Robert Harrington, M.D. July, 2009 BONE AND JOINT INFECTIONS Pathogenesis 1. Bone is normally resistant to infection but large inocula of bacteria, trauma or the presence of foreign bodies may overwhelm host defenses and lead to infection. The inflammatory response to infection raises intraosseous pressure leading to impaired blood flow and ischemic necrosis. 2. Thus, in acute osteomyelitis the histology reveals bacteria, pus and thrombosed blood vessels while necrotic bone sequestra are characteristic of chronic osteomyelitis. Clinical Presentation Hematogenous osteomyelitis (acute > chronic): 1. Children: infection due to hematogenous spread is the most common form of osteomyelitis. Infection is usually located in the metaphyseal area of long bones. Patients present with fever, irritability and local swelling and tenderness. Symptoms have usually been present for < 2 to 3 weeks. A history of recent trauma to the affected area is often elicited. 2. Adults: hematogenous osteomyelitis in adults often involves the vertebral bodies due their rich, sluggish blood supply. Infection starts in one vertebral body and spreads to the adjacent disc and vertebral body via the extensive collateral vasculature. Men are affected twice as often as women and disease is more common after the age of 50. Bacteremia from any source (recent UTI, cellulitis, catheter infection, endocarditis) can set up the infection. Patients present with persistent, dull back pain (often worse at night) and localized tenderness. Systemic symptoms (fever, chills, weight loss) are mild. Long bones are less often affected since their blood supply diminishes with age. Contiguous focus (chronic and acute): 1. Predisposing conditions include recent open fracture, recent surgery, or chronic soft tissue infection (decubitus and/or diabetic ulcers). 2. Most bone infections associated with prostheses or other foreign bodies are the result of direct inoculation at the time of surgery and can be divided into acute (< 12 weeks) or chronic (3 - 24 months) infections. Those that occur late after surgery (> 24 months) are more likely to have become infected from a subsequent episode of bacteremia. 3. Patients with diabetes often have vascular compromise but it is the distal sensory neuropathy associated with diabetes that is key to the development of neuropathic ulcers and osteomyelitis. Diabetic foot ulcers greater than 2 cm in diameter are almost always associated with osteomyelitis. 4. Signs and symptoms of contiguous osteomyelitis include local pain, swelling, edema and draining sinuses. Fever, systemic symptoms and leucocytosis may be present depending on the acuity and extent of the infection. The ESR is usually elevated. Diabetic patients (and others with sensory neuropathies) will not complain of pain. 5. Chronic osteomyelitis implies the presence of a well-established infection that has lead to the development of bony sequestra often with persistent drainage through sinus tracts. Patients complain of chronic pain and local drainage but a paucity of systemic symptoms. The ESR is often > 100. Complications of chronic osteomyelitis include pathologic fractures, sinus tract epithelial cell cancers and secondary amyloidosis. Cierny-Mader staging An alternative classification scheme based on the anatomy of the infection and the immune status of the host: Anatomic stage Stage 1 – medullary infection only, usually due to hematogenous spread or spread through an intramedullary prosthesis Stage 2 – superficial infection, always due to a contiguous soft tissue infection, could also be termed osteotis Stage 3 – localized infection, full thickness infection (one cortex), but one that can be resected without compromising the stability of the bone Stage 4 – diffuse infection (both cortexes) that destabilizes the bone or resection of which would destabilize the bone Host status A – normal host B – local or systemic condition that compromises healing C – treatment would be worse than the disease Microbiology S. aureus predominates in all types of osteomyelitis. Coagulase negative staphylococci - foreign bodies. Streptococci – neonates (group B streptococci), the eldery (enterococci), bites, diabetic foot osteomyelitis (enterococci). Gram negative rods – IVDU (P. aeruginosa, S. marcescens), nosocomial, diabetic foot osteomyelitis (E. coli, P. aeruginosa, P. mirabilis), open fracture, decubitus ulcers (E. coli). Anaerobes - diabetic foot osteomyelitis, decubitus ulcers, bites. Bartonella – HIV. Brucella - exposed populations. Fungi (Candida > dimorphic fungi > molds) - immunocompromised, catheter assoc, IVDU. Tuberculosis - exposed populations. Diagnosis 1. Exam, elevated ESR, elevated WBC (acute osteomyelitis). 