(1)
Department of Medicine, Section of Infectious Diseases, University of Illinois at Chicago, Chicago, IL, USA
(2)
Department of Medicine; Section of Infectious Diseases, Immunology, and International Medicine, University of Illinois at Chicago, Chicago, IL, USA
(3)
Department of Internal Medicine, Jesse Brown VA, Chicago, IL, USA
(4)
Infectious Disease, Alexian Brothers Medical Center, Elk Grove Village, Chicago, IL, USA
Keywords
DiabetesWound infectionsOsteomyelitisCellulitisSkin and soft-tissue infectionsIntroduction
Throughout history, wound infections have had an important impact on public health. No story provides greater illustration of the importance of wound infections than statistics from historic conflicts. Prior to the development of effective antimicrobials, early amputation was considered the most effective way to treat wound infections [1], and battlefield wound infections historically had an estimated mortality as high as 38–62 % [2]. Historians estimate that prior to World War II, more victims of war died of infectious causes than of battle-related injuries [3, 4].
Though the development of antibiotics improved survival of those with infected wounds, wound infections continue to be a major problem in the modern era. Alarmingly, reports from current war zones show a high rate of wound colonization with multidrug-resistant (MDR) pathogens [5, 6]. As the frequency of MDR organisms continues to increase in battlefield wounds, these wounds may become progressively more difficult to treat.
Compared to acute traumatic wounds in young healthy soldiers, chronic wounds in patients with multiple comorbidities may present a larger and more costly medical challenge. A primary risk factor for lower extremity wounds is diabetes; patients with diabetes have a 25 % lifetime risk of developing an ulcer, and half of those ulcers will become infected [7]. Diabetic wound infections have been shown to increase the risk for hospitalization and lower extremity amputation by 55- and 150-fold, respectively [7]. Due to increasing rates of diabetes, increased obesity in the population, and a longer life span of patients with diabetes, it is expected that lower extremity wounds will become an increasingly burdensome public health problem in the coming years [8].
Infection of a skin ulcer has been shown to lead to decreased healing, increased treatment costs, and increased morbidity for patients. One study found that subjects with postsurgical wound infections had a twofold increase in the average number of hospitalization days compared to uninfected patients [9]. Increased hospitalization days, decreased healing, and increased need for therapeutic interventions have all been associated with increased costs [10].
Clinical Manifestations of the Infected Wound
Given the morbidity associated with wound infections, it is extremely important to accurately and promptly identify an infected wound. Additionally, we must also consider the clinical impact of overtreating the uninfected wound. By treating uninfected ulcers, we unnecessarily place patients at risk for complications such as Clostridium difficile-associated diarrhea, development of antibiotic resistance, and an increased cost of care due to the expense of unnecessary antimicrobials. Not only are these outcomes potentially problematic to the individual; they are also costly to the health-care system as a whole.
The Wound Infection Continuum
One of the most important concepts to understand in the pathogenesis of wound infections is that of microbial contamination/colonization and the subsequent path to infection. Wound contamination is defined as the presence of nonreplicating organisms in a wound. Sources for organisms present in a contaminated wound include environmental sources, normal skin flora, or endogenous sources (gastrointestinal, genitourinary, etc.) [11]. Wound contamination is the first step in what is known as the wound infection continuum [11, 12]. It is the interaction between these bacteria and the host’s immune system that can lead to infection [13, 14].
The next stage in the wound infection continuum is wound colonization . A wound is defined as colonized when the microorganisms present are dividing and multiplying, but are not causing injury to the host tissue [13–15]. Exposed tissue in acute or chronic wounds provides an excellent environment for pathogens to proliferate [16].
Critical colonization is a term first defined by E. Davis in 1996 as “multiplication of organisms without invasion but interfering with wound healing.” However, this definition lacked either a clear clinical or microbiological meaning [17]. Later it was redefined as the inability of the wound to maintain a balance between increasing “bioburden” of bacterial replication and the host immune system [18]. Some studies have suggested that a bacterial load >105 colony-forming units (CFU) per gram of tissue may provide a quantitative estimate of the point of critical colonization, above which colony count infection becomes increasingly likely. However, this is a controversial subject, and definitive proof about the presence of a specific colony count associated with critical colonization is lacking.
