1. Infectious Disease I: Bone and Joint Infections
Courses in Therapeutics and Disease State Management

2. Learning Objectives (Slide 1 of 3)
Compare the epidemiology of osteomyelitis when categorized by the mechanism of the organism reaching the bone
Differentiate the characteristics of infectious arthritis
Contrast the most common characteristics of hematogenous osteomyelitis
Compare the pathophysiology of osteomyelitis by age group
Select the most frequent organisms causing hematogenous osteomyelitis

3. Learning Objectives (Slide 2 of 3)
Contrast the most common characteristics of contiguous- spread osteomyelitis
Discuss the organism sources of infectious arthritis
Differentiate the risk factors for developing adult infectious arthritis
Compare the etiologies of adult infectious arthritis subgroups
Design a laboratory monitoring strategy for bone and joint infections

4. Learning Objectives (Slide 3 of 3)
Contrast the usefulness of culture sites with bone and joint infections
Choose the preferred duration of therapy for patients with bone and joint infections
Discuss the patient selection characteristics for oral antibiotic regimens treating osteomyelitis
Critique the use of oral fluoroquinolones in the treatment of bone and joint infections
Construct an empiric antibiotic regimen for different patient categories with bone or joint infections

5. Required Reading
Armstrong EP, Shehab Z. Chapter 96. Bone and Joint Infections. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014.

6. Topic Overview
Bone and Joint infections are divided into two distinct disease processes with different infecting organisms, signs and symptom
Septic or infective arthritis is the infection of a joint or synovial fluid
Osteomyelitis is the infection of a bone
Early initiation of antibiotic therapy and prolonged courses are required to reduce long term morbidity
Osteomyelitis is an uncommon infectious disease, while septic arthritis is one of the most common causes of new cases of arthritis.
These infections are difficult to treat and lead to progressive and long lasting destruction of the bones and joints affected.

7. Osteomyelitis: Overview
Classification
Manner of a acquisition
Seeding or direct inoculation of microorganism via the blood into the bone is considered hematogenous osteomyelitis
Spread of microorganisms from adjacent soft tissues and joints is considered contiguous osteomyelitis
Direct inoculation of microorganism via puncture wounds, trauma, or surgery is considered inoculation osteomyelitis
Duration
Acute osteomyelitis has a duration of days to weeks
Chronic osteomyelitis has a duration of weeks to months
Osteomyelitis is classified based on the mode of acquisition of the bone infection.
Patients with peripheral vascular disease and diabetes are at risk contiguous osteomyelitis due to reduced perfusion and sensation in the lower extremities
Patients with bacteremia are at risk for the development of hematogenous osteomyelitis

8. Osteomyelitis: Pathophysiology
Hematogenous
Contiguous
Inoculation
Link to figure of cross section of normal bone
Hematogenous osteomyelitis occurs most often in children under the age of 16 whose bone are still growing. Adult patients over 50 years old may experience hematogenous osteomyelitis in the vertebrae.
The vascular structure of the long bone predisposes the bone to infections via the blood. The movement of blood from the arterioles, through the hairpin turns of the capillary bed, to the slow flow of the veins allow microorganism to deposit into the growth plate of growing bones.
Trauma is a common antecedent to osteomyelitis via hematogenous spread
The more bacteria proliferates into the bone tissue, the damage to the bone and possibly spread adjacent joints becomes more extensive
Chronic osteomyelitis is more likely to occur if large segments of bone become avascular and necrotic.
Inoculation osteomyelitis is due to direct entrance of organisms from a source outside the body:
penetrating wounds (stepping on a nail)
open fractures
invasive orthopedic procedures
Contiguous osteomyelitis can result from the spread of microorganism from adjacent pressure ulcers or soft tissue infections
Microorganisms from infected teeth or sinus infections can spread to the mandible

