CHAPTER 19 James A. Orsini, DVM, Diplomate ACVS, Yvonne A. Elce, DVM, Diplomate ACVS, and Beth Kraus, DVM, Diplomate ACVS When managing serious wound infections in horses, it is important to consider the wound’s entire ecology, including the source and extent of contamination, the presence of bacterial refugia (foreign bodies, surgical implants, devitalized tissue, inflammatory/necrotic debris, bacterial biofilms), the patient’s immunocompetence, and tissue perfusion. In addition, the wound’s pathogens and their antibiotic sensitivities must be identified. Culture‐guided selection of antibiotic therapy and the use of local or regional modes of antibiotic delivery may be critical for success. By itself, antibiotic therapy may be insufficient to resolve bacterial infection in the presence of factors that contribute to the persistence or progression of infection and that otherwise delay wound healing. Wound infections usually are obvious clinically because they comprise the following readily identifiable elements: Any full‐thickness disruption of the skin permits the entry of surface bacteria into the tissue(s) deep to the skin, which elicits an inflammatory response, but relatively few wounds become severely infected. Serious infections complicate wound management, so they are the focus of this chapter. A wound infection should be considered severe or at least serious when it has evidently evaded or overwhelmed the body’s defenses or when infection could have career‐ending or life‐threatening consequences. Examples include the following: Severely infected wounds are a particular challenge in this era of multiple antibiotic resistance in common bacterial pathogens. Examples include, but are by no means limited to, methicillin‐resistant Staphylococcus aureus (MRSA)1–5 and Staphylococcus epidermidis (MRSE),6–9 vancomycin‐resistant Enterococcus species (VRE),10–14 heteroresistant vancomycin‐intermediate S. aureus (hVISA),15–18 penicillin‐resistant Actinobacillus species,19,20 aminoglycoside‐resistant Escherichia coli,21–24 and strains of Pseudomonas aeruginosa that are resistant to several commonly used antibiotics.25,26 These multidrug‐resistant strains are still relatively uncommon in equine practice, but their increase in prevalence and diversity – particularly in hospitalized patients (i.e., nosocomial infections) but also on‐farm (i.e., community‐acquired infections) – continues unabated2–5,7–13,19–31 and spurs us to seek approaches to treatment that extend beyond a reliance on antibiotics. Targeted antibiotic therapy directed by the results of bacterial culture and antibiotic sensitivity testing remains a cornerstone of effective management for severely infected wounds. Because of the character of these wounds, however, other factors beyond in vitro antibiotic sensitivity become crucial to a successful outcome. In this chapter, we briefly review several factors that may be involved in the development or persistence of severe wound infection and then discuss targeted approaches to treatment for each. A healthy body has the immunologic resources to deal with most instances of bacterial invasion, so in most wounds bacterial infection remains localized and is dealt with quickly and effectively by the patient, with or without the aid of veterinary treatment. Therefore, for a patient with a severe wound infection, effective treatment begins with a question: Why has this infection persisted and progressed? Most severe wound infections are the result of at least one, and usually a combination, of the following factors: Extensive contamination results in an overwhelming number of bacteria in the wound. Examples include the following. Although the site of the wound and the source of contamination are factors to consider when empirically choosing an antibiotic (discussed later), extensive contamination is less about the specific source and types of bacteria and more about the sheer numbers of bacteria invading the tissue and overwhelming the host’s defenses. In this context, a refugium is any substance or circumstance that protects bacteria within the wound from the host’s defenses and from effective concentrations of antibiotic drugs, thus enabling the infection to persist and perhaps to progress. Refugia commonly associated with persistent wound infections in horses include the following: The presence of bacterial biofilms in wounds is not a new phenomenon, but the importance of biofilms in the persistence and resistance of wound infections in animals has only lately come to light.32,33 Bacterial biofilms are gel‐like substances composed of an extracellular matrix of polysaccharides, proteins, glycolipids, bacterial DNA, water, the bacteria that secreted the matrix, and often other microbes that are taking advantage of the protected environment.32–35 Although a well‐established biofilm may be discernible as a thin, slimy coating or sheen on an abiotic surface (e.g., orthopedic device or catheter),35 the macroscopic identification of biofilms on biotic surfaces, particularly chronic wounds, is