INTRODUCTION

Judicious use of antibiotics along with infection control is the cornerstone for the prevention of emergence of drug-resistant organism in intensive care unit (ICU) or non-ICU setup. Antibiotics were initially developed to treat short-term bacterial infection but with passage of time antibiotics are not only being used for treating short-term bacterial infection but also for treating chronic infectious diseases on long-term basis, like pyelonephritis, prophylaxis for chronic urinary tract infection (UTI), bacterial endocarditis, infections in transplant recipients, etc. Pitfalls associated with long-term antibiotic use include development of antimicrobial resistance (AMR) and cumulative risk of adverse events. AMR is a growing global concern with Multidrug Resistant organism and is responsible for high mortality and morbidity all over the world.

Consequences of overuse of antibiotics:

• A new CDC (Centers for Disease Control and Prevention) study showed that children given antibiotics for routine upper respiratory tract infections are more susceptible to develop aggressive antibiotic-resistant strains of Clostridium difficile infection.
  The study found that 71% of children who suffered from C. difficile infections had been given courses of antibiotics for respiratory, ear, or nose infection 10–12 weeks before infection.
• Our intestines contain around 100 trillion of bacteria of various strains. While some of them can be deadly and some are good bacteria. These helpful bacteria, known as gut flora, are responsible for supporting immunity and proper digestion. Aggressive antibiotic uses while helpful when we have a serious infection can wipe out many good bacteria in the gut while leaving those bacteria which are immune to antibiotics and thus help those bacteria to flourish. That is the case with C. difficile diarrheal infections (Table 1).
• Bacteria have evolved defenses against antibiotics through the process known as horizontal gene transfer. Essentially, bacteria do not need to reproduce to pass along their genetic information like protection from antibiotics. They can simply pass along these genes to fellow bacteria like students passing notes in a classroom.
• Along with C. difficile cases of antibiotic-resistant gonorrhea are emerging nowadays. This untreatable gonorrhea not only causes pelvic pain but also has been linked to pelvic inflammatory disease, ectopic pregnancy, tubal infertility, and neonatal eye infections, etc.
• With the spread of antibiotic resistance, the more often common antibiotics including many available as generics can no longer be used. This means that more patients suffering from different infection now require longer, more expensive, and new forms of therapy.

HOW TO DEAL WITH THE PROBLEM?

• Antimicrobial stewardship is the coordinated and systematic interventions designed to promote optimal use of antibiotics by selection of appropriate antimicrobial drug regimens (including proper dosing, duration of therapy, and route of administration).
• Goal: The goal of antimicrobial stewardship is to optimize clinical outcomes in terms of control of infection adequately while minimizing unintended consequences of antimicrobial use (including toxicity, the emergence of AMR, or development of antibiotic associated C. difficile infection)
• Initiating empiric therapy:
  • Initiation of empiric antibacterial therapy consists of the following:
    • Determining that antibiotics are actually indicated.
    • Choosing the optimal antimicrobial regimen [after obtaining culture(s) from relevant sites], taking into consideration:
      • The severity and trajectory of illness
      • The likely pathogens and their anatomic source (with consideration of source control), based on information from Gram stain and other rapid tests as appropriate
      • The likelihood of drug resistance (like, known colonization with resistant pathogens, recent antimicrobial use, exposure to healthcare facilities, and local resistance patterns)
      • Host factors, including those that may preclude use of a particular antimicrobial class (such as allergy), increase the risk of toxicity (like marginal or unstable renal function), or influence spectrum of coverage (as in immunocompromised patient)
    • Determining the appropriate dosing and route of administration
    • Initiating antimicrobial therapy as promptly as possible, especially in the presence of sepsis
  • Tailoring antimicrobial therapy: In patients receiving empiric antimicrobial therapy, the regimen should be reevaluated on a continuing basis. As the clinical status evolves and microbiology results become available (often after 48–72 hours), an assessment should be performed that involves reviewing clinical and microbiology results and adjusting antimicrobial therapy from empiric to definitive antimicrobial therapy. The spectrum of coverage may be narrowed or broadened as appropriate as per culture sensitivity reports, the dose may be adjusted as needed, and unnecessary components of the regimen should be eliminated.
  • Converting from intravenous to oral antimicrobial administration: Antimicrobial regimens should be converted from intravenous to oral form when clinically indicated and as soon as patient’s hemodynamics improves.
  • Using the shortest effective duration of therapy: An important step in the safe use of antimicrobials lies in restricting their administration to the minimum duration required for maximum efficacy so as to minimize their toxic effect.
  • Serum serial procalcitonin measurements have been demonstrated as a good tool to discontinue therapy in critically ill patients with suspected bacterial pneumonia or undifferentiated sepsis.
  • Setting up of a local protocol is very much required in antimicrobial stewardship programs for common infections based on local epidemiology, according to available facility and susceptibility patterns of organisms, and drug availability or preference (Tables 2 and 3 for management of C. difficile infection)
  • Pharmacokinetic (PK) and pharmacodynamic (PD) monitoring: Optimal antimicrobial dosing and administration requires adherence to relevant PK/PD principles. Individual PK monitoring should be implemented for patients receiving aminoglycosides antibiotics or vancomycin. PK monitoring increases the likelihood of obtaining serum concentrations within the therapeutic range and reduces costs of therapy. Some studies have also observed reductions in nephrotoxicity, length of stay, and mortality with proper uses of PK/PD guidelines.

