19 A penicillinase-resistant penicillin (e.g., dicloxacillin) or cephalexin will be

effective in most cases. The choice between these agents should be based on

tolerability and cost. Alternative agents include clindamycin,

amoxicillin/clavulanate, or levofloxacin. If anaerobes are suspected (based on

malodorous aroma, if the infection is severe or long-standing or has recently been

treated with antibiotics), clindamycin or amoxicillin/clavulanate monotherapy can be

used or metronidazole can be added to the regimen.

18

If metronidazole is selected,

concurrent use of an antibiotic with good activity against aerobic pathogens is

required, because metronidazole has no activity against aerobic bacteria. In patients

with significant vascular compromise, crepitus, or gangrene, a radiograph should be

taken to identify any bone involvement suggestive of osteomyelitis.

For treatment of moderate-to-severe infections, oral or parenteral antibiotics (IV

recommended for severe) may be used depending on signs and symptoms and should

be selected based on suspected organisms. For staphylococci, streptococci, and

enterobacteriaceae, therapeutic options include levofloxacin, cefoxitin, ceftriaxone,

ampicillin/sulbactam, moxifloxacin, ertapenem, and imipenem/cilastatin, or

tigecycline.

20.21 Levofloxacin and ceftriaxone have no anaerobic coverage; thus,

clindamycin or metronidazole should be added if anaerobes are suspected (ischemic

or necrotic wounds).

22

It is important to consider that clindamycin may be more likely

to cause Clostridium difficile-associated diarrhea.

Other considerations in antibiotic selection should include MRSA or P. aeruginosa

when risk factors are present. Infections due to MRSA can be treated with

vancomycin, daptomycin, or linezolid. Newer antibiotics, including dalbavancin,

telavancin, oritavancin, and ceftaroline, have activity against MRSA skin and soft

tissue infections, but there is a lack of efficacy data in diabetic foot infections.

23

Infections due to P. aeruginosa may be more common in patients in areas with high

local prevalence, warmer climates, and frequent exposure of foot to water, and can

be treated with piperacillin/tazobactam. Other antibiotics with activity against P.

aeruginosa include, cefepime, ceftazidime, aztreonam, imipenem/cilastatin,

meropenem, or doripenem. Aminoglycosides are associated with serious toxicity if

used for an extended period and should probably be avoided in diabetic patients.

Because T.U. is an elderly diabetic patient with systemic signs and symptoms of

infection (moderate to severe), empiric therapy with cefoxitin, ceftriaxone,

ampicillin/sulbactam, levofloxacin, moxifloxacin, or ertapenem would be

appropriate because he does not have risk factors for MRSA or P. aeruginosa

infection.

CASE 74-5, QUESTION 3: Despite aggressive antibiotic therapy and debridement, T.U.’s infection spreads

and an amputation is required. How long should antibiotics be prescribed for T.U. after surgery?

Antibiotics may be continued until signs and symptoms of infection have resolved.

Typical treatment duration is 1 to 2 weeks; however, longer treatment duration (2–4

weeks) may be necessary in patients with moderate-to-severe infections or in

patients with infections that are slow to resolve.

20 Oral therapy should be considered

once the patient has clinically improved; treatment can be stopped even if the

underlying ulcer has not completely healed.

18

,

20

The best option for uncontrollable, life-threatening infections often is amputation

to remove the infected area. Once the infected area has been removed, antibiotic

therapy should be continued for 2 to 5 days.

20

CASE 74-5, QUESTION 4: What measures could have been taken to prevent this complication in T.U.?

Many of the foot problems associated with diabetes can be prevented with proper

foot care (Table 74-2), and these preventive measures must be emphasized. Diabetic

patients with neuropathies or those who are elderly should carefully examine their

feet every 1 to 2 days.

Necrotizing Soft Tissue Infections

Skin and soft tissue infections are described as necrotizing when the inflammation is

rapidly progressing and necrosis of the skin or underlying tissue is present. The

following clinical signs suggest necrotizing infections, as opposed to simple

cellulitis: edema beyond the area of erythema, skin blisters or bullae, localized

pallor or discoloration, gas in the subcutaneous tissues (crepitus), and the absence of

lymphangitis and lymphadenitis. Common clinical features include high temperature,

disorientation, lethargy, or the hard wood feel of the infected area.

2 Occasionally, a

broad erythematous track along the route of infection may also be present.