Several studies have suggested that it may not be the bacterial load but rather the presence of a particular species of bacteria or a specific host response to colonization that define the concept of critical colonization [19]. Regardless, the process of critical colonization and its clinical significance warrant further investigation as this process may represent an opportunity for early intervention and healing as well as potentially decreased need for systemic antimicrobials [11].
While the concept and definition of critical colonization remain an ongoing discussion among wound care experts, there is little scientific evidence to support impaired wound healing based on bacterial burden or critical colonization alone [8, 11, 13, 17]. Most experts do agree that there are instances in which a wound may not display overt or classic signs of infection but instead display secondary signs that signal the presence of a subclinical infection. These signs include delayed healing, friable granulation tissue, increased serous drainage, or increased pain. Early antimicrobial therapy may be warranted in the setting of these secondary signs of infection, but clear guidelines for when to initiate treatment in patients with secondary signs of infection are lacking [8, 11] (Fig. 46.1).
Fig. 46.1
The wound infection continuum, starting with contamination and leading to infection
Wound infection represents the final stage of the infection continuum. An acute or chronic wound can progress to infection after colonization occurs and when the right conditions are present for tissue invasion. An infected wound is defined as invasion of microorganisms within the wound area, leading to cell injury, tissue damage, and inflammation [20].
Clinical Spectrum of Skin and Soft-Tissue Infections
Understanding the anatomy of skin structures and the various clinical manifestations of skin infections can be helpful in determining likely pathogens for a given patient. Infectious syndromes involving skin and soft-tissue structures can be caused by a variety of organisms, but certain syndromes are highly associated with specific pathogens. This may help the clinician predict the pathogen and select appropriate empiric therapy (Fig. 46.2).
Fig. 46.2
The layers of skin structure and the skin and soft-tissue infections associated with each level
Erysipelas is defined as infection of the superficial layers of the dermis without subcutaneous involvement. Erysipelas can travel through lymphatic tissue and spread quickly. Erysipelas is typically caused by Streptococci. In contrast, cellulitis is an infection of the skin and underlying connective tissue. Streptococcus pyogenes can play an important role in both erysipelas and cellulitis. Large studies have shown that Streptococci may be the most common cause of cellulitis [21, 22]. Staphylococcus aureus (including MRSA) plays an important role as well and is more common in the setting of cellulitis with purulence [23].
Impetigo (easily identifiable due to the characteristic associated honey-colored exudate) and ecthyma are both infections of the superficial dermis. Ecthyma is an ulcerative pyoderma of the skin that extends into the deeper tissues. Ecthyma is typically referred to as a deeper form of impetigo. Both impetigo and ecthyma are commonly caused by Staphylococcal and Streptococcal spp. Similarly, furuncles and carbuncles (both forms of cutaneous abscesses) involve these same structures and pathogens.
Diabetic infections can involve multiple tissue planes and are typically polymicrobial. Highly pathogenic organisms such as Pseudomonas spp. can be involved in these infections. Though this association is well known, the contribution of this organism to underlying pathology of diabetic foot infections has recently been questioned. A recent randomized controlled trial challenged the idea that empiric antimicrobials that cover Pseudomonas species are necessary in diabetic foot infections [24]. Given the difficulty in obtaining and interpreting appropriate culture samples for microbiologic diagnosis in wound infections, it is always prudent to monitor patients closely once therapy has been initiated.
Surgical site infections can involve superficial incisional tissues, deep incisional tissues, or deep organ spaces. These infections can be caused by typical causative organisms involved in skin infections or by normal flora of the organs involved in specific procedures. Finally, vascular surgical wounds or ischemic wounds can have a variety of organisms. Postoperative infectious complications from vascular surgery cause significant morbidity and are common [25]. Infected anatomical sites and risk of infection are typically dependent on the degree of hypoxia in the affected tissues [25]. A case series of vascular cases from Sri Lanka demonstrated that Pseudomonas was involved in many of its infections [26] (Table 46.1).
