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p. 1533

OSTEOMYELITIS

Acute hematogenous osteomyelitis is characterized by the abrupt onset

of localized pain and tenderness at a single site, fever, and increased

inflammatory markers (erythrocyte sedimentation rate, C-reactive

protein). Imaging techniques and blood and bone cultures (if done) may

reveal findings consistent with bone changes in osteomyelitis and the

responsible pathogen.

Case 73-1 (Questions 1, 2),

Table 73-1

Initial empiric antibiotic therapy for acute hematogenous osteomyelitis

should be directed at gram-positive cocci, including methicillin-resistant

Staphylococcus aureus (MRSA). Protein binding and bone

concentrations of antibiotics are not critical factors in predicting

successful treatment, as long as the responsible pathogen is susceptible

to the chosen therapy, and treatment is given in high doses for long

duration.

Case 73-1 (Question 3),

Table 73-2

If blood or bone cultures grow the likely pathogen, then therapy should

be de-escalated when possible based on organism susceptibilities.

Assuming no allergies, methicillin-sensitive Staphylococcus aureus

(MSSA) should be treated with oxacillin or nafcillin. The overall

duration of therapy (by intravenous [IV] route and possibly orally)

should be at least 4 weeks.

Case 73-1 (Questions 4–6),

Tables 73-2, 73-3

Osteomyelitis secondary to a contiguous focus of infection typically

occurs after trauma and the consequent orthopedic corrective surgery.

Common symptoms are pain, tenderness, erythema, and drainage at the

site of injury or infection. Imaging studies usually show bone changes

consistent with infection.

Case 73-2 (Questions 1, 2),

Table 73-1

Secondary osteomyelitis is often polymicrobial. Surgical efforts should be

instituted to reassess the site of bone injury and infection, with deep

tissue or bone samples obtained for culture. Treatment is IV therapy for

at least 4 weeks, and the antibiotics chosen should depend on the

cultured organisms and their antibiotic susceptibilities.

Case 73-2 (Questions 3, 4)

Osteomyelitis associated with vascular insufficiency most often occurs in

patients with diabetes mellitus. Neuropathy and impaired blood flow lead

to the development of chronic lower extremity cellulitis and underlying

Case 73-3 (Questions 1, 2)

osteomyelitis. Multiple gram-positive and gram-negative aerobic and

anaerobic bacteria may be involved; thus, initial empiric treatment

typically includes vancomycin and an antipseudomonal beta-lactam.

Definitive therapy should be based on the results of deep surgical

cultures. Duration of treatment should be 6 or more weeks, with chronic

suppressive therapy considered thereafter.

Chronic osteomyelitis can present years later at a site of previous bone

infection and is usually characterized by a draining sinus tract from bone

to skin. Chronically infected dead bone is involved, and surgery is

important in removing necrotic bone when possible. Chronic

osteomyelitis is often polymicrobial, and the same organism (especially

S. aureus) that was causative of a previous bone infection could still be

involved in chronic infection. High-dose IV therapy directed at the

results of bone cultures for at least 6 weeks is recommended to offer

the best chances of preventing the extension of infection to adjacent

uninfected bone.

Case 73-4 (Questions 1–4)

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p. 1535

Prosthetic joint infection with adjacent bone osteomyelitis usually

requires surgical removal of the infected prosthesis for cure. Antibiotics

should be directed at the cultured bacteria from a joint aspirate or from

deep surgicalspecimens. The most common pathogens are S. aureus

and coagulase-negative staphylococci. In a situation in which the

prosthesis cannot be totally removed, lifelong, chronic suppressive oral

therapy should be considered.

Case 73-5 (Questions 1–3)

SEPTIC ARTHRITIS

Nongonococcalseptic arthritis is characterized by fever, and the acute

onset of joint pain and effusion in a single joint. Infection is typically

acquired hematogenously from an originating site that may not always

be easily identified. S. aureus is the most common pathogen. Duration

of treatment should be 6 weeks, with oral therapy for the final 2 weeks.

