骨科感染性疾病之治療

成大醫院藥劑部林妏娟

2009.5.23

骨科感染性疾病

Infectious arthritis 感染性關節炎

Osteomyelitis 骨髓炎

Outline

• Pathophysiology

• Microbiology

• Clinical features

• Diagnosis

• Treatment

Acute Bacterial Arthritis

Septic arthritis, pyogenic arthritis Incidence

– 2~10 cases per 100,000 per year– 28~38 cases per 100,000 per year

Morbidity:50% Mortality:10-30%

Pathophysiology

Hematogenously acquired

Direct inoculation of bacteria into the joint through surgery, trauma, percutaneous puncture

Contiguous spread from adjacent infected soft tissue or bone

Predisposing Factors

Joint disease– Rheumatoid arthritis– Crystal-induced arthritis– Osteoarthritis

Chronic systemic disease– DM, chronic renal failure, chronic liver disease, malignancy, sickle

cell disease Immunosuppression

– HIV infection, immunosuppressant therapy, organ and bone marrow transplantation

Trauma– Surgery, penetrating injury, intra-articular injection

Prosthetic joint IV drug use Endocarditis Skin disease or lesions

Microbiology-1 Organism Isolates No.(% of total)

Microbiology-2 Rheumatoid arthritis S. aureus

IV drug use S. aureus, Pseudomonas aeruginosa

Diabetes, malignancy S. aureus, group B streptococci

Immuno-compromised hosts S. aureus, streptococci, enteric Gram-negative bacilli

Neonates, children < 2y/o Gram-negative bacilli, Kingella kingae

Cat or dog bite Pasteurella multocida, Capnocytophaga sp., anaerobes

Human bite Eikenella corrodens, anaerobes, other oral flora

Rat bite Streptobacillus moniliformis

Postpartum women Mycoplasma hominis

Residents or travelers to Southeast Asia

Burkholderia pseudomallei

Microbiology-3

GNB– 5-20%– Neonates, elderly, IV drug users, immunoco

mpromised hosts– Escherichia coli– Pseudomonas aeruginosa– Kingella kingae

Cultures of synovial fluid or blood:10-20% Polymicrobial flora:8%

Clinical Features

Monarticular– Knee, shoulder, wrist, ankle; hips; small joints of

the foot & hand Polyarticular

– RA, immunosuppression, bacteremia Symptoms

– Pain, loss of function, swelling, redness, increased warmth of the infected joint, fever, malaise

– ESR, CRP– Purulent, low-viscosity synovial fluid, PMN– Culture: synovial fluid, blood– Gram stain

Diagnosis

Definitive etiologic diagnosis Blood, wound, skin lesions Synovial fluid examination CT or MRI Acute attacks of the crystalline joint

disease, gout; preexist-rheumatoid or other inflammatory arthritis

Treatment

Antibiotics, joint drainage, joint rest joint drainage

– Needle aspiration (hip?)– Arthroscopy– Open surgical drainage

Antimicrobial therapy should be delayed until arthrocentesis and cultures are obtained

Initial antimicrobial therapy– Synovial fluid Gram staining– Likely infecting pathogens

Definitive treatment– Cultures

Recommended Empirical Therapy for Adult Native Joint Bacterial Arthritis

Gram Stain Antimicrobial

GPC

No risk factors for MRSA

Oxacillin 2 g q4h

Cefazolin 2g q8h

Clinidamycin 900mg q8h

Vancomycin 1g q12h

Risk factors for MRSA Vancomycin 1g q12h

GNC Ceftriaxone 1g q24h

GNR Ceftazidime or cefepime 2g q8h

Piperacillin-tazobactam 4.5g q6h

Imipenem 500mg q6h

Meropenem 1g q8h

Azetreonam 2g q8h

Ciprofloxacin 400mg q12h

Levofloxacin 750mg qd

Recommended Empirical Therapy for Adult Native Joint Bacterial Arthritis

Gram Stain Antimicrobial

Gram stain negative Regimen for gram-positive cocci above plus

Ceftazidime

Ciprofloxacin

Levofloxacin)