speculative and often based on a color induced by the overpopulating dominant sessile or planktonic aggregates of microbes. For example, P. aeruginosa produces a greenish pigment.35 However, discoloration of the wound surface or dressing is not a reliable indicator of the presence of a specific pathogen nor of a biofilm. In fact, biofilms in wounds can only be recognized by microscopic techniques with appropriate staining methods.35a The following dynamics are described for experimentally created bacterial biofilms that are similar to those found in wounds.35 As discussed later, this timeline is a useful guide for the management of biofilm‐infected wounds: The biofilm provides a secure attachment for the bacteria and a moist, stable environment that protects against desiccation, deluge, and other adverse physical conditions.34,35 It also protects the bacteria from the host’s defenses and from potentially lethal concentrations of antibiotic drugs.35,36 Depending on the antibiotic, diffusion through the matrix may be impeded and/or the drug may be inactivated by chemical constituents of the matrix. In the presence of a mature biofilm, the minimum inhibitory concentration (MIC) of an antibiotic or disinfectant to which the wound pathogens are susceptible in vitro may be increased by as little as 2‐fold and as much as 1000‐fold.32–39 Furthermore, bacteria within a biofilm alter their metabolism and gene expression in ways that promote their survival. These alterations include the formation of subpopulations that are metabolically inactive (quiescent) and thus relatively invulnerable to antibiotics at any concentration.35,36,40 These quiescent or dormant bacteria within the biofilm are a source of persistent or recurrent infection.32,33 Even more problematic is the sharing of antibiotic resistance among bacteria within the biofilm. In a polymicrobial biofilm, antibiotic‐binding or antibiotic‐degrading substances secreted by bacteria that are resistant to a particular drug may also protect bacteria within the biofilm that are susceptible to that drug. In addition, antibiotic‐resistance genes can sometimes be transferred from one bacterial species to another within the protected environment of the biofilm.35,36 Polymicrobial biofilms are documented to occur in various types of equine wounds (traumatic and surgical, acute and chronic).41,42 Under experimental conditions, many different bacteria isolated from wounds or the normal skin of horses are capable of producing biofilms;40,42 however, the conditions under which clinically relevant biofilms form in equine wounds require further study. In humans, problematic biofilms are most common in poorly perfused wounds, in malnourished patients, and in patients with co‐morbidities that impair immune function, such as in those with diabetic ulcers or severe burns.34–36 This aspect of wound care is critical when dealing with a biofilm‐infected wound. Even though many different wound pathogens are capable of producing a clinically relevant biofilm, most do not because tissue perfusion and bactericidal host defenses are adequate to prevent its establishment. So, when confronted with a biofilm‐infected wound, the crucial question is not what, but why. When the factors that favor formation of a biofilm are identified, appropriate treatment can begin. The patient’s immunocompetence is of primary importance in preventing or resolving a wound infection. A number of conditions or circumstances may compromise the patient’s ability to prevent or resolve bacterial infection, including the following: (*Hyperglycemia is a risk factor for wound infections and biofilm formation in human patients,34 but there is little evidence that wound infections are more likely or more problematic in horses with hyperglycemia unrelated to PPID, possibly because hyperglycemia is an inconsistent feature of equine metabolic syndrome and because diabetes mellitus is relatively rare in horses.) It is important to bear in mind that antibiotic therapy alone is inadequate in the face of an incompetent immune system. The administration of antibiotic drugs should be considered an adjunctive therapy, albeit a very important component of therapy for severely infected wounds. An effective immune response to bacterial invasion relies not just on local tissue resources but also on the delivery of leukocytes and specific molecules (complement, antibodies, oxygen, nutrients, etc.) to the site of infection via the systemic circulation. Thus, any circumstance that limits optimal blood flow to, or at, the site of infection inevitably limits the host’s immune response, as well as its ability to repair the wound, which renders the wound vulnerable to re‐infection. Examples include the following: Edema occurs so commonly with infected wounds that it is easily overlooked as an adverse factor in wound healing. Not only does severe edema cause the patient discomfort and negatively influence the client’s perception of efficacy of treatment, it may impede perfusion of tissue in the wound by creating local