Case 73-6 (Questions 1, 2)

Neisseria gonorrhoeae is the most common cause of polyarticular

arthritis in a young, sexually active adult. Skin lesions may also be

present in disseminated gonococcal infection (DGI). The diagnosis is

frequently based on the clinicalsyndrome and sexual history, because

joint fluid aspirate and blood cultures are frequently negative.

Intravenous ceftriaxone is the treatment of choice and should be

continued for 1 to 2 days after improvement begins. Treatment duration

is 7–14 days.

Case 73-7 (Questions 1–3)

OSTEOMYELITIS

Osteomyelitis is an inflammation of the bone marrow and surrounding bone

associated with infection. Any bone can be involved, and substantial morbidity is

possible even with early diagnosis and treatment. Despite the continued refinement of

diagnostic procedures (e.g., radionuclide imaging, computed tomography, magnetic

resonance imaging), advances in antimicrobial therapy, and the use of prophylactic

antibiotics before orthopedic procedures, osteomyelitis continues to be difficult to

cure.

Osteomyelitis can affect all age groups. The most common causative

microorganisms of acute osteomyelitis have historically been streptococci and

staphylococci. Staphylococcus aureus remains the most causative organism,

accounting for more than 50% of all cases, although the prevalence of infection

caused by methicillin-resistant S. aureus (MRSA) is increasing across all agegroups. Additionally, osteomyelitis caused by gram-negative and anaerobic bacilli is

becoming more common.

1

Bone may be infected by three routes: hematogenous spread of bacteria from a

distant infection site, direct infection of bone from an adjacent or contiguous source

of infection, and infection of bone secondary to vascular insufficiency. Table 73-1

summarizes characteristics associated with osteomyelitis.

1–3 Patients with recurrent

osteomyelitis are considered to have chronic osteomyelitis.

Bone Anatomy and Physiology

The bone is divided into three sections: the epiphysis, located at the end of the bone;

the metaphysis (adjacent to the epiphysis and part of the epiphyseal growth plate);

and the diaphysis (midsection of the bone). The rapidly growing area of the bone is

supported by many blood vessels. Surrounding most of the bone is a fibrous, cellular

envelope. The external portion of this envelope is the periosteum, and the internal

portion is the endosteum.

Blood vessels that supply bone tissue are located predominantly in the epiphysis

and metaphysis of the bone. Nutrient arteries enter the bone at the metaphyseal side of

the epiphyseal growth plate and lead to capillaries that form sharp loops within the

growth plate. These capillaries lead to large sinusoidal veins that eventually exit the

metaphysis through a nutrient vein. Within the sinusoidal veins, blood flow is slowed

considerably, and infection is possible with bacterial colonization.

4

Differences in the vasculature of bone in different age groups lead to different

forms of osteomyelitis. In neonates and adults, vascular communications are present

between the metaphysis and epiphysis, which can allow infection to spread from

bone to the adjacent joint. During childhood, however, this area often is protected

from infection because the epiphyseal plate separates the vascular supply for these

two regions.

4

Hematogenous Osteomyelitis

Hematogenous osteomyelitis predominantly occurs in prepubertal children but may

be seen in older adults, patients with indwelling central catheters, and intravenous

drug users.

1 Osteomyelitis in children tends to be acute, hematogenous, and is often

responsive to antibiotic therapy alone. In comparison, osteomyelitis in adults tends to

be subacute or chronic, commonly results from trauma, infection of prosthetic

devices, or other insult, and often requires surgical debridement in addition to

antimicrobial therapy.

1–3

Infection in children develops primarily in the metaphysis of the rapidly growing

long bones of the body where the slowed blood flow allows bacteria to colonize and

multiply. The acute infectious process (e.g., edema, inflammation, small vessel

thrombosis) increases bone pressure, which compromises blood flow and eventually

leads to necrosis. Released cytokines alter bone integrity by promoting osteoclast

activity. Eventually, the elevated pressure and necrosis cause devitalized bone to

fragment from healthy bone (sequestra). With continued spread of the infection into

the outer layers of the bone and soft tissue, abscess and draining sinus tracts form.

1

,

3

Hematogenous infection in children most commonly occurs in the long bones with

a single focus in the femur and tibia.