2. Blood cultures are positive in 50% of cases of acute osteomyelitis 3. Diabetic foot ulcers: probing to bone at the bedside with blunt stainless steel eye probe detected osteomyelitis in 33 (66%) of 50 ulcers. PPV 89%, NPP only 56%. 1. Imaging Plain films a. Need 30 to 50% mineral loss for x-ray changes to be evident - takes at least 14 days b. Sensitivity 43-75%, specificity 75-83% c. Plain films are insensitive with acute osteomyelitis d. Finding in chronic infection - sclerosis, periosteal elevation and sequestra. CT a. Best method for detecting small areas of necrosis, gas, foreign bodies. b. Metallic foreign bodies compromise the image. MRI a. Sensitivity 82-100%, b. Specificity only 53-94% (tumors, fractures, post surgery, sympathetic edema, infarction – all can look the same – light up on T2 weighted image) c. Combine with Nu med scans to increase specificity. d. Not helpful in assessing response to treatment since marrow edema persists for months after microbiological cure Bone scan (TC-99 labeled phosphorus) a. Soft tissue infection will be positive in the immediate (blood flow) and15 minute (blood pool) phases while osteomyelitis will be positive in these 2 plus the delayed (> 4 hour) images. b. Sensitivity 69-100% (> 95% in acute osteomyelitis), specificity 38-82% (tumors, fractures, post-surgery, septic arthritis, Paget’s disease) WBC scan (Ind-111) a. Will be positive prior to bone scan b. Useful p-surgery (better than MRI) which will always be abnormal c. When combined with bone scan has specificity in the 90% range, sensitivity in the 70% range and PP value in the 90% range d. Low sensitivity for chronic OM of axial skeleton Ga-67 a. Non-specific b. Combined with bone scan - sensitivity ~79%, specificity 83-93% c. Not as useful as Ind-111 WBC scan except for spinal osteo when WBC scans can be obscured by GI localization of tracer d. Poorer image quality than bone or WBC scans d. Useful when combined with bone scan in sorting out infarction (sickle cell disease) from osteomyelitis Tc99-Radolableled monoclonal antibodies or Fab fragments that are attached to WBCs (anti-CD15) a. Sensitivity 84% b. Specificity 85% (if delay imaging) (Rubello, Nu Med Comm, 2004) Streptavidin/In-111-biotin a. Biotin taken up and accumulates in bacteria b. In study of 55 patients with vertebral OM: Biotin scan + in 32/34 with infection (sensitivity 94%) and negative in 19/21 without infection (95% specific) (Lazzeri, Eur J Nucl med, 2004) PET scanning (FDG) a. Most useful in detection of chronic OM of spine b. limitations are use patients with diabetes and cancer and those with recent bone surgery or trauma (early bone healing will give + PET scan) (Pineda, Inf Dic Clin of N America, 2006) 1. Cultures a. Gold standard is open bone biopsy for histopathology and culture. b. Needle biopsy has a sensitivity of 87% and a specificity of 93%. However, in the postoperative or post-trauma setting its performance is compromised. Histopathology of needle biopsies can increase sensitivity for diagnosis of osteomyelitis even if a specific organism is not identified c. Superficial or sinus tract cultures correlate poorly with bone cultures in most studies (< 50%). One study (Perry, 1991) found a 62% correlation between wound swab and operative specimen cultures and a 55% correlation between needle biopsy and operative specimen cultures. Even better correlations demonstrated for monomicrobial infections (80 and 76%) and S. aureus infections (69 and 74%). Another study (White, 1995) showed only 42% sensitivity of needle biopsy cultures but 84% sensitivity when culture and histopathology considered. Bottom line: don't trust sinus cultures unless its a single organism or S. aureus. Treatment Acute hematogenous osteomyelitis 1. If treating before extensive bone necrosis occurs - antibiotic therapy for 4 to 6 weeks achieves high cure rates. 2. If acute osteomyelitis is unresponsive to abx, may need surgical decompression of intramedullary or subperiosteal pus. Other indications for surgery are the presence of a soft tissue abscess or joint involvement. 3. Vetebral osteomyelitis: surgery reserved for cord decompression, spine stablization or to drain paravertebral abscesses. Contiguous focus osteomyelitis 4. Recurrence rates are 20 to 30% 5. Combined surgical and medical approach needed. Guiding principles are debridement of necrotic bone and prolonged antibiotic therapy. Best results may be with serial debridements (average of 4), prolonged IV antibiotics (4 to 6 weeks) followed by oral antibiotics (Eckardt, 1994). 