ANTIBIOTIC RESISTANCE

The treatment of gram-negative sepsis is becoming increasingly complicated by the rising prevalence of multidrug resistant (MDR) bugs. Normally, susceptible Enterobacteriaceae may become resistant to antimicrobial agents by acquiring resistance genes or through the mechanism of mutation. Other pathogens, such as Pseudomonas, Acinetobacter baumannii, and Stenotrophomonas maltophilia have inherent resistance to certain antimicrobials and may acquire additional mechanisms for resistance by mutation.

    Extended-spectrum β-lactamases

Extended-spectrum β-lactamase (ESBL) organisms may confer resistance to β-lactam agents. Plasmids that carry ESBLs typically carry other resistance genes as well; thus, these organisms are frequently MDR.

Traditionally, the majority of infections with ESBL producers were caused by Klebsiella pneumoniae. However, over the past decade, ESBL-producing Escherichia coli has emerged as an important cause of both community-acquired and hospital-acquired pneumonia worldwide.

Following are the risk factors for infection with an ESBL-producing organism:

• Admission from a nursing home
• The presence of a gastrostomy tube
• Transplant recipient
• Chronic renal failure
• Receipt of antibiotics within the preceding 30 days
• Length of hospital stay before infection

Carbapenem group of antibiotics (imipenem, meropenem, and ertapenem) remain the drugs of choice for bacteremia caused by ESBL-producing gram-negative bacilli.

    Carbapenem-resistant Enterobacteriaceae

• The widespread use of carbapenems for suspected cases of ESBL-producing bacteria has contributed to the development of carbapenem resistance in many species of bacteria (Table 4 for treatment option). The prevalence of carbapenem-resistant K. pneumoniae increased from 1% in 2,000 to >8% in 2007.
• Other carbapenemase classes have increased in prevalence as well.

• A metallo-β-lactamase, the New Delhi metallo-β-lactamase 1 (NDM-1), was discovered in 2009 and has subsequently been identified in numerous other countries.
• Additionally, OXA-48, a class D carbapenemase typically found in A. baumannii, was described for the first time in K. pneumoniae in a patient in Turkey.
• The most important risk factor for development of infection due to a carbapenemase-producing organism is receipt of prior antimicrobial therapy.

    Carbapenem-resistant Enterobacter: OXA-48, OXA-48-like Carbapenemases Producers

• Aminoglycosides group of antibiotics can be used as monotherapy for susceptible CRE UTIs when other options are limited.
• Nitrofurantoin and fosfomycin are effective for simple cystitis but neither agent should be used for complicated UTIs (e.g., pyelonephritis) or for infections outside the urinary tract.
• Fosfomycin should only be used for simple cystitis caused by E. coli.

CONCLUSION

Development of AMR by microbial pathogens and commensals represents a major threat to animal and public health. Although the economic impact of AMR is unknown, it is clear that the decreased efficacy of commonly used antibacterial agents and the need to use more expensive drugs not only limit therapeutic options but inflate the expense of treating infectious diseases. So we have to be extra careful while choosing our antibiotics for treating infection and implement antibiotic stewardship program to prevent the development of AMR.

SUGGESTED READINGS

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2.   Lau JSY, Korman TM, Woolley I. Life-long antimicrobial therapy: where is the evidence? J Antimicrob Chemother. 2018;73(10):2601-12.

3.   Lau JSY, Bhatt S, Streitberg R, Bryant M, Korman TM, Woolley I. Surveillance of life-long antibiotics-A cross-sectional cohort study assessing patient attitudes and understanding of long-term antibiotic consumption. Infect Dis Health. 2019;24(4):179-86.

4.   CDC. Antibiotic Resistance Threats in the United States, 2019. Atlanta, GA, USA: U.S. Department of Health and Human Services, CDC; 2019.

5.   Barlam TF, Cosgrove SE, Abbo LM, MacDougall C, Schuetz AN, Septimus EJ, et al. Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62(10):e51-77.

6.   Chow JW. Aminoglycoside resistance in enterococci. Clin Infect Dis. 2000; 31:586-9.

7.   Centers for Disease Control and Prevention. (2014). The Core Elements of Hospital Antibiotic Stewardship Programs. [online] Available from http://www.cdc.gov/antibiotic-use/healthcare/pdfs/core-elements.pdf [Last accessed November, 2023].

8.   Grayson ML, Eliopoulos GM, Wennersten CB, Ruoff KL, De Girolami PC, Ferraro MJ, et al. Increasing resistance to beta-lactam antibiotics among clinical isolates of Enterococcus faecium: a 22-year review at one institution. Antimicrob Agents Chemother. 1991;35(11):2180-4.

9.   Fontana R, Ligozzi M, Pittaluga F, Satta G. Intrinsic penicillin resistance in enterococci. Microb Drug Resist. 1996;2:209-13.

10. Rice LB, Bellais S, Carias LL, Hutton-Thomas R, Bonomo RA, Caspers P, et al. Impact of specific pbp5 mutations on expression of beta-lactam resistance in Enterococcus faecium. Antimicrob Agents Chemother. 2004;48(8):3028-32.