interstitial pressures that exceed the perfusion pressure of the microvasculature.43 Antibiotic treatment may fail to resolve the infection for one or more of the following reasons: This list illustrates the intersection and interdependence of pharmacology, physiology, pathology, and microbiology in clinical practice. Focusing primarily or exclusively on the pharmacologic aspect of treating complicated wounds, such as those discussed in this chapter, is likely to yield unsatisfactory results. Reliance on clinical experience alone to guide antibiotic therapy may result in the selection of antibiotic(s) to which the wound pathogens are not susceptible or for which therapeutic concentrations are not achieved at the site of infection. With wounds that are severely infected or at risk of becoming so, use of interim antibiotic therapy based on empiric choices can be crucial while awaiting results of culture and antibiotic sensitivity testing. An empiric choice, however, is little more than an educated guess. Because an incorrect choice of antibiotic drug may have disastrous consequences when treating a serious wound infection, empiric therapy must not take the place of specific therapy directed by bacterial culture and antibiotic sensitivity testing. This matter has become ever more important with the increasing prevalence and variety of multidrug‐resistant strains of bacterial pathogens found in equine wounds. The usual response by clinicians to a severe, intractable wound infection is to change or add antibiotics, increase the antibiotic dosage(s), and/or add local or regional delivery to systemic administration of antibiotics – in other words, to continue to rely primarily on antibiotic therapy. Certainly, if culture and sensitivity results indicate that a change of drug is indicated or that a polymicrobial infection is present that necessitates the addition of a different class of antibiotic drug, then these measures must be implemented without delay. In addition, local and regional modes of antibiotic delivery have dramatically improved our ability to manage difficult infections in horses, such as septic arthritis and osteomyelitis. In this era of multidrug resistance, however, when pharmacologic options may be unattractive or unavailable, the solution may be much more simple and direct, involving such measures as altering the physical environment within the wound to make it less hospitable to the bacteria. Here, our fundamental understanding of mammalian physiology and the basic biology of the invading bacteria may mean the difference between success and failure. The silver lining to this cloud, where we can no longer assume that every infection can be resolved simply with antibiotic therapy, is that we are forced back to basic principles of wound management, which we find still apply. Identifying the factors involved in the persistence and progression of a wound infection allows us to formulate a targeted approach to treatment that optimizes the patient’s defensive and reparative processes and the efficacy of the antibiotic drugs selected. For wounds that remain contaminated with fecal matter or other material with a large bacterial load, the following dictum is useful: “The solution to pollution is dilution.” Extravasation of serous fluid at the site of infection (as part of the inflammatory response) serves this purpose to some extent, but only if the fluid is allowed to drain from the wound. Furthermore, this natural process is limited in efficacy because it is restricted in volume. Hence, the following interventions are indicated. Thoroughly irrigate the wound with sterile isotonic fluid until all visible contamination and purulent discharge have been removed. The goal of irrigation is simple: to substantially reduce bacterial numbers in the wound by physical expulsion of contaminated material, without causing more damage or deeper infection. Surgical debridement is another important component of managing wounds that contain heavily contaminated and compromised tissue. Not only does debridement reduce bacterial numbers by removing heavily contaminated debris from the wound, it also enhances the effectiveness of irrigation by removing physical impediments to fluid flow. In addition, debridement aids subsequent drainage of inflammatory debris and infectious material from the wound. Discharge from severely infected wounds tends to be effusive and often purulent. This bacteria‐laden, inflammatory exudate must have an egress for the immune system to control the infection and orchestrate wound repair. Thus, drainage is a key component of wound management, not just for extensively contaminated wounds but for every severely infected wound. Movement may extend additional benefits by optimizing blood flow to, from, and within the wound; by limiting or preventing restrictive fibrosis; by preventing or resolving digestive and musculoskeletal problems associated with inactivity; by relieving the stress, social isolation, and boredom of confinement; and by improving the patient’s physical and