9. Osteomyelitis: Pathophysiology
Types of Osteomyelitis, Age Distribution, Common Sites, and Risk Factors
Type of Osteomyelitis
Typical Age (years)
Site(s) Involved
Risk Factors
Hematogenous
Less than 1
Long bones and joints
Prematurity, umbilical or other central venous catheter or venous cutdown, respiratory distress syndrome, and perinatal asphyxia
1–20
Long bones (femur, tibia, and humerus)
Infection (pharyngitis, cellulitis, and respiratory infections), trauma, and sickle cell disease
Older than 50
Vertebrae
Diabetes mellitus, blunt trauma to spine, and urinary tract infection
Contiguous
Femur, tibia, and mandible
Hip fractures and open fractures
Puncture
Less than 18
Foot
Puncture injury to foot
Vascular insufficiency
Feet and toes
Diabetes mellitus, peripheral vascular disease, and pressure sores
From AccessPharmacy: accesspharmacy.mhmedical.com, Copyright© McGraw-Hill Education. All rights reserved.
Chapter 96. Bone and Joint Infections, Table 96-1
Pharmacotherapy: A Pathophysiologic Approach, 9e, 2014
Joseph T. DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey

10. Osteomyelitis: Pathophysiology, Most Common Pathogens
Contiguous
With vascular insufficiency
Adults > 50
S. aureus (MRSA)
Enterobacteriaceae
Pseudomonas aeruginosa
Enterococcus spp.
Anaerobes
without vascular insufficiency
Adult > 50
S. aureus
Inoculation
Gram negative pathogens
Hematogenous
Neonates
S. aureus
E. coli
Group B streptococci
Pre-pubertal Children
Elderly
Staphylococcus aureus is the most common pathogen for the majority of hematogenous and contiguous osteomyelitis. Therefore any empiric therapy should include coverage for Staphylococcus aureus including MRSA. Empiric therapy can be further directed by the age group of the patient.
The implementation of wide spread vaccination efforts has decreased the incidence of osteomyelitis caused by Haemophilus influenzae type b (Hib) and pneumococcal disease
Osteomyelitis resulting from puncture injuries to the feet are associated with gram-negative infection

11. Osteomyelitis: Clinical Presentation
Signs and Symptoms
Laboratory tests
Systemic
Fevers
Chills
Malaise
Localized
Pain or tenderness
Edema
Erythema
Inflammation
Decreased range of motion
Elevated WBC
Elevated inflammatory markers
Erythrocyte sedimentation rate (ESR)
C-reactive protein (CRP)
Positive blood cultures
Bone biopsy cultures
Bone changes on radiograph
Magnetic resonance imaging
Technetium scans
Presentation of osteomyelitis is slow and non specific making early identification of this infection difficult for clinicians
Bone changes on radiograph can be seen 10 to 14 days after start of infection
Accurate culture information can be difficult to obtain from patients, but is extremely important for the management of antimicrobial therapy. Blood cultures are able to be obtained easily, but are only positive in 50% of cases. Bone aspiration and bone biopsy are invasive procedure, but can provide accurate microbiologic data.
Open draining sinuses should not be trusted for culture data, as they may be contaminated with normal skin flora

12. Osteomyelitis: Treatment Overview
Antibiotics must have adequate bone concentrations
Duration of Antibiotics
4 to 6 weeks
May be able to switch to oral antibiotics
Monitoring for Efficacy
Clinical improvement of signs in symptoms in 48 to 72 hours
Reduction in CRP 1 week after therapy
Observe for adverse effects associated with long term antimicrobial therapy
Parenteral antibiotics are initiated first, followed by oral therapy.
Oral antibiotics may be utilized if the following conditions are met
Confirmed osteomyelitis
Initial clinical response to parenteral antibiotics
Suitable oral agent available
Compliance ensured
Children and adults without diabetes are considered good candidates for oral therapy after responding to initial IV antibiotics
Ciprofloxacin has excellent oral absorption, bone penetration, and gram negative coverage
dicloxacillin, cephalexin, or clindamycin can be used for MSSA infections