6. Surgical principles are Removal of all necrotic tissue Dead space obliteration (antibiotic beads – later replaced by bone grafts, bone grafts, muscle flaps) Soft tissue coverage of bone to promote re-vasculaturization Fracture stablization Best results reported by Patzakis (1993) using the following sequence: debridement (antibiotics started intraoperatively after cultures taken) with external fixation applied followed by re-debridement and soft tissue transfer 5 days later and bone grafting (if necessary) performed 6 weeks later. Parenteral antibiotics given for mean of 21 days followed by oral. Cured 35 (96%) of 36 patients. Recent publication by Schuster (J Neurosurg, 2000) identified 39/47 patients (no follow-up on 8) who had had bone allografts placed at the time of surgical debridement for spine infections (4 of 39 were TB). Follow-up of 17 months: 2/39 had possible recurrent infections. 4. Ilizarov technique (for long bone chronic osteomyelitis) - involves complete resection of diseased bone leaving a large gap and a cut far up-stream of the necrotic bone which creates an intermediate fragment which is slowly translocated (by means of guidewires attached to an elaborate external fixation device) leading to the growth of new bone along the axis thus, filling the gap. 5. Antibiotics: Ideally, antibiotic selection is based on reliable culture and sensitivity results. In general, antibiotics are initially given parenterally. After 2 weeks of intravenous therapy antibiotics may then be given orally provided an acceptable oral regimen is available, the infection is responding to therapy and the patient is reliable or can be monitored closely. Two studies of Staphylococcus osteomyelitis involving prosthetic devices documented the effectiveness of rifampin/quinolone regimens without prosthesis removal. i Drancourt, 1993: treated patients with rifampin (900 mg/d) and ofloxacin (600 mg/d). Hips - treated for 6 months with unstable prothesis removal at 5 months (42% removed) - 81% cured, knees - treated for 9 months with prothesis removal at 6 months if needed (60% removed) - 69% cured and bone plates treated for 6 months with plate removal at 3 months if needed (50% removed) - 69% cured. Note: Most (8 of 11) failures occurred in those without device removal. Mean duration of infection in all patients - 16 months. ii Zimmerli, 1998: First (only) randomized controlled trial for treatment of osteomyelitis (Staphylococcal implant related infections). N=33, culture proven Staphylococcus infections and stable implants (8 hips, 7 knees and 18 plates or rods). All treated with initial debridement (without removal of implant) and 2 weeks of rifampin and either flucloxacillin or vancomycin followed by either cipro-rifampin or cipro-placebo. Cure rates: 12/12 for cipro-rifampin vs 7/12 for cipro-placebo (5/7 dropouts eventually treated with rifampin-cipro were also cured). Note - median duration of symptoms was only 4-5 days with maximun of 21 days. iii Ceftriaxone for osteomyelitis: Study by Guglielmo (2000); 22 patients, all received 1-2 weeks of either nafcillin, cefazolin or vancomycin prior to ceftriaxone, all had native bone infection or had prosthesis removed at the start of therapy. Treated with ceftriaxone at 2 grams/day for 4-5 weeks. Results: 17/22 cured, 2/22 indeterminate, 3/22 failed (all 3 had necrotic bone that could not be removed). iiii Linezolid: Results of Compassionate Use Experience (Rayner, 2004): Only 22 of 55 cases were considered evaluable (for unclear reasons). Six months post treatment: cure rate 82% (18/22), for infections with MRSA 64% (7/11). Another prospective study reported 100% (11/11) success (Rao, 2004) Marrow toxicity (mostly thrombocytopenia) in 7-8% and rarely irreversible peripheral neuropathy (Falagas, Int J Antimirobial Agents, 2007). Recent study of linezolid in children (most with MRSA) – 11/13 cured with linezolid for a month – but all had received vanco for ~ 1month prior and linezolid was used as “step down (oral) therapy (Chen, Ped J of Infec Dis, 2007). v. Daptomycin??: Preliminary study of Daptomycin for foot and ankle OM (Holtom, 2007). 25 patients, MRSA in 15/25. At short follow-up (2 months) 19/25 resolved, 3/25 improved and 3/25 no response. 