Syndrome | Anatomy | Microbiology |
|---|---|---|
Erysipelas | Epidermis | Group A Streptococcus |
Cellulitis | Dermis | Group A Streptococcus Group G Streptococcus S. aureus |
Furuncles | Epidermis | S. aureus |
Carbuncles | Epidermis, dermis | S. aureus |
Diabetic foot infection | Epidermis, dermis, fascia, bone | Polymicrobial |
Surgical site infection | Epidermis, dermis, fascia, deep organs | S. aureus, Streptococci, anaerobes |
Vascular surgery and ischemic limbs | Multiple tissue planes, depends on level of tissue hypoxia | S. aureus, Streptococci, anaerobes |
Microbiology of Wound Infections
Wound infections have a complex microbiology that is dependent on interactions between the host and their environment. Understanding the microbiology of infected wounds is of importance for clinicians in order to properly identify infected wounds, accurately interpret microbiologic data, and make appropriate medical decisions regarding patient care.
Organisms can colonize wounds from a variety of sources. Normal skin flora, largely composed of Gram-positive organisms, is the most common source of colonization in wounds. Organisms from other mucosal surfaces and anatomical compartments (e.g., Gram-negative organisms from the gastrointestinal tract or upper airway) can also migrate to the wound. Finally, the environment can play a key role, as organisms from the environment can be introduced into a wound through direct contact [16].
Endogenous Sources
The skin microbiota consists mostly of Gram-positive bacteria such as Staphylococcus epidermidis, other coagulase-negative Staphylococci, and Propionibacterium acnes. These bacteria coexist with human beings in a delicate balance of natural immune barriers and bacterial properties that confer a propensity toward survival and persistence rather than aggressive virulence and host-damaging properties [27]. However, these organisms can easily migrate to deeper tissues when natural skin barriers are compromised, and in that setting, skin commensals can play a pathogenic role [28, 29]. As evidence for their contribution to the pathology of wound infections, the resistance pattern of skin commensals has been linked with overall mortality [30].
Other endogenous sources of importance are the oral, genital, and gastrointestinal mucosa. A large study of surgical wounds showed that the predominant organisms in abdominal infections were primarily endogenous gastrointestinal organisms including E. coli, Streptococcus species, Bacteroides, Peptostreptococcus, and Clostridium species [31]. Similarly, a study of decubitus ulcers in children showed the presence of enteric pathogens as well as Pseudomonas [32].
Exogenous Sources
The environment can play an important role in the colonization of wound infections. Once only diagnosed in patients with contact with health care, the so-called hospital-acquired multidrug-resistant pathogens have now spread to the community. A study assessing the prevalence of MDR organisms in diabetics and nondiabetics showed that the prevalence of these organisms can be as high as 63 % [33]. Animals have been shown to serve as a reservoir of drug-resistant organisms, and contact with animals can be associated with subsequent transmission of MDR organisms to the community [34]. Infection control measures have decreased the burden of transmission of MDR organisms in the hospital setting [35], but colonization through exogenous contamination remains a problem both in the hospital setting and in the community .
Anaerobes
Due to the difficulty in isolating anaerobic bacteria, the role of anaerobes in wound infections has been neglected in the past by the scientific community [9, 16, 29]. However, multiple recent studies have consistently shown that anaerobic organisms may play a major role in the microbiology of contaminated and infected wounds [28, 29, 36]. Microbiologic data from over half a dozen studies demonstrated that anaerobes were present in about 38 % of wounds [16]. Hence, the presence of anaerobic organisms should always be considered as contributing to the pathology of infected and noninfected wounds.
Variables Affecting Microbial Proliferation
An acute or chronic wound that has been colonized with bacteria can progress to infection when the right conditions are present for tissue invasion and bacterial replication. Factors that favor the development of wound infection include tissue hypoxia and patient comorbidities.
Tissue Oxygenation and Bacterial Growth
Perhaps the most important factor affecting the transition from colonization to infection is tissue perfusion. A hypoxic environment allows for increased microbial growth, as oxygen is a key component of oxidative reactions in polymorphonuclear leukocytes [37]. Chronic nonhealing ulcers are frequently hypoxic and therefore are more susceptible to infection than well-perfused tissues [38]. Surgical wounds in anatomical sites that have excellent tissue perfusion typically heal rapidly and have less likelihood of infection [39]. Studies have shown that wounds will likely heal adequately if tissue oxygen tension is above 40 mmHg; however, when perfusion fell to levels of less than 20 mmHg, healing was found to be less likely and infection more common [39].