13. Osteomyelitis: Nonpharmacological Treatment
Surgical drainage of abscesses
Hyperbaric oxygen

14. Osteomyelitis: Pharmacological Treatment
Patient Subtype
Likely Infecting Organism
Antibiotica
Recommendation Gradesb
Newborn
Staphylococcus aureus, group B streptococci, Escherichia coli
Nafcillin or oxacillin 50–150 mg/kg/day IV plus cefotaxime 100–200 mg/kg/day IV
B-3
Children 5 years of age or younger
1. If vaccinated for Haemophilus influenzae type b: S. aureus or streptococci
1. Nafcillin or oxacillin 150–200 mg/kg/day IV or cefazolin 100 mg/kg/day IV
2. If not vaccinated against H. influenzae type b
2. Cefuroxime 150 mg/kg/day IV
Children older than 5 years of age
S. aureus
Nafcillin or oxacillin 150–200 mg/kg/day IV or cefazolin 100 mg/kg/day IV
A-3
Adults
Nafcillin or oxacillin 2 g IV every 4 hours or cefazolin 2 g IV every 8 hours
IV drug abusers
Pseudomonas
Ciprofloxacin 750 mg PO twice daily or ceftazidime or cefepime 2 g IV every 8 hours
Postoperative or posttrauma patients
Gram-positive and gram-negative organisms
Nafcillin or oxacillin 2 g IV every 4 hours plus ceftazidime or cefepime 2 g IV every 8 hours or ticarcillin–clavulanate 3.1 g IV every 4 hours
Patients with vascular insufficiency
Nafcillin or oxacillin 2 g IV every 4 hours or cefazolin 2 g IV every 8 hours plus ceftazidime or cefepime 2 g IV every 8 hours
If anaerobes suspected
Cefotetan 2 g IV every 12 hours or clindamycin 900 mg IV every 8 hours plus ceftazidime or cefepime 2 g IV every 8 hours
C-3
Empiric therapy is guided by the most common pathogen to cause osteomyelitis in the specific patient population. Antimicrobial therapy can be narrowed (de-escalated) once more specific culture data is available.
From AccessPharmacy: accesspharmacy.mhmedical.com, Copyright© McGraw-Hill Education. All rights reserved.
Chapter 96. Bone and Joint Infections, Table 96-4 Empirical Treatment of Osteomyelitis Pharmacotherapy: A Pathophysiologic Approach, 9e, 2014
Joseph T. DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey
PO, orally.
aDosage should be adjusted for some agents in patients with renal and/or hepatic dysfunction.
bStrength of recommendations: A, B, C = good, moderate, and poor evidence to support recommendation, respectively. Quality of evidence: 1 = Evidence from more than one properly randomized, controlled studies or multiple time series; or dramatic results from uncontrolled experiments. 2 = Evidence from more than one well-designed clinical trial with randomization, from cohort or case-controlled analytic studies. 3 = Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert communities.

15. Septic Arthritis: Overview
An inflammatory reaction within the joint space
Joint Infection that can be caused by several different microorganisms
Classification by manner of a acquisition
Seeding or direct inoculation of microorganism via the blood into the bone is considered hematogenous spread
Spread of microorganisms from adjacent soft tissues and joints is considered contiguous spread
Direct inoculation of microorganism via puncture wounds, trauma, or surgery is considered inoculation spread
Most often affects only one joint, but can involve more than one joint
Hematogenous spread microorganisms into the joints is the most common form of septic arthritis.
Affects young children and adults

16. Septic Arthritis: Pathophysiology
Feature
Finding
Peak incidence
Children younger than 16 years
Adults older than 50 years
Clinical findings
Fever of 38–40°C (100.4–104°F) in children; painful swollen joint in the absence of trauma
Physical examination: Effusion, restriction of joint motion, tenderness, redness, and warmth of joint
Most commonly affected joints
Knee, hip, ankle, elbow, wrist, and shoulder
Laboratory findings
Erythrocyte sedimentation rate
Elevated in 90% of cases
White blood cell count
Elevated in 30–60% of cases
Left shift
Seen in two thirds of patients
Blood culture
Positive in 40% of cases
Needle aspiration of joint
Gram-stain diagnostic in 30–50% of cases. Synovial fluid cultures are positive in 60–80% of cases. Synovial fluid differential reveals 90% polymorphonuclear leukocytes. Synovial fluid glucose decreased relative to serum glucose. Lactic acid levels elevated in nongonococcal infectious arthritis, but not in gonococcal infectious arthritis
Hematogenous spread is the most common form septic arthritis due to the highly vascularized synovial tissue without a basement membrane. This allows easy enter of bacteria into the synovial fluid via the blood
From AccessPharmacy: accesspharmacy.mhmedical.com, Copyright© McGraw-Hill Education. All rights reserved.
Chapter 96. Bone and Joint Infections, Table 96-2 Characteristics of Acute Infectious Arthritis Pharmacotherapy: A Pathophysiologic Approach, 9e, 2014
Joseph T. DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey

