Practicing Stewardship of Antibiotics for the Management of Chronic Wounds

Antimicrobials, especially antibiotics, are now under great scrutiny due to issues with emerging antibiotic resistance, secondary infections, and increased cost. What is the best prevention and/or treatment for the patient with present resources, and how can present tools be preserved for future patients?

As clinicians who provide chronic wound care daily to many patients, we all want the most effective tools to produce the best outcomes. Wound care providers have accepted the responsibility of wound healing and, in most patients, that responsibility extends to the use or misuse of antibiotics. Antimicrobials, especially antibiotics, are now under great scrutiny due to issues associated with emerging antibiotic resistance, secondary infections such as Clostridium difficile, and increased costs. Yet, in the treatment of a specific patient, it is the individual clinician who must decide if there are microbes present in the wound. If so, we must ask ourselves: Are those microbes causing harm to the host (infection)? What is the best prevention and/or treatment for this patient at that time with present resources? How can present tools be preserved for a future patient? There are guiding principles emerging in antibiotic stewardship that can assist clinicians, but these principles can sometimes be in conflict with each other and with current practices. This article will provide guidance to wound care providers.

Preventing Antibiotic Resistance

One stated goal of antimicrobial stewardship is to produce the best clinical outcomes for a specific infection while limiting emergence of antibiotic-resistant organisms. For the present discussion, the use of antibiotic resistance will be limited to the resistance conferred by mobile genetic elements such as mecA cassettes (commonly carried by methicillin-resistant Staphylococcus aureus [MRSA]), extended spectrum beta-lactamases (ESBLs), and other mobile genes/clusters of genes (genomic mutations are a minor contributor to resistance). For phenotypic antibiotic properties, such as seen with microbes expressing biofilm phenotype mode of growth, the ineffectiveness of antibiotics is referred to as “tolerance.” Both resistance and tolerance are conditions in which antibiotics are less effective, but it is important not to confuse the mechanisms that limit antibiotic success.

There are literally dozens of guiding principles for antibiotic stewardship to prevent antibiotic resistance, but the one we will focus on for this article is to “understand presentation, diagnosis, management, and appropriate antimicrobial use, including appropriate duration of therapy associated with common infection syndromes including ... skin, soft tissue, bone and joint, diabetic infection...”¹ To state this principle more simply, it is important in managing chronic wounds that the clinician use an antibiotic that will be effective against the microbes present, use a high enough concentration to achieve “sufficient” killing, and use a satisfactory duration all the while using the least amount of antibiotic possible.

Fortunately, guidelines set forth by the European Society for Clinical Microbiology and Infectious Diseases have recently provided some clarity for the management of chronic wound microbiota.² This guideline states that “biofilms cause chronic infections in tissues...” and these guidelines specifically uses a chronic wound as a “hallmark chronic infection.” Biofilms produce chronic infections that typically persist despite routinely adequate antibiotic therapy. In fact, clinically, it is often the failure of an appropriate antibiotic that defines an infection as “chronic.”  Yet, the mechanism for this failure is usually not antibiotic resistance as defined here, but rather antibiotic tolerance due to biofilm phenotype. Therefore, to fulfill this antibiotic stewardship principle we have to delve deeper into the chronic wound to “understand the presentation, diagnosis, [and] management” of chronic wounds to determine the “appropriate antimicrobial use.”