Aminoglycoside

Tobramycin

Gentamicin 5-7mg/kg once

daily or 5mg/kg in three

divided doses per day

MRSA

IV vancomycin Linezolid and daptomycin may be an opti

on for patients with joint infection with MRSA who are allergic to, intolerant of, or not clinically responding after 3-5 days of vancomycin

※Risk factors: recent inpatient, nursing home resident, leg ulcers or catheters..

Gonococcal arthritis

Ceftriaxone, cefotaxime, ceftizoxime Oral ciprofloxacin or levofloxacin Therapy can be switched on the fourth d

ay to oral amoxicillin or to doxycycline or tetracycline

Special Populations

< I month– Broad-spectrum– Oxacillin + AG

<5 years– H. influenzae– Nafcillin, oxacillin, cefazolin

>5 y/o and adults– S. aureus– Penicillinase resistant penicillin, clindamycin, vancomycin, li

nezolid IV drug abuses

– P. aeruginosa– Combination of AG

Antimicrobial therapy

Septic arthritis related to animal or human bites– Aerobic and anaerobic oral flora– Ampicillin-sulbactam, amoxicillin-clavulanat

e, clindamycin+ciprofloxacin The penetration of inflamed joints is ade

quate for most intravenous and some oral antimicrobials.

Duration

2-4 weeks S. aureus, including MRSA, gram-negati

ve bacilli Gram-negative septic arthritis in which t

he organism is susceptible to FQ Gonococcal arthritis

Monitor

Culture and sensitivity WBC CRP ESR Clinical signs of inflammation

Fungal Arthritis

Fungal Arthritis

Healthy hosts– Direct trauma or injury, penetrating foreign b

ody– Blastomyces dermatitidis, Coccidioides spp.,

Paracoccidioides brasiliensis, Sporothrix schenckii

Immunocompromised hosts– Penetrating injury or hematogenous spread – Candida spp., Cryptococcus, Aspergillus

Fungal Arthritis-Candida Arthritis

Risk factors– Loss of skin integrity– Diabetes– Malignancy– Malnutrition– Premature birth– IV drugs use– Immunosuppressive therapy– Prolonged use of broad-spectrum A/B– Central intravenous catheters

Fungal Arthritis-Candida Arthritis

Candida albicans Candida tropicalis, Candida parapsilosis,Can

dida guilliermondii, Candida glabrata Knee Fever Synovial fluid: polymorphonuclear leukocytosi

s, low measured glucose Gram stain, cultures… Blood cultures: <50%

Treatment

Combined medical and surgical modalities Amphotericin B with or without flucytosine Native joint Candida arthritis:

– Amphotericin B 0.5-1mg/kg/day for 2-3 weeks followed by fluconazole to complete a total duration of therapy of 6-12 months

– Fluconazole 6 mg/kg/day for 6-12 months– Caspofungin may be an option for Candida spp. isol

ates that are resistant to azole drugs in patients who are intolerant of amphotericin B

Treatment Cryptococcal arthritis

– Amphotericin B followed by oral fluconazole

Coccidioides, Blastomyces, Histoplasma, Sporothrix– Isolated joint infection without CNS involve

ment– itraconazole 200-400mg/day for 12 months

Voriconazle– Aspergillus

Mycobacterial Arthritis

Mycobacterial Arthritis

All TB: 1-3% Extra-pulmonary TB: 10-11% Risk factors

– Lower socioeconomic class, alcohol abuse, debilitating illness, IV drug use, immunosuppressive drug therapy, HIV infection, preexisting joint disease

