Infectious Disease (Bone and Soft Tissue)

MARK KOSINSKI

The Host Response to Infection

Infection can have a profound systemic effect on the human body. In the event of severe lower extremity infections, sepsis and even death can occur. In 1992, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) introduced definitions for bacteremia, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome. Table 4-1 lists the definitions for sepsis and organ failure.¹

Table 4-1. Definitions for Infection and Sepsis

Infection

The inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms.

Bacteremia

The presence of viable bacteria in the blood.

Systemic Inflammatory Response Syndrome

The systemic response to inflammation, either infectious or noninfectious.

Two or more of the following conditions:

Temperature >38°C or <36°C
Heart rate > 90 beats per minute
Respiratory rate >20 breaths per minute or Paco₂ <32 mm Hg
WBC count > 12,000 per mm³, <4,000 per mm³, or >10% immature (band) forms

Sepsis

The systemic response to infection.

Two or more of the following conditions as a result of infection:

Temperature >38°C or <36°C
Heart rate > 90 beats per minute
Respiratory rate >20 breaths per minute or Paco₂ <32 mm Hg
WBC count > 12,000 per mm³, <4,000 per mm³, or >10% immature (band) forms.

Severe Sepsis

Sepsis is associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to lactic acidosis, oliguria, or an acute alteration in mental status.

Septic Shock

Sepsis induced with hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are receiving inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured.

Sepsis-Induced Hypotension

Systolic blood pressure <90 mm Hg or a reduction of >40 mm Hg from baseline in the absence of other causes of hypotension.

Multiple Organ Dysfunction Syndrome

Presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention.

Reprinted from Bone RC, Balk RA, Cerra FB, et al. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864-874, with permission.

Infection can be defined as an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms.¹ Bacteremia can be
defined as the presence of viable bacteria in the blood. Sepsis is defined as severe systemic inflammation in response to invading pathogens, or an uncontrolled hyperinflammatory response.² SIRS is the systemic response to an infectious or noninfectious insult and is characterized by two or more of the following: body temperature >38°C or <36°C, tachycardia (>90 beats per minute), respiratory rate >20 breaths per minute, Paco₂ < 32 mm Hg, and leukocytosis (>12,000 or <4,000 per mm³) or 10% immature (band) forms. It is nonspecific as to etiology. Sepsis, on the other hand, is defined as the systemic response specifically to infection, its criteria being otherwise identical to SIRS.³

Purpura Fulminans as the Host Response to Sepsis

Sepsis is associated with multiple alterations in procoagulating and anticoagulating mechanisms,⁴,⁵ which may lead to full-blown disseminated intravascular coagulation.

Sepsis-induced purpura fulminans (sometimes referred to as disseminated intravascular coagulation syndrome) is a relatively rare, multisystem disorder characterized by cutaneous hemorrhagic infarction, occlusion of dermal venules and capillaries by microthrombi. Skin necrosis may ultimately result in dry, gangrenous changes to the fingers and toes (Fig. 4-1). It is caused by disseminated intravascular coagulation and dermal vascular thrombosis.

FIGURE 4-1. Patient with purpura fulminans. Note gangrenous changes to both feet and toes. (From Mark Kosinski, DPM, FIDSA, with permission).

Acute infectious purpura fulminans presents concurrently with the signs and symptoms of sepsis. Clinically, the patient with purpura fulminans has concomitant disorders including septicemia, shock, and disseminated intravascular coagulation.⁶

Cutaneous necrosis begins with a region of skin discomfort that quickly progresses within hours to petechiae, which coalesce to form ecchymoses.⁷ Purpuric skin lesions develop over the distal aspects of the feet and toes and tend to be symmetrical. These lesions can rapidly progress to hemorrhagic necrosis. Proximal extension of lower extremity lesions and diffuse patchy involvement of the abdomen and upper extremities can occur. Vascular changes are not limited to the skin; thrombosis and hemorrhagic necrosis are also common in other organ systems including the lungs, kidney, and adrenal glands, leading to multiorgan failure.