Necrotizing soft tissue infections can progress rapidly to cause additional local

effects (e.g., necrosis and loss of skin sensation) and severe systemic effects (e.g.,

hypotension, shock).

24 Necrotizing soft tissue infections are rare, with approximately

1,000 cases/year in the United States, but they can be lethal.

25

,

26 Necrotizing

infections can occur in healthy individuals, but are more commonly associated with

IV or subcutaneous injections of illicit drugs.

27

Table 74-2

Foot Care for the Diabetic Patient

Inspect feet daily for cuts, blisters, or scratches. Pay particular attention to the area between the toes and use a

mirror to examine the bottom of the foot.

Wash feet daily in tepid water and dry thoroughly.

Apply lotion to feet to prevent calluses and cracking.

Ensure that shoes fit properly (not too tight or too loose) and inspect them daily.

Trim nails regularly, making sure to cut straight across the nail.

Do not use chemical agents to remove corns or calluses.

p. 1550

p. 1551

Necrotizing cellulitis involves the skin and subcutaneous tissues. Necrotizing

fasciitis involves both superficial and deep fascia, and necrotizing infections

involving the muscle are termed myonecrosis. Group A β-hemolytic streptococci, S.

aureus, other staphylococci, Pseudomonas species, other Gram-negative organisms,

Clostridium perfringens, Peptostreptococcus, B. fragilis, and Vibrio species can

cause necrotizing infections.

24

,

28 Gas gangrene is myonecrosis caused by a

Clostridium subspecies, most commonly C. perfringens (70%).

24 Gas in a wound is

not necessarily indicative of gas gangrene caused by C. perfringens. Gram-negative

organisms (e.g., E. coli, Proteus species, Klebsiella species) or anaerobic

streptococci can produce gas in a wound. Air also could have been introduced at the

time of the injury. Gas gangrene is characterized by acute onset of worsening pain

that is usually out of proportion to the degree of injury. Clostridial myonecrosis (true

gas gangrene), streptococcal gangrene (caused by group A β-hemolytic streptococci),

and synergistic bacterial gangrene (caused by anaerobic and aerobic bacteria, usually

Gram negative) are other terms used to describe necrotizing skin and soft tissue

infections. Fournier gangrene (a type of synergistic bacterial gangrene of the

scrotum), nonclostridial crepitant gangrene (nonclostridial gas gangrene), and

necrotizing fasciitis (all necrotizing soft tissue infections other than clostridial

myonecrosis, or sometimes just streptococcal gangrene) are other commonly used

terms.

24 The primary treatment for necrotizing soft tissue infections involves

extensive debridement of the area to remove all necrotic tissue and drainage. Early

fluid resuscitation and broad-spectrum antibiotics are also imperative.

25

CASE 74-6

QUESTION 1: M.T., a 45-year-old alcoholic homeless man, presents to the ED with a broken nose and facial

lacerations, which he received after a fight outside one of the local taverns. On examination, in addition to the

facial wounds, an area of severe inflammation, erythema, and necrosis is evident on his left calf. The area is

very painful, crepitation is felt over the area, and a purulent discharge is present. M.T. states he believes the

infection is because of a knife wound he experienced approximately 1 week ago. What antibacterial treatment

should be provided?

In addition to setting the broken nose and suturing the facial lacerations, the

clinician should evaluate the infection on M.T.’s calf. A Gram stain and culture of the

purulent discharge should take place before initiating antimicrobial therapy. Because

crepitus is present, the area should be incised, and a specimen of the infected tissue

should be obtained for Gram stain and culture. Because the presence of crepitus may

suggest a necrotizing infection, an immediate surgical consultation will be required

for M.T. Pending the surgical evaluation, fluid resuscitation and IV antibiotics should

be initiated. Gas in the tissues could be caused by many organisms, and empiric

broad-spectrum antibiotic therapy with coverage against Gram-positive organisms,

the enterobacteriaceae, and B. fragilis should be started. Initial therapy with

piperacillin/tazobactam, ampicillin/sulbactam, or a carbapenem plus anti-MRSA

antibiotic (vancomycin, daptomycin, or linezolid) should be used.

2 Clindamycin is

often added for suspicion of group A streptococci, not for its antibacterial effects but

because it inhibits protein synthesis, which may reduce toxin expression by the

bacteria, and cytokine response by the host.

