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

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

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

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

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.

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.

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

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

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

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

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

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

Osteomyelitis: Nonpharmacological Treatment Surgical drainage of abscesses Hyperbaric oxygen

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.

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

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

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

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.

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.

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

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

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

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

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.