Infections in Burns

INTRODUCTION

Septic morbidity in severely burned patients poses an enormous challenge to

even the most experienced critical care physician. Many features unique to burn

patients make diagnosis and management of infection especially difficult. Burn

injury represents the most extreme endpoint along the spectrum of traumatic

injury and as such is associated with profound alterations in host defense mechanisms

and immune function. These derangements predispose thermally injured

patients to local and systemic invasion by microbial pathogens.

Many of the clinical signs and symptoms used to diagnose infection in other

settings are unreliable in the burn intensive care unit since they are often present

even in the absence of true underlying infection. Advances in critical care such as

earlier resuscitation and support of the hypermetabolic response have decreased

burn mortality, but infections are still pervasive in severely burned patients and

account for significant morbidity and mortality.

With regard to burn wound infection, the cornerstone of management continues

to be aggressive early debridement of devitalized and infected tissue. Unfortunately,

burn patients are rapidly colonized by nosocomial pathogens and foci

of invasive infection must be identified and treated quickly with appropriate antimicrobial

therapy. In addition to the burn wound, other potential foci for invasive

infection include the tracheobronchial tree, the lungs, the gastrointestinal tract,

central venous catheters, and the urinary tract.

Once an infection is disseminated hematogenously and becomes established

in a burn patient, it is very difficult to eradicate, even with large doses of broadspectrum

antimicrobial therapy. Traditional thinking would argue for beginning

broad-spectrum coverage at the first signs of infection and then narrowing the

coverage as results of cultures come back. While this is clearly true for many critically

ill patients, burns represent a unique situation, which may merit more aggressive

management.

The role of systemic antimicrobial therapy in the treatment of infection in

burn patients is still very controversial. New emerging strains of multiresistant

organisms represent an ominous threat in the burn unit and monotherapy with

conventional antimicrobials may be inadequate for some infections. Development

of newer and more potent agents targeted at these pathogens holds some promise

for the future. In the meantime, treatment with two or more agents is becoming

necessary in the management of these gram-negative invasive infections.

CHANGING SCOPE OF INFECTIOUS MORBIDITY IN BURNS

Before the advent of early excision and grafting and the development of topical

antimicrobial agents, burn wound sepsis invariably resulted in the death of

severely burned patients. Near total burn wound excision early in the hospital

course has led to a precipitous decline in mortality.1 This is due at least in part to

a concomitant reduction in the incidence of burn wound sepsis. In addition to

early excision and closure of the burn wound, topical antimicrobials have made a

significant impact on septic morbidity from invasive burn wound infection. While

great strides have been made in the area of burn wound infection, pulmonary

infection has taken over as the primary cause of septic mortality in burn patients.

Nosocomial pneumonias in the setting of inhalation injury and a large cutaneous

burn are associated with mortality as high as 60%.2 Inevitably, a downward spiral

of progressive pulmonary insufficiency ensues, as pneumonia leads to prolonged

ventilatory dependence, iatrogenic barotrauma, and respiratory failure.

In addition to pneumonia, fungal infections are becoming more commonplace

in the burn intensive care unit. While systemic candidiasis has been around

for some time, angioinvasive infections with Fusarium and Aspergillus are being

seen more frequently. While burn patients used to die from inadequate resuscitation

and burn wound sepsis, they now die from inhalation injury, pneumonia,

and rampant fungal septicemia. Antifungal chemotherapy has also emerged as an

important modality for managing complicated fungal infection in thermally injured

patients

BURN-INDUCED IMMUNOSUPPRESSION

Thermal injury is associated with a state of generalized immunosuppression

which is characterized by an impairment of host defense mechanisms and defects

in humoral and cell-mediated immunity. There are several specific alterations in

host defense which are intrinsic to the burn injury itself and which predispose

these patients to microbial invasion. Superimposed on these intrinsic alterations

are extrinsic factors unrelated to the burn injury which increase the likelihood of

invasive infection.