2

,

29 Alternative options include

ceftriaxone plus metronidazole, or a fluoroquinolone plus metronidazole. If a Gram

stain of the infected tissue clearly shows the predominance of Gram-positive cocci,

consideration of narrowing the spectrum of antibiotic therapy is appropriate. Flesheating disease is usually a necrotizing fasciitis caused by virulent strains of group A

streptococci. High-dose penicillin G (3 million units every 4 hours) plus clindamycin

(900 mg IV every 8 hours) are the drugs of choice for this condition, as well as for

gas clostridial myonecrosis.

2

,

29

Potential adjunctive therapy for streptococcal necrotizing skin infections includes

IV immunoglobulin G (IVIG) 2 g/kg as a single dose or 0.4 g/kg daily for 2 days.

Alternative dosage regimens have included 1 g/kg on day 1 with 0.5 g/kg on days 2

and 3.

30 No clinical trials have proven the definitive benefit of IVIG, and the optimal

dose, if used, is unknown. If it truly provides benefit, IVIG is thought to work by

binding to the superantigens released by the streptococcal bacteria that are involved

in the systemic effects of the infection.

30

,

31

ANIMAL BITE WOUNDS

Any wound caused by an animal that results in the skin being cut or punctured should

be examined to ensure no underlying tissue damage has occurred. This is especially

true in patients with bites of the hand or around other joints. The wound should be

washed thoroughly with clean water as soon as possible after the bite.

32

Irrigation of

the wound, including puncture sites, should be extensive to reduce the risk of

infection. Obtaining specimens for cultures is not required, and wound irrigation

should begin as soon as possible.

Animal bites may develop bacterial infections due to aerobic or anaerobic

organisms in up to 18% of cases.

33 Although purulent wounds or abscesses are likely

to contain mixed aerobic and anaerobic organisms, nonpurulent wounds are more

commonly caused by streptococci or staphylococci.

2 Pasteurella multocida is

commonly isolated and is particularly significant in cat bites because it is present in

up to 75% of the oral flora of cats.

2

,

33 Although antibiotic treatment is not required

for some dog bites, reports of a greater than 75% incidence of infection after cat bites

suggest that all patients with cat bites should receive antibiotics.

32

CASE 74-7

QUESTION 1: P.J., a 18-year-old boy, presents to the ED 3 hours after being bitten on the leg by a

neighbor’s dog. He has a laceration, 14 cm long, on his medial calf. Four distinct puncture marks, suggestive of

teeth marks, also are present on the calf. There is no suggestion of bone injury. P.J. was healthy before the

attack and has no chronic illness. Should P.J. receive any treatment other than suturing of his laceration?

The standard of care for all bites involves wound irrigation and decontamination

of the wound.

32 P.J.’s wound should be evaluated for deep tissue injury,

devascularization of any tissue, and bone injury. Loose suturing or closure with

adhesive strips is appropriate for lacerations after irrigation.

32 Although the safety of

closure of bite wounds has been debated, a good therapeutic response has been

obtained after the closure of wounds.

CASE 74-7, QUESTION 2: Because P.J. has several punctures that are difficult to irrigate, he is a candidate

for antibiotic therapy. Which antibiotic(s) should he receive?

The need for antibiotics is controversial and guided by wound severity and patient

immunocompetency.

2

,

34 The patient should receive a course of antibiotics if the

wound involves the hand or is near joints, if it involves deep punctures or is difficult

to irrigate, if the patient is immunocompromised (e.g., diabetes, splenectomy), or if

the wound is not well perfused.

p. 1551

p. 1552

Antibiotics are not required for dog bites in which no deep tissue injury is present

and the wound can be well irrigated, particularly if the wound is on the lower

extremities in healthy adults or children.

32

The selection of the appropriate antibiotic is based on the most likely pathogens

from the specific animal bite. Although P. multocida often is considered the primary

pathogen of dog bites, antibiotic coverage also must address the other common

pathogens. Monotherapy with amoxicillin/clavulanate 875/125 mg orally every 12

hours is recommended.

2

,

32 Alternative options include second-generation

cephalosporins (e.g., cefuroxime) plus an agent with anaerobic coverage

(clindamycin or metronidazole). If the patient is allergic to penicillin, doxycycline,

moxifloxacin, or a carbapenem provides adequate coverage.