1 Hematogenous osteomyelitis in neonates is an

especially serious disease that often involves multiple bones, especially the long

bones. Rapid infection spreading across the epiphyseal plate to the adjacent joint can

lead to septic arthritis, necessitating immediate and aggressive treatment. Vertebrae

involvement is seen more frequently in adults.

1–3

The most common organism causing hematogenous osteomyelitis is S. aureus,

responsible for up to 85% of pediatric cases.

4 The emergence of both hospital- and

community-associated strains of MRSA has challenged the management of

osteomyelitis. MRSA infections are associated with an increased risk of antibiotic

treatment failures and complications, including abscess formation, deep vein

thrombosis, and septic emboli.

5 Gram-negative bacilli (Escherichia coli, Klebsiella,

Proteus, Salmonella, and Pseudomonas) are responsible for an increasing number of

cases of osteomyelitis as well. Pseudomonas aeruginosa is more commonly seen in

patients with indwelling central catheters and in intravenous (IV) drug users, whereas

S. aureus and Salmonella species are common causes in patients with sickle cell

anemia.

1

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p. 1536

Table 73-1

Features of Osteomyelitis

Feature Hematogenous

Adjacent/Contiguous

Site of Infection Vascular Insufficiency

Usual onset: pediatric or Predominantly pediatric Adult Adult

adult

Sites of infection Tibia, femur (children);

vertebrae (adults)

Femur, fibula, tibia, skull,

mandible

Foot

Risk factors Bacteremia Surgery, trauma, cellulitis,

joint prosthesis

Diabetes, peripheral

vascular disease

Common bacteria S. aureus, gram-negative

bacilli; usually one

organism

S. aureus, streptococci,

gram-negative bacilli,

anaerobic organisms;

often polymicrobial

S. aureus, coagulasenegative staphylococci,

streptococci, gramnegative bacilli, anaerobic

organisms; often

polymicrobial

Clinical findings Fever, chills, local

tenderness, swelling;

limitation of motion

Fever, warmth, swelling;

unstable joint

Pain, swelling, drainage,

ulcer formation

Clinical features of hematogenous osteomyelitis vary, depending on the patient’s

age and the infection site. In children, infection usually is characterized by an abrupt

onset of high fever and chills, localized pain, tenderness, and swelling. Systemic

symptoms often are absent in neonates, potentially delaying the diagnosis. A

diagnosis, therefore, must be made on the basis of localized symptoms such as edema

and restricted limb movement. Systemic symptoms are also less common in adults,

although patients with vertebral osteomyelitis can present with the insidious onset of

localized back pain and tenderness.

1

,

3

Acute Osteomyelitis

USUAL CLINICAL PRESENTATION

CASE 73-1

QUESTION 1: L.D., a 7-year-old girl, is unable to go to school today because of fever and worsening leg

pain. Her upper left leg started to hurt 3 to 4 days ago, and last night she began limping. Her parents report no

history of trauma to the area. Her past medical history is significant only for two episodes of otitis media at ages

2 and 5. In the pediatrician’s office, maximal tenderness is localized over the left distal femur without knee joint

effusion. No signs of swelling, warmth, or trauma are seen. Her white blood cell (WBC) count is 8,000/μL with

a normal WBC differential. Plain radiographic studies of the left leg are normal, but the erythrocyte

sedimentation rate (ESR) is 58 mm/hour (normal ≤30 mm/hour). Two blood samples are obtained for culture,

and L.D. is sent home with directions for bed rest and use of acetaminophen as needed for fever. Two days

later, she is admitted to the hospital with severe pain and tenderness in her left leg and a fever of 38.8°C. The

blood cultures obtained 2 days ago are positive for S. aureus with susceptibilities still pending. C-reactive protein

(CRP) is 14 mg/dL (normal, <2 mg/dL). Another plain radiographic study is normal, but a magnetic resonance

imaging (MRI) scan reveals inflammation in her left distal femur. What findings in L.D. are consistent with

hematogenous osteomyelitis?

L.D. displays the usual signs and symptoms of acute hematogenous osteomyelitis in

children. She is a previously healthy child who experienced acute localized pain and

tenderness of the left distal femur, abrupt onset of high fever, and an elevated ESR

and CRP. Her plain radiographic studies were normal on two occasions; however,

destructive changes to bone often do not appear on plain radiographs for at least 10

to 14 days after onset of infection.

