Antibiotic Resistance

Function

Antibiotic resistance occurs when bacteria evolve to evade the effect of antibiotics through multiple different mechanisms. Dissemination of antibiotic resistance genes is an ecological and public health concern. Certain bacteria are able to neutralize an antibiotic by altering its component to render it ineffective. Others might be able to export the antibiotics out of the bacteria, and some can modify their outer structure and receptors so that antibiotics cannot attach to them. These mechanisms might lead to some bacteria surviving the use of the specific antibiotic and developing a resistance that can be passed to other bacteria as they multiply. Bacteria also can become resistant through mutation of their genetic material.

The mechanism of antibiotic resistance is commonly categorized into the following four groups:

1. Intrinsic Resistance: Bacteria might survive an antibiotic due to intrinsic resistance through evolution by changing their structure or components. For example, an antibiotic that affects the wall-building mechanism of the bacteria, such as penicillin, cannot affect bacteria that do not have a cell wall.
2. Acquired Resistance: Bacteria can obtain the ability to resist the activity of a particular antimicrobial agent to which it was previously susceptible. Bacteria can acquire resistance through a new genetic mutation that helps the bacterium survive or by getting DNA from a bacterium that already is resistant. An example is Mycobacterium tuberculosis resistance to rifamycin.
3. Genetic Change: Bacterium DNA might change and alter the production of protein, leading to different bacterial components and receptors which render the bacteria unrecognized by the antibiotic. Bacteria sharing the environment might harbor intrinsic genetic determinants of resistance that would alter the genomics of the bacteria. An example is Escherichia coli (E. coli) and Haemophilus influenza resistance to trimethoprim.
4. DNA Transfer: Bacteria can share genetic components with other bacteria and transfer the resistant DNA through a horizontal gene transfer. Usually, bacteria acquire external genetic material through three main stages:

• Transformation (through naked DNA incorporation)
• Transduction (through the process of phagocytosis)
• Conjugation (through direct contact).

An example is Staphylococcus aureus resistance to methicillin (MRSA).

Several organisms are resistant to multiple antibiotics. For example, isolated E. coli and Enterococcus that are inhibited by cefoxitin, ciprofloxacin, or erythromycin are usually resistant to at least one antibiotic and sometimes multiple antibiotic types including macrolides, tetracyclines, beta-lactams, quinolones, sulfonamides, tetracyclines, and rifamycin.

Issues of Concern

In the past, medicine was able to stay ahead of antimicrobial resistance through research and the development of new agents to overcome the different types of resistance patterns; however, with the recent development of vancomycin-resistant enterococci and the new subtypes of methicillin-resistant Staphylococcus aureus, antibiotic resistance is more prevalent and only can be minimized through stewardship. To combat the rising use of antibiotics, medical and public health professionals have to collaborate to reduce the inappropriate use of antibiotics. Physicians will have to balance the risks of not treating or inadequately treating against the risk of antibiotic use regarding adverse effects, drug interactions, cost, and antibiotic resistance. From a clinical perspective, many providers may not be highly concerned about their antibiotic prescribing habits since many patients expect to get an antibiotic when they visit a physician for an issue they perceive as bacterial. A didactic educational discussion with the patient is necessary to change the overprescribing phenomenon. Patients should be educated on the viral etiology of different infectious disease syndromes in which antibiotics are unnecessary. The prescription of antibiotics in these circumstances is futile. It exposes the patients to undesirable side effects or drug-drug interactions and increases healthcare costs, in addition to contributing to the development of antimicrobial resistance. For instance, a patient with infectious mononucleosis is treated with oral amoxicillin and develops a rash.[4][5]

Antibiotic stewardship aims to provide a guide for the appropriate use of antibiotics. One of the general principles is to manage patients empirically and then tailor antibiotic therapy based on microbiology results. There are multiple strategies a stewardship program can focus on such as educational, antimicrobial formulary restrictions, prospective audit and feedback, computer-assisted notifications, molecular testing technology, application of management guidelines, and interprofessional strategies. The core components of an antibiotic stewardship program are leadership commitment, accountability, antibiotic expertise, actions to tailor antibiotic use, tracking of antibiotic use, reporting antibiotic use, and educating clinicians on appropriate antibiotic use.

Clinical Significance

It is important to recognize that the concept of antimicrobial resistance in clinical practice is a relative phenomenon with high complexity. Engaging patients is crucial for successful antimicrobial stewardship to reduce rates of antibiotic resistance. Educating patients on what they can do to keep themselves safe is part of the discussion on improving antibiotic use. This includes raising awareness about the adverse effects of antibiotics as well as the potential consequences of unnecessary antibiotic use. Also, finding different diagnostic tools to help in guiding the antibiotic treatment is highly beneficial, such as the Overlap2 Method, a new initiative to determine the synergic effect of antibiotics on different antimicrobials. Clinical approach to antimicrobial stewardship might differ from outpatient to inpatient settings; however, all share the goal of improving antibiotic use as a core component of fighting antibiotic resistance.[6][7]

Measuring the clinical significance of antimicrobial stewardship is complicated and can be assessed by clinical and economic outcomes. A recent study compared the use of continuous antibiotics versus intermittent antibiotics to manage bronchiectasis (by assessing the reduction in the frequency and duration of exacerbations) to the risks of managing antibiotic resistance and minimizing side effects demonstrated a lack of high-evidence studies assessing the impact of stewardship programs. Hence, more prospective clinical trials are needed to evaluate the impact of antimicrobial stewardship on clinical outcomes. Outcome measures to utilize are decreased in the length of stay, lower readmission rates, and shorten the period to place the patient on proper effective therapy. On the other hand, economic outcomes provide stronger results showing the benefits of such stewardship programs. Economic outcomes do not only refer to the antimicrobial expenditure, but also include the costs of the drug, microbiology, length of stay, and infectious disease specialists. More significant savings can result from improved clinical outcomes due to decreased length of stay and reduction in complications related to antibiotic use, such as with Clostridium difficile associated disease.

Other Issues

Antibiotic Stewardship guidelines by the Infectious Diseases Society of America (IDSA) mainly focus on the following:[8]

• Incorporate direct interaction and feedback to the prescriber to reduce inappropriate antimicrobial use
• Restrict formulary antimicrobial use by requiring specialized authorizations
• Develop institution-specific clinical pathways based on local microbiology and resistance patterns
• Streamlining and de-escalate therapy to eliminate redundant combination therapy
• Ensure dose optimization based site of infection, pharmacokinetic, and pharmacodynamic characteristics
• Develop clinical pathways advising providers about appropriate parenteral to oral conversions

Enhancing Healthcare Team Outcomes

In 2017, the Joint Commission announced new stewardship standards requiring every hospital in the United States to have a stewardship program. However, many hospitals have yet to adopt these programs, and many institutions fear that smaller hospitals may not have the ability to develop effective stewardship programs. There are a few possible solutions to overcome these barriers such as joining a larger healthcare system to utilize their resources, pooling resources from other hospitals, and facilitating the use of their state's health department resources. Stewardship is a function of a health system that is usually managed by the government to oversee and regulate healthcare. Antimicrobial stewardship programs require a systematic measurement and coordinated interventions between clinicians, infection control personnel, pharmacists, and informational technology designed to promote the optimal use of antibiotic agents, including their choice, dosing, route, and duration of administration.[9][10]