The most important intrinsic factor is breach of the mechanical barrier provided

by the skin. While there is a normal resident skin flora, invasive infection is

rare through an intact epithelial barrier. The skin has bacteriostatic properties

that normally limit the degree of colonization. The local microenvironment is not

supportive for growth of microbial pathogens. This changes drastically with a severe

burn injury. The burn wound provides a warm and moist microenvironment

in which bacterial proliferation is fostered. Microbial growth is rapid as once nonpathogenic

organisms are now allowed to flourish. It is important to realize that

the most important intrinsic factor is breach of the mechanical skin barrier, since

this has implications for the overall approach to infection control. It is the fundamental

and primary defect. Antimicrobial therapy and wound care can be viewed

as temporizing measures to stave off infection until the primary defect is repaired.

This is what makes early excision and closure of the burn wound so important.

In addition to breaching the skin barrier, burn injury also results in transient

mesenteric vasoconstriction, which leads to intestinal ischemia. Mesenteric ischemia

following thermal injury is associated with a loss of gut mucosal integrity,

which then predisposes patients to bacterial translocation from the gastrointestinal

tract.

Patients with large cutaneous flame burns often have an associated smoke inhalation

injury. Another significant intrinsic alteration is impairment of the

mucociliary clearance mechanism following smoke inhalation. This predisposes

patients to microbial invasion of the tracheobronchial tree as the bacterial load

increases secondary to inadequate clearance of secretions and cellular debris by

the mucociliary escalator. In addition to these alterations in host defense, there

are specific defects in humoral and cell-mediated immunity which occur following

severe burn injury. The most important is impaired function of natural killer

cells. Dysfunction of natural killer cells has been demonstrated in several studies.3

In addition, the generalized immunosuppression of burn injury is also characterized

by specific alterations in B and T cell function.

Extrinsic factors synergize with the intrinsic factors described above to produce

the picture of a patient who is profoundly susceptible to invasive infection.

Intubation and mechanical ventilation increase the risk of colonization of the

tracheobronchial tree. It is important to recognize that the burn intensive care

unit is a reservoir of potential microbial pathogens. Tracheostomies represent a

similar hazard and have been shown to increase the risk of colonization and nosocomial

pneumonia. Immobilization is another extrinsic factor associated with the

development of nosocomial pneumonia. Indwelling Foley catheters predispose

patients to the development of urinary tract infection. Prolonged central venous

catheterization is associated with an increased risk of sepsis. In general, extrinsic

and iatrogenic risk factors should be minimized in order to decrease the chance of

opportunistic infection in a patient who is already prone to infection secondary

to factors which are intrinsic to the injury.

DIAGNOSIS AND MANAGEMENT OF SPECIFIC INFECTIONS

BURN WOUND INFECTION

The diagnosis and management of burn wound infection is based on early

identification of an infected wound. Clinically, burn wound infection is most often

recognized based on gross appearance or conversion of a partial thickness to a

full thickness wound. Once there is clinical suspicion of invasive burn wound sepsis,

it is imperative to obtain quantitative wound cultures. Generally, wound cultures

growing organisms at greater than 1x 105 organisms/gm of tissue are considered

indicative of a wound at significant risk for invasive sepsis. It is important to

realize, however, that histologic confirmation of actual tissue invasion by the microbial

pathogens is the only way to clearly establish the diagnosis of invasive burn

wound sepsis. The most common pathogens include methicillin-sensitive and

methicillin-resistant Staphylococcus species and Pseudomonas aeruginosa.

Topical antimicrobial agents play an important role in decreasing the incidence

of burn wound infection. The astute clinician must be cognizant, however,

that antimicrobial therapy is not a substitute for aggressive debridement of grossly

infected and devitalized tissue. Excision of all infected tissue continues to be the

mainstay of treatment. Nonetheless, topical antimicrobial agents are useful and it

is important to be familiar with them. There are several commonly used agents

which include silver sulfadiazine, mafenide acetate, and silver nitrate. In addition,

sodium hypochlorite or Dakins solution is often helpful in certain situations.

Silver sulfadiazine is advantageous in that it is painless on application. Unfortunately

it does not penetrate through eschar very well, which makes it inadequate

for deep partial thickness and full thickness burns. In sharp contrast, mafenide

acetate is associated with much better penetration but causes pain upon application

and may cause a metabolic acidosis secondary to inhibition of carbonic anhydrase.