Once thought to be the result of septic embolization, purpura fulminans is caused by enhanced expression of the natural procoagulants and depletion of the natural anticoagulant proteins, particularly protein C.⁶ Sepsis-related purpura fulminans is associated with severe, acute bacterial or viral infection, and has been most commonly associated with infections because of meningococci, Neisseria meningitidis, Streptococcus pneumoniae Gram-negative bacteria, Haemophilus influenza, group A and B streptococci, Staphylococci and rickettsia.⁸,⁹,¹⁰,¹¹ The cutaneous lesions of sepsis-induced purpura fulminans are similar, regardless of the causative organism. Cultures of skin lesions are usually negative, although bacterial colonization may occur with time. Amputation of the gangrenous portion of the extremity after demarcation may become necessary in severe cases.¹²,¹³

Diabetic Foot Infections

Diabetic foot infections (DFIs) are perhaps the most common and most limb-threatening infectious complications of systemic disease. It is estimated that approximately one in four people with diabetes will develop an ulcer during their lifetime and that as many as half of these ulcerations will develop an infection.¹⁴ Approximately 15% to 20% of the estimated 16 million persons in the United States with diabetes mellitus will be hospitalized with a foot complication at some time during the course of their disease.¹⁵ For those with diabetes, it has been estimated that the lifetime risk of developing a DFI is about 15% to 25%, although only about half of DFIs are clinically infected on presentation.¹⁶,¹⁷

Treatment of DFIs, whether bone or soft tissue, should be conducted as part of a multidisciplinary approach, with tight control of blood glucose and revascularization when necessary.

Most of the writings on DFI throughout the 1980s and into the early 1990s were based on studies from the 1970s that seemed to suggest that all DFIs were polymicrobial. We now know that mildly infected diabetic wounds harbor predominantly aerobic
Gram-positive cocci, not anaerobes. Staphylococcus aureus and Group B Streptococcus are by far the most common pathogens in the infected diabetic foot ulcerations. Unfortunately, there is a serious concern about increasing rates of multidrug-resistant organisms (MDROs) in general and methicillin resistance in S. aureus isolates in particular.

There have been many attempts to classify DFIs. Probably the most commonly used was introduced by Wagner,¹⁸ which originally addressed only the dysvascular foot, but did not adequately address all diabetic foot ulcerations and infections.

The Infectious Diseases Society of America (IDSA) Practice Guidelines for the Diagnosis and Treatment of DFIs is perhaps the most widely used treatment-based classification system in current use and has been validated as a useful tool for grading foot infections.¹⁹ This system can assist the clinician in deciding whether or not an antibiotic is indicated, which antibiotic to choose, when to use a parenteral versus an oral antibiotic agent, when to hospitalize a patient, and when to consider surgical intervention. Under these guidelines, DFIs are classified as being mild, moderate, or severe.

Noninfected Ulcerations

Noninfected wounds, by definition, do not require antibiotic therapy. Routine culturing of wounds that do not appear clinically infected (i.e., no cellulitis, purulence, erythema) should be avoided because even noninfected ulcerations are colonized with multiple organisms.²⁰

The use of antibiotics to “prevent” infection is not supported by currently available medical evidence and may lead to the development of resistant organisms²¹ that may make subsequent infections more difficult to treat. In at least one study, microbial load and diversity has been shown not to be predictive of weeks-to-closure or percent reduction in surface area per week.²² Antibiotics should be used to treat infections, not heal wounds.

A common misconception is that patients with diabetes do not respond with cellulitis. Although there may be muted response to some of the signs of infection, it is extremely unlikely that there would be no evidence of cellulitis at all. Cellulitis is therefore a reliable indicator of infection in all but the most arterially compromised patients.

Mild Infection

The belief that all DFIs are polymicrobial has changed. Decades ago, it was thought that even mildly infected diabetic wounds harbored anaerobic bacteria such as Bacteroides fragilis, leading to treatment with broad spectrum antibiotics even in the face of negative anaerobic cultures.

We now know that mildly infected diabetic wounds harbor predominantly aerobic Gram-positive cocci. Whether the infection is mild, moderate, or severe, S. aureus and Group B Streptococcus are far and away the most common pathogens encountered.

Wounds with a mild infection show at least two of the signs and symptoms of a host response. There is usually localized cellulitis around the wound that extends <2 cm from the wound border. Purulent exudate may be present; however, the infection remains localized. There is no deep extension or proximal spread. There is no lymphangiitis or lymphadenopathy. There are no systemic signs or symptoms of infection, and the patient’s white blood cell (WBC) count and blood glucose are not above the patient’s usual range.

Mildly infected diabetic ulcers are treated no differently with respect to antibiotic choice and duration compared with similar wounds in nondiabetic patients and can usually be treated on an outpatient basis with oral antibiotic therapy. Antibiotic therapy should be directed against S. aureus and Streptococcus, with the caveat that there are increasing rates of methicillin-resistant S. aureus (MRSA) in these patients. Anaerobic coverage in these wounds is unnecessary. The use of broad spectrum agents such as amoxicillin/clavulanate or moxifloxacin, while not wrong, can be considered overkill.²³

Some patients may require debridement or incision and drainage for a small abscess or offloading of pressure areas. It is recommended that the patient follow up in a few days to review the results of culture and sensitivity tests and to ensure there has been an adequate response to treatment.

