BONE AND JOINT INFECTIONS: CRASH COURSE. Objectives: Technicians. Objectives: Pharmacists. Overview 2/27/2015. Osteomyelitis (OM)

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1 BONE AND JOINT INFECTIONS: CRASH COURSE Yanina Pasikhova, Pharm.D., BCPS AQ-ID, AAHIVP Infectious Diseases Clinical Pharmacist Moffitt Cancer Center Last Updated: 03/2015 Objectives: Pharmacists Objectives: Technicians Define and differentiate between bone and joint infections Osteomyelitis Septic arthritis Prosthetic joint infections Understand pathophysiology and diagnosis of bone and joint infections Select appropriate empiric and pathogen targeted therapy Identify common bone and joint infections Understand risk factors associated with bone and joint infections Identify commonly used antimicrobials Overview Hematogenous Contiguous Vascular insufficiency Bacterial, nongonococcal Bacterial, gonococcal Other (mycobacterial, fungal) Osteomyelitis (OM) Infection of the bone Can involve the marrow, cortex, and periosteum Acute osteomyelitis (AOM) Infection present for < 6 weeks Chronic osteomyelitis (COM) Infection present for > 6 weeks Prosthetic joint infections 1

2 Overview Bone Septic arthritis (aka infections arthritis) Inflammation in a joint 2 to infection of synovial or periarticular tissue Prosthetic joint infection (PJI) Infection following joint replacement surgery Categorized by timing of symptom post-op Early-onset: < 3 months after surgery Delayed-onset: 3-12 months after surgery Late-onset: >12 months after surgery Prosthetic Joint Natural Joint Patient Case: I 40 y/o male with history of IVDU reports to the ER CC: Fever and back pain VS: T=39 C, BP=110/55, HR=120, RR= 24 PE: Tenderness over thoracic spine on percussion Blood cultures drawn, empiric antibiotics started Differential Diagnoses? Additional Tests or Imaging? Likely organism? Initial antibiotics? Osteomyelitis Classification Route of infection Hematogenous Contiguous Vascular insufficiency Time of clinical presentation Acute OM Chronic OM Route of Infection Hematogenous 2

3 Hematogenous Vertebral Osteomyelitis Acute Chronic rare in developed countries Bacteremia seeding of the bone tissue Local trauma to bone may be a contributing factor Infants/children > adults 20% of cases of osteomyelitis in adults Most commonly affects the vertebrae May affect other bones Long bones, pelvis, clavicle Most common form of hematogenous osteomyelitis Vertebral OM +/- epidural abscess Lumbar spine Associated factors IVDU HD Immunocompromised Contiguous Focus Route of Infection Contiguous Focus Majority of osteomyelitis cases in adults Tibia and femur Acute or chronic Traumatic bone injury or spread of infection from a nearby source Biphasic Younger pts: trauma and related surgery Older pts: decubitus ulcers Contiguous Focus Associated factors Surgery RIF, prosthetic devices Open fractures Chronic or regional soft tissue infections Decubitus ulcers Burns Route of Infection Vascular Insufficiency 3

4 Vascular Insufficiency Impaired blood supply to susceptible tissues Predominantly in the small bones of the feet Usually in older patients 2 to Diabetes mellitus Severe atherosclerosis Diabetic Foot Infections Risk factors for OM Wounds that extended to bone or joint Previous history of a wound Recurrent or multiple wounds OM more likely if ulcer Large (>2 cm in diameter) Deep (>3 mm) CRP >3.2 mg/dl or ESR >60 mm/hour Positive probe to bone test Bone exposure Positive Probe to Bone Acute versus Chronic OM Acute OM Chronic OM Onset Less than 6 weeks More than 6 weeks Symptoms Fever, chills, malaise Infection site: Pain, limited range of motion, and redness, warmth or swelling May present as septic arthritis Chronic low-grade fever Infection site: Chronic localized pain, and a draining sinus tract Present for months or even years Pathophysiology Hematogenous or contiguous IVDU, trauma Before development of sequestra Imaging X-Ray: +/- MRI: Very sensitive Contiguous or vascular insufficiency Wounds, injury, DM Formation of sequestra / involucrum Local bone loss X-Ray: + MRI: May overestimate extent/duration Pathophysiology Bone scan: The sensitivity and specificity varies depending on the appearance of correlative radiographs. False-positive may occur with noninfectious changes. False-negative in AOM or in COM with impaired blood flow or infarction 4