2

In all cases, patients

should be instructed to watch for improvement; if the wound does not heal or it

worsens within 48 hours, the patient needs to be re-evaluated. Antibiotic treatment

should not extend beyond 5 days unless signs of an infection remain. If the patient

presents with an established infection, parenteral therapy is warranted if the infection

is over a joint, has lymphatic spread, or involves the hand or head. Parenteral therapy

should be continued until the infection has resolved, and therapy should then be

continued with oral antibiotics for at least 7 days or until all clinical signs of the

infection have resolved.

Prophylaxis for rabies is required only if the animal is from an area with endemic

rabies or if the bite was the result of an unprovoked attack by a wild animal.

32 The

local health board should be contacted to determine the recent rabies risk in the area.

If P.J. has not received a tetanus toxoid booster within the past 5 years, a booster

should be administered. If P.J. has never been immunized for tetanus, tetanus immune

globulin should be administered in addition to the tetanus toxoid.

HUMAN BITE WOUNDS

CASE 74-8

QUESTION 1: C.K., a 40-year-old man, presents with a sore arm 24 hours after receiving a bite to his left

forearm by his neighbor in a “discussion over property boundaries.” C.K. was previously healthy and has no

chronic diseases. A 6 × 8 cm area of his left forearm is swollen and erythematous, and includes several distinct

puncture marks consistent with a human bite. No joint deformity or bone abnormality is detected on clinical

examination. How should C.K. be treated?

Treating a human bite is similar to any other laceration, including cleansing,

irrigating, exploring, debriding, draining, excising, and suturing, as required.

32 All

human bites should be cleansed as soon as possible, and any lacerations or punctures

irrigated copiously. Surgical exploration with debridement, drainage, or excision

should be undertaken if deeper tissues may have been injured or if pus collection

could have occurred. With evidence of pus accumulation in his wound, the area

should be explored and drained. E.D. also should receive systemic antibiotic therapy

to eradicate potential infecting organisms. If the wound is severe (i.e., involves

subcutaneous tissues, a joint, or a large area) or if the patient is unlikely to be

compliant with oral antibiotics, parenteral administration of antibiotics is required.

The most common pathogens in human bites are β-hemolytic streptococci, S. aureus,

Eikenella corrodens, Fusobacterium, Peptostreptococcus, Prevotella, and

Porphyromonas sp. Corynebacterium subspecies.

2 Treatment with

amoxicillin/clavulanate, ampicillin/sulbactam, or ertapenem is appropriate. For

penicillin-allergic patients, alternatives include ciprofloxacin or levofloxacin plus

metronidazole or moxifloxacin alone.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

Bonnetblanc JM, Bedane C. Erysipelas: recognition and management. Am J Clin Dermatol. 2003;4:157. (15)

Kilburn SA et al. Interventions for cellulitis and erysipelas. Cochrane Database Syst Rev. 2010;(6):CD004299. (4)

Kosinski MA, Lipsky BA. Current medical management of diabetic foot infections. Expert Rev Anti Infect Ther.

2010;8(11):1293–1305. (23)

Lipsky BA. Medical treatment of diabetic foot infections. Clin Infect Dis. 2004;39(Suppl 2):S104. (22)

Lipsky BA et al. Clinical practice guidelines for the diagnosis and treatment of diabetic foot infections. Clin Infect

Dis. 2012;54:e132–e173. (20)

Liu C et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of

methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:e18. (5)

Looke D, Dendle C. Bites (mammalian). Clin Evid. 2010;7:914. (33)

Matthews PC et al. Clinical management of diabetic foot infection: diagnostics, therapeutics and the future. Expert

Rev Anti Infect Ther. 2007;5:117. (18)

Moran GJ et al. Antimicrobial prophylaxis for wounds and procedures in the emergency department. Infect Dis

Clin North Am. 2008;22:117. (32)

Stevens DL et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014

update by the Infectious Disease Society of America. Clin Infect Dis. 2014;59(2):e10–e52. (2)

COMPLETE REFERENCES CHAPTER 74 SKIN AND SOFT

TISSUE INFECTIONS

Dryden MS. Complicated skin and soft tissue infections. J Antimicrob Chemother. 2010;65(Suppl 3):iii35.

Stevens DL et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014

update by the infectious diseases society of America. Clin Infect Dis. 2014;59(2):e10–e52.

Moellering RC Jr. The growing menace of community-acquired methicillin-resistant Staphylococcus aureus. Ann

Intern Med. 2006;144:368.