4/25 patients with implant related infection cured (all had implant removed). More recent study – POST HOC analysis of patients with S aureus(mostly MRSA) bacteremia treated with either dapto or vanco who had OM – cure rates: dapto 14/21 (67%) Vs vanco 6/11 (55%) (Lalani, JAC, 2008). vi. Oral therapy: Daver, J Infection, 2007;54:539-44 Retrospective review of 72 patients with S. aureus osteomyelitis Two groups: Group I: IV therapy for > 4ks Group II: IV therapy for < 4 wks followed by oral therapy IV Rx was mostly vanco or beta-lactams, PO Rx was mostly rifampin + quinolone or TMPSMX or clindamycin Cure rates IV Rx = 69% Oral Rx = 78% Cure rates similar regardless of time of IV Rx Rifampin/Vanco combo was inferior to Rifampin/other combo Cure rate for MRSA 65% vs 83% for MSSA Corti, Arch Dis Child, 2003 N=103 Acute hematogenous osteomyelitis IV Abx of > 2.5 weeks provided no added benefit when total duration of treatment was at least 6 to 7 wks LeSaux, BMJ Inf Dis, 2002 Review of 12 prospective cohort studies Hematogenous osteomyelitis Cure rate of 95% with < 7 days of IV + mean of 32 days of oral Abx (betalactam or clindamycin) Zaoutis, Pediatrics, 2009 Retropspecitve cohort study of 1969 children Treatment assigned based on discharge code regarding central catheter placement – if no DRG for this then it was assumed they were treated with oral meds Failure rate 5% with IV therapy Vs 4% with oral therapy 3.4% of children on IV therapy were readmitted with catheter complications 6. Osteomyelitis accompanied by a poor vascular supply: If the vascular insufficiency is the result of correctable large vessel disease, revascularization surgery should be performed. If re-vascularization is not possible or unlikely to correct tissue hypoxia then the patient may be offered amputation or chronic suppressive therapy with oral antibiotics, although in the latter case amputation is often ultimately necessary. Finally, hyperbaric oxygen treatment may be of benefit in those cases where tissue oxygen tension is low and not amenable to treatment with a tissue flap. Hyperbaric oxygen leads to improved tissue oxygenation that enhances PMN and macrophage activity and augments collagen synthesis and wound healing. A nonrandomized (but controlled) study found no benefit of hyperbaric oxygen on outcomes, case series are more encouraging. 7. Cierny-Mader staging Stage 1 – Children without hardware are often treated with antibiotics alone. All patients with rods in place require removal. Adults without hardware may require medullary reaming. Stage 2 – Debride to bleeding bone and antibiotics Stage 3 – Follow principles of removal of necrotic bone, elimination of dead space and soft tissue coverage plus antibiotics Stage 4 – Same as stage 3 plus fracture stabilization. Prosthetic joint infection 1. Microbiology: CNS 30-43%, S. sureus 12-13%, polymicrobial 10-11%, streptococci 9-10%, GNB 3-6%, enterococci 3-7%, anaerobes 2-4%, culture negative 11% 2. Clinical a. Early: < 3 months (pain, erythema, fever, drainage) b. Delayed: 3-24 months (pain and loosening) c. Late: > 24 moths (pain and loosening) 3. Diagnosis a. Synovial fluid formula: > 1700 wbc (sensitivity 94%, specificity 88%), or > 65% PMN (sensitivity 97%, specificity 98%) b. Synovial fliud Gm stain: sensitivity 26%, specificity 97% c. Culture: synovial fluid 45-100%, peri-prosthesis tissue 65-94% 4. Treatment a. Rifampin useful when added to quinolone for staphylococcus infections b. Surgical options: 1) debridement with retention, 2) single stage replacement, 3) two stage replacement, 4) resection arthroplasty, 5) suppressive antibiotics i. Debridement with retention: symptoms for < 3 weeks, stable implant easily treated organism: success 82-100% ii. Single stage replacement: symptoms for > 3 weeks, soft tissue in good shape, no co-morbidities, easily treated organism, success in 86-100% (more commonly done with hips) iii. Two stage replacement: if above conditions are not met. Time between surgeries 2 to 6 weeks (for tough to treat organisms, MRSA, resistant GNR, enterococci, fungi – delay should be 6 to 8 weeks). Stop abx 1 to 2 weeks before 2nd surgery – if cultures taken at 2nd surgery are negative – can stop antibiotics, if cultures are positive – treat for 3 months total (if knees – 6 months) iv. Resection arthroplasty – for serious infection in patient with anatomical, medical or social (IVDU) condition that prevents prosthesis replacement v. Supressive antibiotics – in patient at high risk for surgical complications (TMP/SMX or tetracycline commonly used) c. Duration of abx: 3 months minimum, 6 months for knees d. Treatment with retention of prosthesis i. Meehan, CID, 2003 ii. Prosthetic Joint Infection with Penicillin Susceptible Streptococci iii. N=19 iv. Presented between 52 and 4788 days post-op v. All prostheses were well fixed vi. All were debrided within 4 days of symptoms vii. Cure rate at 1 year: 89% Diabetic foot osteomyelitis 1. Present in up to 2/3 of patients with diabetic foot ulcers 2. Pathophysiology: Multifactorial. Neuropathy most important risk factor. Decreased sensation permits local trauma to go unnoticed, motor neuropathies lead to gait disturbances and the development of pressure ulcers, autonomic neuropathy impairs sweating and promotes dry cracked skin that leads to bacterial invasion. Many patients also have peripheral vascular disease causing decreased tissue oxygen tension which compromises antibacterial activity. Finally, diabetes is associated with impaired PMN chemotaxis, phagocytosis and superoxide production and intracellular killing. 