ESPID New Bone and Joint Infection Guidelines Theoklis Zaoutis, MD, MSCE Professor of Pediatrics and Epidemiology Perelman School of Medicine at the University of Pennsylvania Chief, Division of Infectious Diseases The Children s Hospital of Philadelphia Scientific Director, CLEO
Overview Epidemiology Pathogenesis Clinical Features Diagnosis Treatment
Abbreviations Bone and Joint Infection - BJI Septic Arthritis SA Osteomyelitis - OM
Criteria Used for Writing Guideline I = Good evidence: Randomized trials, high quality meta-analyses and systematic reviews of clinical trials II = Moderate evidence: well designed observational studies III = Poor evidence: Expert opinion, case series Strength of recommendation A = Strong recommendation B = Moderate recommendation C = Weak recommendation
OM: Epidemiology and Risk factors 1 in 5000 each year in US 1% of pediatric hospitalizations 50% occur before 5 years old Twice as common in males 1/3 have preceding minor trauma Staph aureus, GAS, S. pneumoniae, H. flu, Salmonella
Epidemiology and Risk Factors Upper respiratory tract infection K. kingae Sickle cell disease Salmonella Penetrating wounds Pseudomonas Animal handling/ lab work Brucella and Coxiella spp. Contact with pulmonary TB Immunodeficiency depends on specific defect
Etiology and Pathogenesis Most BJI infections are of hematogenous origin Less frequently than adults, BJI can be secondary to an adjacent infection, prosthetic material or trauma
Pathogenesis of Osteomyelitis
Pathogenesis of Osteomyelitis
Distribution of Osteomyelitis in Children
Age distribution (top) and localization and proportional distribution of the causative agents (bottom) among the 130 children with acute septic arthritis. Peltola H et al. Clin Infect Dis. 2009;48:1201-121 2009 by the Infectious Diseases Society of America
Epidemiology: Pathogens Neonate (< 3 month) Group B streptococcus Staph aureus Candida sp. E. coli and other GNR Infant (3 mo to 5 years) S. aureus Kingella kingae S. pyogenes S. pneumoniae H. influenzae* Older Child > 5 S. aureus S. pyogenes Salmonella sp. *pre-hib vaccine accounted for 10-15 % of cases
Epidemiology: Colonization and Infection with S. aureus Common colonizer of humans, primates, other mammmals Causes many infections, ranging from mild to lifethreatining Colonization typically precedes infection Infection arises when local damage of colonized skin or mucus membranes permits entry of S. aureus Hematogeneous dissemination of the organism.
Clinical Features Osteomyelitis more insidious onset (6-7 days) 81% pain 70% localized signs and symptoms 62% fever 50% reduced range of motion 50% reduced weight bearing/limping Septic arthritis more frequently fever, swelling, decreased range of motion (3-4 days) More occult in sacroiliac and vertebra
Question What diagnostic tests should be performed?
Laboratory Tests Complete blood count, CRP and ESR usually recommended CRP and ESR have high sensitivity, low specificity (IIB)Lack of evidence to support procalcitonin Cultures of bone, joint or blood is the gold standard (IIA) yield of blood culture is 50-60% Arthrocentesis as part of therapy. For OM, bone aspiration does not seem to affect outcome Inoculate blood culture bottles with synovial fluid increased yield of Kingella
Question What radiologic imaging would you like and what is its accuracy for diagnosing osteomyelitis?
Question What radiologic imaging would you like and what is its accuracy for diagnosing osteomyelitis? Ultrasound has high sensitivity for diagnosis of SA, MRI is the most reliable imaging study for BJI overall (IIA)
X- ray imaging Always at baseline, rule out other diseases and for follow-up Can miss joint effusions (esp. hip) Findings: Early (3-10 days) Soft tissue swelling Loss of fat planes around bone Late (10-20 days) Periosteal thickening or elevation Focal osteopenia Osteolytic lesions (requires >30-50% bone loss) Very late (>30 days) Sclerosis
Scintigraphy/Bone Scan Study of choice if Poorly localized pain (e.g., pelvis or vertebral osteomyelitis) Suspect multiple or unusual sites of infection Limitation Normal in 5% to 20% during first few days of illness (sensitivity ~90%) Cannot differentiate infection from tumor or trauma (poor specificity) Not useful in neonates
MRI/CT Scan MRI Study of choice High sensitivity (92% to 100%) Detects subperiosteal and adjacent soft tissue abscesses and sinus tracts More anatomic information than radiographs, scintigraphy, and CT Within 3-5 days of disease onset CT Consider if MRI not available Higher radiation
Question Is surgical drainage necessary (open surgery or fine needle aspirate)?