Chronic wounds are stuck in a persistent inflammatory state that is a commonality of chronic infections.^3-5 The host cellular immune response to a chronic infection, probably in part determined by the microbial species present, is dominated by either neutrophils or mononuclear cells.^6-8 Also, chronic infections possess a similar biochemistry with elevated proinflammatory cytokines as well as elevated host protease activity.^9-11 This biochemistry and cellularity is also present in chronic wounds. The clinical presentation of chronic wounds is most consistent with chronic infections.¹²

Because of the innate properties of microbes in the biofilm mode of growth being polymicrobial and viable, but not culturable, cultivation methods are inadequate for identifying microorganisms from chronic infections. Culture-independent methods are recommended to diagnose the microbiota of chronic wounds.¹³ Culture-independent methods such as sequencing, polymerase chain reaction (PCR), and/or mass spectroscopy are able to identify microorganisms sampled from chronic infections with higher sensitivity and specificity than even targeted culturing methods.^14-16 It is important to remember for the management of chronic wounds that chronic wounds, due to their accessibility, offer multiple management options to control the wound microbiota other than antibiotics. Many adjuncts are as simple as controlling the environment — such as moisture, pH, exudate control, temperature, etc. Another adjunct, debridement, physically removes large numbers of bacterial cells; disrupts the wound biofilm matrix, which impairs biofilm defenses; and, most importantly, opens a time-dependent window during which antibiotics are more effective.¹⁷ Also, quorum sensing inhibitors that target Staphylococcus (hamamelitannin, which inhibits accessory gene regulator expression),¹⁸ Streptococcus mutans (furanone compound 30, which inhibits luxS expression),¹⁹ and Pseudomonas aeruginosa (synthetic furanones, which inhibit homoserine lactone activity)²⁰ can be applied topically. Quorum sensing inhibitors have the ability to improve the efficacy of appropriate antibiotics.¹³

This leaves us with choosing an “appropriate” antibiotic. This can be as simple as selecting the first antibiotic listed in the culture and sensitivity that shows an “S,” or the clinician may add other selection criteria such as cost or route of administration. However, to be a diligent steward is to consider how to limit the amount of antibiotic given (especially antibiotics considered “the last line of defense” against certain infections such as MRSA) while ensuring the antibiotic is above therapeutic thresholds. An appropriate antibiotic administered at subtherapeutic thresholds induces resistance. This is especially important to remember in that biofilm phenotype bacteria require hundreds to even one thousand times normal minimum inhibitory concentration (MIC) for adequate bactericidal activity.²¹ Also, biofilm possesses augmented horizontal gene transfer (far more efficient than planktonic phenotype), which allows for the efficient transfer of mobile genetic elements to rapidly spread antibiotic resistance.^22,23 Therefore, in a chronic infection, selecting the appropriate antibiotic entails accurate identification of the microbes present, determining the mobile genetic elements (resistance factors) present, knowledge of the local antibiogram for empiric treatment, and, importantly, methods for administering antibiotics at doses that will be above therapeutic thresholds.

Considerations When Choosing Antibiotics

In choosing the appropriate antibiotic, an infectious disease specialist would evaluate the different classes of antibiotics and their properties, types of allergic reaction, drug interactions, propensity to produce secondary infections (C. diff), antibiotic shortages, cost, local antibiogram, local formulary, and host of other factors.¹ This is exactly why there’s no consensus algorithm for determining an “appropriate antibiotic.”  Depending on what the final decision-maker values most for an antibiotic in a specific wound, these values can lead to widely varying choices. For a chronic wound with P. aeruginosa, a clinician may choose amikacin for its higher efficacy or gentamicin because of fewer side effects. Or, the clinician may choose a carbapenem to avoid resistance or piperacillin/tazobactam for its lower cost and no shortage. Then again, the clinician may choose ceftolozane/tazobactam to overcome resistance issues only to find colistin is the only antibiotic on the formulary for multidrug-resistant P. aeruginosa.  There are guidelines but no clear scientific selection methods to arrive at the “appropriate” antibiotic for a given situation. Fortunately, in chronic wounds, by including adjunctive methods antibiotics do not have to do all the work in suppressing the wound microbiota. Because chronic wounds are accessible, topical administration of antibiotics is possible and may be effective. The topical use of antibiotics is the “gold standard” for several other accessible chronic infections such as otitis externa,²⁴ chronic otitis media with tubes,²⁵ and conjunctivitis.²⁶ Topical antibiotics can achieve concentrations > 1,000 mcg/cc (antibiofilm dose), which is far greater than most antibiotics can obtain systemically. Also, antimicrobial spectrums change at high levels of antibiotics. For instance, amikacin shows a 94% efficacy against MRSA when delivered topically²⁷ and rifampin, which traditionally shows an MIC of > 32 mcg/cc for P. aeruginosa, becomes an excellent combination antibiotic at higher concentrations for this microbe.²⁸ Topical administration of antibiotics carries a lower risk for antibiotic resistance,²⁹ probably because it is well above therapeutic thresholds and limits the antibiotic exposure of commensals and other microorganisms not related to the wound. Also, fewer antibiotic allergies have been reported with topical antibiotics,³⁰ possibly because of the lower volume of distribution and therefore less host tissue exposed to the drug. Topical administration of antibiotics meets the most fundamental principles of good antibiotic stewardship.