Moderate and Severe Infections

Moderate and severe infections are often classified together. The choice of antibiotics to treat each group is often similar, owing to the similarity of the spectrum of infecting organisms. However, moderate infections are limb threatening, whereas severe infections are life threatening.

According to the 2012 IDSA guidelines,¹⁹ moderate infections can be defined as those with cellulitis extending >2 cm from the wound margin or penetration of infection into the deeper tissues, such as fascia, tendon, muscle, or bone. Lymphadenopathy or lymphangiitis may be present. The patient is systemically well and metabolically stable, although there may be a mild elevation of the WBC count. Blood glucose levels may be higher than the patient’s usual values.

Compared with a moderate infection, the hallmark of a severe infection is evidence of a septic state. The patient may be febrile, hypotensive, and confused or have significant metabolic imbalance (e.g., azotemia and acidosis). Distinct from mild infections, moderate and severe infections tend to be polymicrobial. S. aureus, including MRSA and Streptococci (Group B), are still the predominant pathogens, but Gram-negative organisms are commonly found.

There has been some debate as to the need to direct antibiotic therapy toward Gram-negative organisms in general and Pseudomonas aeruginosa in particular. Although an important pathogen in respiratory tract and urinary tract infections, there are data to suggest that P. aeruginosa when cultured from skin and soft tissue infections may exist as a commensal rather than a true pathogen, and therapy directed against this bacteria may not be necessary to effect a cure in diabetic lower
extremity skin and skin structure infections.²³,²⁴ Anaerobic bacteria such as Bacteroides fragilis are more frequently seen in these wounds, and whether suspected or cultured, it is often prudent to direct therapy toward them.²⁵,²⁶ This is especially true in the case of infections in which gas is seen on X-ray.

The Role of Anaerobes in DFIS

The presence of anaerobic bacteria in DFIs is probably overestimated by most physicians. When present in lower extremity infections, anaerobes such as Bacteroides spp. are more commonly seen in moderate to severe infections, rarely if ever in mild infections, and almost never present as solitary organisms. Anaerobic bacteria require specialized culture media, rapid transport to the lab, and strict anaerobic conditions when cultured. Because of this, it may be more useful to employ 16s polymerase chain reaction (PCR) and pyrosequencing to detect their presence, rather than relying on traditional culture methods. Unfortunately, as of this writing, these tests are costly and not widely available.

There is a timeworn saying, “all that is gas is not clostridia.” Although the presence of gas in soft tissue on X-ray can indeed indicate the presence of anaerobic bacteria, it is probably more often than not caused by gas-producing Gram-negative bacteria such as Klebsiella, Proteus, or Escherichia coli rather than obligate anaerobes. There are even nonbacterial causes of “gas in tissue,” including the use of high-pressure irrigation in the operating room or the use of hydrogen peroxide flushes employed by the patient. In a recent literature review concerning the epidemiology, antibiotic susceptibility, and clinical significance of anaerobic isolates in patients with DFIs, 44 published studies were found, involving a total of 13,012 patients. Of these, the incidence of anaerobic pathogens was only 11%.²⁷ No epidemiologic survey to date has reported a worse outcome for wounds from which anaerobic bacteria were isolated compared with no-anaerobes, with the possible exception of Clostridium spp.²⁸

Nonetheless, it has become standard practice by many to employ broad spectrum antibiotics with anaerobic activity in most if not all moderate to severe DFIs. Long-term coverage of anaerobic bacteria may not only be unnecessary, but may have the unwanted side effect of driving antibiotic resistance and increase health care costs. Antibiotics are not without their adverse events. In a recently published study from Istanbul, Turkey, almost 20% of patients receiving piperacillin/tazobactam for >10 days developed neutropenia (neutrophil count of <2,000 cells per mm³).²⁹

The Problem of Drug-Resistant Organisms in DFIS

In the past decade, one of the important changes in the microbiology of DFIs is the increasing isolation of MDROs. An MDRO can be defined as an organism with decreased susceptibility to multiple (usually two or three) classes of antimicrobial agents to which the organism would normally be susceptible.³⁰

One of the most important Gram-positive MDROs is MRSA. In a survey of 97 US hospitals conducted between 2003 and 2007, the prevalence of MRSA in hospitalized patients with a DFI almost doubled, from 11.6% to 21.9%.³¹

Despite the prevalence of MRSA, treating every DFI for MRSA is unnecessary and likely to lead to a further increase in resistance as well as raise the cost of health care.³² Although the isolation of MRSA would seem to be a factor associated with treatment failure in patients with DFIs,³³ it has not been demonstrated to be associated with longer hospitalization or a higher incidence of amputations.³²,³⁴ In fact, studies by Hartemann-Huertier et al.³⁵ as well as Richard et al.³⁶ found that the presence of MDROs, most notably MRSA, had no significant impact on healing time of diabetic foot wounds when compared with methicillin-susceptible S. aureus.