Kilburn SA et al. Interventions for cellulitis and erysipelas. Cochrane Database Syst Rev. 2010;(6):CD004299.

Liu C et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of

methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:e18.

Rajendran PM et al. Randomized, double-blind, placebo-controlled trial of cephalexin for treatment of

uncomplicated skin abscesses in a population at risk for community-acquired methicillin-resistant

Staphylococcus aureus infection. Antimicrob Agents Chemother. 2007;51:4044.

Wells RD et al. Comparison of initial antibiotic choice and treatment of cellulitis in the pre- and post-communityacquired methicillin-resistant Staphylococcus aureus eras. Am J Emerg Med. 2009;27:436.

Madaras-Kelly KJ et al. Efficacy of oral beta-lactam versus non-beta-lactam treatment of uncomplicated cellulitis.

Am J Med. 2008;121:419.

Khawcharoenporn T, Tice A. Empiric outpatient therapy with trimethoprim-sulfamethoxazole, cephalexin, or

clindamycin for cellulitis. Am J Med. 2010;123:942.

Jenkins TC et al. Skin and soft-tissue infections requiring hospitalization at an academic medical center:

opportunities for antimicrobialstewardship. Clin Infect Dis. 2010;51:895.

Pangilinan R et al. Topical antibiotic treatment for uncomplicated skin and skin structure infections: review of the

literature. Expert Rev Anti Infect Ther. 2009;7(8):957.

Bergkvist PI, Sjobeck K. Antibiotic and prednisolone therapy of erysipelas: A randomized double blind placebo

controlled study. Scand J Infect Dis. 1997;29:377–382.

Dall L et al. Rapid resolution of cellulitis in patients managed with combination antibiotic and anti-inflammatory

therapy. Cutis. 2005; 75:177–180.

Barton M et al. Guidelines for the prevention and management of community-associated methicillin-resistant

Staphylococcus aureus: a perspective for Canadian health care providers. Can J Infect Dis Med Microbiol.

2006;17(Suppl C):4C.

Bonnetblanc JM, Bedane C. Erysipelas: recognition and management. Am J Clin Dermatol. 2003;4:157.

Pereira de Godoy JM et al. Epidemiological data and comorbidities of428 patients hospitalized with erysipelas.

Angiology. 2010;61:492.

Bernard P. Management of common bacterial infections of the skin. Curr Opin Infect Dis. 2008;21:122.

Matthews PC et al. Clinical management of diabetic foot infection: diagnostics, therapeutics and the future.

Expert Rev Anti Infect Ther. 2007;5:117.

Cunha BA. Antibiotic selection for diabetic foot infections: a review. J Foot Ankle Surg. 2000;39:253.

Lipsky BA et al. Clinical practice guidelines for the diagnosis and treatment of diabetic foot infections. Clin Infect

Dis. 2012;54:e132–e173.

Rao N, Lipsky BA. Optimising antimicrobial therapy in diabetic foot infections. Drugs. 2007;67:195.

Lipsky BA. Medical treatment of diabetic foot infections. Clin Infect Dis. 2004;39(Suppl 2):S104.

Kosinski MA, Lipsky BA. Current medical management of diabetic foot infections. Expert Rev Anti Infect Ther.

2010;8(11):1293–1305.

Kihiczak GG et al. Necrotizing fasciitis: a deadly infection. J Eur Acad Dermatol Venereol. 2006;20:365.

Hasham S et al. Necrotising fasciitis. BMJ. 2005;330:830.

Sarani B et al. Necrotizing fasciitis: current concepts and review of the literature. J Am Coll Surg. 2009;208:279.

Phan HH, Cocanour CS. Necrotizing soft tissue infections in the intensive care unit. Crit Care Med.

2010;38(Suppl): S460.

Wong CN et al. Necrotizing fasciitis: Clinical presentation, Microbiology and determinants of mortality. J Bone

Joint Surg Am. 2003;85(8):1454–1460.

Seal DV. Necrotizing fasciitis. Curr Opin Infect Dis. 2001;14:127.

Darenberg J et al. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European

randomized, double-blind placebo-controlled trial. Clin Infect Dis. 2003;37:333.

Johnansson L et al. Getting under the skin: the immuno-pathogenesis of Streptococcus pyogenes deep tissue

infections. Clin Infect Dis. 2010;51:58.