Management of Microbiota

The management strategies required to suppress biofilm phenotype bacteria are more than adequate to totally eradicate planktonic bacteria. Therefore, it may be more prudent to approach the wound microbiota as if it were biofilm. The management of biofilm requires multiple different strategies applied simultaneously, which include physical disruption of the biofilm (debridement), antibiofilm agents, and bactericidal agents. New nonantibiotic, antibiofilm therapies that exploit synergies between multiple treating agents (AQUACEL^® AG EXTRA^TM [ConvaTec Inc.] - benzethonium chloride, ethylenediaminetetraacetic acid; Next Science^TM Gel [Next Science Inc.] - benzalkonium chloride and a pH buffer system of an acid and its conjugate base) are emerging and demonstrate the importance of simultaneous tactics to prevent the microbiota from adapting. These multiple concurrent dynamic strategies target the different aspects of biofilm function and structure to mitigate the advantages biofilm has gained through genetic diversity, phenotypic diversity, and physical structure. This is important in that it allows the clinician to use the least amount of antibiotics while obtaining the best outcomes. Molecular diagnostics such as sequencing, PCR, and mass spectroscopy have the ability to identify microorganisms (bacteria and fungus) with scientific certainty, but also are able to quantitate each species present within the biofilm.^31,32 Wound biofilm is overwhelmingly polymicrobial and, because of synergies between species, it is important to identify every bacterial species present.³³ Also, bacterial species present in low abundance can dramatically alter the pathogenicity and response to treatment of the biofilm.³⁴ Once the wound biofilm is fully diagnosed, specific antibiotics can be compounded into a drug-delivery gel (LipoGel^® [Progressive Wound Care^®]) that releases a high, steady state of antibiotic over a prolonged period of time.³⁵  Experiments demonstrated that pulsed, high dose antibiotics are not as effective against biofilm as continuous high dose antibiotics.^{23, 36}  The diversity found within a wound biofilm can typically be managed with one or two (no more than three) different topical antibiotics.  This allows the entire constituency of the wound biofilm to be treated simultaneously and prevents an untreated species from proliferating.

Systemic antibiotics are usually ineffective when given as the only treatment of biofilm disease, but are an important adjunct in the initial treatment of a chronic wound. Systemic antibiotics, even though they are at low concentrations, can reach the wound biofilm that has extended into the host tissues and suppress the metabolically active bacteria within the biofilm.³⁷

Chronic Wounds As Chronic Infections

To date, most of the recommendations for the routine management of the wound microbiota have been based on culture methods. This has led to recommendations of not diagnosing the wound microbiota³⁸ and, more importantly, not using antibiotics unless the wound is infected as per guidelines set forth by the Infectious Diseases Society of America.³⁹ More concisely stated, antibiotics are not used to heal the wound, but rather to treat infection.⁴⁰ It is theorized that the “overuse” of antibiotics in chronic wounds may be driving some of the antibiotic-resistant microorganisms that are emerging today.⁴¹ Yet, 78% of patients living with chronic wounds received at least one course of systemic antibiotics.⁴² Wound care providers behaved as if the wound microbiota in general is an important barrier to wound healing, yet the recommendations from our key opinion leaders is to only use antibiotics for wound infection that meets stringent criteria.