Surgery - SA Should be treated with joint drainage by arthrocentesis, arthrotomy, or arthroscopy depending on preference of the treating clinicians and surgeons (IIB) Arthrocentesis may be appropriate as the only procedure in uncomplicated SA cases (IIB)
Indications for Surgery -OM Drain subperiosteal, intra-osseus, or intraarticular abscess Failure of medical management after 72-96 hours. Remove sequestra or infected foreign material Debride and drain puncture-associated infection Chronic osteomyelitis
Drainage Mandatory for OM? Many authors emphasize need to drain abscesses or drill bone for diagnostic as well as therapeutic reasons. 1982: Cole et al. demonstrate early acute osteo successfully treated without drilling bone and only aspirating abscesses. No controlled trials in literature.
Question Empirical antibiotic coverage?
Empirical Antibiotic Therapy Should be started as soon as possible after collecting appropriate microbiologic samples (IIA) Coverage for MSSA and MRSA (if local prevalence > 10-15% (IIA) Coverage for K. kingae in relevant areas (e.g., Spain, France, UK) (IIA) First generation cephalosporins, anti-staphylococcal penicillins and clindamycin (IIA) If MRSA documented or suspected, clindamycin or if clindamycin resistance > 10-15%, glycopeptide or linezolid (IIB) In neonate add gentamicin or cefotaxime
Antibiotic Therapy: Directed Organism Antibiotic B. burgdorferi Amoxicillin, doxycycline, or ceftriaxone Group A/B Streptococcus Penicillin H. influenzae Ceftriaxone Klebsiella spp. or E. coli Ceftriaxone or cefotaxime K. kingae Penicillin or ampicillin N. gonorrhoeae Ceftriaxone or cefotaxime S. aureus (MSSA) Oxacillin, nafcillin, or cefazolin S. aureus (MRSA) Clindamycin, vancomycin, or linezolid S. pneumoniae Ampicillin, ceftriaxone, or cefotaxime
Question What route of therapy should be used to treat BJI?
Route of Therapy Short intravenous therapy followed by oral therapy is appropriate for the majority of children with uncomplicated BJI based on absence of complications and favorable outcome (IA). For culture-negative infections continue with oral antibiotic similar to class used for IV
Route of Therapy: Tetzlaff 1978 IV until signs of d inflammation (mean 7.3 d) Followed by PO (mean 19.8 d) Conditions for conversion to PO: Organism identified (blood, bone, joint) Peak bactericidal titer > 1:8 Hospitalized for duration of treatment (including oral therapy) Only 1/22 developed chronic osteo
Route of Therapy: Cole 1982 Minimize surgery: bone aspiration for abscess drainage only (22%) Minimize duration of IV therapy (mean 3 d) Complete oral therapy as outpatient No bactericidal levels measured Cured after 6 weeks of therapy: 44/48 with early acute osteo (fever < 48 h) 2/8 with late acute osteo (symptoms >5 days, all with abscess)
Route of Therapy: Peltola 1997 50 patients with S. aureus AO Surgery (needle aspiration or drilling) Conversion to high-dose 1 st generation oral cephalosporin after 3-4 days Serum bactericidal activity and antibiotic concentrations not measured 3-4 weeks total therapy (mean 23 days) Intensive f/u with ESR x 8; CRP x 12 in 30 d. Mean 11 days of hospitalization No complications with 1 year follow-up
Route of Therapy: Le Saux 2002 Systematic review Clinical cure rate at 6 months: IV: short course (< 7 d) vs. long-course (>7d) Then switch to PO antibiotics. 12 case series or small observational studies: 7 short-course and 5 long-course therapy. Clinical cure rate Short-course = 95.2% (95% CI; 90.4, 97.7) Long-course = 98.8% (95% CI: 93.6, 99.8) No Difference
Safety of Prolonged IV Therapy IV x 5d, then PO No rehospitalization No return to ED AO n=80 n-=5 IV x 2wks with CVC n=75 31/75 (41%) developed complications 17 (23%) CVC malfunction or displacement 8 (11%) catheter-assoc bloodstream infection 8 (11%) fever with negative blood cx 4 (5%) local skin infection at CVC site Ruebner 2005 Pediatrics
Treatment Outcomes of AO Zaoutis T, et al Pediatrics 2009
From: Comparative Effectiveness of Intravenous vs Oral Antibiotics for Postdischarge Treatment of Acute Osteomyelitis in Children JAMA Pediatr. 2015;169(2):120-128. doi:10.1001/jamapediatrics.2014.2822 Table Title: Adverse Outcomes a Date of download: 10/20/2017 Copyright 2015 American Medical Association. All rights reserved.