Moran GJ et al. Antimicrobial prophylaxis for wounds and procedures in the emergency department. Infect Dis

Clin North Am. 2008;22:117.

Looke D, Dendle C. Bites (mammalian). Clin Evid. 2010;7:914.

Smith PF et al. Treating mammalian bite wounds. J Clin Pharm Ther. 2000;25:85.

p. 1552

DEFINITIONS

As a consequence of select cancer chemotherapies, patients may

experience neutropenia (defined as an absolute neutrophil count <500

cells/μL or anticipated to drop to <500 cells/μL within 48 hours) and

fever (defined as a single oral temperature of ≥38.3°C [101°F] or a

temperature of ≥38.0°C [100.4°F] for >1 hour).

Case 75-1 (Question 4)

Bacteria are the primary pathogens associated with infection in febrile

neutropenic patients (especially those occurring early).

Case 75-1 (Questions 1, 6)

CLINICAL PRESENTATION

Fever is usually the earliest (and often the only) sign of infection. Case 75-1 (Question 4)

An accurate history and complete physical examination should be

completed. Chest radiographs and oximetry should be completed if signs

and symptoms point to the respiratory tract.

Case 75-1 (Question 5)

Before antibiotics are initiated, two sets of blood cultures (with each set

consisting of two culture bottles) should be obtained. Additionalsitespecific cultures should also be obtained if such infections are

suspected. A complete blood count, serum electrolytes, coagulation, Creactive protein, urinalysis, and assessment of organ function (e.g., liver

and kidney function) should be assessed.

Case 75-1 (Question 5)

KEY TREATMENT INFORMATION

Risk stratification should be undertaken to identify patients most likely to

experience significant infection-related complications. Patients at

highest risk include those with prolonged (>7 days) and profound (<100

cells/μL) neutropenia or select comorbidities (hypotension, severe

mucositis interfering with swallowing or causing diarrhea, pneumonia,

new-onset abdominal pain, hepatic or renal insufficiency, or neurologic

changes). Highest-risk patients should be considered for antibacterial

and antifungal prophylaxis.

Case 75-1 (Questions 2, 3, 7)

In the absence of evidence of site- or pathogen-specific etiologies or

clinical instability, initial empiric monotherapy is most commonly an

Case 75-1 (Questions 7–9),

Case 75-2 (Questions 1, 2, 4,

antipseudomonal third-generation cephalosporin (e.g., ceftazidime), a

fourth-generation cephalosporin (e.g., cefepime), or an antipseudomonal

carbapenem (e.g., imipenem–cilastatin or meropenem). Prolonged

infusion of β-lactam (3-4 hours) should be considered in order to

optimize their pharmacodynamic properties. Additional agents may be

added (such as vancomycin, an aminoglycoside, or fluoroquinolone) to

initial therapy in patients who are hemodynamically unstable. Antiviral

therapy is generally restricted to patients with serologic or clinical

evidence of viral infection.

5),

Case 75-4 (Question 4)

MONITORING PARAMETERS

The need for (and timing of) modification of the initial empiric therapy is

dependent on the risk group (i.e., low vs. high risk), establishment of an

infection site or causative pathogen, persistence or defervescence of

fever, and clinicalstability.

Case 75-2 (Question 6)

p. 1553

p. 1554

High-risk patients unresponsive to initial empiric antibacterial therapy

should be considered for the addition of antifungal therapy at days 4

through 7. In addition to coverage for Candida species, highest-risk

patients with persistent or recurrent fever after 4 to 7 days of

appropriate antibacterial therapy with prolonged (i.e., >10 days)

neutropenia should be considered for antimold therapy. Low-risk

patients who are clinically stable do not routinely need antifungal

therapy.

Case 75-3 (Questions 1, 2),

Case 75-4 (Questions 1, 2)

THERAPEUTIC CONTROVERSIES

The role of vancomycin as part of the initial empiric regimen remains

controversial. In general, routine use of vancomycin as part of initial

empiric therapy for fever in neutropenic patients without other evidence

of infection should be discouraged (except in clinically unstable

patients).

Case 75-2 (Question 3)

The ideal initial empiric antifungal agent is debatable. However, patients

receiving fluconazole prophylaxis requiring addition of empiric

antifungals should be considered for antifungals with activity against

azole-resistant Candida species and mold infections.