Silver nitrate provides broad-spectrum coverage but fails to penetrate.

Sodium hypochlorite in low concentration provides excellent bactericidal activity

and does not impair wound healing. In higher concentrations, it may impair wound

healing, however. With the exception of transient exposure for procedures, povidone-

iodine should generally be avoided since it is associated with impaired wound

healing and inhibition of fibroblasts and also can cause thyroid and immune dysfunction.

Other topical agents include Bactroban, Bacitracin, Polymyxin B, and

Mycostatin. Bactroban provides excellent staphylococcal coverage; however cost

may be prohibitive. Bacitracin is useful for minor wounds, and is most often combined

with Neomycin and Polymyxin into a triple antibiotic ointment. Polymyxin

is petroleum based and thus keeps grafts moist. Mycostatin may be combined

with either Polymyxin or Silvadene in order to extend the coverage of these agents.

Tables 7.1 and 7.2 summarize the topical agents.

Table 7.1. Topical antimicrobials

Topical Agents Advantages Disadvantages

Silver Sulfadiazine Painless Lack of penetration

Mafenide Acetate Penetrates Painful, Carbonic anhydrase inhibitor

Silver Nitrate Broad spectrum Limited penetration

Sodium Hypochlorite Broad spectrum Impairs wound healing in high doses

Table 7.2. Other topical agents

Bacitracin Gram-positive Minimal

coverage Often combined with polymyxin

and neomycin into triple

ointment

Polymyxin B Petroleum-based Often combined with mycostatin

Keeps grafts moist into “Polymyco”

Polymyco

(Polymyxin and mycostatin) Extended coverage

Bactroban Staphylococcal Very expensive

coverage Useful for ghosted grafts

Silvamyco

(Silvadene and mycostatin) Extended coverage

CATHETER RELATED INFECTIONS

Central line sepsis is associated with prolonged indwelling central venous catheters.

Meticulous sterile technique is essential during line placement to avoid introduction

of potential pathogens. All areas should be carefully prepped and draped

with Betadine or Hibiclens solution and the physician gowned and gloved appropriately

prior to insertion. Central line sepsis may be primary in which the central

line is the original focus of infection. It also may be secondary, in which case, the

catheter tip is seeded and serves as a nidus for continued shedding of microorganisms

into the blood stream. Signs of erythema or inflammation around the insertion

site should alert the clinician to the potential for a line infection. However it

is important to realize that there may be significant infection of the catheter tip

even when skin surrounding the insertion site appears normal. Central lines can

be associated with the development of both gram negative and gram positive sepsis.

The key concept to recognize is that central lines represent an avascular foreign

body and as such are prone to microbial seeding. There is significant controversy

with regard to the frequency of line changes necessary to avoid catheterrelated

infection. It is the author’s preference that central venous catheters be

changed over a wire by the Seldinger method every 3-5 days. More frequent line

changes may actually increase the risk of central line sepsis. Once a catheter-related

infection is suspected, the central venous line should be promptly removed

and the tip cultured. Systemic antimicrobial therapy can be initiated for a short

time, but generally once the source of infection has been removed the patient

should improve quickly.

URINARY TRACT INFECTION

Urinary tract infections can generally be divided into upper and lower urinary

tract infection. True pyelonephritis is very rare in thermally injured patients; however,

lower urinary tract infection can occur as a result of a chronic indwelling

Foley catheter. The diagnosis should be suspected when there are greater than

1 x 105 organisms cultured from a urine specimen. Also urinalysis may reveal white

cells and cellular debris associated with active infection. The most common organisms

are gram negative pathogens such as Escherichia coli. The appropriate

treatment consists of a 7-10 day course of an antimicrobial with good gram negative

coverage. Fluoroquinolones such as ciprofloxacin are often very effective for

uncomplicated cases. If there is suspicion of an ascending infection, then more

aggressive treatment with prolonged systemic antimicrobials is warranted.