psychologic health and well‐being. These aspects of nursing care are particularly important when the nature of the wound necessitates that the horse be confined to a stall for weeks or months. Drainage may also be achieved with negative‐pressure wound therapy (NPWT), also known as vacuum‐assisted closure. Subatmospheric pressure between −75 and −125 mmHg is applied to the wound using a small vacuum pump and an occlusive dressing (Figure 19.1). This technique speeds wound closure, evacuates inflammatory fluid and debris (including bacteria) from the wound, and improves microcirculation within the wound.49,50 Originally developed for use in human medicine, NPWT is increasingly used in small‐animal medicine for grossly contaminated or otherwise complicated wounds.51–57 Improvements in the design of the dressing and in the size and portability of the pump make NPWT a good option for use in horses as well.58 For more information on negative‐pressure wound therapy, see Chapter 22. Figure 19.1 Vacuum‐assisted closure. Source: Orsini 2004.48 Reproduced with permission of Elsevier. The wound must be protected from additional contamination until the infection is under control. It may be protected by following these steps: Daily treatment may initially be required for biofilm‐infected wounds (discussed later). Daily dressing changes may also be needed for effusive wounds, such as those involving a synovial structure. A bandage that is wet all the way through to its outer surface may wick bacteria into the protected and nutrient‐rich environment of the wound dressing. Similarly, a dressing moistened by water, urine, or fecal liquor no longer protects the wound and should be changed immediately. On the one hand, frequently changing the dressing on an open wound can disrupt the granulation bed and the fragile neoepithelium, thereby impeding wound repair. On the other hand, persistent infection prevents effective wound repair. When treating any type of wound, a fine balance must be achieved between protecting the repair tissue and controlling infection, but when dealing with a severely infected wound, the latter is initially the most pressing concern. Not only do infected wounds in animals carry the potential for human infection (zoonosis), but humans can transmit pathogenic bacteria, such as S. aureus, S. epidermidis, and E. coli and other enterobacteria, to the animal patient (i.e., reverse zoonosis or “humanosis”).59 The presence of a bacterial refuge in an infected wound is not always obvious. When the convention is to focus on identifying the bacterial pathogens and determining their antibiotic susceptibility, the question of whether the chosen drug can reach the pathogen at a therapeutic concentration may not come up until the infection has failed to respond to antibiotic therapy. By this time, the infection and resulting inflammatory response may have caused considerable tissue damage, thereby creating a refuge in the form of devitalized tissue or a pool of purulent material, or the pathogens may have created their own refuge in the form of a biofilm. The problem, and thus the solution, however, is not always so complicated. Sometimes identifying and removing a foreign body, problematic surgical implant, or sequestrum, or draining an abscess, are sufficient to tip the scales in favor of the host. The presence of a non‐surgically implanted foreign body within the wound can often be deduced from the cause of the wound (if known) and from the subsequent dynamics of the wound. For example, when a wound caused by collision with a wooden or metallic object fails to heal, despite standard wound care, and continues to drain purulent material from its depths, it likely houses a piece of wood or metal, or possibly a sequestrum of some kind, such as bone or devitalized connective tissue. Diagnostic imaging is indicated for such wounds. Removal of a surgical implant may be indicated for some severely infected wounds. Surgical implants often loosen or otherwise fail at the site of infection. A loose implant no longer contributes to repair, and its repeated movement may cause tissue damage. In addition, surgical implants contribute to the infection if they harbor bacterial biofilms (discussed later). Even very smooth surfaces, such as metal bone plates and pins may become coated in a biofilm and thus become a site of persistent or recurrent infection. Biofilms can also form on embedded suture material.60 Furthermore, surgical inspection and, if indicated, removal of the implant provide the opportunity to directly examine and treat the site of infection. The wound can be irrigated, debrided, and drained during surgical inspection, the implant can be swabbed for culture and sensitivity testing, and, if needed, antibiotic‐impregnated materials can be placed in the wound (discussed later). Submitting the implant or a sterile swab of its surface for bacterial culture and antibiotic sensitivity testing is essential. Confirming that the bacteria cultured from the implant are the same as those cultured from the wound’s