5 Osteomyelitis Diagnosis Gold Standard Bacteria from a bone biopsy + histopathology Swab, superficial wounds, sinus tracts cultures and aspiration of material adjacent to the periosteum NOT DIAGNOSTIC of OM Poor correlation with bone biopsy culture results Bone biopsy Stop antibiotics 48 to 72 hours prior the procedure May increase the microbiological yield Often positive regardless of prior antibiotic therapy Histopathology and Labs Necrotic bone with extensive resorption adjacent to an inflammatory exudate Laboratory tests nonspecific Leukocytosis Elevated ESR/CRP May be normal Blood cultures Positive in 50% of AOM cases Isolated organism likely cause of OM Osteomyelitis No official guidelines for OM PJI, DFI, VOM (P) Acute OM easier to treat vs. chronic OM Historically IV antibiotics used More published data on PO than IV Show similar outcomes Duration 4-6 weeks (or longer) Intravenous vs. Oral Antibiotics Review of Literature 5

6 Review studies published since In adults with COM Are certain antibiotic agents preferred choices? Are oral regimens acceptable for selected cases? For how long should antibiotic therapy be given? and Is surgical debridement always necessary for cure? Pharmacology: IV ß- lactams Bone concentration ~5-20 % High plasma levels bone levels exceed target MIC Vancomycin and daptomycin Similar to ß- lactams Clin Infect Dis Feb 1;54(3): Clin Infect Dis Feb 1;54(3): Pharmacology: PO ß- lactams Plasma levels <10% of IV Unlikely to achieve adequate bone levels Fluoroquinolones, linezolid, TMP (TMP-SMX) Bone concentration ~50% Clindamycin Bone concentration 40-70% Rifampin and metronidazole Bone plasma Clin Infect Dis Feb 1;54(3): Randomized clinical trials 2009 meta analysis evaluating treatment of COM 8 small trials, total n = trials compared IV to PO No significant difference at remission rates at 12 months Moderate or severe adverse events higher in IV 15.5 vs 4.8% Clin Infect Dis Feb 1;54(3): Randomized clinical trials 6 studies compared PO fluoroquinolone vs. IV Similar cure rates IV cloxacillin vs. PO TMP-SMX + rifampin for MSSA COM All patient received debridement 20% had prosthetic implants Similar cure rates 91 vs. 89% Randomized clinical trials Adjunctive rifampin Increased cure rated in S. aureus COM (2 studies) 85 vs. 57% Increased cure rates in S. aureus PJI 100 vs. 58% Clin Infect Dis Feb 1;54(3): Clin Infect Dis Feb 1;54(3):

7 CULTURES BEFORE ABX!!!! If blood cx positive No need for invasive cx assume the same organism If blood cx negative Need bone cx DO NOT culture sinus tract drainage Not predictive of bone cx No empiric therapy for Chronic OM Vascular insufficiency Unless acutely ill Hematogenous: Empiric Diagnosis Extremity OM Vertebral OM Sickle Cell / thalassemia Etiologies (Usual) S. aureus GAS GNR (rare) S. aureus (many other) Salmonella, other GNR (Primary) MRSA possible: Vancomycin MRSA possible: Vancomycin Ciprofloxacin (+/- 3 rd gen ceph) (Alternative) MRSA not possible: Nafcillin / Oxacillin (Clindamycin, TMP-SMX, Linezolid*) MRSA not possible Nafcillin / Oxacillin Levofloxacin (+/- 3 rd gen ceph) Comments Cx prior to ABX, micro diagnosis is essential If Gram stain GNR add cefepime or ceftazidime MRI to evaluate for epidural abscess Increased resistance to FQ Contiguous w/o Vascular Insufficiency: Empiric Diagnosis OM secondary to nail through tennis shoe OM of long bone postinternal fixation of fracture Etiologies (Usual) (Primary) P. aeruginosa Ciprofloxacin or Levofloxacin S. aureus, GNR, P. aeruginosa Vancomycin + Cefepime or Ceftazidime (Alternative) Cefepime or Ceftazidime Linezolid, Clindamycin, TMP-SMX + Cefepime or Ceftazidime Comments OM in 1-2% of plantar puncture wounds If no OM, debridement and removal of foreign body, no ABX Tetanus prophylaxis May need hardware removal and revascularization Contiguous w/ Vascular Insufficiency: Empiric Most patients will have DM Polymicrobial No empiric therapy Unless acutely ill based on cultures Revascularization if possible Chronic OM No empiric therapy Patient Case: I A 40 y/o male with history of IVDU reports to the ER CC: Fever and back pain, BCx: GPC S. aureus Differential Diagnoses? Bacteremia with vertebral OM ± epidural abscess Additional Tests or Imaging? MRI Likely organism? S. aureus Initial antibiotics? Vancomycin or Nafcillin / Oxacillin Vertebral Osteomyelitis Review of Literature 7