3. Diagnosis: Clinically: Larger (> 2cm, 92% specificity) and deeper ( > 3mm) associated with osteo Probe to bone – 66% sensitivity and 85% specificity - recent large study (Lavery, Diabetes Care, 2007), N=199 (30 with osteo) demonstrated sensitivity of 87%, specificity of 91%, PPV only 57% (due to low prevalence of osteo cases) but NPV 98% ESR > 70 – 100% specificity (only 28% sensitivity) Imaging: MRI sensitivity > 90%, specificity > 80% (out performed bone scans, WBC scans and plain radiography in large meta-analysis, Kapoor, Arch Int Med, 2007). Classic appearance – marrow is hypointense on T1 and hyperintense on T2 Distinguishing osteo from Neuropathic arthropathy (Charcot’s arthropathy)– on MR: Osteo is almost always contiguous to ulcer and usually affect the calcaneous or malleoli. Neuropathoic arthropathy usually affects the tarsal-metatarsal joints or metatarsal-phalangeal joints- the findings on the MR are joint-centered (Donavan, Radiol Clin N Am, 2008) Leukocyte scans (indium and technetium): sensitivity 85%, specificity 75%. 111-In WBC scans used with bone scans or MRI perform best (also help to distinguish osteomyelitis from soft tissue infection and non-infectious destructive bone disease – Charcot’s neuropathic osteoarthropathy.). Radiolabeled anti-granulocyte Fab fragments – promising, sensitivity 67-90%, specificity 75-85% Bone biopsy: The gold standard. Percutaneous needle biopsy has sensitivity of up to 92% (culture and histopathology) 4. Microbiology: most are polymicrobial; S. aureus (40%) > aerobic gpc (streptococci 30%, CNS 25%) > aerobic gnr (40%) > anaerobes (anaerobes more likely to play a role in large destructive infections). Poor correlation between bone and soft tissue results. If bone cultures not available: must cover S. aureus, otherwise individualize treatment. 5. Treatment: best approach is aggressive surgical debridement/resection of involved bone, revascularization (if needed) and long-term appropriate antibiotics. a. Several recent retrospective studies suggest antibiotics alone (or with minimal debridement can arrest the infection in 2/3 of cases (summarized in Jeffcoate, CID, 2004) b. Linezolid??: R,MC,OL trial or linezolid vs amp/sulbactam-amox-calvulinic (Lipsky, CID, 2004): 77 cases of osteo a. Cure rates of 61% (27/44) vs 69% (11/16) in evaluable patients b. 5% of the linezolid patients received aztreonam as well, 4.6% developed anemia, 3.7% developed thrombosytopenia 6. Randomized and non-randomized studies support the use of hyperbaric oxygen (HBO) in diabetic foot ulcers (not osteomyelitis specifically). HBO is associated with more complete healing and lower amputation rates. Pyogenic Vertebral Osteomyelitis Large study by McHenry (CID, 2002): retrospective study with average follow-up of 6.5 years, n= 253! 1. Clinically i. Location: 28/255 cervical, 78/255 thoracic, 150/255 lumbar-sacral ii. Motor deficits associated with cervical location, diabetes, age > 50 iii. Time to diagnosis (after symptoms): median of 1.8 months 2. Outcomes: i. 146 (57%) recovered ii. 80 (31%) qualified recovery (left with pain or neurological deficits) iii. 29 (11%) died iv. Adverse outcome associated with motor deficits at presentation, longer time from symptoms to diagnosis, hospital acquisition (weighted for spinal surgery, trauma victums) 3. Relapse: i. 36 (14%) relapsed ii. 29/30 - the same organism iii. Relapse risk associated with recurrent bacteremia, chronic draining sinuses, paravertebral abscess, gibbous deformity and involvement of greater than 3 contiguous vertebral bodies 4. Author recommends: diagnose it early (use MRI), treat it longer (3 to 6 months) Kowalski, TJ CID, 2007: Retrospective study of 30 patients with early vertebral OM and 51 with late disease (> 30 days post surgery) Early onset infection – 2 yr disease- free survival 71%. If given suppressive oral therapy (median duration 303 days) after initial debridement – cure increased to 80%. Without suppressive therapy cure rate 33% Late-onset infection – 2 yr disease free survival 66%. If implant removed, cure increase to 84%, without removal 36% Problems with paper – retrospective study, not randomized, no multivariate analysis of risks for failure Livorsi, DJ, J of Infection, 2008: Retrospective review of 35 patients with hematogenous vertebral osteomyelitis due to S aureus. 