TRACHEOBRONCHITIS

Smoke inhalation injury is a chemical tracheobronchitis that results from the

inhalation of the incomplete products of combustion and is often found in association

with severe burn injury. Inhalation injury impairs the mucociliary transport

mechanism and predisposes patients to colonization of the tracheobronchial

tree by microorganisms. In addition, direct cellular injury to the respiratory epithelium

results in the formation of extensive fibrinous casts composed of inflammatory

exudate and sloughed cells. Increased bronchial blood flow leads to increased

airway edema. As necrotic debris accumulates and airway edema is increased,

patients become susceptible to postobstructive atelectasis and pneumonia.

There is no specific treatment for tracheobronchitis other than aggressive

pulmonary toilet and supportive measures. It is important to realize, however,

that an upper respiratory infection can quickly turn into a lower respiratory infection

with significant mortality.

PNEUMONIA

The diagnosis of pneumonia in severely burned patients is exceedingly problematic.

During the acute phase of injury these patients demonstrate a hypermetabolic

response characterized by increased basal metabolic rate and resetting

of their hypothalamic temperature setpoint. Increased levels of catecholamines

result in a hyperdynamic circulation. For these reasons, many of the usual signs

and symptoms of pneumonia are unreliable in the severely burned. Fever, leukocytosis,

tachypnea, and tachycardia may all be present even in the absence of an

infection. Sputum examination is rarely helpful since specimens are often contaminated

with oropharyngeal flora. More invasive sampling techniques such as

bronchoalveolar lavage have been advocated; however, these, have also been shown

to be less than ideal for establishing a diagnosis of pneumonia. Radiographic findings

can be helpful if they reveal lobar consolidation. Unfortunately, concomitant

inhalation injury and changes in pulmonary vascular permeability more often

result in diffuse nonspecific radiographic changes consistent with noncardiogenic

pulmonary edema. Pneumonias can result from descending infection of the tracheobronchial

tree or from hematogenous dissemination of microbial pathogens.

Inhalation injury is associated with descending infection and has clearly been shown

to increase the incidence and the mortality of nosocomial pneumonia in the burn

population. Generally, patients with a significant inhalation injury and a pneumonia

develop atelectasis, ventilation-perfusion mismatch, arterial hypoxia, and

respiratory failure. Prolonged mechanical ventilation leads to inevitable barotrauma

and further worsening of pulmonary status in these patients. While bronchoalveolar

lavage has been shown to correlate better with the presence of tracheobronchitis

than with radiographic evidence of true pneumonia, it is the best available tool.4

For this reason, a positive lavage in the appropriate clinical context mandates aggressive

intervention. These nosocomial pneumonias are generally gram negative

infections and systemic antimicrobial therapy with multiple agents is generally

required until the infection resolves clinically. Amikacin and piperacillin or

ceftazidime are generally recommended for serious infections, but antibiotics

should be selected on the basis of susceptibility patterns in each hospital. Once

cultures are returned, antimicrobial coverage may be narrowed appropriately.

INVASIVE FUNGAL INFECTIONS

Invasive fungal infections are occurring more frequently in the burn population

today. There should be a high index of suspicion for invasive fungal sepsis

anytime there is a severely burned patient who presents with a septic picture, but

has negative blood cultures and is unresponsive to antibiotic therapy. Systemic

candidiasis is a known complication of thermal injury and is most likely directly

related to generalized immunosuppression and broad-spectrum antimicrobial

therapy. Treatment with intravenous amphotericin B is the mainstay of treatment.

More recently, angioinvasive infections with Fusarium, Aspergillus, and Mucor have

been seen. These fungi have a predilection for endothelial invasion and thus can

spread quickly leading to rampant septicemia. Treatment generally consists of

itraconazole as first line therapy and fluconazole, or amphotericin B in selected

cases. Unfortunately, many fungi are rapidly becoming resistant to amphotericin

B, making other agents necessary. These infections are often fatal since they result

in widespread dissemination and extensive direct tissue invasion.

SEPSIS

Sepsis may result from seeding of the bloodstream from the burn wound, the

respiratory tract, the gastrointestinal tract, the urinary tract, and central venous

catheters. The burn wound and the lungs account for the vast majority of cases. It

is important to differentiate bacteremia from septicemia. Bacteremia refers to the

presence of bacteria in the blood stream and may occur transiently after burn

wound manipulation or excision. This transient bacteremia generally resolves and

is not associated with any significant morbidity. Septicemia, however, implies a

widespread response at the tissue level to bacteria or their products and toxins.

