Among the greatest triumphs of modern medicine were the identification and naming of the Penicillium mold by Alexander Fleming in 1928, and its ability to inhibit bacteria growth on culture medium. Penicillin was then developed by the team of Heatley, Chain, and Florey in England during the Second World War.¹ This miracle brought about the ability to cure previously untreatable diseases and devastating infections that had high morbidity and mortality rates. Along with the great efficacy of penicillin was the added benefit of very few side effects. This area of research brought about the era of antibiotic production, which began in the 1950s.

Mechanisms of Antibiotic Resistance and Implications for Health Care

Antibiotics target one or multiple modes of cellular communication which allow microorganisms to proliferate. These include cell wall, membrane transport, RNA function, DNA synthesis, protein function, or enzyme activity.² Interrupting cellular communication and thus proliferation has made antibiotics very effective against a broad range of microoganisms. In looking at the history of multidrug-resistant organisms (MDROs) we must remember that there are two sides to every coin, and with the positive side of clinical efficacy against microoganisms there is also a downside.

To ensure their survival, it has become necessary for microorganisms to evolve and genetically mutate. These processes have caused the organisms of today to be much different from the organisms of yesterday, much more virulent, and more multidrug resistant. Antibiotic and antimicrobial resistance has become a crisis in health care and, simply put, has emerged from the overuse and inappropriate use of antibiotics and antimicrobials. These resistant elements of bacteria, viruses, fungi, and parasites have made diseases that were once easily treatable deadly again.³

We must understand the difference as well because antimicrobial resistance refers to the loss of effectiveness across the entire range of organisms, whereas antibiotic resistance refers only to bacterial resistance to medications. As rapidly as new generations of antibiotics and antimicrobials are developed, the genetics of microorganisms change to enhance their resistance. With this come higher health care costs, poorer outcomes, and a higher risk of death for patients infected with resistant strains.⁴ The pressure to use antibiotics and antimicrobials, and the fact that the process cannot be reversed or undone, will guarantee that MDRO numbers will increase, be persistent phenomena, and occur more rapidly than new generations of antimicrobials can be developed.⁵ In the United States there are an estimated 23,000 deaths and more than 2 million illnesses resulting from resistant organisms. The direct costs exceed $20 billion annually, and the indirect costs are in excess of $35 billion.⁴

Specific Multidrug-Resistant Pathogens

MDROs are bacteria, fungus, yeast, and viruses that have developed resistance to antimicrobial drugs.⁶ The most common include the following:

• MRSA – Methicillin/oxacillin-resistant Staphylococcus aureus
• VRE – Vancomycin-resistant enterococcus
• ESBLs – Extended-spectrum beta-lactamases (which are resistant to cephalosporins and monobactams)
• PRSP – Penicillin-resistant Streptococcus pneumoniae
• MDRTB – Multidrug-resistant tuberculosis

Risk Factors for Multidrug-resistant Colonization and Infection

Risk factors that increase the chance of both colonization and infection with the organisms include the following:

• Severity of illness
• Previous exposure to antimicrobial agents
• Underlying diseases and comorbid conditions, such as:
  • Chronic renal disease
  • Diabetes mellitus
  • Peripheral vascular disease
  • Dermatitis or skin lesions
• Invasive procedures, such as:
  • Dialysis
  • Presence of invasive devices
  • Urinary catheterization
• Repeated hospitalization
• Previous colonization with MDROs
• Advanced age

Role of Biofilm Formation in Chronic Wound Care

In chronic wound care, bacterial colonization, biofilm production, and infection are huge global problems, compounded by the increased incidence of MDROs found in these patient’s wounds.⁷ Chronic wounds have a complex microenvironment that houses multiple bacterial species. There is a lack of evidence on the effectiveness of antibiotic therapy in chronic wounds, the optimal regimens, or specific clinical indications for treatment. However, as is typically the case, more often than not antibiotics are frequently made a part of the treatment regimen, and these individuals receive a significantly higher number of antibiotic prescriptions, both systemic and topical, than do patients with other maladies.⁸ A study conducted among patients with chronic wounds found that MDROs are common and can produce moderate to high levels of biofilms that can initiate drug resistance and further contribute to multidrug resistance.⁹