57% due to MRSA Mean duration of treatment 62 days 19/20 with MRSA received Vancomycin and 13/20 received rifampin at some point in their treatment course (mean duration of rifampin Rx 24 days), 9/20 received oral therapy after vancomycin (gati – 5, TMPSMX - 3, linezolid -1) 5 relapsed (failures) (MRSA -2, MSSA – 3) Factors associated with relapse – undrained abscess. Trend for failur in those not on rifampin 6. Follow-up assessment: MRI Imaging to assess cure: Kowalski, Am J Neuroradiology, 2007: 1. Follow-up MRI showed: 1. Loss of vertebral body height, 2. Less epidural enhancement, 3. Less epidural abscess compared to baseline scans 2. No single MR finding was associated with clinical cure or failure. 3. Important point is that worsening MR findings did not signal clinical failure Skeletal Tuberculosis 1. Pathogenesis: In developed countries skeletal TB is a disease of adults and represents reactivation of an old focus of infection. In the developing world mast cases of skeletal TB occur in patients who acquired their infection within a year and, thus, many infections develop in childhood. Many patients give a history of recent trauma to the involved area. 2. Skeletal TB accounts for 35% of cases of extrapulmonary TB and 2% of all cases of TB 3. Clinically: Indolent course, average duration of symptoms prior to diagnosis 16 to 19 months. Local swelling, pain, fluctuance; systemic symptoms (fever, sweats, etc) often absent. Pulmonary disease present in 30%. PPD+ in > 85% Pott’s disease (tuberculous spondylitis) responsible for 1/3 of cases of skeletal TB. Infection begins in the anterior aspect of the vertebral body leading to anterior collapse and spread of the infection along the anterior ligament Most cases involve the lumber and lower thoracic spine 50% of cases have associated abscesses (if calcified is diagnostic for TB) 50% have weakness or paralysis at the time of presentation or during Rx 50% associated with disc involvement 50% without disc involvement are younger and more likely to have other skeletal lesions 77% have epidural involvement by MRI (Pertuiset, 1999) Other bones: any bone; weight bearing, flat, ribs - relatively unique to TB Diagnosis: AFB stain and culture of biopsy specimen (sensitivity ~85%) 4. Treatment: Chemotherapy, duration: 9 to 18 months of therapy, although recent studies suggest that 6 months of therapy, when combined with surgery, is as effective as longer course of antibiotics Debridement of abscesses will lead to faster resolution and less kyphosis in those with severe disease at presentation. Criteria for surgical intervention in Pott’s: neurological deficit, spinal instability, cervical spine disease, failure of medical therapy, non-adherence to medical therapy. 5. Sequential imaging studies may show apparent worsening of the infection for the first 6 months, despite clinical improvement, and should not be interpreted as a failure of treatment. INFECTIOUS ARTHRITIS Non-gonococcal bacterial Pathogenesis: 1. Usually hematogenously acquired - synovium has no basement membrane, abundant vascular supply and is easily seeded. 2. Direct inoculation - contiguous osteomyelitis, intra-articular injection, trauma, prosthetic joint replacement. 3. Proteolytic enzymes from PMNs lead to cartilage and bone destruction, increased inflammation and pressure. Later, proliferating synovial cells invade the cartilage-bone matrix. 4. Post infectious arthritis (not reactive) may occur after sterilization of joint - may be due to persistent microbial antigens or exo- or endotoxins. Microbiology: 1. S. aureus is most common (> 40% of all cases, > 80% of cases with rheumatoid arthritis). 2. Streptococci (group A but also nongroup A - B,C,G). 3. GNR (E. coli and P. aeruginosa) becoming more common (IVDU, immunocompromised and the elderly). H. influenzae formerly common in infants. 4. S. pneumonia - common in the pre-antibiotic era, now ~ 10%. 5. Coagulase negative staph - prosthetic joints. 6. No pathogen identified in 10 to 20%. 7. Mycobacterial and fungal (especially in HIV infected persons). 2. If polyarticular, and not GC, less likely to be S.aureus and more likely to be H. influenza, or one of the pyogenic strep (A, B, C, G). 3. Prosthetic joints: if infection due to inoculation at time of surgery: CNS, corynebacterium, S. aureus. If due to hematogenous seeding: S. aureus > streptococci, GNR and anaerobes Risk factors: 1. Phagocytic defects (CGD and Chediak-Higashi). 2. Other: hypogmmaglobulinemia, cancer, cirrhosis, steroids, old age, diabetes, hemophilia (hemarthrosis), sickle cell disease 3. Chronic arthritis - especially rheumatioid arthritis. 