Comorbidities
Comorbidities present in the host may contribute both to colonization and subsequent infection of the wound. Comorbidities that cause decreased perfusion or alteration in the innate or acquired immune system may increase the risk of wound infections and also lead to impaired wound healing in the event of infection. Recently debrided or amputated tissue has been shown to have decreased concentration of antibiotics compared to serum levels, demonstrating an important mechanism by which poor perfusion leads to impaired wound healing [40].
Foot infections have been shown to be the most common cause of hospitalization among patients with diabetes [8]. Large observational studies show that peripheral artery disease (PAD) plays a key role in diabetic foot infections, as almost half of the patients enrolled in these studies had evidence of such [8]. Other comorbidities that lead to PAD can therefore predispose patients to wound infections and decreased healing .
Diagnosis of Wound Infections
Diagnosis of wound infections is based primarily on clinical signs and symptoms (Table 46.2). Most studies relating to diagnosis of wound infections have been conducted on patients with diabetic foot wounds. In 1994, Cutting and Harding first identified criteria to diagnose an infected wound, which included the classic signs of inflammation: erythema, warmth, pain, and edema [41]. The current Infectious Disease Society of America (IDSA) guidelines for diabetic foot infections recommend diagnosing a diabetic foot infection based on the presence of at least two of these classic signs or symptoms of inflammation in addition to purulence from the wound [2, 42].
Table 46.2
Clinical signs of wound infections
Classic | Secondary | Systemic |
|---|---|---|
Erythema | Malodor | Tachycardia |
New or increased pain/tenderness | Friable granulation tissue | Fever/chills |
Purulence | Delayed healing | Hypotension |
Swelling or induration | Increased nonpurulent secretions | Delirium |
Discoloration | ||
Pocketing at base of wound |
However, it is necessary to take into account all of the clinical features of an individual patient’s presentation to make appropriate clinical decisions, as the classic signs of infection may be absent in some patients with an infected wound [28]. In particular, patients with limb ischemia may lack erythema and warmth, and those with peripheral neuropathy may not present with pain. In these circumstances, the presence of secondary signs of infection such as an increase in nonpurulent secretions, friable granulation tissue, foul odor, undermining of the wound edges, or delayed wound healing can be helpful in making the diagnosis of a wound infection [41].
Once a wound has been identified as infected, it can then be further defined as mild, moderate, or severe. Determining the severity of a wound infection can help determine how best to manage the patient. The IDSA and the International Working Group of the Diabetic Foot (IWGDF ) have developed a classification for determining the severity of a diabetic foot infection (Table 46.3). Per this classification system, mild infection involves only the skin and subcutaneous tissue, with a limited area (if any) of surrounding erythema. A moderate infection is defined as either a superficial infection involving a larger area (>2 cm) of the skin surrounding the ulcer or an infection that involves deeper structures (i.e., an abscess, osteomyelitis, fasciitis). Finally, a severe infection is any local infection associated with two or more of the following SIRS criteria: a leukocyte count >12,000/μL or <4000/μL or >10 % immature (band) forms, temperature >38 °C or less than 36 °C, heart rate of more than 90 beats per minute, respiratory rate of more than 20 breaths per minute, or arterial carbon dioxide tension (PaCO2) of less than 32 mmHg [43]. Patients with severe infections require hospitalization, while those with mild infection can typically be managed as outpatients. In regard to those with moderate infections, many can be managed as an outpatient, with the exception of those with critical ischemia [8].
Infection severity | Signs/symptoms |
|---|---|
Uninfected | No signs or symptoms of infection |
Infected | At least two of the following: • Pain/tenderness • Erythema • Warmth • Swelling or induration • Purulent discharge |
Mild infection | • Local infection: involves only the skin and subcutaneous tissue • Erythema >0.5 cm to <2 cm around ulcer • No other etiology for inflammatory response of the skin (thrombosis, venous stasis, gout, etc.) |
Moderate infection | • Local infection with • Erythema >2 cm or • Involving deeper structures than the skin and • No systemic inflammatory response signs |
Severe infection | Local infection with signs of SIRS; at least two of the following: • Temp >38 °C or <36 • Heart rate >90 beats/min • Respiratory rate >20 breaths/min or PaCO2 <32 mmHg • White blood cell count >12,000 or <4000 or >10 % bands |
Although the IDSA/IWGDF classification system has primarily been validated in patients with diabetes and may not be applicable to other patient populations, it is likely that all patients with a wound infection would at least benefit from a determination of the severity of their wound and a strategy of intensifying care based on the severity level of the wound.