1 Hence, a normal plain film does not rule out acute

osteomyelitis if obtained within the first 2 weeks of infection. Diagnosis includes

radionuclide imaging (bone scans), computed tomography (CT), or MRI.

1

,

4 MRI is

more sensitive than CT for the assessment of soft tissue and detecting early bone

marrow edema; however, it often requires sedation for children.

4 The sensitivity of

bone scan detection of osteomyelitis has been lowest when the infection was caused

by community-associated MRSA (CA-MRSA).

4 L.D.’s MRI scan on hospitalization

detected inflammation in the left distal femur. Although L.D. did not have a bone

biopsy sent for culture, her clinical picture, a positive MRI scan, and blood cultures

positive for S. aureus establish the diagnosis of osteomyelitis. The specific event that

caused bacteremia with dissemination to bone is unknown, as is often the case in

children.

4

Laboratory tests that should be routinely obtained in every child suspected of

having osteomyelitis include a complete blood count (CBC), ESR, and serum CRP.

Although these tests are not specific for the diagnosis of osteomyelitis, they help

confirm the clinical diagnosis. An increased WBC count is consistent with

osteomyelitis, but leukocytosis is absent in many children with osteomyelitis at the

initial examination. Thus, L.D.’s WBC count of 8,000/μL is not unusual. In adults,

leukocytosis is more common in an acute infection rather than with recurrent or

chronic disease. Both ESR and CRP are nonspecific markers of systemic

inflammation when elevated.

Predisposing factors for hematogenous osteomyelitis include any risk factors for

bacteremia (e.g., indwelling catheters such as hemodialysis shunts and chronic

central venous catheters). Other risk factors that can potentially lead to bacteremia

and subsequently hematogenous osteomyelitis include IV drug use and a distant focus

of infection in the gastrointestinal or urinary tract. None of these factors exist in L.D.

In children such as L.D. who have no history of trauma, fractures, or penetrating

injury, the most common cause of acute hematogenous osteomyelitis is S. aureus and

the possibility of CA-MRSA must be considered.

1

,

5,6

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p. 1537

PATIENT WORKUP

CASE 73-1, QUESTION 2: What additional patient and diagnostic information should be obtained before

L.D. receives her first dose of antibiotics?

Before L.D. receives antibiotic therapy, she should be assessed for drug allergies,

especially penicillin allergy. Patient interviews, discussions with her parents, and a

comprehensive review of her medical record are necessary, especially with a history

of allergy. Details of an allergic reaction, including symptoms, onset of the reaction,

probable causative agent, treatment, and exposure to related antimicrobials should be

evaluated.

Cultures of blood and bone aspirate material optimally identify the pathogen and

must be part of the initial workup prior to the start of antibiotics. Cultures taken after

antibiotics have been initiated are often negative. Positive blood cultures are seen in

33%–50% of pediatric bone and joint infections.

6

In L.D.’s case, the positive blood culture and MRI establish the diagnosis of

osteomyelitis. If the blood cultures had been negative, however, a bone aspirate

would be recommended to identify the pathogen.

1 Once material has been obtained

for culture, empiric antibiotic therapy should start as soon as possible.

TREATMENT

Empiric Antibiotic Therapy

CASE 73-1, QUESTION 3: L.D. has no history of drug allergies. She took amoxicillin for the previous

episodes of acute otitis media without incident. What empiric antibiotic(s) should be started? What is the

relevance of bone concentrations or protein binding of antibiotics in the selection of therapy for osteomyelitis?

The chosen agent should be administered IV at high doses to optimize drug

concentration in infected bone. Treatment should be initiated as soon as possible to

improve the chances for complete eradication of infection and to avoid the need for

surgery. Thus, empiric antibiotic therapy is often administered while bacterial

cultures are pending or before antibiotic susceptibility results are known.

Although cultures are pending or with negative cultures, the age of the child can

predict the likely pathogen and guide empiric antibiotic selection. For example, S.

aureus and Streptococcus species are commonly responsible for osteomyelitis in the

neonate.