In dozens of animal models in mice,^43,44 rabbits,⁴⁵ rats, hamsters, guinea pigs, and young pigs⁴⁶ investigators have found that seeding microorganisms into a skin lesion is a consistent way to produce a wound in the animal model that behaves like the clinical chronic wound in humans.  Animal models for impaired healing may include repetitive trauma, applying immunosuppressants, applying chemotherapeutic agents, and, more yet, the addition of microorganisms is the most reliable and most utilized method for producing a chronic wound in these models. In a rabbit ear model, the more P. aeruginosa the more delayed the healing;⁴⁵ in a burn mouse model, the more P. aeruginosa the more delayed the healing;⁴⁷ and in the young pig model, the addition of P. aeruginosa, S. aureus, or both significantly delayed wound healing.⁴⁶ However, each wound used as a control for the animal model does not have the addition of microorganisms and will heal like an acute wound. Animal models have taught us unequivocally that the microbiota (both the virulence of the microbes and the amount) delays wound healing whether or not there are clinical signs and symptoms of wound infection. And in a corollary, even in these models with impaired animals, wounds without significant microbiota tend to heal with a normal wound healing trajectory. Also, it does not seem prudent, especially in the high-risk diabetic foot ulcer (DFU), to not address the microbiota in the wound bed. Even if the wound is progressing (in a delayed fashion) it is an unreasonable risk for the clinician to force the host immune system to do 100% of the containment of the microbiota, especially with cost-effective tools and techniques that can reduce the microbes present. Some pushback has been “we don't know which microorganisms are pathogens in the wound bed environment.” The term “pathogen” may need to be retired.⁴⁸ But if we don’t abandon the concept that some bacterial species are “bad” and some bacterial species are “good,” regardless of their activity, then there is still the animal data that shows better healing with fewer microbes in the wound. Also, multiple randomized controlled trials of bactericidal agents (eg, silver, cadexomer iodine, etc.) demonstrate fewer microbes leads to improved healing. And, perhaps most importantly, some infectious disease experts state unequivocally that chronic wounds are chronic infections produced by biofilm phenotype microbes.²

Just as importantly, when the microbiota of all chronic wounds is specifically targeted wound healing outcomes are improved. In a recent study, by pursuing multiple concurrent strategies for the purpose of suppressing the microorganisms identified on the surface of chronic wounds, regardless of signs and symptoms of infection, much less antibiotic was utilized and outcomes were improved.⁴⁹ By applying antibiotics topically, a one-month’s supply for a small wound contains as much antibiotic as a single dose given systemically, yet the concentration that the bacteria encounters is far higher. With topical antibiotics and the use of adjuncts, such as quorum-sensing inhibitors, selective biocides, and repetitive debridement, the total amount of antibiotics was reduced, the use of new antibiotics (daptomycin, linezolid, etc.) was significantly reduced, and the total cost of healing DFUs was reduced by over half.

Conclusion

In the near term it is antibiotics that will do the heavy lifting in managing the wound microbiota. However, in the long term many nonantibiotic options are emerging. Today, by closing the chronic wound rapidly through the aggressive and targeted use of antibiotics, a high-risk reservoir of microbes is eliminated from patients within the healthcare system. This keeps the microbiota within a chronic wound from seeing multiple short-duration, subtherapeutic doses of antibiotics for the treatment of other infections. By utilizing antibiotics either topically and/or systemically to anchor a multiple simultaneous strategy for closing wounds, the clinician may actually be reducing the risk for antibiotic resistance from chronic wound microbiota and is fulfilling the principles of antibiotic stewardship.

Randall Wolcott is founder of Southwest Regional Wound Care Center, Lubbock, TX, and serves on the TWC editorial board.

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