4. Recent joint trauma. 5. IVDU, indwelling catheters. Clinically: 1.Usully monoarticular: knee (50%) > shoulder, wrist, hip (children), elbow and interphalangeal joints, IVDU - sternoclavicular joints. More indolent presentation in deep joints (hip) 2. Most often a source is evident, BC positive in 30 to 50%, joint fluid culture positive in 85-95%. 3. Most (> 70%) are febrile, leukocytosis in 60%, elevated ESR in 90% Diagnosis 1. Joint fliud - WBC 50,000 to 200,000 (90% polys), low glucose. 2. Gram's stain+ 75% (staph), 50% (GNR). 3. Culture + in 90% of cases. 4. CT and MRI scans helpful for SI and sternoclavicular joints and for demonstrating effusions and associated osteomyelitis. US is helpful in demonstrating joint effusions in deep joints (hip). Treatment 1. Antibiotics (if Gram's stain negative - choose antibiotics that will cover S. aureus and streptococci), drainage and rest. 2. Antibiotic - duration: 2 to 6 weeks (depends on presence of osteomyelitis, chronicity of infection, identification and susceptibility of organism). Shorter courses needed for streptococci and H. influenza and longer therapy for S. aureus, enterobacteriaceae and pseudomonas Peltola, CID, 2009: R,MC trial of 130 children with septic arthritis – Rx with either 10 or 30 days of clindamycin or first gen cephalosporin Five in 10 day group had their treatment had their treatment extended to between 17 and 21 days and four in the 30 day group had their treatment extended to between 37 to 93 days ~90% follow up at one year post infection – only 1 child had relapsed (in the 30 day group) 3. Drainage: repeat closed needle aspiration (usually for 5 to 7 days). Arthroscopy and open drainage necessary for: hips, sometimes shoulders, gram-negative infections, if osteomyelitis is present and if pus is thick and cannot be aspirated. 4. After acute phase of infection - passive range of motion should be started ASAP. Gonococcal Disseminated gonococcal infection (DGI) develops in 0.5 to 3% of cases of mucosal GC and is the most common cause of infective arthrits in the US Pathogenesis: 1. Specific GC strains are more often found in patients with DGI: more resistant to complement, more sensitive to penicillin, transparent colony type (lack Protein II), have specific nutritional requirements (arginine, hypoxanthine and uracil - AHU) and belong to serotype P.IA. 2. The dramatic response to antibiotics and the lack of response to steroids argues for direct infection causing disease despite the low rate of recovery of GC from joint fluid. 3. However, in animal models, injection of killed GC into joints creates an arthritis indistinguishable from that caused by live organisms. Risks: 1. Complement deficiency (C7 and C8), women > men (and especially while pregnant or during menses). Clinically: 1. Most are young healthy adults. 2. Initially - migratory polyarthralgia, fever, tenosynovitis and dermatitis (small maculopapular, pustular, necrotic or vesicular lesions on the trunk and extremities are characteristic -bullae, purpura, erythema mutiforme have also been reported), fewer than 30, face is spared 3. Tenosynovitis picture in 2/3 (usually hands and fingers), polyarthritis in 50%. 4. Mucosal infection is usually asymptomatic. 5. BC positive is < 20% and joint fluid culture positive in < 50% of all cases (more + in purulent arthritis), joint fluid Gram's stain+ < 25%, genitourinary cultures are + in 80% of cases of DGI. PCR to detect GC in joint fluid probably better test (sensitivity of ~80%, specificity of > 95%). Treatment: 1. Initial therapy with parenteral 3rd generation cepahlosporin (e.g. ceftriaxone) (or a penicillin if susceptible) until 24 to 48 hours after improvement - followed by oral therapy (cefixime or a quinolone) to complete a week of treatment. 2. Effusions should be serially aspirated but open drainage rarely needed. Reactive Arthritis Inflammatory but sterile arthritis Pathogenesis: 1. Studies have demonstrated both bacterial antigens and DNA in synovial tissue and fluid in post-enteric reactive arthritis. 2. More compelling evidence for the presence of Chlamydia in synovial tissue and fluid (antigens, DNA, RNA and whole organisms [by EM]) in post-genital reactive arthritis. Chlamydia has been identified as the preceding infection in 42 to 69% of patients with reactive arthritis in the US. 3. HLA-B27 may present bacterial antigens in a fashion that often leads to crossreactivity to host tissue. 