Case 75-4 (Questions 3, 4)

Although hematopoietic colony-stimulating factors prevent neutropenia in

high-risk cancer patients, use of these agents as treatment of febrile

neutropenia unresponsive to antibiotics remains controversial.

Case 75-1 (Question 3),

Case 75-4 (Question 5)

Many patients with both solid tumor and hematologic malignancies have had their

lives prolonged through therapeutic advances in chemotherapy, immunotherapy, and

hematologic stem cell transplantation (HSCT). Despite such advances, infectious

complications continue to be a major cause of morbidity and mortality in these

patients. Risk assessment, prevention, rapid detection, and effective management of

infections, while a major challenge, can lead to improved outcomes in such

immunocompromised hosts.

1

,

2

This chapter focuses on infectious complications in patients with

immunosuppression as a consequence of cancer. The following topics are addressed:

risks and epidemiology of infection, principles of prophylactic antimicrobials,

empiric initial antibacterial selection, modification and duration of therapy, empiric

antifungal and antiviral use, and the use of hematopoietic growth factors.

RISK FACTORS FOR INFECTION

Patients are rendered immunocompromised when there is a significant disruption or

deficiency of one or more of the host defenses as a result of the underlying disease or

chemotherapy. These risk factors include neutropenia and impairment in both

humoral (antibody and complement) and cell-mediated immune defenses. Disruption

of barriers to infection resulting from chemotherapy-related damage to skin and

mucosal barriers further increases the risk of infection. As a result, bacteria, fungi,

viruses, and (less commonly) protozoa may infect various sites (depending on the

specific immunodeficiency).

Neutropenia

Granulocytes, or granular leukocytes, represent an important defense against

bacterial and fungal infections. Neutropenia (a reduction in the number of circulating

granulocytes or neutrophils) predisposes the host to infections. The terms

granulocytopenia and neutropenia are often used interchangeably. The degree of

neutropenia is expressed in terms of the absolute neutrophil count (ANC) or the total

number of granulocytes (polymorphonuclear leukocytes and band forms) present in

the circulating pool of white blood cells (WBCs).

For purposes of guideline development and clinical trials, neutropenia is most

commonly defined as an ANC less than 500 cells/μLor less than 1,000 cells/μL with

an anticipated to drop to less than 500 cells/μL within 48 hours.

2–4 The risk, severity,

and type of infection in the neutropenic patient are proportional to the severity, rate

of decline, and duration of neutropenia.

5

In general, the relative risk of infection is

low when the ANC exceeds 1,000 cells/μL, with the frequency and severity of

infection inversely proportional to the ANC.

3

,

5,6 Because the ANC drops to less than

500 cells/μL, the risk of infection rapidly increases. Conversely, recovery of the

ANC is one of the most important factors determining the outcome of infectious

complications in the neutropenic patient. Febrile patients with short durations of

neutropenia (≤7 days) or in whom neutropenia is not severe (<100 cells/μL) less

frequently experience serious, life-threatening infections.

2

,

3,7

In contrast, patients with

severe neutropenia lasting more than 7 days are at significant risk of severe

infection.

2

,

3,8

Damage to Physical Barriers

The intact skin and mucosal surfaces of the body (GI, sinus, pulmonary, and

genitourinary) constitute the host’s primary physical defense against microbial

invasion. The integrity of this physical barrier may be disrupted by tumor, treatment

(e.g., surgery, radiation), or various medical procedures (e.g., insertion of

intravenous [IV] or urinary catheters, venipuncture, measurement of rectal

temperature). Device-related infections, including those associated with central

venous catheters, are commonly caused by migration of skin flora (e.g.,

staphylococci) through the cutaneous insertion site. Infections secondary to damaged

mucosal lining of the gastrointestinal (GI) tract such as mucositis (usually secondary

to chemotherapy or graft-versus-host disease [GVHD]) are usually caused by enteric

bacteria and fungi such as Candida species.

Malignancy-Related Alterations in the Immune System

Malignancies such as leukemia [acute and chronic], lymphoma (e.g., non-Hodgkin

lymphoma) and myelodysplastic syndrome may invade bone marrow, resulting in

leukopenia. This is most notable in patients with advanced or refractory malignancy,

which may reflect either bone marrow invasion or as a consequence of multiple

courses of immunosuppressive chemotherapy. In contrast, predisposition to infection

in patients with solid tumors is often associated with anatomic abnormalities (such

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p. 1555

as obstruction or erosion). Such risks may be enhanced as a consequence of surgery,

chemotherapy, and/or radiation to correct the underlying tumor.