~J Microbiol Immunol Infect 2007;40:493-499

~J Microbiol Immunol Infect 2007;40:493-499

Mycobacterial Arthritis

Mycobacterium tuberculosis Knee, hip, ankle Fever and other symptoms Tuberculin skin testing Synovial fluid:

– leukocytes counts 10000-20000 cells/mm3– Staining (acid-fast bacilli)– Culture (80%)– Synovial biopsy

Mycobacterial Arthritis

CDC recommendation– Skeletal TB in adults without pulmonary TB– Isoniazid, rifampin, ethambutol, and pyrazi

namide – 8 weeks– Followed by isonizid and rifampin to compl

ete 6 months of therapy Adjuvant surgical therapy

Prosthetic joint infection

Prosthetic joint infection

Early– First 3 months– Surgical procedure

Delay– 3 months ~2 years– Surgical procedure

Late– >2 years– Hematogenous spread

Staphylococcus aureus Staphylococcus epidermidis Genitourinary and Gastrointestinal tract

procedures infections (Gram negative rods, Enterococci and anaerobes)

Dental infection (viridans streptococci, Peptococcus spp. and Peptostreptococcus spp.)

Skin infections (Streptococcus spp.)

Prosthetic joint infection

Biofilms

S. aureus and coagulase-negative staphylococci (CoNS)

10–1000 times bacteriain in biofilms are surrounded by

an extracellular matrix

~NEJM 2004;351:1645-54

Prosthetic joint infection

Diagnosis: sum Antimicrobial therapy

– no standards (agents, ideal regimen, duration )– Rifampicin has excellent efficacy against stationar

y phase staphylococci– Vancomycin, teicoplanin, fusidic acid, minocycline,

trimethoprim/sulfamethoxazole, linezolid, daptomycin, tigecycline

Surgical therapy– 6 wks– 6 months (knee), 3 months (hip)

Management of Joint Prosthesis–Related Infection Caused by Staphylococcus aureus or Coagulase-NegativeStaphylococci.

~N Engl J Med 2004;350:1422-9.

Outcome

Gonococcal arthritis Staphylococcal arthritis Risk for long-term sequelae

– Symptoms > 7days before therapy– Hip joint– Gram-negative organisms

Long-term residual effects– Limited joint motion– Persistent pain…

Osteomyelitis

Osteomyelitis

One of the most difficult to teat infectious disease

Progressive destruction of bone Formation of sequestra

– Bacteria produce a local inflammatory reaction that promotes bone necrosis and the formation of sequestra

Osteomyelitis

Classification -1– Hematogenous seeding– Contiguous spread from adjacent soft tissues

and joints• Direct inoculation of microorganism into the bone

as a result of trauma or surgery

Classification -2– Acute– Chronic

Osteomyelitis

Classification -3– Cierny and Mader claissified osteomyelitis– Lee and Waldvogel classified osteomyelitis

Staging System of Osteomyelitis-1

Anatomic type– Stage 1: Medullary osteomeylitis– Stage 2: Superficial osteomeylitis– Stage 3: Localized osteomeylitis– Stage 4: Diffuse osteomeylitis

Physiologic class– A Host: Normal host– B Host

• Systemic compromise,

• Local compromise

• Systemic and local compromise

Staging System of Osteomyelitis-2Systemic or local factors that affect immune surveillance, metabolism, and local vascularity

Systemic Malnutrition Renal, hepatic failure DM Chronic hypoxia Immune disease Malignancy Extremes of age Immunosuppression

Local Chronic lymphedema Major vessel compromise Small vessel disease Vasculitis Venous stasis Extensive scarring Radiation fibrosis Neuropathy Tobacco abuse

Microbiology of Osteomyelitis

Common (>50% of class)– Staphylococcus aureus– Coagulase-negative staphy

lococci Occasionally encountered

(>25% of class) – Streptococci– Enterococci– Pseudomonas spp.– Enterobacter spp.– Proteus spp.– Escherichia coli– Serratia spp.– Anaerobes