4. HLA-B27 shares homology with certain bacterial proteins - suggesting serologic cross-reativity Clinically: 1. Asymmetric, additive polyarthritis predominantly in large joints of the lower extremities. Usually occurs 1 to 2 weeks after an infection. Knees 70%, ankles, 57%, wrists and fingers 45%, toes 35%. SI joints common in Chlamydia associated RA 2. Extra-articular features: skin and eye involvement, enthesitis (especially in heels), dactylitis (sausage digits) 3. Reiter's syndrome: triad of conjunctivitis, urethritis and arthritis occurs in minority of patients. 4. HLA-B27 association: with sacroiliitis (54%), post-enteric (50-80%), post-genital (90%). Not associated with rheumatoid factor. 5. Post-enteric (Salmonella, Shigella, Yersinia and Campylobacter infections): M=F Better prognosis (complete resolution in 80 to 90% - less after Salmonella) than post-genital Recurrent attaks unusual after Yersina-associated disease 6. Post-gential (Chlamydia): M>F More relapses than post-enteric (re-infection?) 7. Associated with inflammatory bowel disease (10 to 20%), often occurs when IBD flares, usually large joint - oligoarthrits, minimally symptomatic. 7. Duration of disease is 3 to 5 months with ~15% developing chronic disease. 8. HIV associated reactive arthrits - resembles typical reactive arthritis, psoriatic arthritis or undifferentiated spondyloarthropahy - becoming less common in developed countries where HAART is available. Treatment: 1. Antibiotics not helpful in post-enteric reative arthritis. 2. Antibiotics (e.g. tetracyclines) for 1 to 3 month may benefit patients with post-genital (post Chlamydia) reactive arthritis. Probably depends on the state of Chlamydia in the joint. If organism is in persistent state (not the vegetative state) it may express different set of genes and not be susceptible to antibiotics that have activity against organisms in the vegetative state. This may account for the variable response of Chlamydia-associated RA. 3. Prompt treatment of genital chlamydia infection may reduce the incidence of STD associated reactive arthritits. 3. Anti-inflammatory agents: NSAIDs, methotrexate and azothioprine, intra-articular steroids. Sulfasalazine may be of benefit, especially in reactive arthritis associated with inflammatory bowel disease. Prosthetic joint (see Osteomyelitis section above) 1. 0.5 to 2 percent rate of infection over 10 years, but 5 to 10% in prosthetic joint revisions. 2. Early (within 12 weeks) likely due to operative contamination, later infections the result of bacteremia with seeding of the joint. 3. Microbiology: coagulase negative staph (40%) > S. aureus (20%) > GNR, polymicrobial and anerobic infections > fungi. Early: CNS and S. aureus. Late: S. aureus, streptococci, GNR and anaerobes. 4. Indolent pain, erythema and drainage = early. Pain = late. Fever uncommon. 5. Radiographic evidence of loosening in 66% of late and < 50% early infections. 6. Joint aspiration necessary for diagnosis, histopathology also helpful (especially* when cultures are negative). 7. Treatment: see Osteomyelitis section. Other infectious and non-infectious causes of arthritis Mycobacterial - insidious onset, single (usually weight-bearing) joint is classic description. More recent reports are of older and immunosuppressed individuals presenting with systemic symptoms and multiple joint involvement with periarticular cold abscesses. Oligoarticular disease is also associated with HIV. 50% have concurrent pulmonary disease, 90% are PPD+. Joint fliud: AFB stain + in 20%, culture + in 80% and synovial culture + in 90%. Treatment is medical unless there is significant joint destruction or instability that requires surgery. Fungal - insidious onset, single joint (or oligoarticular), associated with HIV. Viral (Rubella, Mumps, Parvovirus, Hepatitis B, Hepatitis C, HIV) - polyarthritis, fever and rash. Lyme - local epidemiology, history of erythema migrans, tick bites. Infectious endocarditis. Crystal disease - history of same in past, crystals in joint fluid. CVD - RA, Still's disease, SLE, vasculitis, psoriasis. Rheumatic fever - in adults: arthrits and fever >> carditis, nodules and rash; may be additive rather than migratory arthritis; check ASO titers. Poststreptoccal reactive arthritis – shorter incubation than that seen in RA, more involvement of small joints and axial skeleton, protracted course compared to RF, poor response to ASA and NSAIDS, low incidence of carditis Osteonecrosis of the mandible – associated wilth bisphosphonate treatment FMF - usually in childhood; recurrent bouts of fever, arthritis, abdominal and pleuritic pain. Cancers - leukemia in children. Sarcoidosis Kawasaki's REFERENCES 1. Green, S., Osteomyelitis. Orthopedic Infection, 1991. 22(3): p. 515-521. 2. 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