Patients with immunoglobulin deficiencies (e.g., hypogammaglobulinemia, chronic

lymphocytic leukemia, or splenectomy) are at increased risk for infections with

encapsulated bacteria, which undergo antibody opsonization for efficient

phagocytosis. Such bacteria include Neisseria meningitidis, Haemophilus influenzae,

and Streptococcus pneumoniae. Hodgkin disease, organ transplantation, and human

immunodeficiency virus (HIV) disease can disrupt the cellular immune system,

increasing the risk for infections with obligate and facultative intracellular organisms

such as mycobacteria, Listeria, Toxoplasma, viruses, and fungi. Certain hematologic

malignancies and myelodysplastic syndromes may also be associated with

immunodeficiencies secondary to replacement of leukocytes with malignant cells.

Medications Impacting Host Defenses

Some chemotherapeutic agents (such as fludarabine) have profound effects on both

cellular and humoral defenses.

9

,

10 Corticosteroids exert their immunosuppressive

effects on the cellular immune system, particularly at the T lymphocyte and

macrophage level. Therefore, patients receiving corticosteroids (such as HSCT

recipients with GVHD) have increased susceptibility to viral, bacterial, protozoal,

and fungal infections.

11

Infectious complications secondary to glucocorticoids are

dose-dependent. The risk of infection increases with daily doses greater than 10 mg

or cumulative doses greater than 700 mg of prednisone or its equivalent.

11 Thus,

patients receiving corticosteroids in either high doses (>20 mg prednisone or its

equivalent daily) or for prolonged periods are at increased risk for infections caused

by opportunistic pathogens. In addition, corticosteroids may blunt the usual signs of

infection such as fever and inflammation. Severe cell-mediated immunodeficiency

may also be caused by GVHD and its treatment.

2

,

3,9 More recently, chemotherapeutic

monoclonal options (such as alemtuzumab, bortezomib, rituximab, and ofatumumab)

significantly weaken the immune system, predisposing recipients to viral, bacterial,

and fungal infections.

12

,

13

Colonization or Prior Infection

Colonization is characterized as isolation of an organism from any particular site

(e.g., stool, nasopharynx) without clinical signs of infection. Most infections in

neutropenic patients are caused by either the host’s endogenous microflora or

hospital-acquired pathogens that have colonized the alimentary tract, upper

respiratory tract, or skin. Therefore, microbial colonization can be a prerequisite to

infection in neutropenic patients. This is perhaps best studied in patients colonized

with methicillin-resistant Staphylococcus aureus (MRSA). Prior infection (especially

in the pre-engraftment phase of HSCT recipients) is a risk factor for infection during

immunosuppression, particularly for viral infections (such as cytomegalovirus

[CMV], herpes simplex virus [HSV], and Varicella zoster virus [VZV]). Infections

with these pathogens during immunosuppression are generally considered to be a

consequence of latent infection rather than new infection.

2

,

3,9,14,15

Hematopoietic Stem Cell Transplantation

Transplantation of bone marrow predisposes patients to the development of

opportunistic infections secondary to both intensive immunosuppressive therapy and

transmission.

9 These infections may be acquired or may represent reactivation of

latent host infection. The introduction of new therapeutic approaches for treatment of

the underlying malignancy (including nucleoside analogs and monoclonal antibodies

to CD20 and CD52), along with use of unrelated stem cell donors, has increased the

potential for infections in these patients.

9 When compared with autologous or

syngeneic HSCT recipients, allogeneic HSCT patients have an increased risk of

infection, particularly in those patients undergoing therapy for GVHD.

9 The

pathogens causing infections vary with the time since transplantation. The use of

immunosuppressives after transplantation (such as corticosteroids, antithymocyte

globulin, and alemtuzumab) also significantly increases the risk for infection.

9

Radiation Therapy

Side effects associated with the use of radiation therapy for the treatment of

malignancy (e.g., mucositis, skin breakdown, or reduction in blood counts) also

predispose a patient with neutropenia to infection.

Functional Asplenia

The spleen is responsible for production of opsonizing antibodies, assisting in

protection against encapsulated bacteria (such as S. pneumoniae, H. influenzae, and

N. meningitidis). Functional asplenia may occur secondary to irradiation or as a

complication of GVHD.

3