8 Multicenter, open-label, non-inferiority, randomized, controlled trial 71 medical care centers in France. 18 years or older with microbiologically confirmed pyogenic VOM and typical radiological features MRI or CT scan Exclusion criteria Life expectancy of less than 1 year Pregnancy or breastfeeding Vertebral implant Recurrence of spondylodiscitis Fungal, brucellar, or mycobacterial infection Absence of microbiological identification Published online November 5, Published online November 5, Published online November 5, Antibiotics did not differ between the groups Median duration of IV did not differ 6 week = 15 days 12 week =14 days Factors associated with failure Age 75 years Infection with S. aureus Retrospective study of patients with 1 VOM in Switzerland seen by ID Exclusion criteria IE SSI following spine surgery Spinal Implants Tuberculous VO Published online November 5, BMC Infectious Diseases 2014, 14:226 8

9 N = 61 Most common organisms S. aureus (21%) (~5% MRSA) CoNS (17%) 21 patients were switch to PO after 2 weeks of IV Fluoroquinolone monotherapy (35%) Fluoroquinolone + rifampin (26%) Baseline CRP Independent predictor for switching to PO after 2 weeks Outcomes 97% success rate at 1 year in the ITT group 2 patients died secondary to metastatic Ca No treatment failures No re-hospitalizations for VO BMC Infectious Diseases 2014, 14:226 BMC Infectious Diseases 2014, 14:226 Patient Case: II 23 y/o female presents to the ER CC: 2 days of diffuse arthralgias, low grade fever subsequently followed the development of swelling and pain in her right wrist Social history: Sexually active, new boyfriend Diagnoses? Likely organism?? Septic Arthritis Classification Based on organism Bacterial Nongonococcal Gonococcal Fungal Mycobacterial Based on joint type Natural vs. prosthetic Pathophysiology Hematogenous spread to the bone Most common Direct inoculation of bacteria Surgery Bites / trauma Spread from adjacent infected bone Rare Bacterial infection most common Fungal, Mycobacterial 9

10 Associated Factors Age > 80 years old DM Rheumatoid arthritis (RA) Recent joint surgery Prosthetic joint Skin infection, cutaneous ulcers Previous intra-articular corticosteroid injection IV drug abuse, alcoholism Bacterial Nongonococcal Clinical Presentation Diagnosis Acute Monoarticular 20% of pts oligoartiular or polyarticular (2 or 3 joints) Patients with RA or overwhelming sepsis Knee, wrist, ankle and hips IVDU: sternoclavicular or sternomanubrial Joint pain, swelling, restricted movement Fevers Elderly persons are more likely to be afebrile Identification of bacteria from synovial fluid Synovial fluid aspiration Gram stain Culture Leukocyte count and differential Blood cultures Positive in 50% of patients CBC with differential ESR, CRP Diagnosis Synovial Fluid Synovial fluid culture Positive in majority of patients with nongonococcal septic arthritis Negative cultures can occur Recent antibiotics Fastidious organisms (Mycoplasma spp., some streptococci) Gram stain Often positive (not always) False positive Precipitated crystal violet and mucin GPC Measure Normal Noninflammatory Inflammatory Septic Hemorrhagic Volume* <3.5 Often >3.5 Often >3.5 Often >3.5 Usually >3.5 Clarity Transparent Transparent Translucentopaque Opaque Bloody Color Clear Yellow Yellow to opalescent Yellow to green Viscosity High High Low Variable Variable WBC < ,000 1, ,000 >100, ,000 PMN % <25 < Culture Negative Negative Positive Negative (often) Protein Glucose ~ Blood ~ Blood >25, lower than blood < 25, much lower than blood Red ~ blood * Knee in ml 10