Empiric coverage for MRSA should be started for patients with known risk factors, and for those patients with severe infections in whom failure to promptly treat would lead to loss of life or limb.

Risk factors associated with MRSA infection of foot ulcers include the presence of MDROs, history of an MRSA DFI, and a positive MRSA nasal culture.³²

There are currently two newly approved antibiotics to treat MRSA infections. Ceftaroline is a parenteral-only extended spectrum cephalosporin that is active against MRSA and has the Gram-negative activity of a third-generation cephalosporin. Tedizolid is a newer oxazolidinone, similar to linezolid, except with once-daily dosing and without the serotonin syndrome risk.

The other MDRO seen with an increasing incidence is extended spectrum β-lactamase (ESBL)-producing Gram negatives (so named because they produce enzymes that hydrolyze extended spectrum cephalosporins). The increase in ESBL-producing strains jeopardizes the usefulness of β-lactam agents, leading to increases in costs and treatment failures. These organisms are being found with increasing frequency in DFIs.³⁷,³⁸

ESBLs are found in many commonly encountered Gram-negative organisms including Klebsiella, E. coli, Acinetobacter, Citrobacter, Enterobacter, Morganella, Proteus, Pseudomonas, Salmonella, and Serratia. ESBLs can hydrolyze oxyimino cephalosporins (ceftazidime, ceftriaxone, cefepime, cefotaxime) and monobactams (aztreonam) but cannot hydrolyze carbapenems (imipenem, meropenem, ertapenem).

Unfortunately, Gram-negative active agents such as aminoglycosides, trimethoprim-sulfamethoxazole (TMP/SMX), and quinolones may not be effective either. Plasmids w/genes encoding for ESBLs may also carry genes conferring resistance to aminoglycosides, TMP/SMX, and quinolones. Even when plasmid-encoded decrease in quinolone susceptibility is not present, there is a strong association between quinolone resistance and ESBL production.

The carbapenems have therefore emerged as the “go-to” class of antibiotics for treatment of ESBL Gram-negative infections, and for many years have held the top spot in this regard.

Unfortunately, some Gram-negative organisms have developed resistance to even the carbapenems. Collectively known as CRE (carbapenem-resistant Enterobacteriaceae), these organisms are resistant to not only carbapenems, but to penicillins, cephalosporins, and monobactams as well.³⁹ The most common type of carbapenemase (enzyme) currently seen in the United States is Klebsiella pneumonia carbapenemase. However, other enzymes capable of inactivating carbapenems have been discovered as well; among them are New Delhi metallo β-lactamase⁴⁰,⁴¹ and Verona integron-encoded metallo β-lactamase-1.⁴²

Current treatment options for CRE infections are limited and include tigecycline and colistin. Newer drugs are under development. One such drug, avibactam, has been shown to inhibit extended spectrum β-lactamase and carbapenemase enzymes produced by Gram negatives in much the same way that tazobactam, sulbactam, and clavulanic acid inhibit β-lactamase produced by S. aureus. The addition of avibactam to existing antibiotics such as aztreonam and ceftaroline will result in a new compound with extended activity against a wide range of multidrug-resistant Gram-negative organisms.

Diabetic Foot Osteomyelitis

It has been estimated that approximately 15% of diabetic foot ulcers are complicated by osteomyelitis, and in some centers approximately 20% of patients who present with a DFI have involvement of the underlying bone.⁴³ Most cases of diabetic foot osteomyelitis are chronic by the time they present. Infection of bone in the foot of a patient with diabetes usually occurs via contiguous spread from an overlying soft tissue ulceration. The presence of osteomyelitis increases the likelihood of lower extremity amputation. Thus, accurately diagnosing and treating diabetic foot osteomyelitis is of critical importance. Bone biopsy with culture and histopathology is still considered the criterion standard for diagnosing diabetic foot osteomyelitis, whereas magnetic resonance imaging (MRI) is currently considered the imaging modality of choice.

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