When to switch to oral therapy? Afebrile or decreased temperature for 24-28 hours Improvement of symptoms Decrease in CRP of 30-50% Negative blood cultures if initially positive Usually about 5 days average Neonates may be longer IV (10 14 day) personal experiences Virulent pathogen switch (MRSA, Salmonella, role of PVL positive?
Question What is the length of therapy?
Duration of Therapy The minimum duration of antibiotic theray should be 2-3 weeks for SA and 3-4 weeks for OM (IA). Following patients may need longer durations (IIB): Young infants Complicated or high risk BJI Salmonella, MRSA, PVL +
Duration of Therapy: Dich 1975 Immediate needle aspiration of subperiosteal space and bone. Drainage through bone window if pus found on needle aspiration. Exclusive IV antibiotics Duration of IV therapy Recurrent or chronic osteo 21 days 7/37 (19%) >21 days 1/47 (2%)
Short-Course Therapy Prospective, randomized trial 131 children with culture positive osteomyelitis Aged 3 month-15 years Randomized to 20 versus 30 days of clindamycin or first generation cephalosporin 89% S. aureus IV for 2-4 days followed by oral No complications, 1 minor sequelae in each group Peltola H, et al PIDJ 2010
Short Course Therapy for SA Peltola H et al. Clin Infect Dis. 2009;48:1201-121 2009 by the Infectious Diseases Society of America
FIGURE 1. Short- Versus Long-term Antimicrobial Treatment for Acute Hematogenous Osteomyelitis of Childhood: Prospective, Randomized Trial on 131 Culture-positive Cases. Peltola, Heikki; Paakkonen, Markus; Kallio, Pentti; MD, PhD; Kallio, Markku Pediatric Infectious Disease Journal. 29(12):1123-1128, December 2010. DOI: 10.1097/INF.0b013e3181f55a89 FIGURE 1. C-reactive protein level (CRP), erythrocyte sedimentation rate (ESR), and blood leukocyte count (WBC) of the 67 cases in the short-term and 64 cases in the long-term treatment groups. Curves depicted with standard error of mean (SEM). 2010 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
Serum C-reactive protein (CRP) level (±SEM), erythrocyte sedimentation rate (ESR), and WBC count in the 67 patients in the 30-day treatment group, compared with those in the 63 patients in the 10-day treatment group. Peltola H et al. Clin Infect Dis. 2009;48:1201-121 2009 by the Infectious Diseases Society of America
Serum C-reactive protein (CRP) level (±SEM) and erythrocyte sedimentation rate (ESR; ±SEM) in 16 children who underwent arthrotomy or joint lavage by arthroscopy or with needles, compared with those in the 110 children who underwent diagnostic aspiration only. Peltola H et al. Clin Infect Dis. 2009;48:1201-121 2009 by the Infectious Diseases Society of America
Complicated BJI Risk factors associated with sequelae (IIB): Young infants and newborns Infections caused by MRSA or PVL+ Longer duration of symptoms before therapy Hip involvement Children with these risk factors should be followed more closely and for longer period of time to rule out or treat sequelae (IIB)
Follow-up A multidisciplinary team should follow children with BJI until osteoarticular function is restored and sequelae are resolved. If bone growth is the only concern, and orthopedic specialist will suffice. Infants with BJI in hip or with any physis involvement should be followed closely for extended periods of time (IIB).
The origin of evidence-based medicine