11 Septic Arthritis: Pathogens Organism Clinical consideration S. aureus Healthy adults, skin breakdown, prosthetic joint, previous damage (eg. RA) Streptococcal species Healthy adults, splenic dysfunction N. gonorrhea Young sexually active adults Aerobic GNR Immunocompromised, GI infection Anaerobic GNR Immunocompromised, GI infection Mycobacterial species Immunocompromised, recent travel to endemic area Fungal species Immunocompromised (sporotrichosis, cryptococcus, blastomycosis, coccidiodomycosis) Spirochete (Borellia burgdorferi) Mycoplasma hominis Exposure to ticks, rash, knee joint involvement Immunocompromised with prior urinary tract manipulation Antimicrobial choice is based on Most likely cause Clinical presentation Gram stain Gram stain with GPC Vancomycin Gram stain with GNR 3 rd generation cephalosporin or anti-psa β-lactam* Ciprofloxacin if allergy Gram stain negative Immunocompetent Vancomycin Immunocompromised, IVDU Vancomycin + 3 rd generation cephalosporin or anti-psa* Ciprofloxacin if allergy Modify antibiotics based on culture results Duration No randomized trials IV X 14 days followed by PO 14 days Longer IV for bacteremia and certain pathogens Bacterial Gonococcal Clinical Presentation Most common cause of septic arthritis One of the manifestations of disseminated gonococcal infection (DGI) N. gonorrhoeae Untreated mucosal infection Asymptomatic infection Usually 1 or 2 large joints are affected Most commonly knees, wrists, ankles, elbows Joints are hot, painful, swollen with restricted movement 11

12 Patient Case: II Ceftriaxone 1g IV q24 hrs X 7-14 days Up to 21 days Joint drainage Concurrent treatment for Chlamydia Doxycycline 100mg PO BID X 7 days Sex partner Referred for evaluation and treatment 23 y/o female presents to the ER CC: 2 days of diffuse arthralgias, low grade fever and then the development of swelling and pain in her right wrist Social history: Sexually active, new boyfriend Diagnoses? DGI with septic arthritis Likely organism? N. gonorrhoeae? Ceftriaxone 1g IV q24 hrs X 7-14 days & joint drainage Definition Prosthetic Joint Infections Sinus tract that communicates with the prosthesis Purulence without another known etiology surrounding the prosthesis 2 or more intraoperative cultures or preoperative aspiration and intraoperative culture that grows the same organism Growth of a virulent organism (S. aureus) in one specimen can represent PJI Management Surgical Options Almost always: surgery + prolonged ABX Preoperative ESR and CRP Blood cultures If febrile or acute onset of symptoms Diagnostic arthrocentesis If possible withhold antibiotics for 2 weeks prior Intraoperative At least 3 sets of cultures, optimally 5 or 6 tissue samples for cultures or prosthesis itself If possible hold antibiotics for 2 weeks prior Debridement and retention of prosthesis Well-fixed prosthesis, no sinus tract, within 30 days of implantation or < 3 weeks of symptoms 2 stage exchange Most common in US 1 stage exchange May be greater risk of failure Permanent resection arthroplasty Amputation 12

13 Staphylococcal PJI Medical Management Debridement and Retention or 1-Stage Exchange Total 3 months of pathogen-specific therapy Total hip arthroplasty (THA) Total elbow arthroplasty Total shoulder arthroplasty Total ankle arthroplasty Total 6 months of pathogen-specific therapy Total knee arthroplasty (TKA) 2-6 weeks of IV antibiotics + rifampin Followed by PO antibiotic + rifampin Staphylococcal PJI If rifampin cannot be used 4-6 weeks of IV antibiotics For chronic suppression evaluate Ability to use rifampin in the initial treatment Progressive implant loosening Loss of bone stock Risk of prolonged antibiotics Generally reserved for patients Unsuitable / refuse further exchange revision, excision arthroplasty or amputation PJI due to other organisms 4 6 weeks of pathogen-specific antibiotics IV or PO (if with good bioavailability) May consider chronic suppression therapy After initial therapy and not candidate for further surgery Not unanimously recommended if FQ are used as initial therapy for GNR infections Management Medical Management Resection Arthroplasty With or Without Reimplantation 4 6 weeks of pathogen-specific antibiotics IV or PO (with good bioavailability) Medical treatment following amputation 24 to 48 hours of pathogen-specific antibiotics after amputation All infected tissue has been surgically removed No concomitant sepsis or bacteremia Concomitant sepsis or bacteremia duration based on those specific syndromes 13