tissues or exudate is valuable; discovering that bacteria cultured from the implant are different is more valuable still, particularly if the wound is complicated by a biofilm. Whether or not the implant should be replaced depends on the stage of healing, the quality of the remaining tissue after debridement, and whether an implant is still needed for structural support during healing. Structural defects of functional significance (e.g., complete fracture, large abdominal wall hernia) require some means of support, although external stabilization may be appropriate in some cases (e.g., external fixator and/or cast for a limb facture, belly band for an abdominal wall hernia). In making these decisions, access to the wound must be considered because the infection is not always resolved simply by removing the implant. Subsequent wound care is similar to that described earlier for extensively contaminated wounds. Interim antibiotic therapy while awaiting results of culture and antibiotic sensitivity testing is discussed later. When an implant must remain in place or when debridement was necessarily incomplete, the various methods of local or regional antibiotic delivery, such as regional limb perfusion and insertion of antibiotic‐impregnated implants, are particularly useful. These techniques are discussed later in the chapter. Devitalized tissue, whether skin, connective tissue, muscle, bone, or other tissue, may form a sequestrum, which acts as a bacterial refuge similar to a foreign body. Management, likewise, is similar to that for managing a wound containing a foreign body, but care should be taken to debride only the tissue that is devitalized. If the infection involves a structure, the loss of which the horse can accommodate, such as the common digital extensor tendon, complete surgical resection may be warranted if that structure is extensively contaminated or severely infected.61 An abscess can act as a bacterial refuge by protecting the bacteria from host defenses in its avascular and relatively hypoxic liquid or inspissated contents. Formation of an abscess creates conditions, such as low pH, that inactivate certain antibiotic drugs. Aminoglycosides, in particular, do not perform well in the presence of purulent exudate.62 When the presence of an abscess is confirmed using diagnostic imaging and/or needle aspiration, the abscess should be surgically drained, if possible, and then debrided and irrigated as described for extensively contaminated wounds. Bacterial biofilms present a particular therapeutic challenge. Not only do they protect the bacteria contained within them from the host’s defenses and from antibiotics, they are also highly resistant to chemical damage. A mature biofilm is relatively impervious to common antiseptics, alcohols, acids, bleach, hydrogen peroxide, and other generators of oxygen radicals (e.g., ozone), unless these products are used at a concentration toxic to the host’s cells.36,37 Plaque on dental enamel is a good example of a biofilm and a handy reminder of how quickly bacterial biofilms can form (and re‐form) in a suitable environment and what is required to remove them. The biofilm on teeth must be physically degraded to expose the bacteria within to antibacterial substances, which then slow the re‐formation of the biofilm. Antiseptic mouthwashes are of little and short‐term benefit if they are not preceded by thorough brushing and flossing. Another essential element in treating biofilms is to remove the biofilm repeatedly (i.e., regular tooth brushing). Ridding an infected wound of a biofilm requires the same basic approach as ridding the teeth of plaque (oral biofilm). The following is a step‐by‐step summary of what to do and what to avoid:35–37,63 (*These are the most studied methods in human wound care.) The goal is to remove as much of the biofilm and associated bacteria as possible and to expose the remaining bacteria to a biocide (Step 2). Surfactants, such as polyhexamethylene biguanide (polyhexanide or PHMB), may be useful adjuncts because they reduce the surface tension of the biofilm, which facilitates degradation and removal of the biofilm. Gloves should be worn to protect against zoonotic and reverse‐zoonotic infections. A surgical mask and protective eyewear should also be worn when using pulsed water‐jet irrigation, particularly if the wound is known to be, or suspected to be, infected with MRSA or other multidrug‐resistant bacteria. Because this step may be uncomfortable for the patient, the horse should be sedated, and the wound desensitized by using local or regional anesthesia. The horse may need to be anesthetized, at least for the first debridement, if the wound is deep or extensive, or if the horse is uncooperative. In most cases, bacteria found in biofilm are susceptible to a wide variety of biocides immediately after debridement, including ionic silver solutions36,67 and ozone,36,68–70 but the best choices may be those that have a residual effect by virtue of their adherent properties (e.g., gels, creams, honey). Antimicrobial