1 Kingella kingae, a facultatively anaerobic, gram-negative hemolytic

bacillus, is being detected with increasing frequency in children under 3 years of age,

especially in the day care setting.

7

,

8 Table 73-2 summarizes the common causative

organisms of acute hematogenous osteomyelitis in children and recommended drugs

and doses for treatment.

2

,

4,9,10

Considering the epidemiology of L.D.’s infection and the blood cultures, she

should be treated for S. aureus osteomyelitis. In both children and adults, the number

of acute osteomyelitis cases caused by MRSA continues to increase.

4

,

6 Empiric IV

vancomycin should be administered pending susceptibility results. Alternative

empiric therapy for L.D. with MRSA coverage includes daptomycin or linezolid.

9

Due to limited clinical experience, these two agents should be reserved for

vancomycin-intolerant cases. Clindamycin is not an option for L.D., but may be used

empirically for stable patients without bacteremia or intravascular infection.

9

The importance of antibiotic bone concentration when treating osteomyelitis is

unclear, and bone concentrations do not always predict outcome of therapy.

2

,

11

Theoretically, protein binding could influence clinical efficacy because free drug is

thought to diffuse from plasma into bone tissue and protein-bound drug does not.

However, cefazolin (for sensitive gram-positive cocci) and ceftriaxone (for sensitive

gram-negative rods and streptococci), both highly protein-bound drugs, are wellestablished treatments for osteomyelitis when appropriate doses and duration are

used. Therefore, antibiotic bone concentrations and protein binding of antibiotics (in

appropriate doses) are not significant factors in the selection of appropriate therapy

for osteomyelitis.

2

,

11

Directed Antibiotic Therapy

CASE 73-1, QUESTION 4: The S. aureus grown from L.D.’s blood culture is methicillin sensitive.

Considering these results, what is the optimal antibiotic regimen? Would other antibiotics given less frequently

also be adequate?

L.D. is not allergic to penicillin. Although vancomycin is active against MSSA, it

is inferior to β-lactams; thus, β-lactam-based therapy should be used for susceptible

organisms.

1

,

6 De-escalating from vancomycin to oxacillin (or nafcillin) at 150

mg/kg/day every 6 hours is appropriate.

2 Nafcillin and oxacillin are therapeutically

equivalent and are given in similar doses; therefore, selection typically depends on

hospital formulary considerations. Her prior exposure to amoxicillin is irrelevant

except to establish the absence of a penicillin allergy.

Continuing to treat L.D. with IV oxacillin (or nafcillin) every 6 hours follows

treatment recommendations for MSSA osteomyelitis. Antistaphylococcal penicillins

are effective therapy with appropriate doses and duration. Changing L.D. to cefazolin

would allow slightly less frequent dosing (every 8 hours), a potential advantage for

home treatment. Vancomycin use should be discouraged in L.D.’s case because

cultures revealed a methicillin-sensitive organism, and vancomycin is more likely to

be associated with treatment failure.

1

,

6

In the absence of susceptibility results or of

methicillin resistance, IV vancomycin would be required for the duration of therapy.

Although the logistics of outpatient therapy in L.D. are being investigated, she should

remain on oxacillin while in the hospital.

Duration of Therapy

CASE 73-1, QUESTION 5: Both of L.D.’s parents are employed, and their work schedules prevent them

from leaving their jobs to transport her to an outpatient antibiotic treatment center. Is L.D. a candidate for

outpatient IV antibiotic therapy at home, or is oral antibiotic treatment an option? Must L.D. remain in the

hospital to receive her oxacillin?

Initially, all patients should receive IV antibiotics because early, aggressive

therapy offers the best chance to cure the infection. L.D., however, does not

necessarily need to stay in the hospital for the duration of therapy. A peripherally

inserted central catheter (PICC) can be placed, and antibiotics can be administered.

The decision to use home IV antibiotic administration must be decided in concert

with L.D.’s parents. If L.D.’s parents do not have the resources or are unwilling to

oversee IV treatment at home, L.D. should remain hospitalized for a minimum of 1

week to assess the efficacy of IV treatment. Transition to oral therapy should be

considered at discharge due to the frequency of PICC line complications and the cost

and inconvenience of several weeks of IV therapy at home.

7

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