14 Organism-Specific Chronic Oral Suppression Additional Pearls Summary Adjust antimicrobial therapy according to Susceptibility Allergies Renal function / Hepatic function Target vancomycin trough mcg/ml Patient counseling Side affects Possibility of C. difficile Monitoring of baseline labs Bone and joint infections represent a wide spectrum of conditions OM Septic arthritis PJI Empiric therapy for OM is not always indicated Acute YES Chronic NO 14

15 Summary Questions Therapy selection for septic arthritis is based on Risk factors Gram stain and culture PJI almost always require surgery + ABX For all bone and joint infections, therapy should be adjusted based on Allergies Renal and hepatic function Culture result References 1. Berbari EF, Steckelberg JM, Osmon DR. Osteomyelitis. In: Principles and Practice of Infectious Diseases, 6, Mandell GL et al (eds) (Ed), Elsevier, Philadelphia p Lew DP, Waldvogel FA. Osteomyelitis. Lancet 2004; 364: Mader JT, Shirtliff M, Calhoun JH. Staging and staging application in osteomyelitis. Clin Infect Dis 1997; 25: Lew DP, Waldvogel FA. Osteomyelitis. N Engl J Med 1997; 336: Waldvogel FA, Medoff G, Swartz MN. Osteomyelitis: a review of clinical features, therapeutic considerations and unusual aspects. N Engl J Med 1970; 282: David R, Barron BJ, Madewell JE. Osteomyelitis, acute and chronic. Radiol Clin North Am 1987; 25: Cierny G 3rd, Mader JT, Penninck JJ. A clinical staging system for adult osteomyelitis. Clin Orthop Relat Res 2003; :7. 8. Norden CW. Experimental chronic staphylococcal osteomyelitis in rabbits: treatment with rifampin alone and in combination with other antimicrobial agents. Rev Infect Dis 1983; 5 Suppl 3:S Henry NK, Rouse MS, Whitesell AL, et al. of methicillin-resistant Staphylococcus aureus experimental osteomyelitis with ciprofloxacin or vancomycin alone or in combination with rifampin. Am J Med 1987; 82: Pineda C, Vargas A, Rodríguez AV. Imaging of osteomyelitis: current concepts. Infect Dis Clin North Am 2006; 20: Shmerling RH, Delbanco TL, Tosteson AN, Trentham DE. Synovial fluid tests. What should be ordered? JAMA 1990; 264:1009. References 12. Jeng GW, Wang CR, Liu ST, et al. Measurement of synovial tumor necrosis factor-alpha in diagnosing emergency patients with bacterial arthritis. Am J Emerg Med 1997; 15: Margaretten ME, Kohlwes J, Moore D, Bent S. Does this adult patient have septic arthritis? JAMA 2007; 297: Mathews CJ, Coakley G. Septic arthritis: current diagnostic and therapeutic algorithm. Curr Opin Rheumatol 2008; 20: Goldenberg DL. Septic arthritis and other infections of rheumatologic significance. Rheum Dis Clin North Am 1991; 17: Goldenberg DL, Reed JI. Bacterial arthritis. N Engl J Med 1985; 312: Morgan DS, Fisher D, Merianos A, Currie BJ. An 18 year clinical review of septic arthritis from tropical Australia. Epidemiol Infect 1996; 117: Gavet F, Tournadre A, Soubrier M, et al. Septic arthritis in patients aged 80 and older: a comparison with younger adults. J Am Geriatr Soc 2005; 53: Sapico FL, Liquete JA, Sarma RJ. Bone and joint infections in patients with infective endocarditis: review of a 4-year experience. Clin Infect Dis 1996; 22: Ross JJ, Saltzman CL, Carling P, Shapiro DS. Pneumococcal septic arthritis: review of 190 cases. Clin Infect Dis 2003; 36: "Diagnosis and Management of Prosthetic Joint Infection: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clin Infect Dis; 2013;56 :