When to Obtain a Culture
As described previously, all chronic wounds are at the very least colonized with bacteria. For this reason, it is imperative that wounds are not routinely cultured unless there is suspicion for infection.
Most wounds that are clinically believed to be infected should be cultured. The sole exception would be in the case of a mild infection in an antibiotic naïve individual with low risk for MRSA infection. In that setting, a wound culture may be unnecessary as these types of infections are invariably caused by Streptococci or Staphylococci, and an empiric regimen covering these organisms is typically a sufficient therapy [8]. In all other cases of presumed wound infection, however, wound culture should be obtained. Whenever possible, culture samples should be obtained prior to the initiation of antimicrobial therapy [8].
What Type of Wound Culture to Obtain
Obtaining an adequate sample from an infected wound may be challenging. Potential types of samples include superficial swabs, deep tissue cultures, sterile needle aspiration, tissue biopsy, and others.
Superficial wound swabs have been shown to have an extremely poor ability to identify the true pathogens responsible for a wound infection. In particular, if a wound has not been properly debrided, the swab may be contaminated by normal skin flora, and anaerobic or fastidious aerobic organisms may fail to grow. A meta-analysis demonstrated that superficial wound swabs had a sensitivity as low as 49 % and a specificity of 62 % to identify the causative organisms of an infection; these cultures were therefore deemed incapable of directing antimicrobial therapy [44]. Because these samples may confuse clinicians and expose the patient to unnecessarily broad antimicrobials, it is generally recommended to limit the use of wound swabs to infection control purposes and possibly to help identify future empiric regimens if the patient decompensates.
Compared to superficial wound swabs, deep tissue cultures may be more likely to identify the truly invasive and pathogenic organism in any given case [16]. If a significant amount of fluid is present, for example, in the case of an intact abscess, an alternative method is needle aspiration which has been shown to have good sensitivity for the diagnosis of skin and soft-tissue infections [45].
The clinician may obtain valuable information from superficial or deep samples, but ultimately proper management will require close observation to assess for clinical improvement. Due to these limitations, investigators are studying the use of novel PCR- and molecular-based techniques for bacteriologic diagnoses in wound infections [46].
How to Obtain a Culture
Culture samples should be obtained only after the wound has been cleansed and debrided. If the wound is open, whenever possible the tissue sample should be obtained from the debrided base. The samples should then be sent to the laboratory in a sterile and properly labeled container for aerobic and anaerobic culture [8, 16]. Regardless of the specimen type obtained, prompt transportation to the laboratory is essential to increase the likelihood of isolating all microorganisms, in particular anaerobic bacteria.
Quantitative Significance of Colonies
As early as 1964 a study showed that an increased (>106 CFU/mL) bacterial load of wound cultures may be related to the progression of wound ulcers and infection [47]. Since that original study, the pendulum has swung on both sides, but the overall weight evidence demonstrates that higher CFUs are associated with increased rates of infection and inadequate wound healing. Recent studies continue to confirm this observation, with one study showing that a bacterial concentration over 104 CFU must be reached to cause infection in lower extremity wounds [48].
Other Diagnostic Studies
A comprehensive evaluation of the patient with a suspected wound infection is essential. This includes examination of the patient as a whole, not just focusing on the wound or affected limb. Signs and symptoms such as tachycardia, altered mentation, hypotension, or fever may be present and are suggestive of a systemic illness that warrants more aggressive care. Additionally, the work-up should include a complete blood count with differential to evaluate for a leukocytosis or a neutrophilia, erythrocyte sedimentation rate (ESR), and a C-reactive protein level (CRP). Recently, several prospective studies have shown the promising role of procalcitonin (PCT) as an indicator of bacterial infection in diabetic foot infections [8]. Jafari et al. [49] showed that PCT could help distinguish between uninfected and infected ulcers. However, PCT was found to be highest in severe diabetic foot infections, but only slightly increased in mild infections. For that reason, the highest sensitivity in distinguishing uninfected ulcers from infected ulcers was by combining PCT with another marker such as ESR or CRP [19]. If a patient appears systemically ill or is classified as having a severe infection, blood cultures should be obtained in addition to tissue culture prior to the initiation of broad-spectrum antibiotics .