17. Septic Arthritis: Pathophysiology, Most Common Pathogens
Overall
Staphylococcus aureus
Streptococcal infection
Gram negative pathogens
E. coli
Pseudomonas aeruginosa
Specific Groups
Neonates
S. aureus
Group B streptococci
Gram negative pathogens
Pre-pubertal Children
Streptococcal infection
IV drug abusers
Pseudomonas aeruginosa
Staphylococcus aureus is the most common pathogen in septic arthritis, with streptococcal and gram negative infections second and third most common respectively. Therefore any empiric therapy should include coverage for Staphylococcus aureus including MRSA. Empiric therapy can be further directed by the age group of the patient.
Patients with disseminated Gonococcal infections are at high risk for developing Gonococcal septic arthritis
As with osteomyelitis, the implementation of wide spread vaccination efforts has decreased the incidence of septic arthritis caused by Haemophilus influenzae type b (Hib) and pneumococcal disease

18. Septic Arthritis: Clinical Presentation
Signs and Symptoms
Laboratory tests
Systemic
Fevers
Chills
Malaise
Localized
Joint pain or tenderness
Edema
Erythema
Inflammation
Decreased range of motion
Elevated WBC is rare
Elevated inflammatory markers are less common
Erythrocyte sedimentation rate (ESR)
C-reactive protein (CRP)
Positive blood cultures
Joint aspiration fluid
Presence of purulent fluid
Gram stain
Culture
Prosthetic joint material cultures
Presentation of septic arthritis almost always presents with a fever
The knee is the most commonly involved joint, but can occur in any joint.
Due to hematogenous spread being the most common form of septic arthritis blood cultures are helpful for the proper identification of the infecting microbe.
Contaminated prosthetic joint devices usually present within one year of implantation.

19. Septic Arthritis: Treatment Overview
Antibiotics must have adequate synovial fluid concentrations
Duration of Antibiotics
2 to 3 weeks
May be able to switch to oral antibiotics
Clinical improvement of signs in symptoms in is generally rapid after initiation of antibiotic therapy and joint aspiration
Parenteral antibiotics are initiated first, followed by oral therapy.
After culture and susceptibility results are available and the organism is determined to be susceptible, therapy can be switched on the fourth day to cefixime, oral amoxicillin or to doxycycline or tetracycline to complete the 7- to 10-day course.

20. Septic Arthritis: Nonpharmacological Treatment
Closed-needle aspiration is recommended for all infected joints except the hip
Joint rest
Passive range of motion exercises once joint pain subsides
Aspiration of the joint can be repeated daily for 5 to 7 days
Hip joint infections require open drainage

21. Septic Arthritis: Pharmacological Treatment
Infants < 1 month of age
Nafcillin or Oxacillin
Plus
3rd generation cephalosporin
Children <5 years of age immunized for Hib
 Nafcillin, Oxacillin, or Cefazolin
Children >5 years of age and adults
MSSA suspected
Nafcillin, Oxacillin, or Cefazolin
MRSA suspected
Clindamycin, Vancomycin, or Linezolid
Empiric therapy is guided by the most common pathogen to cause osteomyelitis in the specific patient population. Antimicrobial therapy can be narrowed (de-escalated) once more specific culture data is available.
Disseminated gonococcal infections should be treated with Ceftriaxone for 7 to 10 days in adults

22. Overall Monitoring of Bone and Joint Infections
Parameter
Frequency
Notes
Culture and susceptibility
At initiation of treatment
White blood cell count
One time per week until within normal range
C-reactive protein or erythrocyte sedimentation rate
Weekly
May not decrease to normal range until several weeks of therapy
Clinical signs of inflammation (redness, pain, swelling, tenderness, and fever)
Daily during initiation of therapy
Compliance of outpatient therapy
Reinforce before starting oral therapy and with each healthcare visit
Compliance is critical if treatment is to be successful
From AccessPharmacy: accesspharmacy.mhmedical.com, Copyright© McGraw-Hill Education. All rights reserved.
Chapter 96. Bone and Joint Infections, Table 96-5 Monitoring Protocol Pharmacotherapy: A Pathophysiologic Approach, 9e, 2014
Joseph T. DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey

23. Summary
Osteomyletitis and septic arthritis are infections of the bone and joints respectively
S. aureus is the most common pathogen
Intravenous Antibiotics
Bone and joint penetration must be considered
Narrow antibiotics based on cultures and sensitivities
Duration of antibiotics
Osteomyelitis 4 to 6 weeks
Septic Arthritis 2 to3 weeks
Initiate oral antibiotics when appropriate

24. Reference
Armstrong EP, Shehab Z. Chapter 96. Bone and Joint Infections. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014.