Traditionally sepsis is categorized as gram positive or gram negative. Gram negative

sepsis is by far the most predominant in severely burned patients. The diagnosis

of sepsis is a clinical diagnosis. Laboratory studies are supportive. A patient

who is adequately resuscitated and becomes hemodynamically unstable should

alert the clinician to the possibility of either active bleeding or the development of

septic shock. The five cardinal signs of sepsis are hyperventilation, thrombocytopenia,

hyperglycemia, obtundation, and hypothermia. Leukocytosis and fever

are also important, but must be interpreted with caution in this setting. Patients

who develop florid sepsis and progress to septic shock will manifest decreased

systemic vascular resistance and hypotension. In these cases, inotropic support is

needed in addition to systemic antimicrobial therapy. Blood cultures are helpful if

they are positive, but unfortunately they are often negative even in a critically

septic patient.

THE DILEMMA OF SYSTEMIC ANTIMICROBIAL THERAPY IN BURNS

AGGRESSIVE CHEMOPROPHYLAXIS VERSUS CONSERVATIVE MANAGEMENT

The use of systemic antimicrobial chemoprophylaxis in severely burned patients

is a subject of much controversy. Conventional wisdom holds that topical

antimicrobial therapy and aggressive wound care are sufficient for severely burned

patients in the absence of significant signs of infection. Proponents of this philosophy

maintain that only after clinical suspicion of an infection exists, should

systemic antimicrobial therapy be initiated. At this point, appropriate cultures are

drawn and coverage is adjusted. Proponents of conservative management further

hold that injudicious use of antimicrobials selects for multiple resistant organisms

and predisposes patients to superinfection. Unfortunately, this strategy may

be somewhat inappropriate in patients with massive burns. Because of the generalized

immunosuppression and the derangements in host defense that occur following

burns, these patients are already at substantial risk for invasive infection.

The question then becomes not “will this patient become infected?” but “when

will this patient become infected?” Clearly, once disseminated infection has occurred,

antimicrobial therapy is much less efficacious. Nonetheless, caution must

be exercised with over aggressive antibiotic use since these agents are often nephrotoxic

and burn patients may already have marginal renal status secondary to inadequate or delayed resuscitation. Proponents of aggressive antimicrobial chemoprophylaxis

would argue that it decreases the incidence of sepsis following massive

excision and appears to reduce mortality. In addition, bacterial surveillance

cultures can usually be used to discern the pathogens a patient is most likely to be

infected with ahead of time. While neither aggressive antimicrobial chemoprophylaxis

nor conservative management has been shown to be superior, either approach

is valid, provided the clinician is prepared to frequently reevaluate the

patient and has the appropriate resources in place to guide empiric antimicrobial

selection. Some would propose using burn size as a guideline for determining the

need for empiric coverage. In general, when a septic picture emerges in a patient

with a massive burn, aggressive treatment is mandated. In our institution, we routinely

begin empiric therapy with vancomycin, imipenem, and levofloxacin. Antimicrobial

coverage is then adjusted as appropriate, based on culture and

sensitivities.

REFERENCES

1. Herndon DN, Parks DH. Comparison of serial debridement and autografting

and early massive excision with cadaver skin overlay in the treatment of large

burns in children. J Trauma 1986; 26:149-52.

2. Shirani KZ, Pruitt BA, Mason AD Jr. The influence of inhalation injury and pneumonia

on burn mortality. Ann Surg 1987; 20:82.

3. Stein MD, Gamble DN, Klimpel KD et al. Natural killer cell defects resulting

from thermal injury. Cell Immunol 1984; 86:551-556

4. Ramzy PI, Herndon DN, Wolf SE et al. Correlation of bronchial lavage with radiographic

evidence of pneumonia in severe burns [abstract 117]. In Proceedings

of the American Burn Association, Chicago: J Burn Care Rehabil 1998;

19(1):S193

Table 7.3. Cardinal signs of sepsis

Clinical Laboratory

Hypothermia Thrombocytopenia

Hyperventilation Hyperglycemia

Obtundation