

4D	=	Right Drug, Dose and Duration of therapy, and the De-escalation
AMR	=	Antimicrobial-resistant
CARAT	=	Council for Appropriate and Rational Antibiotic Therapy
KPC	=	Carbapenem-resistant Klebsiella pneumoniae
MRSA	=	Methicillin-resistant Staphylococcus aureus
CD	=	Clostridioides difficile
RDU	=	Rational Drug Use
AST	=	Antimicrobial Susceptibility Testing
PK	=	Pharmacokinetic
PD	=	Pharmacodynamic
AI	=	Artificial intelligence
MDR	=	Multi drug resistant
ICU	=	Intensive Care Unit
PCR	=	Polymerase Chain Reaction
LFA	=	Lateral Flow Assays
NAAT	=	Nucleic Acid Amplification Test
MALDI-TOF	=	Matrix Assisted Laser Desorption Ionization Time of Flight
MIC	=	Minimum Inhibitory Concentration
ADME	=	Absorption, Distribution, Metabolism and Excretion.
UTI	=	Urinary tract infection
CAP	=	Community Acquired Pneumonia
DSS	=	Decision Support Systems
EMR	=	Electronic Medical Records
WAAW	=	World Antimicrobial Awareness Week
WHO	=	World Health Organization
POC	=	Point of Care
ESBL	=	Extended spectrum beta-lactamase

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or mending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors have substantially contributed to the conception, design of the review article and interpretation of the relevant literature. Dr. Archana Angrup helped in improving its quality and readability.

Additional information

Funding

This work was supported by grants awarded to Niraj Kumar from the Indian Council of Medical Research Govt. of India (Grant No. AMR/Adhoc/233/2020-ECD-II) and Translational Health Science and Technology Institute Faridabad, India. RS received Senior Research Fellowship from the Council of Scientific and Industrial Research, Govt. of India, and SS and LT received Junior Research Fellowship from the Department of Biotechnology, Govt. of India.