Rarely encountered (<5% of class)

– Mycobacterium tuberculosis– Mycobacterium avium comp

lex– Dimorphic fungi– Candida spp.– Aspergillus spp.– Mycoplasma spp.– Tropheryma whipplei– Brucella spp.– Salmonella sppp.– Actinomyces

蘭陽溪口濕地

Types of Osteomyelitis, Age Distribution, Common Sites, Risk Factors

Types of Osteomyelitis

Typical Age (y)

Sites involved

Risk Factors

Hematogenous <1 Long bones and joints

Prematurity, umbilical catheter or venous cutdown, RDS, perinatal asphyxia

1-20 Long bones Infection, trauma, sickle cell disease, puncture wounds to feet

>50 Vertebrae DM, blunt trauma to spine, UTI

Contiguous >50 Femur, tibia, mandible

Hip fractures, open fractures

Clinical Features

Vague symptoms Nonspecific pain around the involved site w

ith the absence of systemic signs and symptoms

Fever Chills Local swelling Erythema

Diagnosis

Clinical grounds Radiologic, microbiologic and pathologic

tests ESR, CRP, WBC CT & MRI Causative microorganism

– Surgical sampling or needle aspiration– Swab cultures

Treatment-General Approach..1

Experimental animal models, expert opinion, respective cohort studies

S. aureus can survive in a dormant and phenotypically altered state for a long time

The optimal duration of antimicrobial therapy after surgical debridement

Treatment-General Approach..2

Goal: eradicate the infection and restore function

Medial and surgical therapy All antimicrobials should be withheld if

possible until…..…unless…. 4-6 weeks Short duration...

Treatment-General Approach..3

Antibiotic in adequate doses for a sufficient length of time

3-4 times a day Biofilm vs. Rrifampin

– Osteomyelitis – Prosthetic device-related infections

No respond – Fever, local swelling, redness, pain

~Arch Intern Med 2008;168(8):805-819

Antimicrobial Therapy of Chronic Osteomyelitis in Adults for Selected Microorganisms

OSSA– First choice

• Nafcillin or oxacillin 1.5-2g q4h IV• Cefazolin 1-2g q8h IV

– Alternative choice• Vancomycin 15mg/kg q12h IV• Nafcillin/oxacillin +rifampin 600mg qd po

Antimicrobial Therapy of Chronic Osteomyelitis in Adults for Selected Microorganisms

MRSA– First choice

• Vancomycin 15mg/kg q12h IV

– Alternative choice• Linezolid 600mg q12h PO/IV for 6 wk• Levofloxacin 500-750 mg/day PO/IV• Plus rifampin 600-900 mg/day

Antimicrobial Therapy of Chronic Osteomyelitis in Adults for Selected Microorganisms

Penicillin-sensitive streptococci– First choice

• Aqueous crystalline penicillin G 20*106 U/24 hr IV

• Ceftriaxone 1-2g q24h IV or IM • Cefazolin 1-2g q8h IV

– Alternative choice• Vancomycin 15mg/kg q12h IV

Antimicrobial Therapy of Chronic Osteomyelitis in Adults for Selected Microorganisms

Enterococci or streptococci with MIC≥ 0.5 μg/mL, Abiotrophia and Granulicatella spp.– First choice

• Aqueous crystalline penicillin G 20*106 U/24 hr IV • Ampicillin 12g/24hr IV• Plus gentamicin 1mg/kg q8h IV or IM for 1-2 wk

– Alternative choice• Vancomycin 15mg/kg q12h IV • Plus gentamicin 1mg/kg q8h IV or IM for 1-2 wk

Antimicrobial Therapy of Chronic Osteomyelitis in Adults for Selected Microorganisms