dressings, such as silver‐impregnated wound dressings, inhibit bacterial biofilms,67,71–73 but, because their efficacy drops after the first 24 hours,72 these dressings must be changed frequently. An added advantage to topically applied silver and other antimicrobial agents is that they increase the susceptibility of bacteria to antibiotic drugs, which may help counteract the antibiotic resistance acquired by bacteria in biofilms.36,72 Topical application of plasma (natural or hyperimmune) to the wound may also be useful because plasma inhibits bacterial adhesion and growth.74–76 Platelet‐rich plasma speeds wound healing, but the components of plasma other than platelets appear to provide plasma’s bacteriostatic effect.76 Whether or not antigen‐specific equine hyperimmune plasma (see Immunocompromise, later) is superior to plain plasma for inhibiting the formation or re‐formation of a biofilm remains to be determined, but an antigen‐specific hyperimmune plasma might be of great benefit if the specific pathogen targeted by the hyperimmune plasma is present within the wound. Other antibiofilm agents under investigation include lactoferrin, xylitol, ethylenediaminetetra‐acetic acid (EDTA), RNA III inhibiting peptide, dispersin B (a bacterial glycoside hydrolase), gallium, acetylsalicylic acid, various phytochemicals, bacteriophages (antibacterial viruses), glucose oxidase, proteases, ultraviolet light, and low‐voltage pulsed electric fields.36,77,78 Regardless of which methods are selected to degrade the biofilm, the biofilm bacteria should be targeted from above (topically) and below (systemically and/or regionally). Most biofilms are microscopic, and bacterial culture of biofilm‐protected inhabitants may be unrewarding,35,41,42 so until a practical, stall‐side test is available to identify the presence of a biofilm, clinical signs of persistent infection are the best guide. The wound should be reassessed frequently, and the method of debridement (Step 1) or inhibition (Step 2) should be changed if wound healing is not proceeding as expected. Each step is equally important. Degrading the biofilm helps restore the susceptibility of the bacteria to antibacterial agents, but when a severely infected wound has a well‐established or mature biofilm, one round of treatment to degrade the biofilm is insufficient. The wound must be treated daily, or at least every other day, using a combination approach (i.e., Steps 1 and 2) until the infection is resolved or is well on its way to complete resolution.35–37,63 This intensity of treatment disrupts the wound bed and interferes with repair of an uncomplicated wound, but wounds containing a bacterial biofilm are not simple or straightforward wounds, and many are chronic.34 Wound repair cannot proceed normally in the presence of a bacterial biofilm, so the priority should be to degrade the biofilm and prevent it from reforming, and thereby resolve the infection. Thereafter, the intensity and invasiveness of treatment can be reduced and tailored to the rate and quality of wound repair. The higher initial costs of this approach are counterbalanced by lower overall costs because chronic wounds are a considerable and protracted financial drain. In human patients with chronic wounds that are complicated by biofilms, frequently debriding the wound as part of a multifaceted approach to wound care shortens the duration of treatment and decreases the overall costs of treatment.37 Biofilms on unstable surgical implants are best resolved by removing the implant. Biofilms on surgical implants that are still performing the function for which they were applied (e.g., bone plate stabilizing a complete fracture) are more of a challenge, because there may be no indication for implant removal, other than removal of the biofilm, and good indications to leave the implant in place. In such cases, it may be best to anesthetize the horse, surgically expose the implant (or the infected portion thereof) and perform Steps 1 and 2 in a sterile surgical suite, and then pack the wound with an antibiotic‐impregnated material79 (discussed later). Reminder: Biofilms in wounds are most likely to form and persist if the horse is immunocompromised and/or if perfusion of the wound is poor. These problems must be identified and addressed for treatment to be effective. Typically, patients with severely infected wounds have already undergone initial systemic assessment and treatment. Even so, taking the following steps is wise:
Management of Severely Infected Wounds
Summary
Introduction
Origins of severe wound infections
Extensive contamination
Refugia
Bacterial biofilms
Immunocompromise
Poor perfusion
Antibiotic insensitivity
Empiric antibiotic therapy
Over‐reliance on antibiotics
Targeted treatment approach
Extensive contamination
Irrigation
Debridement
Drainage
Negative‐pressure wound therapy
Wound protection
Refugia
Foreign bodies
Surgical implants
Sequestra
Abscesses
Bacterial biofilms
Biofilms on surgical implants
Immunocompromise
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