Because of the spectrum of resistance and the finding that biofilms may affect effective penetration of antibiotics into the wound bed, MDROs generally require treatment with broad-spectrum antimicrobials for long periods of time. Biofilms contain microcolonies that can facilitate intercellular communication, horizontal gene transfer, and altered gene expression, all which can alter wound healing. As discussed earlier, infections with MDROs can significantly prolong hospital length of stay and subsequently increase the risk of acquiring other hospital-acquired infections, thereby increasing morbidity and mortality risks.

The Post-Antibiotic Era: Where Do We Go From Here?

According to a report from the World Health Organizations (WHO),¹⁰ antimicrobial resistance currently impedes and threatens the future of effective prevention and treatment of the continually expanding range of infections caused by bacteria, parasites, viruses, and fungi. Increasing numbers of global governments are joining the fight to find a solution to this problem, which is so serious that it threatens the achievements of modern medicine. The report further explains that we are entering a post-antibiotic era, which although it is far from the fantasy of an apocalyptic event it is a very real possibility the global community is facing. Health care practitioners who deal with wounds and wound management should understand how and why organisms become drug resistant to choose appropriate treatment options to control microbial infection in wounds.¹¹ For this reason it is imperative that health care providers become good stewards and use antibiotics and antimicrobials judiciously.

Best-Practice Guidelines for Antimicrobial Stewardship

Curbing the current crisis of antimicrobial resistance will hinge on the development of novel strategies to fight MDRO pathogens by combining antimicrobial drugs with other agents that counteract and obstruct the antibiotic resistant mechanisms expressed by the pathogen. It will also require a more personalized approach based on precise diagnosis tools that will ensure that proper treatments can be promptly applied, leading to more targeted and effective therapies other than using antibiotics as the first choice.⁵ A WHO report¹⁰ discussed the main impact of MDROs on human health, the contributing factors, and consequences. The report explained how these go far beyond health and require a comprehensive and integrated approach to addressing the issue at global, regional, and national levels. The report also explained how this must involve all segments of human and veterinary medicine, agriculture, environmental control, and consumer awareness.

World Health Organization Priority Pathogens Report

In response to the global crisis of MDROs and to promote the research and development of new antibiotics, the WHO published the 2017 Priority Pathogens report. In the report pathogens are divided into three categories: critical, high, and medium priority.¹² The goal of the report was to focus on the need for development of new antibiotics to treat drug-resistant bacterial infections and tuberculosis. It also noted that once completed, the same process should be followed for viral, fungal, and parasitic infections. The report also stated that this must be a high-priority item in the global political agenda of world leaders and health policy makers linked to the development of appropriate health care delivery services and stewardship that will safeguard the use of current and future medications.

The committee stressed that the only possible defense against the global crisis of antimicrobial and antibiotic resistance is a targeted and coordinated global effort by all stakeholders on a mission to ensure health for all. We should be reminded that although preventive measures exist, they are not always implemented or implemented correctly to be effective. For this reason the WHO is implementing programs for both education and standardization on infection control strategies with a focus on antibiotic stewardship initiatives for health care providers and public awareness campaigns on a global level.¹²

Interdisciplinary Approach to Antibiotic Prescribing

A position paper published by the British Society for Antimicrobial Chemotherapy and the European Wound Management Association supports the fact that although all open wounds will be colonized with bacteria, antibiotic therapy is required only for those wounds that are clinically infected. Prescribing of antibiotic therapy should take on an interdisciplinary approach and only be done once infection is confirmed by culture. Interdisciplinary team members should include specialists in infection management and pharmacy, with input from clinicians providing the patients’ care and from administrative personnel.¹³ The committee recommended that the principles of antimicrobial stewardship be followed and include those listed here:

• Avoid prescribing antibiotics for uninfected wounds, and optimize early management of serious infection.
• Optimize diagnostic sensitivity and specificity of wound cultures and, ensure proper interpretation of the results.
• Minimize unnecessary use of antibiotics, optimize antibiotic choice, and promote use of narrow-spectrum regimens.
• Optimize collection of specimens for culture, antibiotic delivery, and wound healing.
• Avoid overly broad-spectrum regimens, thereby aiming to minimize risk of development of antimicrobial resistance, drug-related adverse effects, and Clostridium difficile disease.
• Promote awareness of risks of inappropriate antimicrobial therapy, and use benchmarking (comparing with local and national data) to help drive quality improvement.
• Ensure quality improvement in clinical practice through broadly based clinician and case review.
• Promote awareness of, and local development and adherence to, antimicrobial stewardship guidance and optimization of antibiotic therapy and treatment outcomes.

The committee also believed this strategy would ensure that the safest and most clinically effective therapy would be implemented for patients with infected wounds. Although evidence is limited, applying the principles of antimicrobial stewardship to the care of patients with chronic wounds should help reduce the unnecessary use of topical and systemic antibiotics and antimicrobials.

References

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2. Husted N, Durocher D. The control of DNA repair by the cell cycle. Nat Cell Biol. 2017;19:1-9. doi: 10.1038/ncb3452.

3. Brown ED, Wright GD. Antibacterial drug discovery in the resistance era. Nature 2016;529(27):336-43. doi: 10.1038/nature17042.

4. World Health Organization. Antimicrobial Resistance: Global Report on Surveillance. Geneva, Switzerland: World Health Organization; 2014.

5. Medina E, Pieper DH. Tackling threats and future problems of multidrug-resistant bacteria. In: Stadler M, Dersch P, eds. How to Overcome the Antibiotic Crisis: Facts, Challenges, Technologies, and Future Perspectives. Cambridge, MA: Springer; 2016:3-3.

6. Occupational Safety & Health Administration. Healthcare wide hazards: MDRO – Multi-drug resistant organisms. 2018. Available at: https://www.osha.gov/SLTC/etools/hospital/hazards/mro/mro.html. Accessed February 17, 2018.

7. Dryden MS. Reactive oxygen species treatment in the management of wounds. In: Recent Clinical Techniques, Results, and Research in Wounds. Cham, Switzerland; Springer; 2017:1-10. Retrieved from https://doi.org/10.1007/15695_2017_39 .

8. Tzaneva V, Mladenova I, Todorova G, Petkov D. Antibiotic treatment and resistance in chronic wounds of vascular origin. Clujul Med. 2016;89(3):365-70. doi: 10.15386/cjmed-647. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990431/. Accessed February 17, 2018.

9. Murali TS, Kavitha S, Spoorthi J, et al. Characteristics of microbial drug resistance and its correlates in chronic diabetic foot ulcer infections. J Med Microbiol. 2014;63(10):1377-85. doi: 10.1099/jmm.0.076034-0.

10. World Health Organization. World Health Assembly Report: Combating Antimicrobial Resistance, Including Antibiotic Resistance. Geneva, Switzerland: World Health Organization; 2014. Available at: http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf. Accessed February 17, 2018.

11. Bessa LJ, Fazii P, Giulio MD, Cellini L. Bacterial isolates from infected wounds ant and their antibiotic susceptibility pattern: some remarks about wound infection. Int Wound J. 2013;12(1):47-52. doi: 10.1111/iwj.12049.

12. World Health Organization. Prioritization of Pathogens to Guide Discovery, Research, and Development of New Antibiotics for Drug Resistant Bacterial Infections, Including Tuberculosis. Geneva, Switzerland: World Health Organization; 2017. Available at: http://www.who.int/medicines/areas/rational_use/prioritization-of-patho…. Accessed February 17, 2018.

13. Lipsky BA, Dryden M, Gottrup F, Nathwani D, Seaton RA, Stryja J. Antimicrobial stewardship in wound care: a position paper from the British Society for Antimicrobial Chemotherapy and European Wound Management Association. J Antimicrob Chemother. 2016;71(11):3026-35. doi:10.1093/jac/dkw287.