Enterobacteriaceae – First choice

• Ceftriaxone 1-2g q24h– Alternative choice

• Ciprofloxacin 500-750 mg q12h po Pseudomonas aeruginosa or Enterobacter s

pp.– First choice

• Cefepime 2g q12h IV • Meropenem 1g q8h IV

– Alternative choice• Ciprofloxacin 750 mg q12h po• Ceftazidime 2g q8h IV

Antimicrobial Drugs of Choice for Anaerobic Bacteria

J Orthop Sci (2008) 13:160–169

J Orthop Sci (2008) 13:160–169

Antimicrobial Drugs of Choice for Anaerobic Bacteria

Special Populations Sickle cell anemia

– Salmonella or S. aureus– Ceftriaxone or cefotaxime– Chloramphenicol and ciprofloxacin

IV drug abuse– Gram-negative organisms– Ceftazidime 2g q8h+AGs

Vascular insufficiency– S. aureus, Streptococcus, anaerobes, Gram–negative o

rganisms– Penicillinase-resistant penicillin+ceftazidime– Antianaerobic cephalosporin, clindamycin+ceftazidime– Ampicillin for..

Vancomycin

MRSA, ARE Marrow suppression Ototoxicity Renal toxicity Rash TDM

Linezolid

Staphylococci, streptococci, VRE Oral form, Bioavailability Bacteriostatic Pancytopenia, peripheral neuropathy High cost Experimental models: failure rate Vancomycin resistant enterococci Intolerant of vancomycin

Daptomycin

Multiple drug resistant gram positive pathogens

Well tolerated Once daily Concentration-dependent bactericidal activit

y Biofilm No need for TDM Case reports and retrospective study

Oral Antibiotic Therapy Criteria

– Confirmed osteomyelitis– Initial clinical response to parenteral antibiotic

s– Suitable oral agent available– Compliance ensured

Timing Children, Adults FQ

– Children <16-18y/o– Pregnant

Dicloxacillin, cloxacillin, cephalexin (100mg/kg/day)

Adjunctive Treatment Hyperbaric oxygen高壓氧

–提高白血球的殺菌力–直接殺死細菌、抑制細菌製造毒素–使纖維母細胞恢復活性，修補局部的組織–刺激血管新生–加成抗生素的療效

Adjunctive Treatment-Antibiotic-impregnated implant

Injury, Int. J. Care Injured (2006) 37, S95—S104

A hand-made articulating knee spacer

~J Bone Joint Surg Am. 2007;89:871-882

Antibiotic in Local Therapy

Power form Heat (70-120 )℃ Against the targeted microbial pathogen

s Vancomycin(185-188), tobramycin(168),

gentamicin(102-108), penicillin (ampicillin:199-202), erythromycin(191), colistin(200-220), cephalosporines (cefazolin:198-200), polymyxin

Local Antibiotic Therapy

Advantages – High local antibiotic concentration– Extended duration– Without exceeding systemic toxicity

Biofilm Bone cement PMMA, polymethylmethacrylate (聚甲丙烯酸甲酯 )

– Delivery vehicle– Dentistry, 1941– Orthopedic surgery, 1945– Charnley introduced PMMA bone cement to stabilize metal

hip implants , 1970– Buchholz and Engelbrecht reported the incorporation of an

tibiotics into PMMA bone cement to reduce the infection rate in arthroplasty, 1970

Septopal

Injury, Int. J. Care Injured (2006) 37, S95—S104

Preparation of Delivery Systems

Antimicrobial agents that can be used for antibiotic bead preparation (with the suggested dose in grams of powder per 40 g of PMMA cement) are as follows:– Tobramycin (3.6 g)– Vancomycin (4 g)– Cefepime (4 g)– Cefazolin (6 g)– Nafcillin (6 g)– Imipenem (4 g)

Open fractures, infected nonunions, osteomyelitis

Outcome

Acute osteomyelitis – Cure rates>80%

Chronic osteomyelitis– Dead bone and other necrotic material fro

m the infection act s a bacterial reservoir

Thank You for Your Attention!!!