Treatment
General Approach to Antibiotic Therapy
In the era of increasing antimicrobial resistance and multidrug-resistant organisms, it is imperative to exercise judicious use of antibiotics to both minimize the emergence of drug resistance and the risk to patients of adverse side effects. Whenever feasible, antibiotic therapy should be guided by microbiologic culture with antibiotic susceptibility testing. Empiric choices of antibiotics should be directed against the most common pathogens and narrowed accordingly when further microbiologic information is available.
It is important to note that not all wound infections require the use of systemic antibiotics. If the infection appears mild and there are no clinical signs of sepsis as defined by the SIRS criteria [43], then the patient may not require systemic antibiotic therapy; in this setting, local wound care or an incision and drainage (if there is evidence of localized, purulent infection) may suffice.
Conventional teaching has historically stated that a bactericidal antibiotic is preferred over a bacteriostatic antibiotic. A bactericidal antibiotic is defined as one that kills bacteria. In contrast, a bacteriostatic organism suppresses the growth of bacteria in order to allow the host’s immune system to kill bacteria [50]. Although conventional wisdom has favored the use of bactericidal bacteria, for most infections outcomes using bacteriostatic versus bactericidal antibiotics are similar. Generally, it is recommended to choose a bactericidal antibiotic for infections likely to have an impaired contribution from the host immune system either due to a neutropenic or immunocompromised patient or in the setting of infections such as osteomyelitis where the immune system has impaired access to the site of infection. In all other cases, bacteriostatic and bactericidal antibiotics are likely to have similar outcomes [50, 51].
The initial choice between oral and parenteral antibiotics should be based on the clinical presentation of the patient. If the patient is defined as having a severe infection according to the IDSA/IWGDF, parenteral antibiotics are recommended. When signs of sepsis are absent, oral regimens are acceptable.
The specific choice of antibiotics will depend on the clinical history and the presentation of the patient. As discussed earlier in the chapter, Staphylococcus aureus and Streptococcal spp. are the most common microbiologic cause of infections. Accordingly, initial antibiotic therapy should be directed against these most common etiologic bacteria. Ideally, appropriate culture samples will be obtained prior to antibiotic initiation and therapy can be tapered when culture results are available.
Staphylococcus aureus
MRSA
Choosing an antibiotic that is effective against methicillin-resistant Staphylococcus aureus (MRSA ) is recommended pending microbiologic data to further guide therapeutic decisions. Studies have shown high rates of MRSA (ranging from 15 to 74 %) in community-acquired, purulent skin and soft-tissue infections in the USA [52]. The “best” antibiotic with which to treat MRSA wound infections is not clear. A systematic review to assess for the best choice of antibiotic to treat MRSA-infected nonsurgical wounds was unable to find any difference in outcomes between those treated with vancomycin versus daptomycin [53]. The IDSA recommendations for MRSA skin and soft-tissue infections (SSTIs) suggest oral clindamycin, Bactrim, or a tetracycline (doxycycline or minocycline) for mild infections where systemic antibiotic therapy is indicated. Linezolid is available in both oral and intravenous formations but remains expensive. For more serious infections, intravenous therapy with vancomycin, daptomycin, linezolid, or ceftaroline is recommended [23]. In summary, the choice of antibiotic for MRSA disease is an interplay between disease severity, patient profile (allergies, interacting medications, comorbidities, etc.), and clinician experience (Table 46.4).
Antibiotic | Dose (adults) | Dose (children) | Adverse effects | Comment |
|---|---|---|---|---|
Vancomycin | 30 mg/kg/day in two divided doses IV | 40 mg/kg/day in four divided doses IV | Nephrotoxicity Ototoxicity Red man syndrome | Drug of choice in PCN allergic patients |
Daptomycin | 4 mg/kg every 24 h IV | n/a | Rhabdomyolysis | Bactericidal |
Linezolid | 600 mg every 12 h IV or 600 mg bid po
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